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【结 构 式】 
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【分子编号】10722 【品名】1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 【CA登记号】77-76-9 |
【 分 子 式 】C5H12O2 【 分 子 量 】104.14908 【元素组成】C 57.66% H 11.61% O 30.72% |
合成路线1
该中间体在本合成路线中的序号：(III)The partial reduction of dimethyl hydroxyterephthalate (I) with NaBH4 in refluxing methanol gives methyl-3-hydroxy-4-(hydroxymethyl)benzoate (II), which by reaction with 2,2-dimethoxypropane (III) by means of p-toluenesulfonic acid in benzene is converted into the benzo-1,3-dioxane (IV). The reduction of (IV) with sodium dihydro-bis(2-methoxyethoxy)aluminate (V) affords the protected benzyl alcohol (VI), which is oxidized with CrO3 to the benzaldehyde (VII). The reaction of (VII) with NaCN and ammonia in methanol yields the aminonitrile (VIII), which is finally hydrolyzed with Ba(OH)2 and afterwards with H2SO4.
| 【1】 Yoshizawa, J.; Ushijima, R.; Umezawa, H.; Takeuchi, T.; Morishima, H.; Synthesis of forphenicinol and forphenicine. J Antibiot 1982, 35, 11, 1500-06. |
| 【2】 Aoyagi, T.; Ishizuka, M.; Matsumoto, I,. Morishima, H.; Takeuchi, T.; Umezawa, H.; Yamamoto, T. (Microbial Chemistry Research Foundation); Pharmacological cpd. with immunopotentiating activity and production and uses thereof. US 4238507 . |
| 【3】 Arrigoni-Martelli, E.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Forphenicinol. Drugs Fut 1983, 8, 7, 587. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 36152 | methyl 4-(acetoxy)-3-hydroxybenzoate | C10H10O5 | 详情 | 详情 | |
| (II) | 36153 | methyl 3-hydroxy-4-(hydroxymethyl)benzoate | C9H10O4 | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 36154 | methyl 2,2-dimethyl-4H-1,3-benzodioxine-7-carboxylate | C12H14O4 | 详情 | 详情 | |
| (VI) | 36155 | (2,2-dimethyl-4H-1,3-benzodioxin-7-yl)methanol | C11H14O3 | 详情 | 详情 | |
| (VII) | 36156 | 2,2-dimethyl-4H-1,3-benzodioxine-7-carbaldehyde | C11H12O3 | 详情 | 详情 | |
| (VIII) | 36157 | 2-amino-2-(2,2-dimethyl-4H-1,3-benzodioxin-7-yl)acetonitrile | C12H14N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)L-threonic acid (XI), which is readily available from L-ascorbic acid (IX), is converted to L-N-benzyloxycarbonyl-4-hydroxyallothreoninamide (VIII). This in turn is transformed to (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid (XVIII). Condensation of the azetidinone (XVIII) with the activated aminothiazole portion (XIX) followed by a necessary deprotection step affords the monocyclic beta-lactam. Dissolution of the beta-lactam in aqueous sodium acetate yields the disodium salt, carumonam. Other routes of synthesis have been discussed.
| 【1】 Weigele, M.; Wei, C.; Tengi, J.; Ro-172301 (AMA-1080), a new monocyclic beta-lactam antibiotic: Stereorational synthesis. Intersci Conf Antimicrob Agents Chemother 1983, Abst 324. |
| 【2】 Hachiguchi, S.; Ochiai, M.; Kishimoto, S.; Matsuo, T.; Kondo, M.; Sendai, M.; Tomimoto, M.; Chemical modification of sulfazecin: Synthesis of 4-(substituted methyl)-2-azetidinone-1-sulfonic acid derivatives. J Antibiot 1985, 38, 3, 346-371. |
| 【3】 Christenson, J.; Squires, E.; Carumonam Sodium. Drugs Fut 1985, 10, 12, 967. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 28759 | benzyl (1S,2R)-1-(aminocarbonyl)-2,3-dihydroxypropylcarbamate | C12H16N2O5 | 详情 | 详情 | |
| (IX) | 29820 | (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2(5H)-furanone | 50-81-7 | C6H8O6 | 详情 | 详情 |
| (X) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XI) | 29821 | calcium di[(2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethanoate] | C14H22CaO10 | 详情 | 详情 | |
| (XII) | 29822 | (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethanamide | C7H13NO4 | 详情 | 详情 | |
| (XIII) | 29823 | (2S)-2-azido-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamide | C7H12N4O3 | 详情 | 详情 | |
| (XIV) | 29824 | benzyl (1S)-2-amino-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylcarbamate | C15H20N2O5 | 详情 | 详情 | |
| (XV) | 29825 | (2R,3S)-4-amino-3-[[(benzyloxy)carbonyl]amino]-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-oxobutyl 2-chloroacetate | C17H23ClN2O6S | 详情 | 详情 | |
| (XVI) | 29826 | N,N,N-tributyl-1-butanaminium (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-oxo-1-azetidinesulfonate | C28H49N3O7S | 详情 | 详情 | |
| (XVII) | 13713 | 2-Chloroacetyl isocyanate | 4461-30-7 | C3H2ClNO2 | 详情 | 详情 |
| (XVIII) | 29827 | (2S,3S)-2-[[(aminocarbonyl)oxy]methyl]-3-ammonio-4-oxo-1-azetidinesulfonate | C5H9N3O6S | 详情 | 详情 | |
| (XIX) | 29828 | tert-butyl 2-([[(Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino]oxy)acetate | C18H18N4O4S3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)This compound can be prepared by several different ways: 1) The reaction of 5-fluorouridine (I) with 2,2-dimethoxypropane (A) by means of p-toluenesulfonic acid gives 2',3'-isopropylidene-5-fluorouridine (III), which is treated with triphenylphosphite methiodide in DMF to afford 5'-deoxy-5'-iodo-2',3'-isopropylidene-5-fluorouridine (IV). The reduction of (IV) with H2 over Pd/C in methanol-triethyl-amine yields 5'-deoxy-2',3'-isopropylidene-5-fluorouridine (V), which is finally hydrolyzed with aqueous trifluoroacetic acid. 2) The hydrolysis of compound (IV) with aqueous trifluoroacetic acid as before gives 5'-deoxy-5'-iodouridine (II), which is finally reduced with H2 over Pd/C as before. 3) Compound (II) can also be obtained by reaction of (I) with triphenyl phosphite methiodide as before. 4) It can also be prepared via reduction of the 5'-chloro intermediate with tributyltin hydride.
| 【1】 Beranek, J.; Hrebabecky, H.; Analogs of nucleosides. XVI. 5'-Halo-2',3'-sulfites in the synthesis of 2',5'-dideoxy-5-fluorouridine and related analogs. Coll Czech Chem Commun 1978, 43, 15, 3268-78. |
| 【2】 Cook, A.F.; et al.; Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5'-deoxy-5-fluoropyrimidine nucleosides. J Med Chem 1979, 22, 11, 1330-35. |
| 【3】 Cook, A.F. (Hoffmann-La Roche, Inc.); 5'-Deoxy-5-fluoropyrimidine nucleosides. DE 2756653; ES 471584; FR 2374334; GB 1589688; JP 53095982; US 4071680 . |
| 【4】 Castaner, J.; Albonico, S.M.; Serradell, M.N.; Blancafort, P.; Doxifluridine. Drugs Fut 1981, 6, 2, 80. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (I) | 32205 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluorouridine | 316-46-1 | C9H11FN2O6 | 详情 | 详情 |
| (II) | 32206 | 1-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(iodomethyl)tetrahydro-2-furanyl]-5-fluoro-2,4(1H,3H)-pyrimidinedione | C9H10FIN2O5 | 详情 | 详情 | |
| (III) | 32207 | 2',3'-Isopropylidene-5-fluorouridine; 5-Fluoro-1-[(4R,6R)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C12H15FN2O6 | 详情 | 详情 | |
| (IV) | 32208 | 5-Fluoro-1-[(4R,6S)-6-(iodomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione; 5'-Deoxy-5'-iodo-2',3'-isopropylidene-5-fluorouridine | C12H14FIN2O5 | 详情 | 详情 | |
| (V) | 32209 | 5'-Deoxy-2',3'-isopropylidene-5-fluorouridine; 5-Fluoro-1-[(4R,6R)-2,2,6-trimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2,4(1H,3H)-pyrimidinedione | C12H15FN2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVIII)The reaction of 5-(benzyloxy)-3(E)-penten-2-one (I) with trimethylsilyl cyanide (II) by means of a chiral Ti catalyst gives the chiral pentenenitrile (III), which is treated with HCl in ethanol and reduced with DIBAL and NaBH4 in methanol to yield the chiral diol (IV). The selective monosilylation of (IV) by means of TipsCl and imidazole affords the secondary alcohol (V), which is protected with Mom-Cl and DIEA in dichloromethane to provide compound (VI). The debenzylation of (VI) by means of lithium di-t-butyl biphenylide (LiDBB) gives the primary alcohol (VII), which is oxidized with TPAP and NMO in dichloromethane to yield the carbaldehyde (VIII). The reductive allylation of (VIII) by means of allyl trimethoxy silane (IX), AgF and a chiral catalyst affords the secondary alcohol (X), which is esterified with acryloyl chloride (XI) and TEA to provide the acrylate ester (XII). Ester (XII) is submitted to a ring closing metathesis reaction, catalyzed by a Ru catalyst giving the dihydropyranone compound (XIII), which is desilylated by means of HF and TEA in THF to yield the primary alcohol (XIV). The oxidation of (XIV) with DMP in dichloromethane affords the aldehyde (XV), which is condensed with 4-(trimethylsilyl)-3-butyn-2-one (XVI), by means of a chiral La catalyst to provide the acetylenic hydroxyketone (XVII). The reaction of (XVII) with 2,2-dimethoxypropane (XVIII) by means of PPTS gives the acetonide (XIX), which is enantioselectively reduced and catalyzed by a chiral Ru catalyst to yield the secondary alcohol (XX). The reaction of (XX) with Tbdms-OTf affords the silyl ether (XXI), which is treated with NIS and AgNO3 to provide the iodoacetylene derivative (XXII). The diimide reduction of (XXII) using o-nitrobenzenesulfonyl hydrazide (NBSH) gives the cis-iodovinyl compound (XXIII).
| 【1】 Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M.; Formal catalytic asymmetric total synthesis of fostriecin. Org Lett 2003, 5, 5, 733. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 61446 | (E)-5-(benzyloxy)-3-penten-2-one | C12H14O2 | 详情 | 详情 | |
| (II) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
| (III) | 61448 | (2R,3E)-5-(benzyloxy)-2-methyl-2-[(trimethylsilyl)oxy]-3-pentenenitrile | C16H23NO2Si | 详情 | 详情 | |
| (IV) | 61449 | (2R,3E)-5-(benzyloxy)-2-methyl-3-pentene-1,2-diol | C13H18O3 | 详情 | 详情 | |
| (V) | 61450 | (2R,3E)-5-(benzyloxy)-2-methyl-1-[(triisopropylsilyl)oxy]-3-penten-2-ol | C22H38O3Si | 详情 | 详情 | |
| (VI) | 61542 | (5R)-5-[(E)-3-(benzyloxy)-1-propenyl]-8,8-diisopropyl-5,9-dimethyl-2,4,7-trioxa-8-siladecane; benzyl (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenyl ether | C24H42O4Si | 详情 | 详情 | |
| (VII) | 61543 | (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-penten-1-ol | C17H36O4Si | 详情 | 详情 | |
| (VIII) | 61544 | (E,4R)-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenal | C17H34O4Si | 详情 | 详情 | |
| (IX) | 61545 | Allyltrimethoxysilane; Allyltrimethoxysilane | 2551-83-9 | C6H14O3Si | 详情 | 详情 |
| (X) | 61546 | (4R,5E,7R)-7-(methoxymethoxy)-7-methyl-8-[(triisopropylsilyl)oxy]-1,5-octadien-4-ol | C20H40O4Si | 详情 | 详情 | |
| (XI) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XII) | 61547 | (1R,2E,4R)-1-allyl-4-(methoxymethoxy)-4-methyl-5-[(triisopropylsilyl)oxy]-2-pentenyl acrylate | C23H42O5Si | 详情 | 详情 | |
| (XIII) | 61548 | (6R)-6-{(E,3R)-3-(methoxymethoxy)-3-methyl-4-[(triisopropylsilyl)oxy]-1-butenyl}-5,6-dihydro-2H-pyran-2-one | C21H38O5Si | 详情 | 详情 | |
| (XIV) | 61549 | (6R)-6-[(E,3R)-4-hydroxy-3-(methoxymethoxy)-3-methyl-1-butenyl]-5,6-dihydro-2H-pyran-2-one | C12H18O5 | 详情 | 详情 | |
| (XV) | 61550 | (2R,3E)-2-(methoxymethoxy)-2-methyl-4-[(2R)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-3-butenal | C12H16O5 | 详情 | 详情 | |
| (XVI) | 61551 | 4-Trimethylsilyl-3-butyn-2-one; 4-(TRIMETHYLSILYL)-3-BUTYN-2-ONE | 5930-98-3 | C7H12OSi | 详情 | 详情 |
| (XVII) | 61552 | (6R)-6-[(E,3R)-4-hydroxy-3-(methoxymethoxy)-3-methyl-6-oxo-8-(trimethylsilyl)-1-octen-7-ynyl]-5,6-dihydro-2H-pyran-2-one | C19H28O6Si | 详情 | 详情 | |
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIX) | 61553 | (6R)-6-((E)-2-{(4R)-2,2,4-trimethyl-5-[2-oxo-4-(trimethylsilyl)-3-butynyl]-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C20H28O5Si | 详情 | 详情 | |
| (XX) | 61554 | (6R)-6-((E)-2-{(4R,5R)-5-[(2R)-2-hydroxy-4-(trimethylsilyl)-3-butynyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C20H30O5Si | 详情 | 详情 | |
| (XXI) | 61555 | (6R)-6-((E)-2-{(4R,5R)-5-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(trimethylsilyl)-3-butynyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}ethenyl)-5,6-dihydro-2H-pyran-2-one | C26H44O5Si2 | 详情 | 详情 | |
| (XXII) | 61556 | (6R)-6-{(E)-2-[(4R,5R)-5-((2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-iodo-3-butynyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one | C23H35IO5Si | 详情 | 详情 | |
| (XXIII) | 61557 | (6R)-6-{(E)-2-[(4R,5R)-5-((2R,3Z)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-iodo-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one | C23H37IO5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reaction of D-ribose (I) with 2,2-dimethoxypropane (II) by means of HClO4 in methanol gives the isopropylidene derivative (III), which is oxidized with PCC in benzene to yield the tetrahydrofuranone (IV). The reaction of (IV) with the lithium salt of dimethyl methylphosphonate (V) affords the chiral cyclopentenone (VI), which is condensed with tert-butyl methyl ether (VII) by means of tBu-OK and sec-BuLi in THF to provide the cyclopentenol derivative (VIII). The reaction of (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the corresponding acetate (IX), which is submitted to rearrangement catalyzed by PdCl2(acetonitrile)2 and benzoquinone in refluxing THF to yield the regioisomeric acetate (X). The hydrolysis of (X) by means of K2CO3 in methanol yields the corresponding alcohol (XI), which is condensed with 6-chloropurine (XII) by means of PPh3 and DIEA to afford the adduct (XIII). The reaction of (XIII) with ammonia in ethanol at 80 C in a steel bomb affords the protected adenine nucleoside (XIV), which is finally deprotected with aqueous TFA to provide the target cyclopentenyl nucleoside.
| 【1】 Ali, S.M.; et al.; Efficient enantioselective syntheses of carbocyclic nucleoside and prostaglandin synthons. Tetrahedron Lett 1990, 31, 11, 1509. |
| 【2】 Song, G.Y.; et al.; Enantiomeric synthesis of D-and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J Med Chem 2001, 44, 23, 3985. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 49594 | Methyl 2,3-O-Isopropylidene-beta-D-Ribofuranoside | C9H16O5 | 详情 | 详情 | |
| (IV) | 49585 | (3aS,6aR)-6-methoxy-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C8H12O5 | 详情 | 详情 | |
| (V) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (VI) | 49586 | (3aS,6aS)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C8H10O3 | 详情 | 详情 | |
| (VII) | 49587 | 2-methoxy-2-methylpropane; tert-butyl methyl ether | C5H12O | 详情 | 详情 | |
| (VIII) | 49588 | tert-Butylmethyl ether; Methyl tert-butyl ether | 1634-04-4 | C13H22O4 | 详情 | 详情 |
| (IX) | 49589 | (3aS,4S,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (X) | 49590 | (3aR,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (XI) | 49591 | (3aS,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C13H22O4 | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XIII) | 49592 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; [(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl tert-butyl ether | C18H23ClN4O3 | 详情 | 详情 | |
| (XIV) | 49593 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C18H25N5O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)A new method for the synthesis of paclitaxel side chain has been developed: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with benzoyl chloride and pyridine to the benzoyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]benzamide (VI) with a 95% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyl-5-(2-thiazolyl)oxazolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carbaldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield (4S,5R)-3-benzoyl-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (X), the side chain of paclitaxel suitably protected.
