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【结 构 式】 
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【分子编号】14182 【品名】ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 【CA登记号】1099-45-2 |
【 分 子 式 】C22H21O2P 【 分 子 量 】348.381302 【元素组成】C 75.85% H 6.08% O 9.18% P 8.89% |
合成路线1
该中间体在本合成路线中的序号：(IV)A new total synthesis of sertraline has been described: The reduction of N,N-dibenzyl-D-phenylglycine methyl ester (I) with LiAlH4 in THF gives alcohol (II), which is oxidized to aldehyde (III) with oxalyl chloride in dichloromethane. The condensation of (III) with the phosphorane (IV) in benzene yields the unsaturated ester (V), which is reduced with Mg in methanol affording the saturated methyl ester (VI). Reduction of (VI) with LiAlH4 in THF provides the corresponding butanol derivative (VII), which is oxidized to the aldehyde (VIII) with pyridinium dichromate (PDC) in dichloromethane. The Grignard reaction of (VIII) with 3,4-dichlorophenylmagnesium bromide (IX) in THF affords the secondary alcohol (X), which is cyclized by means of AlCl3 in dichloromethane yielding a mixture of the desired cis-isomer (XI) along with some trans-isomer separated by column chromatography. Debenzylation of (XI) by H2 over Pd(OH)2 in methanol, followed by protection with Boc2O yields the carbamate (XII), which is methylated with methyl iodide and NaH in THF to afford the protected intermediate (XIII). Finally, compound (XIII) is deprotected with TFA in dichloromethane.
| 【1】 Chandrasekhar, S.; Reddy, M.V.; An expedient total synthesis of cis-(+)-sertraline from D-phenylglycine. Tetrahedron 2000, 56, 8, 1111. |
| 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) | 46527 | methyl (2R)-2-(dibenzylamino)-2-phenylethanoate | C23H23NO2 | 详情 | 详情 | |
| (II) | 46528 | (2R)-2-(dibenzylamino)-2-phenyl-1-ethanol | C22H23NO | 详情 | 详情 | |
| (III) | 46529 | (2R)-2-(dibenzylamino)-2-phenylethanal | C22H21NO | 详情 | 详情 | |
| (IV) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (V) | 46530 | ethyl (E,4S)-4-(dibenzylamino)-4-phenyl-2-butenoate | C26H27NO2 | 详情 | 详情 | |
| (VI) | 46531 | methyl (4S)-4-(dibenzylamino)-4-phenylbutanoate | C25H27NO2 | 详情 | 详情 | |
| (VII) | 46532 | (4S)-4-(dibenzylamino)-4-phenyl-1-butanol | C24H27NO | 详情 | 详情 | |
| (VIII) | 46533 | (4S)-4-(dibenzylamino)-4-phenylbutanal | C24H25NO | 详情 | 详情 | |
| (IX) | 10069 | Bromo(3,4-dichlorophenyl)magnesium | 79175-35-2 | C6H3BrCl2Mg | 详情 | 详情 |
| (X) | 46534 | (4S)-4-(dibenzylamino)-1-(3,4-dichlorophenyl)-4-phenyl-1-butanol | C30H29Cl2NO | 详情 | 详情 | |
| (XI) | 46535 | N,N-dibenzyl-N-[(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]amine; (1S,4S)-N,N-dibenzyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine | C30H27Cl2N | 详情 | 详情 | |
| (XII) | 46536 | tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate | C21H23Cl2NO2 | 详情 | 详情 | |
| (XIII) | 46537 | tert-butyl (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl(methyl)carbamate | C22H25Cl2NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The chiral amine intermediate (XV) has been obtained as follows: The alkylation of 4-fluorophenol (I) with allyl bromide (II) and K2CO3 gives the allyl ether (III), which by thermal rearrangement at 210 C yields 2-allyl-4-fluorophenol (IV). The silylation of (IV) with TBDMS-Cl and imidazole affords the silyl ether (V), which is submitted to hydroboration with BH3 and H2O2 to provide the propanol (VI). The oxidation of (VI) with Dess Martin periodinane (DMP) gives the aldehyde (VII), which is condensed with the phosphorane (VIII) to yield the pentenoic ester (IX). The reduction of (IX) with DIBAL affords the unsaturated alcohol, which is desilylated with TBAF in THF furnishing the diol (XI). The treatment of (XI) under the Sharpless asymmetric epoxidation conditions ((-)-DET and titanium tetraisopropoxide) gives, after cyclization with NaOH, 1(R)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(S)-yl)-1,2-ethanediol (XII), which is selectively tosylated with TsCl and pyridine yielding the monotosylate (XIII). The reaction of (XIII) with sodium azide in DMF affords the azide (XIV), which is reduced to the corresponding amine (XV) with H2 over Pd/C in ethanol.
| 【1】 Chandrasekhar, S.; Reddy, M.V.; Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. Tetrahedron 2000, 56, 34, 6339. |
| 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) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (II) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (III) | 40848 | 1-(allyloxy)-4-fluorobenzene; allyl 4-fluorophenyl ether | C9H9FO | 详情 | 详情 | |
| (IV) | 40849 | 2-allyl-4-fluorophenol | C9H9FO | 详情 | 详情 | |
| (V) | 40850 | (2-allyl-4-fluorophenoxy)(tert-butyl)dimethylsilane; 2-allyl-4-fluorophenyl tert-butyl(dimethyl)silyl ether | C15H23FOSi | 详情 | 详情 | |
| (VI) | 40851 | 3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-1-propanol | C15H25FO2Si | 详情 | 详情 | |
| (VII) | 40852 | 3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)propanal | C15H23FO2Si | 详情 | 详情 | |
| (VIII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IX) | 40853 | ethyl (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-pentenoate | C19H29FO3Si | 详情 | 详情 | |
| (X) | 40854 | (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-penten-1-ol | C17H27FO2Si | 详情 | 详情 | |
| (XI) | 40855 | 4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol | C11H13FO2 | 详情 | 详情 | |
| (XII) | 40856 | (1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol | C11H13FO3 | 详情 | 详情 | |
| (XIII) | 40857 | (2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate | C18H19FO5S | 详情 | 详情 | |
| (XIV) | 40858 | (1R)-2-azido-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol | C11H12FN3O2 | 详情 | 详情 | |
| (XV) | 40859 | (1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol | C11H14FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)The selective protection of the primary OH group of hydroxymethyl tetrahydropyran-3-ol (X) with trityl chloride and pyridine gives the cyclohexanol (XI), which is methylated by means of methyl iodide and NaH to yield the dimethoxy derivative (XII). The cleavage of the trityl group of (XII) by means of HCl in methanol affords the methanol derivative (XIII), which is oxidized by means of DMP to the corresponding carbaldehyde (XIV). The condensation of (XIV) with 2(S)-methyl-5-(trimethylsilyl)-4-pentynyl iodide (XV) by means of t-BuLi and MgBr2 provides the acetylenic alcohol (XVI), which is methylated with methyl iodide and NaH giving the trimethoxy derivative (XVII). The hydrolysis of the acetal group of (XVII) with Ac-OH yields the hemiacetal (XVIII), which is olefinated with the phosphorane (XIX) in refluxing benzene to afford the unsaturated tridecanoic ester (XX). The reduction of (XX) with DIBAL provides the unsaturated diol (XXI), which is submitted to an asymmetric dihydroxylation by means of Ti(O-iPr)4, (+)-diethyl tartrate and tert-butyl hydroperoxide to give the chiral tetrahydropyran diol (XXII). The iodination of the triple bond of (XXII) with AlMe3, Cp2ZrCl2 and iodine yields the iodovinyl compound (XXIII), which is protected by means of Tbdms-Cl, DMAP and imidazole to afford the silylated compound (XXIV). The condensation of (XXIV) with the intermediate spiroenone (IX) by means of t-BuLi provides the open chain intermediate (XXV).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 57305 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H71NO10Si | 详情 | 详情 | |
| (X) | 57306 | (2R,3S,5R,6S)-2-(hydroxymethyl)-6-methoxy-5-methyltetrahydro-2H-pyran-3-ol | C8H16O4 | 详情 | 详情 | |
| (XI) | 57307 | (2R,3S,5R,6S)-6-methoxy-5-methyl-2-[(trityloxy)methyl]tetrahydro-2H-pyran-3-ol | C27H30O4 | 详情 | 详情 | |
| (XII) | 57308 | (2S,3R,5S,6R)-2,5-dimethoxy-3-methyl-6-[(trityloxy)methyl]tetrahydro-2H-pyran; [(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]methyl trityl ether | C28H32O4 | 详情 | 详情 | |
| (XIII) | 57309 | [(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]methanol | C9H18O4 | 详情 | 详情 | |
| (XIV) | 57310 | (2S,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-carbaldehyde | C9H16O4 | 详情 | 详情 | |
| (XV) | 57311 | [(4S)-5-iodo-4-methyl-1-pentynyl](trimethyl)silane | C9H17ISi | 详情 | 详情 | |
| (XVI) | 57312 | (1S,3S)-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3-methyl-6-(trimethylsilyl)-5-hexyn-1-ol | C18H34O4Si | 详情 | 详情 | |
| (XVII) | 57313 | (1S,3S)-1-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-3-methyl-6-(trimethylsilyl)-5-hexynyl methyl ether; {(4S,6S)-6-[(2R,3S,5R,6S)-3,6-dimethoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-4-methyl-1-hexynyl}(trimethyl)silane | C19H36O4Si | 详情 | 详情 | |
| (XVIII) | 57314 | (3R,5S,6R)-5-methoxy-6-[(1S,3S)-1-methoxy-3-methyl-6-(trimethylsilyl)-5-hexynyl]-3-methyltetrahydro-2H-pyran-2-ol | C18H34O4Si | 详情 | 详情 | |
