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【结 构 式】 
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【分子编号】28895 【品名】4,5-dihydro-1,3-thiazol-2-ylhydrosulfide 【CA登记号】96-53-7 |
【 分 子 式 】C3H5NS2 【 分 子 量 】119.21144 【元素组成】C 30.23% H 4.23% N 11.75% S 53.8% |
合成路线1
该中间体在本合成路线中的序号：(III)Antineopleston A10 (A10) can be obtained by two different ways: 1) A10 has been synthesized in two steps: Condensation of phenylacetic acid (I) with L-glutamine (V) to give phenylacetyl-L-glutamine (VI), followed by intramolecular cyclization of the latter. In the first step (I) is activated by reacting with various reagents such as HOSu (N-hydroxysuccinimide) (II) in the presence of DCC, DCC (N,N-dicyclohexylcarbodiimide) or 2-mercaptothiazoline (III) in the presence of DCC to afford the intermediates (IVa), (IVb) and (IVc), respectively. Without isolation, the intermediate (IVa), (IVb) or (IVc) is treated with a solution of L-glutamine in CH3CN:H2O (2:1) containing NaHCO3 to give (VI) in 60, 87 and 82% yields, respectively. In the second step (VI) is converted to the activated intermediate (IXa) or (IXb) by treatment with CDI (1,1'-carbonydiimidazole) (VII) or HOSu (VIII) in the presence of DCC. Finally, intramolecular cyclization of (IXa) or (IXb) is effected by treating the latter at 80 C to yield A10 in 85 or 82% yield, respectively. 2) Reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords phenylacetyl-L-glutamine (VI), which is heated at 160 C to give A10.
| 【1】 Verhoef, J.; Schmitz, F.-J.; Fluit, A.C.; Milatovic, D.; 13th Intl Cong Chemother (Aug. 28-Sept. 2, Vienna) 1983, 50, 2, PS 12.4-11-4. |
| 【2】 Burzynski, S.R. (Burzynski Research Institute); Purified antineoplaston factions and methods of treating neoplastic disease. EP 0069232; JP 5032548; JP 5058886; JP 58010521; US 4470970 . |
| 【3】 Burzynski, S.R.; Hai, T.T.; Antineoplaston A10. Drugs Fut 1985, 10, 2, 103. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (IVa) | 24947 | 1-[(2-phenylacetyl)oxy]-2,5-pyrrolidinedione | C12H11NO4 | 详情 | 详情 | |
| (IVb) | 28896 | phenylacetic anhydride | C16H14O3 | 详情 | 详情 | |
| (IVc) | 28897 | 2-phenyl-1-(2-thioxo-1,3-thiazolidin-3-yl)-1-ethanone | C11H11NOS2 | 详情 | 详情 | |
| (IXa) | 28899 | (3S)-4-(1H-imidazol-1-yl)-4-oxo-3-[(2-phenylacetyl)amino]butanamide | C15H16N4O3 | 详情 | 详情 | |
| (IXb) | 28900 | (3S)-4-[(2,5-dioxo-1-pyrrolidinyl)oxy]-4-oxo-3-[(2-phenylacetyl)amino]butanamide | C16H17N3O6 | 详情 | 详情 | |
| (I) | 16148 | Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid | 103-82-2 | C8H8O2 | 详情 | 详情 |
| (II) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (III) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
| (V) | 24948 | L-glutamine | 56-85-9 | C5H10N2O3 | 详情 | 详情 |
| (VI) | 28898 | (2S)-4-amino-4-oxo-2-[(2-phenylacetyl)amino]butyric acid | C12H14N2O4 | 详情 | 详情 | |
| (VII) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (VIII) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).
| 【1】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 31396 | 1-azabicyclo[1.1.0]butane | C3H5N | 详情 | 详情 | |
| (XI) | 31404 | 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol | 179337-57-6 | C6H10N2S2 | 详情 | 详情 |
| (XIV) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
| (XV) | 31407 | 3-azetidinyl 4,5-dihydro-1,3-thiazol-2-yl sulfide; 2-(3-azetidinylsulfanyl)-4,5-dihydro-1,3-thiazole | C6H10N2S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)A further procedure consisted in the opening of 1-azabicyclobutane (III) with 2-mercaptothiazoline (XIV) to give (XV). Subsequent rearrangement of (XV) in the presence of methanesulfonic acid produced thiazolinyl azetidine (XI).
