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【结 构 式】 
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【分子编号】69233 【品名】(3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate 【CA登记号】 |
【 分 子 式 】C15H28N2O5 【 分 子 量 】316.3978 【元素组成】C 56.94% H 8.92% N 8.85% O 25.28% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)Stereospecific methods to prepare aminopyrrolidine (X) have been developed starting from both enantiomers of trans-N-benzyl-2,3-dihydroxysuccinimide (XXIXa) and (XXIXb), generated respectively from D- and L-tartaric acid. Monoprotection of the (S,S)-diol (XXIXa) with one equivalent of TBDMSCl in the presence of imidazole in cold DMF followed by imide reduction with borane-THF complex leads to the pyrrolidine (XXXa), which after debenzylation with H2 and Pd/C and reprotection with Boc2O provides the tert-butyl carbamate (XXXIa). Alcohol (XXXIa) is then converted to the corresponding mesylate, which undergoes nucleophilic displacement by NaN3 in DMF to give the cis-azide (XXXII). Azide (XXXII) is then reduced by catalytic hydrogenation over Pd/C to afford the corresponding amine, which is protected with Boc2O, followed by desilylation with tetrabutylammonium fluoride to give the cis-alcohol (XXXIII). Inversion of the configuration of alcohol (XXXIII) to the trans-isomer (XXVIII) is then accomplished by mesylation with MsCl and Et3N followed by displacement with potassium acetate in DMF and acetate hydrolysis with K2CO3 in MeOH. Finally, compound (XXVIII) is methylated with iodomethane and NaH and subsequently deprotected with p-TsOH in i-PrOH .
Alternatively, the (R,R)-imide (XXIXb) is converted to the trans-diol derivative (XXXb) as before, and the N-benzyl group is then exchanged for a Boc group, giving alcohol (XXXIb). Alkylation of compound (XXXIb) with iodomethane and NaH affords the corresponding methyl ether, which is desilylated to alcohol (XXXIV) by means of TBAF in THF. Mesylation of alcohol (XXXIV), followed by displacement with lithium acetate produces the methoxy acetate (XXXV), which is hydrolyzed to the cis-alcohol (XXXVI) using K2CO3 in MeOH. Mesylation of alcohol (XXXVI) followed by displacement with NaN3 provides the azide (XXXVII). After reduction with H2 and Pd/C, the resulting amine is protected as the Boc derivative (XXXVIII) with Boc2O in EtOH. Finally, amine (XXXVIII) is alkylated with iodomethane and NaH, followed by deprotection with p-TsOH (X) .
| 【1】 Tsuzuku, Y., Chiba, K., Hino, K. Efficient stereospecific synthesis of (S,S)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Asymmetry 2001, 12(12): 1793-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIXa) | 69222 | trans-N-benzyl-2,3-dihydroxysuccinimide; (3S,4S)-3,4-dihydroxy-1-(phenylmethyl)-2,5-Pyrrolidinedione; (3S-trans)-3,4-dihydroxy-1-(phenylmethyl)-2,5-Pyrrolidinedione | 187032-53-7 | C11H11NO4 | 详情 | 详情 |
| (XXIXb) | 33017 | (3R,4R)-1-benzyl-3,4-dihydroxy-2,5-pyrrolidinedione | 75172-31-5 | C11H11NO4 | 详情 | 详情 |
| (XXXa) | 69223 | (3S,4S)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-3-ol | C17H29NO2Si | 详情 | 详情 | |
| (XXXb) | 69224 | (3R,4R)-1-benzyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidin-3-ol | C17H29NO2Si | 详情 | 详情 | |
| (XXXIa) | 69226 | (3S,4S)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-4-hydroxypyrrolidine-1-carboxylate | C15H31NO4Si | 详情 | 详情 | |
| (XXXIb) | 69225 | (3R,4R)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-4-hydroxypyrrolidine-1-carboxylate | C15H31NO4Si | 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 | |
| (XXVIII) | 69221 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 | |
| (XXXII) | 69228 | (3R,4S)-tert-butyl 3-azido-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylate | C15H30N4O3Si | 详情 | 详情 | |
| (XXXIII) | 69229 | (3R,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypyrrolidine-1-carboxylate | C14H26N2O5 | 详情 | 详情 | |
| (XXXIV) | 69227 | (3R,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate | C10H19NO4 | 详情 | 详情 | |
| (XXXV) | 69230 | (3S,4R)-tert-butyl 3-acetoxy-4-methoxypyrrolidine-1-carboxylate | C12H21NO5 | 详情 | 详情 | |
| (XXXVI) | 69231 | (3S,4R)-tert-butyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate | C10H19NO4 | 详情 | 详情 | |
| (XXXVII) | 69232 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate;trans-3-Azido-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester;TRANS-3-AZIDO-1-BOC-4-METHOXYPYRROLIDINE | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (XXXVIII) | 69233 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVIII)Intermediate (XXXVIII) can be prepared by several alternative methods. Protection of diallylamine (XXXIX) with benzyl chloroformate and Et3N in CH2Cl2 yields the benzyloxycarbonyl derivative (XL), which undergoes ring-closing metathesis in the presence of Grubbs’ catalyst to give 1-Cbz-3-pyrroline (XLI). Reaction of compound (XLI) with NBS in aqueous DMSO followed by treatment of the resulting bromohydrin with 1 N NaOH leads to epoxide (XLII), which undergoes ring opening with NaN3 in aqueous dioxane to afford the racemic trans-azidoalcohol (XLIII). Resolution of rac-(XLIII) is then effected by incubation with lipase PS in the presence of vinyl acetate in i-Pr2O to give the (R,R)-acetate (XLIV) along with unreacted (S,S)-alcohol (XLIII). Methylation of (S,S)-alcohol (XLIII) with iodomethane and NaH affords ether (XLV), which is submitted to azide group reduction by means of PPh3 in THF/H2O to give amine (XLVI). Protection of amine (XLVI) with Boc2O and Et3N followed by selective removal of the Cbz group in the resulting bis-carbamate (XLVII) using poly(methylhydrosiloxane) and Pd/C in EtOH leads to the pyrrolidine (XLVIII), which is finally treated with Boc2O and Et3N .