| (XIX) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XX) | 57315 | ethyl (E,4R,6S,7R,8S,10S)-7-hydroxy-6,8-dimethoxy-4,10-dimethyl-13-(trimethylsilyl)-2-tridecen-12-ynoate | C22H40O5Si | 详情 | 详情 | |
| (XXI) | 57316 | (E,4R,6S,7R,8S,10S)-6,8-dimethoxy-4,10-dimethyl-13-(trimethylsilyl)-2-tridecen-12-yne-1,7-diol | C20H38O4Si | 详情 | 详情 | |
| (XXII) | 57317 | (1S)-1-{(2R,3R,5S,6R)-5-methoxy-6-[(1S,3S)-1-methoxy-3-methyl-6-(trimethylsilyl)-5-hexynyl]-3-methyltetrahydro-2H-pyran-2-yl}-1,2-ethanediol | C20H38O5Si | 详情 | 详情 | |
| (XXIII) | 57318 | (1S)-1-{(2R,3R,5S,6R)-6-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl}-1,2-ethanediol | C18H33IO5 | 详情 | 详情 | |
| (XXIV) | 57319 | (2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methyltetrahydro-2H-pyran-3-yl methyl ether; (5S)-5-{(2R,3R,5S,6R)-6-[(1S,3S,5E)-6-iodo-1-methoxy-3,5-dimethyl-5-hexenyl]-5-methoxy-3-methyltetrahydro-2H-pyran-2-yl}-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane | C30H61IO5Si2 | 详情 | 详情 | |
| (XXV) | 57320 | 2-[(1S,2E)-1-[(1R)-1-((4S,6R,11R)-11-{(E,4S,6S)-6-[(2R,3S,5R,6R)-6-((1S)-1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-methoxy-5-methyltetrahydro-2H-pyran-2-yl]-6-methoxy-2,4-dimethyl-1-hexenyl}-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H133NO15Si3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)An asymmetric synthesis of the C(17)-C(27)-segment of bryostatin 1 has been described: The asymmetric dihydroxylation of 1,4(E)-hexadiene (I) with AD-mix-beta in tert-butanol gives the diol (II), which is protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, yielding the bis(silyl) ether (III). The oxidation of (III) with OsO4 and NaIO4 affords the aldehyde (IV), which is condensed with triphenylphosphoranylideneacetic acid ethyl ester (V) in dichloromethane to give 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-2(E)-heptenoic acid ethyl ester (VI). The reduction of (VI) with dibutylaluminum hydride (DIBAL-H) yields the primary alcohol (VII), which is epoxidized with (-)-DET, Ti(OPr)4 and tert-butyl peroxide in dichloromethane to the epoxy-alcohol (VIII). The reductive opening of the epoxide ring of (VIII) with REDAL affords the diol (IX), which by reaction with 4-methoxybenzaldehyde dimethylacetal [PMB(OMe)2] and PPTS in DMF is converted to the acetal (X). The reductive cleavage of (X) with DIBAL-H in dichloromethane affords 5(R),6(R)-bis(tert-butyldimethylsilyloxy)-3(S)-(4-methoxybenzyloxy)-1-h eptanol (XI), which is oxidized with oxalyl chloride to the corresponding aldehyde (XII). The condensation of (XII) with phosphorane (V) in dichloromethane gives 7(R),8(R)-bis(tert-butyldimethylsilyloxy)-5(S)-(4-methoxybenzyloxy)-2(E)-nonenoic acid ethyl ester (XIII), which is asymmetrically dihydroxylated with AD-mix-beta as before to the dihydroxy ester (XIV). The protection of (XIV) by reaction with 2,2-dimethoxypropane and PPTS yields the isopropylidene ketal (XV), which is submitted to a Claisen condensation with the lithium enolate of methyl isobutyrate, affording the keto ester (XVI). Selective deprotection of (XVI) with HF.pyridine affords the diol (XVII), which is acylated with pivaloyl chloride (Pv-Cl) and pyridine in dichloromethane, giving the bispivaloyloxy derivative (XVIII). A new selective deprotection of (XVIII) with DDQ in dichloromethane yields the hydroxy ester (XIX), which is submitted to cyclization with Amberlyst-15 H+ and acetyl chloride in methanol to afford the perhydrofuropyran derivative (XX). The oxidation of the hydroxy group of (XX) with RuCl3 and NaIO4 in acetonitrile/CCl4 gives the corresponding ketonic compound (XXI), which is finally submitted to a condensation with triphenylphosphoranylideneacetic acid methyl ester in dichloromethane to afford 2(E)-[5(S)-[2(R),3(R)-bis(pivaloyloxy)butyl]-3a(S)-methoxy-2,2-dimethyl-7a(S)-perhydrofuro[3,2-a]pyran-7-ylidene]acetic acid methyl ester (XXII), which includes the C(17)-C(27)-fragment of bryostatin 1 with the correct stereochemistry.
| 【1】 Manaviazar, S.; Lennon, J.A.; Javaid, M.H.; Hobbs, C.J.; Hale, K.J.; Asymmetric synthesis of the C17-C27 segment of the antineoplastic macrolide bryostatin 1. Tetrahedron Lett 1995, 36, 8, 1359. |
| 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) | 14178 | (4E)-1,4-Hexadiene; 1,4-Hexadiene | 592-45-0 | C6H10 | 详情 | 详情 |
| (II) | 14179 | (2R,3R)-5-Hexene-2,3-diol | C6H12O2 | 详情 | 详情 | |
| (III) | 14180 | tert-Butyl(dimethyl)silyl (1R)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3-butenyl ether; (5R,6R)-5-Allyl-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane | C18H40O2Si2 | 详情 | 详情 | |
| (IV) | 14181 | (3R,4R)-3,4-Bis[[tert-butyl(dimethyl)silyl]oxy]pentanal | C17H38O3Si2 | 详情 | 详情 | |
| (V) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (VI) | 14183 | ethyl (E,5R,6R)-5,6-bis[[tert-butyl(dimethyl)silyl]oxy]-2-heptenoate | C21H44O4Si2 | 详情 | 详情 | |
| (VII) | 14184 | (E,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-hepten-1-ol | C19H42O3Si2 | 详情 | 详情 | |
| (VIII) | 14185 | [(2R,3R)-3-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)oxiranyl]methanol | C19H42O4Si2 | 详情 | 详情 | |
| (IX) | 14186 | (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-1,3-heptanediol | C19H44O4Si2 | 详情 | 详情 | |
| (X) | 14187 | (5R,6R)-5-[[(4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methyl]-2,2,3,3,6,8,8,9,9-nonamethyl-4,7-dioxa-3,8-disiladecane; 4-[(4S)-4-((2R,3R)-2,3-Bis[[tert-butyl(dimethyl)silyl]oxy]butyl)-1,3-dioxan-2-yl]phenyl methyl ether | C27H50O5Si2 | 详情 | 详情 | |
| (XI) | 14188 | (3S,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]-1-heptanol | C27H52O5Si2 | 详情 | 详情 | |
| (XII) | 14189 | (3R,5R,6R)-5,6-Bis[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]heptanal | C27H50O5Si2 | 详情 | 详情 | |
| (XIII) | 14190 | ethyl (E,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-5-[(4-methoxybenzyl)oxy]-2-nonenoate | C31H56O6Si2 | 详情 | 详情 | |
| (XIV) | 14191 | ethyl (2S,3R,5S,7R,8R)-7,8-bis[[tert-butyl(dimethyl)silyl]oxy]-2,3-dihydroxy-5-[(4-methoxybenzyl)oxy]nonanoate | C31H58O8Si2 | 详情 | 详情 | |
| (XV) | 14192 | ethyl (4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate | C34H62O8Si2 | 详情 | 详情 | |
| (XVI) | 14193 | methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate | C37H66O9Si2 | 详情 | 详情 | |
| (XVII) | 14194 | methyl 3-((4S,5R)-5-[(2R,4R,5R)-4,5-dihydroxy-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate | C25H38O9 | 详情 | 详情 | |
| (XVIII) | 14195 | methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-[(4-methoxybenzyl)oxy]hexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate | C35H54O11 | 详情 | 详情 | |
| (XIX) | 14196 | methyl 3-((4S,5R)-5-[(2S,4R,5R)-4,5-bis[(2,2-dimethylpropanoyl)oxy]-2-hydroxyhexyl]-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-3-oxopropanoate | C27H46O10 | 详情 | 详情 | |
| (XX) | 14197 | (1R,2R)-3-[(3aS,5S,7R,7aS)-7-hydroxy-3a-methoxy-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate | C24H40O9 | 详情 | 详情 | |
| (XXI) | 14198 | (1R,2R)-3-[(3aS,5R,7aS)-3a-methoxy-3,3-dimethyl-2,7-dioxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate | C24H38O9 | 详情 | 详情 | |
| (XXII) | 14199 | (1R,2R)-3-[(3aS,5S,7aS)-3a-methoxy-7-[(E)-2-methoxy-2-oxoethylidene]-3,3-dimethyl-2-oxohexahydro-2H-furo[3,2-b]pyran-5-yl]-2-[(2,2-dimethylpropanoyl)oxy]-1-methylpropyl pivalate | C27H42O10 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXVIII)6) Mass labeled saprisartan has been obtained as follows: The Wittig condensation of cyclopropylcarbonyl chloride (XXVII) with ethoxycarbonylmethylene triphenylphosphorane (XXVIII) by means of bis(trimethylsilyl)acetamide in dichloromethane gives 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propionic acid ethyl ester (XXIX), which is oxidized with potassium peroxymonosulfate to the dicarbonyl compound (XXX). The cyclization of (XXX) with [all-13C]-propionaldehyde (XXXI) (obtained by hydrogenation of the corresponding acyl chloride (XXXII) with H2 over Pd/C in THF containing 2,6-lutidine) and [15N]-ammonium acetate by means of triethylamine in THF yields 4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIII). The condensation of (XXXIII) with the benzofuran (XXI) (already described in Scheme 2) by means of K2CO3 in dimethylacetamide affords 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIV), which is finally treated sequentially with Fe and acetic acid to reduce the nitro group, with trifluoromethanesulfonic anhydride to acylate the amino group, with NaOH to hydrolyze the ester group, and with carbonyldiimidazole and ammonia to generate the amide group, thus obtaining mass labeled saprisartan. This sequence has already been described in Scheme 19090802a for the unlabeled compound.
