(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】60435

【品名】(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid

【CA登记号】

【分子式】C₁₁H₁₁Cl₂NO₄S

【分子量】324.18408

【元素组成】C 40.75% H 3.42% Cl 21.87% N 4.32% O 19.74% S 9.89%

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：(IV)

Acylation of L-proline t-butyl ester (I) with 3,5-dichlorobenzenesulfonyl chloride (II) affords sulfonamide (III). The tert-butyl ester group of (III) is then cleaved by treatment with aqueous trifluoroacetic acid, yielding carboxylic acid (IV). Coupling of sulfonyl proline (IV) with the racemic 3-endo-amino-bicyclo[2.2.1]heptane-2-endo-carboxylate (V) leads to a mixture of four diastereoisomeric amides, resulting from carboxylate group epimerization. This mixture can be separated into two pairs of diastereoisomers (VI) and (VII) by flash chromatography. The desired diastereoisomeric mixture of esters (VII) is then hydrolyzed under alkaline conditions to furnish the title carboxylic acid along with its epimer (VIII).

参考文献中间体

合成目标

【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325.
【2】 Hagmann, W.K.; MacCoss, M.; Chang, L. (Merck & Co., Inc.); Cyclic amino acid derivs. as cell adhesion inhibitors. JP 2001523711; US 6271252; WO 9926615 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
rac-(V)	60436	ethyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate	C₁₀H₁₇NO₂	详情	详情
(I)	19832	tert-butyl (2S)-2-pyrrolidinecarboxylate	C₉H₁₇NO₂	详情	详情
(II)	59023	3,5-dichlorobenzenesulfonyl chloride	C₆H₃Cl₃O₂S	详情	详情
(III)	60434	tert-butyl (2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylate	C₁₅H₁₉Cl₂NO₄S	详情	详情
(IV)	60435	(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid	C₁₁H₁₁Cl₂NO₄S	详情	详情
(VI)	60437	ethyl (1R,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate	C₂₁H₂₆Cl₂N₂O₅S	详情	详情
(VII)	60438	ethyl (1S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate	C₂₁H₂₆Cl₂N₂O₅S	详情	详情
(VIII)	60439	(1S,2S,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylic acid	C₁₉H₂₂Cl₂N₂O₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

In an alternative procedure, Diels-Alder condensation between methyl (E)-3-nitroacrylate (I) and cyclopentadiene (II) produces a mixture of bicyclic adducts (III) and (IV) in a 6:1 ratio. After chromatographic isolation of the major isomer (III), catalytic hydrogenation of its olefin double bond in the presence of PtO2 yields nitro ester (V). Subsequent nitro group reduction in (V) by transfer hydrogenation with ammonium formate and Pd/C produces the racemic amino ester (VI). Coupling of racemic (VI) with carboxylic acid (VII) leads to a mixture of diastereoisomeric amides (VIII) and (IX). Finally, after alkaline hydrolysis of its methyl ester function, the target carboxylic acid isomer is isolated by flash chromatography.

参考文献中间体

合成目标

【1】 Chang, L.L.; Truong, Q.; Doss, G.; et al.; Orally active, conformationally constrained small molecule VLA-4 antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 325.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
rac-(V)	60443	methyl (1S,2R,3R,4R)-3-nitrobicyclo[2.2.1]heptane-2-carboxylate	C₉H₁₃NO₄	详情	详情
rac-(VI)	60444	methyl (1S,2R,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylate	C₉H₁₅NO₂	详情	详情
(I)	60440	methyl (E)-3-nitro-2-propenoate	C₄H₅NO₄	详情	详情
(II)	11183	1,3-Cyclopentadiene	C₅H₆	详情	详情
(III)	60441	methyl (1R,2R,3R,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate	C₉H₁₁NO₄	详情	详情
(IV)	60442	methyl (1R,2S,3S,4S)-3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate	C₉H₁₁NO₄	详情	详情
(VII)	60435	(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-pyrrolidinecarboxylic acid	C₁₁H₁₁Cl₂NO₄S	详情	详情
(VIII)	60445	methyl (1S,2R,3R,4R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate	C₂₀H₂₄Cl₂N₂O₅S	详情	详情
(IX)	60446	methyl (1R,2S,3S,4S)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]bicyclo[2.2.1]heptane-2-carboxylate	C₂₀H₂₄Cl₂N₂O₅S	详情	详情

Extended Information