Tasosartan, WAY-126756, WAY-ANA-756, ANA-756, Verdia, -Drug Synthesis Database

【结构式】

【药物名称】Tasosartan, WAY-126756, WAY-ANA-756, ANA-756, Verdia

【化学名称】2,4-Dimethyl-8-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one

【CA登记号】145733-36-4

【分子式】C₂₃H₂₁N₇O

【分子量】411.47012

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin AT1 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

1) The cyclization of 2-acetylglutaric acid diethyl ester (I) with acetamidine (II) by means of sodium ethoxide in refluxing ethyl ether gives the pyrimidinone derivative (III), which by treatment with refluxing phosphorus oxychloride is converted into the chloropyrimidine (IV). The cyclization of (IV) with 4-bromobenzylamine (V) by means of NaHCO3 in refluxing butanol affords 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VI), which is condensed with 2-(2-tert-butyltetrazol-5-yl)phenylboronic acid (VII) by means of tetrakis(triphenylphosphine)palladium in refluxing toluene/ethanol to give 8-[2'-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VIII). Finally, this compound is deprotected with methanesulfonic acid in refluxing toluene. (1,2) 2) The boronic acid (VII) has been obtained as follows: The cyclization of 2-bromobenzonitrile (IX) with sodium azide in hot DMF, followed by protection with tert-butanol in trifluoroacetic acid/H2SO4 gives 5-(2-bromophenyl)-2-tertbutyltetrazole (X), which is finally condensed with triisopropyl borate by means of butyllithium in THF and hydrolyzed with HCl. (1,2)

参考文献中间体

【1】 Merlos, M.; Casas, A.; Castaner, J.; Tasosartan. Drugs Fut 1997, 22, 8, 850.
【2】 Ellingboe, J.W.; Nikaido, M.; Bagli, J. (American Home Products Corp.); Substd. pyridopyrimidines useful as angiotensin II antagonists. EP 0539086; US 5149699; US 5256654 .
【3】 Ellingboe, J.W.; Antane, M.; Nguyen, T.T.; et al.; Pyrido[2,3-p]pyrimidine angiotensin II antagonists. J Med Chem 1994, 37, 4, 542-50.

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)	15865	Diethyl 2-acetylglutarate; diethyl 2-acetylpentanedioate	1501-06-0	C₁₁H₁₈O₅	详情	详情
(II)	15866	ethanimidamide		C₂H₆N₂	详情	详情
(III)	15867	ethyl 3-(2,4-dimethyl-6-oxo-1,6-dihydro-5-pyrimidinyl)propanoate		C₁₁H₁₆N₂O₃	详情	详情
(IV)	15868	ethyl 3-(4-chloro-2,6-dimethyl-5-pyrimidinyl)propanoate		C₁₁H₁₅ClN₂O₂	详情	详情
(V)	15869	4-bromobenzylamine; (4-bromophenyl)methanamine	26177-44-6	C₇H₈BrN	详情	详情
(VI)	15870	8-(4-bromobenzyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one		C₁₆H₁₆BrN₃O	详情	详情
(VII)	15871	2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenylboronic acid		C₁₁H₁₅BN₄O₂	详情	详情
(VIII)	15872	8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one		C₂₇H₂₉N₇O	详情	详情
(IX)	15541	o-bromobenzonitrile; 2-bromobenzonitrile	2042-37-7	C₇H₄BrN	详情	详情
(X)	15874	5-(2-bromophenyl)-2-(tert-butyl)-2H-1,2,3,4-tetraazole		C₁₁H₁₃BrN₄	详情	详情

合成路线2

3) The 8-[2'-(2-tert-butyltetrazol-5-yl)biphenyl-4-ylmethyl]-2,4-dimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-7-one (VIII) can also be obtained as follows: The reaction of the previously described 5-(2-bromophenyl)-2-tertbutyltetrazole (X) with Mg in THF catalyzed with 1,2-dibromoethane gives the corresponding Grignard reagent, which is treated with ZnCl2 yielding the organozinc derivative (XI). Finally, this compound is condensed with the previously described intermediate 8-(4-bromobenzyl)-2,4-dimethyl-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-7-one (VI) catalyzed by bis(triphenylphosphine)palladium and diisobutylaluminum hydride in THF.

