(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine -Drug Synthesis Database

【结构式】

【分子编号】26651

【品名】(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine

【CA登记号】

【分子式】C₁₂H₁₈N₂O

【分子量】206.2878

【元素组成】C 69.87% H 8.79% N 13.58% O 7.76%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(X)

The chiral intermediate, the pyrrolidine (VIII) has been obtained as follows: The optical resolution of (trans)-3-amino-1-benzyl-4-methoxypyrroloidine (rac)-(X) with D-tartaric acid gives the enathiomer (S,S)(XI), which is treated with tert-butoxycarbonyl anhydride in methanol to yield the carbamate (XII). The reduction of (XII) with LiAlH4 in THF followed by reprotection with tert-butoxycarbonyl anhydride in dichloromethane affords (S,S)-1-benzyl-3-[N-(tert-butoxycarbonyl)-N-methylamino]-4-methoxypyrrolidine (XIII), which is finally debenzylated to the target compound (VIII) by hydrogenation with H2 over Pd/C in ethanol.

参考文献中间体

合成目标

【1】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	26649	tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate	C₁₁H₂₂N₂O₃	详情	详情
(X)	26651	(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine	C₁₂H₁₈N₂O	详情	详情
(XI)	26651	(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine	C₁₂H₁₈N₂O	详情	详情
(XII)	26652	tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate	C₁₇H₂₆N₂O₃	详情	详情
(XIII)	26653	tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate	C₁₈H₂₈N₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

参考文献中间体

合成目标

【1】 Tomita, K.; Chiba, K.; Kashimoto, S.; Shibamori, K.; Tsuzuki, Y. (Dainippon Pharmaceutical Co., Ltd.); Novel cpd., process for producing the same, and antitumor agent. EP 0787726; US 5817669; WO 9534559 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIII)	26649	tert-butyl (3S,4S)-4-methoxypyrrolidinyl(methyl)carbamate	C₁₁H₂₂N₂O₃	详情	详情
(X)	26651	(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine	C₁₂H₁₈N₂O	详情	详情
(XI)	26651	(3S,4S)-1-benzyl-4-methoxy-3-pyrrolidinamine	C₁₂H₁₈N₂O	详情	详情
(XII)	26652	tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate	C₁₇H₂₆N₂O₃	详情	详情
(XIII)	26653	tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate	C₁₈H₂₈N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XX)

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) .

参考文献中间体

合成目标

【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

Extended Information