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【结 构 式】 
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【分子编号】16362 【品名】(4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide 【CA登记号】 |
【 分 子 式 】C23H28N4O7 【 分 子 量 】472.49808 【元素组成】C 58.47% H 5.97% N 11.86% O 23.7% |
合成路线1
该中间体在本合成路线中的序号：(III)This compound can be obtained by two related ways:1) The nitration of minocycline (I) by means of NaNO3 and H2SO4 gives the 9-nitro derivative (II), which is hydrogenated with H2 over Pd/C in 2-methoxyethanol to yield the 9-amino derivative (III). Finally, this compound is acylated with sarcosyl chloride (IV) by means of Na2CO3 in acetonitrile/dimethylpropylenurea.2) The acylation of the 9-amino derivative (III) with N-(succinimidyloxycarbonyl)carbamic acid tert-butyl ester (V) by means of sodium acetate in THF gives the 9-(tert-butoxycarbonyl)glycylamino substituted compound (VI), which is deprotected with trifluoroacetic acid to afford the 9-glycylamino compound (VII). Finally, this compound is methylated with formaldehyde and simultaneous hydrogenation with H2 over Pd/C in 2-methoxyethanol.
| 【1】 Hlavka, J.J.; Gluzman, Y.; Tally, F.P.; Bloom, J.D.; Testa, R.T.; Ellestad, G.A.; Lee, V.J.; Sum, P.-E.; The discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 431. |
| 【2】 Fromtling, R.A.; Castañer, J.; DMG-MINO. Drugs Fut 1995, 20, 11, 1116. |
| 【3】 Hlavka, J.J.; Sum, P.-E.; Gluzman, Y.; Lee, V.J.; Ross, A.A. (American Cyanamid Co.); Novel 7-substd.-9-substd. amino-6-demethyl-6-deoxytetracyclines. EP 0536515; JP 1993255219; US 5494903 . |
| 【4】 Sum, P.-E.; Lee, V.J.; Testa, R.T.; Hlavka, J.J.; Ellestad, G.A.; Bloom, J.D.; Gluzman, Y.; Tally, F.P.; Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 1994, 37, 1, 184-8. |
| 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) | 16360 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | 10118-90-8 | C23H27N3O7 | 详情 | 详情 |
| (II) | 16361 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H26N4O9 | 详情 | 详情 | |
| (III) | 16362 | (4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H28N4O7 | 详情 | 详情 | |
| (IV) | 16359 | 2-(dimethylamino)acetyl chloride | C4H8ClNO | 详情 | 详情 | |
| (V) | 16364 | tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester | 3392-07-2 | C11H16N2O6 | 详情 | 详情 |
| (VI) | 16365 | tert-butyl 2-[[(5aR,6aS,7S,10aS)-9-(aminocarbonyl)-4,7-bis(dimethylamino)-1,8,10a,11-tetrahydroxy-10,12-dioxo-5,5a,6,6a,7,10,10a,12-octahydro-2-naphthacenyl]amino]-2-oxoethylcarbamate | C30H39N5O10 | 详情 | 详情 | |
| (VII) | 16366 | (4S,4aS,5aR,12aS)-9-[(2-aminoacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C25H31N5O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Nitration of minocycline (I) with KNO3 and H2SO4 gives the 9-nitro derivative (II), which is reduced with H2 over Pd/C in 2-methoxyethanol/2N H2SO4 to provide 9-aminominocycline (III). Acylation of compound (III) with 2-bromoacetyl bromide (IV) in N,N-dimethylpropyleneurea (DMPU) affords 9-(2-bromoacetamido)minocycline (V). Finally, this compound is treated with tert-butylamine (VI) to yield, after purification, GAR-936.
| 【1】 Hunter, P.A.; Castaner, J.; GAR-936. Drugs Fut 2001, 26, 9, 851. |
| 【2】 Sum, P.-E.; Petersen, P.; Synthesis and structure-activity relationship of novel glycylcline derivatives leading to the discovery of GAR-936. Bioorg Med Chem Lett 1999, 9, 10, 1459. |
| 【3】 Sum, P.-E.; Lee, V.J. (American Cyanamid Co.); Method of producing 7-(substd.)-9-[(substd. glycyl)amidol]-6-demethyl-6-deoxytetracyclines. EP 0582790; US 5284963 . |
| 【4】 Sum, P.-E.; Lee, V.J.; Testa, R.T.; Hlavka, J.J.; Ellestad, G.A.; Bloom, J.D.; Gluzman, Y.; Tally, F.P.; Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 1994, 37, 1, 184-8. |
| 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) | 16360 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | 10118-90-8 | C23H27N3O7 | 详情 | 详情 |
| (II) | 16361 | (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H26N4O9 | 详情 | 详情 | |
| (III) | 16362 | (4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C23H28N4O7 | 详情 | 详情 | |
| (IV) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (V) | 48570 | (4S,4aS,5aR,12aS)-9-[(2-bromoacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide | C25H29BrN4O8 | 详情 | 详情 | |
| (VI) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
| (VII) | 48571 | 2-(tert-butylamino)acetyl chloride | C6H12ClNO | 详情 | 详情 |