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【结 构 式】 
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【分子编号】19797 【品名】Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 【CA登记号】630-19-3 |
【 分 子 式 】C5H10O 【 分 子 量 】86.1338 【元素组成】C 69.72% H 11.7% O 18.58% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new asymmetric synthesis of orlistat has been described: Reaction of the chiral aminoindanol (I) with octanoyl chloride (II) in pyridine gives the chiral ester (III), which is condensed with cinnamaldehyde (IV) by means of TiCl4, DIEA and Bu2BOTf in dichloromethane yielding, after chromatographic purification, the anti-aldol adduct (V). Hydrolysis of the chiral auxiliary of (V) with lithium hydroperoxide affords the beta-hydroxy acid (VI), which is protected as the 1,3-dioxan-4-one (VIII) by reaction with pivalaldehyde (VII), TMS-OTf and isopropoxytrimethylsilane (TMS-O-i-Pr). Ozonolysis of (VIII) with O3 in dichloromethane yields the aldehyde (IX), which is condensed with 1-nitrododecane (X) by means of TBAF in DMF to provide the nitroaldol (XI). The dehydration of (XI) with DCC and CuCl in hot acetonitrile gives the nitroalkene (XII), which is reduced with Zn/HOAc to oxime (XIII). Oxidative hydrolysis of (XIII) with ceric ammonium nitrate (CAN) and HNO3 yields diketone (XIV), which is hydrolyzed with HCl in THF providing the beta-hydroxy acid (XV). Esterification of (XV) with benzyl iodide and CsCO3 gives the benzyl ester (XVI), which is estereoselectively reduced with Me4NB(OAc)3H in HOAc/acetonitrile yielding the chiral anti-1,3-diol (XVII). The selective protection of (XVII) with TIPS-OTf and 2,6-lutidine affords the monosilylated ester (XVIII), which is treated with H2 over Pd(OH)2 in ethyl acetate/methanol to furnish the free beta-hydroxy acid (XIX). Cyclization of acid (XIX) by means of PhSO2Cl in pyridine affords the beta-lactone (XX), which is desilylated with TBAF and HOAc in THF giving lactone (XXI). Finally, lactone (XXI) is esterified under Mitsunobu conditions with N-formyl-L-leucine (XXII) by means of DIAD and PPh3 in THF.
| 【1】 Ghosh, A.K.; Fidanze, S.; Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-based strategy. Org Lett 2000, 2, 16, 2405. |
| 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) | 41710 | N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-4-methylbenzenesulfonamide | C16H17NO3S | 详情 | 详情 | |
| (II) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (III) | 41711 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl octanoate | C24H31NO4S | 详情 | 详情 | |
| (IV) | 41712 | (E)-3-phenyl-2-propenal | 14371-10-9 | C9H8O | 详情 | 详情 |
| (V) | 41713 | (1S,2R)-1-[[(4-methylphenyl)sulfonyl]amino]-2,3-dihydro-1H-inden-2-yl (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoate | C33H39NO5S | 详情 | 详情 | |
| (VI) | 41714 | (2S,3S,4E)-2-hexyl-3-hydroxy-5-phenyl-4-pentenoic acid | C17H24O3 | 详情 | 详情 | |
| (VII) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VIII) | 41715 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-phenylethenyl]-1,3-dioxan-4-one | C22H32O3 | 详情 | 详情 | |
| (IX) | 41716 | (2S,4R,5S)-2-(tert-butyl)-5-hexyl-6-oxo-1,3-dioxane-4-carbaldehyde | C15H26O4 | 详情 | 详情 | |
| (X) | 41717 | 1-nitroundecane | C11H23NO2 | 详情 | 详情 | |
| (XI) | 41718 | (2S,5S,6R)-2-(tert-butyl)-5-hexyl-6-(1-hydroxy-2-nitrododecyl)-1,3-dioxan-4-one | C26H49NO6 | 详情 | 详情 | |
