3,5-dichlorobenzenesulfonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】59023

【品名】3,5-dichlorobenzenesulfonyl chloride

【CA登记号】

【分子式】C₆H₃Cl₃O₂S

【分子量】245.51272

【元素组成】C 29.35% H 1.23% Cl 43.32% O 13.03% S 13.06%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(XIV)

Coupling of p-aminophenylacetic acid (IX) with o-tolyl isocyanate (X) produces urea (XI). This is subsequently condensed with the intermediate tripeptide (VIII) in the presence of HATU to yield amide (XII). Hydrogenolysis of the N-benzyloxycarbonyl group of (XII) then gives amine (XIII). Finally, acylation of amine (XIII) with 3,5-dichlorobenzensulfonyl chloride (XIV), followed by alkaline hydrolysis of the methyl ester group furnishes the title compound.

参考文献中间体

合成目标

【1】 Lee, W.-C.; Scott, D.; Cornebise, M.; Petter, R. (Biogen Idec Inc.); Cell adhesion inhibitors. EP 1265606; JP 2003506491; US 6630503; WO 0112186 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	64990	phenylmethyl 2-[({3-{[4-methyl-2-(methylamino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate		C₂₅H₃₈N₄O₆	详情	详情
(IX)	21229	2-(4-Aminophenyl)acetic acid	5345-54-0	C₈H₉NO₂	详情	详情
(X)	27106	1-isocyanato-2-methylbenzene	614-68-6	C₈H₇NO	详情	详情
(XI)	27107	2-[4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid		C₁₆H₁₆N₂O₃	详情	详情
(XII)	64991	phenylmethyl 2-[({3-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-1-[(methyloxy)carbonyl]propyl}amino)carbonyl]-1-pyrrolidinecarboxylate		C₄₁H₅₂N₆O₈	详情	详情
(XIII)	64992	methyl 4-{[4-methyl-2-(methyl{2-[4-({[(2-methylphenyl)amino]carbonyl}amino)phenyl]acetyl}amino)pentanoyl]amino}-2-[(2-pyrrolidinylcarbonyl)amino]butanoate		C₃₃H₄₆N₆O₆	详情	详情
(XIV)	59023	3,5-dichlorobenzenesulfonyl chloride		C₆H₃Cl₃O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Condensation of 3,5-dichlorobenzenesulfonyl chloride (VIII) with (S)-azetidine-2-carboxylic acid (IX) under Schotten-Baumann conditions gives sulfonamide (X). This is subsequently coupled with aminoester (VII) by means of PyBOP to afford amide (XI). The methyl ester group of (XI) is finally hydrolyzed to the target carboxylic acid employing LiOH.

参考文献中间体

合成目标

【1】 Kopka, I.E.; Mumford, R.A.; Lin, L.S.; et al.; The discovery of acylated beta-amino acids as potent and orally bioavailable VLA-4 antagonists. Bioorg Med Chem Lett 2002, 12, 4, 611.
【2】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Kopka, I.E.; Mills, S.G.; MacCoss, M.; Magriotis, P.A. (Merck & Co., Inc.); Substd. beta-alanine derivs. as cell adhesion inhibitors. WO 0071572 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	59023	3,5-dichlorobenzenesulfonyl chloride		C₆H₃Cl₃O₂S	详情	详情
(IX)	26204	(2S)-2-azetidinecarboxylic acid; (S)-(-)-Azetidine carboxylic acid	2133-34-8	C₄H₇NO₂	详情	详情
(X)	59024	(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-azetidinecarboxylic acid		C₁₀H₉Cl₂NO₄S	详情	详情
(XI)	59022	methyl (3R)-3-amino-3-(4-methoxyphenyl)propanoate		C₁₁H₁₅NO₃	详情	详情
(XII)	59025	methyl (3R)-3-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]azetidinyl}carbonyl)amino]-3-(4-methoxyphenyl)propanoate		C₂₁H₂₂Cl₂N₂O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

N-Boc-L-Phenylalanine (I) is converted into the tert-butyl ester (II) upon treatment with tert-butyl trichloroacetimidate and boron trifluoride. Then, selective removal of the N-Boc group of (II) with HCl in EtOAc provides L-phenylalanine ester (III). Coupling of (III) with N-Cbz-2-methylproline (IV) furnishes dipeptide (V). After hydrogenolysis of the N-Cbz group of (V), the resultant amine (VI) is acylated by means of 3,5-dichlorobenzenesulfonyl chloride (VII), yielding sulfonamide (VIII). The tert-butyl ester group of (VIII) is finally cleaved by treatment with trifluoroacetic acid in CH2Cl2

参考文献中间体

合成目标

【1】 Hagmann, W.K.; Durette, P.L.; Mumford, R.A.; Mills, S.G.; Kevin, N.J.; Schmidt, J.A.; MacCoss, M.; Van Riper, G.M. (Merck & Co., Inc.); Heterocyclic amide cpds. as cell adhesion inhibitors. EP 1001764; WO 9853814 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	61667	tert-butyl 2,2,2-trichloroethanimidoate	C₆H₁₀Cl₃NO	详情	详情
(I)	22184	(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid	C₁₄H₁₉NO₄	详情	详情
(II)	60836	tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate	C₁₈H₂₇NO₄	详情	详情
(III)	60837	tert-butyl (2S)-2-amino-3-phenylpropanoate	C₁₃H₁₉NO₂	详情	详情
(IV)	60838	(2S)-1-[(benzyloxy)carbonyl]-2-methyl-2-pyrrolidinecarboxylic acid	C₁₄H₁₇NO₄	详情	详情
(V)	60839	benzyl (2S)-2-({[(1S)-1-benzyl-2-(tert-butoxy)-2-oxoethyl]amino}carbonyl)-2-methyl-1-pyrrolidinecarboxylate	C₂₇H₃₄N₂O₅	详情	详情
(VI)	60840	tert-butyl (2S)-2-({[(2S)-2-methylpyrrolidinyl]carbonyl}amino)-3-phenylpropanoate	C₁₉H₂₈N₂O₃	详情	详情
(VII)	59023	3,5-dichlorobenzenesulfonyl chloride	C₆H₃Cl₃O₂S	详情	详情
(VIII)	60841	tert-butyl (2S)-2-[({(2S)-1-[(3,5-dichlorophenyl)sulfonyl]-2-methylpyrrolidinyl}carbonyl)amino]-3-phenylpropanoate	C₂₅H₃₀Cl₂N₂O₅S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

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

Extended Information