| 【1】 Kamal, A., Shaik, A.A., Sandbhor, M., Malik, M.S., Kaga, H. Chemoenzymatic synthesis of (3S,4S)- and (3R,4R)-3-methoxy-4-methylaminopyrrolidine. Tetrahedron Lett 2004, 45(43): 8057-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 69233 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XXXIX) | 68044 | diallylamine;Di-2-propenylamine;N-2-Propenyl-2-propen-1-amine | 124-02-7 | C6H11N | 详情 | 详情 |
| (XL) | 69234 | benzyl diallylcarbamate | C14H17NO2 | 详情 | 详情 | |
| (XLI) | 15923 | 1-Benzyloxycarbonyl-3-pyrroline;3-Pyrroline-1-carboxylicacid, benzyl ester ;N-(Benzyloxycarbonyl)-3-pyrroline;Benzyl 3-pyrroline-1-carboxylate;2H,5H-Pyrrole-1-carboxylicacid benzyl ester;2,5-Dihydropyrrole-1-carboxylic acid benzyl ester;benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 31970-04-4 | C12H13NO2 | 详情 | 详情 |
| (XLII) | 69235 | benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C12H13NO3 | 详情 | 详情 | |
| (XLIII) | 69236 | (3S,4S)-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate | C12H14N4O3 | 详情 | 详情 | |
| (XLIV) | 69237 | (3R,4R)-benzyl 3-acetoxy-4-azidopyrrolidine-1-carboxylate | C14H16N4O4 | 详情 | 详情 | |
| (XLV) | 69238 | (3S,4S)-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate | C13H16N4O3 | 详情 | 详情 | |
| (XLVI) | 69241 | (3S,4S)-benzyl 3-amino-4-methoxypyrrolidine-1-carboxylate | C13H18N2O3 | 详情 | 详情 | |
| (XLVII) | 69239 | (3S,4S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C18H26N2O5 | 详情 | 详情 | |
| (XLVIII) | 69240 | tert-butyl ((3S,4S)-4-methoxypyrrolidin-3-yl)carbamate | C10H20N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXXVIII)Treatment of the known diol (XLIX) with tosyl chloride in cold pyridine gives the primary tosylate (L), which is reacted with NaN3 in DMF to give azidoalcohol (LI). Subsequent alkylation of the secondary alcohol (LI) with MeI and NaH followed by acidic ketal hydrolysis of the resulting methyl ether (LII) affords the diol (LIII), which is converted to ditosylate (LIV) using p-TsCl and Et3N. Reduction of azide (LIV) using PPh3 in refluxing MeOH occurs with concomitant cyclization to give the pyrrolidine (LV), which is then protected as the N-Boc derivative (LVI) under standard conditions. The remaining tosylate group of (LVI) is then displaced with NaN3 in DMF to furnish azide (LVII). After reduction by catalytic hydrogenation over Pd/C, the obtained amine (LVIII) is finally protected with Boc2O and Et3N in CH2Cl2 .
| 【1】 Kumar, A.R., Reddy, J.S., Rao, B.V. A short, simple and general approach for the synthesis of (3S,4S)-3-methoxy-4-methylamino pyrrolidine and (3S,4R)-3-methoxy-4-methylamino pyrrolidine. Tetrahedron Lett 2003, 44(30): 5687-9. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXVIII) | 69233 | (3S,4S)-tert-butyl 3-((tert-butoxycarbonyl)amino)-4-methoxypyrrolidine-1-carboxylate | C15H28N2O5 | 详情 | 详情 | |
| (XLIX) | 69242 | (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol | C7H14O4 | 详情 | 详情 | |
| (L) | 69243 | (R)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyethyl 4-methylbenzenesulfonate | C14H20O6S | 详情 | 详情 | |
| (LI) | 69244 | (R)-2-azido-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethanol | C7H13N3O3 | 详情 | 详情 | |
| (LII) | 69245 | (R)-4-((S)-2-azido-1-methoxyethyl)-2,2-dimethyl-1,3-dioxolane | C8H15N3O3 | 详情 | 详情 | |
| (LIII) | 69246 | (2S,3R)-4-azido-3-methoxybutane-1,2-diol | C5H11N3O3 | 详情 | 详情 | |
| (LIV) | 69247 | (2S,3R)-4-azido-3-methoxybutane-1,2-diyl bis(4-methylbenzenesulfonate) | C19H23N3O7S2 | 详情 | 详情 | |
| (LV) | 69248 | (3S,4R)-4-methoxypyrrolidin-3-yl 4-methylbenzenesulfonate | C12H17NO4S | 详情 | 详情 | |
| (LVI) | 69249 | (3S,4R)-tert-butyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate | C17H25NO6S | 详情 | 详情 | |
| (LVII) | 69250 | (3S,4S)-tert-butyl 3-azido-4-methoxypyrrolidine-1-carboxylate | 429673-78-9 | C10H18N4O3 | 详情 | 详情 |
| (LVIII) | 69251 | trans-3-Amino-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester;(3S,4S)-tert-butyl 3-amino-4-methoxypyrrolidine-1-carboxylate | 429673-79-0 | C10H20N2O3 | 详情 | 详情 |