| (XII) | 41719 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[(E)-2-nitro-1-dodecenyl]-1,3-dioxan-4-one | C26H47NO5 | 详情 | 详情 | |
| (XIII) | 41720 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-[2-(hydroxyimino)dodecyl]-1,3-dioxan-4-one | C26H49NO4 | 详情 | 详情 | |
| (XIV) | 41721 | (2S,5S,6S)-2-(tert-butyl)-5-hexyl-6-(2-oxododecyl)-1,3-dioxan-4-one | C26H48O4 | 详情 | 详情 | |
| (XV) | 41722 | (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoic acid | C21H40O4 | 详情 | 详情 | |
| (XVI) | 41723 | benzyl (2S,3S)-2-hexyl-3-hydroxy-5-oxopentadecanoate | C28H46O4 | 详情 | 详情 | |
| (XVII) | 41724 | benzyl (2S,3S,5R)-2-hexyl-3,5-dihydroxypentadecanoate | C28H48O4 | 详情 | 详情 | |
| (XVIII) | 41725 | benzyl (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoate | C37H68O4Si | 详情 | 详情 | |
| (XIX) | 41726 | (2S,3S,5R)-2-hexyl-3-hydroxy-5-[(triisopropylsilyl)oxy]pentadecanoic acid | C30H62O4Si | 详情 | 详情 | |
| (XX) | 41727 | (3S,4S)-3-hexyl-4-[(2R)-2-[(triisopropylsilyl)oxy]dodecyl]-2-oxetanone | C30H60O3Si | 详情 | 详情 | |
| (XXI) | 41728 | (3S,4S)-3-hexyl-4-[(2R)-2-hydroxydodecyl]-2-oxetanone | C21H40O3 | 详情 | 详情 | |
| (XXII) | 11081 | N-Formyl-L-leucine; (2S)-2-(Formylamino)-4-methylpentanoic acid | 6113-61-7 | C7H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)This compound has been obtained by three related ways: 1) The condensation of (R)-tryptophan (I) with 2,2-dimethylpropanal (II) by means of NaOH in refluxing methanol yields the corresponding inmine (III), which is cyclized with ethyl chloroformate (IV) in dichloromethane to afford the oxazolidine (V). the regioselective methylation of (V) with methyl iodide and lithium diisopropylamide (LDA) in THF gives the new methylated oxazolidine (VI), which is finally hydrolyzed with refluxing 6N HCl. 2) Ring opening of oxazolidine (VI) with LiOH in methanol gives (R)-N-(ethoxycarbonyl)-alpha-methyltryptophan methyl ester (VII), which is hydrolyzed with 6N HCl as before. 3) Ring opening of oxazolidine (VI) with LiOH in methanol/water gives (R)-N-(ethoxycarbonyl)-alpha-methyltryptophan (VIII), which is hydrolyzed with 6N HCl as before.
| 【1】 Zhang, L.J.; Finn, J.M.; A facile method for the asymmetric synthesis of alpha-methyltryptophan. J Org Chem 1995, 60, 17, 5719. |
| 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) | 19796 | D-2-Amino-3-(3-indolyl)propionic acid; D-tryptophan | 153-94-6 | C11H12N2O2 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 19798 | 2(R)-(2,2-Dimethylpropylideneamino)-3-(1H-indol-3-yl)proionic acid sodium salt | C16H19N2NaO2 | 详情 | 详情 | |
| (IV) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (V) | 19800 | ethyl (2R,4S)-2-(tert-butyl)-4-(1H-indol-3-ylmethyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C19H24N2O4 | 详情 | 详情 | |
| (VI) | 19801 | ethyl (2R,4R)-2-(tert-butyl)-4-(1H-indol-3-ylmethyl)-4-methyl-5-oxo-1,3-oxazolidine-3-carboxylate | C20H26N2O4 | 详情 | 详情 | |
| (VII) | 19802 | methyl (2R)-2-[(ethoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C16H20N2O4 | 详情 | 详情 | |
| (VIII) | 19802 | methyl (2R)-2-[(ethoxycarbonyl)amino]-3-(1H-indol-3-yl)-2-methylpropanoate | C16H20N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 2(R)-(2,2-dimethyl-5-oxo-1,3-dioxolan-4(S)-yl)-4,4-dimethylpentanoic acid (I) with 2,2-dimethylpropanal (II), ter-butyl isocyanide (III) and ammonia in methanol gives the intermediate (IV), which, without isolation is treated with hydroxylamine to yield the target compound as a mixture of diastereomers.
