Sitagliptin phosphate, MK-0431, MK-431, ONO-5435, Januvia, Xelevia, -Drug Synthesis Database

【结构式】

【药物名称】Sitagliptin phosphate, MK-0431, MK-431, ONO-5435, Januvia, Xelevia

【化学名称】(3R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one phosphate

【CA登记号】654671-78-0, 486460-32-6 (as free base)

【分子式】C₁₆H₁₅F₆N₅O.H₃O₄P

【分子量】505.3102

【开发单位】Merck & Co., Inc. (US); Banyu Pharmaceutical Co., Ltd. (JP); Ono Pharmaceutical Co., Ltd. (JP).

【药理作用】Agent for Type 2 Diabetes, Dipeptidyl-Peptidase IV (CD26) Inhibitor

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】 Wenslow RM, Armstrong JD, Chen AM, et al. 2005. Novel crystal forms of a dihydrogen phosphate salt of a trizolopyrazine dipeptidyl peptidase IV inhibitor. W0 2005020920
【2】 Xiao Y, Armstrong JD, Krska SW, et aL. 2004. Process for the preparation of chiral β-amino acid derivatives by asymmetric hydrogenation of enamino esters and amides using trasition-metal complexed chiral ferrocenyldiphasphines. W0 2004085378

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)	27344	hydrazine	302-01-2	H₄N₂	详情	详情
(II)	66702	N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide		C₄H₄ClF₃N₂O₂	详情	详情
(III)	66703	2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole	723286-98-4	C₄H₂ClF₃N₂O	详情	详情
(IV)	66704	(Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide	763105-70-0	C₆H₉F₃N₄O	详情	详情
(V)	66705	3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride	486460-21-3	C₆H₇F₃N₄.HCl	详情	详情
(VI)	66706	2-(2,4,5-trifluorophenyl)acetic acid	209995-38-0	C₈H₅F₃O₂	详情	详情
(VII)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(VIII)	66707	5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione		C₁₄H₁₁F₃O₅	详情	详情
(IX)	66708	1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione	764667-65-4	C₁₆H₁₂F₆N₄O₂	详情	详情
(X)	66709	(Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one	767340-03-4	C₁₆H₁₃F₆N₅O	详情	详情

合成路线2

参考文献中间体

【1】 Dreher SD. Ikemoto N, Njolito E et aL. 2004. Process for preparation of chiral β-anuno acid derivatives. W0 2004085661

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	66706	2-(2,4,5-trifluorophenyl)acetic acid	209995-38-0	C₈H₅F₃O₂	详情	详情
(I)	27344	hydrazine	302-01-2	H₄N₂	详情	详情
(II)	66702	N'-(2-chloroacetyl)-2,2,2-trifluoroacetohydrazide		C₄H₄ClF₃N₂O₂	详情	详情
(III)	66703	2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole	723286-98-4	C₄H₂ClF₃N₂O	详情	详情
(IV)	66704	(Z)-2,2,2-trifluoro-N'-(piperazin-2-ylidene)acetohydrazide	763105-70-0	C₆H₉F₃N₄O	详情	详情
(V)	66705	3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride	486460-21-3	C₆H₇F₃N₄.HCl	详情	详情
(VII)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(VIII)	66707	5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione		C₁₄H₁₁F₃O₅	详情	详情
(IX)	66708	1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione	764667-65-4	C₁₆H₁₂F₆N₄O₂	详情	详情
(X)	66710	（R）-2-amino-2-phenylacetamide		C₈H₁₀N₂O	详情	详情
(XI)	66711	(R,Z)-2-((4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)but-2-en-2-yl)amino)-2-phenylacetamide		C₂₄H₂₀F₆N₆O₂	详情	详情
(XII)	66712	(2R)-2-((4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)amino)-2-phenylacetamide		C₂₄H₂₂F₆N₆O₂	详情	详情

合成路线3

参考文献中间体

【1】 Hansen KB, Balsells J. Dreher S et a1. 2005. First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin. Org Proc Rea.Dev.,9(5): 634～639.