| 【1】 Abe, T.; Isoda, T.; Sato, C.; Mihira, A.; Tamai, S.; Kumagai, T. (Lederle (Japan), Ltd.); 2-(1-(1,3-Thiazolin-2-yl)azetidin-3-yl)thio-carbapenem derivs.. EP 0632039; EP 0717042; JP 1996053453; US 5534510; US 5659043; US 5783703 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 31396 | 1-azabicyclo[1.1.0]butane | C3H5N | 详情 | 详情 | |
| (XI) | 31404 | 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinylhydrosulfide; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinethiol | 179337-57-6 | C6H10N2S2 | 详情 | 详情 |
| (XIV) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
| (XV) | 31407 | 3-azetidinyl 4,5-dihydro-1,3-thiazol-2-yl sulfide; 2-(3-azetidinylsulfanyl)-4,5-dihydro-1,3-thiazole | C6H10N2S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Kojic acid (I) was chlorinated with neat thionyl chloride, and the resultant chloride (II) was further reduced to the methyl derivative (III) employing Zn and HCl. The hydroxymethylation of (III) with formaldehyde in the presence NaOH provided alcohol (IV). After protection of the 3-hydroxyl group of (IV) as the benzyl ether (V), the primary alcohol of (V) was oxidized to aldehyde (VI) using SO3-pyridine complex and DMSO. Further oxidation of aldehyde (VI) with sodium chlorite furnished the carboxylic acid (VII). Activation of acid (VII) was achieved by coupling with 2-mercaptothiazoline (VIII) using DCC and DMAP. The resulting thiazolidine amide (IX) was then reacted with methylamine in CH2Cl2 under mild conditions to give the N-methyl amide (X). Further treatment of (X) with a methanolic solution of methylamine in a sealed tube at 70 C converted the pyranone ring to the pyridone (XI). The benzyl protecting group of (XI) was then removed by catalytic hydrogenation, and the title compound was finally isolated as the hydrochloride salt.
| 【1】 Liu, Z.D.; et al.; Synthesis of 2-amino-3-hydroxypyridin-4(1H)-ones: Novel iron chelators with enhanced pFe3+ values. Bioorg Med Chem 2001, 9, 3, 563. |
| 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) | 13501 | Kojic acid; 5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one | 501-30-4 | C6H6O4 | 详情 | 详情 |
| (II) | 48642 | (2-Chloromethyl)-5-hydroxy-4H-pyran-4-one | C6H5ClO3 | 详情 | 详情 | |
| (III) | 45934 | 5-hydroxy-2-methyl-4H-pyran-4-one | C6H6O3 | 详情 | 详情 | |
| (IV) | 48643 | 3-hydroxy-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C7H8O4 | 详情 | 详情 | |
| (V) | 48644 | 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one | C14H14O4 | 详情 | 详情 | |
| (VI) | 48645 | 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carbaldehyde | C14H12O4 | 详情 | 详情 | |
| (VII) | 48646 | 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid | C14H12O5 | 详情 | 详情 | |
| (VIII) | 28895 | 4,5-dihydro-1,3-thiazol-2-ylhydrosulfide | 96-53-7 | C3H5NS2 | 详情 | 详情 |
| (IX) | 48647 | 3-(benzyloxy)-6-methyl-2-[(2-thioxo-1,3-thiazolidin-3-yl)carbonyl]-4H-pyran-4-one | C17H15NO4S2 | 详情 | 详情 | |
| (X) | 48648 | 3-(benzyloxy)-N,6-dimethyl-4-oxo-4H-pyran-2-carboxamide | C15H15NO4 | 详情 | 详情 | |
| (XI) | 48649 | 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydro-2-pyridinecarboxamide | C16H18N2O3 | 详情 | 详情 |