| 【1】 Flygare, J.; Medina, J.; Shan, B.; Clark, D.; Rosen, T. (Tularik Inc.); Pentafluorobenzenesulfonamides and analogs. EP 0939627; WO 9805315 . |
| 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) | 20478 | (2R)-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid | C11H18O5 | 详情 | 详情 | |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 20480 | tert-butyl(methylidyne)-lambda(5)-azane | C5H11N | 详情 | 详情 | |
| (IV) | 20481 | (2R)-N-[1-[(tert-butylamino)carbonyl]-2,2-dimethylpropyl]-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide | C21H38N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The chiral intermediate (V) can also be obtained as follows: The cyclization of L-proline (VII) with pivalaldehyde (VIII) by means of LDA gives the pyrrolooxazolidinone (IX), which is condensed with the benzaldehyde (X) by means of LDA in THF yielding the alcohol (XI). The reaction of (XI) with I2, PPh3 and imidazole affords the corresponding iodide (XII), which is deiodinated with SmI2 to the intermediate (XIII). The hydrolysis of the oxazolidinone ring of (XIII) with refluxing methanol/water gives the pyrrolidine-carboxylic acid (XIV), which is reduced with BH3 in THF yielding the carbinol (XV). The protection of the NH group of (XV) with Boc2O in THF affords the carbamate (XVI), which is treated with trimethylsilyl bromide in dichloromethane to provide he diol (XVII). The cyclization of (XVII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in ether gives the chiral protected spiro-benzopyran (XVIII), which is finally deprotected with TFA in dichloromethane to afford the desired chiral intermediate (V).
| 【1】 Usse, S.; et al.; Synthesis of a chiral spiranic aminochroan derivative from L-proline. J Org Chem 2000, 65, 3, 914. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 33127 | (R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine] | C13H17NO2 | 详情 | 详情 | |
| (VII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (VIII) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (IX) | 33128 | (3R,7aS)-3-(tert-butyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one | C10H17NO2 | 详情 | 详情 | |
| (X) | 33129 | 2-methoxy-6-(methoxymethoxy)benzaldehyde | C10H12O4 | 详情 | 详情 | |
| (XI) | 33130 | (3R,7aR)-3-(tert-butyl)-7a-[(R)-hydroxy[2-methoxy-6-(methoxymethoxy)phenyl]methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one | C20H29NO6 | 详情 | 详情 | |
| (XII) | 33131 | (3R,7aS)-3-(tert-butyl)-7a-[(R)-iodo[2-methoxy-6-(methoxymethoxy)phenyl]methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one | C20H28INO5 | 详情 | 详情 | |
| (XIII) | 33132 | (3R,7aR)-3-(tert-butyl)-7a-[2-methoxy-6-(methoxymethoxy)benzyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one | C20H29NO5 | 详情 | 详情 | |
| (XIV) | 33133 | (2R)-2-[2-methoxy-6-(methoxymethoxy)benzyl]-2-pyrrolidinecarboxylic acid | C15H21NO5 | 详情 | 详情 | |
| (XV) | 33134 | [(2R)-2-[2-methoxy-6-(methoxymethoxy)benzyl]pyrrolidinyl]methanol | C15H23NO4 | 详情 | 详情 | |
| (XVI) | 33135 | tert-butyl (2R)-2-(hydroxymethyl)-2-[2-methoxy-6-(methoxymethoxy)benzyl]-1-pyrrolidinecarboxylate | C20H31NO6 | 详情 | 详情 | |
| (XVII) | 33136 | tert-butyl (2R)-2-(2-hydroxy-6-methoxybenzyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C18H27NO5 | 详情 | 详情 | |
| (XVIII) | 33137 | (R)-5-Methoxy-3,4-dihydro-2H-spiro[1-benzopyran-3,2'-pyrrolidine]-1'-carboxylic acid tert-buytyl ester | C18H25NO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50ºC in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.
