Amadacycline, PTK-0796, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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

Drug NewChemical Entity Original Patent(1)