| 【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| (I) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 10718 | methyl (2S)-2-(benzoylamino)-2-phenylethanoate | C16H15NO3 | 详情 | 详情 | |
| (IV) | 10719 | N-[(1S)-2-Oxo-1-phenylethyl]benzamide | C15H13NO2 | 详情 | 详情 | |
| (V) | 10720 | 2-(Trimethylsilyl)-1,3-thiazole | 79265-30-8 | C6H11NSSi | 详情 | 详情 |
| (VI) | 10721 | N-[(1S,2R)-2-Hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]benzamide | C18H16N2O2S | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 10723 | [(4S,5R)-2,2-Dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolidin-3-yl](phenyl)methanone | C21H20N2O2S | 详情 | 详情 | |
| (IX) | 10724 | (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carbaldehyde | C19H19NO3 | 详情 | 详情 | |
| (X) | 10725 | (4S,5R)-3-Benzoyl-2,2-dimethyl-4-phenyl-1,3-oxazolidine-5-carboxylic acid | C19H19NO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Synthesis of oxazolidine intermediate (XVI): The reaction of dimethyl L-tartrate (I) with benzaldehyde and Ts-OH gives the benzylidene ketal (II), which is reduced with LiAlH4/AlCl3 to yield the monobenzylated tetrol (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and TsOH affords the acetonide (V), which is protected at the primary OH group with Mpm-Cl and NaH to provide the corresponding ether (VI). The debenzylation of (VI) with H2 over Raney-Ni in ethanol, followed by reaction with MsCl and TEA in dichloromethane, gives the mesylate (VII), which is treated with HCl in methanol to yield the diol (VIII). The reaction of (VIII) with K2CO3 in methanol affords the epoxide (IX), which is opened with NaN3 in refluxing ethanol to provide the azide (X). The selective monosilylation of (X) with Tbdps-Cl, TEA and DMAP in dichloromethane furnishes the silyl ether (XI). The reduction of the azido group of (XI) with PPh3 in THF/water gives the amine (XII), which is protected with Troc-Cl and NaHCO3 to afford the carbamate (XIII). The reaction of (XIII) with 2,2-dimethoxypropane (IV) and TsOH provides the oxazolidine (XIV), which is selectively deprotected at the Mpm group with DDQ in dichloromethane, giving the primary alcohol (XV). Finally, this compound is esterified with Tf2O and TEA in CH2Cl2 to obtain the desired oxazolidine intermediate (XVI).
| 【1】 Al-Hakim, A.H.; et al.; Synthesis of 1,2-O-isopropylidene-L-threitol and its conversion to (R)-1,2-O-isopropylideneglycerol. Synthesis 1985, 207. |
| 【2】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946. |
| 【3】 Ohno, M.; et al.; An enantioselective synthesis of platelet-activating factors, their enantiomers, and their analogues from D- and L-tartaric acids. Chem Pharm Bull 1985, 33, 2, 572. |
| 【4】 Yoshino, T.; et al.; Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments. Tetrahedron Lett 1996, 37, 20, 3475. |
| 【5】 Yoshino, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments. Tetrahedron 1997, 53, 30, 10239. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28476 | dimethyl (2S,3S)-2,3-dimethylbutanedioate | C6H10O6 | 详情 | 详情 | |
| (II) | 47374 | dimethyl (4R,5R)-2-phenyl-1,3-dioxolane-4,5-dicarboxylate | 38270-72-3 | C13H14O6 | 详情 | 详情 |
| (III) | 43826 | (2S,3S)-3-(benzyloxy)-1,2,4-butanetriol | C11H16O4 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 47375 | (2S)-2-(benzyloxy)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol | C14H20O4 | 详情 | 详情 | |
| (VI) | 47376 | (4S)-4-[(1S)-1-(benzyloxy)-2-[(4-methoxybenzyl)oxy]ethyl]-2,2-dimethyl-1,3-dioxolane; benzyl (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl ether | C22H28O5 | 详情 | 详情 | |
| (VII) | 47377 | (1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(4-methoxybenzyl)oxy]ethyl methanesulfonate | C16H24O7S | 详情 | 详情 | |
| (VIII) | 47378 | (1S,2S)-2,3-dihydroxy-1-[[(4-methoxybenzyl)oxy]methyl]propyl methanesulfonate | C13H20O7S | 详情 | 详情 | |
| (IX) | 47379 | ((2S,3R)-3-[[(4-methoxybenzyl)oxy]methyl]oxiranyl)methanol | C12H16O4 | 详情 | 详情 | |
| (X) | 47380 | (2R,3S)-2-azido-4-[(4-methoxybenzyl)oxy]-1,3-butanediol | C12H17N3O4 | 详情 | 详情 | |
| (XI) | 47381 | (2S,3R)-3-azido-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol | C28H35N3O4Si | 详情 | 详情 | |
| (XII) | 47382 | (2S,3R)-3-amino-4-[[tert-butyl(diphenyl)silyl]oxy]-1-[(4-methoxybenzyl)oxy]-2-butanol | C28H37NO4Si | 详情 | 详情 | |
| (XIII) | 47383 | 2,2,2-trichloroethyl (1R,2S)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2-hydroxy-3-[(4-methoxybenzyl)oxy]propylcarbamate | C31H38Cl3NO6Si | 详情 | 详情 | |
| (XIV) | 47384 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-[[(4-methoxybenzyl)oxy]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C34H42Cl3NO6Si | 详情 | 详情 | |
| (XV) | 47385 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-5-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C26H34Cl3NO5Si | 详情 | 详情 | |
| (XVI) | 47386 | 2,2,2-trichloroethyl (4R)-4-([[tert-butyl(diphenyl)silyl]oxy]methyl)-2,2-dimethyl-5-([[(trifluoromethyl)sulfonyl]oxy]methyl)-1,3-oxazolidine-3-carboxylate | C27H33Cl3F3NO7SSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(VII)A new method for the synthesis of the docetaxel side-chain has been reported: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with tert-butoxycarbonyl anhydride to the tert-butoxycarbonyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]carbamic acid tert-butyl ester (VI) with 88% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-(tert-butoxycarbonyl)-2,3-dimethyl-4-phenyl-5-(2-thiazolyl)ox azolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb aldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield the corresponding carboxylic acid, the (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb oxylic acid (X), the side-chain of taxotere suitably protected.
| 【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13214 | Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate | 24424-99-5 | C10H18O5 | 详情 | 详情 | |
| (I) | 10716 | (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine | 2935-35-5 | C8H9NO2 | 详情 | 详情 |
| (II) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 | |
| (III) | 12485 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 45428 | tert-butyl (1S)-2-oxo-1-phenylethylcarbamate | C13H17NO3 | 详情 | 详情 | |
| (V) | 10720 | 2-(Trimethylsilyl)-1,3-thiazole | 79265-30-8 | C6H11NSSi | 详情 | 详情 |
| (VI) | 12488 | tert-butyl N-[(1S,2R)-2-hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]carbamate | C16H20N2O3S | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 12490 | tert-butyl (4S,5R)-2,2-dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolane-3-carboxylate | C19H24N2O3S | 详情 | 详情 | |
| (IX) | 12491 | tert-butyl (4S,5R)-5-formyl-2,2-dimethyl-4-phenyl-1,3-oxazolane-3-carboxylate | C17H23NO4 | 详情 | 详情 | |
| (X) | 12492 | (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid | C17H23NO5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IX)The resulting diol (VIII) was converted to the isopropylidene ketal (X) by means of dimethoxypropane (IX) and camphorsulfonic acid. Both pivaloyl groups of (X) were reductively removed with LiAlH4, and then selective protection of the primary hydroxyl group gave monopivalate (XI). The secondary hydroxyl group of (XI) was further oxidized to ketone (XII) with PCC. Aldol condensation of (XII) with 3-methyl-2-butanone (XIII) in the presence of LDA afforded (XIV) as a 3:7 diastereomeric mixture. Hydrolysis of pivalate ester of (XIV) with NaOMe was accompanied by intramolecular cyclization to the tetrahydrofuran (XV). This unstable intermediate was dehydrated with warm aqueous AcOH to produce furan (XVI) along with a minor amount of the ketal-hydrolyzed analogue. A trimethylsilyl group was introduced at position 5 of the furan ring of (XVI) through lithiation with n-BuLi, followed by treatment with trimethylsilyl chloride yielding (XVII).
| 【1】 Shiraki, R.; et al.; Total synthesis of PI-091. Tetrahedron Lett 1995, 36, 31, 5551. |
| 【2】 Shiraki, R.; et al.; Total synthesis of natural PI-091, a new platelet aggregation inhibitor of microbial origin. J Org Chem 1996, 61, 8, 2845. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 26139 | (2R,3R,4S)-2-[(2,2-dimethylpropanoyl)oxy]-3,4-dihydroxy-4-methyldecyl pivalate | C21H40O6 | 详情 | 详情 | |
| (IX) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (X) | 26140 | (1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]ethyl pivalate | C24H44O6 | 详情 | 详情 | |
| (XI) | 26141 | (2R)-2-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl pivalate | C19H36O5 | 详情 | 详情 | |
| (XII) | 26142 | 2-[(4S,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-oxoethyl pivalate | C19H34O5 | 详情 | 详情 | |
| (XIII) | 26143 | 3-methyl-2-butanone | 563-80-4 | C5H10O | 详情 | 详情 |
| (XIV) | 26144 | 2-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-hydroxy-5-methyl-4-oxohexyl pivalate | C24H44O6 | 详情 | 详情 | |
| (XV) | 26145 | 4-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-2-isopropyltetrahydro-2,4-furandiol | C19H36O5 | 详情 | 详情 | |
| (XVI) | 26146 | (4S,5R)-4-hexyl-5-(5-isopropyl-3-furyl)-2,2,4-trimethyl-1,3-dioxolane | C19H32O3 | 详情 | 详情 | |
| (XVII) | 26147 | [3-[(4R,5S)-5-hexyl-2,2,5-trimethyl-1,3-dioxolan-4-yl]-5-isopropyl-2-furyl](trimethyl)silane | C22H40O3Si | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(Va)Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (Ib) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (IIIb) | 12876 | ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate | C18H25NO5 | 详情 | 详情 | |
| (Ia) | 14505 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine | 1161-13-3 | C17H17NO4 | 详情 | 详情 |
| (IIIa) | 14508 | ethyl (4S)-4-[[(benzyloxy)carbonyl]amino]-3-oxo-5-phenylpentanoate | C21H23NO5 | 详情 | 详情 | |
| (IVa) | 14510 | ethyl (3R,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-phenylpentanoate | C21H25NO5 | 详情 | 详情 | |
| (VIa) | 14514 | benzyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C24H29NO5 | 详情 | 详情 | |
| (VIb) | 14515 | ethyl 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetate | C21H31NO5 | 详情 | 详情 | |
| (VIIa) | 14516 | 2-[(4S,5R)-4-benzyl-3-[(benzyloxy)carbonyl]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C22H25NO5 | 详情 | 详情 | |
| (VIIb) | 14517 | 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid | C19H27NO5 | 详情 | 详情 | |
| (VIIIa) | 14518 | benzyl (4S,5S)-4-benzyl-5-(bromomethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate | C21H24BrNO3 | 详情 | 详情 | |
| (VIIIb) | 14519 | (4S,5S)-4-benzyl-5-(bromomethyl)-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolane | C18H26BrNO3 | 详情 | 详情 | |
| (IXa) | 14520 | benzyl N-[(1S,2S)-1-benzyl-3-bromo-2-hydroxypropyl]carbamate | C18H20BrNO3 | 详情 | 详情 | |
| (IXb) | 14521 | (2S,3S)-1-bromo-3-[[(2,2-dimethylpropanoyl)oxy]amino]-4-phenyl-2-butanol | C15H22BrNO3 | 详情 | 详情 | |
| (Xa) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (XIIa) | 14526 | benzyl (1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropylcarbamate | C32H45N3O4 | 详情 | 详情 | |
| (XIIb) | 14527 | (3S,4aS,8aS)-N-(tert-butyl)-2-((2R,3S)-3-[[(2,2-dimethylpropanoyl)oxy]amino]-2-hydroxy-4-phenylbutyl)decahydro-3-isoquinolinecarboxamide | C29H47N3O4 | 详情 | 详情 | |
| (IXb) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (IVb) | 25725 | 2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid | C17H23NO5 | 详情 | 详情 | |
| (II) | 14507 | Malonic acid monoethyl ester magnesium salt | C5H6MgO4 | 详情 | 详情 | |
| (XI) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XIV) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (XV) | 14530 | benzyl (1S)-1-[([(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]amino)carbonyl]-3-amino-3-oxopropylcarbamate | C36H51N5O6 | 详情 | 详情 | |
| (XVI) | 14531 | (2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide | C28H45N5O4 | 详情 | 详情 | |
| (XVII) | 14532 | 2-Quinolinecarboxylic acid; Quinaldic Acid | 93-10-7 | C10H7NO2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(IV)By esterification of the acetonide of pantothenic acid (I) with (1S,2S)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]-cyclohexanol (II) by means of dimethylaminopyridine (DMAP) and tosyl chloride in ethyl acetate (1) or DMAP and dicyclohexylcarbodiimide (DCC) in refluxing toluene (2). The starting compounds (I) and (II) have been prepared as follows: 1) The cyclization of pantothenic acid calcium salt (III) with 2,2-dimethoxypropane (IV) by means of oxalic acid and p-toluenesulfonic acid in refluxing acetones gives the acetonide (I). 2) The condensation of the carbamate (V) with the secondary amine (VI) by heating at 120 C yields the urea derivative (II).
