1-(3-chloro-4-fluorobenzoyl)-4-piperidinone -Drug Synthesis Database

【结构式】

【分子编号】24372

【品名】1-(3-chloro-4-fluorobenzoyl)-4-piperidinone

【CA登记号】

【分子式】C₁₂H₁₁ClFNO₂

【分子量】255.6759832

【元素组成】C 56.37% H 4.34% Cl 13.87% F 7.43% N 5.48% O 12.52%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The pyridine-2-carboxaldehyde (XII) was prepared by reduction of ethyl 6-chloro-5-methylpyridine-2-carboxylate (X) with NaBH4, followed by displacement of the chloro group by ethanolic methylamine in a sealed vessel at 100 C yielding pyridinealcohol (XI), which was further oxidized to the desired aldehyde (XII) using MnO2. The title compound was then obtained by condensation of amine (IX) with aldehyde (XII), followed by reduction of the intermediate imine with KBH4 in MeOH.

参考文献中间体

合成目标

【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648.
【2】 Vacher, B.; Bonnaud, B.; Koek, W. (Pierre Fabre Medicament); Pyridin-2-yl-methylamine derivs., method of preparing and application as medicine. EP 0946546; JP 2001504129; US 6020345; WO 9822459 .

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)	11338	1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal	177-11-7	C₇H₁₃NO₂	详情	详情
(II)	24370	3-chloro-4-fluorobenzoyl chloride	65055-17-6	C₇H₃Cl₂FO	详情	详情
(III)	24371	(3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone		C₁₄H₁₅ClFNO₃	详情	详情
(IV)	24372	1-(3-chloro-4-fluorobenzoyl)-4-piperidinone		C₁₂H₁₁ClFNO₂	详情	详情
(V)	24373	(3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone		C₁₃H₁₃ClFNO₂	详情	详情
(VI)	24374	(3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone		C₁₃H₁₄ClF₂NO₂	详情	详情
(VII)	24375	[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl 4-methylbenzenesulfonate		C₂₀H₂₀ClF₂NO₄S	详情	详情
(VIII)	24376	2-[[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl]-1H-isoindole-1,3(2H)-dione		C₂₁H₁₇ClF₂N₂O₃	详情	详情
(IX)	24377	[4-(aminomethyl)-4-fluoro-1-piperidinyl](3-chloro-4-fluorophenyl)methanone		C₁₃H₁₅ClF₂N₂O	详情	详情
(X)	24378	ethyl 6-chloro-5-methyl-2-pyridinecarboxylate		C₉H₁₀ClNO₂	详情	详情
(XI)	24379	[5-methyl-6-(methylamino)-2-pyridinyl]methanol		C₈H₁₂N₂O	详情	详情
(XII)	24380	5-methyl-6-(methylamino)-2-pyridinecarbaldehyde		C₈H₁₀N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The title compound was then obtained by condensation of 6-(dimethylamino)pyridine-2-carboxaldehyde (X) with amine (IX), followed by reduction of the intermediate imine with KBH4 in MeOH.

参考文献中间体

合成目标

【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648.

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)	11338	1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal	177-11-7	C₇H₁₃NO₂	详情	详情
(II)	24370	3-chloro-4-fluorobenzoyl chloride	65055-17-6	C₇H₃Cl₂FO	详情	详情
(III)	24371	(3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone		C₁₄H₁₅ClFNO₃	详情	详情
(IV)	24372	1-(3-chloro-4-fluorobenzoyl)-4-piperidinone		C₁₂H₁₁ClFNO₂	详情	详情
(V)	24373	(3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone		C₁₃H₁₃ClFNO₂	详情	详情
(VI)	24374	(3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone		C₁₃H₁₄ClF₂NO₂	详情	详情
(VII)	24735	tert-Butyl 2-iodoacetate		C₆H₁₁IO₂	详情	详情
(VIII)	24336	5-cyano-5H-dibenzo[b,f]azepine		C₁₅H₁₀N₂	详情	详情
(IX)	24337	5-cyano-10-nitro-5H-dibenzo[b,f]azepine		C₁₅H₉N₃O₂	详情	详情
(X)	24381	6-(dimethylamino)-2-pyridinecarbaldehyde		C₈H₁₀N₂O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