| 【1】 Grover, P.T.; et al.; Chiral mandelic acid template provides a highly practical solution for (S)-oxybutynin synthesis. J Org Chem 2000, 65, 19, 6283. |
| 【2】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 51214 | (2R)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid | C14H18O3 | 详情 | 详情 | |
| (Ib),(IV) | 51215 | (2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid | C14H18O3 | 详情 | 详情 | |
| (II) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (III) | 51216 | n/a | C24H31NO6 | 详情 | 详情 | |
| (V) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (VI) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VII) | 31681 | (2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one | C13H16O3 | 详情 | 详情 | |
| (VIII) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (IX) | 51217 | (2S,5R)-2-(tert-butyl)-5-(1-hydroxycyclohexyl)-5-phenyl-1,3-dioxolan-4-one | C19H26O4 | 详情 | 详情 | |
| (X) | 51218 | (2S,5S)-2-(tert-butyl)-5-(1-cyclohexen-1-yl)-5-phenyl-1,3-dioxolan-4-one | C19H24O3 | 详情 | 详情 | |
| (XI) | 51219 | (2S)-2-(1-cyclohexen-1-yl)-2-hydroxy-2-phenylethanoic acid | C14H16O3 | 详情 | 详情 | |
| (XII) | 51220 | (2S,5S)-2-(tert-butyl)-5-cyclohexyl-5-phenyl-1,3-dioxolan-4-one | C19H26O3 | 详情 | 详情 | |
| (XIII) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (XIV) | 51221 | (2S,5S)-2-(tert-butyl)-5-[(1R)-2-cyclohexen-1-yl]-5-phenyl-1,3-dioxolan-4-one | C19H24O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The cyclization of L-serine (I) with pivalaldehyde (II) by means of LDA in THF gives the oxazolidine (III), which is acylated with formic and acetic anhydride yielding the N-formyloxazolidine (IV). The reaction of (IV) with LDA affords the chiral enol (V), which is treated with allyl bromide in THF to give the chiral 4-allyloxazolidine (VI). Cleavage of the oxazolidine ring with acetyl chloride and treatment with benzyl chloroformate yields the protected chiral 2-allylserine (VII), which is oxidized with oxalyl chloride to the corresponding aldehyde (VIII). The Wittig condensation of (VIII) with triphenylphosphoranylideneacetic acid methyl ester (IX) affords the intermediate (X), which is submitted to UV irradiation with an Hanovia medium pressure mercury lamp through a Pyrex filter in benzene containing benzophenone. A mixture of isomeric bicyclic compounds from which the desired compound (XI) is isolated by column chromatography. The hydrogenation of (IX) with H2 over Pd/C in methanol provides the bicyclic aminoester (XII), which is finally hydrolyzed with 6N HCl.
| 【1】 von Diester, S.; et al.; Stereoselektive Alkylierung an C(alpha) von Serin, Glycerinsaure, Threonin und Weinsaure uber heterocyclische Enolate mit exocyclischer Doppelbindung. Helv Chim Acta 1987, 70, 1194-1216. |
| 【2】 Kozikowski, A.P.; et al.; Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J Med Chem 1998, 41, 10, 1641. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| (I) | 20915 | methyl (2S)-2-amino-3-hydroxypropanoate | 5680-80-8 | C4H9NO3 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 36839 | methyl (4S)-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate | C9H17NO3 | 详情 | 详情 | |
| (IV) | 36840 | methyl (4S)-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate | C10H17NO4 | 详情 | 详情 | |
| (V) | 36841 | lithium [(2R)-2-(tert-butyl)-3-formyl-1,3-oxazolidin-4-ylidene](methoxy)methanolate | C10H16LiNO4 | 详情 | 详情 | |
| (VI) | 36842 | methyl (2R,4S)-4-allyl-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate | C13H21NO4 | 详情 | 详情 | |
| (VII) | 36843 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate | C15H19NO5 | 详情 | 详情 | |
| (VIII) | 36844 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(2-oxoethyl)-4-pentenoate | C16H19NO5 | 详情 | 详情 | |
| (IX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (X) | 36845 | dimethyl (E,4S)-4-allyl-4-[[(benzyloxy)carbonyl]amino]-2-pentenedioate | C18H21NO6 | 详情 | 详情 | |
| (XI) | 36846 | dimethyl (1R,2S,4R,5S)-2-[[(benzyloxy)carbonyl]amino]bicyclo[2.1.1]hexane-2,5-dicarboxylate | C18H21NO6 | 详情 | 详情 | |
| (XII) | 36847 | dimethyl (1R,2S,4R,5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylate | C10H15NO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). Reduction of the ester function of (X) with Ca(BH4)2 gave alcohol (XI), which was finally oxidized under Swern conditions to the target aldehyde.