| 【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453. |
| 【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129. |
| 【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 . |
| 【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 15956 | 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)-1-benzofuran | C15H9Br2NO3 | 详情 | 详情 | |
| (XXVII) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (XXVIII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXIX) | 15964 | ethyl 3-cyclopropyl-3-oxo-2-(triphenyl-lambda(5)-phosphanylidene)propanoate | C26H25O3P | 详情 | 详情 | |
| (XXX) | 15965 | ethyl 3-cyclopropyl-2,3-dioxopropanoate | C8H10O4 | 详情 | 详情 | |
| (XXXI) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (XXXI) | 45291 | propionaldehyde | C3H6O | 详情 | 详情 | |
| (XXXII) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (XXXII) | 45290 | propanoyl chloride | C3H5ClO | 详情 | 详情 | |
| (XXXIII) | 15944 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (XXXIII) | 15968 | ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C11H16N2O2 | 详情 | 详情 | |
| (XXXIV) | 15957 | ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H24BrN3O5 | 详情 | 详情 | |
| (XXXIV) | 15969 | ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate | C26H24BrN3O5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Swern oxidation of N,N-dibenzyl-O-(tert-butyldimethylsilyl)serinol (I) afforded the intermediate aldehyde (II), which was condensed with phenylmagnesium bromide to give carbinol (III) as the major diastereoisomer. Displacement of the hydroxyl group of (III) with diphenylphosphoryl azide in the presence of diethyl azodicarboxylate and triphenylphosphine provided azide (IV). This was reduced to the corresponding amine with concomitant desilylation using LiAlH4. Further in situ addition of (Boc)2O produced carbamate (V). The alcohol function of (V) was then oxidized under Swern conditions, and the resulting aldehyde (VI) was condensed with phosphonate (VII) to yield unsaturated ester (VIII). Reduction of (VIII) to the saturated ester (IX) with Mg in MeOH, and further reduction of the ester group employing lithium borohydride gave rise to alcohol (X). After conversion of (X) to mesylate (XI), cyclization in the presence of NaH in THF furnished piperidine (XII). Debenzylation of (XII) afforded primary amine (XIII), which was reductively alkylated with 2-methoxybenzaldehyde (XIV) in the presence of NaCNBH3 to provide (XV). Finally, acid deprotection of the Boc group of (XV) yielded the title compound.
| 【1】 Chandrasekhar, S.; Mohanty, P.K.; Stereoselective synthesis of (+)-CP-99,994: A substance P non-peptide antagonist. Tetrahedron Lett 1999, 40, 27, 5071. |
| 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) | 31745 | (2R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-propanol | C23H35NO2Si | 详情 | 详情 | |
| (II) | 31746 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)propanal | C23H33NO2Si | 详情 | 详情 | |
| (III) | 31747 | (1R,2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-phenyl-1-propanol | C29H39NO2Si | 详情 | 详情 | |
| (IV) | 31748 | N-[(1R,2S)-2-azido-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-phenylethyl]-N,N-dibenzylamine; (1S,2R)-1-azido-N,N-dibenzyl-3-[[tert-butyl(dimethyl)silyl]oxy]-1-phenyl-2-propanamine | C29H38N4OSi | 详情 | 详情 | |
| (V) | 31749 | tert-butyl (1S,2R)-2-(dibenzylamino)-3-hydroxy-1-phenylpropylcarbamate | C28H34N2O3 | 详情 | 详情 | |
| (VI) | 31750 | tert-butyl (1S,2R)-2-(dibenzylamino)-3-oxo-1-phenylpropylcarbamate | C28H32N2O3 | 详情 | 详情 | |
| (VII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (VIII) | 31751 | ethyl (E,4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenyl-2-pentenoate | C32H38N2O4 | 详情 | 详情 | |
| (IX) | 31752 | ethyl (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenylpentanoate | C32H40N2O4 | 详情 | 详情 | |
| (X) | 31753 | tert-butyl (1S,2S)-2-(dibenzylamino)-5-hydroxy-1-phenylpentylcarbamate | C30H38N2O3 | 详情 | 详情 | |
| (XI) | 31754 | (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-(dibenzylamino)-5-phenylpentyl methanesulfonate | C31H40N2O5S | 详情 | 详情 | |
| (XII) | 31755 | tert-butyl (2S,3S)-3-(dibenzylamino)-2-phenyl-1-piperidinecarboxylate | C30H36N2O2 | 详情 | 详情 | |
| (XIII) | 31756 | tert-butyl (2S,3S)-3-amino-2-phenyl-1-piperidinecarboxylate | C16H24N2O2 | 详情 | 详情 | |
| (XIV) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XV) | 31757 | tert-butyl (2S,3S)-3-[(2-methoxybenzyl)amino]-2-phenyl-1-piperidinecarboxylate | C24H32N2O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XXXI)Advanced intermediate phosphonium salt (XLI). The protection of (R)(+)-glycidol (XXV) with Pmb-Cl and NaH gives the benzyl ether (XXVI). Which is condensed with methyl phenyl sulfone (XXVII) by means of BuLi in THF/HMPA to yield the secondary alcohol (XXVIII). The reaction of (XXVIII) with Tbdms-OTf and lutidine affords the silyl ether (XXIX) (3), which is converted into the aldehyde (XXX) by debenzylation with DDQ, followed by oxidation with DMP. The condensation of (XXX) with phosphorane (XXXI) in refluxing benzene gives the unsaturated ester (XXXII), which is reduced with DIBAL in dichloromethane and protected with Ph-CH2Br and NaH to yield the benzyl ether (XXXIII). The condensation of sulfone (XXXIII) with the iodomethyl intermediate (XXIV) by means of BuLi in THF/HMPA affords the adduct (XXXIV), which is desulfurized by reaction with BuLi, diiodomethane and isopropylmagnesium chloride to provide the methylene compound (XXXV). The elimination of the benzyl protecting group of (XXXV) by means of LiDBB, followed by oxidation with DMP gives the carbaldehyde (XXXVI), which is condensed with CH2=PPh3 in THF to yield compound (XXXVII) (2).
| 【1】 Smith, A.B. III; Lin, Q.; Pettit, G.R.; Chapuis, G.R.; Chapuis, J.-C.; Schmidt, J.M.; Synthesis and in vitro cancer cell growth inhibitory activity of monocyclic model cpds. containing spongistatin triene side-chains. Bioorg Med Chem Lett 1998, 8, 6, 567. |
| 【2】 Smith, A.B. III; Lin, Q.; Doughty, V.A.; Zhuang, L.; McBriar, M.D.; Kerns, J.K.; Brook, C.S.; Murase, N.; Nakayama, K.; The spongistatins: Architecturally complex natural products - Part two: Synthesis of the C(29-51) subunit, fragment assembly, and final elaboration to (+)-spongistatin 2. Angew Chem. Int Ed 2001, 40, 1, 196. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 64616 | tert-butyl[((2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (2R,4S,5S,6R)-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-{(S)-{(2R,3S,4R,5R,6S)-6-(iodomethyl)-3-methyl-4,5-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}[(triethylsilyl)oxy]methyl}-2-methoxy-5-methyltetrahydro-2H-pyran-4-yl ether | C59H109IO8Si5 | 详情 | 详情 | |
| (XXV) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (XXVI) | 63135 | 4-methoxybenzyl (2R)oxiranylmethyl ether; (2R)-2-{[(4-methoxybenzyl)oxy]methyl}oxirane | C11H14O3 | 详情 | 详情 | |
| (XXVII) | 23622 | methyl phenyl sulfone; methyl(dioxo)phenyl-lambda(6)-sulfane | 3112-85-4 | C7H8O2S | 详情 | 详情 |
| (XXVIII) | 64617 | (2S)-1-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)-2-butanol | C18H22O5S | 详情 | 详情 | |
| (XXIX) | 64618 | (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[(4-methoxybenzyl)oxy]butyl phenyl sulfone; tert-butyl{[(1S)-1-{[(4-methoxybenzyl)oxy]methyl}-3-(phenylsulfonyl)propyl]oxy}dimethylsilane | C24H36O5SSi | 详情 | 详情 | |
| (XXX) | 64619 | (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(phenylsulfonyl)butanal | C16H26O4SSi | 详情 | 详情 | |
| (XXXI) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXXII) | 64620 | ethyl (E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(phenylsulfonyl)-2-hexenoate | C20H32O5SSi | 详情 | 详情 | |
| (XXXIII) | 64621 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[2-(phenylsulfonyl)ethyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C25H36O4SSi | 详情 | 详情 | |
| (XXXIV) | 64622 | (3S,4E)-6-(benzyloxy)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-4-hexenyl phenyl sulfone; ({(1S,2E)-4-(benzyloxy)-1-[3-{(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}-2-(phenylsulfonyl)propyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane | C84H144O12SSi6 | 详情 | 详情 | |
| (XXXV) | 64623 | ({(1S,2E)-4-(benzyloxy)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2-butenyl}oxy)(tert-butyl)dimethylsilane; benzyl (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienyl ether | C79H140O10Si6 | 详情 | 详情 | |
| (XXXVI) | 64624 | (2E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2,6-heptadienal | C72H132O10Si6 | 详情 | 详情 | |
| (XXXVII) | 64625 | tert-butyl({(1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl}oxy)dimethylsilane; tert-butyl(dimethyl)silyl (1S,2E)-1-[2-({(2R,3R,4R,5S,6R)-6-{(S)-[(2R,4S,5S,6R)-4-{[tert-butyl(dimethyl)silyl]oxy}-6-(4-{[tert-butyl(diphenyl)silyl]oxy}butyl)-2-methoxy-5-methyltetrahydro-2H-pyran-2-yl][(triethylsilyl)oxy]methyl}-5-methyl-3,4-bis[(triethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}methyl)-2-propenyl]-2,4-pentadienyl ether | C73H134O9Si6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(X)Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn, Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III), which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV). The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI), which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII). Regioselective monodesilylation of (VII) by means of TBAF/HOAc in THF gives the primary alcohol (VIII), which is oxidized with oxalyl chloride to the corresponding aldehyde (IX). The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI), which is methylated with Me2CuLi and Tms-Cl in THF, affording the tetramethyl diester (XII). The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane, providing the 8-hydroxyoctanal derivative (XIII), which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV). Finally, this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).
