|
【结 构 式】 
|
【分子编号】14489 【品名】(2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 【CA登记号】51-35-4 |
【 分 子 式 】C5H9NO3 【 分 子 量 】131.1314 【元素组成】C 45.8% H 6.92% N 10.68% O 36.6% |
合成路线1
该中间体在本合成路线中的序号：(XII)The protection of the NH group of trans-4-hydroxy-L-proline (XII) with tert-butoxycarbonyl anhydride and NaOH in tert-butanol/water gives the N-protected proline (XIII), which is esterified with benzyl alcohol and triethylamine to the benzyl ester (XIV). The tosylation of (XIV) with tosyl chloride and pyridine affords the tosylate (XV), which is debenzylated with H2 over Pd/C yielding the tosylated proline (XVI). The arylation of (XVI) with phenyllithium (XVII) and CuBr in ether/THF affords 1-(tert-butoxycarbonyl)-4(S)-phenyl)-L-proline (XVIII), which is deprotected with TFA in chloroform giving 4(S)-phenyl-L-proline (XIX). Finally, this compound is reduced with H2 over PtO2 in ethanol providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).
| 【1】 Moniot, J.L.; Thottathil, J.K.; Littium diphenylcuprate reactions with 4-tosyloxy-L-prolines; An interesting stereochemical outcome. A synthesis of trans-4-phenyl-L-proline. Tetrahedron Lett 1986, 27, 2, 151. |
| 【2】 Floyd, D.; Thottathil, J.K.; Brandt, S.; Moniot, J.L. (Bristol-Myers Squibb Co.); Method for making substd. prolines. DE 3434121; US 4501901 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 | |
| (XII) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XIII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (XIV) | 38568 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C17H23NO5 | 详情 | 详情 | |
| (XV) | 38569 | 2-benzyl 1-(tert-butyl) (2S,4R)-4-[[(4-methylphenyl)sulfonyl]oxy]-1,2-pyrrolidinedicarboxylate | C24H29NO7S | 详情 | 详情 | |
| (XVI) | 38570 | (2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-methylphenyl)sulfonyl]oxy]-2-pyrrolidinecarboxylic acid | C17H23NO7S | 详情 | 详情 | |
| (XVII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (XVIII) | 38571 | (2S,4S)-1-(tert-butoxycarbonyl)-4-phenyl-2-pyrrolidinecarboxylic acid | C16H21NO4 | 详情 | 详情 | |
| (XIX) | 38572 | (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid | C11H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The mercaptopyrrolidine (XIII) is prepared as follows: trans-4-hydroxy-L-proline (XV) is protected with 4-nitrobenzyl chloride (XVI) giving trans 4-hydroxy-N-(4-nitrobenzyloxycarbonyl)-L-proline (XVII), which is esterified with 4-methoxy benzyl chloride (XVIII) to the corresponding ester (XIX). The reaction of (XIX) with thioacetic acid by means of diethyl azodicarboxylate arid triphenyl-phosphine in THF affords the 4-acetylthio derivative (XX), which is partially hydrolyzed with trifluoroacetic acid and anisole to 4beta-(acetylthio)-N-(4-nitrobenzyloxycarbonyl)pyrrolidine-2beta-carboxylic acid (XXI). The condensation of (XXI) with dimethylamine by means of dicyclohexylcarbodiimide (DCC) gives the fully protected dimethylamide (XXII), which is deacetylated with NaOH in water to atford the desired product (XIII).