参考文献中间体

【1】 Merlos, M.; Casas, A.; Castaner, J.; Tasosartan. Drugs Fut 1997, 22, 8, 850.
【2】 Giguere, P.; Iera, S.; Bernatchez, M.; Barreca, G.; Castaldi, G.; Cannata, V. (American Home Products Corp.); Process for preparation of biphenyl derivs. WO 9640684 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	15870	8-(4-bromobenzyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₁₆H₁₆BrN₃O	详情	详情
(VIII)	15872	8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-2,4-dimethyl-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₂₇H₂₉N₇O	详情	详情
(X)	15874	5-(2-bromophenyl)-2-(tert-butyl)-2H-1,2,3,4-tetraazole	C₁₁H₁₃BrN₄	详情	详情
(XI)	15875	[2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenyl](chloro)zinc	C₁₁H₁₃ClN₄Zn	详情	详情

合成路线3

1) The oxidation of tasosartan (V) with KMnO4 and NaOH in water gives metabolite (I). 2) The condensation of tasosartan (V) with 2,3,4-tri-O-acetyl-1alpha-bromo-1-deoxy-D-glucopyranosyluronic acid methyl ester (VI) by means of KOH in refluxing acetone gives the acetylated glucuronide methyl ester (VII), which is deacetylated with KCN in methanol yielding glucuronide methyl ester (VIII). Finally, this compound is hydrolyzed with NaOH in methanol to afford metabolite (II).

参考文献中间体

【1】 Ellingboe, J.W.; Collini, M.D.; Quagliato, D.; Chen, J.; Antane, M.; Schmid, J.; Hartupee, D.; White, V.; Park, C.H.; Tanikella, T.; Bagli, J.F.; Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic group. J Med Chem 1998, 41, 22, 4251.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26023	5-hydroxy-2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₂₃H₂₁N₇O₂	详情	详情
(II)	26024	sodium (2S,3S,4S,5R,6R)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate	C₂₉H₂₈N₇NaO₇	详情	详情
(V)	26025	2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one	C₂₃H₂₁N₇O	详情	详情
(VI)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate	C₁₃H₁₇BrO₉	详情	详情
(VII)	26026	methyl (2S,3R,4S,5R,6R)-3,4,5-tris(acetoxy)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]tetrahydro-2H-pyran-2-carboxylate	C₃₆H₃₇N₇O₁₀	详情	详情
(VIII)	26027	methyl (2S,3S,4S,5R,6R)-6-[5-(4'-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl]methyl][1,1'-biphenyl]-2-yl)-2H-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate	C₃₀H₃₁N₇O₇	详情	详情

合成路线4

3) The iodination of 2,6-dimethylpyrimidin-4-ol (IX) with I2/NaOH in refluxing water gives 5-iodo-2,6-dimethylpyrimidin-4-ol (X), which is treated with POCl3 in refluxig toluene yielding 4-chloro-5-iodo-2,6-dimethylpyrimidine (XI). The reaction of (XI) with (1-ethoxyvinyl)tributyltin (XII) catalyzed by tetrakis(triphenylphosphine)palladium in refluxing dioxane affords 4-chloro-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (XIII), which is condensed with 4-bromobenzylamine (XIV) by means of NaHCO3 in refluxing butanol giving 4-(4-bromobenzylamino)-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine (XV). The hydrolysis of (XV) with HCl in refluxing acetone yields the corresponding acetyl derivative (XVI), which is condensed with 2-(2-tert-butyl-2H-tetrazol-5-yl)phenylboronic acid (XVII) by means of tetrakis(triphenylphosphine)palladium to afford the biphenyl derivative (XVIII). The cyclization of (XVIII) with diethyl carbonate and NaH in hot THF gives 8-[2'-(2-tert-butyl-2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5-hydroxy-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one (XIX), which is finally deprotected with trifluoromethanesulfonic acid in refluxing toluene to give metabolite (III).