| 【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575. |
| 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) | 44474 | methyl (3S,4E)-3-[dimethyl(phenyl)silyl]-4-hexenoate | C15H22O2Si | 详情 | 详情 | |
| (II) | 44475 | 2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde | C18H22O2Si | 详情 | 详情 | |
| (III) | 44476 | methyl (E,5S,6R)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate | C32H40O4Si | 详情 | 详情 | |
| (IV) | 44477 | (2R,3R)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal | C28H34O3Si | 详情 | 详情 | |
| (V) | 44478 | 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal | 31469-16-6 | C9H20O2Si | 详情 | 详情 |
| (VI) | 44479 | ethyl (3R,4S,5R)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate | C34H46O5Si | 详情 | 详情 | |
| (VII) | 44480 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate | C40H60O5Si2 | 详情 | 详情 | |
| (VIII) | 44481 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate | C24H42O5Si | 详情 | 详情 | |
| (IX) | 44482 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate | C24H40O5Si | 详情 | 详情 | |
| (X) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XI) | 44483 | diethyl (E,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate | C28H46O6Si | 详情 | 详情 | |
| (XII) | 44484 | diethyl (3R,4R,5S,6S)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate | C29H50O6Si | 详情 | 详情 | |
| (XIII) | 44485 | (3S,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal | C25H44O4Si | 详情 | 详情 | |
| (XIV) | 44486 | (3S,4S,5R,6R)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal | C31H58O4Si2 | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 44487 | (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether | C32H60O3Si2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XII)The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI).
| 【1】 Adhikari, S.S.; Hymavathi, L.; Sadalapure, K.; Sharma, G.V.M.; Sreenivas, P.; Mhaskar, S.V.; Lalitha, S.V.S.; Chorghade, M.S.; Murugaiah, A.M.S.; Prasad, T.R.; Reddy, B.S.; Gurjar, M.K.; Reddy, V.G.; Krishna, P.R. (LeukoSite, Inc.); Substd. oxygen alicyclic cpds., including methods for synthesis thereof. WO 0001381 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 | |
| (I) | 19639 | 4-fluorophenol | 371-41-5 | C6H5FO | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 22150 | 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether | 18123-82-5 | C9H9FO2 | 详情 | 详情 |
| (IV) | 32985 | (2R)-3-(4-fluorophenoxy)-1,2-propanediol | C9H11FO3 | 详情 | 详情 | |
| (V) | 32986 | 4-fluorophenyl (2S)oxiranylmethyl ether; (2S)-2-[(4-fluorophenoxy)methyl]oxirane | 108648-25-5 | C9H9FO2 | 详情 | 详情 |
| (VI) | 32987 | (2S)-3-(4-fluorophenoxy)-2-hydroxypropyl 4-methylbenzenesulfonate | C16H17FO5S | 详情 | 详情 | |
| (VII) | 22150 | 2-[(4-fluorophenoxy)methyl]oxirane; 4-fluorophenyl 2-oxiranylmethyl ether | 18123-82-5 | C9H9FO2 | 详情 | 详情 |
| (VIII) | 10386 | Allyl(bromo)magnesium | 1730-25-2 | C3H5BrMg | 详情 | 详情 |
| (IX) | 32988 | (2R)-1-(4-fluorophenoxy)-5-hexen-2-ol | C12H15FO2 | 详情 | 详情 | |
| (X) | 32989 | (1R)-1-[(4-fluorophenoxy)methyl]-4-pentenyl benzenesulfonate | C18H19FO4S | 详情 | 详情 | |
| (XI) | 32990 | (1R)-1-[(4-fluorophenoxy)methyl]-4-oxobutyl benzenesulfonate | C17H17FO5S | 详情 | 详情 | |
| (XII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XIII) | 32991 | ethyl (E,6R)-7-(4-fluorophenoxy)-6-[(phenylsulfonyl)oxy]-2-heptenoate | C21H23FO6S | 详情 | 详情 | |
| (XIV) | 32992 | (1R,4E)-1-[(4-fluorophenoxy)methyl]-6-hydroxy-4-hexenyl benzenesulfonate | C19H21FO5S | 详情 | 详情 | |
| (XV) | 32993 | (1R)-1-[(4-fluorophenoxy)methyl]-3-[(2R,3S)-3-(hydroxymethyl)oxiranyl]propyl benzenesulfonate | C19H21FO6S | 详情 | 详情 | |
| (XVI) | 32994 | (1R)-3-[(2R,3R)-3-(chloromethyl)oxiranyl]-1-[(4-fluorophenoxy)methyl]propyl benzenesulfonate | C19H20ClFO5S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XLII)Treatment of allofuranose derivative (XXXIX) with Bu2SnO in toluene followed by treatment with benzyl bromide and CsF provides (XL), which is then oxidized with Jones reagent to afford ketone (XLI). Wittig reaction of (XLI) with (ethoxycarbonymethylene)triphenylphosphorane (XLII) in toluene yields olefin (XLIII), which is then reduced by means of DIBAL to give (XLIV). Alcohol (XLIV) is then converted into trichloroacetimidate (XLV) by treatment with NaH and trichloroacetonitrile (CCl3CN) in Et2O. Rearrangement of (XLV) by heating with toluene affords derivative (XLVI), which is hydrolyzed by means of TFA/H2O to yield a mixture of diols that are chromatographically separated, providing (XLVII). Oxidation of (XLVII) in MeOH by means of NaIO4 provides hemiaminal derivative (XLVIII), which is further oxidized with Jones reagent to afford lactam (IL). Removal of protecting (N-trichloroacetyl and O-formyl) groups by treatment of (IL) with NaBH4 in MeOH gives partially deprotected derivative (L).
| 【1】 Chida, N.; et al.; Stereoselective total synthesis of (+)-lactacystin from D-glucose. Tetrahedron 1997, 53, 48, 16287. |
| 【2】 Corey, E.J.; Li, W.-D.Z.; Total synthesis and biological activity of lactacystin, omuralide and analogs. Chem Pharm Bull 1999, 47, 1, 1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLIIIa) | 43623 | ethyl (E)-3-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenoate | C21H28O6 | 详情 | 详情 | |
| (XLIIIb) | 43624 | ethyl (Z)-3-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenoate | C21H28O6 | 详情 | 详情 | |
| (XLIVa) | 43625 | (Z)-3-[(3aR,5S,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-buten-1-ol | C19H26O5 | 详情 | 详情 | |
| (XLIVb) | 43626 | (E)-3-[(3aR,5S,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-buten-1-ol | C19H26O5 | 详情 | 详情 | |
| (XLVa) | 43627 | (Z)-3-[(3aR,5S,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenyl 2,2,2-trichloroethanimidoate | C21H26Cl3NO5 | 详情 | 详情 | |
| (XLVb) | 43628 | (E)-3-[(3aR,5S,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenyl 2,2,2-trichloroethanimidoate | C21H26Cl3NO5 | 详情 | 详情 | |
| (XLVIa) | 43629 | N-[(1R)-1-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1-[(benzyloxy)methyl]-2-propenyl]-2,2,2-trichloroacetamide | C21H26Cl3NO5 | 详情 | 详情 | |
| (XLVIb) | 43630 | N-[(1S)-1-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1-[(benzyloxy)methyl]-2-propenyl]-2,2,2-trichloroacetamide | C21H26Cl3NO5 | 详情 | 详情 | |
| (XLVIIIa) | 43632 | (2R,3S,4R,5R)-2-[(benzyloxy)methyl]-5-hydroxy-4-methyl-1-(2,2,2-trichloroacetyl)-2-vinylpyrrolidinyl formate | C18H20Cl3NO5 | 详情 | 详情 | |
| (XLVIIIb) | 43633 | (2R,3S,4R,5S)-2-[(benzyloxy)methyl]-5-hydroxy-4-methyl-1-(2,2,2-trichloroacetyl)-2-vinylpyrrolidinyl formate | C18H20Cl3NO5 | 详情 | 详情 | |
| (IL) | 43634 | (2R,3S,4R)-2-[(benzyloxy)methyl]-4-methyl-5-oxo-1-(2,2,2-trichloroacetyl)-2-vinylpyrrolidinyl formate | C18H18Cl3NO5 | 详情 | 详情 | |
| (XXXIX) | 43620 | (1R)-1-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1,2-ethanediol | C10H18O5 | 详情 | 详情 | |
| (XL) | 43621 | (1R)-1-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-(benzyloxy)-1-ethanol | C17H24O5 | 详情 | 详情 | |
| (XLI) | 43622 | 1-[(3aR,6R,6aR)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-(benzyloxy)-1-ethanone | C17H22O5 | 详情 | 详情 | |
| (XLII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XLVII) | 43631 | N-[(1R)-1-[(benzyloxy)methyl]-1-[(3S,4R,5S)-4,5-dihydroxy-3-methyltetrahydro-2-furanyl]-2-propenyl]-2,2,2-trichloroacetamide | C18H22Cl3NO5 | 详情 | 详情 | |
| (L) | 43635 | (3R,4S,5R)-5-[(benzyloxy)methyl]-4-hydroxy-3-methyl-5-vinyl-2-pyrrolidinone | C15H19NO3 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)The condensation of the formyl pyrrolidine (I) with ethyl (triphenylphosphoranylidene)acetate (II) in dichloromethane gives acrylate (III), which is reduced with DIBAL in THF to yield the substituted allyl alcohol (IV). The condensation of (IV) with phthalimide (V) by means of PPh3 and DEAD in THF affords the adduct (VI), which is treated with hydrazine ethanol to provide the amino derivative (VII). The reaction of (VII) with Ms-Cl and TEA in dichloromethane gives the sulfonamide (VIII), which is desilylated by means of TBAF in THF, yielding the pyrrolidinol (IX). The reaction of (IX) with Ms-Cl and TEA in dichloromethane affords the sulfonate (X), which is treated with potassium thioacetate in refluxing acetonitrile to provide the acetylsulfanylpyrrolidine (XI). The hydrolysis of (XI) with NaOH in methanol gives the thiol (XII), which is condensed with the carbapenem derivative (XIII) by means of DIEA in acetonitrile to yield the protected adduct (XIV). Finally, this compound is treated with PdCl2(PPh3)2 and Bu3SnH in dichloromethane in order to eliminate the allyl protecting groups.