| 【1】 Fukasawa, M.; Inoue, T.; Kato, M.; Matsumura, H.; Sunagawa, M. (Sumitomo Pharmaceuticals Co., Ltd.); Thiopyrrolidinyl-beta-lactam derivs.. EP 0126587; ES 8600305; JP 1985001186; JP 1985019787; JP 1991041066; US 4933333; US 4943569; US 5122604 . |
| 【2】 Prous, J.; Castaner, J.; SM-7338. Drugs Fut 1988, 13, 6, 534. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | ||
| (XIII) | 22578 | 4-nitrobenzyl (2S,4S)-2-[(dimethylamino)carbonyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C15H19N3O5S | 详情 | 详情 | |
| (XV) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVI) | 22580 | 1-(chloromethyl)-4-nitrobenzene | 100-14-1 | C7H6ClNO2 | 详情 | 详情 |
| (XVII) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (XVIII) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (XIX) | 22583 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C21H22N2O8 | 详情 | 详情 | |
| (XX) | 22584 | 2-(4-methoxybenzyl) 1-(4-nitrobenzyl) (2S,4S)-4-(acetylsulfanyl)-1,2-pyrrolidinedicarboxylate | C23H24N2O8S | 详情 | 详情 | |
| (XXI) | 18241 | (2S,4S)-4-(acetylsulfanyl)-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C15H16N2O7S | 详情 | 详情 | |
| (XXII) | 22586 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate | C17H21N3O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Darifenacin can be obtained by three related ways: 1) The decarboxylation of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) by heating at 154 C in cyclohexanol/2-cyclohexenone gives 3(R)-hydroxypyrrolidine (II), which is N-tosylated with p-toluenesulfonyl chloride and pyridine yielding (III). The reaction of (III) with methyl p-toluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords 1-tosyl-3(S)-(tosyloxy)pyrrolidine (IV), which is condensed with 2,2-diphenylacetonitrile (V) by means of NaH in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(S)-yl]acetonitrile (VI). Elimination of the tosyl group of (VI) with HBr and phenol in refluxing water yields 2,2-diphenyl-2-[2(S)-pyrrolidinyl]acetonitrile (VII), which by treatment with 95% H2SO4 at 100 C is converted into the corresponding acetamide (VIII). The condensation of (VIII) with 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) by means of potassium carbonate in industrial methylated spirits affords the ketonic amide (X), which is finally reduced with H2 over Pd/C in acetic acid. The intermediate 5-(chloroacetyl)-2,3-dihydrobenzofuran (IX) has been obtained by Friedel-Crafts condensation of 2,3-dihydrobenzofuran (XI) with chloroacetyl chloride by means of AlCl3 in dichloromethane. 3) The condensation of 5-(2-bromoethyl)benzofuran (XV), with the previously obtained acetamide (VIII) by means of K2CO3 in refluxing acetonitrile affords the condensation product (XVI), which is hydrogenated with H2 over Pd/C in hot acetic acid.
| 【1】 Graul, A.; Castaner, J.; Darifenacin. Drugs Fut 1996, 21, 11, 1105. |
| 【2】 Cross, P.E.; Mackenzie, A.R. (Pfizer Inc.); Pyrrolidine derivs. AU 9051402; EP 0388054; JP 1990282360; JP 1995149640; US 5096890 . |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 14490 | (3R)tetrahydro-1H-pyrrol-3-ol; R-3-hydroxypyrrolidine | 2799-21-5 | C4H9NO | 详情 | 详情 |
| (III) | 14491 | (3R)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-ol | C11H15NO3S | 详情 | 详情 | |
| (IV) | 14492 | (3S)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl 4-methylbenzenesulfonate | C18H21NO5S2 | 详情 | 详情 | |
| (V) | 14493 | alpha-phenylbenzeneacetonitrile; 2,2-diphenylacetonitrile; Diphenylacetonitrile | 86-29-3 | C14H11N | 详情 | 详情 |
| (VI) | 14494 | 2-[(3S)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetonitrile | C25H24N2O2S | 详情 | 详情 | |
| (VII) | 14495 | 2,2-diphenyl-2-[(3S)tetrahydro-1H-pyrrol-3-yl]acetonitrile | C18H18N2 | 详情 | 详情 | |
| (VIII) | 14496 | 2,2-diphenyl-2-[(3S)tetrahydro-1H-pyrrol-3-yl]acetamide | C18H20N2O | 详情 | 详情 | |
| (IX) | 14497 | 2-chloro-1-(2,3-dihydro-1-benzofuran-5-yl)-1-ethanone | C10H9ClO2 | 详情 | 详情 | |
| (X) | 14498 | 2-[(3S)-1-[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetamide | C28H28N2O3 | 详情 | 详情 | |
| (XI) | 14499 | 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran | 496-16-2 | C8H8O | 详情 | 详情 |
| (XII) | 14500 | 2-(2,3-dihydro-1-benzofuran-5-yl)acetic acid | 69999-16-2 | C10H10O3 | 详情 | 详情 |
| (XIII) | 14501 | 2-(2,3-dihydro-1-benzofuran-5-yl)-1-ethanol | C10H12O2 | 详情 | 详情 | |