| 【1】 Ikawa, H.; Matsumoto, H.; Kobayashi, N.; Kusunoki, J. (UCB Japan); Pantothenic acid derivs. EP 0421441; JP 1991218340; JP 1991218350; JP 1991218366; US 5120738 . |
| 【2】 Ikawa, H.; Matsumoto, H. (UCB Japan); Methods of producing pantothenic acid deriv. and its starting materials for producing the same. EP 0612740 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17387 | 3-[[(2,2,5,5-tetramethyl-1,3-dioxan-4-yl)carbonyl]amino]propionic acid | C12H21NO5 | 详情 | 详情 | |
| (II) | 17388 | N'-[(1S,2S)-2-hydroxycyclohexyl]-N-neopentyl-N-nonylurea | C21H42N2O2 | 详情 | 详情 | |
| (III) | 17389 | 3-[(2,4-dihydroxy-3,3-dimethylbutanoyl)amino]propanoate | C18H32N2O10 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 17391 | phenyl N-[(1S,2S)-2-hydroxycyclohexyl]carbamate | C13H17NO3 | 详情 | 详情 | |
| (VI) | 17392 | N-neopentyl-1-nonanamine; N-neopentyl-N-nonylamine | C14H31N | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(XXIX)3) The condensation of 4-cyano-3(R)-hydroxybutyric acid ethyl ester (XXXV) with N,N-diphenylacetamide (R1 = R2 = Ph in XXVI) by means of LDA in THF gives 6-cyano-5(R)-hydroxy-3-oxo-N,N-diphenylhexanamide (XXVII), which is reduced with diethylmethoxyborane and NaBH4 in THF yielding 6-cyano-3(R),5(R)-dihydroxy-N,N-diphenylhexanamide (XXVIII). The protection of the two OH groups of (XXVIII) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XXX), which by reduction of its CN group by hydrogenation with H2 over RaNi in methanol/liquid ammonia gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N-diphenylacetamide (XXXI). The cyclization of (XXXI) with 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) (its synthesis is in section 6, Scheme 18007204a) in refluxing toluene yields the protected dihydroxyheptanamide (XXXIII), which is deprotected with HCl in methanol to afford (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxy-N,N-diphenylheptanamide (XXXIV). Finally, this compound is hydrolyzed with NaOH and treated with calcium acetate in water. 4) The preceding reaction pathway can be repeated using other substituents for R1 and R2 in acetamide (XXVI) such as R1 = R2 = CH2Ph; R1 = R2 = Et; R1 = Bu, R2 = Me; R1 = t-Bu, R2 = CH2Ph; R1,R2 = -(CH2)5-.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Butler, D.E.; Le, T.V.; Nanninga, T.N. (Pfizer Inc.); Process for trans-6-[2-(substd.-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis. US 5298627 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVIa) | 15400 | N,N-dibenzylacetamide | C16H17NO | 详情 | 详情 | |
| (XXVIb) | 15401 | N,N-diethylacetamide; Diethylacetamide | 685-91-6 | C6H13NO | 详情 | 详情 |
| (XXVIc) | 15402 | N-butyl-N-methylacetamide | C7H15NO | 详情 | 详情 | |
| (XXVId) | 15403 | N-benzyl-N-(tert-butyl)acetamide | C13H19NO | 详情 | 详情 | |
| (XXVIe) | 15404 | 1-piperidino-1-ethanone | 618-42-8 | C7H13NO | 详情 | 详情 |
| (XXVIIa) | 15405 | (5R)-N,N-dibenzyl-6-cyano-5-hydroxy-3-oxohexanamide | C21H22N2O3 | 详情 | 详情 | |
| (XXVIIb) | 15406 | (5R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide | C11H18N2O3 | 详情 | 详情 | |
| (XXVIIc) | 15407 | (5R)-N-butyl-6-cyano-5-hydroxy-N-methyl-3-oxohexanamide | C12H20N2O3 | 详情 | 详情 | |
| (XXVIId) | 15408 | (5R)-N-benzyl-N-(tert-butyl)-6-cyano-5-hydroxy-3-oxohexanamide | C18H24N2O3 | 详情 | 详情 | |
| (XXVIIe) | 15409 | (3R)-3-hydroxy-5,7-dioxo-7-piperidinoheptanenitrile | C12H18N2O3 | 详情 | 详情 | |
| (XXVIIIa) | 15410 | (3R,5R)-N,N-dibenzyl-6-cyano-3,5-dihydroxyhexanamide | C21H24N2O3 | 详情 | 详情 | |
| (XXVIIIb) | 15411 | (3R,5R)-6-cyano-N,N-diethyl-3,5-dihydroxyhexanamide | C11H20N2O3 | 详情 | 详情 | |
| (XXVIIIc) | 15412 | (3R,5R)-N-butyl-6-cyano-3,5-dihydroxy-N-methylhexanamide | C12H22N2O3 | 详情 | 详情 | |
| (XXVIIId) | 15413 | (3R,5R)-N-benzyl-N-(tert-butyl)-6-cyano-3,5-dihydroxyhexanamide | C18H26N2O3 | 详情 | 详情 | |
| (XXVIIIe) | 15414 | (3R,5R)-3,5-dihydroxy-7-oxo-7-piperidinoheptanenitrile | C12H20N2O3 | 详情 | 详情 | |
| (XXXa) | 15416 | N,N-dibenzyl-2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetamide | C24H28N2O3 | 详情 | 详情 | |
| (XXXb) | 15417 | 2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N-diethylacetamide | C14H24N2O3 | 详情 | 详情 | |
| (XXXc) | 15418 | N-butyl-2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N-methylacetamide | C15H26N2O3 | 详情 | 详情 | |
| (XXXd) | 15419 | N-benzyl-N-(tert-butyl)-2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetamide | C21H30N2O3 | 详情 | 详情 | |
| (XXXe) | 15420 | 2-[(4R,6R)-2,2-dimethyl-6-(2-oxo-2-piperidinoethyl)-1,3-dioxan-4-yl]acetonitrile | C15H24N2O3 | 详情 | 详情 | |
| (XXXIa) | 15421 | 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N-dibenzylacetamide | C24H32N2O3 | 详情 | 详情 | |
| (XXXIb) | 15422 | 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N,N-diethylacetamide | C14H28N2O3 | 详情 | 详情 | |
| (XXXIc) | 15423 | 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N-butyl-N-methylacetamide | C15H30N2O3 | 详情 | 详情 | |
| (XXXId) | 15424 | 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-N-benzyl-N-(tert-butyl)acetamide | C21H34N2O3 | 详情 | 详情 | |
| (XXXIe) | 15425 | 2-[(4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]-1-piperidino-1-ethanone | C15H28N2O3 | 详情 | 详情 | |
| (XXXIIIa) | 15427 | 1-(2-[(4R,6R)-6-[2-(dibenzylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C50H52FN3O4 | 详情 | 详情 | |
| (XXXIIIb) | 15428 | 1-(2-[(4R,6R)-6-[2-(diethylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C40H48FN3O4 | 详情 | 详情 | |
| (XXXIIIc) | 15429 | 1-[2-((4R,6R)-6-[2-[butyl(methyl)amino]-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H50FN3O4 | 详情 | 详情 | |
| (XXXIIId) | 15430 | 1-[2-((4R,6R)-6-[2-[benzyl(tert-butyl)amino]-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C47H54FN3O4 | 详情 | 详情 | |
| (XXXIIIe) | 15431 | 1-(2-[(4R,6R)-2,2-dimethyl-6-[2-oxo-2-(1-piperidinyl)ethyl]-1,3-dioxan-4-yl]ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C41H48FN3O4 | 详情 | 详情 | |
| (XXXIVa) | 15432 | 1-[(3R,5R)-7-(dibenzylamino)-3,5-dihydroxy-7-oxoheptyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C47H48FN3O4 | 详情 | 详情 | |
| (XXXIVb) | 15433 | 1-[(3R,5R)-7-(diethylamino)-3,5-dihydroxy-7-oxoheptyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C37H44FN3O4 | 详情 | 详情 | |
| (XXXIVc) | 15434 | 1-[(3R,5R)-7-[butyl(methyl)amino]-3,5-dihydroxy-7-oxoheptyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C38H46FN3O4 | 详情 | 详情 | |
| (XXXIVd) | 15435 | 1-[(3R,5R)-7-[benzyl(tert-butyl)amino]-3,5-dihydroxy-7-oxoheptyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C44H50FN3O4 | 详情 | 详情 | |
| (XXXIVe) | 15436 | 1-[(3R,5R)-3,5-dihydroxy-7-oxo-7-(1-piperidinyl)heptyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide | C38H44FN3O4 | 详情 | 详情 | |
| (XXV) | 15399 | ethyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate | C9H13NO4 | 详情 | 详情 | |
| (XXIX) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXXII) | 15426 | 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide | 125971-96-2 | C26H24FNO3 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(XXIX)5) The hydrolysis of methyl (Et or Bu) 3(R)-(tert-butyldimethylsilyloxy)-4-cyanobutyrate (XXV) with NaOH gives the corresponding free acid (XXXVI), which is condensed with malonic acid mono-tert-butyl ester magnesium salt (XXXVII) by means of carbonyldiimidazole (CDI) yielding tert-butyl 5(R)-(tert-butyldimethylsilyloxy)-6-cyano-3-oxohexanoate (XXXVIII). The desilylation of (XXXVIII) with tetrabutylammonium fluoride in acetic acid affords the expected hydroxylated ketoester (XXXIX), which is reduced with diethylmethoxyborane and NaBH4 in methanol giving tert-butyl 6-cyano-3(R),5(R)-dihydroxyhexanoate (XL). The protection of the two OH groups of (XL) with acetone dimethylketal (XXIX) and methanesulfonic acid affords the 1,3-dioxane (XLI) (6), which by reduction of its CN group by hydrogenation with H2 over Pd/C gives intermediate (4R,6R)-2-[6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLII). 6) The (4R,6R)-2-[6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLI) can also be obtained by reaction of (4R,6R)-2-[6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid tert-butyl ester (XLVIII) with tosyl chloride to give the corresponding tosylate (XVIX), which is then treated with NaCN. 7) The tert-butyl 6-cyano-5(R)-hydroxy-3-oxohexanoate (XXXIX) can also be obtained by condensation of methyl 4-cyano-3(R)-hydroxybutyrate (L) with tert-butyl acetate (XXIII) by means of LDA in THF.
| 【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956. |
| 【2】 Roth, B.D.; Baumann, K.L.; Butler, D.E.; Deering, C.F.; Mennen, K.E.; Millar, A.; Nanninga, T.N.; Palmer, C.W.; The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2283-4. |
| 【3】 Brower, P.L.; Butler, D.E.; Deering, C.F.; Le, T.V.; Millar, A.; Nanninga, T.N.; Roth, B.D.; The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase. Tetrahedron Lett 1992, 33, 17, 2279-82. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIII) | 15097 | 7-[(2-aminopropyl)amino]-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C17H20FN3O3 | 详情 | 详情 | |
| (XXIX) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXXV) | 15437 | methyl (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutanoate | C12H23NO3Si | 详情 | 详情 | |
| (XXXVI) | 15438 | (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-cyanobutyric acid | C11H21NO3Si | 详情 | 详情 | |
| (XXXVII) | 15439 | Bis(malonic acid mono-tert-butyl ester)magnesium salt | C14H22MgO8 | 详情 | 详情 | |
| (XXXVIII) | 15440 | tert-butyl (5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-cyano-3-oxohexanoate | C17H31NO4Si | 详情 | 详情 | |
| (XXXIX) | 15441 | tert-butyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate | C11H17NO4 | 详情 | 详情 | |
| (XL) | 15442 | tert-butyl (3R,5R)-6-cyano-3,5-dihydroxyhexanoate | C11H19NO4 | 详情 | 详情 | |
| (XLI) | 15443 | tert-Butyl (4R,3R)-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate；tert-butyl 2-[(4R,6R)-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate | 125971-94-0 | C14H23NO4 | 详情 | 详情 |
| (XLII) | 15444 | (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate | 125995-13-3 | C14H27NO4 | 详情 | 详情 |
| (XLVIII) | 15445 | tert-butyl 2-[(4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate | 124655-09-0 | C13H24O5 | 详情 | 详情 |
| (XLIX) | 15446 | tert-butyl 2-[(4R,6S)-2,2-dimethyl-6-([[(4-methylphenyl)sulfonyl]oxy]methyl)-1,3-dioxan-4-yl]acetate | C20H30O7S | 详情 | 详情 | |
| (L) | 15447 | methyl (5R)-6-cyano-5-hydroxy-3-oxohexanoate | C8H11NO4 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XXXVII)7) The potassium salt (XIV), immediate precursor of sanfetrinem cilexetil can also be obtained as an enantiomeric mixture by the following sequence: The reduction of 2-oxocyclohexanecarboxylic acid ethyl ester (XXIX) with H2 over PtO2 in ethanol gives a mixture of the cis- and trans-2-hydroxycyclohexane (XXX), which is separated by distillation and treated with tert-butyldimethylsilyl chloride and imidazole in THF to yield cis-2-(tert-butyldimethylsilyloxy)cyclohexanecarboxylic acid ethyl ester (XXXI) as an enantiomeric mixture cis-(S,R)/cis-(R,S) (for the sake of clarity only one of the enantiomers is presented). The reduction of (XXXI) with diisobutylaluminum hydride (DIBAL) in ether affords the corresponding aldehyde (XXXII), which is treated with lithium trimethylsilylamide in THF to give the silylated imine (XXXIII). The cyclization of (XXXIII) with lithium tert-butyl acetate (XXXIV) in THF yields the silylated azetidinone (XXXV), which is deprotected by treatment with tetrabutylammonium fluoride (TBAF) in THF affording the hydroxyazetidinone (XXXVI). The reaction of (XXXVI) with 2,2-dimethoxypropane (XXXVII) and BF3 ethearate in dichloromethane gives the acetonide (XXXVIII), which is condensed with acetyltrimethylsilane (XXXIX) by means of lithium diisopropylamide (LDA) and potassium tert-butoxide (in order to introduce the 1-hydroxyethyl group) yielding the alkylated acetonide (XL). The trimethylsilyl protection of (XL) was removed and substituted with a more stable tert-butyldimethylsilyl (TBS) group affording (XLI), which is treated with pyridine chlorochromate (PCC) to give the previously reported 2-oxocyclohexylazetidinone (XVII) (Scheme 2), but as an enantiomeric mixture. The reaction sequence was continued (XVII) -> (XVIII) -> (XIX) -> (VIII) as in Scheme 2, and (VIII) -> (IX) -> (X) -> (XI) -> potassium salt (XIV) (all the compounds as enantiomeric mixtures). Note that if the starting compound is 2-oxocyclohexane-1(S)-carboxylic acid ethyl ester, instead of the racemic compound (XXIX), the potassium salt (XIV) can be obtained in enantiomerically pure form.
| 【1】 Camerini, R.; Panunzio, M.; Bonanomi, G.; Donati, D.; Perboni, A.; Highly stereocontrolled synthesis of a novel tribactam by reaction of an ester enolate with a N-trimethylsilylimine. Tetrahedron Lett 1996, 37, 14, 2467-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 15566 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone | C18H33NO4Si | 详情 | 详情 | |
| (IX) | 15567 | benzyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-4-oxoazetidinyl]-2-oxoacetate | C27H39NO7Si | 详情 | 详情 | |
| (X) | 15568 | benzyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C27H39NO5Si | 详情 | 详情 | |
| (XI) | 15569 | benzyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C21H25NO5 | 详情 | 详情 | |
| (XIV) | 15572 | potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate | C14H18KNO5 | 详情 | 详情 | |
| (XVII) | 15575 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-2-oxocyclohexyl]-2-azetanone | C17H31NO3Si | 详情 | 详情 | |
| (XVIII) | 15576 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-2-cyclohexen-1-yl]-2-azetanone | C17H31NO2Si | 详情 | 详情 | |
| (XIX) | 15577 | (3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S,2R,6R)-7-oxabicyclo[4.1.0]hept-2-yl]-2-azetidinone | C17H31NO3Si | 详情 | 详情 | |
| (XXIX) | 11889 | ethyl 2-oxocyclohexanecarboxylate; Ethyl 2-cyclohexanonecarboxylate | 1655-07-8 | C9H14O3 | 详情 | 详情 |
| (XXX) | 15589 | ethyl 2-hydroxycyclohexanecarboxylate; Ethyl cis-2-hydroxy-1-cyclohexanecarboxylate | 6149-52-6 | C9H16O3 | 详情 | 详情 |
| (XXXI) | 15590 | ethyl (1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexanecarboxylate | C15H30O3Si | 详情 | 详情 | |
| (XXXII) | 15591 | (1S,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexanecarbaldehyde | C13H26O2Si | 详情 | 详情 | |
| (XXXIII) | 15592 | N-[(E)-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)methylidene](trimethyl)silanamine; N-[(E)-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)methylidene]-N-(trimethylsilyl)amine | C16H35NOSi2 | 详情 | 详情 | |
| (XXXIV) | 15593 | [2-(tert-butoxy)-2-oxoethyl]lithium | C6H11LiO2 | 详情 | 详情 | |
| (XXXV) | 15594 | (4S)-4-((1R,2R)-2-[[tert-butyl(dimethyl)silyl]oxy]cyclohexyl)-2-azetanone | C15H29NO2Si | 详情 | 详情 | |
| (XXXVI) | 15595 | (4S)-4-[(1R,2R)-2-hydroxycyclohexyl]-2-azetanone | C9H15NO2 | 详情 | 详情 | |
| (XXXVII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXXVIII) | 15597 | (5aR,9aR,9bS)-4,4-dimethyloctahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C12H19NO2 | 详情 | 详情 | |
| (XXXIX) | 15598 | 1-(trimethylsilyl)-1-ethanone | 13411-48-8 | C5H12OSi | 详情 | 详情 |
| (XL) | 15599 | (1R,5aR,9aR,9bR)-4,4-dimethyl-1-[(1R)-1-methyl-2-(trimethylsilyl)ethyl]octahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C18H33NO2Si | 详情 | 详情 | |
| (XLI) | 15600 | (1S,5aR,9aR,9bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4,4-dimethyloctahydro-2H-azeto[1,2-c][1,3]benzoxazin-2-one | C20H37NO3Si | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：(V)The condensation of diethyl malonate (I) with (R)-(-)-epichlorohydrin (II) by means of NaOEt in ethanol gives (3aS,4aR)-3-oxo-3,3a,4,4a-tetrahydro-1H-cyclopropa[c]furan-3a-carboxylic acid ethyl ester (III), which is selectively reduced at the lactone group by means of sodium borohydride in ethanol to yield (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylic acid ethyl ester (IV). The protection of (IV) with 2,2-dimethoxypropane (V) and Ts-OH in DMF affords the cyclic acetonide (VI), which is reduced with LiBH4 in THF to provide the hydroxymethyl acetonide (VII). The protection of the OH group of (VII) with benzyl bromide and NaH in DMF gives the benzyl ether (VIII), which is treated with HCl in THF/water to cleave the acetonide ring and yield the bis hydroxymethyl compound (IX). The acylation of (IX) with benzoyl chloride and pyridine affords the dibenzoate (X), which is debenzylated with H2 over Pd/C in ethanol/acetic acid to provide (1S,2R)-1,2-bis(benzoyloxymethyl)cyclopropanemethanol (XI). The reaction of (XI) with Ts-OH and DMAP in dichloromethane gives the corresponding tosylate (XII), which is condensed with 6-O-benzylguanine (XIII) by means of K2CO3 in DMF to yield the fully protected nucleoside (XIV). The hydrolysis of the benzoyl group of (XIV) by means of NaOMe in methanol affords the dihydroxy compound (XV), which is finally debenzylated by means of HCl in ethanol/water to provide the target guanine cyclopropyl nucleoside.
| 【1】 Sekiyama, T.; et al.; Synthesis and antiviral activity of novel acyclic nucleosides: Discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses. J Med Chem 1998, 41, 8, 1284. |
| 【2】 Hatsuya, S.; Sekiyama, T.; Tsuji, T.; Iwayama, S.; Okunishi, M. (Ajinomoto Co., Inc.); Cyclopropane deriv.. EP 0502690; JP 1993194421; US 5342840; US 5449840 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (III) | 38068 | ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate | C8H10O4 | 详情 | 详情 | |
| (IV) | 38069 | ethyl (1R,2R)-1,2-bis(hydroxymethyl)cyclopropanecarboxylate | C8H14O4 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 53924 | ethyl (1R,7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane-1-carboxylate | C11H18O4 | 详情 | 详情 | |
| (VII) | 53925 | [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methanol | C9H16O3 | 详情 | 详情 | |
| (VIII) | 53926 | benzyl [(7R)-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]oct-1-yl]methyl ether; (1S,7R)-1-[(benzyloxy)methyl]-4,4-dimethyl-3,5-dioxabicyclo[5.1.0]octane | C16H22O3 | 详情 | 详情 | |
| (IX) | 53927 | [(1R,2R)-2-[(benzyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methanol | C13H18O3 | 详情 | 详情 | |
| (X) | 53928 | {(1R,2S)-2-[(benzoyloxy)methyl]-2-[(benzyloxy)methyl]cyclopropyl}methyl benzoate | C27H26O5 | 详情 | 详情 | |
| (XI) | 53929 | [(1R,2S)-2-[(benzoyloxy)methyl]-2-(hydroxymethyl)cyclopropyl]methyl benzoate | C20H20O5 | 详情 | 详情 | |
| (XII) | 53930 | [(1R,2R)-2-[(benzoyloxy)methyl]-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)cyclopropyl]methyl benzoate | C27H26O7S | 详情 | 详情 | |
| (XIII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (XIV) | 53931 | {(1R,2S)-2-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-[(benzoyloxy)methyl]cyclopropyl}methyl benzoate | C32H29N5O5 | 详情 | 详情 | |
| (XV) | 53932 | [(1S,2R)-1-{[2-amino-6-(benzyloxy)-9H-purin-9-yl]methyl}-2-(hydroxymethyl)cyclopropyl]methanol | n/a | C18H21N5O3 | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：Treatment of 5-(1-naphthyl)cyclohexane-1,3-dione (I) with 2,2-dimethoxypropane and MeOH in the presence of p-toluenesulfonic acid provided enol ether (II). Condensation of (II) with n-octylmagnesium bromide in cold THF, followed by acidic treatment of intermediate (III) yielded enone (IV). The subsequent oxidative cleavage of (IV) with NaIO4 and a catalytic amount of ruthenium oxide gave ketoacid (V), which was converted into the oxime (VI) on treatment with hydroxylamine. Reduction of oxime (VI) with NaBH4 in AcOH gave the hydroxylamine (VII). Then, cyclization to the piperidone acid in the presence of silica gel in refluxing benzene, followed by chromatographic separation of the cis isomer, provided the target compound.
