Losartan potassium, L-158086, MK-0954, E-3340, MK-954, Ex-89(free acid), DuP-753, Covance, Nu-Lotan, Losaprex, Lorzaar, Cozaar, -Drug Synthesis Database

【结构式】

【药物名称】Losartan potassium, L-158086, MK-0954, E-3340, MK-954, Ex-89(free acid), DuP-753, Covance, Nu-Lotan, Losaprex, Lorzaar, Cozaar

【化学名称】2-Butyl-4-chloro-5-(hydroxymethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole potassium salt

【CA登记号】124750-99-8, 114798-26-4 (free acid)

【分子式】C₂₂H₂₂ClKN₆O

【分子量】461.01524

【开发单位】Banyu (Originator), Merck & Co. (Originator), Ranbaxy (Not Determined)

【药理作用】CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Diabetic Nephropathy, Agents for, ENDOCRINE DRUGS, Heart Failure Therapy, Hypertension, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Diabetic Complications, 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6

合成路线1

Synthesis of imidazole (V) first entails the conversion of valeronitrile (I) to its imidate ester (II). Subsequent reaction with 1,3-dihydroxyacetone dimer and ammonia leads to imidazole (III). Chlorination with N-chlorosuccinimide yields the 4-chloroimidazole (IV). Oxidation with manganese dioxide finally yields imidazole-5-carboxaldehyde (V).

参考文献中间体

【1】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47.
【2】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305.

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)	13921	Pentanenitrile; n-Valeronitrile	110-59-8	C₅H₉N	详情	详情
(II)	13922	Methyl pentanimidoate hydrocloride		C₆H₁₄ClNO	详情	详情
(III)	13923	2-Butyl-5-hydroxymethylimidazole; (2-Butyl-1H-imidazol-5-yl)methanol	68283-19-2	C₈H₁₄N₂O	详情	详情
(IV)	13924	2-Butyl-4-chloro-5-(hydroxymethyl)imidazole; (2-Butyl-4-chloro-1H-imidazol-5-yl)methanol	79047-41-9	C₈H₁₃ClN₂O	详情	详情
(V)	13925	2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde	83857-96-9	C₈H₁₁ClN₂O	详情	详情

合成路线2

The synthesis of the biphenyl tail involves first the conversion of 2-methoxybenzoic acid (VI) into oxazoline (VII), followed by displacement of the methoxy group by 4-tolylmagnesium bromide to yield biphenyloxazoline (VIII). Oxazoline (VIII) may be converted into biphenylnitrile (IX) by reaction with phosphorous oxychloride in pyridine. Reaction of biphenylnitrile (VIII) with tri-n-butyltin azide in refluxing xylenes, followed by destannylation and protection with a triphenylmethyl group, yields triphenylmethyl-protected biphenyltetrazole (X). Benzylic bromination yields the completed tail (XI)

参考文献中间体

【1】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305.
【2】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47.

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)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(VII)	13927	2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether	57598-33-1	C₁₂H₁₅NO₂	详情	详情
(VIII)	13928	4,4-Dimethyl-2-(4'-methyl-2-biphenyllyl)2-oxazoline; 4,4-Dimethyl-2-(4'-methyl[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,3-oxazole	84392-32-5	C₁₈H₁₉NO	详情	详情
(IX)	13929	2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile	114772-53-1	C₁₄H₁₁N	详情	详情
(X)	13930	5-(4'-Methyl[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₃H₂₆N₄	详情	详情
(XI)	13931	5-(4'-Bromo[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₂H₂₃BrN₄	详情	详情

合成路线3

The compound is assembled by connecting the imidazole head (V) to the biphenyltetrazole tail (XI). The aldehyde (V) undergoes regioselective alkylation with bromide (XI). Subsequent reduction of the aldehyde group in the same pot yields adduct (XII). Deprotection in acid, followed by conversion to the potassium salt, yields DuP-753.

参考文献中间体

【1】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47.
【2】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	13925	2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde	83857-96-9	C₈H₁₁ClN₂O	详情	详情
(XI)	13931	5-(4'-Bromo[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₂H₂₃BrN₄	详情	详情
(XII)	13932	(2-Butyl-4-chloro-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol		C₄₁H₃₇ClN₆O	详情	详情

合成路线4

A synthesis of [14C]-losartan has been described: The bromination of 4'-methylbiphenyl-2-carbonitrile (I) with Br2 and silver trifluoroacetate in dichloromethane gives 3'-bromo-4'-methylbiphenyl-2-carbonitrile (II), which is treated first with trimethylstannyl azide in refluxing toluene, and then with trityl chloride and triethylamine in hot dichloromethane, yielding 5-(3'-bromo-4'-methylbiphenyl-2-yl)-2-(triphenylmethyl)tetrazole (III). The bromination of (III) with N-bromosuccinimide (NBS) in refluxing carbon tetrachloride affords the corresponding bromomethyl derivative (IV), which is then condensed with 2-butyl-5-(tert-butyldimethylsilyloxymethyl)-4-chloro-1H-imidazole (V) by means of NaH in DMF to give (VI). The deprotection of (VI) with HCl in methanol yields the bromolosartan derivative (VII), which is finally tritiated by debromination with tritiated sodium borohydride and palladium acetate in methanol-THF.