Acylation of 4-piperidone ethylene ketal (I) with 3-chloro-4-fluorobenzoyl chloride (II) in the presence of Et3N gave amide (III). After ketal hydrolysis of (III) using 80% formic acid and CuSO4, treatment of the resulting N-acyl piperidone (IV) with dimethyloxosulfonium methylide provided epoxide (V). Subsequent ring opening of (V) with HF-pyridine complex afforded the fluoro alcohol (VI), which was converted to tosylate (VII). Then, Gabriel synthesis via the corresponding phthalimide (VIII) produced amine (IX). The title compound was then obtained by condensation of 6-(2-furanyl)pyridine-2-carboxaldehyde (X) with amine (IX), followed by reduction of the intermediate imine with KBH4 in MeOH.

参考文献中间体

合成目标

【1】 Koek, W.; Cosi, C.; Jubault, N.; Funes, P.; Assié, M.-B.; Vacher, B.; Kleven, M.; Bonnaud, B.; Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors. J Med Chem 1999, 42, 9, 1648.

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)	11338	1,4-Dioxa-8-azaspiro[4.5]decane; 4-Piperidone ethylene ketal	177-11-7	C₇H₁₃NO₂	详情	详情
(II)	24370	3-chloro-4-fluorobenzoyl chloride	65055-17-6	C₇H₃Cl₂FO	详情	详情
(III)	24371	(3-chloro-4-fluorophenyl)(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methanone		C₁₄H₁₅ClFNO₃	详情	详情
(IV)	24372	1-(3-chloro-4-fluorobenzoyl)-4-piperidinone		C₁₂H₁₁ClFNO₂	详情	详情
(V)	24373	(3-chloro-4-fluorophenyl)(1-oxa-6-azaspiro[2.5]oct-6-yl)methanone		C₁₃H₁₃ClFNO₂	详情	详情
(VI)	24374	(3-chloro-4-fluorophenyl)[4-fluoro-4-(hydroxymethyl)-1-piperidinyl]methanone		C₁₃H₁₄ClF₂NO₂	详情	详情
(VII)	24375	[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl 4-methylbenzenesulfonate		C₂₀H₂₀ClF₂NO₄S	详情	详情
(VIII)	24376	2-[[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]methyl]-1H-isoindole-1,3(2H)-dione		C₂₁H₁₇ClF₂N₂O₃	详情	详情
(IX)	27377	2-chloro-N-cyclohexylacetamide		C₈H₁₄ClNO	详情	详情
(X)	24382	6-(2-furyl)-2-pyridinecarbaldehyde		C₁₀H₇NO₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

In an alternative, shorter route, 1-(3-chloro-4-fluorobenzoyl)-4-piperidinone (I) is subjected to Darzens condensation with chloroacetonitrile in the presence of NaOH and a phase-transfer catalyst to furnish the epoxy nitrile (II). Epoxide opening in (II) with HF-pyridine gives rise to the fluoro hydroxy nitrile (III). This is finally condensed with (5-methylpyridin-2-yl)methylamine (IV) under reductive amination conditions to produce the title compound.

参考文献中间体

合成目标

【1】 Bonnaud, B.; Maurel, J.-L.; Vacher, B.; Ribet, J.-P. (Pierre Fabre Medicament); Synthesis method and intermediates of pyridin-2-yl-methylamine. WO 0264585 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	24372	1-(3-chloro-4-fluorobenzoyl)-4-piperidinone	C₁₂H₁₁ClFNO₂	详情	详情
(II)	64959	6-(3-chloro-4-fluorobenzoyl)-1-oxa-6-azaspiro[2.5]octane-2-carbonitrile	C₁₄H₁₂ClFN₂O₂	详情	详情
(III)	64960	2-[1-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-piperidinyl]-2-hydroxyacetonitrile	C₁₄H₁₃ClF₂N₂O₂	详情	详情
(IV)	64961	(5-methyl-2-pyridinyl)methanamine; (5-methyl-2-pyridinyl)methylamine	C₇H₁₀N₂	详情	详情

Extended Information