ethyl 2-cyano-4,4-diethoxybutanoate -Drug Synthesis Database

【结构式】

【分子编号】14789

【品名】ethyl 2-cyano-4,4-diethoxybutanoate

【CA登记号】

【分子式】C₁₁H₁₉NO₄

【分子量】229.2762

【元素组成】C 57.63% H 8.35% N 6.11% O 27.91%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(III)

1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.

参考文献中间体

合成目标

【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498.
【2】 Taylor, E.C.; Design and synthesis of inhibitors of folate-dependent enzymes as antitumor agents. Adv Exp Med Biol 1993, 338, 387-408.
【3】 Taylor, E.C.; Kuhnt, D.G.; Shih, C.; Grindey, G.B. (Eli Lilly and Company; Princeton University); N-(Pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivs. AU 9167791; EP 0432677; JP 1996003166; US 5028608 .
【4】 Jannatipour, M.; Kuhnt, D.; Shih, C.; Rinzel, S.M.; Grindey, G.B.; Taylor, E.C.; Moran, R.G.; Barredo, J.; A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992, 35, 23, 4450-4.

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)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(II)	12113	2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal	2032-35-1	C₆H₁₃BrO₂	详情	详情
(III)	14789	ethyl 2-cyano-4,4-diethoxybutanoate		C₁₁H₁₉NO₄	详情	详情
(IV)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(V)	14791	2,6-diamino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone		C₁₀H₁₈N₄O₃	详情	详情
(VI)	14792	2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one	7355-55-7	C₆H₆N₄O	详情	详情
(VII)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(VIII)	14794	2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide		C₁₁H₁₄N₄O₂	详情	详情
(IX)	14795	N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₁H₁₂I₂N₄O₂	详情	详情
(X)	14796	N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide		C₁₁H₁₃IN₄O₂	详情	详情
(XI)	14797	dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate		C₁₆H₁₇NO₅	详情	详情
(XII)	14798	dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate		C₂₇H₂₉N₅O₇	详情	详情
(XIII)	14799	dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate		C₂₇H₃₃N₅O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of cyano ester (I) with formamidine in the presence of NaOEt afforded the pyrimidinone derivative (II). Acetal hydrolysis of (II) with concomitant intramolecular cyclization under acidic conditions produced the pyrrolopyrimidinone (III), which was further chlorinated to (IV) in refluxing POCl3. Displacement of the 4-chloro of (IV) with 3-chloro-4-fluoroaniline (V) in the presence of silver triflate in hot DMF afforded the anilino pyrrolopyrimidine (VI). Oxidation of (VI) using pyridinium bromide perbromide furnished the alpha,alpha-dibromo lactam (VII). Reductive debromination of (VII) by means of zinc dust in AcOH gave intermediate (VIII).

参考文献中间体

合成目标

【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 .

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)	14789	ethyl 2-cyano-4,4-diethoxybutanoate		C₁₁H₁₉NO₄	详情	详情
(II)	60644	2-[4-bromo-2-(2-fluorobenzoyl)anilino]-2-oxoethyl 4-methylbenzenesulfonate		C₂₂H₁₇BrFNO₅S	详情	详情
(III)	60045	3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one		C₆H₅N₃O	详情	详情
(IV)	60046	4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine	3680-69-1	C₆H₄ClN₃	详情	详情
(V)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(VI)	60850	N-(3-chloro-4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; N-(3-chloro-4-fluorophenyl)-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine		C₁₂H₈ClFN₄	详情	详情
(VII)	60851	5,5-dibromo-4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₁₂H₆Br₂ClFN₄O	详情	详情
(VIII)	60852	4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₁₂H₈ClFN₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Condensation of 2-cyano-4,4-diethoxybutyric acid ethyl ester (I) with formamidine hydrochloride (II) in the presence of NaOEt provides the pyrimidine derivative (III). Subsequent hydrolysis of the diethyl acetal of (III) under acidic conditions leads to the pyrrolopyrimidinone (IV). This is converted to the 4-chloro derivative (V) upon treatment with POCl3. Then, oxidation of (V) by means of pyridinium bromide perbromide furnishes the dibromo pyrrolopyridinone (VI), which is further debrominated to (VII) employing zinc dust in AcOH

参考文献中间体

合成目标

【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 .

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)	14789	ethyl 2-cyano-4,4-diethoxybutanoate		C₁₁H₁₉NO₄	详情	详情
(II)	15369	Iminoformamide; Methanimidamide	463-52-5	CH₄N₂	详情	详情
(III)	60044	6-amino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone		C₁₀H₁₇N₃O₃	详情	详情
(IV)	60045	3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one		C₆H₅N₃O	详情	详情
(V)	60046	4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine	3680-69-1	C₆H₄ClN₃	详情	详情
(VI)	60047	5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₆H₂Br₂ClN₃O	详情	详情
(VII)	60048	4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one		C₆H₄ClN₃O	详情	详情

Extended Information