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【结 构 式】 
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【分子编号】12567 【品名】(2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine 【CA登记号】1113-41-3 |
【 分 子 式 】C5H11NO2S 【 分 子 量 】149.21388 【元素组成】C 40.25% H 7.43% N 9.39% O 21.44% S 21.49% |
合成路线1
该中间体在本合成路线中的序号：(X)5) The cyclization of D-penicillamine (X) with 2-methoxybenzaldehyde (XI) in ethanol gives (4S)-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XII), which by acetylation with hot acetic anhydride and fractional crystallization yields the chiral (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethylthiazolidine-4-carboxylic acid (XIII). The esterification of (XIII) with the hydroxyl group of benzothiazinone (I) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in DMF affords a diastereomeric mixture of esters, which is separated by fractional crystallization giving ester (XIV). Elimination of the chiral auxiliar by treatment with calcium borohydride in THF or sodium borohydride in ethanol (2) gives (R)-2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XV), which is condensed with 3-bromopropanol (XVI) by means of triphenylphosphine and diethyl azodicarboxylate in DMF or THF yielding (R)-2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (XVII). Finally, this compound is condensed with the secondary amine (IV) by means of NaI and NaHCO3 as already described, and treated with fumaric acid as before.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229. |
| 【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 . |
| 【3】 Iwao, J.; Iso, T.; Kawashima, Y. (Santen Pharmaceutical Co., Ltd.); Sulfur-containing polycyclic cpds. JP 1988104969 . |
| 【4】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905. |
| 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) | 12567 | (2S)-2-Amino-3-methyl-3-sulfanylbutyric acid; Penicillamine; 3-Mercapto-L-valine | 1113-41-3 | C5H11NO2S | 详情 | 详情 |
| (XI) | 12568 | 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde | 135-02-4 | C8H8O2 | 详情 | 详情 |
| (XII) | 12569 | (4S)-2-(2-Methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C13H17NO3S | 详情 | 详情 | |
| (XIII) | 12570 | (2S,4S)-3-Acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C15H19NO4S | 详情 | 详情 | |
| (XIV) | 12571 | 4-methoxy-2-[(2R)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl]phenyl (2S,4S)-3-acetyl-2-(2-methoxyphenyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate | C31H32N2O6S2 | 详情 | 详情 | |
| (XV) | 12572 | (2R)-2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C16H15NO3S | 详情 | 详情 | |
| (XVI) | 12573 | 3-Bromo-1-propanol; 3-Bromopropanol | 627-18-9 | C3H7BrO | 详情 | 详情 |
| (XVII) | 12574 | (2R)-2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C19H20BrNO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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).
| 【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3
该中间体在本合成路线中的序号：(I)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.
| 【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4
该中间体在本合成路线中的序号：(I)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).
| 【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 |
合成路线5
该中间体在本合成路线中的序号：(I)Treatment of penicillamine (I) with formaldehyde produced thiazolidine (II), which was then protected with Boc2O to give carbamate (III). Coupling of (III) with 2-methylbenzylamine (IV) by means of either diphenylphosphoryl chloride (DPPCl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) or dicyclohexylcarbodiimide (DCC) afforded the corresponding amide (V). After acid cleavage of the Boc group of (V), the deprotected thiazolidine (VI) was coupled with N-Boc-(S,S)-3-amino-2-hydroxy-4-phenylbutyric acid (VII) using EDC to give diamide (VIII). Further acid deprotection of the Boc group of (VIII) yielded (IX). This was finally coupled with 3-hydroxy-2-methylbenzoic acid (X) to furnish the title compound. Alternatively, amine (IX) was coupled with 3-acetoxy-2-methylbenzoic acid (XI) to afford (XII), which was then deacetylated using NaOH in MeOH.