| (XIV) | 14502 | 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran | C10H11BrO | 详情 | 详情 | |
| (XV) | 14503 | 5-(2-bromoethyl)-1-benzofuran | C10H9BrO | 详情 | 详情 | |
| (XVI) | 14504 | 2-[(3S)-1-[2-(1-benzofuran-5-yl)ethyl]tetrahydro-1H-pyrrol-3-yl]-2,2-diphenylacetamide | C28H28N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Danofloxacin (XI) is synthesized by the addition of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) and 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X), and further converted to its monomethanesulfonate salt as outlined in Scheme 17912701a: The diazabicycloalkane sidechain (VII) is prepared in one of two ways, both routes starting with trans-4-hydroxy-L-proline (I). In the first sequence, the amino acid (I) is selectively monotosylated on nitrogen by stirring an aqueous solution of (I) in the presence of p-toluenesulfonyl chloride (TsCl) with sodium carbonate as base. The monotosylate (II) is then reduced to the diol (III) with diborane generated in situ. The diol (III) is next converted to either the tritosylate (IV) selectively or to a mixture of (IV) and the monochloride (V) by treatment with excess TsCl in pyridine at either 0 C or room temperature, respectively. Either pure (IV) or a mixture of (IV) and (V) can be cyclized equally well to the bicyclic intermediate (VI) by treatment with methylamine in a sealed container. Finally, (VI) can be deprotected to give the desired (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) in excellent overall yield by treatment with 30% anhydrous hydrogen bromide in acetic acid. By an alternative route, (I) is esterified under Fischer conditions and treated with excess p-toluenesulfonyl chloride in the presence of pyridine and triethylamine. The resulting ester (VIII) is then treated with methylamine to obtain the amide (IX), which is reductively cyclized with lithium aluminum hydride to the bicyclic intermediate (VI). Finally, (VI) is deprotected as described above to give (VII). The reaction of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (VII) with 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (X) to give danofloxacin free base (XI) is effected by the action of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in pyridine. Conversion of (XI) to danofloxacin mesylate using one equivalent of methanesulfonic acid in ethanol completes the synthesis.
| 【1】 Fox, D.E.; Braish, T.F.; Synthesis of (S,S)- and (R,R)-2-alkyl-2,5-diazabicyclo[2.2.1]heptanes. J Org Chem 1990, 55, 1684-7. |
| 【2】 Braish, T.F.; Fox, D.E. (Pfizer Inc.); Process for optically active 2-alkyl-2,5-diazabicyclo(2.2.1)heptanes. US 5013839 . |
| 【3】 McGuirk, P.R.; Jefson, M.R.; Mann, D.D.; et al.; Synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine. J Med Chem 1992, 35, 4, 611. |
| 【4】 Jefson, M.R.; Shryock, T.R.; Schaaf, T.K.; McGuirk, P.R.; The synthesis and antibacterial activity of danofloxacin (CP-76,136): A new quinolone for veterinary medicine. 29th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, Houston) 1989, Abst 1187. |
| 【5】 McGuirk, P.R.; Jefson, M.R.; Danofloxacin Mesylate. Drugs Fut 1992, 17, 2, 93. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15318 | (2S,4R)-4-hydroxy-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrole-2-carboxylic acid | C12H15NO5S | 详情 | 详情 | |
| (III) | 15319 | (3R,5S)-5-(hydroxymethyl)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-ol | C12H17NO4S | 详情 | 详情 | |
| (IV) | 15320 | (3R,5S)-1-[(4-methylphenyl)sulfonyl]-5-([[(4-methylphenyl)sulfonyl]oxy]methyl)pyrrolidinyl 4-methylbenzenesulfonate | C26H29NO8S3 | 详情 | 详情 | |
| (V) | 15321 | (3R,5S)-5-(chloromethyl)-1-[(4-methylphenyl)sulfonyl]tetrahydro-1H-pyrrol-3-yl 4-methylbenzenesulfonate | C19H22ClNO5S2 | 详情 | 详情 | |
| (VI) | 15322 | (1S,4S)-2-methyl-5-[(4-methylphenyl)sulfonyl]-2,5-diazabicyclo[2.2.1]heptane | C13H18N2O2S | 详情 | 详情 | |
| (VII) | 15323 | (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane | C6H12N2 | 详情 | 详情 | |
| (VIII) | 15324 | methyl (2S,4R)-1-[(4-methylphenyl)sulfonyl]-4-[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-1H-pyrrole-2-carboxylate | C20H23NO7S2 | 详情 | 详情 | |
| (IX) | 15325 | (3R,5S)-5-[(methylamino)carbonyl]-1-[(4-methylphenyl)sulfonyl]pyrrolidinyl 4-methylbenzenesulfonate | C20H24N2O6S2 | 详情 | 详情 | |
