Tigilcycline, Tigecycline, WAY-GAR-936, GAR-936, TBG-MINO, -Drug Synthesis Database

【结构式】

【药物名称】Tigilcycline, Tigecycline, WAY-GAR-936, GAR-936, TBG-MINO

【化学名称】(4S,4aS,5aR,12aS)-9-(N-tert-Butyl-glycylamino)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12-octahydronaphthacene-2-carboxamide
　　　　　　9-(N-tert-Butylglycylamido)-6-demethyl-6-deoxy-7-(dimethylamino)tetracycline

【CA登记号】220620-09-7

【分子式】C₂₉H₃₉N₅O₈

【分子量】585.66288

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Tetracyclines

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

参考文献中间体

【1】 Krishnan L, Sum PE, Daigneault S, et aL. 2006. Process for the prepantion of tigecycline and methods of preparing 9-aminominocycline. W0 2006130500
【2】 Krishnan L, Sum PE, Daigneault S, et al. 2006. Preparation of tigecycline and 9-nitrominocycline. W0 2006130501

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	66846	(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 hydrochloride		C₂₃H₂₈N₄O₇.HCl	详情	详情
(I)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(II)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(III)	66841	tert-butyl 2-(tert-butylamino)acetate		C₁₀H₂₁NO₂	详情	详情
(IV)	66842	2-(tert-butylamino)acetic acid hydrochloride		C₆H₁₃NO₂.HCl	详情	详情
(V)	66843	2-(tert-butylamino)acetyl chloride hydrochloride		C₆H₁₂ClNO.HCl	详情	详情
(VI)	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
(VII)	66844	(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 monosulfate		C₂₃H₂₆N₄O₉.2H₂SO₄	详情	详情
(VIII)	66845	(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 monosulfate		C₂₃H₂₈N₄O₇.2H₂SO₄	详情	详情

合成路线2

参考文献中间体

【1】 Krishnan L, Sum PE, Daigneault S, et aL. 2006. Process for the prepantion of tigecycline and methods of preparing 9-aminominocycline. W0 2006130500
【2】 Krishnan L, Sum PE, Daigneault S, et al. 2006. Preparation of tigecycline and 9-nitrominocycline. W0 2006130501

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	66847	(4S,4aS,5aR,12aS)-9-[(2-chloroacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide		C₂₅H₂₉ClN₄O₈	详情	详情
(I)	66846	(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 hydrochloride		C₂₃H₂₈N₄O₇.HCl	详情	详情

合成路线3

参考文献中间体

【1】 Sum PE, How DB, Hopper DW, et al. 2005. Preparation of oxazole derivatives of tetracyclines as antibacterial agents. W0 2005056538

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)	66844	(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 monosulfate		C₂₃H₂₆N₄O₉.2H₂SO₄	详情	详情
(III)	66845	(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 monosulfate		C₂₃H₂₈N₄O₇.2H₂SO₄	详情	详情
(IV)	66848	(4S,4aS,5aR,12aS)-2-(chloromethyl)-5,8-bis(dimethylamino)-9,11a,12-trihydroxy-11,13-dioxo-6,6a,7,7a,8,11,11a,13-octahydro-1H-cyclopenta[a]tetracene-10-carboxamide		C₂₇H₃₀ClN₃O₆	详情	详情

合成路线4

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.

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)