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【结 构 式】 
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【分子编号】34776 【品名】(4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid 【CA登记号】72778-00-8 |
【 分 子 式 】C6H11NO2S 【 分 子 量 】161.22488 【元素组成】C 44.7% H 6.88% N 8.69% O 19.85% S 19.89% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(I)L-5,5-Dimethylthiazolidine-4-carboxylic acid (I) was protected as the N-Boc derivative (II) by treatment with Boc2O and subsequently coupled with L-methionine methyl ester (III) employing EDC and HOBt. The resulting Boc-dipeptide (IV) was then deprotected with trifluoroacetic acid to give (V). On the other hand, Boc-isoleucine (VI) was converted to the N-methoxy amide (VII) by condensation with N,O-dimethylhydroxylamine in the presence of O-benzotriazolyl tetramethyluronium hexafluorophosphate. Reduction of (VII) with LiAlH4 in cold Et2O produced the corresponding aldehyde (VIII). Reductive condensation of thiazolidine (V) with aldehyde (VIII) yielded adduct (IX). The Boc group of (IX) was then deprotected with trifluoroacetic acid to give (X).
| 【1】 Dong, Z.X.; Kim, S.H. (Biomeasure Inc.); Inhibitors of prenyl transferases. WO 9800409 . |
| 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) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (II) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (III) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (IV) | 38786 | tert-butyl (4R)-4-([[(1S)-1-(methoxycarbonyl)-3-(methylsulfanyl)propyl]amino]carbonyl)-5,5-dimethyl-1,3-thiazolidine-3-carboxylate | C17H30N2O5S2 | 详情 | 详情 | |
| (V) | 38787 | methyl (2S)-2-([[(4R)-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl]amino)-4-(methylsulfanyl)butanoate | C12H22N2O3S2 | 详情 | 详情 | |
| (VI) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (VII) | 38788 | tert-butyl (1S,2S)-1-[[methoxy(methyl)amino]carbonyl]-2-methylbutylcarbamate | 3350-19-4 | C13H26N2O4 | 详情 | 详情 |
| (VIII) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IX) | 38789 | methyl (2S)-2-[[((4R)-3-[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C23H43N3O5S2 | 详情 | 详情 | |
| (X) | 38790 | methyl (2S)-2-[([(4R)-3-[(2S,3S)-2-amino-3-methylpentyl]-5,5-dimethyl-1,3-thiazolidin-4-yl]carbonyl)amino]-4-(methylsulfanyl)butanoate | C18H35N3O3S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)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 |
合成路线4
该中间体在本合成路线中的序号：(VI)N-Boc-L-Tyrosine methyl ester (I) was alkylated with either 3-(dimethylamino)-1-propanol (II) under Mitsunobu conditions or with N,N-dimethyl-3-chloropropylamine (III) in the presence of K2CO3 to afford N-Boc-L-4-(3-dimethylaminopropoxy)phenylalanine methyl ester (IV). Subsequent acidic cleavage of the N-Boc protecting group of (IV) gave amino ester (V). N-Tosyl-L-5,5-dimethylthiaproline (VII) was obtained by treatment of L-5,5-dimethylthiaproline (VI) with p-toluenesulfonyl chloride in the presence of NaOH. Acid (VII) was then coupled to amino ester (V) using EDC and HOBt to furnish amide (VIII). Finally, basic hydrolysis of the methyl ester group of (VIII) yielded the title compound.
