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【结 构 式】

【分子编号】23801

【品名】1-piperazinecarbaldehyde; N-Formylpiperazine

【CA登记号】7755-92-2

【 分 子 式 】C5H10N2O

【 分 子 量 】114.14728

【元素组成】C 52.61% H 8.83% N 24.54% O 14.02%
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：(II)

N-(2,2-Diphenylacetyl)piperazine (IV) was prepared by acylation of N-formylpiperazine (II) with 2,2-diphenylacetyl chloride (I), followed by acid-promoted formyl deprotection of the resulting amide (III). Condensation of 5-hydroxyquinoline (VI) with epichlorohydrin (V) in the presence of potassium tert-butoxide in DMF at 90 C provided 5-(2,3-epoxypropoxy)quinoline (VII), which was subsequently coupled with acylpiperazine (IV) in boiling isopropanol to yield (VIII). This was finally treated with fumaric acid (IX) in MeOH to furnish the title sesquifumarate salt.

参考文献 中间体
合成目标
【1】 Suzuki, T.; et al.; Structure-activity relationship of newly synthesiz. J Med Chem 1997, 40, 13, 2047.
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) 23800 Diphenylacetyl chloride; 2,2-diphenylacetyl chloride 1871-76-7 C14H11ClO 详情 详情
(II) 23801 1-piperazinecarbaldehyde; N-Formylpiperazine 7755-92-2 C5H10N2O 详情 详情
(III) 23802 4-(2,2-diphenylacetyl)-1-piperazinecarbaldehyde C19H20N2O2 详情 详情
(IV) 23803 2,2-diphenyl-1-(1-piperazinyl)-1-ethanone C18H20N2O 详情 详情
(V) 10146 Epichlorohydrin; 2-(Chloromethyl)oxirane 106-89-8 C3H5ClO 详情 详情
(VI) 23805 5-quinolinol 578-67-6 C9H7NO 详情 详情
(VII) 23806 5-(2-oxiranylmethoxy)quinoline; 2-oxiranylmethyl 5-quinolinyl ether C12H11NO2 详情 详情
(VIII) 23807 1-[4-[2-hydroxy-3-(5-quinolinyloxy)propyl]-1-piperazinyl]-2,2-diphenyl-1-ethanone C30H31N3O3 详情 详情
(IX) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Condensation of dibenzosuberenone (I) with sodium 2-chloro-2,2-difluoroacetate (II) in diglyme at 165 C gives 10,11-(difluoromethano)benzosuberone (III), which is reduced with NaBH4 in THF/methanol to yield the corresponding syn-alcohol (IV). Reaction of alcohol (IV) with hot SOCl2 affords a mixture of the syn- and anti-chloro derivatives (V). This mixture (V) is treated with 1-for-mylpiperazine (VI) in refluxing acetonitrile to provide a mixture of syn- and anti-4-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine-1-carbaldehyde (VI), which is separated by chromatography. The desired anti-isomer (VII) is then treated with KOH in refluxing ethanol/water to give the piperazine derivative (VIII), which is finally condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in refluxing isopranol. 5-[2(R),3-Epoxypropoxy]quinoline (IX) is obtained by reaction of 5-hydroxyquinoline (X) with (R)-glycidyl tosylate (XI) by means of NaH in DMF.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【2】 Knaus, E.E.; Vo, D.; Wolowyk, M.W.; Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines. Drug Des Discov 1992, 9, 1, 69.
【3】 Bruno, N.A.; Nelson, J.T.; Wu, H.; Muehldorf, A.V.; Makra, F.; Cheung, P.; Slate, D.L.; Zutshi, N.; Casey, S.M.; Pfister, J.R.; Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents. Bioorg Med Chem Lett 1995, 5, 21, 2473.
【4】 Pfister, J.R.; Slate, D.L. (Syntex (USA) LLC); 10,11-Methanodibenzosuberane derivs. used as chemosensitizing agents. EP 0695293; EP 0866063; JP 1996509223; WO 9424107 .
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) 29151 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone 2222-33-5 C15H10O 详情 详情
(II) 59522 sodium 2-chloro-2,2-difluoroacetate C2ClF2NaO2 详情 详情
(III) 56203 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one C16H10F2O 详情 详情
(IV) 56204 (1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-ol C16H12F2O 详情 详情
(V) 56205 6-chloro-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene C16H11ClF2 详情 详情
(VI) 23801 1-piperazinecarbaldehyde; N-Formylpiperazine 7755-92-2 C5H10N2O 详情 详情
(VII) 56206 4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-1-piperazinecarbaldehyde C21H20F2N2O 详情 详情
(VIII) 56207 1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine C20H20F2N2 详情 详情
(IX) 56211 (2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline C12H11NO2 详情 详情
(X) 23805 5-quinolinol 578-67-6 C9H7NO 详情 详情
(XI) 16242 (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 113826-06-5 C10H12O4S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The alkylation of N-formylpiperazine (II) with 2-(chloromethyl)quinoline (I) produced the disubstituted piperazine (III). The formyl group of (III) was then cleaved by means of H2SO4 in boiling EtOH, yielding quinolylmethylpiperazine (IV). Subsequent alkylation of (IV) with 1-bromo-3-chloropropane (V) afforded the chloropropyl derivative (VI). This was finally condensed with 7-hydroxybenzothiazinone (VII) in the presence of K2CO3 and a phase-transfer catalyst to furnish the title compound.