| 【1】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 . |
| 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) | 50600 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C15H27NO4Si | 详情 | 详情 | |
| (II) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (III) | 50601 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-pyrrolidinecarboxylate | C19H33NO5Si | 详情 | 详情 | |
| (IV) | 50602 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-hydroxy-1-propenyl]-1-pyrrolidinecarboxylate | C17H31NO4Si | 详情 | 详情 | |
| (V) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (VI) | 50603 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-1-pyrrolidinecarboxylate | C25H34N2O5Si | 详情 | 详情 | |
| (VII) | 50604 | allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate | C17H32N2O3Si | 详情 | 详情 | |
| (VIII) | 50605 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C18H34N2O5SSi | 详情 | 详情 | |
| (IX) | 50606 | allyl (2S,4R)-4-hydroxy-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C12H20N2O5S | 详情 | 详情 | |
| (X) | 50598 | allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H22N2O7S2 | 详情 | 详情 | |
| (XI) | 49451 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C14H22N2O5S2 | 详情 | 详情 | |
| (XII) | 49452 | allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C12H20N2O4S2 | 详情 | 详情 | |
| (XIII) | 32617 | allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H26NO8P | 详情 | 详情 | |
| (XIV) | 49454 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C25H35N3O8S2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IV)Treatment of 1,2,4-butanetriol (I) with acetone and p-toluenesulfonic acid gave the isopropylidene ketal (II). Subsequent Swern oxidation of the unprotected alcohol group of (II) produced aldehyde (III), which was condensed with phosphorane (IV) to afford unsaturated ester (V). Ketal hydrolysis of (V) gave ethyl 5,6-dihydroxy-2-hexenoate (VI), which was cyclized by means of iodine and NaHCO3 to produce the (tetrahydrofuranyl)-2-iodoacetate (VII). Further oxidation of the hydroxyl group of (VII) by means of Jones reagent yielded iodoketone (VIII). This was cyclized in the presence of DBU to generate the bicyclic compound (IX). The Bucherer-Bergs reac-tion of (IX) with potassium cyanide and ammonium carbonate produced the spiro hydantoin (X). Resolution of (X) was then achieved by ethyl ester hydrolysis, followed by recrystallization of the corresponding diastereomeric salt with (R)-2-phenylglycinol. Basic hydrolysis of the hydantoin ring of the required isomer (XII) then yielded the title compound.
| 【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. US 5688826 . |
| 【2】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. EP 0774461; JP 2000500748; WO 9718199 . |
| 【3】 Levine, L.R. (Eli Lilly and Company); Treatment for premenstrual dysphoric disorder. WO 9832436 . |
| 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) | 30088 | 1,2,4-butanetriol | 3068-00-6 | C4H10O3 | 详情 | 详情 |
| (II) | 30089 | 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-1-ethanol | C7H14O3 | 详情 | 详情 | |
| (III) | 30090 | 2-(2,2-dimethyl-1,3-dioxolan-4-yl)acetaldehyde | C7H12O3 | 详情 | 详情 | |
| (IV) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (V) | 30091 | ethyl (E)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-butenoate | C11H18O4 | 详情 | 详情 | |
| (VI) | 30092 | ethyl (E)-5,6-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (VII) | 30093 | ethyl 2-(4-hydroxytetrahydro-2-furanyl)-2-iodoacetate | C8H13IO4 | 详情 | 详情 | |
| (VIII) | 30094 | ethyl 2-iodo-2-(4-oxotetrahydro-2-furanyl)acetate | C8H11IO4 | 详情 | 详情 | |
| (IX) | 30095 | ethyl 4-oxo-2-oxabicyclo[3.1.0]hexane-6-carboxylate | C8H10O4 | 详情 | 详情 | |
| (X) | 30096 | 2,5-Dioxospiro[oxazolidine-4,4'-[2]oxaabicyclo[3,1,0]hexane]-6'-carboxylic acid ethyl ester | C10H11NO6 | 详情 | 详情 | |
| (XII) | 30097 | (1'R,4S,5'S,6'S)-2,5-Dioxospiro[imidazolidine-4,4'-[2]oxabicyclo[3,1,0]hexane]-6'-carboxylic acid | C8H8N2O5 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(IV)In a related procedure, the chiral triol (XIII) was protected as the ketal (XIV), and then oxidized to aldehyde (XV). Subsequent Wittig condensation of (XV) with phosphorane (IV) afforded unsaturated ester (XVI). After ketal hydrolysis of (XVI), cyclization by means of I2 and NaHCO3 yielded cyclic ether (XVIII). Oxidation of (XVIII) to ketone (XIX) and cyclization in the presence of DBU produced bicyclic compound (XX). This was converted to the chiral spiro hydantoin (XXI) with KCN and (NH4)2CO3 and finally hydrolyzed with NaOH to give the corresponding dicarboxylic acid.
| 【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid derivs.. US 5688826 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XIII) | 30098 | (2S)-1,2,4-butanetriol; (S)-1,2,4-butanetriol | 42890-76-6 | C4H10O3 | 详情 | 详情 |
| (XIV) | 30099 | 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol | C7H14O3 | 详情 | 详情 | |
| (XV) | 30100 | 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]acetaldehyde | C7H12O3 | 详情 | 详情 | |
| (XVI) | 30101 | ethyl (E)-4-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-butenoate | C11H18O4 | 详情 | 详情 | |
| (XVII) | 30102 | ethyl (E,5S)-5,6-dihydroxy-2-hexenoate | C8H14O4 | 详情 | 详情 | |
| (XVIII) | 30103 | ethyl (2S)-2-[(2R,4S)-4-hydroxytetrahydro-2-furanyl]-2-iodoethanoate | C8H13IO4 | 详情 | 详情 | |
| (XIX) | 30104 | ethyl (2S)-2-iodo-2-[(2R)-4-oxotetrahydro-2-furanyl]ethanoate | C8H11IO4 | 详情 | 详情 | |
| (XX) | 30105 | ethyl (1R,5R)-4-oxo-2-oxabicyclo[3.1.0]hexane-6-carboxylate | C8H10O4 | 详情 | 详情 | |
| (XXI) | 30106 | (1'R,4S,5'S,6'S)-2,5-Dioxospiro[imidazolidine-4,4'-[2]oxabicyclo[3,1,0]hexane]-6'-carboxylic acid ethyl ester | C10H12N2O5 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(XX)The chiral unsaturated aldehyde intermediate (XXV) has been obtained as follows. The reaction of the chiral lactone (XVII) first with N,O-dimethylhydroxylamine and then with PmbO-(C=NH)CCl3 gives the Weinreb amide (XVIII), which is reduced with Bu2AlH to yield the butyraldehyde (XIX). The condensation of (XIX) with phosphorane (XX) affords the unsaturated ester (XXI), which is reduced with Bu2AlH to provide the unsaturated alcohol (XXII). The reaction of (XXII) with TrCl and lutidine gives the trityl ether (XXIII), which is desilylated by means of TBAF to yield the primary alcohol (XXIV). Finally, this compound is oxidized with DMP to afford the desired unsaturated aldehyde intermediate (XXV).
