BMS-181100, BMY-14802-1, -Drug Synthesis Database

【结构式】

【药物名称】BMS-181100, BMY-14802-1

【化学名称】1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]butan-1-ol hydrochloride

【CA登记号】99931-60-9

【分子式】C₁₈H₂₃ClF₂N₄O

【分子量】384.86001

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Antipsychotic Drugs, PSYCHOPHARMACOLOGIC DRUGS, sigma Receptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

A new synthesis for [18F]-labeled BMY-14802 has been reported: The compound can be prepared by two related ways: 1) The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-FK and Kryptofix 2.2.2 gives 4-fluorophenyl cyclopropyl methanone (II), which is treated with HCl in methanol yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (IV) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol. 2) The reduction of butanone (III) with NaBH4 in methanol gives 4-chloro-1-(4-fluorophenyl)-1-butanol (VI), which is then condensed with pyrimidine (IV) as before.

参考文献中间体

【1】 Yevich, J.P.; Frick, M.P.; Shiue, G.G.; Huang, H.; Pleus, R.C.; Shiue, C.-Y.; Bai, L.-Q.; Catt, J.D.; Rysavy, J.A.; Fluorine-18 labeled BMY 14802: Synthesis and anatomical distribution in rodents. J Label Compd Radiopharm 1993, 32, 501.

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)	11423	Cyclopropyl(4-nitrophenyl)methanone		C₁₀H₉NO₃	详情	详情
(II)	11424	Cyclopropyl(4-fluorophenyl)methanone		C₁₀H₉FO	详情	详情
(II)	27427	cyclopropyl(4-fluorophenyl)methanone	772-31-6	C₁₀H₉FO	详情	详情
(III)	11425	4-Chloro-1-(4-fluorophenyl)-1-butanone		C₁₀H₁₀ClFO	详情	详情
(III)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情
(IV)	11426	5-Fluoro-2-piperazinopyrimidine		C₈H₁₁FN₄	详情	详情
(V)	11427	1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)piperazino]-1-butanone		C₁₈H₂₀F₂N₄O	详情	详情
(V)	28204	1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanone		C₁₈H₂₀F₂N₄O	详情	详情
(VI)	11428	4-Chloro-1-(4-fluorophenyl)-1-butanol		C₁₀H₁₂ClFO	详情	详情
(VI)	45061	4-chloro-1-(4-fluorophenyl)-1-butanol		C₁₀H₁₂ClFO	详情	详情

合成路线2

A new synthesis of [18F]-labeled BMY-14802 has been described: The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-CsF in DMSO - 5% water at 180 C gives 4-fluorophenylcyclopropylmethanone (II), which is treated with HCl in methanol, yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (VI) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol.

参考文献中间体

【1】 Shea, C.; Taylor, D.P.; Ding, Y.S.; Wolf, A.P.; Logan, J.; Volkow, N.D.; Gatley, S.J.; Fowler, J.S.; Dewey, S.L.; Synthesis and PET studies of fluorine-18-BMY-14802 - A potential antipsychotic drug. J Nucl Med 1993, 34, 2, 246.

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)	11423	Cyclopropyl(4-nitrophenyl)methanone		C₁₀H₉NO₃	详情	详情
(II)	11424	Cyclopropyl(4-fluorophenyl)methanone		C₁₀H₉FO	详情	详情
(II)	27427	cyclopropyl(4-fluorophenyl)methanone	772-31-6	C₁₀H₉FO	详情	详情
(III)	11431	4-Chloro-1-(4-fluorophenyl)-1-butanone		C₁₀H₁₀ClFO	详情	详情
(III)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情
(IV)	11426	5-Fluoro-2-piperazinopyrimidine		C₈H₁₁FN₄	详情	详情
(V)	11427	1-(4-Fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)piperazino]-1-butanone		C₁₈H₂₀F₂N₄O	详情	详情
(V)	28024	(2S)-2-(chloromethyl)-1-ethylpyrrolidine		C₇H₁₄ClN	详情	详情

合成路线3

The reaction of 2-chloro-5-fluoro-4-(methylsulfanyl)pyrimidine (I) with N-carbethoxypiperazine (II) yields (III), which upon treatment with Raney Nickel affords ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate (IV). Hydrolysis and decarboxylation of (IV) generates 5-fluoro-2-(1-piperazinyl)pyrimidine (V). The reaction of (V) with the alpha-chloroketal (VI) generates the butyrophenone derivative (VII). Sodium borohydride reduction of (VII) and treatment with ethanolic hydrochloric acid yields BMY-14802-1.

参考文献中间体

【1】 Lobeck, W.G. Jr.; Yevich, J.P. (Bristol-Myers Squibb Co.); Antipsychotic 1-fluorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives. AU 8539449; BE 0901880; CH 663022; DE 3507983; ES 8607254; FR 2560878; GB 2155925; JP 1986000075; US 4605655 .
【2】 Yocca, F.D.; Yevich, J.P.; New, J.S.; BMY-14802-1. Drugs Fut 1987, 12, 8, 752.

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)	28200	2-chloro-5-fluoro-4-(methylsulfanyl)pyrimidine		C₅H₄ClFN₂S	详情	详情
(II)	24694	N-ethoxycarbonylpiperidine; Ethyl 1-piperazinecarboxylate; N-Ethoxycarbonyl piperazine; N-Carbethoxy piperazine	120-43-4	C₇H₁₄N₂O₂	详情	详情
(III)	28201	ethyl 4-[5-fluoro-4-(methylsulfanyl)-2-pyrimidinyl]-1-piperazinecarboxylate		C₁₂H₁₇FN₄O₂S	详情	详情
(IV)	28202	ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate		C₁₁H₁₅FN₄O₂	详情	详情
(V)	11426	5-Fluoro-2-piperazinopyrimidine		C₈H₁₁FN₄	详情	详情
(VI)	28203	2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane	3308-94-9	C₁₂H₁₄ClFO₂	详情	详情
(VII)	28204	1-(4-fluorophenyl)-4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]-1-butanone		C₁₈H₂₀F₂N₄O	详情	详情

Extended Information