| 【1】 Honn, K.V.; Johnson, C.R.; Chen, Y.-F.; Shimoji, K.; Marnett, L.J. (Vanderbilt University; Wayne State University); Cyclic hydroxamic acids. US 5234933; WO 9308803 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 | |
| (I) | 18717 | 3-hydroxy-5-(1-naphthyl)-2-cyclohexen-1-one | C16H14O2 | 详情 | 详情 | |
| (II) | 18718 | 3-methoxy-5-(1-naphthyl)-2-cyclohexen-1-one | C17H16O2 | 详情 | 详情 | |
| (III) | 18719 | 3-Methoxy-5-(1-naphthyl)-1-octyl-2-cyclohexen-1-ol bromomagnesium salt | C25H33BrMgO2 | 详情 | 详情 | |
| (IV) | 18720 | 5-(1-naphthyl)-3-octyl-2-cyclohexen-1-one | C24H30O | 详情 | 详情 | |
| (V) | 18721 | 3-(1-naphthyl)-5-oxotridecanoic acid | C23H30O3 | 详情 | 详情 | |
| (VI) | 18722 | 5-(hydroxyimino)-3-(1-naphthyl)tridecanoic acid | C23H31NO3 | 详情 | 详情 | |
| (VII) | 18723 | 5-(hydroxyamino)-3-(1-naphthyl)tridecanoic acid | C23H33NO3 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(II)The reaction of D-tartaric acid (I) with 2,2-dimethoxypropane (II) and Ts-OH gives the acetonide (III), which is reduced with NaBH4 in ethanol to yield the diol (IV). The reaction of (IV) with Ts-OH and TEA affords the ditosylate (V), whose acetonide is cleaved with HCl to provide the diol (VI). The reaction of (VI) with SOCl2 in dichloromethane gives the cyclic sulfite (VII), which is oxidized with NaIO4 and RuCl3 to yield the cyclic sulfate (VIII). The reaction of (VIII) with sodium azide in acetone/water affords the azide (IX), which is treated with sulfuric acid in THF/water to provide the azido alcohol (X). The reduction of the azido group of (X) with H2 over Pd/C affords the amino alcohol (XI), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (XII) by means of TEA in THF, providing the intermediate amide (XIII). Spontaneous cyclization of the amide (XIII) under the reaction conditions gives the oxazoline (XIV), which is condensed with the perhydroisoquinoline (XV) by means of K2CO3 in isopropanol to yield the oxazoline intermediate (XVI). Finally, the cleavage of the oxazoline ring of (XVI) by means of thiophenol (XVII) affords the target compound.
| 【1】 Albizati, K.F.; et al.; A synthesis of the HIV-protease inhibitor nelfinavir from D-tartaric acid. Tetrahedron Lett 2001, 42, 37, 6481. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 55018 | (4S,5S)-1,3-dioxolane-4,5-dicarboxylic acid | C5H6O6 | 详情 | 详情 | |
| (IV) | 55019 | [(4R,5R)-5-(hydroxymethyl)-1,3-dioxolan-4-yl]methanol | C5H10O4 | 详情 | 详情 | |
| (V) | 55020 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate | C19H22O8S2 | 详情 | 详情 | |
| (VI) | 55021 | (2R,3R)-2,3-dihydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H22O8S2 | 详情 | 详情 | |
| (VII) | 55022 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxo-1,3,2lambda~4~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O9S3 | 详情 | 详情 | |
| (VIII) | 55023 | [(4R,5R)-5-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,2-dioxo-1,3,2lambda~6~-dioxathiolan-4-yl]methyl 4-methylbenzenesulfonate | C18H20O10S3 | 详情 | 详情 | |
| (IX) | 55024 | C18H20N3NaO10S3 | 详情 | 详情 | ||
| (X) | 55025 | (2S,3S)-3-azido-2-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H21N3O7S2 | 详情 | 详情 | |
| (XI) | 55026 | (2S,3S)-2-amino-3-hydroxy-4-{[(4-methylphenyl)sulfonyl]oxy}butyl 4-methylbenzenesulfonate | C18H23NO7S2 | 详情 | 详情 | |
| (XII) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (XIII) | 55027 | 3-({[(1S,2S)-2-hydroxy-3-{[(4-methylphenyl)sulfonyl]oxy}-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)propyl]amino}carbonyl)-2-methylphenyl acetate | C28H31NO10S2 | 详情 | 详情 | |
| (XIV) | 55028 | 3-[(4S)-4-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-4,5-dihydro-1,3-oxazol-2-yl]-2-methylphenyl acetate | C21H23NO7S | 详情 | 详情 | |
| (XV) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XVI) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
| (XVII) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(V)Treatment of butanedioate derivative (I) with methallyl iodide (II) and LDA in THF affords alkene (III), which is then reduced by hydrogenation over Pd/C and subjected to saponification by means of KOH in dioxane to yield succinic acid (IV). Protection of (IV) with 2,2-dimethoxypropane (V) and p-TsOH in DMF provides derivative (VI), which is then coupled with pentafluorophenol (VII) by using EDC in CH2Cl2 to furnish activated ester (VIII). Displacement of the pentafluorophenol moiety of (VIII) by treatment with L-tert-leucine methylamide (IX) in DMF gives methylamide derivative (X), which is deprotected with THF and HCl and condensed with O-benzylhydroxylamine (XI) by means of EDC to afford derivative (XII). Finally, (XII) is debenzylated by hydrogenation over Pd/C in EtOH to give the target compound.
| 【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983. |
| 【2】 Dickens, J.P.; Crimmin, M.J.; Beckett, R.P. (British Biotech plc); Natural amino acid derivs. as metalloproteinase inhibitors. EP 0651738; EP 0651739; GB 2268933; GB 2268934; JP 1995509460; JP 1998204081; WO 9402446; WO 9402447 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 43782 | diisopropyl (2S)-2-hydroxybutanedioate | C10H18O5 | 详情 | 详情 | |
| (II) | 43783 | 3-iodo-2-methyl-1-propene | C4H7I | 详情 | 详情 | |
| (III) | 43784 | diisopropyl (2S,3R)-2-hydroxy-3-(2-methyl-2-propenyl)butanedioate | C14H24O5 | 详情 | 详情 | |
| (IV) | 43785 | (2S,3R)-2-hydroxy-3-isobutylbutanedioic acid | C8H14O5 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 43786 | (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid | C11H18O5 | 详情 | 详情 | |
| (VII) | 22662 | 2,3,4,5,6-pentafluorophenol | 771-61-9 | C6HF5O | 详情 | 详情 |
| (VIII) | 43787 | 2,3,4,5,6-pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate | C17H17F5O5 | 详情 | 详情 | |
| (IX) | 18843 | (2S)-2-amino-N,3,3-trimethylbutanamide | 89226-12-0 | C7H16N2O | 详情 | 详情 |
| (X) | 43788 | (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide | C18H32N2O5 | 详情 | 详情 | |
| (XI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XII) | 43789 | (2S,3R)-N(1)-(benzyloxy)-N(4)-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-hydroxy-3-isobutylbutanediamide | C22H35N3O5 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(XVIII)Iodomethyl tetrahydropyran intermediate (XLVII): The condensation between epoxides (XLII), (XLIV) and silylated 1,3-dithiane (XLIII) gives the dihydroxy compound (XLV), which is treated first with 2,2-dimethoxypropane (XVIII) to create an acetonide group, and then with Hg(ClO4)2 to promote cyclization to yield the tetrahydropyran derivative (XLVI). Finally, the TsO group of (XLVI) is treated with lithium iodide in methanol to afford the desired iodomethyl tetrahydropyran intermediate (XLVII)
| 【1】 Smith, A.B.; et al.; The spongistatins: Architecturally complex natural products - Part one: A formal synthesis of (+)-spongistatin 1 by construction of an advanced ABCD fragment. Angew Chem. Int Ed 2001, 40, 1, 191. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XLII) | 64630 | tert-butyl(diphenyl)silyl (3S)-4-[(2S)oxiranyl]-3-[(triethylsilyl)oxy]butyl ether; (7S)-9,9-diethyl-2,2-dimethyl-7-[(2S)oxiranylmethyl]-3,3-diphenyl-4,8-dioxa-3,9-disilaundecane | C28H44O3Si2 | 详情 | 详情 | |
| (XLIII) | 64631 | tert-butyl(1,3-dithian-2-yl)dimethylsilane | C10H22S2Si | 详情 | 详情 | |
| (XLIV) | 64632 | (4R)-2,2-dimethyl-4-{[(2S)-2-methyloxiranyl]methyl}-1,3-dioxolane | C9H16O3 | 详情 | 详情 | |
| (XLV) | 64633 | (2R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[2-((2S,4S)-6-{[tert-butyl(diphenyl)silyl]oxy}-2,4-dihydroxyhexyl)-1,3-dithian-2-yl]-2,4-dimethylpentyl 4-methylbenzenesulfonate | C46H72O7S3Si2 | 详情 | 详情 | |
| (XLVI) | 64634 | ((2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-methoxy-4-methyltetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate | C46H70O9SSi2 | 详情 | 详情 | |
| (XLVII) | 64635 | tert-butyl(dimethyl)silyl (2R,4S,6R)-2-{[(4S,6S)-6-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2,2-dimethyl-1,3-dioxan-4-yl]methyl}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-4-yl ether; tert-butyl[2-((4S,6S)-6-{[(2R,4S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(iodomethyl)-2-methoxy-4-methyltetrahydro-2H-pyran-2-yl]methyl}-2,2-dimethyl-1,3-dioxan-4-yl)ethoxy]diphenylsilane | C39H63IO6Si2 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(II)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (Via) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi. The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(A)The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (I) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (II) | 35676 | tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether | C9H21IOSi | 详情 | 详情 | |
| (III) | 35677 | dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate | C14H28O5Si | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 35678 | dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate | C17H32O5Si | 详情 | 详情 | |
| (VI) | 35679 | 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol | C15H32O3Si | 详情 | 详情 | |
| (VII) | 35680 | 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane | C18H36O3Si | 详情 | 详情 | |
| (VIII) | 35681 | 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde | C17H34O4Si | 详情 | 详情 | |
| (IX) | 17966 | cyclohexanamine; cyclohexyl amine; cyclohexylamine | 108-91-8 | C6H13N | 详情 | 详情 |
| (X) | 35682 | N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine | C23H45NO3Si | 详情 | 详情 | |
| (XI) | 35683 | (E)-8-decenal | C10H18O | 详情 | 详情 | |
| (XII) | 35684 | (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal | C27H50O4Si | 详情 | 详情 | |
| (XIII) | 35685 | tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether | C35H58O4Si | 详情 | 详情 | |
| (XIV) | 35686 | 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol | C29H44O4 | 详情 | 详情 | |
| (XV) | 35687 | 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal | C29H42O4 | 详情 | 详情 | |
| (XVI) | 35688 | (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane | C13H27IOSi | 详情 | 详情 | |
| (XVII) | 35689 | (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one | C42H68O5Si | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(II)1) The reaction of (-)-quinic acid (I) with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid in refluxing acetone gives the protected lactone (III), which by treatment with sodium ethoxide in ethanol yields the ethyl ester (IV). The acylation of (IV) with mesyl chloride and TEA in dichloromethane affords the mesylate (V), which is dehydrated with SO2Cl2 in dichloromethane, giving the cyclohexenecarboxylate (VI). The transketalization of (VI) with 3-pentanone and HClO4 affords the 3,4-pentylidene ketal (VII), which is cleaved with borane methyl sulfide complex to the 3-pentyl ether (VIII). The epoxidation of (VIII) by treatment with KHCO3 in hot ethanol affords the epoxide (IX), which is opened with sodium azide and ammonium chloride in ethanol/water, resulting in the the azido alcohol (X). The cyclization of (X) with triphenylphosphine in refluxing THF/acetonitrile or trimethylphosphine in anhydrous acetonitrile yields aziridine (XI), which is opened by means of sodium azide in hot DMF to the azidoamine (XII). The acetylation of (XII) with acetic anhydride provides the azidoacetamide (XIII), which is reduced with H2 over Lindlar catalyst or over RaNi in ethanol and treated with 85% phosphoric acid.
| 【1】 Rohloff, J.C.; Kent, K.M.; Postich, M.J.; et al.; Practical total synthesis of the anti-influenza drug GS-4104. J Org Chem 1998, 63, 13, 4545. |
| 【2】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【3】 McGee, L.R.; Kent, K.M.; Portich, M.J.; Kim, C.U.; Williams, M.A.; Zhang, L.; Prisbe, E.J.; Rohloff, J.C.; Munger, J.D.; St. John, D.E. (Gilead Sciences Inc.); Preparation of cyclohexene carboxylate derivs.. WO 9807685 . |
| 【4】 Postich, M.J.; Williams, M.A.; Rohloff, J.C.; Prisbe, E.J.; McGee, L.R.; Kent, K.M.; Munger, J.D.; Zhang, L.; Kim, C.U.; Kelly, D.E. (Gilead Sciences Inc.); Preparation of carbocyclic cpds.. US 5886213 . |
| 【5】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Mills, R.G.; Hitchcock, M.J.M.; Dahl, T.C.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Cpds. containing six-membered rings, processes for their preparation, and their use as medicaments. EP 1015417; WO 9914185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (I) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 29896 | (1R,2R,6R,8S)-8-hydroxy-4,4-dimethyl-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C10H14O5 | 详情 | 详情 | |
| (IV) | 29897 | ethyl (3aR,5R,7R,7aS)-5,7-dihydroxy-2,2-dimethylhexahydro-1,3-benzodioxole-5-carboxylate | C12H20O6 | 详情 | 详情 | |
| (V) | 29898 | ethyl (3aR,5S,7R,7aR)-5-hydroxy-2,2-dimethyl-7-[(methylsulfonyl)oxy]hexahydro-1,3-benzodioxole-5-carboxylate | C13H22O8S | 详情 | 详情 | |
| (VI) | 29899 | ethyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C13H20O7S | 详情 | 详情 | |
| (VII) | 29900 | ethyl (3aR,7R,7aR)-2,2-diethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C15H24O7S | 详情 | 详情 | |
| (VIII) | 29901 | ethyl (3R,4R,5R)-3-(1-ethylpropoxy)-4-hydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C15H26O7S | 详情 | 详情 | |
| (IX) | 29902 | ethyl (1S,5R,6S)-5-(1-ethylpropoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 29903 | ethyl (3R,4S,5R)-5-azido-3-(1-ethylpropoxy)-4-hydroxy-1-cyclohexene-1-carboxylate | C14H23N3O4 | 详情 | 详情 | |
| (XI) | 29904 | ethyl (1R,5R,6R)-5-(1-ethylpropoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C14H23NO3 | 详情 | 详情 | |
| (XII) | 29905 | ethyl (3R,4R,5S)-4-amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C14H24N4O3 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(II)2) The esterification of Shikimic acid (XIV) with MeOH/TsOH gives the methyl ester (XV), which is treated with 2,2-dimethoxypropane (II) and TsOH to yield the acetonide (XVI). The mesylation of (XVI) with mesyl chloride and TEA in dichloromethane gives the mesylated acetonide (XVII), which is hydrolyzed with HCl, yielding the dihydroxy ester (XVIII). The epoxidation of (XVIII) with DBU in THF affords the epoxide (XIX), which is protected with methyl chloromethyl ether to give compound (XX). The reaction of (XX) with sodium azide in refluxing methanol/water provides the hydroxy azide (XXI), which is acylated with mesyl chloride to the mesylate (XXII). The cyclization of (XXII) by means of triphenylphosphine in THF affords the aziridine (XXIII), which is treated with sodium azide in hot DMF to give the amino azide (XXIV). The deprotection of (XXIV) with HCl followed by tritylation of the free amino group with trityl chloride and TEA yields compound (XXV), which is cyclized by means of mesyl chloride and TEA to afford the tritylaziridine (XXVI). The cleavage of the aziridine ring of (XXVI) with 3-pentanol, followed by acetylation of the resulting amino group, affords the acetamido aziridine (XXVII), which is hydrolyzed at the ester group with KOH in THF/water to give the carboxylic acid (XXVIII). The esterification of (XXVIII) with ethanol, DCC and DMAP in dichloromethane affords the azido ester (XIII), which is finally reduced with triphenylphosphine in hot THF/water.