| (X) | 15326 | 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C13H9F2NO3 | 详情 | 详情 | |
| (XI) | 15327 | 1-Cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid; Danofloxacin | C19H20FN3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XVI)2) The esterification of trans-4-hydroxy-L-proline (XVI) with SOCl2 and methanol gives the methyl ester (XVII), which is condensed with 3-(methanesulfonyloxymethyl)pyridine (XVIII), obtained by treatment of 3-(hydroxymethyl)pyridine (XIX) with methanesulfonyl chloride, by means of triethylamine yielding trans-N-(3-pyridylmethyl)-4-hydroxy-L-proline methyl ester (XX). The treatment of (XX) with methanesulfonyl chloride affords the corresponding mesylate (XXI), which by reaction with LiCl in hot polyethylene glycol gives cis-4-chloro-N-(3-pyridylmethyl)-L-proline methyl ester (XXII). The reaction of (XXII) with sodium azide in DMSO yields the trans-4-azido derivative (XXIII), which is reduced with triphenylphosphine in hot ethyl acetate to the corresponding trans-4-amino compound (XXIV). The treatment of (XXIV) with 4-chlorophenylsulfonyl chloride (VIII) and triethylamine in ethyl acetate affords the sulfonamide (XXV), which is reduced with diisobutylaluminum hydride in toluene/dichloromethane giving (2S,4R)-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidine-2-carbaldehyde (XXVI). Finally, this compound is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium chloride (XXVII) and potassium tert-butoxide in THF.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Kagara, K.; Goto, S.; Yonishi, S.; Ikushima, M.; Baba, Y.; Horiai, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for producing pyrrolidine deriv. and salt thereof. WO 9401400 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XVI) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVII) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (XVIII) | 15797 | 3-pyridinylmethyl methanesulfonate | C7H9NO3S | 详情 | 详情 | |
| (XIX) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (XX) | 15799 | methyl (2S,4R)-4-hydroxy-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H16N2O3 | 详情 | 详情 | |
| (XXI) | 15800 | methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (XXII) | 15801 | methyl (2S,4S)-4-chloro-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15ClN2O2 | 详情 | 详情 | |
| (XXIII) | 15802 | methyl (2S,4R)-4-azido-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15N5O2 | 详情 | 详情 | |
| (XXIV) | 15803 | methyl (2S,4R)-4-amino-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H17N3O2 | 详情 | 详情 | |
| (XXV) | 15804 | methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C18H20ClN3O4S | 详情 | 详情 | |
| (XXVI) | 15805 | 4-chloro-N-[(3R,5S)-5-formyl-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-3-yl]benzenesulfonamide | C17H18ClN3O3S | 详情 | 详情 | |
| (XXVII) | 28718 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)A new synthesis of S-4661 has been reported: The esterification of trans-4-hydroxy-L-proline (I) with methanol/HCl gives the corresponding methyl ester (II), which is N-protected as trans-N-(4-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline methyl ester (III). The mesylation of (III) with methanesulfonyl chloride and triethylamine in dichloromethane affords the 4-O-mesylate (IV), which is treated with sodium triphenylmethylsulfide giving cis-N-(4-methoxybenzyloxycarbonyl)-4-(triphenylmethylsulfanyl)-L-prolin e methyl ester (V). The reduction of (V) with LiBH4 in THF yields the corresponding methanol (VI), which is mesylated as before affording (VII). The reaction of (VII) with potassium phthalimide (VIII) gives the adduct (IX), which is cleaved with hydrazine yielding (2S,4S)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphenylmeth ylsulfanyl)pyrrolidine (X). The condensation of (X) with N-(4-methoxybenzyl)sulfamoyl chloride (XI) by means of triethylamine affords the corresponding protected sulfamide (XII). Deprotection of the trityl group of (XII) by treatment with silver nitrate and pyridine affords compound (XIII) with a free SH group. The reaction of (XIII) with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-methoxybenzyl ester (XIV) by means of diisopropylethylamine yields the protected final product (XV), which is finally treated with AlCl3 in anisole to eliminate the protecting groups.