| 【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 24385 | sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate | C14H18NNaO2 | 详情 | 详情 | |
| (IV) | 24386 | benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C22H25NO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 24388 | benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C25H29NO4 | 详情 | 详情 | |
| (VII) | 24389 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C24H27NO5 | 详情 | 详情 | |
| (VIII) | 24390 | methyl (2S)-2-amino-4-phenylbutanoate | C11H15NO2 | 详情 | 详情 | |
| (IX) | 24391 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C35H42N2O6 | 详情 | 详情 | |
| (X) | 24392 | methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate | C30H32N2O5 | 详情 | 详情 | |
| (XI) | 24393 | benzyl (3R)-3-benzyl-1-[(1S)-1-(hydroxymethyl)-3-phenylpropyl]-2-oxopyrrolidinylcarbamate | C29H32N2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). The carbobenzoxy group of (X) was then removed by hydrogenolysis over Pd/C, and the resulting amine was acylated with benzenesulfonyl chloride to produce sulfonamide (XI). Finally, the target aldehyde was obtained by the sequence of ester reduction of (XI) with Ca(BH4)2, followed by Swern oxidation of the resulting alcohol.
| 【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (III) | 24385 | sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate | C14H18NNaO2 | 详情 | 详情 | |
| (IV) | 24386 | benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C22H25NO4 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 24388 | benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C25H29NO4 | 详情 | 详情 | |
| (VII) | 24389 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate | C24H27NO5 | 详情 | 详情 | |
| (VIII) | 24390 | methyl (2S)-2-amino-4-phenylbutanoate | C11H15NO2 | 详情 | 详情 | |
| (IX) | 24391 | benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C35H42N2O6 | 详情 | 详情 | |
| (X) | 24392 | methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate | C30H32N2O5 | 详情 | 详情 | |
| (XI) | 24394 | methyl (2S)-2-[(3R)-3-benzyl-2-oxo-3-[(phenylsulfonyl)amino]pyrrolidinyl]-4-phenylbutanoate | C28H30N2O5S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)The reaction of N-(tert-butoxycarbonyl)-D-alanine (I) with 3,5-dichloroaniline (II) by means of isobutyl chloroformate and NMM gives the corresponding protected amide (III), which is deprotected with TFA to yield alaninamide (IV). The cyclization of (IV) with pivalaldehyde (V) in hot toluene affords the imidazolidinone (VI), which is acylated with TFAA and TEA in THF to provide the trifluoroacetyl derivative (VII). The alkylation of (VII) with 4-bromobenzyl bromide (VIII) and LHMDS in THF gives the benzyl derivative (IX), which is treated first with benzyl trimethylammonium chloride and NaOH and then with 6N HCl (or t-BuOK in THF/water) to yield the propionamide derivative (X). The cyclization of (X) with methyl chloroformate and TEA in THF affords the imidazolidinedione (XI), which is finally methylated with methyl iodide and LHMDS to provide the target compound.