| 【1】 Castañer, J.; Leeson, P.A.; Graul, A.; Oseltamivir Phosphate. Drugs Fut 1999, 24, 11, 1189. |
| 【2】 Bischofberger, N.W.; Kim, C.U.; Lew, W.; Liu, H.; Williams, M.A. (Gilead Sciences Inc.); Novel selective inhibitors of viral or bacterial neuraminidases. EP 0759917; EP 0976734; JP 1999501908; WO 9626933 . |
| 【3】 Bischofberger, N.W.; Kim, C.U.; Williams, M.A.; Lew, W.; Liu, H. (Gilead Sciences Inc.); Carbocyclic cpds.. US 5763483 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 18319 | Chloro(methoxy)methane; Chloromethyl methyl ether | 107-30-2 | C2H5ClO | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIII) | 29906 | ethyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C16H26N4O4 | 详情 | 详情 | |
| (XIV) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XV) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVI) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XVII) | 29910 | methyl (3aR,7R,7aR)-2,2-dimethyl-7-[(methylsulfonyl)oxy]-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C12H18O7S | 详情 | 详情 | |
| (XVIII) | 29911 | methyl (3R,4R,5R)-3,4-dihydroxy-5-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C9H14O7S | 详情 | 详情 | |
| (XIX) | 29912 | methyl (1S,5R,6R)-5-hydroxy-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C8H10O4 | 详情 | 详情 | |
| (XX) | 29913 | methyl (1S,5R,6S)-5-(methoxymethoxy)-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H14O5 | 详情 | 详情 | |
| (XXI) | 29914 | methyl (3R,4S,5R)-5-azido-4-hydroxy-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXII) | 29915 | methyl (3R,4S,5R)-5-azido-3-(methoxymethoxy)-4-[(methylsulfonyl)oxy]-1-cyclohexene-1-carboxylate | C11H17N3O7S | 详情 | 详情 | |
| (XXIII) | 29916 | methyl (1R,5R,6R)-5-(methoxymethoxy)-7-azabicyclo[4.1.0]hept-3-ene-3-carboxylate | C10H15NO4 | 详情 | 详情 | |
| (XXIV) | 29917 | methyl (3R,4R,5S)-4-amino-5-azido-3-(methoxymethoxy)-1-cyclohexene-1-carboxylate | C10H16N4O4 | 详情 | 详情 | |
| (XXV) | 29918 | methyl (3R,4R,5S)-5-azido-3-hydroxy-4-(tritylamino)-1-cyclohexene-1-carboxylate | C27H26N4O3 | 详情 | 详情 | |
| (XXVI) | 29919 | methyl (1S,5S,6S)-5-azido-7-trityl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate | C27H24N4O2 | 详情 | 详情 | |
| (XXVII) | 29920 | methyl (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate | C15H24N4O4 | 详情 | 详情 | |
| (XXVIII) | 29921 | (3R,4R,5S)-4-(acetamido)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid | C14H22N4O4 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：(IV)Synthesis of intermediate monosaccharide (VIII): The reaction of the tetraacetyl-L-arabinose (I) with Ph-SH and SnCl4 gives the thioglycoside (II), which is deacetylated with NaOMe in methanol, yielding compound (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and CSA in dichloromethane affords the acetonide (V), which is acetylated with Ac2O, DMAP and TEA to provide the acetate (VI). Elimination of the acetonide group of (VI) with Amberlite IR-118B furnishes diol (VII), which is selectively silylated with Tes-OTf and lutidine in dichloromethane to afford the desired intermediate monosaccharide (VIII).
| 【1】 Jin, Z.; Yu, W.; A new strategy for the stereoselective introduction of steroid side chain via alpha-alkoxy vinyl cuprates: Total synthesis of a highly potent antitumor natural product OSW-1. J Am Chem Soc 2001, 123, 14, 3369. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 48936 | D-Arabinose tetraacetate | C13H18O9 | 详情 | 详情 | |
| (II) | 48937 | (2S,3R,4S,5S)-3,5-bis(acetoxy)-2-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl acetate | C17H20O7S | 详情 | 详情 | |
| (III) | 48938 | (2S,3R,4S,5S)-2-(phenylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol | C11H14O4S | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 48939 | (3aS,6S,7R,7aR)-2,2-dimethyl-6-(phenylsulfanyl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C14H18O4S | 详情 | 详情 | |
| (VI) | 48940 | (3aS,6S,7R,7aS)-2,2-dimethyl-6-(phenylsulfanyl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl acetate | C16H20O5S | 详情 | 详情 | |
| (VII) | 48941 | (2S,3R,4S,5S)-4,5-dihydroxy-2-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl acetate | C13H16O5S | 详情 | 详情 | |
| (VIII) | 48942 | (2S,3R,4R,5S)-4-hydroxy-2-(phenylsulfanyl)-5-[(triethylsilyl)oxy]tetrahydro-2H-pyran-3-yl acetate | C19H30O5SSi | 详情 | 详情 |
合成路线25
该中间体在本合成路线中的序号：(III)Synthesis of intermediate monosaccharide (VI): The reaction of L-arabinose (I) with benzyl alcohol and HCl (gas) gives 1-O-benzyl-L-arabinose (II), which is treated with 2,2-dimethoxypropane (III) and TsOH to yield the 3,4-O-isopropylidene derivative (IV). The selective acetylation of (IV) with Ac2O and pyridine affords the 2-O-acetyl derivative (V), which is finally treated with HOAc in hot water to provide the intermediate 2-O-acetyl-1-O-benzyl-L-arabinose (VI).
| 【1】 Deng, S.; et al.; First total synthesis of an exceptionally potent antitumor saponin, OSW-1. J Org Chem 1999, 64, 1, 202. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17520 | (3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose | 7296-56-2 | C5H10O5 | 详情 | 详情 |
| (II) | 48966 | 2-Benzyloxytetrahydropyran-3,4,5-triol | C12H16O5 | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 48967 | (3aS,6S,7R,7aR)-6-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C15H20O5 | 详情 | 详情 | |
| (V) | 48968 | (3aS,6S,7R,7aS)-6-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl acetate | C17H22O6 | 详情 | 详情 | |
| (VI) | 48969 | (2S,3R,4S,5S)-2-(benzyloxy)-4,5-dihydroxytetrahydro-2H-pyran-3-yl acetate | C14H18O6 | 详情 | 详情 |
合成路线26
该中间体在本合成路线中的序号：(IV). L- Arabinose monosaccharide intermediate (VIII): The reaction of tetraacetyl-L-arabinose (I) with Ph-SH by means of SnCl4 in dichloromethane gives the acetylated thioglycoside (II), which is deacetylated by means of NaOMe in methanol to yield thioglycoside (III). The reaction of (III) with 2,2-dimethoxypropane (IV) and CSA in dichloromethane affords the acetonide (V), which is acetylated with Ac2O, TEA and DMAP to provide monoacetate (VI). The cleavage of the acetonide group of (VI) by means of Amberlite IR-118H leads to the monoacetylated thioglycoside (VII), which is finally selectively monosilylated with Tms-OTf and lutidine in dichloromethane the target L-arabinose intermediate (VIII)
| 【1】 Yu, W.; Jin, Z.; Total synthesis of the anticancer natural product OSW-1. J Am Chem Soc 2002, 124, 23, 6576. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 48936 | D-Arabinose tetraacetate | C13H18O9 | 详情 | 详情 | |
| (II) | 48937 | (2S,3R,4S,5S)-3,5-bis(acetoxy)-2-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl acetate | C17H20O7S | 详情 | 详情 | |
| (III) | 48938 | (2S,3R,4S,5S)-2-(phenylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol | C11H14O4S | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 48939 | (3aS,6S,7R,7aR)-2,2-dimethyl-6-(phenylsulfanyl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C14H18O4S | 详情 | 详情 | |
| (VI) | 48940 | (3aS,6S,7R,7aS)-2,2-dimethyl-6-(phenylsulfanyl)tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl acetate | C16H20O5S | 详情 | 详情 | |
| (VII) | 48941 | (2S,3R,4S,5S)-4,5-dihydroxy-2-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl acetate | C13H16O5S | 详情 | 详情 | |
| (VIII) | 48942 | (2S,3R,4R,5S)-4-hydroxy-2-(phenylsulfanyl)-5-[(triethylsilyl)oxy]tetrahydro-2H-pyran-3-yl acetate | C19H30O5SSi | 详情 | 详情 |
合成路线27
该中间体在本合成路线中的序号：(VII)The synthesis of DMP-851 has been performed as follows: The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene affording the free diamine (V). The cyclization of (V) with carbonyldiimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII) [Pierce, M.E. et al. J Org Chem 1996, 61(2): 444]. The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with butyl iodide/NaH in DMF giving the N-monobutyl derivative (X). A new alkylation of (X) with 3-cyano-4-fluorobenzyl bromide (XI) in refluxing acetonitrile yields the disubstituted cyclic urea (XII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring, and treated with HCl in methanol to eliminate the acetonide group.
| 【1】 Rodgers, J.D.; Lam, P.Y.S.; Johnson, B.L.; Wang, H.; Li, R.; Ru, Y.; Ko, S.S.; Seitz, S.P.; Trainor, G.L.; Anderson, P.S.; Klabe, R.M.; Bacheler, L.T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M.R.; Chang, C.-H.; Erickson-Viitanen, S.; Design and selection of DMP 850 and DMP 851: The next generation of cyclic urea HIV protease inhibitors. Chem Biol 1998, 5, 10, 597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27228 | benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 27884 | benzyl (1R)-1-benzyl-2-oxoethylcarbamate | C17H17NO3 | 详情 | 详情 | |
| (III) | 19618 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (IV) | 27221 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylcarbamate | C46H64N2O6Si2 | 详情 | 详情 | |
| (V) | 27222 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylamine | C30H52N2O2Si2 | 详情 | 详情 | |
| (VI) | 27223 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one | C19H22N2O3 | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 27049 | (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethylhexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | C22H26N2O3 | 详情 | 详情 | |
| (IX) | 27224 | (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether | C23H28N2O3 | 详情 | 详情 | |
| (X) | 27885 | (3aS,4R,8R,8aS)-4,8-dibenzyl-5-butyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether | C27H36N2O3 | 详情 | 详情 | |
| (XI) | 27225 | 5-(bromomethyl)-2-fluorobenzonitrile | C8H5BrFN | 详情 | 详情 | |
| (XII) | 27886 | 5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-7-butyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile | C34H38FN3O3 | 详情 | 详情 |
合成路线28
该中间体在本合成路线中的序号：(VII)The oxidation of N-(benzyloxycarbonyl)-D-phenylalaninol (I) with NaOCl catalized by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr in water gives the corresponding aldehyde (II), which is dimerized by means of the Coulton's reagent (VCl3/Zn/THF) to the pinacol (III)(1). The silylation of (III) with triethylsilyl chloride and imidazole in DMF yields the silylated diol (IV), which is submitted to hydrogenolysis with H2 over Pd/C in toluene to afford the free diamine (V). The cyclization of (V) with carbonyldimidazole (CDI) in toluene followed by desilylation with 1N HCl gives (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxyperhydro-1,3-diazepin-2-one (VI), which is treated with 2,2-dimethoxypropane (VII) and p-toluenesulfonic acid in DMF yielding the corresponding acetonide (VIII). The methylation of (VIII) with methyl triflate in refluxing dichloroethane affords the cyclic isourea (IX), which is alkylated with 3-cyano-4-fluorobenzyl bromide (X)/NaH in DMF giving the N-monobenzyl derivative (XI). A new alkylation of (XI) with benzyl bromide (XII) in refluxing acetonitrile yields the disubstituted cyclic urea (XIII), which is finally treated with hydrazine in refluxing butanol to generate the indazole ring and treated with HCl in methanol to eliminate the acetonide group.
| 【1】 Rodgers, J.D.; Lam, P.Y.S.; Johnson, B.L.; Wang, H.; Li, R.; Ru, Y.; Ko, S.S.; Seitz, S.P.; Trainor, G.L.; Anderson, P.S.; Klabe, R.M.; Bacheler, L.T.; Cordova, B.; Garber, S.; Reid, C.; Wright, M.R.; Chang, C.-H.; Erickson-Viitanen, S.; Design and selection of DMP 850 and DMP 851: The next generation of cyclic urea HIV protease inhibitors. Chem Biol 1998, 5, 10, 597. |
| 【2】 Pierce, M.E.; et al.; Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323. J Org Chem 1996, 61, 2, 444. |
| 【3】 Rodgers, J.D.; Sun, J.-H. (DuPont Pharmaceuticals Co.); Method for preparing N-monosubstd. and N,N'-disubstd. unsymmetrical cyclic ureas. AU 96059868; EP 0837855; EP 1029859; US 5532357; WO 9640652 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 27228 | benzyl (1R)-1-benzyl-2-hydroxyethylcarbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 27220 | benzyl (1R)-1-benzyl-3-oxopropylcarbamate | C18H19NO3 | 详情 | 详情 | |
| (III) | 19618 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (IV) | 27221 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylcarbamate | C46H64N2O6Si2 | 详情 | 详情 | |
| (V) | 27222 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[(triethylsilyl)oxy]pentylamine | C30H52N2O2Si2 | 详情 | 详情 | |
| (VI) | 27223 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one | C19H22N2O3 | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 27049 | (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethylhexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one | C22H26N2O3 | 详情 | 详情 | |
| (IX) | 27224 | (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-4,5,8,8a-tetrahydro-3aH-[1,3]dioxolo[4,5-e][1,3]diazepin-6-yl methyl ether | C23H28N2O3 | 详情 | 详情 | |
| (X) | 27225 | 5-(bromomethyl)-2-fluorobenzonitrile | C8H5BrFN | 详情 | 详情 | |
| (XI) | 27226 | 5-[[(3aS,4R,8R,8aS)-4,8-dibenzyl-6-methoxy-2,2-dimethyl-3a,4,8,8a-tetrahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile | C31H32FN3O3 | 详情 | 详情 | |
| (XII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XIII) | 27227 | 5-[[(3aS,4R,8R,8aS)-4,7,8-tribenzyl-2,2-dimethyl-6-oxohexahydro-5H-[1,3]dioxolo[4,5-e][1,3]diazepin-5-yl]methyl]-2-fluorobenzonitrile | C37H36FN3O3 | 详情 | 详情 |
合成路线29
该中间体在本合成路线中的序号：(II)The reaction of (S)-malic acid (I) with dimethoxypropane (II) and Ts-OH gives the carboxymethyldioxolanone (III), which is reduced with BH3/DMS and Ts-OH in toluene, yielding the chiral 2-hydroxybutyrolactone (IV). The silylation of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is methylated to the lactol (VIa) by means of methyl lithium in THF. The condensation of the partially silylated dihydroxypentanone (VIb) (tautomer of (VIa)) with thiazolylphosphonium salt (VII) by means of LiHMDS in THF provides the unsaturated primary alcohol (VIII), which by Swern oxidation is converted into the corresponding aldehyde (IX). The condensation of (IX) with phosphonate (X) by means of KHMDS in THF furnishes the heptadienoic ester (XI), which is reduced with DIBAL in THF to give the primary alcohol (XII). The reaction of (XII) with I2 and PPh3 in acetonitrile/Et2O gives the allylic iodide (XIII), which is condensed with sulfone (XIV) by means of KHMDS and Na/Hg in MeOH/THF, yielding the protected diol (XVII). The sulfone (XIV) has been obtained by condensation of the chiral propanol (XV) with methylphenylsulfone (XVI) by means of Ts-Cl and BuLi . The selective deprotection of the primary silyl ether of (XVIII) with CSA in methanol/dichloromethane affords the primary alcohol (XVIII), which is finally oxidized with DMP in dichloromethane to afford the target intermediate carbaldehyde (XIX).
| 【1】 Mulzer, J.; et al.; Total synthesis of epothilones B and D. J Org Chem 2000, 65, 22, 7456. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (VIb) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (IV) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (V) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (VII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (VIII) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (IX) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (X) | 42703 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate | C8H11F6O5P | 详情 | 详情 | |
| (XI) | 46134 | propyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C22H37NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46136 | 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-iodo-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-5-iodo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether | C19H32INOSSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 46135 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-propanol | C10H24O2Si | 详情 | 详情 | |
| (XVI) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XVII) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVIII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XIX) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 |
合成路线30
该中间体在本合成路线中的序号：(A)The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (I) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (II) | 35676 | tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether | C9H21IOSi | 详情 | 详情 | |
| (III) | 35677 | dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate | C14H28O5Si | 详情 | 详情 | |
| (IV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (V) | 35678 | dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate | C17H32O5Si | 详情 | 详情 | |
| (VI) | 35679 | 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol | C15H32O3Si | 详情 | 详情 | |
| (VII) | 35680 | 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane | C18H36O3Si | 详情 | 详情 | |
| (VIII) | 35681 | 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde | C17H34O4Si | 详情 | 详情 | |
| (IX) | 17966 | cyclohexanamine; cyclohexyl amine; cyclohexylamine | 108-91-8 | C6H13N | 详情 | 详情 |
| (X) | 35682 | N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine | C23H45NO3Si | 详情 | 详情 | |
| (XI) | 35683 | (E)-8-decenal | C10H18O | 详情 | 详情 | |
| (XII) | 35684 | (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal | C27H50O4Si | 详情 | 详情 | |
| (XIII) | 35685 | tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether | C35H58O4Si | 详情 | 详情 | |
| (XIV) | 35686 | 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol | C29H44O4 | 详情 | 详情 | |
| (XV) | 35687 | 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal | C29H42O4 | 详情 | 详情 | |
| (XVI) | 35688 | (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane | C13H27IOSi | 详情 | 详情 | |
| (XVII) | 35689 | (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one | C42H68O5Si | 详情 | 详情 |
合成路线31
该中间体在本合成路线中的序号：(IV)Glycosylation of sugar (I) with the idopyranosyl fluoride (II) by means of BF3.Et2O and molecular sieves in dichloromethane gives the disaccharide fragment (III), which is then converted into acetonide (V) by saponification of the ester functions with t-BuOK, followed by reaction with 2,2-dimethoxypropane (IV) in DMF and acidification with p-toluensulfonic acid. Methylation of acetonide (V) with MeI and NaH in DMF/MeOH provides the disaccharide (VI), which is then treated with HOAc to yield the 4',6'-diol (VII). Selective silylation of the diol (VII) with tert-butyldimethylsilyl chloride (TBDMSCl) in pyridine leads to the 6'-O-TBDMS derivative (VIII), which is condensed with levulinic acid (IX) by means of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in dioxane to give the ester (X). Compound (X) is then submitted to simultaneous Jones oxidation and TBDMS removal with CrO3 and H2SO4/H2O in acetone to provide the iduronic acid derivative (XI), which is converted into the key intermediate (XII), first by esterification with MeI and KHCO3 in DMF and then by removal of the 4'-O-levulinoyl protecting group with HOAc and hydrazine hydrate in pyridine.
