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【结 构 式】 
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【药物名称】Carumonam sodium, Ro-17-2301/006, AMA-1080, Mobactam, Amasulin 【化学名称】(2S)-3beta-[2-(2-Aminothiazol-4-yl)-2(Z)-(carboxymethoxyimino)acetamido]-2beta-(carbamoyloxymethyl)-4-oxoazetidine-1-sulfonic acid disodium salt 【CA登记号】86832-68-0, 87638-04-8 (free acid) 【 分 子 式 】C12H12N6Na2O10S2 【 分 子 量 】510.37124 |
【开发单位】Takeda (Originator), Bracco (Licensee) 【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Monobactams |
合成路线1
Two related syntheses of a known intermediate of carumonam are presented: 1) The reaction of calcium L-threonate (I) with HBr in acetic acid - acetic anhydride and then with refluxing methanol gives methyl (2S,3S)-2,4-dibromo-3-hydroxybutanoate (II), which by reaction with concentrated NH4OH is converted into (2S, 3R)-3-(bromomethyl)oxiranecarboxamide (III). The reaction of (III) with KI and potassium acetate in hot DMF affords (2R, 3S)-3-(acetoxymethyl)oxiranecarboxamide (IV), which is treated with concentrated NH4OH at 60 C and then with benzyl chloroformate (V) to give (2S, 3R)-2-(benzyloxycarbonylamino)-3,4-dihydroxybutanamide (VIII), an intermediate compound previously obtained in the synthesis described in Drugs Fut 1985, 10: 967. 2) The treatment of dibromide (II) with KI and potassium acetate in hot DMF gives methyl (2S,3S)-4-acetoxy-2,3-epoxybutanoate (VI), which is treated first with NaOH in methanol and then with hot NH4OH to yield (2S, 3R)-2-amino-3,4-dihydroxybutanamide (VII). Finally, this compound is treated with benzyl chloroformate (V) as before to give the intermediate (VIII) previously mentioned.
| 【1】 Manchand, P.S.; Luk, K.-C.; Belica, P.S.; Choudhry, S.C.; Wei, C.C.; Soukup, M.; A novel synthesis of the monobactam antibiotic carumonam. J Org Chem 1988, 53, 23, 5507. |
| 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) | 21521 | calcium di[(2R,3S)-2,3,4-trihydroxybutanoate] | C8H14CaO10 | 详情 | 详情 | |
| (II) | 21522 | methyl (2S,3S)-2,4-dibromo-3-hydroxybutanoate | C5H8Br2O3 | 详情 | 详情 | |
| (III) | 21523 | (2R,3R)-3-(bromomethyl)-2-oxiranecarboxamide | C4H6BrNO2 | 详情 | 详情 | |
| (IV) | 21524 | [(2S,3R)-3-(aminocarbonyl)oxiranyl]methyl acetate | C6H9NO4 | 详情 | 详情 | |
| (V) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VI) | 21525 | methyl (2R,3S)-3-[(acetoxy)methyl]-2-oxiranecarboxylate | C7H10O5 | 详情 | 详情 | |
| (VII) | 21526 | (2S,3R)-2-amino-3,4-dihydroxybutanamide | C4H10N2O3 | 详情 | 详情 | |
| (VIII) | 28759 | benzyl (1S,2R)-1-(aminocarbonyl)-2,3-dihydroxypropylcarbamate | C12H16N2O5 | 详情 | 详情 |
合成路线2
L-threonic acid (XI), which is readily available from L-ascorbic acid (IX), is converted to L-N-benzyloxycarbonyl-4-hydroxyallothreoninamide (VIII). This in turn is transformed to (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid (XVIII). Condensation of the azetidinone (XVIII) with the activated aminothiazole portion (XIX) followed by a necessary deprotection step affords the monocyclic beta-lactam. Dissolution of the beta-lactam in aqueous sodium acetate yields the disodium salt, carumonam. Other routes of synthesis have been discussed.
| 【1】 Weigele, M.; Wei, C.; Tengi, J.; Ro-172301 (AMA-1080), a new monocyclic beta-lactam antibiotic: Stereorational synthesis. Intersci Conf Antimicrob Agents Chemother 1983, Abst 324. |
| 【2】 Hachiguchi, S.; Ochiai, M.; Kishimoto, S.; Matsuo, T.; Kondo, M.; Sendai, M.; Tomimoto, M.; Chemical modification of sulfazecin: Synthesis of 4-(substituted methyl)-2-azetidinone-1-sulfonic acid derivatives. J Antibiot 1985, 38, 3, 346-371. |
| 【3】 Christenson, J.; Squires, E.; Carumonam Sodium. Drugs Fut 1985, 10, 12, 967. |
| 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) | 28759 | benzyl (1S,2R)-1-(aminocarbonyl)-2,3-dihydroxypropylcarbamate | C12H16N2O5 | 详情 | 详情 | |
| (IX) | 29820 | (5R)-5-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-2(5H)-furanone | 50-81-7 | C6H8O6 | 详情 | 详情 |
| (X) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XI) | 29821 | calcium di[(2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethanoate] | C14H22CaO10 | 详情 | 详情 | |
| (XII) | 29822 | (2R)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethanamide | C7H13NO4 | 详情 | 详情 | |
| (XIII) | 29823 | (2S)-2-azido-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanamide | C7H12N4O3 | 详情 | 详情 | |
| (XIV) | 29824 | benzyl (1S)-2-amino-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethylcarbamate | C15H20N2O5 | 详情 | 详情 | |
| (XV) | 29825 | (2R,3S)-4-amino-3-[[(benzyloxy)carbonyl]amino]-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-oxobutyl 2-chloroacetate | C17H23ClN2O6S | 详情 | 详情 | |
| (XVI) | 29826 | N,N,N-tributyl-1-butanaminium (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-oxo-1-azetidinesulfonate | C28H49N3O7S | 详情 | 详情 | |
| (XVII) | 13713 | 2-Chloroacetyl isocyanate | 4461-30-7 | C3H2ClNO2 | 详情 | 详情 |
| (XVIII) | 29827 | (2S,3S)-2-[[(aminocarbonyl)oxy]methyl]-3-ammonio-4-oxo-1-azetidinesulfonate | C5H9N3O6S | 详情 | 详情 | |
| (XIX) | 29828 | tert-butyl 2-([[(Z)-1-(2-amino-1,3-thiazol-4-yl)-2-(1,3-benzothiazol-2-ylsulfanyl)-2-oxoethylidene]amino]oxy)acetate | C18H18N4O4S3 | 详情 | 详情 |