| 【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63307 | 1,1,1-trichloro-3-(4-methoxyphenyl)-2-propanimine | C10H10Cl3NO | 详情 | 详情 | ||
| (XVII) | 63880 | 4-{[tert-butyl(diphenyl)silyl]oxy}-2-oxetanone | C19H22O3Si | 详情 | 详情 | |
| (XVIII) | 63881 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-3-[(4-methoxybenzyl)oxy]-N-methylbutanamide | C30H39NO5Si | 详情 | 详情 | |
| (XIX) | 63882 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-[(4-methoxybenzyl)oxy]butanal | C28H34O4Si | 详情 | 详情 | |
| (XX) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXI) | 63884 | ethyl (E,5S)-6-{[tert-butyl(diphenyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexenoate | C32H40O5Si | 详情 | 详情 | |
| (XXII) | 63885 | (E,5S)-6-{[tert-butyl(diphenyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2-hexen-1-ol | C30H38O4Si | 详情 | 详情 | |
| (XXIII) | 63883 | tert-butyl(diphenyl)silyl (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenyl]oxy}diphenylsilane | C49H52O4Si | 详情 | 详情 | |
| (XXIV) | 63886 | (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexen-1-ol | C33H34O4 | 详情 | 详情 | |
| (XXV) | 63887 | (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal | C33H32O4 | 详情 | 详情 |
合成路线15
该中间体在本合成路线中的序号：Ethyl 6-azaindole-3-carboxylate (I) was formylated using dichloromethyl methyl ether and AlCl3 to provide aldehyde (II). Nitrogen protection in (II) with benzenesulfonyl chloride and NaH gave sulfonyl derivative (III). Subsequent Wittig condensation of (III) with (ethoxycarbonylmethylene)triphenyl phosphorane produced the unsaturated ester (IV). Finally, removal of the benzenesulfonyl protecting group of (IV) was effected by treatment with ethanolic NaOEt.
| 【1】 Le Hyaric, M.; Doisy, X.; Dekhane, M.; et al.; Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of omega1 selective ligands. Bioorg Med Chem 1999, 7, 5, 921. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 | |
| 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 | |
| 40668 | dichloro(methoxy)methane; dichloromethyl methyl ether | 4885-02-3 | C2H4Cl2O | 详情 | 详情 | |
| (I) | 26182 | ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C10H10N2O2 | 详情 | 详情 | |
| (II) | 26183 | ethyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C11H10N2O3 | 详情 | 详情 | |
| (III) | 26184 | ethyl 3-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C17H14N2O5S | 详情 | 详情 | |
| (IV) | 26185 | ethyl 3-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C21H20N2O6S | 详情 | 详情 |
合成路线16
该中间体在本合成路线中的序号：(III)Vilsmeier formylation of orcinol (I) by means of POCl3 and DMF afforded 2,4-dihydroxy-6-methylbenzaldehyde (II). Coumarin (V) was then prepared by Wittig condensation of (II) with carbethoxymethylene triphenylphosphorane (III) followed by intramolecular cyclization in refluxing xylene. Alkylation of (V) with 3-chloro-3-methyl-1-butyne (VI) in the presence of K2CO3 and KI produced the corresponding alpha,alpha-dimethylpropargyl ether (VII), and subsequent thermal cyclization in refluxing N,N-diethylaniline gave rise to the tricyclic system (VIII). Osmium-catalyzed asymmetric dihydroxylation of (VIII) in the presence of the enantioselective ligand hydroquinone 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQ)2-PYR] produced the required (R,R)-(+)-cis-diol (IX). This was finally acylated with (S)-(-)-camphanic chloride (X) in the presence of pyridine to produce the target dicamphanoyl ester.
| 【1】 Takeuchi, Y.; Xie, L.; Lee, K.-H.; Cosentino, L.M.; Anti-AIDS agents. 37.(1) synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents. J Med Chem 1999, 42, 14, 2662. |
| 【2】 Xie, L.; Takeuchi, Y.; Cosentino, L.M.; Lee, K.-H.; Anti-AIDS agent 33. Synthesis and anti-HIV activity of mono-methyl substituted 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) analogues. Bioorg Med Chem Lett 1998, 8, 16, 2151. |
| 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) | 27257 | 5-Methyl-1,3-benzenediol; Orcinol | 505-15-4 | C7H8O2 | 详情 | 详情 |
| (II) | 34435 | 2,4-dihydroxy-6-methylbenzaldehyde | C8H8O3 | 详情 | 详情 | |
| (III) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IV) | 34436 | ethyl (E)-3-(2,4-dihydroxy-6-methylphenyl)-2-propenoate | C12H14O4 | 详情 | 详情 | |
| (V) | 34437 | 7-hydroxy-5-methyl-2H-chromen-2-one | C10H8O3 | 详情 | 详情 | |
| (VI) | 22416 | 3-chloro-3-methyl-1-butyne | 1111-97-3 | C5H7Cl | 详情 | 详情 |
| (VII) | 34438 | 7-[(1,1-dimethyl-2-propynyl)oxy]-5-methyl-2H-chromen-2-one | C15H14O3 | 详情 | 详情 | |
| (VIII) | 34439 | 5,8,8-trimethyl-2H,8H-pyrano[2,3-f]chromen-2-one | C15H14O3 | 详情 | 详情 | |
| (IX) | 34440 | (9R,10R)-9,10-dihydroxy-5,8,8-trimethyl-9,10-dihydro-2H,8H-pyrano[2,3-f]chromen-2-one | C15H16O5 | 详情 | 详情 | |
| (X) | 16583 | (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride; (-)-Camphanic chloride | 39637-74-6 | C10H13ClO3 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(V)Treatment of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (I) with ammonium hydroxide provided the aminopyrimidine (II). After reduction of the ethyl ester (II) to alcohol (III) with LiAlH4, oxidation with MnO2 in chloroform yielded aldehyde (IV). Wittig condensation of (IV) with phosphorane (V) afforded the unsaturated ester (VI), which was cyclized to the pyridopyrimidinone (VII) upon treatment with DBU in diisopropylethylamine. Then, alkylation of (VII) with 2-iodopropane in the presence of NaH in DMF gave rise to the 8-isopropyl pyridopyrimidinone (VIII). Subsequent oxidation of the sulfide group of (VIII) to sulfoxide (X) was carried out employing trans-2-(phenylsulfonyl)-3-phenyloxaziridine (IX). Finally, displacement of the methylsulfinyl group of (X) with 4-(4-methylpiperazin-1-yl)aniline (XI) at 175 C yielded the title compound.
| 【1】 Dobrusin, E.M.; Fattacy, A.; Boschelli, D.H.; Fry, D.W.; Wu, Z.; Doherty, A.M.; Kallmeyer, S.T.; Barvian, M.R. (Pfizer Inc.); Pyrido[2,3-d]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation. WO 9833798 . |
| 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) | 18198 | ethyl 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarboxylate; ETHYL 4-CHLORO-2-METHYLTHIO-5-PYRIMIDINECARBOXYLATE | 5909-24-0 | C8H9ClN2O2S | 详情 | 详情 |
| (II) | 31828 | ethyl 4-amino-2-(methylsulfanyl)-5-pyrimidinecarboxylate | C8H11N3O2S | 详情 | 详情 | |
| (III) | 31829 | [4-amino-2-(methylsulfanyl)-5-pyrimidinyl]methanol | C6H9N3OS | 详情 | 详情 | |
| (IV) | 31830 | 4-amino-2-(methylsulfanyl)-5-pyrimidinecarbaldehyde | C6H7N3OS | 详情 | 详情 | |
| (V) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (VI) | 31831 | ethyl (E)-3-[4-amino-2-(methylsulfanyl)-5-pyrimidinyl]-2-propenoate | C10H13N3O2S | 详情 | 详情 | |
| (VII) | 31832 | 2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C8H7N3OS | 详情 | 详情 | |
| (VIII) | 31833 | 8-isopropyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C11H13N3OS | 详情 | 详情 | |
| (IX) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (X) | 31835 | 8-isopropyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C11H13N3O2S | 详情 | 详情 | |
| (XI) | 31836 | 4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)aniline | C11H17N3 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(III)The reduction of 4,4-dimethyltetrahydropyran-2-one (I) with iBuAlH in THF gives 4,4-dimethyltetrahydropyran-2-ol (II), which is condensed with phosphorane (III) in refluxing acetonitrile to yield the heptenoic ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is reduced at the double bond with H2 over Pd/C in ethyl acetate to provide the heptanoate ester (VI). The reduction of the ester group of (VI) with iBu2AlH in THF gives the primary alcohol (VII), which is protected with dihydropyran and PPTS, yielding the tetrahydropyranyl ether (VIII). The desilylation of (VIII) with TBAF in THF affords the heptanol derivative (IX), which by oxidation with tetrapropylammonium perruthenate (TPAP) in dichloromethane is converted into the aldehyde (X). The condensation of (X) with CBr4 and PPh3 in dichloromethane provides the dibromovinyl compound (XI), which is condensed with hexafluoroacetone (XII) by means of BuLi in THF to give the acetylenic alcohol (XIII). The deprotection of (XIII) with pyridinium p-toluenesulfonate (PPTS) in methanol yields the acetylenic diol (XIV), which is selectively reduced with H2 over Pd/C in ethyl acetate to afford the (Z)-ethylenic diol (XV). The oxidation of the primary alcohol of (XV) with pyridinium dichromate in dichloromethane provides the aldehyde (XVI), which is silylated with Tms-Cl, TEA and DMAP in dichloromethane to give the silylated unsaturated aldehyde (XVII).