| 【1】 Grant, F.S.; Dressen, D.B.; Dappen, M.S.; et al.; CT747: A very potent and highly selective small molecule inhibitor of VLA4 that is metabolically stable. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 135. |
| 【2】 Ashwell, S.; Konradi, A.W.; Lombardo, L.J.; Dappen, M.S.; Baudy, R.B.; Kreft, A.; Grant, F.S.; Sarantakis, D.; Pleiss, M.A.; Semko, C.M.; Dressen, D.B.; Thorsett, E.D. (American Home Products Corp.; Athena Neurosciences, Inc.); Substd. phenylalanine type cpds. which inhibit leukocyte adhesion mediated by VLA-4. WO 9906431 . |
| 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) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
| (II) | 37173 | 3-(dimethylamino)-1-propanol | 3179-63-3 | C5H13NO | 详情 | 详情 |
| (III) | 24581 | 3-(Dimethylamino)propyl chloride; 3-Chloro-N,N-dimethyl-1-propanamine | 5407-04-5 | C5H12ClN | 详情 | 详情 |
| (IV) | 45680 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C20H32N2O5 | 详情 | 详情 | |
| (V) | 45681 | methyl (2S)-2-amino-3-[4-[3-(dimethylamino)propoxy]phenyl]propanoate | C15H24N2O3 | 详情 | 详情 | |
| (VI) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (VII) | 45682 | (4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidine-4-carboxylic acid | C13H17NO4S2 | 详情 | 详情 | |
| (VIII) | 45683 | methyl (2S)-3-[4-[3-(dimethylamino)propoxy]phenyl]-2-[([(4R)-5,5-dimethyl-3-[(4-methylphenyl)sulfonyl]-1,3-thiazolidin-4-yl]carbonyl)amino]propanoate | C28H39N3O6S2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)5,5-Dimethylthiazolidine-4-carboxylic acid (I) is protected as the N-Boc derivative (II), and subsequently treated with allyl bromide (III) and triethylamine to form the allyl ester (IV). Acidic Boc group cleavage in (IV) provides amino ester (V), which is further coupled to the lactone acid (VI) to furnish amide (VII). The allyl ester group of (VII) is then removed by treatment with morpholine and Pd(PPh3)4, yielding acid (VIII). This is then coupled to (3,5-dimethylisothiazol-4-yl)methyl amine (IX) employing EDC/HOAt to afford the corresponding amide (X). Lactone ring opening in (X) by hydrolysis with LiOH gives rise to the hydroxy acid (XI), which is further protected as the silyl ether (XII) employing t-butyldimethylsilyl triflate.
| 【1】 Bohn, J.; Lu, Z.; Raghavan, S.; Charest, M.; Stahlhut, M.; Rutkowski, C.A.; Himmelberger, A.L.; Olsen, D.B.; Scheleif, W.A.; Carella, A.; Gabryelski, L.; Jin, L.; Lin, J.H.; Tata, J.R.; Chapman, K.; Synthesis of highly potent HIV protease inhibitors with activity against protease resistant virus. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 205. |
| 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) | 34776 | (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | 72778-00-8 | C6H11NO2S | 详情 | 详情 |
| (II) | 34777 | (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C11H19NO4S | 详情 | 详情 | |
| (III) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (IV) | 65046 | 4-allyl 3-(tert-butyl) (4R)-5,5-dimethyl-1,3-thiazolidine-3,4-dicarboxylate | C14H23NO4S | 详情 | 详情 | |
| (V) | 65047 | allyl (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate | C9H15NO2S | 详情 | 详情 | |
| (VI) | 65048 | (2S,4R)-4-benzyl-5-oxotetrahydro-2-furancarboxylic acid | C12H12O4 | 详情 | 详情 | |
| (VII) | 65049 | allyl (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylate | C21H25NO5S | 详情 | 详情 | |
| (VIII) | 65050 | (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid | C18H21NO5S | 详情 | 详情 | |
| (IX) | 65059 | (3,5-dimethyl-4-isothiazolyl)methanamine; (3,5-dimethyl-4-isothiazolyl)methylamine | C6H10N2S | 详情 | 详情 | |
| (X) | 65060 | (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-N-[(3,5-dimethyl-4-isothiazolyl)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide | C24H29N3O4S2 | 详情 | 详情 | |
| (XI) | 65061 | (2R,4S)-2-benzyl-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-4-hydroxy-5-oxopentanoic acid | C24H31N3O5S2 | 详情 | 详情 | |
| (XII) | 65062 | (2R,4S)-2-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-5-oxopentanoic acid | C30H45N3O5S2Si | 详情 | 详情 |