| 【1】 Iso, Y.; Motokawa, K.; Nishitani, Y.; Nishino, Y.; Irie, T.; A novel 1beta-methylcarbapenem antibiotic, S-4661. Synthesis and structure-activity relationships of 2-(5-substituted pyrrolidin-3-ylthio)-1beta-methylcarbapenems. J Antibiot 1996, 49, 2, 199. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 16080 | 1-(4-methoxybenzyl) 2-methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C15H19NO6 | 详情 | 详情 | |
| (IV) | 16081 | 1-(4-methoxybenzyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C16H21NO8S | 详情 | 详情 | |
| (V) | 16082 | 1-(4-methoxybenzyl) 2-methyl (2S,4S)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C34H33NO5S | 详情 | 详情 | |
| (VI) | 16083 | 4-methoxybenzyl (2S,4S)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C33H33NO4S | 详情 | 详情 | |
| (VII) | 16084 | 4-methoxybenzyl (2S,4S)-2-[[(methylsulfonyl)oxy]methyl]-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C34H35NO6S2 | 详情 | 详情 | |
| (VIII) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (IX) | 16086 | 4-methoxybenzyl (2S,4S)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C41H36N2O5S | 详情 | 详情 | |
| (X) | 16087 | 4-methoxybenzyl (2S,4S)-2-(aminomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C33H34N2O3S | 详情 | 详情 | |
| (XI) | 16088 | chloro([[(4-methoxybenzyl)oxy]carbonyl]amino)dioxo-lambda(6)-sulfane | C9H10ClNO5S | 详情 | 详情 | |
| (XII) | 16089 | 4-methoxybenzyl (2S,4S)-2-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C42H43N3O8S2 | 详情 | 详情 | |
| (XIII) | 16090 | 4-methoxybenzyl (2S,4S)-2-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)-4-sulfanyl-1-pyrrolidinecarboxylate | C23H29N3O8S2 | 详情 | 详情 | |
| (XIV) | 16075 | 4-methoxybenzyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C30H30NO9P | 详情 | 详情 | |
| (XV) | 16092 | 4-methoxybenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-[[(3S,5S)-1-[[(4-methoxybenzyl)oxy]carbonyl]-5-([[([[(4-methoxybenzyl)oxy]carbonyl]amino)sulfonyl]amino]methyl)pyrrolidinyl]sulfanyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C41H48N4O13S2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)A new synthesis of S-4661 has been reported: The protection of trans-4-hydroxy-L-proline with tert-butoxycarbonyl anhydride gives N-(tert-butoxycarbonyl)-4(R)-hydroxy-L-proline (II), which is successively treated with ethyl chloroformate, mesylated with mesyl chloride and reduced with NaBH4 yielding (2S,4R)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine (III). The reaction of (III) with potassium thioacetate affords Compound (IV), which is condensed with N-(tert-butoxycarbonyl)sulfamide (V) by means of diethyl azodicarboxylate and triphenylphosphine to give the protected pyrrolidinesulfamide (VI). The deacetylation of (VI) with sodium methoxide yields (2S,4S)-1-(tert-butoxycarbonyl)-2-[N-(tert-butoxycarbonyl)-N-sulfamoylaminomethyl]-4-sulfanylpyrrolidine (VII), which is then condensed with (1R,5S,6S)-2-(diphenoxyphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (VIII) by means of diisopropylethylamine to afford the protected final product (IX). Finally, this compound is deprotected with AlCl3 in anisole.
| 【1】 Motokawa, K.; Nishitani, Y.; Iso, Y.; Kii, M.; Irie, T.; Sendo, Y.; Iwaki, T.; Synthesis and modification of a novel 1beta-methyl carbapenem antibiotic, S-4661. J Antibiot 1996, 49, 5, 478. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (III) | 16095 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1-carboxylate | C11H21NO6S | 详情 | 详情 | |
| (IV) | 16096 | tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)tetrahydro-1H-pyrrole-1-carboxylate | C12H21NO4S | 详情 | 详情 | |
| (V) | 16097 | tert-butyl 2,2-dioxo-2lambda(6)-diazathiane-1-carboxylate | 148017-28-1 | C5H12N2O4S | 详情 | 详情 |
| (VI) | 16098 | tert-butyl (2S,4S)-4-(acetylsulfanyl)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]tetrahydro-1H-pyrrole-1-carboxylate | C17H31N3O7S2 | 详情 | 详情 | |
| (VII) | 16099 | tert-butyl (2S,4S)-2-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-4-sulfanyltetrahydro-1H-pyrrole-1-carboxylate | C15H29N3O6S2 | 详情 | 详情 | |
| (VIII) | 16100 | benzhydryl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C35H32NO8P | 详情 | 详情 | |
| (IX) | 16101 | benzhydryl (4R,5S,6S)-3-[[(3S,5S)-5-[[(aminosulfonyl)(tert-butoxycarbonyl)amino]methyl]-1-(tert-butoxycarbonyl)pyrrolidinyl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C38H50N4O10S2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.
