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【结 构 式】 
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【分子编号】22837 【品名】tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate 【CA登记号】190792-74-6 |
【 分 子 式 】C9H18N2O3 【 分 子 量 】202.2536 【元素组成】C 53.45% H 8.97% N 13.85% O 23.73% |
合成路线1
该中间体在本合成路线中的序号：(V)3-Pyrroline (I) was protected with di-tert-buyl dicarbonate to give N-Boc-pyrroline (II), which was then epoxidized with meta-chloroperbenzoic acid. The resulting epoxide (III) was opened with sodium azide in aqueous MeOH to yield trans-azidoalcohol (IV). Subsequent reduction of the azide (IV) to aminoalcohol (V) was effected by hydrogenation over Pd/C (1). Condensation of the racemic trans-aminoalcohol (V) with N-Cbz-L-leucine (VI) in the presence of EDC and HOBt provided amide (VII) as a diastereomeric mixture. The N-Boc group of (VII) was then deprotected with HCl in EtOAc, and the resulting amine (VIII) was coupled with another N-Cbz-L-leucine (VI) unit to give (IX). Oxidation of the alcohol group of (IX) to the target ketone was accomplished with Jones reagent in acetone. The diastereomeric mixture was separated by reverse phase-HPLC, however the diastereomers were not configurationally stable and reequilibrated spontaneusly to the original mixture.
| 【1】 Marquis, R.W.; Yamashita, D.S.; Ru, Y.; LoCastro, S.M.; Oh, H.J.; Erhard, K.F.; DesJarlais, R.L.; Head, M.S.; Smith, W.W.; Zhao, B.; Janson, C.A.; Abdel-Meguid, S.S.; Tomaszek, T.A.; Levy, M.A.; Veber, D.F.; Conformationally constrained 1,3-diamino ketones: a series of potent inhibitors of the cysteine protease cathepsin K. J Med Chem 1998, 41, 19, 3563. |
| 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) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (II) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (III) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (IV) | 22836 | tert-butyl (3R,4S)-3-azido-4-hydroxy-1-pyrrolidinecarboxylate | 143700-05-4 | C9H16N4O3 | 详情 | 详情 |
| (V) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (VI) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 22839 | tert-butyl 3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate | C23H35N3O6 | 详情 | 详情 | |
| (VIII) | 22840 | benzyl (1S)-1-[[(4-hydroxy-3-pyrrolidinyl)amino]carbonyl]-3-methylbutylcarbamate | C18H27N3O4 | 详情 | 详情 | |
| (IX) | 22841 | benzyl (1S)-1-([3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinyl]carbonyl)-3-methylbutylcarbamate | C32H44N4O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Protection of 3-pyrroline (XII) with Boc2O in MeOH followed by oxidation of the resulting N-Boc-pyrroline (XIII) with m-CPBA in CH2Cl2 provides epoxide (XIV), which is also alternatively prepared by reaction of 1-Boc-3-pyrroline (XIII) with NBS in aqueous DMSO and subsequent cyclization of the obtained bromohydrin (XV) in 1 N NaOH. A further method to prepare pyrroline (XIII) is by condensation of cis-1,4-dichloro-2-butene (XVI) with tert-butyl carbamate in the presence of NaH in dry DMF. Ring opening of epoxide (XIV) with NaN3 in dioxane/H2O leads to the trans-azidoalcohol (XVII), which is alkylated with iodomethane and NaH in THF to give the methyl ether (XVIII). After catalytic hydrogenation of azide (XVIII) over Pd/C, the N-Boc protecting group in the resulting amine (XIX) is replaced with a benzyl group by acidic hydrolysis followed by alkylation with benzyl chloride and Et3N to give the protected pyrrolidine (XX) . Optical resolution of racemic trans-3-amino-1-benzyl-4-methoxypyrrolidine (XX) using D-(+)-tartaric acid provides the target (S,S)-enantiomer, which is then protected as the tert-butyl carbamate (XXI) by treatment with Boc2O in MeOH. Subsequent reduction of carbamate (XXI) with LiAlH4 in THF followed by reprotection of the resulting Nmethylamine with Boc2O in CH2Cl2 provides compound (XXII), which is finally debenzylated by catalytic hydrogenation over Pd/C in EtOH to the desired pyrrolidine (VIII) .
