cyclopropanecarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】27238

【品名】cyclopropanecarbonitrile

【CA登记号】5500-21-0

【分子式】C₄H₅N

【分子量】67.09044

【元素组成】C 71.61% H 7.51% N 20.88%

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：(II)

Condensation of methyl 3-amino-4-methoxybenzoate (I) with cyclopropyl cyanide (II) in the presence of p-toluenesulfonic acid at 180 C gave amidine (III). Subsequent reaction of (III) with sodium hypochlorite in methanolic HCl, followed by treatment of the intermediate chloroimine with aqueous Na2CO3, furnished the benzimidazole (IV). The ester group of (IV) was reduced to alcohol (V) with DIBAL-H, and then oxidized to aldehyde (VI) using activated MnO2. Protection of the imidazole N-H of (VI) was effected by means of 2-(trimethylsilyl)ethoxymethyl chloride (VII) and NaH to afford the 1-(2-trimethylsilyl)ethoxymethylimidazole (VIII) accompanied by some amounts of the 3-substituted analogue. The Baeyer-Villiger rearrangement of the formyl group employing m-chloroperbenzoic acid then produced phenol (IX), together with the 3-protected imidazole. The pyridylmethanol derivative (XIII) was obtained from 4-nitro-3,5-dimethylpyridine N-oxide (X) through conversion to the bromopyridine (XI) with PBr3, followed by lithium-halogen exchange and condensation with DMF to give aldehyde (XII), and then reduction of (XII) with NaBH4 to (XIII). Condensation of the hydroxybenzimidazole (IX) with pyridylmethanol (XIII) using diisopropylazodicarboxylate and triphenylphosphine gave ether (XIV), which was finally deprotected with HCl in boiling aqueous methanol to yield the target compound.

参考文献中间体

合成目标

【1】 Cox, P.J.; Bower, S.; Aldous, D.J.; Astles, P.C.; McGarry, D.G.; Hulme, C.; Regan, J.R.; Huang, F.-C.; Djuric, S.W.; Moriarty, K.J.; Mathew, R.M.; Poli, G.B. (Aventis Pharma SA); Substd. azabicyclic cpds. and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. EP 0934307; JP 2000509719; WO 9748697 .

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)	25130	methyl 3-amino-4-methoxybenzoate	24812-90-6	C₉H₁₁NO₃	详情	详情
(II)	27238	cyclopropanecarbonitrile	5500-21-0	C₄H₅N	详情	详情
(III)	27239	methyl 3-[[cyclopropyl(imino)methyl]amino]-4-methoxybenzoate		C₁₃H₁₆N₂O₃	详情	详情
(IV)	27240	methyl 2-cyclopropyl-4-methoxy-1H-benzimidazole-7-carboxylate		C₁₃H₁₄N₂O₃	详情	详情
(V)	27241	(2-cyclopropyl-4-methoxy-1H-benzimidazol-7-yl)methanol		C₁₂H₁₄N₂O₂	详情	详情
(VI)	27242	2-cyclopropyl-4-methoxy-1H-benzimidazole-7-carbaldehyde		C₁₂H₁₂N₂O₂	详情	详情
(VII)	27243	[2-(chloromethoxy)ethyl](trimethyl)silane	76513-69-4	C₆H₁₅ClOSi	详情	详情
(VIII)	27244	2-cyclopropyl-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-benzimidazole-7-carbaldehyde		C₁₈H₂₆N₂O₃Si	详情	详情
(IX)	27245	2-cyclopropyl-4-methoxy-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-benzimidazol-7-ol		C₁₇H₂₆N₂O₃Si	详情	详情
(X)	27246	3,5-dimethyl-4-nitro-1-pyridiniumolate		C₇H₈N₂O₃	详情	详情
(XI)	27247	4-bromo-3,5-dimethylpyridine		C₇H₈BrN	详情	详情
(XII)	27248	3,5-dimethylisonicotinaldehyde		C₈H₉NO	详情	详情
(XIII)	27249	(3,5-dimethyl-4-pyridinyl)methanol		C₈H₁₁NO	详情	详情
(XIV)	27250	[2-cyclopropyl-7-[(3,5-dimethyl-4-pyridinyl)methoxy]-4-methoxy-1H-benzimidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether		C₂₅H₃₅N₃O₃Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Reaction of the Grignard reagent prepared from 2-fluorobenzyl bromide (I) and Mg in ether with cyclopropyl cyanide (II) in the same solvent gives 1-cyclopropyl-2-(2-fluorophenyl)ethanone (III), which is brominated with Br2 in CCl4 to yield the a-bromoketone (IV). Condensation of ketone (IV) with 2,3,4,5,6,7-hexahydrothieno[3,2-c]pyridin-2-one hydrochloride (V) by means of K2CO3 in DMF affords the adduct (VI), which is finally treated with acetic anhydride and NaH in DMF.

参考文献中间体

合成目标

【2】 Koike, H.; Asai, F.; Sugidachi, A.; Kimura, T.; Inoue, T.; Nishino, S.; Tsuzaki, Y. (Sankyo Co., Ltd.; Ube Industries, Ltd.); Tetrahydrothienopyridine derivs., furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation. EP 0542411; JP 1994041139; US 5288726; US 5436242 .
【1】 Castaner, J.; Mealy, N.E.; Doggrell, S.A.; CS-747 and R-99224. Drugs Fut 2001, 21, 9, 835.

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)	38775	1-(bromomethyl)-2-fluorobenzene	446-48-0	C₇H₆BrF	详情	详情
(II)	27238	cyclopropanecarbonitrile	5500-21-0	C₄H₅N	详情	详情
(III)	48583	1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone	150322-73-9	C₁₁H₁₁FO	详情	详情
(IV)	48584	2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-1-ethanone	204205-33-4	C₁₁H₁₀BrFO	详情	详情
(V)	48585	4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one	178688-48-7	C₇H₉NOS	详情	详情
(VI)	48586	5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one	951380-42-0	C₁₈H₁₈FNO₂S	详情	详情

Extended Information