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)	24075	2-chloropyrazine	14508-49-7	C₄H₃ClN₂	详情	详情
(II)	66713	2-Hydrazinopyrazine	54608-52-5	C₄H₆N₄	详情	详情
(III)	66714			C₈H₄F₆N₄O₂	详情	详情
(IV)	66715	3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine		C₆H₃F₃N₄	详情	详情
(V)	66705	3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride	486460-21-3	C₆H₇F₃N₄.HCl	详情	详情
(VI)	66716	methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate	769195-26-8	C₁₁H₉F₃O₃	详情	详情
(VII)	66717	(R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid		C₁₀H₉F₃O₃	详情	详情
(VIII)	66718	(R)-N-(benzyloxy)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanamide		C₁₇H₁₆F₃NO₃	详情	详情
(IX)	66719	(R)-1-(benzyloxy)-4-(2,4,5-trifluorobenzyl)azetidin-2-one		C₁₇H₁₄F₃NO₂	详情	详情
(X)	66720	(R)-3-((benzyloxy)amino)-4-(2,4,5-trifluorophenyl)butanoic acid		C₁₇H₁₆F₃NO₃	详情	详情
(XI)	66721	(R)-3-((benzyloxy)amino)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one		C₂₃H₂₁F₆N₅O₂	详情	详情
(XII)	66722	(R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one	486460-32-6	C₁₆H₁₅F₆N₅O	详情	详情

合成路线4

参考文献中间体

【1】 Kim D, Wang LP, Becoru M, et al. 2005. (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}l-(2,4,5-trifluorophenyl)butan-2-amine:a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem, 48(1):141～151

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)	66723	1-(bromomethyl)-2,4,5-trifluorobenzene		C₇H₄BrF₃	详情	详情
(I)	10296	(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine; (3R)-3-Isopropyl-5-methoxy-3,6-dihydro-2-pyrazinyl methyl ether; (2R)-2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine	109838-85-9	C₉H₁₆N₂O₂	详情	详情
(III)	66724	(2S,5R)-2-isopropyl-3,6-dimethoxy-5-(2,4,5-trifluorobenzyl)-2,5-dihydropyrazine		C₁₆H₁₉F₃N₂O₂	详情	详情
(IV)	66725	(R)-methyl 2-amino-3-(2,4,5-trifluorophenyl)propanoate		C₁₀H₁₀F₃NO₂	详情	详情
(V)	66729	(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2,4,5-trifluorophenyl)propanoate		C₁₅H₁₈F₃NO₄	详情	详情
(VI)	66728	(R)-2-((tert-butoxycarbonyl)amino)-3-(2,4,5-trifluorophenyl)propanoic acid		C₁₄H₁₆F₃NO₄	详情	详情
(VII)	66727	(R)-tert-butyl (4-diazo-3-oxo-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate		C₁₅H₁₆F₃N₃O₃	详情	详情
(VIII)	66726	(R)-3-((tert-butoxycarbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid		C₁₅H₁₈F₃NO₄	详情	详情
(IX)	24075	2-chloropyrazine	14508-49-7	C₄H₃ClN₂	详情	详情
(X)	66713	2-Hydrazinopyrazine	54608-52-5	C₄H₆N₄	详情	详情
(XI)	66730	2,2,2-trifluoro-N'-(pyrazin-2-yl)acetohydrazide 2,2,2-trifluoroacetate		C₆H₅F₃N₄O.C₂HF₃O₂	详情	详情
(XII)	66715	3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine		C₆H₃F₃N₄	详情	详情
(XIII)	66731	3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine		C₆H₇F₃N₄	详情	详情
(XIV)	66732	(R)-tert-butyl (4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate		C₂₁H₂₃F₆N₅O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)