Prinomastat, AG-3362(maleate), AG-3354(HCl), AG-3340, -Drug Synthesis Database

【结构式】

【药物名称】Prinomastat, AG-3362(maleate), AG-3354(HCl), AG-3340

【化学名称】2,2-Dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]perhydro-1,4-thiazine-3(S)-carbohydroxamic acid
　　　　　　N-Hydroxy-2,2-dimethyl-4-[4-(4-pyridinyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxamide

【CA登记号】192329-42-3

【分子式】C₁₈H₂₁N₃O₅S₂

【分子量】423.51317

【开发单位】Agouron (Originator)

【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, Glioblastoma MultiformeTherapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, OCULAR MEDICATIONS, Oncolytic Drugs, Ophthalmic Drugs, Prostate Cancer Therapy, Treatment of Age-Related Macular Degeneration, Angiogenesis Inhibitors, MMP-2 (Gelatinase A) Inhibitors, MMP-9 (Gelatinase B) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

1) The esterification of D-penicillamine (I) with trimethylsilyl chloride and DBU in DMF gives the expected ester (II), which is cyclized with 1,2-dibromoethane by means of DBU and DIEA in DMF and protected at the amino group with Fmoc-Cl and NMM to afford 4-(9-fluorenylmethoxycarbonyl)-2,2-dimethylthiomorpholine-3(S)-carboxylic acid (III), which by treatment with O-[tert-butyl(diphenyl)silyl]hydroxylamine (TBDPSO-NH2) and EDC in dichloro-methane yields the silylated carbohydroxamic acid (IV). The removal of the Fmoc group of (IV) with diethylamine in THF affords (V), which is sulfonated with 4-(4-pyridyloxy)phenylsulfonyl chloride (VI) and NMM in dichloroethane to give the protected prinomastat (VII). Finally, this compound is desilylated with concentrated HCl in methanol. The intermediate (VI) is obtained by condensation of 4-chloropyridine (VIII) with phenol (IX) at 150 C to give 4-phenoxypyridine (X), which is then sulfonated with chlorosulfonic acid and treated with oxalyl chloride to afford the desired sulfonyl chloride (VI).

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150.
【2】 Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses. US 5753653 .
【3】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .

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)	12567	(2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine	1113-41-3	C₅H₁₁NO₂S	详情	详情
(II)	32883	trimethylsilyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate		C₈H₁₉NO₂SSi	详情	详情
(III)	32884	(3S)-4-[(9H-fluoren-9-ylmethoxy)carbonyl]-2,2-dimethyl-3-thiomorpholinecarboxylic acid		C₂₂H₂₃NO₄S	详情	详情
(IV)	32885	9H-fluoren-9-ylmethyl (3S)-3-[([[tert-butyl(diphenyl)silyl]oxy]amino)carbonyl]-2,2-dimethyl-4-thiomorpholinecarboxylate		C₃₈H₄₂N₂O₄SSi	详情	详情
(V)	32886	(3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-3-thiomorpholinecarboxamide		C₂₃H₃₂N₂O₂SSi	详情	详情
(VI)	32887	4-(4-pyridinyloxy)benzenesulfonyl chloride		C₁₁H₈ClNO₃S	详情	详情
(VII)	32888	(3S)-N-[[tert-butyl(diphenyl)silyl]oxy]-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxamide		C₃₄H₃₉N₃O₅S₂Si	详情	详情
(VIII)	32889	4-chloropyridine	7379-35-3	C₅H₄ClN	详情	详情
(IX)	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(X)	32890	4-phenoxypyridine; phenyl 4-pyridinyl ether	4783-86-2	C₁₁H₉NO	详情	详情

合成路线2

The silylation of D-penicillamine (I) with dimethylhexylsilyl chloride (Dmhs-Cl) and DBU gives the ester (XI), which is cyclized with 1,2-dichloroethane and DBU in DMF, yielding 2,2-dimethylthiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XII). The sulfonation of (XII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid dimethylhexylsilyl ester (XIII), which is desilylated in refluxing methanol to give the free acid (XIV) Finally, this compound is treated with oxalyl chloride and hydroxylamine in dichloromethane.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150.
【2】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .

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)	12567	(2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine	1113-41-3	C₅H₁₁NO₂S	详情	详情
(VI)	32887	4-(4-pyridinyloxy)benzenesulfonyl chloride		C₁₁H₈ClNO₃S	详情	详情
(XI)	32891	dimethyl(1,1,2-trimethylpropyl)silyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate		C₁₃H₂₉NO₂SSi	详情	详情
(XII)	32892	dimethyl(1,1,2-trimethylpropyl)silyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate		C₁₅H₃₁NO₂SSi	详情	详情
(XIII)	32893	dimethyl(1,1,2-trimethylpropyl)silyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate		C₂₆H₃₈N₂O₅S₂Si	详情	详情
(XIV)	32894	(3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid		C₁₈H₂₀N₂O₅S₂	详情	详情

合成路线3

The cyclization of D-penicillamine (I) with 1,2-dichloroethane by means of DBU and TMS-Cl in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid (XV), which is treated with isobutylene (XVI) and sulfuric acid in dioxane to yield the corresponding tert-butyl ester (XVII). The sulfonation of (XVII) with the sulfonyl chloride (VI) as before affords 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid tert-butyl ester (XVIII), which is finally treated with HCl in refluxing dioxane to give the previously reported free acid intermediate (XIV). The cyclization of D-penicillamine methyl ester (XIX) with 1,2-dibromoethane by means of DBU in DMF gives 2,2-dimethylthiomorpholine-3(S)-carboxylic acid methyl ester (XX), which is sulfonated with the sulfonyl chloride (VI) as before, affording 2,2-dimethyl-4-[4-(4-pyridyloxy)phenylsulfonyl]thiomorpholine-3(S)-carboxylic acid methyl ester (XXI). Finally, this compound is hydrolyzed with refluxing aqueous HCl to yield the previously reported intermediate (XIV).

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Prinomastat. Drugs Fut 2000, 25, 2, 150.
【2】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .

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)	12567	(2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine	1113-41-3	C₅H₁₁NO₂S	详情	详情
(VI)	32887	4-(4-pyridinyloxy)benzenesulfonyl chloride		C₁₁H₈ClNO₃S	详情	详情
(XIV)	32894	(3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylic acid		C₁₈H₂₀N₂O₅S₂	详情	详情
(XV)	32895	(3S)-2,2-dimethyl-3-thiomorpholinecarboxylic acid		C₇H₁₃NO₂S	详情	详情
(XVI)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(XVII)	32896	tert-butyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate		C₁₁H₂₁NO₂S	详情	详情
(XVIII)	32897	tert-butyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate		C₂₂H₂₈N₂O₅S₂	详情	详情
(XIX)	32898	methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate; methyl (2S)-2-amino-3-methyl-3-sulfanylbutanoate		C₆H₁₃NO₂S	详情	详情
(XX)	32899	methyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylate		C₈H₁₅NO₂S	详情	详情
(XXI)	32900	methyl (3S)-2,2-dimethyl-4-[[4-(4-pyridinyloxy)phenyl]sulfonyl]-3-thiomorpholinecarboxylate		C₁₉H₂₂N₂O₅S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)