参考文献中间体

【1】 Ellingboe, J.W.; Collini, M.D.; Quagliato, D.; Chen, J.; Antane, M.; Schmid, J.; Hartupee, D.; White, V.; Park, C.H.; Tanikella, T.; Bagli, J.F.; Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic group. J Med Chem 1998, 41, 22, 4251.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	26028	5-hydroxy-2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrido[2,3-d]pyrimidin-7(8H)-one		C₂₃H₁₉N₇O₂	详情	详情
(IX)	26029	2,6-dimethyl-4-pyrimidinol	6622-92-0	C₆H₈N₂O	详情	详情
(X)	26030	5-iodo-2,6-dimethyl-4-pyrimidinol		C₆H₇IN₂O	详情	详情
(XI)	26031	4-chloro-5-iodo-2,6-dimethylpyrimidine		C₆H₆ClIN₂	详情	详情
(XII)	19760	ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane	97674-02-7	C₁₆H₃₄OSn	详情	详情
(XIII)	26032	1-(4-chloro-2,6-dimethyl-5-pyrimidinyl)vinyl ethyl ether; 4-chloro-5-(1-ethoxyvinyl)-2,6-dimethylpyrimidine		C₁₀H₁₃ClN₂O	详情	详情
(XIV)	15869	4-bromobenzylamine; (4-bromophenyl)methanamine	26177-44-6	C₇H₈BrN	详情	详情
(XV)	26033	N-(4-bromobenzyl)-5-(1-ethoxyvinyl)-2,6-dimethyl-4-pyrimidinamine; N-(4-bromobenzyl)-N-[5-(1-ethoxyvinyl)-2,6-dimethyl-4-pyrimidinyl]amine		C₁₇H₂₀BrN₃O	详情	详情
(XVI)	26034	1-[4-[(4-bromobenzyl)amino]-2,6-dimethyl-5-pyrimidinyl]-1-ethanone		C₁₅H₁₆BrN₃O	详情	详情
(XVII)	15871	2-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl]phenylboronic acid		C₁₁H₁₅BN₄O₂	详情	详情
(XVIII)	26035	1-[4-[([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)amino]-2,6-dimethyl-5-pyrimidinyl]-1-ethanone		C₂₆H₂₉N₇O	详情	详情
(XIX)	26036	8-([2'-[2-(tert-butyl)-2H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-5-hydroxy-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one		C₂₇H₂₇N₇O₂	详情	详情

合成路线5

4) The condensation of 2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one (XX) with 4'-(bromomethyl)biphenyl-2-carbonitrile (XXI) by means of NaH in DMF gives 8-(2'-cyanobiphenyl-4-ylmethyl)-2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one (XIX), which is then cyclized with sodium azide in refluxing xylene to afford metabolite (IV).

参考文献中间体

【1】 Ellingboe, J.W.; Collini, M.D.; Quagliato, D.; Chen, J.; Antane, M.; Schmid, J.; Hartupee, D.; White, V.; Park, C.H.; Tanikella, T.; Bagli, J.F.; Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic group. J Med Chem 1998, 41, 22, 4251.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	26039	2,4-dimethyl-8-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]pyrido[2,3-d]pyrimidin-7(8H)-one		C₂₃H₁₉N₇O	详情	详情
(XX)	26037	2,4-dimethylpyrido[2,3-d]pyrimidin-7(8H)-one		C₉H₉N₃O	详情	详情
(XXI)	15332	4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl	114772-54-2	C₁₄H₁₀BrN	详情	详情
(XXII)	26038	4'-[[2,4-dimethyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl]methyl][1,1'-biphenyl]-2-carbonitrile		C₂₃H₁₈N₄O	详情	详情

Extended Information