| 【1】 Frutos, R.P.; et al.; An improved synthesis of N-aryl-hydantoin LFA-1 antagonists via the enantiospecific alkylation of a isobutyraldehyde-derived imidazolidinone template. Tetrahedron Asymmetry 2001, 12, 1, 101. |
| 【2】 Yee, N.K.; Self-regeneration of stereocenters: A practical enantiospecific synthesis of LFA-1 antagonist BIRT-377. Org Lett 2000, 2, 18, 2781. |
| 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) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (II) | 26542 | 3,5-dichloroaniline | 626-43-7 | C6H5Cl2N | 详情 | 详情 |
| (III) | 47927 | tert-butyl (1R)-2-(3,5-dichloroanilino)-1-methyl-2-oxoethylcarbamate | C14H18Cl2N2O3 | 详情 | 详情 | |
| (IV) | 47928 | (2R)-2-amino-N-(3,5-dichlorophenyl)propanamide | C9H10Cl2N2O | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 47929 | (2S,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-4-imidazolidinone | C14H18Cl2N2O | 详情 | 详情 | |
| (VII) | 47930 | (2R,5R)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C16H17Cl2F3N2O2 | 详情 | 详情 | |
| (VIII) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (IX) | 47931 | (2R,5R)-5-(4-bromobenzyl)-2-(tert-butyl)-3-(3,5-dichlorophenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-4-imidazolidinone | C23H22BrCl2F3N2O2 | 详情 | 详情 | |
| (X) | 47932 | (2R)-2-amino-3-(4-bromophenyl)-N-(3,5-dichlorophenyl)-2-methylpropanamide | C16H15BrCl2N2O | 详情 | 详情 | |
| (XI) | 47933 | (5R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-2,4-imidazolidinedione | C17H13BrCl2N2O2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(V)Condensation of 2-fluoro-4-methylpyridine (I) with ethyl 4-fluorobenzoate (II) by means of sodium bis(trimethylsilyl)amide provides the diaryl ethanone (III). Subsequent nitrosation of ketone (III) with tert-butyl nitrite under acidic conditions furnishes oxime (IV). Cyclization of keto oxime (IV) with trimethylacetaldehyde (V) in the presence of ammonium acetate in boiling AcOH proceeds with concomitant hydrolysis of the fluoro group to produce the N-hydroxy imidazole (VI). Reduction of (VI) employing TiCl3 gives imidazole (VII). Finally, the photochemical cyclization of diarylimidazole (VII) leads to the target tetracyclic compound (1, 2).
| 【1】 Thompson, J.E.; Cubbon, R.M.; Cummings, R.T.; Wicker, L.S.; Franksun, R.; Cunningham, B.R.; Cameron, P.M.; Meinke, P.T.; Liverton, N.; Weng, Y.; DeMartino, J.A.; Photochemical preparation of a pyridone containing tetracycle: A jak protein kinase inhibitor. Bioorg Med Chem Lett 2002, 12, 8, 1219. |
| 【2】 Sinclair, P.J.; Goulet, J.L.; Hong, X.; Thompson, J.E.; Cubbon, R.M.; Cummings, R.T. (Merck & Co., Inc.); Benzimidazo[4,5-f]isoquinolinone derivs.. WO 0311285 . |
| 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) | 18296 | 2-Fluoro-4-methylpyridine | 461-87-0 | C6H6FN | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 63664 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1-ethanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 63665 | 1-(4-fluorophenyl)-2-(2-fluoro-4-pyridinyl)-1,2-ethanedione 2-oxime | C13H8F2N2O2 | 详情 | 详情 | |
| (V) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VI) | 63666 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1-hydroxy-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O2 | 详情 | 详情 | |
| (VII) | 63667 | 4-[2-(tert-butyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2(1H)-pyridinone | C18H18FN3O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VI)Reaction of 3,5-dichlorobenzamide (V) with pivalaldehyde (VI) in the presence of benzotriazole (VII) gives rise to the benzotriazolyl benzamide (VIII). This is then condensed with the diamino cyclobutene (IV) to afford the racemic adduct (IX), which is finally resolved into the enantiomers employing chiral chromatography.