Epoxide (XIV) is converted to the aminopyrrolidine (X) by two additional strategies. Ring opening of epoxide (XIV) with aqueous methylamine yields the racemic trans-aminoalcohol (XXIII), which is resolved by acylation with N-Boc-L-phenylalanine and EDC in CH2Cl2 followed by separation of the diastereomers by column chromatography. Hydrolysis of the desired diastereomer (XXIV) with 20% NaOH in EtOH affords the (S,S)-enantiomer of amino alcohol (XXIII), which is protected as the bis-carbamate (XXV) using Boc2O in MeOH. Finally, methylation of alcohol (XXV) with iodomethane and NaH in DMF, followed by removal of both Boc groups with p-TsOH in i-PrOH provides the target (S,S)-3-methoxy-4-(methylamino)pyrrolidine ditosylate (X) .
Alternatively, reaction of epoxide (XIV) with benzylamine provides the racemic amino alcohol (XXVI), which can be resolved by recrystallization of the diastereoisomeric salts with (+)-mandelic acid in acetonitrile/water. Subsequent debenzylation of the target enantiomer with H2 and Pd/C in BuOH provides the (S,S)-amino alcohol (XXVII). Protection of the primary amino group of compound (XXVII) with Boc2O in EtOH gives the bis-carbamate (XXVIII), which is finally submitted to N,O-dialkylation with iodomethane and NaH, followed by Boc group cleavage with p-TsOH in THF/MeOH to yield the key intermediate (X) .
| 【1】 Tomita, K., Chiba, K., Kashimoto, S., Shibamori, K., Tsuzuki, Y. (Dainippon Sumitomo Pharma Co., Ltd.). Novel compound, process for producing the same, and antitumor agent. EP 0787726, US 5817669, WO 1995034559. |
| 【2】 Tsuzuki, Y., Chiba, K., Mizuno, K., Tomita, K., Suzuki, K. Practical synthesis of (3S,4S)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Asymmetry 2001, 12(21): 2989-97. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （LVIV） | 69218 | (S,S)-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (VIII) | 26649 | tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate | C11H22N2O3 | 详情 | 详情 | |
| (X) | 69211 | (3S,4S)-4-methoxy-N-methylpyrrolidin-3-amine compound with 1-methyl-4-(methylsulfonyl)benzene (1:2) | C6H14N2O.2C8H10O2S | 详情 | 详情 | |
| (XII) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (XIII) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (XIV) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (XV) | 69212 | (3S,4R)-tert-butyl 3-bromo-4-hydroxypyrrolidine-1-carboxylate | C9H16BrNO3 | 详情 | 详情 | |
| (XVI) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
| (XVII) | 69213 | (3S,4S)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate | C9H16N4O3 | 详情 | 详情 | |
| (XVIII) | 69214 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (XIX) | 69215 | (3S,4S)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate | 429673-79-0 | C10H20N2O3 | 详情 | 详情 |
| (XX) | 26651 | (3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine | C12H18N2O | 详情 | 详情 | |
| (XXI) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (XXII) | 26653 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate | C18H28N2O3 | 详情 | 详情 | |
| (XXIII) | 69216 | rac-tert-butyl 3-hydroxy-4-(methylamino)pyrrolidine-1-carboxylate | C10H20N2O3 | 详情 | 详情 | |
| (XXIV) | 69217 | (3S,4S)-tert-butyl 3-((S)-2-((tert-butoxycarbonyl)amino)-N-methyl-3-phenylpropanamido)-4-hydroxypyrrolidine-1-carboxylate | C24H37N3O6 | 详情 | 详情 | |
| (XXV) | 69219 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XXVI) | 69220 | (3S,4S)-tert-butyl 3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate | 252574-03-1 | C16H24N2O3 | 详情 | 详情 |
| (XXVII) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (XXVIII) | 69221 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 |