| 【1】 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040. |
| 【2】 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (III) | 47730 | (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | C9H13NO5 | 详情 | 详情 | |
| (IV) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (V) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (VI) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VII) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (VIII) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (IX) | 49447 | allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H19NO7S | 详情 | 详情 | |
| (X) | 49448 | allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H19NO6S | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 49449 | allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C20H22N2O7S | 详情 | 详情 | |
| (XIII) | 49450 | allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C12H20N2O5S | 详情 | 详情 | |
| (XIV) | 50598 | allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C13H22N2O7S2 | 详情 | 详情 | |
| (XV) | 49451 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C14H22N2O5S2 | 详情 | 详情 | |
| (XVI) | 49452 | allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C12H20N2O4S2 | 详情 | 详情 | |
| (XVII) | 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 | |
| (XVIII) | 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 | |
| (XIX) | 11687 | (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate | C13H25NO4Si | 详情 | 详情 | |
| (XX) | 50599 | C17H27N3O6Si | 详情 | 详情 | ||
| (XXI) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Treatment of trans-4-hydroxy-L-proline (I) with p-nitrobenzyl chloroformate gave the N-protected 4-hydroxyproline (II), which was esterified to afford the N-protected methyl ester (II). Protection of the hydroxyl group of (III) with t-butyl-dimethylsilyl chloride in the presence of imidazole, followed by reduction of the resulting ester (IV) with lithium borohydride, provided the alcohol (V). This was oxidized using pyridine-sulfur trioxide complex to give the formylpyrrolidine (VI). The vinylpyrrolidine (VII) was obtained by Wittig reaction of aldehyde (VI) with methylene triphenylphosphorane. Dipolar cycloaddition of the nitrile oxide resulting from ethyl chlorooximidoacetate (VIII) and Et3N to vinylpyrrolidine (VII) gave iso-oxazolidine (IX) as a mixture of diastereoisomers. After desilylation of (IX) with tetrabutylammonium fluoride, the resulting alcohol (X) was converted into the diastereomeric mixture of mesylates (XI). Chromatographic separation of the required isomer, followed by reduction with LiBH4, yielded alcohol (XII).
| 【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (III) | 44922 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C14H16N2O7 | 详情 | 详情 | |
| (IV) | 44923 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrrolidinedicarboxylate | C20H30N2O7Si | 详情 | 详情 | |
| (V) | 44924 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H30N2O6Si | 详情 | 详情 | |
| (VI) | 44925 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C19H28N2O6Si | 详情 | 详情 | |
| (VII) | 44926 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinyl-1-pyrrolidinecarboxylate | C20H30N2O5Si | 详情 | 详情 | |
| (VIII) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (IX) | 44927 | ethyl (5R)-5-((2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C24H35N3O8Si | 详情 | 详情 | |
| (X) | 44928 | ethyl (5R)-5-((2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C18H21N3O8 | 详情 | 详情 | |
| (XI) | 44929 | ethyl (5R)-5-((2S,4R)-4-[(methylsulfonyl)oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C19H23N3O10S | 详情 | 详情 | |
| (XII) | 44930 | 4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C17H21N3O9S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)The pyrrolidine intermediate (VIII) has been obtained as follows: Protection of trans-4-hydroxy-L-proline (I) with allyl chloroformate gave carbamate (II). Following esterification of (II) with MeOH and H2SO4, the methyl ester (III) was reduced to diol (IV) by using LiBH4 in THF. Selective silylation of the primary alcohol of (IV) was achieved with TBDMS chloride the presence of DBU to furnish the silyl ether (V). Oxidation of (V) to ketone (VI) was carried out either under Swern conditions or by means of tetrapropylammonium perruthenate (TPAP) in the presence of N-methylmorpholine-N-oxide. Subsequent Wittig reaction of ketone (VI) with methylene triphenylphosphorane provided olefin (VII). The allyloxycarbonyl protecting group of (VII) was then removed by palladium-catalyzed hydrostannolysis with tributyltin hydride to yield the pyrrolidine intermediate (VIII).