| 【1】 del Fresno, M.; Diaz-Ricart, M.; Idraparinux Sodium. Drugs Fut 2002, 27, 7, 639. |
| 【2】 Basten, J.E.M.; van Boeckel, C.A.A.; Westerduin, P.; et al.; Feasible synthesis and biological properties of six "non-glycosamino" glycan analogues of the antithrombin III binding heparin pentasaccharide. Bioorg Med Chem 1994, 2, 11, 1267. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 54143 | (2R,3S,4S,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-ol | n/a | C28H32O6 | 详情 | 详情 |
| (II) | 54144 | (2S,3S,4S,5R)-5-(acetyloxy)-2-[(acetyloxy)methyl]-6-fluoro-4-methoxytetrahydro-2H-pyran-3-yl acetate | n/a | C13H19FO8 | 详情 | 详情 |
| (III) | 54145 | (2R,3R,4S,5S,6S)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-4-methoxytetrahydro-2H-pyran-3-yl acetate | n/a | C41H50O14 | 详情 | 详情 |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 54146 | (4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ol | n/a | C38H48O11 | 详情 | 详情 |
| (VI) | 54147 | (4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-7-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl methyl ether; (4aS,6R,7R,8R,8aS)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-7,8-dimethoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxine | n/a | C39H50O11 | 详情 | 详情 |
| (VII) | 54148 | (2S,3S,4S,5R,6S)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-(hydroxymethyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol | n/a | C36H46O11 | 详情 | 详情 |
| (VIII) | 54149 | (2S,3S,4S,5R,6S)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dimethoxytetrahydro-2H-pyran-3-ol | n/a | C42H60O11Si | 详情 | 详情 |
| (IX) | 36170 | 4-oxopentanoic acid | 123-76-2 | C5H8O3 | 详情 | 详情 |
| (X) | 54150 | (2S,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dimethoxytetrahydro-2H-pyran-3-yl 4-oxopentanoate | n/a | C47H66O13Si | 详情 | 详情 |
| (XI) | 54151 | (2R,3S,4R,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-4,5-dimethoxy-3-[(4-oxopentanoyl)oxy]tetrahydro-2H-pyran-2-carboxylic acid | n/a | C41H50O14 | 详情 | 详情 |
| (XII) | 54152 | methyl (2R,3S,4S,5R,6R)-6-({(2R,3S,4R,5R,6S)-4,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-methoxytetrahydro-2H-pyran-3-yl}oxy)-3-hydroxy-4,5-dimethoxytetrahydro-2H-pyran-2-carboxylate | n/a | C37H46O12 | 详情 | 详情 |
合成路线32
该中间体在本合成路线中的序号：(II)Diol (I) was protected as the isopropylidene ketal (III) by reaction with 2,2-dimethoxypropane (II) and p-toluenesulfonic acid. Then, the N-carbobenzoxy groups of (III) were eliminated by hydrogenolysis on Pd/C to give the diamine (IV), and this was coupled with N-carbobenzoxy-valine (V) using O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU) to afford (VI). A new sequence of hydrogenolytic Cbz deprotection to give diamine (VII) and coupling with N-carbobenzoxy-alanine (VIII) and HBTU provided (IX). Finally, the target compound was obtained by hydrolysis of the isopropylidene ketal in methanol containing p-toluenesulfonic acid.
| 【1】 Lee, T.; et al.; Analysis of the S3 and S3' subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo. Proc Natl Acad Sci USA 1998, 95, 3, 939-944. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 16587 | benzyl (1S,2R,3R,4S)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate | C34H36N2O6 | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 18090 | benzyl (1S)-1-[(4R,5R)-5-((1S)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylcarbamate | C37H40N2O6 | 详情 | 详情 | |
| (IV) | 18091 | (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine | C21H28N2O2 | 详情 | 详情 | |
| (V) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (VI) | 18093 | benzyl (1S)-1-([[(1S)-1-((4R,5R)-5-[(1S)-1-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)amino]-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2-phenylethyl]amino]carbonyl)-2-methylpropylcarbamate | C47H58N4O8 | 详情 | 详情 | |
| (VII) | 18094 | (2S)-2-amino-N-[(1S)-1-[(4R,5R)-5-((1S)-1-[[(2S)-2-amino-3-methylbutanoyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethyl]-3-methylbutanamide | C31H46N4O4 | 详情 | 详情 | |
| (VIII) | 10445 | N-Carbobenzyloxy-L-alanine;N-Benzyloxycarbonyl-L-alanine;Carbobenzyloxy-L-alanine;Z-L-Alanine;Z-Ala-OH;BenzyloxycarbonylLalanine;N-Cbz-L-alanine | 1142-20-7 | C11H13NO4 | 详情 | 详情 |
| (IX) | 18095 | benzyl (1S)-2-[((1S)-1-[[((1S)-1-[(4R,5R)-5-[(1S,4S,7S)-1-benzyl-4-isopropyl-7-methyl-3,6,9-trioxo-11-phenyl-10-oxa-2,5,8-triazaundec-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethyl)amino]carbonyl]-2-methylpropyl)amino]-1-methyl-2-oxoethylcarbam | C53H68N6O10 | 详情 | 详情 |
合成路线33
该中间体在本合成路线中的序号：(XIX)The reduction of (R)-malic acid (I) with BH3/Me2S and NaBH4 gives 1,2(R),4-butane-triol (II), which is treated with benzaldehyde dimethylacetal (III) and Ts-OH to yield the 1,3-dioxane (IV). The oxidation of the hydroxymethyl group of (IV) by means of oxalyl chloride in DMSO/dichloromethane affords the carbaldehyde (V), which is submitted to a Wittig condensation with allyltriphenylphosphonium bromide (VI) and potassium tert-butoxide to provide the butadienyl derivative (VII). The reductive cleavage of the benzylidene acetal (VII) by means of DIBAL, followed by Z/E photoisomerization of the resulting diene gives (E)-3(R)-(benzyloxy)-4,6-heptadien-1-ol (VIII). The reaction of the OH group of (VIII) with TsCl and pyridine yields the corresponding tosylate (IX), which is treated with NaCN in DMSO to afford (E)-4(R)-(benzyloxy)-5 ,7-octadienonitrile (X). The hydrolysis of the CN group of (X) with NaOH in methanol/water provides the carboxylic acid (XI), which is esterified with diazomethane to afford the methyl ester (XII). The reaction of (XII) with hydroxylamine and KOH in methanol provides the hydroxamic acid (XIII), which is oxidized with tetrapropylammonium periodate in water to generate an acylnitroso intermediate (XIV), which undergoes a (4+2) cycloaddition to give the trans-1,2-oxazinolactam (XV) along with some cis isomer that is separated by chromatography. The reductive cleavage of the N-O bond of (XV) by means of sodium amalgam yields the allyl alcohol (XVI), which is silylated with Tbdps-Cl and imidazole affording the silyl ether (XVII). The catalytic dihydroxylation of the double bond of (XVII) by means of OsO4 and NMO provides the diol (XVIII) along with some diastereoisomer that is separated by chromatography. The protection of the OH groups of (XVIII) by reaction of 2,2-dimethoxypropane (XIX) and PPTS gives the acetonide (XX). The reduction of the lactone group of (XX) with LiAlH4 in THF proceeds with simultaneous desilylation yielding the piperidino-alcohol (XXI), which is cyclized by means of CBr4, PPh3 and TEA to provide the indolizidine derivative (XXII). The hydrogenolytic removal of the benzyl group of (XXII) with H2 over PdCl2 gives the alcohol (XXIII), which is finally submitted to hydrolysis of its acetonide group by means of 6N HCl in THF to afford the target swainsonine.
| 【1】 Thiam, M.; et al.; Malic acid as a chiral synthon: Synthesis of 1,2 and 1,3 optically active diols. Synth Commun 1992, 22, 1, 83. |
| 【2】 Naruse, M.; et al.; New chiral route to (-)-swainsonine via an aqueous acylnitroso cycloaddition approach. J Org Chem 1994, 59, 6, 1358. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 30098 | (2S)-1,2,4-butanetriol; (S)-1,2,4-butanetriol | 42890-76-6 | C4H10O3 | 详情 | 详情 |
| (III) | 27515 | Methoxy(phenyl)methyl methyl ether; Dimethylacetal benzaldehyde; Benzaldehyde dimethylacetal | 1125-88-8 | C9H12O2 | 详情 | 详情 |
| (IV) | 62598 | [(2R,4R)-2-phenyl-1,3-dioxan-4-yl]methanol | C11H14O3 | 详情 | 详情 | |
| (V) | 62599 | (2R,4R)-2-phenyl-1,3-dioxane-4-carbaldehyde | C11H12O3 | 详情 | 详情 | |
| (VI) | 62600 | allyl(triphenyl)phosphonium bromide | C21H20BrP | 详情 | 详情 | |
| (VII) | 62601 | (2R,4R)-4-[(1E)-1,3-butadienyl]-2-phenyl-1,3-dioxane | C14H16O2 | 详情 | 详情 | |
| (VIII) | 62602 | (3R,4E)-3-(benzyloxy)-4,6-heptadien-1-ol | C14H18O2 | 详情 | 详情 | |
| (IX) | 62603 | (3R,4E)-3-(benzyloxy)-4,6-heptadienyl 4-methylbenzenesulfonate | C21H24O4S | 详情 | 详情 | |
| (X) | 62604 | (4R,5E)-4-(benzyloxy)-5,7-octadienenitrile | C15H17NO | 详情 | 详情 | |
| (XI) | 62605 | (4R,5E)-4-(benzyloxy)-5,7-octadienoic acid | C15H18O3 | 详情 | 详情 | |
| (XII) | 62606 | methyl (4R,5E)-4-(benzyloxy)-5,7-octadienoate | C16H20O3 | 详情 | 详情 | |
| (XIII) | 62607 | (4R,5E)-4-(benzyloxy)-N-hydroxy-5,7-octadienamide | C15H19NO3 | 详情 | 详情 | |
| (XIV) | 62608 | (4R,5E)-4-(benzyloxy)-N-oxo-5,7-octadienamide | C15H17NO3 | 详情 | 详情 | |
| (XV) | 62609 | (4aS,5R)-5-(benzyloxy)-4a,5,6,7-tetrahydropyrido[1,2-b][1,2]oxazin-8(2H)-one | C15H17NO3 | 详情 | 详情 | |
| (XVI) | 62610 | (5R,6S)-5-(benzyloxy)-6-[(Z)-3-hydroxy-1-propenyl]-2-piperidinone | C15H19NO3 | 详情 | 详情 | |
| (XVII) | 62611 | (5R,6S)-5-(benzyloxy)-6-((Z)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-propenyl)-2-piperidinone | C31H37NO3Si | 详情 | 详情 | |
| (XVIII) | 62612 | (5R,6S)-5-(benzyloxy)-6-((1S,2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1,2-dihydroxypropyl)-2-piperidinone | C31H39NO5Si | 详情 | 详情 | |
| (XIX) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XX) | 62613 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C34H43NO5Si | 详情 | 详情 | |
| (XXI) | 62614 | {(4R,5S)-5-[(2R,3R)-3-(benzyloxy)piperidinyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methanol | C18H27NO4 | 详情 | 详情 | |
| (XXII) | 62615 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-yl benzyl ether; (3aR,9R,9aR,9bS)-9-(benzyloxy)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizine | C18H25NO3 | 详情 | 详情 | |
| (XXIII) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |
合成路线34
该中间体在本合成路线中的序号：(III)The reaction of benzyl alpha-D-mannopyranoside (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is treated with 2,2-dimethoxypropane (III) and CSA in dichloromethane to yield the acetonide (IV). The oxidation of the free OH group of (IV) with PCC in dichloromethane affords the ketone (V), which is reduced with NaBH4 to provide benzyl 6-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-D-talopyranoside (VI) with inverted configuration at C4. The reaction of (VI) with Tf2O and pyridine gives the triflate (VII), which is treated with NaN3 in DMF to yield the 4-azido derivative (VIII) with a new inversion of configuration at C4. The reaction of (VIII) with TBAF, followed by oxidation with PCC afforded the carbaldehyde (IX), which is condensed with the phosphorane (X) to provide the unsaturated azidoaldehyde (XI). The treatment of (XI) with H2 over Pd/C in methanol produces the reduction of the double bond, the reduction of the azide group to amine, and subsequent reductive cyclization of the resulting aminoaldehyde to give the perhydropyranopyridine derivative (XII). Further reductive debenzylation of (XII) with H2 over Pd/C in AcOH produces the formation of a lactol in equilibrium with the open chain aminoaldehyde (XIII), which undergoes a reductive amination to form the acetonide of swainsonine (XIV). Finally, this acetonide is decomposed by reaction with TFA to afford the target swainsonine.
| 【1】 Bashyal, B.P.; et al.; Synthesis of the alpha-mannosidase inhibitors swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine and 1,4-dideoxy-1,4-imino-D-mannitol from mannose. Tetrahedron 1987, 43, 13, 3083. |
| 【2】 Fleet, G.W.J.; et al.; Enantiospecific synthesis of swainsonine (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine, from D-mannose. Tetrahedron Lett 1984, 25, 17, 1853. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62618 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)tetrahydro-2H-pyran-3,4,5-triol | C29H36O6Si | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62619 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (V) | 62620 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C32H38O6Si | 详情 | 详情 | |
| (VI) | 62621 | (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (VII) | 62622 | (3aS,4S,6R,7S,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate | C33H39F3O8SSi | 详情 | 详情 | |
| (VIII) | 62623 | [(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl tert-butyl(diphenyl)silyl ether; {[(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methoxy}(tert-butyl)diphenylsilane | C32H39N3O5Si | 详情 | 详情 | |
| (IX) | 62624 | (3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-carbaldehyde | C16H19N3O5 | 详情 | 详情 | |
| (X) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XI) | 62625 | (E)-3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]-2-propenal | C18H21N3O5 | 详情 | 详情 | |
| (XII) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 | |
| (XIII) | 62627 | (4S,5S)-5-[(2R,3R)-3-hydroxypiperidinyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C11H19NO4 | 详情 | 详情 | |
| (XIV) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |
合成路线35
该中间体在本合成路线中的序号：(XI)The oxidation of 5-(trimethylsilyl)-4-pentyn-1-ol (I) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (II),which is condensed with furan (III) by means of BuLi in THF, yielding 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol (IV). The optical resolution of (IV) by means of diisopropyl-L-tartrate affords the (R)-isomer (V), which is treated with NBS and sodium acetate in THF to provide the dihydropyranone derivative (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of PPTS gives the 1-ethoxyethyl ether as a diastereomeric mixture that is separated by column chromatography affording the desired isomer (VIII). The reduction of the carbonyl group of (VIII) by means of LAH in ethyl ether provides alcohol (IX) along with minor amounts of its diastereomer that is separated by column chromatography. The dihydroxylation of (IX) by means of OsO4 in ethyl ether proceeded diastereoselectively giving triol (X), which is treated with 2,2-dimethoxypropane (XI) and PPTS in acetone to yield the acetonide (XII). The reaction of (XII) with thiocarbonyl diimidazole (TCDI) in dichloroethane affords intermediate (XIII), which is submitted to a radical cyclization by means of Bu3SnH and AIBN in benzene to provide the exomethylene derivative (XIV). The oxidation of the vinylsilane (XIV) by means of NaIO4 and OsO4 in t-butanol/pyridine gives the ketone (XV), which is submitted to a Birch reduction with Na in liquid ammonia to yield alcohol (XVI) along with some of its diastereomer that is separated by chromatography. The reaction (XVI) with benzyl bromide and NaH in THF affords the benzyl ether (XVII), which is treated with HCl in THF to provide the lactol (XVIII). The reduction of (XVIII) with NaBH4 in methanol/dichloromethane gives the diol (XIX), which is selectively monosilylated with Tbdms-Cl, yielding the primary silyl ether (XX). The oxidation of the secondary OH group of (XX) by means of TPAP in dichloromethane affords the cyclopentanone (XXI), which is treated with hydroxylamine and pyridine in methanol to provide the corresponding oxime (XXII). The oxime (XXII) was subjected to a Beckmann rearrangement by means of SOCl2 to give the lactam (XXIII), which is finally desilylated by means of TBAF in THF to yield the primary alcohol (XXIV).