| 【1】 Mimoto, T.; Takaku, H.; Kato, R.; et al.; Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine. J Med Chem 1999, 42, 10, 1789. |
| 【2】 Kiso, Y.; Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors. Yuki Gosei Kagaku Kyokaishi 1998, 56, 11, 896. |
| 【3】 Kato, R.; Mimoto, T.; Fukazawa, T.; Morohashi, N.; Kiso, Y. (Japan Energy Corp.); HIV-protease inhibitors. CA 2179935; EP 0751145; JP 1998025242 . |
| 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) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (III) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (IV) | 34778 | (2-methylphenyl)methanamine; 2-methylbenzylamine | 89-93-0 | C8H11N | 详情 | 详情 |
| (V) | 34779 | tert-butyl (4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidine-3-carboxylate | C19H28N2O3S | 详情 | 详情 | |
| (VI) | 34780 | (4R)-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C14H20N2OS | 详情 | 详情 | |
| (VII) | 34781 | (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-phenylbutyric acid | C16H23NO4 | 详情 | 详情 | |
| (VIII) | 34782 | tert-butyl (1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropylcarbamate | C30H41N3O4S | 详情 | 详情 | |
| (IX) | 34783 | (4R)-3-[(2S,3S)-3-amino-2-methyl-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C25H33N3O2S | 详情 | 详情 | |
| (X) | 16759 | 3-hydroxy-2-methylbenzoic acid | 603-80-5 | C8H8O3 | 详情 | 详情 |
| (XI) | 34784 | 3-(acetoxy)-2-methylbenzoic acid | 168899-58-9 | C10H10O4 | 详情 | 详情 |
| (XII) | 34785 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-methylphenyl acetate | C35H41N3O5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Treatment of penicillamine (I) with formaldehyde produced thiazolidine (II), which was then protected with Boc2O to give carbamate (III). Coupling of (III) with 2-methylbenzylamine (IV) by means of either diphenylphosphoryl chloride (DPP-Cl) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) afforded the corresponding amide (V). After acid cleavage of the Boc group of (V), the deprotected thiazolidine (VI) was coupled with N-Boc-(S,S)-3-amino-2-hydroxy-4-phenylbutyric acid (VII) using EDC to give diamide (VIII). Further acid deprotection of the Boc group of (VIII) yielded (IX). This was finally coupled with 2-ethyl-3-hydroxybenzoic acid (X) to furnish the title compound. Alternatively, amine (IX) was coupled with 3-acetoxy-2-ethylbenzoic acid (XI) to afford (XII), which was then deacetylated using NaOH in MeOH.
| 【1】 Kiso, Y.; Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors. Yuki Gosei Kagaku Kyokaishi 1998, 56, 11, 896. |
| 【2】 Mimoto, T.; Takaku, H.; Kato, R.; et al.; Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine. J Med Chem 1999, 42, 10, 1789. |
| 【3】 Kato, R.; Mimoto, T.; Fukazawa, T.; Morohashi, N.; Kiso, Y. (Japan Energy Corp.); HIV-protease inhibitors. CA 2179935; EP 0751145; JP 1998025242 . |
| 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) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (III) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (IV) | 34778 | (2-methylphenyl)methanamine; 2-methylbenzylamine | 89-93-0 | C8H11N | 详情 | 详情 |
| (V) | 34779 | tert-butyl (4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidine-3-carboxylate | C19H28N2O3S | 详情 | 详情 | |
| (VI) | 34780 | (4R)-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C14H20N2OS | 详情 | 详情 | |
| (VII) | 34781 | (2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-methyl-4-phenylbutyric acid | C16H23NO4 | 详情 | 详情 | |
| (VIII) | 34782 | tert-butyl (1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropylcarbamate | C30H41N3O4S | 详情 | 详情 | |
| (IX) | 34783 | (4R)-3-[(2S,3S)-3-amino-2-methyl-4-phenylbutanoyl]-5,5-dimethyl-N-(2-methylbenzyl)-1,3-thiazolidine-4-carboxamide | C25H33N3O2S | 详情 | 详情 | |
| (X) | 34786 | 2-ethyl-3-hydroxybenzoic acid | C9H10O3 | 详情 | 详情 | |
| (XI) | 34787 | 3-(acetoxy)-2-ethylbenzoic acid | C11H12O4 | 详情 | 详情 | |
| (XII) | 34788 | 3-([[(1S,2S)-1-benzyl-3-((4R)-5,5-dimethyl-4-[[(2-methylbenzyl)amino]carbonyl]-1,3-thiazolidin-3-yl)-2-methyl-3-oxopropyl]amino]carbonyl)-2-ethylphenyl acetate | C36H43N3O5S | 详情 | 详情 |