| 【1】 Kort, M.E.; Gregg, R.J.; Perez-Medrano, A.; et al.; Aminal-containing ATP-sensitive potassium channel openers for the treatment of bladder overactivity. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 351. |
| 【2】 Basha, F.Z.; Carroll, W.A.; Kort, M.E.; Gregg, R.J.; Dinges, J.; Perez Medrano, A. (Abbott Laboratories Inc.); Aminal diones as potassium channel openers. US 2002165264; US 6495576; WO 0262761 . |
| 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) | 57597 | 3-amino-4-[(2-chloro-3-pyridinyl)amino]-3-cyclobutene-1,2-dione | C9H6ClN3O2 | 详情 | 详情 | |
| (V) | 57598 | 2-Amino-3,5-dichlorobenzoic acid; 3,5-Dichloroanthranilic acid | 5980-23-4 | C7H5Cl2NO | 详情 | 详情 |
| (VI) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VII) | 57599 | 1,2,3-Benzotriazole; 1H-Benzotriazole; Azimidobenzene; Benzotriazol | 95-14-7 | C6H5N3 | 详情 | 详情 |
| (VIII) | 57600 | N-[1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-3,5-dichlorobenzamide | C18H18Cl2N4O | 详情 | 详情 | |
| (IX) | 57601 | 3,5-dichloro-N-[1-({2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-2,2-dimethylpropyl]benzamide | C21H19Cl3N4O3 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VII)1) Condensation of minocycline (I) with N-(hydroxymethyl)phthalimide (II) by means of trifluoromethanesulfonic acid and trifluoromethanesulfonic anhydride gives the 2-N,9-bis(phthalimidomethyl) derivative (III) along with minor amounts of the tris(phthalimidomethyl) compound (IV), which are deprotected with methylamine in EtOH, yielding a mixture of primary amines (V) and (VI). Finally, amines (V)/(VI) are reductively alkylated with pivalaldehyde (VII), with concomitant de-aminomethylation of (VI) in the presence of H2 and Pd/C (1) or NaBH(OAc)3 (2). Scheme 1.
2) Reaction of neopentylamine (VIII) with paraformaldehyde in hot hexane gives the triazine derivative (IX), which upon treatment with chloroacetic anhydride (X) in CH2Cl2 gives the N-(acyloxymethyl)amide (XI). Subsequent Tscherniac–Einhorn reaction of (XI) with minocycline (I) in the presence of trifluoromethanesulfonic acid yields the protected compound (XII), which is submitted to acidic hydrolysis of the chloroacetyl and hydroxymethyl groups in 3 N HCl at 70 °C, followed by reequilibration of the partly epimerized C4 center with NaOH or ethanolamine (3). Scheme 1.
| 【1】 Johnston, S., Warchol, T. (Paratek Pharmaceuticals, Inc.). Methods for synthesizing and purifying aminoalkyl tetracycline compounds. US 2008287401, WO 2008134048. |
| 【2】 Bowser, T., Bhatia, B., Chen, J. et al. PTK0796 and other novel tetracycline derivatives exhibiting potent in vitro and in vivo activities against antibiotic resistant Gram-positive bacteria. 43rd Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 14-17, Chicago) 2003, Abst F-755. |
| 【3】 Chung, J.Y.L., Hartner, F.W., Cvetovich, R.J. Synthesis development of an aminomethylcycline antibiotic via an electronically tuned acyliminium Friedel-Crafts reaction. Tetrahedron Lett 2008, 49(42): 6095-100. |
| 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) | 65813 | Minocycline hydrochloride; [4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxonaphthacene-2-carboxamide monohydrochloride | 13614-98-7 | C23H27N3O7.HCl | 详情 | 详情 |
| (II) | 65814 | N-(Hydroxymethyl)phthalimide; 2-(Hydroxymethyl)-1H-isoindole-1,3(2H)-dione | 118-29-6 | C9H7NO3 | 详情 | 详情 |
| (III) | 65815 | C41H37N5O11 | 详情 | 详情 | ||
| (IV) | 65816 | C50H42N6O13 | 详情 | 详情 | ||
| (V) | 65817 | C24H30N4O7 | 详情 | 详情 | ||
| (VI) | 65818 | C25H33N5O7 | 详情 | 详情 | ||
| (VII) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VIII) | 65819 | Neopentylamine; 2,2-dimethylpropan-1-amine | 5813-64-9 | C5H13N | 详情 | 详情 |
| (IX) | 65820 | Hexahydro-1,3,5-Trineopentyl-1,3,5-Triazine | C18H39N3 | 详情 | 详情 | |
| (X) | 65821 | 2-Chloroacetic anhydride; (Bischloroacetic acid) anhydride; Chloracetic anhydride; Chloroacetic acid anhydride | 541-88-8 | C4H4C12O3 | 详情 | 详情 |
| (XI) | 65822 | C10H17Cl2NO3 | 详情 | 详情 | ||
| (XII) | 65823 | C32H43ClN4O9 | 详情 | 详情 |