-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】3-Cyclobutyl-2(R)-[3(S)-(3-fluorophenyl)-4(S)-[4-[N-propyl-N-[5-(trifluoromethyl)pyrimidin-2-yl]amino]piperidin-1-ylmethyl]pyrrolidin-1-yl]propionic acid

【CA登记号】301223-53-0

【分子式】C₃₁H₄₁F₄N₅O₂

【分子量】591.69832

【开发单位】Merck & Co. (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Chemokine CCR5 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

3-Fluorocinnamic acid (I) is activated as the mixed anhydride (II) with pivaloyl chloride and subsequently coupled to the lithium anion of (S)-4-benzyloxazolidin-2-one (III) to provide the N-acyl oxazolidinone (IV). Cycloaddition of the cinnamoyl derivative (IV) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (V) in the presence of trifluoroacetic acid gives rise to a diastereomeric mixture of trans-pyrrolidines (VI) and (VII), separable by column chromatography. The desired isomer (VII) is then reduced by LiAlH4 to alcohol (VIII), which is further protected as the silyl ether (IX). Debenzylation of (IX) by transfer hydrogenolysis with ammonium formate and Pearlman's catalyst furnishes pyrrolidine (X).

参考文献中间体

【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
(I)	63980	m-Fluorocinnamic acid; (E)-3-(3-fluorophenyl)-2-propenoic acid		C₉H₇FO₂	详情	详情
(II)	63981	1,1-dimethylpropanoic (E)-2-(3-fluorophenyl)-2-propenoic anhydride		C₁₄H₁₅FO₃	详情	详情
(III)	63982	(4S)-4-benzyl-1,3-oxazolidin-2-one		C₁₀H₁₁NO₂	详情	详情
(IV)	63983	(4S)-4-benzyl-3-[(E)-3-(3-fluorophenyl)-2-propenoyl]-1,3-oxazolidin-2-one		C₁₉H₁₆FNO₃	详情	详情
(V)	25556	N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine	1871-96-1	C₁₃H₂₃NOSi	详情	详情
(VI)	63984	(4S)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one		C₂₈H₂₇FN₂O₃	详情	详情
(VII)	63985	(4S)-4-benzyl-3-{[(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one		C₂₈H₂₇FN₂O₃	详情	详情
(VIII)	63986	[(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]methanol		C₁₈H₂₀FNO	详情	详情
(IX)	63987	1-[(1S,2S)-4-benzyl-2-propylcyclopentyl]-3-methylbenzene		C₂₂H₂₈	详情	详情
(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

合成路线2

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

【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3

Reductive amination of N-Boc-4-piperidone (XXII) with benzylamine, followed by benzyl group hydrogenolysis of the resultant secondary amine (XXIII) gives rise to N-Boc-4-aminopiperidine (XXIV). This is then condensed with 2-chloro-5-trifluoromethylpyrimidine (XXV) to furnish adduct (XXVI). Subsequent alkylation of amine (XXVI) with allyl bromide in the presence of sodium hexamethyldisilazide affords the N-allyl amine (XXVII), which is further hydrogenated to the N-propyl analogue (XXVIII). Acidic hydrolysis of (XXVIII) then removes the N-Boc protecting group, providing piperidine (XXIX). (1,2)

参考文献中间体

【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	CAS号	分子式	供应商	用于合成
(XXII)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(XXIII)	63999	tert-butyl 4-(benzylamino)-1-piperidinecarboxylate		C₁₇H₂₆N₂O₂	详情	详情
(XXIV)	28914	benzyl 4-ethyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate		C₁₆H₁₉N₃O₂	详情	详情
(XXV)	64000	2-chloro-5-(trifluoromethyl)pyrimidine		C₅H₂ClF₃N₂	详情	详情
(XXVI)	64001	tert-butyl 4-{[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate		C₁₅H₂₁F₃N₄O₂	详情	详情
(XXVII)	64002	tert-butyl 4-{allyl[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate		C₁₈H₂₅F₃N₄O₂	详情	详情
(XXVIII)	64003	tert-butyl 4-{propyl[5-(trifluoromethyl)-2-pyrimidinyl]amino}-1-piperidinecarboxylate		C₁₈H₂₇F₃N₄O₂	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

合成路线4

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

【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

Drug NewChemical Entity Original Patent(1)