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 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) | 49051 | 4,4-dimethyltetrahydro-2H-pyran-2-one | C7H12O2 | 详情 | 详情 | |
| (II) | 49052 | 4,4-dimethyltetrahydro-2H-pyran-2-ol | C7H14O2 | 详情 | 详情 | |
| (III) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IV) | 49053 | ethyl (E)-7-hydroxy-5,5-dimethyl-2-heptenoate | C11H20O3 | 详情 | 详情 | |
| (V) | 49054 | ethyl (E)-7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-2-heptenoate | C17H34O3Si | 详情 | 详情 | |
| (VI) | 49055 | ethyl 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethylheptanoate | C17H36O3Si | 详情 | 详情 | |
| (VII) | 49056 | 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-1-heptanol | C15H34O2Si | 详情 | 详情 | |
| (VIII) | 49057 | tert-butyl(dimethyl)silyl 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl ether; tert-butyl[[3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl]oxy]dimethylsilane | C20H42O3Si | 详情 | 详情 | |
| (IX) | 49058 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1-heptanol | C14H28O3 | 详情 | 详情 | |
| (X) | 49059 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptanal | C14H26O3 | 详情 | 详情 | |
| (XI) | 49060 | 8,8-dibromo-5,5-dimethyl-7-octenyl tetrahydro-2H-pyran-2-yl ether; 2-[(8,8-dibromo-5,5-dimethyl-7-octenyl)oxy]tetrahydro-2H-pyran | C15H26Br2O2 | 详情 | 详情 | |
| (XII) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XIII) | 49061 | 1,1,1-trifluoro-6,6-dimethyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-(trifluoromethyl)-3-decyn-2-ol | C18H26F6O3 | 详情 | 详情 | |
| (XIV) | 49062 | 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol | C13H18F6O2 | 详情 | 详情 | |
| (XV) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (XVI) | 49037 | (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-(trifluoromethyl)-7-decenal | C13H18F6O2 | 详情 | 详情 | |
| (XVII) | 49063 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-9-[(trimethylsilyl)oxy]-7-decenal | C16H26F6O2Si | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(IV)Hydrogenation of 6-nitrocoumarin (I) in the presence of Pd/C and di-tert-butyl dicarbonate provided (II). Partial reduction of the lactone function of (II) with DIBAL at low temperature gave rise to lactol (III), which was submitted to a Wittig condensation with (ethoxycarbonyl)triphenylphosphorane (IV) yielding chromaneacetic acid ethyl ester (V). The Boc protecting group of (V) was then removed with trifluoroacetic acid to afford aniline (VI), which was acylated with 4-cyanobenzoic acid (VII) in the presence of EDC to give amide (VIII). Addition of H2S to the nitrile group of (VIII), followed by S-methylation provided (IX). Then, displacement of the methylthio group of (IX) by ammonium acetate and further treatment with di-tert-butyl dicarbonate yielded the Boc-protected benzamidine (X). Finally, Boc-deprotection with trifluoroacetic acid furnished the title amidino ester.
| 【1】 Fisher, M.J.; Arfstan, A.E.; Giese, U.; et al.; Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa. J Med Chem 1999, 42, 23, 4875. |
| 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) | 36892 | 6-nitro-2H-chromen-2-one | 2725-81-7 | C9H5NO4 | 详情 | 详情 |
| (II) | 36893 | tert-butyl 2-oxo-3,4-dihydro-2H-chromen-6-ylcarbamate | C14H17NO4 | 详情 | 详情 | |
| (III) | 36894 | tert-butyl 2-hydroxy-3,4-dihydro-2H-chromen-6-ylcarbamate | C14H19NO4 | 详情 | 详情 | |
| (IV) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (V) | 36895 | ethyl 2-[6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-2-yl]acetate | C18H25NO5 | 详情 | 详情 | |
| (VI) | 36896 | ethyl 2-(6-amino-3,4-dihydro-2H-chromen-2-yl)acetate | C13H17NO3 | 详情 | 详情 | |
| (VII) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (VIII) | 36898 | ethyl 2-[6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-2-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (IX) | 36899 | ethyl 2-[6-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-2-yl]acetate | C22H24N2O4S | 详情 | 详情 | |
| (X) | 36900 | ethyl 2-[6-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-2-yl]acetate | C26H31N3O6 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：Oxidative cleavage of 4,6-O-ethylidene glucose (I) with sodium periodate afforded 5-hydroxy-2-methyl-1,3-dioxan-4-carbaldehyde (II), which was reduced to alcohol (III) using sodium borohydride (1). Protection of the primary hydroxyl of (III) with tert-butyldimethylsilyl chloride, followed by Moffatt oxidation of the secondary hydroxyl group provided ketone (V). Subsequent Wittig reaction of (V) with ethyl (triphenylphosphoranylidene)acetate gave a mixture of E,Z unsaturated esters (VIa-b). Catalytic hydrogenation of the double bond of (VIa-b) produced the saturated ester (VIIa-b) as a diastereomeric mixture that was separated by column chromatography. Diisobutylaluminum hydride reduction of the desired ester furnished aldehyde (VIII), which was subjected to a Wittig reaction with the sodium salt of (4-carboxybutyl)triphenylphosphonium bromide (IX) yielding acid (X). Conversion of (X) to the methyl ester (XI) by methylation with iodomethane and K2CO3, followed by desilylation with Bu4NF afforded hydroxy ester (XII). Oxidation of the alcohol group of (XII) with Collins' reagent gave aldehyde (XIII). This was converted to the thiosemicarbazone (XV) upon condensation with phenyl thiosemicarbazide (XIV). Finally, the methyl ester group of (XV) was hydrolyzed, and the carboxylic acid was converted to the corresponding sodium salt.
| 【1】 Setoi, H.; Kuroda, A.; Tanaka, H.; Hirai, H.; Marusawa, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Oxygen-containing heterocyclic cpd., processes for their preparation and pharmaceutical compsns. comprising them. EP 0346511 . |
| 【2】 Kuroda, A.; setoi, H.; Motoyama, Y.; Sawada, A.; Seki, J.; Marusawa, H.; Tanaka, H.; Synthesis and biological activity of 4-methyl-3,5-dioxane derivatives as thromboxane A2 receptor antagonists. Bioorg Med Chem 1999, 7, 11, 2635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 | |
| (VIa) | 37365 | ethyl 2-[(2R,4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ylidene]acetate | C16H30O5Si | 详情 | 详情 | |
| (VIb) | 37366 | ethyl 2-[(2R,4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ylidene]acetate | C16H30O5Si | 详情 | 详情 | |
| (VIIa) | 37367 | ethyl 2-[(2R,4R,5R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetate | C16H32O5Si | 详情 | 详情 | |
| (VIIb) | 37368 | ethyl 2-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetate | C16H32O5Si | 详情 | 详情 | |
| (I) | 37360 | (2R,4aR,7R,8R,8aS)-2-methylhexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triol | 13224-99-2 | C8H14O6 | 详情 | 详情 |
| (II) | 37361 | (2R,4R,5R)-5-hydroxy-2-methyl-1,3-dioxane-4-carbaldehyde | C6H10O4 | 详情 | 详情 | |
| (III) | 37362 | (2R,4S,5R)-4-(hydroxymethyl)-2-methyl-1,3-dioxan-5-ol | C6H12O4 | 详情 | 详情 | |
| (IV) | 37363 | (2R,4S,5R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-ol | C12H26O4Si | 详情 | 详情 | |
| (V) | 37364 | (2R,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-one | C12H24O4Si | 详情 | 详情 | |
| (VIII) | 37369 | 2-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]acetaldehyde | C14H28O4Si | 详情 | 详情 | |
| (IX) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (X) | 37370 | (Z)-7-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoic acid | C19H36O5Si | 详情 | 详情 | |
| (XI) | 37371 | methyl (Z)-7-[(2R,4R,5S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoate | C20H38O5Si | 详情 | 详情 | |
| (XII) | 37372 | methyl (Z)-7-[(2R,4R,5S)-4-(hydroxymethyl)-2-methyl-1,3-dioxan-5-yl]-5-heptenoate | C14H24O5 | 详情 | 详情 | |
| (XIII) | 37373 | methyl (Z)-7-[(2R,4R,5S)-4-formyl-2-methyl-1,3-dioxan-5-yl]-5-heptenoate | C14H22O5 | 详情 | 详情 | |
| (XIV) | 37374 | N-phenyl-1-hydrazinecarbothioamide | 5351-69-9 | C7H9N3S | 详情 | 详情 |
| (XV) | 37375 | methyl (Z)-7-((2R,4R,5S)-4-[[(E)-2-(anilinocarbothioyl)hydrazono]methyl]-2-methyl-1,3-dioxan-5-yl)-5-heptenoate | C21H29N3O4S | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(XXVII)An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.