| 【2】 Thurston, D.E.; Howard, P.W. (University of Portsmouth); Compounds. EP 1109812; WO 0012508 . |
| 【1】 Kelland, L.R.; Gregson, S.J.; Brooks, N.A.; Jenkins, T.C.; Thurston, D.E.; Hartley, J.A.; Howard, P.W.; Adams, L.J.; Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem 2001, 44, 5, 737. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 47730 | (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | C9H13NO5 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 47731 | allyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C9H15NO4 | 详情 | 详情 | |
| (V) | 47732 | allyl (2S,4R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C15H29NO4Si | 详情 | 详情 | |
| (VI) | 47733 | allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C15H27NO4Si | 详情 | 详情 | |
| (VII) | 47734 | allyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C16H29NO3Si | 详情 | 详情 | |
| (VIII) | 47735 | (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenepyrrolidine; tert-butyl(dimethyl)silyl [(2S)-4-methylenepyrrolidinyl]methyl ether | C12H25NOSi | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XX)The synthesis of the precursor peptide (XVII) was also reported in solution phase. trans-4-Hydroxy-L-proline (XX) was protected as the N-Boc derivative (XII), which was subsequently activated as the pentafluorophenyl ester (XXI). This was condensed with the dipeptide alanyl-serine (XXII) to furnish the protected tripeptide (XXIII). Acidic cleavage of the Boc protecting group of (XXIII) yielded tripeptide (XXIV).
| 【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
| (XX) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XXI) | 53675 | 1-(tert-butyl) 2-(2,3,4,5,6-pentafluorophenyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | n/a | C16H16F5NO5 | 详情 | 详情 |
| (XXII) | 53676 | (2S)-2-{[(2S)-2-aminopropanoyl]amino}-3-hydroxypropanoic acid | n/a | C6H12N2O4 | 详情 | 详情 |
| (XXIII) | 53677 | (2S)-2-{[(2S)-2-({[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}-3-hydroxypropanoic acid | n/a | C16H27N3O8 | 详情 | 详情 |
| (XXIV) | 53678 | (2S)-3-hydroxy-2-{[(2S)-2-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid | n/a | C11H19N3O6 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)trans-4-Hydroxy-L-proline (I) was esterified with methanolic HCl, generated from acetyl chloride in MeOH, and the resulting 4-hydroxyproline methyl ester (II) was protected with allyl chloroformate to afford the allyl carbamate (III). Mesylation of the hydroxyl group of (III) with methanesulfonyl chloride, followed by reduction of the methyl ester with LiBH4, provided the alcohol (V). The mesylate group of (V) was then displaced by potassium thioacetate yielding thioacetate ester (VI). Iodo compound (VII) was obtained by mesylation of alcohol (VI) followed by substitution with NaI in acetone. 1-Methyl-5-mercaptotetrazole (IX), prepared by reaction of methyl isothiocyanate (VIII) with NaN3, was then condensed with iodide (VII) to give adduct (X). After deacetylation of thioacetate (X) with methanolic NaOH, the resulting pyrrolidinethiol (XI) was coupled with enol phosphate (XII) to give the protected carbapenem (XIII). The allyl ester and carbamate protecting groups of (XIII) were finally removed by treatment with Bu3SnH in the presence of palladium catalyst.
| 【1】 Kim, D.J.; Koo, K.D.; Shin, K.J.; Kim, C.; Park, S.W.; Yoo, K.H.; Synthesis and biological properties of new 1beta-methylcarbapenems having tetrazolothioether moiety. Bioorg Med Chem Lett 2000, 10, 13, 1421. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 42200 | 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C10H15NO5 | 详情 | 详情 | |
| (IV) | 42201 | 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate | C11H17NO7S | 详情 | 详情 | |
| (V) | 42202 | allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H17NO6S | 详情 | 详情 | |
| (VI) | 42203 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C11H17NO4S | 详情 | 详情 | |
| (VII) | 42204 | allyl (2S,4S)-4-(acetylsulfanyl)-2-(iodomethyl)-1-pyrrolidinecarboxylate | C11H16INO3S | 详情 | 详情 | |
| (VIII) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (IX) | 28420 | 5-Mercapto-1-methyl-1H-tetrazole; 1-Methyl-1H-1,2,3,4-tetraazol-5-ylhydrosulfide | 13183-79-4 | C2H4N4S | 详情 | 详情 |
| (X) | 42205 | allyl (2S,4S)-4-(acetylsulfanyl)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-1-pyrrolidinecarboxylate | C13H19N5O3S2 | 详情 | 详情 | |