| 【1】 Honda, T.; et al.; Enantioselective synthesis of indolizidine alkaloids: Formal synthesis of (-)-swainsonine and of (+)-pumiliotoxin 251D. J Chem Soc - Perkins Trans I 1994, 15, 2091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 62628 | 5-(trimethylsilyl)-4-pentyn-1-ol | C8H16OSi | 详情 | 详情 | |
| (II) | 62115 | 5-(trimethylsilyl)-4-pentynal | C8H14OSi | 详情 | 详情 | |
| (III) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (IV) | 62629 | 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (V) | 62630 | (1R)-1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (VI) | 62631 | (2R)-6-hydroxy-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C12H18O3Si | 详情 | 详情 | |
| (VII) | 62632 | 1-propoxyethylene; propyl vinyl ether | C5H10O | 详情 | 详情 | |
| (VIII) | 62633 | (2R,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C17H28O4Si | 详情 | 详情 | |
| (IX) | 62634 | (2R,3S,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-3,6-dihydro-2H-pyran-3-ol | C17H30O4Si | 详情 | 详情 | |
| (X) | 62635 | (2R,3S,4S,5S,6R)-2-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-2H-pyran-3,4,5-triol | C17H32O6Si | 详情 | 详情 | |
| (XI) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XII) | 62636 | (3aS,4R,6R,7R,7aS)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C20H36O6Si | 详情 | 详情 | |
| (XIII) | 62637 | O-{(3aS,4R,6R,7R,7aR)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl} 1H-imidazole-1-carbothioate | C24H38N2O6SSi | 详情 | 详情 | |
| (XIV) | 62638 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-8-[(E)-(trimethylsilyl)methylidene]hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4(4H)-yl 1-propoxyethyl ether; {[(3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-ylidene]methyl}(trimethyl)silane | C20H36O5Si | 详情 | 详情 | |
| (XV) | 62639 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-one | C16H26O6 | 详情 | 详情 | |
| (XVI) | 62640 | (3aS,4R,5aR,8R,8aS,8bS)-2-ethyl-2-methyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8-ol | C17H30O6 | 详情 | 详情 | |
| (XVII) | 62641 | (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-yl 1-propoxyethyl ether; (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran | C23H34O6 | 详情 | 详情 | |
| (XVIII) | 62642 | (3aS,4S,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-ol | C18H24O5 | 详情 | 详情 | |
| (XIX) | 62643 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C18H26O5 | 详情 | 详情 | |
| (XX) | 62644 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C24H40O5Si | 详情 | 详情 | |
| (XXI) | 62645 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone | C24H38O5Si | 详情 | 详情 | |
| (XXII) | 62646 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone oxime | C24H39NO5Si | 详情 | 详情 | |
| (XXIII) | 62647 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C24H39NO5Si | 详情 | 详情 | |
| (XXIV) | 62648 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C18H25NO5 | 详情 | 详情 |
合成路线36
该中间体在本合成路线中的序号：(III)The reaction of benzyl-alpha-D-mannoside (I) with Ts-Cl in pyridine gives the 6-O-tosylate (II), which is treated with 2,2-dimethoxypropane (III), trimethyl orthoacetate and naphthalenesulfonic acid to yield the acetonide (IV). The silylation of the remaining OH group of (IV) with Tms-Cl and TEA in THF affords the silyl ether (V), which is condensed with allylmagnesium bromide (VI) in ethyl ether to provide the olefinic compound (VII). The desilylation of (VII) by means of TBAF in THF gives the secondary alcohol (VIII); which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to yield the ketone derivative (IX). The oxidation of the terminal double bond of (IX) by means of RuO2 and NaIO4 in CCl4/acetonitrile affords the carboxylic acid (X), which is methylated with diazomethane to provide the corresponding methyl ester (XI). Alternatively the propionic ester (XI) can also be obtained by the following sequence: The condensation of the silyl ether (V) with the sodium salt of diethyl malonate (XII) in refluxing toluene gives the malonyl derivative (XIII), which is treated with NaCl at 145 C, yielding the lactone (XIV). The methanolysis of (XIV) with KOH in methanol affords the hydroxyester (XV), which is finally oxidized with PCC in dichloromethane to provide the target ketoester (XI), already reported. The reduction of the carbonyl group of (XI) by means of NaBH4 in ethanol gives the hydroxyester (XVI), which is treated with triflic anhydride and pyridine to yield the corresponding triflate (XVII). The reaction of (XVII) with sodium azide in DMF affords the azido derivative (XVIII), which is reduced with H2 over Pd/C to provide the expected amino derivative (XIX). The cyclization of (XIX) in refluxing toluene gives the lactam (XX), which is finally reduced to the target perhydro-pyrano[3,2-b]pyridine (XXI) intermediate.
| 【1】 Bermejo Gonzalez, F.; et al.; Efficient preparation of a valuable intermediate in the synthesis of (-)-swainsonine. Bull Chem Soc Jpn 1992, 65, 2, 567. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62659 | [(2R,3S,4S,5S,6S)-6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate | C20H24O8S | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62660 | [(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl 4-methylbenzenesulfonate | C23H28O8S | 详情 | 详情 | |
| (V) | 62661 | {(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl 4-methylbenzenesulfonate | C26H36O8SSi | 详情 | 详情 | |
| (VI) | 61128 | C4H8 | 详情 | 详情 | ||
| (VII) | 62662 | (3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trimethylsilyl ether; {[(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl]oxy}(trimethyl)silane | C22H34O5Si | 详情 | 详情 | |
| (VIII) | 62663 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C19H26O5 | 详情 | 详情 | |
| (IX) | 62664 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C19H24O5 | 详情 | 详情 | |
| (X) | 62665 | 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoic acid | C18H22O7 | 详情 | 详情 | |
| (XI) | 62667 | methyl 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H24O7 | 详情 | 详情 | |
| (XII) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (XIII) | 62666 | diethyl 2-({(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl)malonate | C26H40O9Si | 详情 | 详情 | |
| (XIV) | 62669 | (3aS,4S,5aR,9aR,9bR)-4-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-d]pyrano[3,2-b]pyran-8(4H)-one | C18H22O6 | 详情 | 详情 | |
| (XV) | 62668 | methyl 3-[(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVI) | 62670 | methyl 3-[(3aS,4S,6R,7S,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVII) | 62671 | methyl 3-((3aS,4S,6R,7S,7aR)-4-(benzyloxy)-2,2-dimethyl-7-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl)propanoate | C20H25F3O9S | 详情 | 详情 | |
| (XVIII) | 62672 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H25N3O6 | 详情 | 详情 | |
| (XIX) | 62673 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-amino-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H27NO6 | 详情 | 详情 | |
| (XX) | 62674 | (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethylhexahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-8(5aH)-one | C18H23NO5 | 详情 | 详情 | |
| (XXI) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 |
合成路线37
该中间体在本合成路线中的序号：(II)Hydroxy amino ester (I) was protected as the oxazolidine (III) upon heating with 2,2-dimethoxypropane (II) in the presence of p-toluenesulfonic acid. Conversion of the ester group of (III) into aldehyde (V) was accomplished by reduction to alcohol (IV) with LiAlH4, followed by NaOCl oxidation catalyzed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr. Addition of 3-(benzyloxy)propylmagnesium bromide (VI) to aldehyde (V) furnished carbinol (VII), which was further protected as the silyl ether (VIII) by treatment with tert-butyldimethylsilyl chloride and imidazole. After hydrogenolysis of the O-benzyl protecting group of (VIII), the resultant primary alcohol (IX) was converted to bromide (X) employing the N-bromosuccinimide/triphenylphosphine reagent.
| 【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323. |
| 【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 52327 | methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxy-4-phenylbutanoate | C16H23NO5 | 详情 | 详情 | |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 52319 | 3-(1,1-dimethylethyl) 5-methyl 2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3,5-dicarboxylate | C19H27NO5 | 详情 | 详情 | |
| (IV) | 52320 | 1,1-dimethylethyl 5-(hydroxymethyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C18H27NO4 | 详情 | 详情 | |
| (V) | 52321 | 1,1-dimethylethyl 5-formyl-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C18H25NO4 | 详情 | 详情 | |
| (VI) | 52322 | bromo{3-[(phenylmethyl)oxy]propyl}magnesium | C10H13BrMgO | 详情 | 详情 | |
| (VII) | 52323 | 1,1-dimethylethyl 5-{1-hydroxy-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C28H39NO5 | 详情 | 详情 | |
| (VIII) | 52324 | 1,1-dimethylethyl 5-{1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C34H53NO5Si | 详情 | 详情 | |
| (IX) | 52325 | 1,1-dimethylethyl 5-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-hydroxybutyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C27H47NO5Si | 详情 | 详情 | |
| (X) | 52326 | 1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate | C27H46BrNO4Si | 详情 | 详情 |
合成路线38
该中间体在本合成路线中的序号：(XV)Alkylation of 3-hydroxy-4-methoxybenzyl alcohol (I) with 1-bromo-3-methoxypropane (II) gives ether (III). Subsequent conversion of benzyl alcohol (III) into bromide (IV) is carried out using bromotrimetylsilane. The chiral isovaleryloxazolidinone (V) is alkylated with bromide (IV) by means of LiHMDS to afford (VI), which is hydrolyzed to the (S)-2-aryl-2-isopropylpropionic acid (VII) by means of lithium peroxide. The reduction of acid (VII) to the corresponding alcohol with NaBH4/I2 reagent, followed by treatment with PPh3 and NBS, provides bromide (VIII). Alkylation of the chiral dimethoxydihydropyrazin (IX) with bromide (VIII) produces (X). Further hydrolysis of the pyrazine ring of (X) with HCl, followed by Boc protection of the resulting (S,S)-amino ester, yields compound (XI). Reduction of the ester group of (XI) with DIBAL gives aldehyde (XII). This compound is condensed with the Grignard reagent (XIII) to afford the diastereomeric mixture of amino alcohols (XIV). Treatment of mixture (XIV) with 2,2-dimethoxypropane (XV) and TsOH produces a mixture of oxazolidines, from which the required (S,S,S)-isomer (XVI) is isolated by flash chromatography. Hydrogenolitic deprotection of the benzyl ether of (XVI) gives alcohol (XVII).
| 【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139. |
| 【2】 Rigollier, P.; Stutz, S.; Goeschke, R.; Yamaguchi, Y.; Maibaum, J.; Wood, J.; Structural modification of the P2' position of 2,7-dialkyl substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octane-carboxamides: Discovery of a potent non-peptide renin inhibitor active after once daily dosing in marmosets. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.230. |
| 【3】 Göschke, R.; Maibaum, J.K.; Schilling, W.; Stutz, S.; Rigollier, P.; Yamaguchi, Y.; Cohen, N.C.; Herold, P. (Novartis AG); Delta-amino-gamma-hydroxy-omega-aryl alkanoic acid amides with enzyme especially renin inhibiting activities. EP 0678500; EP 0678503; JP 1996053434; JP 1996081430; US 5559111; US 5627182; US 5646143 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 28115 | 5-(hydroxymethyl)-2-methoxyphenol | 4383-06-6 | C8H10O3 | 详情 | 详情 |
| (II) | 17319 | 1-bromo-3-methoxypropane; 3-bromopropyl methyl ether | C4H9BrO | 详情 | 详情 | |
| (III) | 28116 | [4-methoxy-3-(3-methoxypropoxy)phenyl]methanol | 172900-74-2 | C12H18O4 | 详情 | 详情 |
| (IV) | 28117 | 3-[5-(bromomethyl)-2-methoxyphenoxy]propyl methyl ether | 172900-73-1 | C12H17BrO3 | 详情 | 详情 |
| (V) | 28131 | (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one | C15H19NO3 | 详情 | 详情 | |
| (VI) | 28118 | (4S)-4-benzyl-3-[(2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutanoyl]-1,3-oxazolidin-2-one | C27H35NO6 | 详情 | 详情 | |
| (VII) | 28119 | (2R)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyric acid | C17H26O5 | 详情 | 详情 | |
| (VIII) | 28120 | 3-[5-[(2R)-2-(bromomethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether | 172900-69-5 | C17H27BrO3 | 详情 | 详情 |
| (IX) | 10296 | (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | 109838-85-9 | C9H16N2O2 | 详情 | 详情 |
| (X) | 28121 | (2R,5S)-2-isopropyl-3,6-dimethoxy-5-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,5-dihydropyrazine | C26H42N2O5 | 详情 | 详情 | |
| (XI) | 28122 | methyl (2S,4S)-2-[(tert-butoxycarbonyl)amino]-4-[4-methoxy-3-(3-methoxypropoxy)benzyl]-5-methylhexanoate | C25H41NO7 | 详情 | 详情 | |
| (XII) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
| (XIII) | 28124 | [(2S)-2-[(benzyloxy)methyl]-3-methylbutyl](bromo)magnesium | C13H19BrMgO | 详情 | 详情 | |
| (XIV) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
| (XV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XVI) | 28126 | tert-butyl (4S,5S)-5-[(2S)-2-[(benzyloxy)methyl]-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C40H63NO7 | 详情 | 详情 | |
| (XVII) | 28127 | tert-butyl (4S,5S)-5-[(2S)-2-(hydroxymethyl)-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C33H57NO7 | 详情 | 详情 |
合成路线39
该中间体在本合成路线中的序号：(A)Reaction of 5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one (VIII) with 2,2-dimethoxypropane (A) and TsOH in acetone gives the acetonide (IX), which is treated with ethylamine at 140 C, followed by optical resolution with di-O-benzoyl-D-tartaric acid, yielding the chiral cyclopentanecarboxamide (IV).
| 【1】 Martín, L.; Leeson, P.A.; Castañer, J.; Sorbera, L.A.; AMP-579. Drugs Fut 2000, 25, 9, 900. |
| 【2】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive, cardioprotective, a. EP 0758897; EP 1006115; JP 1997512020; US 5561134; WO 9528160 . |
| 【3】 Spada, A.P.; Fink, C.A.; Myers, M.R. (Aventis Pharma SA); Cpds. having antihypertensive and anti-ischemic pr. EP 0550631; JP 1993508864; US 5217982; US 5364862; WO 9205177 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 23850 | (3aR,4S,6R,6aS)-6-amino-N-ethyl-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxamide | C11H20N2O3 | 详情 | 详情 | |
| (VIII) | 40487 | (1R,4S,5R,6S)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-one | C6H9NO3 | 详情 | 详情 | |
| (IX) | 40488 | (1S,2R,6S,7R)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.0(2,6)]decan-9-one | C9H13NO3 | 详情 | 详情 |
合成路线40
该中间体在本合成路线中的序号：(V)The reaction of monolabeled diethyl malonate (I) with 2-benzyloxyethyl bromide (II) by means of NaH in refluxing THF gives the corresponding benzyloxyethyl derivative (III), which is reduced with LiAlH4 in ethyl ether yielding the diol (IV). The protection of (IV) by reaction with 2,2-dimethoxypropane (V) and p-toluenesulfonic acid affords the 1,3-dioxane (VI), which is debenzylated with H2 over Pd/C in THF giving the alcohol (VII). The reaction of (VII) with CBr4 and PPh3 in DMF yields the bromide (VIII), which is condensed with the purine (IX) by means of K2CO3 in DMF affording the expected purin-9-yl derivative (X). The hydrolysis of the 1,3-dioxane group with AcOH /water gives the diol (XI), which is monoacylated with isopropyl chloroformate (XII) by means of cool pyridine yielding the mixture of regioisomers (XIII), (XIV). Finally, this mixture is dechlorinated with ammonium formate over Pd/C in refluxing methanol afffording the target compound also as a mixture of regioisomers.
| 【1】 Kim, D.K.; et al.; Synthesis of carbon-14 labelled 2-amino-9-(3-hydroxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (SK 1875), a potential prodrug of penciclovir. J Label Compd Radiopharm 1999, 42, 6, 597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII),(VIII) | 10916 | 2-(2,2-Dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (XIII),(XIV) | 35533 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (I) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (I) | 45348 | diethyl malonate | C7H12O4 | 详情 | 详情 | |
| (II) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (III) | 35529 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (III) | 45349 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (IV) | 35523 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (IV) | 45350 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 35530 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VI) | 45351 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VII) | 45352 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (VIII) | 45353 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (IX) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (X) | 35531 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine | C13H18ClN5O2 | 详情 | 详情 | |
| (X) | 45354 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine | C13H18ClN5O2 | 详情 | 详情 | |
| (XI) | 35532 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XI) | 45355 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XII) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (XIII) | 45356 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (XIV) | 45357 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 |
合成路线41
该中间体在本合成路线中的序号：(VII)The chiral bicyclic alcohol (I) was converted to the benzyl ether (II) using benzyl bromide and NaH. Subsequent reduction of the ester group of (III) with LiBH4 provided primary alcohol (III), and further Swern oxidation yielded aldehyde (IV). Pinacol coupling of (IV) with D-phenylalaninal (V) by means of VCl3 - (THF)3 and Zn furnished diol (VI) with 85% diastereoselectivity. This was protected as the acetonide (VIII) upon treatment with 2,2-dimethoxypropane (VII) and camphorsulfonic acid. Selective removal of the two N-benzyloxycarbonyl groups of (VIII) by hydrogenation in the presence of Pd/C and NH3 gave diamine (IX), which was cyclized to the urea (X) employing carbonyldiimidazole and pyridine.
| 【1】 Han, W.; Pelletier, J.C.; Hodge, C.N.; Tricyclic ureas: A new class of HIV-1 protease inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3615. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (I) | 29582 | 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate | C19H25NO5 | 详情 | 详情 | |
| (II) | 29583 | 7-benzyl 1-(tert-butyl) (1S,3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate | C26H31NO5 | 详情 | 详情 | |
| (III) | 29584 | benzyl (1S,3R,4R)-3-(benzyloxy)-1-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate | C22H25NO4 | 详情 | 详情 | |
| (IV) | 29585 | benzyl (1S,3R,4R)-3-(benzyloxy)-1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate | C22H23NO4 | 详情 | 详情 | |
| (V) | 27884 | benzyl (1R)-1-benzyl-2-oxoethylcarbamate | C17H17NO3 | 详情 | 详情 | |
| (VI) | 29586 | benzyl (1S,3R,4R)-3-(benzyloxy)-1-((1R,2R,3R)-3-[[(benzyloxy)carbonyl]amino]-1,2-dihydroxy-4-phenylbutyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate | C39H42N2O7 | 详情 | 详情 | |
| (VII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VIII) | 29587 | benzyl (1S,3R,4R)-3-(benzyloxy)-1-[(4R,5R)-5-((1R)-1-[[(benzyloxy)carbonyl]amino]-2-phenylethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-7-azabicyclo[2.2.1]heptane-7-carboxylate | C42H46N2O7 | 详情 | 详情 | |
| (IX) | 29588 | (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1R)-1-[(4R,5R)-5-[(3R,4R)-3-(benzyloxy)-7-azabicyclo[2.2.1]hept-1-yl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine | C26H34N2O3 | 详情 | 详情 | |
| (X) | 29589 | (1S,2R,6R,7R,11R,12R)-7-benzyl-12-(benzyloxy)-4,4-dimethyl-3,5-dioxa-8,10-diazatetracyclo[9.2.2.0(1,10).0(2,6)]pentadecan-9-one | C27H32N2O4 | 详情 | 详情 |
合成路线42
该中间体在本合成路线中的序号：(V)The reaction of N-(benzyloxycarbonyl)-L-serine methyl ester (I) with 2-mercaptobenzothiazole (II) by means of DIAD and PPh3 in THF gives the thioether (III), which is reduced with NaBH4 and CaCl2 in THF to yield the alcohol (IV). The cyclization of (IV) with 2,2-dimethoxypropane (V) by means of TsOH in dichloromethane affords the oxazolidine (VI), which is oxidized at the thioether group by means of Mo7O24(NH4)6 and H2O2 in ethanol to provide the sulfone (VII). The condensation of (VII) with 7-iodoisatin (VIII) employing LiHMDS and DMPU in THF gives the adduct (IX), which is condensed with the boronic ester (X) -obtained by reaction of the tyrosine derivative (XI) with bis(pinacolato)diboron, KOH and Pd(dppf)Cl2 in hot DMSO- by means of K2CO3 and Pd(dppf)Cl2 in aqueous DME to yield the coupled product (XII). The hydrolysis of the ester group of (XII) with LiOH, followed by condensation with asparagine benzyl ester (XIII) by means of HOAT, EDC and NMM in dichloromethane affords the amide (XIV). This is oxidized at its exocyclic double bond by means of OsO4 and pyridine in THF/methanol to provide the diol (XV).
