ethyl pentanimidoate -Drug Synthesis Database

【结构式】

【分子编号】15120

【品名】ethyl pentanimidoate

【CA登记号】

【分子式】C₇H₁₅NO

【分子量】129.20224

【元素组成】C 65.07% H 11.7% N 10.84% O 12.38%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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.

参考文献中间体

合成目标

【1】 Casas, A.; Merlos, M.; Castaner, J.; Irbesartan. Drugs Fut 1997, 22, 5, 481.
【2】 Bernhart, C.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut, P. (Sanofi-Synthélabo ); Heterocyclic N-substd. derivs., their preparation and the pharmaceutical compsns. containing them. EP 0454511; FR 2659967; FR 2665702; JP 1992506222; JP 1998279566; US 5270317; WO 9114679 .
【3】 Caron, A.; Chantreux, D.; Bouloumie, C. (Sanofi-Synthelabo ); Method for the preparation of a tetrazole deriv. under two crystalline forms and novel crystalline form of this deriv. EP 0708103 .
【4】 Bernhart, C.A.; Perreaut, P.M.; Ferrari, B.P.; et al.; A new series of imidazolones: Highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem 1993, 36, 22, 3371-80.
【5】 Bernhart, C.; Clement, J.; Ferrari, B.; et al.; Spiro-dihydro-imidazolones, a new class of non-peptide angiotensin II receptor antagonists. 12th Int Symp Med Chem (Sept 13-17, Basel) 1992, Abst P-084.A..

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)	15113	cyclopentanone	120-92-3	C₅H₈O	详情	详情
(II)	15114	1-aminocyclopentanecarbonitrile		C₆H₁₀N₂	详情	详情
(III)	15115	1-Amino-1-cyclopentane carboxamide; 1-Aminocyclopentanecarboxamide	17193-28-1	C₆H₁₂N₂O	详情	详情
(IV)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(V)	15117	N-[1-(aminocarbonyl)cyclopentyl]pentanamide; 1-(pentanoylamino)cyclopentanecarboxamide		C₁₁H₂₀N₂O₂	详情	详情
(VI)	15118	2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 1,3-Diazaspirol[4,4]non-1-en-4-one,2-butyl	151257-01-1	C₁₁H₁₈N₂O	详情	详情
(VII)	15119	ethyl 1-aminocyclopentanecarboxylate		C₈H₁₅NO₂	详情	详情
(VIII)	15120	ethyl pentanimidoate		C₇H₁₅NO	详情	详情
(IX)	15332	4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl	114772-54-2	C₁₄H₁₀BrN	详情	详情
(X)	15122	4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl][1,1'-biphenyl]-2-carbonitrile		C₂₅H₂₇N₃O	详情	详情
(XI)	15121	2-butyl-3-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one		C₄₄H₄₂N₆O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The reaction of ethyl valerimidate hydrochloride (I) with cyanamide in ethanol yielded cyanoimidate (II), which was converted into the cyanoimidoylglycine (IV) on treatment with glycine ethyl ester (III) and triethylamine. Alkylation of (IV) with the biphenyl derivative (V) in the presence of 1 mole of NaH in DMF gave the intermediate cyanoamidine (VI), which, by further addition of half an equivalent of sodium hydride was cyclized to the imidazole (VII). Acylation of (VII) with 3,3-dimethylacryloyl chloride (VIII) in cold pyridine yielded amide (IX), and then N-alkylation with iodomethane and sodium hydride in DMF provided (X). Acidic treatment with acetic acid in refluxing ethanol removed the trityl group to give (XI).

参考文献中间体

合成目标

【1】 Okazaki, T.; et al.; Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives. Chem Pharm Bull 1998, 46, 6, 973.

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)	15120	ethyl pentanimidoate		C₇H₁₅NO	详情	详情
(II)	17804	ethyl N-cyanopentanimidoate		C₈H₁₄N₂O	详情	详情
(III)	10309	ethyl 2-aminoacetate; Glycine ethyl ester	459-73-4	C₄H₉NO₂	详情	详情
(IV)	17806	ethyl 2-(pentanimidoylamino)acetate		C₁₀H₁₇N₃O₂	详情	详情
(V)	65045	5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-trityl-1H-1,2,3,4-tetraazole		C₃₃H₂₅BrN₄	详情	详情
(VI)	17808	ethyl 2-(pentanimidoyl[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]amino)acetate		C₄₃H₄₁N₇O₂	详情	详情
(VII)	17809	ethyl 4-amino-2-butyl-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate		C₄₃H₄₁N₇O₂	详情	详情
(VIII)	17810	3-methyl-2-butenoyl chloride; 3,3-Dimethylacryloyl chloride	3350-78-5	C₅H₇ClO	详情	详情
(IX)	17811	ethyl 2-butyl-4-[(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate		C₄₈H₄₇N₇O₃	详情	详情
(X)	17812	ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate		C₄₉H₄₉N₇O₃	详情	详情
(XI)	17813	ethyl 2-butyl-4-[methyl(3-methyl-2-butenoyl)amino]-1-[[2'-(1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carboxylate		C₃₀H₃₅N₇O₃	详情	详情

Extended Information