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【结 构 式】

【药物名称】Amadacycline, PTK-0796

【化学名称】(4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-(2,2-dimethylpropylaminomethyl)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide

【CA登记号】389139-89-3

【 分 子 式 】C29H40N4O7

【 分 子 量 】556.6505

【开发单位】Paratek Pharmaceuticals, Inc. (US).

【药理作用】Tetracycline antibiotic

合成路线1

1) Condensation of minocycline (I) with N-(hydroxymethyl)phthalimide (II) by means of trifluoromethanesulfonic acid and trifluoromethanesulfonic anhydride gives the 2-N,9-bis(phthalimidomethyl) derivative (III) along with minor amounts of the tris(phthalimidomethyl) compound (IV), which are deprotected with methylamine in EtOH, yielding a mixture of primary amines (V) and (VI). Finally, amines (V)/(VI) are reductively alkylated with pivalaldehyde (VII), with concomitant de-aminomethylation of (VI) in the presence of H2 and Pd/C (1) or NaBH(OAc)3 (2). Scheme 1.
2) Reaction of neopentylamine (VIII) with paraformaldehyde in hot hexane gives the triazine derivative (IX), which upon treatment with chloroacetic anhydride (X) in CH2Cl2 gives the N-(acyloxymethyl)amide (XI). Subsequent Tscherniac–Einhorn reaction of (XI) with minocycline (I) in the presence of trifluoromethanesulfonic acid yields the protected compound (XII), which is submitted to acidic hydrolysis of the chloroacetyl and hydroxymethyl groups in 3 N HCl at 70 °C, followed by reequilibration of the partly epimerized C4 center with NaOH or ethanolamine (3). Scheme 1.

1 Johnston, S., Warchol, T. (Paratek Pharmaceuticals, Inc.). Methods for synthesizing and purifying aminoalkyl tetracycline compounds. US 2008287401, WO 2008134048.
2 Bowser, T., Bhatia, B., Chen, J. et al. PTK0796 and other novel tetracycline derivatives exhibiting potent in vitro and in vivo activities against antibiotic resistant Gram-positive bacteria. 43rd Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 14-17, Chicago) 2003, Abst F-755.
3 Chung, J.Y.L., Hartner, F.W., Cvetovich, R.J. Synthesis development of an aminomethylcycline antibiotic via an electronically tuned acyliminium Friedel-Crafts reaction. Tetrahedron Lett 2008, 49(42): 6095-100.
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) 65813 Minocycline hydrochloride; [4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxonaphthacene-2-carboxamide monohydrochloride 13614-98-7 C23H27N3O7.HCl 详情 详情
(II) 65814 N-(Hydroxymethyl)phthalimide; 2-(Hydroxymethyl)-1H-isoindole-1,3(2H)-dione 118-29-6 C9H7NO3 详情 详情
(III) 65815     C41H37N5O11 详情 详情
(IV) 65816     C50H42N6O13 详情 详情
(V) 65817     C24H30N4O7 详情 详情
(VI) 65818     C25H33N5O7 详情 详情
(VII) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(VIII) 65819 Neopentylamine; 2,2-dimethylpropan-1-amine 5813-64-9 C5H13N 详情 详情
(IX) 65820 Hexahydro-1,3,5-Trineopentyl-1,3,5-Triazine   C18H39N3 详情 详情
(X) 65821 2-Chloroacetic anhydride; (Bischloroacetic acid) anhydride; Chloracetic anhydride; Chloroacetic acid anhydride 541-88-8 C4H4C12O3 详情 详情
(XI) 65822     C10H17Cl2NO3 详情 详情
(XII) 65823     C32H43ClN4O9 详情 详情

合成路线2

3) Iodination of minocycline (I) by treatment with N-iodosuccinimide in methanesulfonic acid gives compound (XIII) (4), which is converted to aldehyde (XIV) by palladium-catalyzed carbonylation with carbon monoxide gas in the presence of phosphine ligands and triethylsilane. Finally, aldehyde (XIV) is reductively aminated with neopentylamine (VIII) under catalytic hydrogenation conditions (5). Scheme 2.

4 Sheahan, P., Koza, D., Hawkins, P. et al. (Paratek Pharmaceuticals, Inc.; Tufts University). 9-Substituted minocycline compounds. CA 2415178, EP 1301467, EP 1679305, JP 2004502752, JP 2009029785, US 2003125348, US 6846939, WO 2002004406.
5 Seyedi, F., Warchol, T., Grier, M. (Paratek Pharmaceuticals, Inc.). Methods for synthesizing substituted tetracycline compounds. WO 2009009042.
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) 65813 Minocycline hydrochloride; [4S-(4alpha,4aalpha,5aalpha,12aalpha)]-4,7-Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxonaphthacene-2-carboxamide monohydrochloride 13614-98-7 C23H27N3O7.HCl 详情 详情
(VIII) 65819 Neopentylamine; 2,2-dimethylpropan-1-amine 5813-64-9 C5H13N 详情 详情
(XIII) 65824 9-Iodominocycline   C23H26IN3O7 详情 详情
(XIV) 65825 9-Formylminocycline   C24H27N3O8 详情 详情
Extended Information