| (XI) | 42206 | allyl (2S,4S)-2-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C11H17N5O2S2 | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 42207 | allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[[(1-methyl-1H-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C24H32N6O6S2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)Conversion of 4-hydroxy-L-proline (I) into the corresponding cis-N-Boc-4-hydroxy-L-proline methyl ester (II) is performed as follows: Treatment of (I) with SOCl2 in MeOH followed by reaction with Boc2O and Et3N in EtOAc affords the corresponding protected acid chloride; then the methyl ester moiety is formed under Mitsunobu conditions with formic acid, DIAD and PPh3 in THF followed by treatment with NaOH in MeOH. The OH group of (II) is converted into thioether (IV) by first mesylation with MsCl and Et3N in toluene followed by reaction with triphenylmethanethiol (III) in THF in the presence of NaH. Reduction of the methyl ester of (IV) with LiBH4 in THF provides alcohol (V), which is mesylated with MsCl and Et3N in THF and then treated with NaN3 and HMPA to furnish azide (VI). Boc removal in (VI) is performed by treatment with HCl in EtOAc to give derivative (VII), which is then converted into compound (VIII) by condensation with 2-(2,4-difluorobenzoyl)benzoic acid (XI) by means of water-soluble carbodiimide (WSC) and HOBt in DMF (compound (XI) can be obtained by Friedel-Crafts reaction between phthalic anhydride (IX) and 1,3-difluorobenzene (X) in the presence of AlCl3). Reduction of the azido moiety of (VIII) by means of SnCl2 and NaOH in EtOH furnishes amine (XII), which is finally converted into the desired product by condensation with carboxylic acid (XIII) by means of WSC and HOBt (derivative (XIII) can be obtained by Knoevenagel reaction between 4-formyl-benzoic acid (XIV) and 2,4-thiazolidinedione (XV) in refluxing 2-methoxyethanol in the presence of piperidine).
| 【1】 Nishi, K.; Seno, K.; Ono, T.; Yamada, K.; Murakami, Y.; Nakamoto, S.; Okuno, T.; Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: Synthesis of potent and crystallized 4-triphenylmethylthio derivative "pyrrophenone". Bioorg Med Chem Lett 2001, 11, 4, 587. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (III) | 18831 | tritylhydrosulfide; triphenylmethanethiol | 3695-77-0 | C19H16S | 详情 | 详情 |
| (IV) | 50070 | 1-(tert-butyl) 2-methyl (2S,4R)-4-(tritylsulfanyl)-1,2-pyrrolidinedicarboxylate | C30H33NO4S | 详情 | 详情 | |
| (V) | 50071 | tert-butyl (2S,4R)-2-(hydroxymethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H33NO3S | 详情 | 详情 | |
| (VI) | 50072 | tert-butyl (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)-1-pyrrolidinecarboxylate | C29H32N4O2S | 详情 | 详情 | |
| (VII) | 50073 | (2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidine; (3R,5S)-5-(azidomethyl)pyrrolidinyl trityl sulfide | C24H24N4S | 详情 | 详情 | |
| (VIII) | 50074 | [(2S,4R)-2-(azidomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H30F2N4O2S | 详情 | 详情 | |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (XI) | 41002 | 2-(2,4-difluorobenzoyl)benzoic acid | C14H8F2O3 | 详情 | 详情 | |
| (XII) | 50075 | [(2S,4R)-2-(aminomethyl)-4-(tritylsulfanyl)pyrrolidinyl][2-(2,4-difluorobenzoyl)phenyl]methanone | C38H32F2N2O2S | 详情 | 详情 | |
| (XIII) | 50076 | 4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid | C11H7NO4S | 详情 | 详情 | |
| (XIV) | 18922 | 4-formylbenzoic acid | 619-66-9 | C8H6O3 | 详情 | 详情 |
| (XV) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.
| 【1】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 . |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (III) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (IV) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (V) | 43411 | 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VI) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VII) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (VIII) | 55407 | 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (IX) | 21738 | 3,3-dimethylbutanoyl chloride | 7065-46-5 | C6H11ClO | 详情 | 详情 |
| (X) | 55409 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate | C25H38N2O6 | 详情 | 详情 | |
| (XI) | 55410 | methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C20H30N2O4 | 详情 | 详情 | |
| (XII) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (XIII) | 55411 | methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate | C28H36N2O6 | 详情 | 详情 | |
| (XIV) | 55412 | (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid | C27H34N2O6 | 详情 | 详情 | |
| (XV) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XVI) | 55413 | tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate | C36H50N4O7 | 详情 | 详情 |