参考文献中间体

【1】 Rivero, R.A.; Chen, R.; Chakravarty, P.K.; Rosegay, A.; Greenlee, W.J.; Simpson, R.; The synthesis of [3H]-losartan, [3H]-L-158,641 and [3H]-L-158,809. Bioorg Med Chem Lett 1993, 3, 4, 557.

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)	13929	2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile	114772-53-1	C₁₄H₁₁N	详情	详情
(II)	13934	3'-Bromo-4'-methyl[1,1'-biphenyl]-2-carbonitrile		C₁₄H₁₀BrN	详情	详情
(III)	13935	5-(3'-Bromo-4'-methyl[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₃H₂₅BrN₄	详情	详情
(IV)	13936	5-[3'-Bromo-4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-trityl-1H-1,2,3,4-tetraazole		C₃₃H₂₄Br₂N₄	详情	详情
(V)	13937	(2-Butyl-4-chloro-1H-imidazol-5-yl)methyl tert-butyl(dimethyl)silyl ether; 2-Butyl-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-chloro-1H-imidazole		C₁₄H₂₇ClN₂OSi	详情	详情
(VI)	13938	(1-[[3-Bromo-2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-butyl-4-chloro-1H-imidazol-5-yl)methanol		C₄₁H₃₆BrClN₆O	详情	详情
(VII)	13939	(1-[[3-Bromo-2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-butyl-4-chloro-1H-imidazol-5-yl)methanol		C₂₂H₂₂BrClN₆O	详情	详情

合成路线5

Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.

参考文献中间体

【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084.

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)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(II)	34050	methyl pentanimidoate		C₆H₁₃NO	详情	详情
(III)	34051	2-butyl-3,5-dihydro-4H-imidazol-4-one		C₇H₁₂N₂O	详情	详情
(IV)	34052	2-butyl-5-chloro-1H-imidazole		C₇H₁₁ClN₂	详情	详情
(V)	34053	N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine		C₁₀H₁₆ClN₃	详情	详情
(VI)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情
(VII)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(VIII)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(IX)	14576	pentanimidamide	109-51-3	C₅H₁₂N₂	详情	详情
(X)	34054	2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one		C₁₀H₁₇N₃O	详情	详情
(XI)	13925	2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde	83857-96-9	C₈H₁₁ClN₂O	详情	详情
(XII)	20436	glycine	56-40-6	C₂H₅NO₂	详情	详情
(XIII)	34055	2-(pentanimidoylamino)acetic acid		C₇H₁₄N₂O₂	详情	详情
(XIV)	13921	Pentanenitrile; n-Valeronitrile	110-59-8	C₅H₉N	详情	详情

合成路线6

The condensation of 2-butyl-4-chloroimidazole-5-carbaldehyde (I) with 4-bromobenzyl bromide (II) by means of K2CO3 in dimethylacetamide gives 1-(4-bromobenzyl)-2-butyl-4-chloroimidazole-5-carbaldehyde (III), which is reduced with NaBH4 in methanol yielding the corresponding carbinol (IV). The condensation of (IV) with the phenylboronic acid (VI) by means of Pd(OAc)2 and PPh3 affords the biphenyl derivative (VI), which is finally detritylated with H2SO4 in acetonitrile. The intermediate phenylboronic acid (V) has been obtained as follows: The protection of 5-phenyltetrazole (VII) with trityl chloride and TEA in THF gives 5-phenyl-2-(triphenylmethyl)tetrazole (VII), which is then treated with isopropyl borate and BuLi in THF.

参考文献中间体

【1】 Larsen, R.D.; et al.; Efficient synthesis of losartan, a nonpeptide angiotensin II receptor antagonist. J Org Chem 1994, 59, 21, 6391.

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)	13925	2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde	83857-96-9	C₈H₁₁ClN₂O	详情	详情
(II)	16109	1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide	589-15-1	C₇H₆Br₂	详情	详情
(III)	36350	1-(4-bromobenzyl)-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde		C₁₅H₁₆BrClN₂O	详情	详情
(IV)	36351	[1-(4-bromobenzyl)-2-butyl-4-chloro-1H-imidazol-5-yl]methanol		C₁₅H₁₈BrClN₂O	详情	详情
(V)	36352	2-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)phenylboronic acid		C₂₆H₂₁BN₄O₂	详情	详情
(VI)	13932	(2-Butyl-4-chloro-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol		C₄₁H₃₇ClN₆O	详情	详情
(VII)	36353	5-phenyl-2H-1,2,3,4-tetraazole	18039-42-4	C₇H₆N₄	详情	详情
(VIII)	36354	5-phenyl-2-trityl-2H-1,2,3,4-tetraazole		C₂₆H₂₀N₄	详情	详情

Extended Information