| 【1】 Albrecht, B.K.; Williams, R.M.; A concise formal total synthesis of TMC-95A/B proteasome inhibitors. Org Lett 2003, 5, 2, 197. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 51660 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate | C12H15NO5 | 详情 | 详情 | |
| (II) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (III) | 61814 | methyl (2R)-3-(1,3-benzothiazol-2-ylsulfanyl)-2-{[(benzyloxy)carbonyl]amino}propanoate | C19H18N2O4S2 | 详情 | 详情 | |
| (IV) | 61815 | benzyl (1R)-2-(1,3-benzothiazol-2-ylsulfanyl)-1-(hydroxymethyl)ethylcarbamate | C18H18N2O3S2 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 61816 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfanyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O3S2 | 详情 | 详情 | |
| (VII) | 61817 | benzyl (4S)-4-[2-(1,3-benzothiazol-2-ylsulfonyl)ethyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H24N2O5S2 | 详情 | 详情 | |
| (VIII) | 61824 | 7-iodo-1H-indole-2,3-dione | C8H4INO2 | 详情 | 详情 | |
| (IX) | 61818 | benzyl (4S)-4-[(7-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C22H21IN2O4 | 详情 | 详情 | |
| (X) | 61820 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C23H36BNO8 | 详情 | 详情 | |
| (XI) | 61819 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-iodo-4-(methoxymethoxy)phenyl]propanoate | C17H24INO6 | 详情 | 详情 | |
| (XII) | 61821 | benzyl (4S)-4-({7-[5-{(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C39H45N3O10 | 详情 | 详情 | |
| (XIII) | 61825 | benzyl (2S)-2,4-diamino-4-oxobutanoate | C11H14N2O3 | 详情 | 详情 | |
| (XIV) | 61822 | benzyl (4S)-4-({7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-2-oxo-1,2-dihydro-3H-indol-3-ylidene}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C49H55N5O12 | 详情 | 详情 | |
| (XV) | 61823 | benzyl (4R)-4-[(R)-{(3S)-7-[5-{(2S)-3-({(1S)-3-amino-1-[(benzyloxy)carbonyl]-3-oxopropyl}amino)-2-[(tert-butoxycarbonyl)amino]-3-oxopropyl}-2-(methoxymethoxy)phenyl]-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl}(hydroxy)methyl]-2,2-dimethyl-1,3-oxazoli | C49H57N5O14 | 详情 | 详情 |
合成路线43
该中间体在本合成路线中的序号：(IV)Sharpless asymmetric epoxidation of (S)-(-)-perillyl alcohol (I) using tert-butyl hydroperoxide and diethyl L-tartrate produced epoxide (II), which was reduced to diol (III) by means of LiAlH4 in cold THF. Treatment of (III) with 2,2-dimethoxypropane (IV) and p-toluenesulfonic acid then furnished the title isopropylidene ketal.
| 【1】 Ryder, H.; Skoumas, V.; Watson, M.; Moore, M.; Coombes, R.C.; Ashworth, P.A.; Donaldson, M.J.; XR 3054, structurally related to limonene, is a novel inhibitor of farnesyl protein transferase. Eur J Cancer 1999, 35, 6, 1014. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 34756 | [(4S)-4-isopropenyl-1-cyclohexen-1-yl]methanol | 536-59-4 | C10H16O | 详情 | 详情 |
| (II) | 34757 | [(4S,6S)-4-isopropenyl-7-oxabicyclo[4.1.0]hept-1-yl]methanol | C10H16O2 | 详情 | 详情 | |
| (III) | 34758 | 1-(hydroxymethyl)-4-isopropenylcyclohexanol | C10H18O2 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
合成路线44
该中间体在本合成路线中的序号：(IV)The oxidation of the chiral 2(R)-(benzyloxymethyl-4-phenyl-1-butanol (I) with (COCl)2 and TEA in DMSO/dichloromethane gives the corresponding aldehyde (II) , which by a pinacol coupling promoted by VCl3, Zn and 1,3-dimethylimidazolidin-2-one (DMI) in dichloromethane yields the glycol (III) as a mixture of all the possible enantiomers. The protection of the glycol function of (III) by means of 2,2-dimethoxypropane (IV), 2-methoxypropene and CSA in acetone affords the isopropylidene ketal (V), which is debenzylated by hydrogenation with H2 over Pd/C in aq. NaHCO3/EtOAc to provide the hexane-1,6-diol (VI). The oxidation of diol (VI) with RuCl3 and NaIO4 in acetonitrile/water/dichloromethane gives the adipic acid derivative (VII), which is treated with disuccinimidyl carbonate (VIII) to yield the corresponding enantiomeric mixture of activated esters, which is resolved by column chromatography to isolate the (R,R)-activated ester (IX). The reaction of (IX) with (1S,2R)-1-amino-2-indanol (X) in hot dichloroethane (DCE) affords the diamide (XI), which is finally deprotected (elimination of the isopropylidene group) by means of FeCl3.6H2O in dichloromethane to provide the target (R,R,R,R)-dihydroxydiamide.
| 【1】 Muhlman, A.; et al.; Synthesis of novel potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal. J Med Chem 2001, 44, 21, 3407. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (R,R)-(III) | 52454 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (R,S)-(III) | 52455 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (S,S)-(III) | 52456 | 1,8-diphenyl-3,6-bis{[(phenylmethyl)oxy]methyl}-4,5-octanediol | C36H42O4 | 详情 | 详情 | |
| (I) | 52452 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}-1-butanol | C18H22O2 | 详情 | 详情 | |
| (II) | 52453 | 4-phenyl-2-{[(phenylmethyl)oxy]methyl}butanal | C18H20O2 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (V) | 52457 | 2,2-dimethyl-4,5-bis(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolane; 2-[2,2-dimethyl-5-(3-phenyl-1-{[(phenylmethyl)oxy]methyl}propyl)-1,3-dioxolan-4-yl]-4-phenylbutyl phenylmethyl ether | C39H46O4 | 详情 | 详情 | |
| (VI) | 52458 | C25H34O4 | 详情 | 详情 | ||
| (VII) | 52459 | C25H30O6 | 详情 | 详情 | ||
| (VIII) | 20417 | 1-([[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy)-2,5-pyrrolidinedione | 74124-79-1 | C9H8N2O7 | 详情 | 详情 |
| (IX) | 52460 | 1-({2-[5-(1-{[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}-3-phenylpropyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-phenylbutanoyl}oxy)-2,5-pyrrolidinedione | C33H36N2O10 | 详情 | 详情 | |
| (X) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (XI) | 52461 | C43H48N2O6 | 详情 | 详情 |
合成路线45
该中间体在本合成路线中的序号：(IV)
| 【1】 Maibaum J, Stutz S, Goschke R, et al. 2007. Structural modification of the P2' position of 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydro-8-phenyl-octanecarboxamides: the discovery of aliskiren, a potent nonpeptide human renin inhibitor active after once daily dosing in marmosets. J Med Chem, 50(20): 4832～4844 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 66991 | (R)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene | C13H19BrO | 详情 | 详情 | |
| (V) | 66992 | C40H63NO7 | 详情 | 详情 | ||
| (VIII) | 28129 | 3-amino-2,2-dimethylpropanamide | 324763-51-1 | C5H12N2O | 详情 | 详情 |
| (I) | 28123 | tert-butyl (1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentylcarbamate | C24H39NO6 | 详情 | 详情 | |
| (III) | 28125 | tert-butyl (1S,4S)-4-[(benzyloxy)methyl]-2-hydroxy-1-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-5-methylhexylcarbamate | C37H59NO7 | 详情 | 详情 | |
| (IV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 28127 | tert-butyl (4S,5S)-5-[(2S)-2-(hydroxymethyl)-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C33H57NO7 | 详情 | 详情 | |
| (VII) | 28128 | (2S)-2-[((4S,5S)-3-(tert-butoxycarbonyl)-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidin-5-yl)methyl]-3-methylbutyric acid | C33H55NO8 | 详情 | 详情 | |
| (IX) | 28130 | tert-butyl (4S,5S)-5-((2S)-2-[[(3-amino-2,2-dimethyl-3-oxopropyl)amino]carbonyl]-3-methylbutyl)-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C38H65N3O8 | 详情 | 详情 | |
| (X) | 66994 | tert-butyl (8-((3-amino-2,2-dimethyl-3-oxopropyl)carbamoyl)-6-hydroxy-3-(4-methoxy-3-(3-methoxypropoxy)benzyl)-2,9-dimethyldecan-5-yl)carbamate | C35H61N3O8 | 详情 | 详情 | |
| (XII) | 28126 | tert-butyl (4S,5S)-5-[(2S)-2-[(benzyloxy)methyl]-3-methylbutyl]-4-[(2S)-2-[4-methoxy-3-(3-methoxypropoxy)benzyl]-3-methylbutyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C40H63NO7 | 详情 | 详情 |
合成路线46
该中间体在本合成路线中的序号：(XXV)Chiral cyclopropanesulfonyl chloride intermediate (VIII) can be prepared as follows. Lithiation of (trimethylsilyl)acetylene (XVII) with t-BuLi in THF at –78 °C, and subsequent coupling with TBDMS-protected (S)-glycidol (XVIII) in the presence of BF3·Et2O at –78 °C affords the (S)-pentynol derivative (XIX). Then, the TMS-protecting group of intermediate (XIX) is selectively removed by means of K2CO3 in MeOH to give alkyne (XX). Iodoboration of alkyne (XX) with B-I-9-BBN in CH2Cl2 at 0 °C followed by deborination with AcOH yields 4-iodo-4-pentene-1,2(S)-diol (XXI). O-Protection of diol (XXI) with TBDMSOTf and pyridine in THF provides the bis-silyl ether (XXII), which is then submitted to Simmons-Smith cyclopropanation with CH2I2 in the presence of Et2Zn and TFA in DCE to produce 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIII). Desilylation of compound (XXIII) using HCl in THF gives 3-(1-iodocyclopropyl)propane-1,2(S)-diol (XXIV), which by trans-ketalization with 2,2-dimethoxypropane (XXV) by means of PPTS in CH2Cl2 gives 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl-1,3-dioxolane (XXVI). Finally, alkyl iodide (XXVI) is treated with t-BuLi in Et2O at –78 °C, followed by chlorosulfonation with SO2Cl2 in Et2O (3).
Alternatively, deprotonation of dicyclopropyl disulfide (XXVII) with BuLi in THF, followed by alkylation with 4(R)-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (XXVIII) at –78 °C affords the dimeric bis-acetonide (XXIX), which is reductively cleaved to the corresponding thiol monomer (XXX) by treatment with PPh3 and HCl in dioxane/H2O. Air oxidation of cyclopropanethiol derivative (XXX) in the presence of NaOH in DMF gives sodium cyclopropanesulfonate derivative (XXXI), which can also be obtained by direct oxidation of disulfide (XXIX) with H2O2 and NaOAc in AcOH at 80 °C. Finally, sulfonate (XXXI) is chlorinated using POCl3 at 80 °C. Alternatively, sulfonyl chloride (VIII) can be directly obtained from disulfide (XXIX) by oxidative cleavage with NCS in the presence of HCl in MeCN .
| 【1】 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799. |
| 【2】 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011 |
| 【3】 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 67911 | (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride | C10H17ClO3S | 详情 | 详情 | |
| (XVII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XVIII) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (XIX) | 67918 | (S)-1-((tert-butyldimethylsilyl)oxy)-5-(trimethylsilyl)pent-4-yn-2-ol | C14H30O2Si2 | 详情 | 详情 | |
| (XX) | 67919 | (S)-1-((tert-butyldimethylsilyl)oxy)pent-4-yn-2-ol | C11H22O2Si | 详情 | 详情 | |
| (XXI) | 67920 | (S)-4-iodopent-4-ene-1,2-diol | C5H9IO2 | 详情 | 详情 | |
| (XXII) | 67922 | (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C17H37IO2Si2 | 详情 | 详情 | |
| (XXIII) | 67921 | 1,2-O-bis-TBDMS-3-(1-iodocyclopropyl) propane-1,2(S)-diol;(S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C18H39IO2Si2 | 详情 | 详情 | |
| (XXIV) | 67923 | 3-(1-iodocyclopropyl)propane-1,2(S)-diol | C6H11O2I | 详情 | 详情 | |
| (XXV) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XXVI) | 67924 | 4(S)-(1-iodocyclopropylmethyl)-2,2-dimethyl- 1,3-dioxolane | C9H15IO2 | 详情 | 详情 | |
| (XXVII) | 67925 | dicyclopropyl disulfide;Dicyclopropyldisulfide | 68846-57-1 | C6H10S2 | 详情 | 详情 |
| (XXVIII) | 67926 | 4(R)-(bromomethyl)-2,2-dimethyl-1,3- dioxolane | 14437-87-7 | C6H11BrO2 | 详情 | 详情 |
| (XXIX) | 67927 | 1,2-bis(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropyl)disulfane | C18H30O4S2 | 详情 | 详情 | |
| (XXX) | 67929 | (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropanethiol | C9H16O2S | 详情 | 详情 | |
| (XXXI) | 67928 | sodium (R)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonate | C9H15NaO5S | 详情 | 详情 |
合成路线47
该中间体在本合成路线中的序号：(XVIII)The acceptor alcohol (XII) is synthesized by esterification of shikimic acid (XVI) with MeOH in the presence of H2SO4 to give methyl shikimate (XVII), which is then protected as the 3,4-acetonide (XIX) by transketalization with 2,2-dimethoxypropane (XVIII) by means of TsOH in acetonitrile. Hydrogenation of compound (XIX) over PtO2/C in MeOH affords the saturated ester (XX), which by acetylation with Ac2O in the presence of pyridine and DMAP in CH2Cl2 affords acetate (XXI). Deprotection of compound (XXI) by means of 80% aqueous AcOH at 80 °C provides diol (XXII), which is regioselectively converted to tosylate (XXIII) with TsCl in pyridine. Substitution of tosylate (XXIII) with NaN3 in DMF at 80 °C yields the corresponding azide (XXIV), which is then condensed with thioglycoside (XXV) by means of Br2 and Et4NBr in CH2Cl2/DMF/cyclohexene to obtain ether (XXVI). Finally, intermediate (XXVI) is submitted to deacetylation and simultaneous epimerization by means of NaOMe in MeOH, followed by reesterification with CH2N2 in Et2O .
| 【1】 Magnani, J.L., Patton, J.T. Jr., Sarkar, A.K., Svarovsky, S.A., Ernst, B. (GlycoMimetics, Inc.). Heterobifunctional pan-selectin inhibitors. EP 1934236, EP 2264043, JP 2009507031, US 2007054870, US 7728117, WO 2007028050. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 68493 | (1S,3S,4R,5R)-methyl 3-azido-5-hydroxy-4-(((2S,3S,4R,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C35H41N3O8 | 详情 | 详情 | |
| (XVI) | 29907 | (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid; Shikimic acid | 138-59-0 | C7H10O5 | 详情 | 详情 |
| (XVII) | 29908 | methyl (3R,4S,5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylate | C8H12O5 | 详情 | 详情 | |
| (XVIII) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XIX) | 29909 | methyl (3aR,7R,7aS)-7-hydroxy-2,2-dimethyl-3a,6,7,7a-tetrahydro-1,3-benzodioxole-5-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XX) | 68500 | (3aS,7S,7aS)-methyl 7-hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C11H18O5 | 详情 | 详情 | |
| (XXI) | 68499 | (3aS,7S,7aS)-methyl 7-acetoxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxole-5-carboxylate | C13H20O6 | 详情 | 详情 | |
| (XXII) | 68498 | (3R,4S,5S)-methyl 3-acetoxy-4,5-dihydroxycyclohexanecarboxylate | C10H16O6 | 详情 | 详情 | |
| (XXIII) | 68497 | (3R,4S,5S)-methyl 3-acetoxy-4-hydroxy-5-(tosyloxy)cyclohexanecarboxylate | C17H22O8S | 详情 | 详情 | |
| (XXIV) | 68496 | (3R,4S,5R)-methyl 3-acetoxy-5-azido-4-hydroxycyclohexanecarboxylate | C10H15N3O5 | 详情 | 详情 | |
| (XXV) | 68502 | (3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-2-(ethylthio)-6-methyltetrahydro-2H-pyran | C29H34O4S | 详情 | 详情 | |
| (XXVI) | 68501 | (3S,4S,5R)-methyl 3-acetoxy-5-azido-4-(((2R,3S,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)cyclohexanecarboxylate | C37H43N3O9 | 详情 | 详情 |