合成路线:The reaction of cyclopentanone (I) with sodium cyanide,NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II),which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III).The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V),which,without isolation,is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI).This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene.The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X).Cyclization of (X) with tributyltin azide in refluxing xylene,followed by reaction with trityl chloride in DMF,affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI).Finally,this compound is hydrolyzed to irbesartan with HCl in methanol/THF.The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
参考文献标题:Method for the preparation of a tetrazole deriv.under two crystalline forms and novel crystalline form of this deriv
文献作者:Caron,A.; Chantreux,D.; Bouloumie,C.(Sanofi-Synthabo )
参考来源:EP 0708103
合成路线:The reaction of cyclopentanone (I) with sodium cyanide,NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II),which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III).The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V),which,without isolation,is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI).This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene.The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X).Cyclization of (X) with tributyltin azide in refluxing xylene,followed by reaction with trityl chloride in DMF,affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI).Finally,this compound is hydrolyzed to irbesartan with HCl in methanol/THF.The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
参考文献标题:Spiro-dihydro-imidazolones,a new class of non-peptide angiotensin II receptor antagonists
文献作者:Bernhart,C.; Clement,J.; Ferrari,B.; et al.
参考来源:12th Int Symp Med Chem (Sept 13-17,Basel) 1992,Abst P-084.A.
合成路线:The reaction of cyclopentanone (I) with sodium cyanide,NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II),which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III).The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V),which,without isolation,is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI).This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene.The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X).Cyclization of (X) with tributyltin azide in refluxing xylene,followed by reaction with trityl chloride in DMF,affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI).Finally,this compound is hydrolyzed to irbesartan with HCl in methanol/THF.The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
参考文献标题:A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists
文献作者:Bernhart,C.A.; Perreaut,P.M.; Ferrari,B.P.; Muneaux,Y.A.; Assens,J.L.; Clement,J.; Haudricourt,F.; Muneaux,C.F.; Taillades,J.E.; Vigna,M.A.; et al.
参考来源:J Med Chem 1993,36(22),3371-80
合成路线:The reaction of cyclopentanone (I) with sodium cyanide,NH3 and NH4Cl in hot methanol/water gives 1-aminocyclopentanecarbonitrile (II),which is partially hydrolyzed with concentrated H2SO4 to the corresponding amide (III).The acylation of (III) with pentanoyl chloride (IV) by means of triethylamine in THF yields 1-(pentanamido)cyclopentane-1-carboxamide (V),which,without isolation,is cyclized by means of KOH in refluxing methanol/water to afford 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (VI).This compound (VI) can also be obtained by cyclization of 1-aminocyclopentanecarboxylic acid ethyl ester (VII) with pentanimidic ethyl ester (VIII) by means of acetic acid in refluxing xylene.The condensation of (VI) with 4'-(bromomethyl)biphenyl-2-carbonitrile (IX) by means of NaH in DMF gives 4'-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-ylmethyl)biphenyl-2-carbonitrile (X).Cyclization of (X) with tributyltin azide in refluxing xylene,followed by reaction with trityl chloride in DMF,affords 2-butyl-3-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl]-1,3-diazaspiro[4.4]non-1-en-4-one (XI).Finally,this compound is hydrolyzed to irbesartan with HCl in methanol/THF.The final cyclization of (X) with tributyltin azide or sodium azide also directly gives irbesartan.
参考文献标题:Irbesartan
文献作者:Casas,A.; Merlos,M.; Castar,J.
参考来源:Drugs Fut 1997,22(5),481
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