| 【1】 Rao, A.V.R.; et al.; Enantiospecific synthesis of (R)-(+)-alpha-lipoic acid from D-glucose. Carbohydr Res 1986, 148, 1, 51. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 57956 | (4S)-4,6-bis(benzyloxy)hexanal | C20H24O3 | 详情 | 详情 | |
| (XX) | 57950 | [(2R,3S,6S)-3-(acetyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl acetate | C12H20O6 | 详情 | 详情 | |
| (XXI) | 57951 | (2R,3S,6S)-6-ethoxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol | C8H16O4 | 详情 | 详情 | |
| (XXII) | 57952 | (2R,3S,6S)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-ethoxytetrahydro-2H-pyran; benzyl [(2R,3S,6S)-3-(benzyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl ether | C22H28O4 | 详情 | 详情 | |
| (XXIII) | 57953 | (2R,3S)-1,3-bis(benzyloxy)-5-(1,3-dithian-2-yl)-2-pentanol | C23H30O3S2 | 详情 | 详情 | |
| (XXIV) | 57954 | O-[(1R,2S)-2-(benzyloxy)-1-[(benzyloxy)methyl]-4-(1,3-dithian-2-yl)butyl] S-methyl carbonodithioate | C25H32O3S4 | 详情 | 详情 | |
| (XXV) | 57955 | benzyl (1S)-3-(benzyloxy)-1-[2-(1,3-dithian-2-yl)ethyl]propyl ether; 2-[(3S)-3,5-bis(benzyloxy)pentyl]-1,3-dithiane | C23H30O2S2 | 详情 | 详情 | |
| (XXVII) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XXVIII) | 57957 | ethyl (E,6S)-6,8-bis(benzyloxy)-2-octenoate | C24H30O4 | 详情 | 详情 | |
| (XXIX) | 57958 | ethyl (6S)-6,8-dihydroxyoctanoate | C10H20O4 | 详情 | 详情 | |
| (XXX) | 57959 | ethyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate | C12H24O8S2 | 详情 | 详情 | |
| (XXXI) | 57960 | ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate | C10H18O2S2 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(X)Synthesis of intermediate (XVI): The condensation of 3(S)-(phenyldimethylsilyl)-4(E)-hexenoic acid methyl ester (I) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (II) by means of Tms-OBn, Tms-OTf and BF3/Et2O in dichloromethane gives the 3(E)-heptenoic ester (III), which is ozonolyzed with O3 and pyridine in methanol/dichloromethane to yield the aldehyde (IV). The condensation of (IV) with the silyl ketal (V) by means of TiCl4 in dichloromethane affords the partially protected trihydroxyester (VI), which is silylated with Tbdms-OTf and lutidine in dichloromethane to provide the fully protected ester (VII). Regioselective monodesilylation of (VII) by means of TBAF/AcOH in THF gives the primary alcohol (VIII), which is oxidized with oxalyl chloride to the corresponding aldehyde (IX). The condensation of (IX) with phosphorane (X) in refluxing benzene yields the octenedioic diester (XI), which is methylated with Me2CuLi and Tms-Cl in THF, affording the tetramethyl diester (XII). The two ester groups of (XII) were easily differentiated by a reduction with DIBAL in dichloromethane, providing the 8-hydroxyoctanal derivative (XIII), which was silylated with TBdms-Cl and imidazole in DMF to give the fully protected aldehyde (XIV). Finally, this compound was subjected to a Wittig olefination reaction with methyltriphenylphosphonium bromide (XV) and NaHMDS in THF to yield the desired intermediate (XVI).
| 【1】 Panek, J.S.; Zhu, B.; Total synthesis of apothilone A. Org Lett 2000, 2, 17, 2575. |
| 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) | 44474 | methyl (3S,4E)-3-[dimethyl(phenyl)silyl]-4-hexenoate | C15H22O2Si | 详情 | 详情 | |
| (II) | 44475 | 2-[[tert-butyl(diphenyl)silyl]oxy]acetaldehyde | C18H22O2Si | 详情 | 详情 | |
| (III) | 44476 | methyl (E,5S,6R)-6-(benzyloxy)-7-[[tert-butyl(diphenyl)silyl]oxy]-5-methyl-3-heptenoate | C32H40O4Si | 详情 | 详情 | |
| (IV) | 44477 | (2R,3R)-3-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-2-methylbutanal | C28H34O3Si | 详情 | 详情 | |
| (V) | 44478 | 1-Ethoxy-2-methyl-1-trimethylsiloxypropene;1-Ethoxy-2-methyl-1-(trimethylsilyloxy)propene;1-Ethoxy-2-methyl-1-(trimethylsilyl)oxy-1-propene;1-ethoxy-2-methyl-1-propenyl trimethylsilyl ether; [(1-ethoxy-2-methyl-1-propenyl)oxy](trimethyl)silane ;dimethylketene ethyl trimethylsilyl acetal | 31469-16-6 | C9H20O2Si | 详情 | 详情 |
| (VI) | 44479 | ethyl (3R,4S,5R)-5-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxy-2,2,4-trimethylhexanoate | C34H46O5Si | 详情 | 详情 | |
| (VII) | 44480 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-[[tert-butyl(diphenyl)silyl]oxy]-2,2,4-trimethylhexanoate | C40H60O5Si2 | 详情 | 详情 | |
| (VIII) | 44481 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-hydroxy-2,2,4-trimethylhexanoate | C24H42O5Si | 详情 | 详情 | |
| (IX) | 44482 | ethyl (3R,4R,5R)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4-trimethyl-6-oxohexanoate | C24H40O5Si | 详情 | 详情 | |
| (X) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (XI) | 44483 | diethyl (E,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-5,7,7-trimethyl-2-octenedioate | C28H46O6Si | 详情 | 详情 | |
| (XII) | 44484 | diethyl (3R,4R,5S,6S)-5-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,2,4,6-tetramethyloctanedioate | C29H50O6Si | 详情 | 详情 | |
| (XIII) | 44485 | (3S,4S,5R,6R)-4-(benzyloxy)-6-[[tert-butyl(dimethyl)silyl]oxy]-8-hydroxy-3,5,7,7-tetramethyloctanal | C25H44O4Si | 详情 | 详情 | |
| (XIV) | 44486 | (3S,4S,5R,6R)-4-(benzyloxy)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,5,7,7-tetramethyloctanal | C31H58O4Si2 | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 44487 | (5R)-5-[(1R,2S,3S)-2-(benzyloxy)-1,3-dimethyl-5-hexenyl]-2,2,3,3,6,6,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane; benzyl (1S,2S)-1-((1R,2R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1,3,3-trimethylbutyl)-2-methyl-4-pentenyl ether | C32H60O3Si2 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(II)Ethyl 3-fluorocinnamate (III) was prepared by Wittig condensation of 3-fluorobenzaldehyde (I) with phosphorane (II). Conjugate addition of (R)-N-benzyl-alpha-methylbenzylamine (IV) to the unsaturated ester (III) furnished the chiral amino ester (V). The primary amine (VI) was then obtained by hydrogenolysis of the N-benzyl groups in the presence of palladium hydroxyde. Coupling of the known pyrrolidinoneacetic acid (VII) to the amino ester (VI) by means of EDC/HOBt afforded amide (VIII). Finally, saponification of the ethyl ester group of (VIII) led to the corresponding carboxylic acid.
| 【1】 Brashear, K.M.; Hunt, C.A.; Coleman, P.J.; et al.; Non-peptide alphavbeta3 antagonists. Part 3: Identification of potent RGD mimetics incorporating novel beta-amino acids as aspartic acid replacements. Bioorg Med Chem Lett 2002, 12, 1, 31. |
| 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) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (II) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (III) | 59701 | Ethyl (E)-3-(3-fluorophenyl)-2-propenoate; Ethyl 3-fluorocinnamate | C11H11FO2 | 详情 | 详情 | |
| (IV) | 47881 | (1R)-N-benzyl-1-phenyl-1-ethanamine; N-benzyl-N-[(1R)-1-phenylethyl]amine | C15H17N | 详情 | 详情 | |
| (V) | 59702 | ethyl (3S)-3-{benzyl[(1R)-1-phenylethyl]amino}-3-(3-fluorophenyl)propanoate | C26H28FNO2 | 详情 | 详情 | |
| (VI) | 59703 | ethyl (3S)-3-amino-3-(3-fluorophenyl)propanoate | C11H14FNO2 | 详情 | 详情 | |
| (VII) | 59704 | 2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetic acid | C16H21N3O3 | 详情 | 详情 | |
| (VIII) | 59705 | ethyl (3S)-3-(3-fluorophenyl)-3-[(2-{(3S)-2-oxo-3-[2-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)ethyl]pyrrolidinyl}acetyl)amino]propanoate | C27H33FN4O4 | 详情 | 详情 |
合成路线24
该中间体在本合成路线中的序号：3,5-Diisopropyl-4-hydroxybenzaldehyde (VI) is esterified with acetyl chloride, producing acetate (VII). Subsequent Wittig condensation of aldehyde (VII) with carboethoxymethylene triphenylphosphorane leads to the cinnamyl derivative (VIII), which is further hydrogenated to the arylpropionic ester (IX). After saponification of ester (IX) with LiOH, the resultant carboxylic acid (X) is coupled to amine (V), producing amide (XI). Finally, amide reduction with borane in THF gives rise to the target amine.
| 【1】 Auvin, S.; Auget, M.; Navet, E.; Harnett, J.J.; Viossat, I.; Schulz, J.; Bigg, D.; Chabrier, P.-E.; Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties. Bioorg Med Chem Lett 2003, 13, 2, 209. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 | |
| (V) | 63370 | N-[3-(aminomethyl)phenyl]-2-thiophenecarboximidamide | C12H13N3S | 详情 | 详情 | |
| (VI) | 63371 | 4-hydroxy-3,5-bis(1-methylethyl)benzaldehyde | C13H18O2 | 详情 | 详情 | |
| (VII) | 63372 | 4-formyl-2,6-bis(1-methylethyl)phenyl acetate | C15H20O3 | 详情 | 详情 | |
| (VIII) | 63373 | ethyl 3-[4-(acetyloxy)-3,5-bis(1-methylethyl)phenyl]-2-propenoate | C19H26O4 | 详情 | 详情 | |
| (IX) | 63374 | ethyl 3-[4-(acetyloxy)-3,5-bis(1-methylethyl)phenyl]propanoate | C19H28O4 | 详情 | 详情 | |
| (X) | 63375 | 3-[4-hydroxy-3,5-bis(1-methylethyl)phenyl]propanoic acid | C15H22O3 | 详情 | 详情 | |
| (XI) | 63376 | 3-[4-hydroxy-3,5-bis(1-methylethyl)phenyl]-N-[(3-{[imino(2-thiophenyl)methyl]amino}phenyl)methyl]propanamide | C27H33N3O2S | 详情 | 详情 |