benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate -Drug Synthesis Database

【结构式】

【分子编号】63998

【品名】benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate

【CA登记号】

【分子式】C₂₅H₂₈FNO₃

【分子量】409.5006632

【元素组成】C 73.33% H 6.89% F 4.64% N 3.42% O 11.72%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXI)

Condensation of oxalyl chloride (XI) with N,O-dimethylhydroxylamine produces N,N'-dimethyl-N,N'-dimethoxy oxamide (XII). This is then condensed with cyclobutylmethylmagnesium bromide (XIII) to afford the ketoamide (XIV). Asymmetric keto group reduction employing (R)-alpine borane leads to the (S)-alcohol (XV) in 91% enantiomeric excess. Hydrolysis of the N-methoxyamide function of (XV) to provide hydroxyacid (XVI) is then accomplished employing potassium tert-butoxide in the presence of the equimolecular amount of H2O in THF. Alkylation of hydroxyacid (XVI) with benzyl bromide and Et3N furnishes the corresponding benzyl ester (XVII). Treatment of (XVII) with trifluoromethanesulfonic anhydride gives rise to triflate (XVIII), which is further condensed with pyrrolidine (X) to produce (XIX). After desilylation of (XIX) with tetrabutylammonium fluoride, the resultant alcohol (XX) is oxidized to aldehyde (XXI) under Swern conditions.

参考文献中间体

合成目标

【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Kim, R.M. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6498161; WO 0059498 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	63988	(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine; tert-butyl(dimethyl)silyl [(3R,4S)-4-(3-fluorophenyl)pyrrolidinyl]methyl ether		C₁₇H₂₈FNOSi	详情	详情
(XI)	29841	Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride	79-37-8	C₂Cl₂O₂	详情	详情
(XII)	63989	N-methoxy-2-[methoxy(methyl)amino]-N-methyl-2-oxoacetamide		C₆H₁₂N₂O₄	详情	详情
(XIII)	63990	bromo(cyclobutylmethyl)magnesium		C₅H₉BrMg	详情	详情
(XIV)	63991	3-cyclobutyl-N-methoxy-N-methyl-2-oxopropanamide		C₉H₁₅NO₃	详情	详情
(XV)	63992	(2S)-3-cyclobutyl-2-hydroxy-N-methoxy-N-methylpropanamide		C₉H₁₇NO₃	详情	详情
(XVI)	63993	(2S)-3-cyclobutyl-2-hydroxypropanoic acid		C₇H₁₂O₃	详情	详情
(XVII)	63994	benzyl (2S)-3-cyclobutyl-2-hydroxypropanoate		C₁₄H₁₈O₃	详情	详情
(XVIII)	63995	benzyl (2S)-3-cyclobutyl-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate		C₁₅H₁₇F₃O₅S	详情	详情
(XIX)	63997	benzyl (2R)-2-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidinyl]-3-cyclobutylpropanoate		C₃₁H₄₄FNO₃Si	详情	详情
(XX)	63996	benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidinyl]propanoate		C₂₅H₃₀FNO₃	详情	详情
(XXI)	63998	benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate		C₂₅H₂₈FNO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

Catalytic hydrogenolysis of the benzyl ester (XXI) affords the carboxylic acid (XXX). The aldehyde-acid (XXX) is then reductively aminated with piperidine (XXIX) in the presence of NaBH(OAc)3 to produce the title compound. (1,2)

参考文献中间体

合成目标

【1】 1,3,4 Trisubstituted pyrrolidine CCR5 receptor antagonists bearing 4-aminoheterocycle substituted piperidine side chains. Bioorg Med Chem Lett 2003, 13, 3, 427.
【2】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Kim, R.M. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6498161; WO 0059498 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	63998	benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate	C₂₅H₂₈FNO₃	详情	详情
(XXIX)	64004	N-(4-piperidinyl)-N-propyl-5-(trifluoromethyl)-2-pyrimidinamine; N-(4-piperidinyl)-N-propyl-N-[5-(trifluoromethyl)-2-pyrimidinyl]amine	C₁₃H₁₉F₃N₄	详情	详情
(XXX)	64005	(2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoic acid	C₁₈H₂₂FNO₃	详情	详情

Extended Information