参考文献 中间体
合成目标
【1】 Tohma, T.; Onogi, K.; Zang, M.; Timmerman, H.; Wada, Y.; Tamura, M. (Kowa Co., Ltd.); Diamine derivs. and pharmaceutical containing the same. EP 0957100; WO 9902520 .
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) 13162 2-(Chloromethyl)quinoline; alpha-Chloroquinaldine 4377-41-7 C10H8ClN 详情 详情
(II) 23801 1-piperazinecarbaldehyde; N-Formylpiperazine 7755-92-2 C5H10N2O 详情 详情
(III) 41113 4-(2-quinolinylmethyl)-1-piperazinecarbaldehyde C15H17N3O 详情 详情
(IV) 41114 2-(1-piperazinylmethyl)quinoline C14H17N3 详情 详情
(V) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VI) 41115 2-[[4-(3-chloropropyl)-1-piperazinyl]methyl]quinoline C17H22ClN3 详情 详情
(VII) 28290 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one C8H7NO2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Reaction of 4-chloroaniline (I) with gamma-butyrolactone (II) in a refluxing solution of HCl afforded pyrrolidinone (III). Subsequent carboxylation of (III) with diethyl carbonate in the presence of NaH gave ketoester (IV), which was reduced to alcohol (V) using calcium borohydride in MeOH. Further treatment of (V) with methanesulfonyl chloride and Et3N provided the corresponding mesylate (VI). Methoxyethylpiperazine (IX) was prepared by alkylation of formylpiperazine (VII) with 2-methoxyethyl bromide, followed by acid deprotection of the alkylated formylpiperazine (VIII). Then, condensation of mesylate (VI) with piperazine (IX) provided racemic (X). Finally, resolution with D-tartaric acid in EtOH yielded the target (R)-isomer.

参考文献 中间体
合成目标
【1】 Mita, N.; Nagase, H.; Iizuka, H.; Oguchi, T.; Sakai, K.; Horikomi, K.; Miwa, T.; Takahashi, S. (Mitsui Chemicals, Inc.); Pyrrolidinone derivs. and their use as antipsychotic medicaments. EP 0839805; JP 1998182602 .
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) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(II) 20576 dihydro-2(3H)-furanone 96-48-0 C4H6O2 详情 详情
(III) 27732 1-(4-chlorophenyl)-2-pyrrolidinone 7661-33-8 C10H10ClNO 详情 详情
(IV) 27733 ethyl 1-(4-chlorophenyl)-2-oxo-3-pyrrolidinecarboxylate C13H14ClNO3 详情 详情
(V) 27734 1-(4-chlorophenyl)-3-(hydroxymethyl)-2-pyrrolidinone C11H12ClNO2 详情 详情
(VI) 27735 [1-(4-chlorophenyl)-2-oxo-3-pyrrolidinyl]methyl methanesulfonate C12H14ClNO4S 详情 详情
(VII) 23801 1-piperazinecarbaldehyde; N-Formylpiperazine 7755-92-2 C5H10N2O 详情 详情
(VIII) 27736 4-(2-methoxyethyl)-1-piperazinecarbaldehyde C8H16N2O2 详情 详情
(IX) 27737 1-(2-methoxyethyl)piperazine C7H16N2O 详情 详情
(X) 27738 1-(4-chlorophenyl)-3-[[4-(2-methoxyethyl)-1-piperazinyl]methyl]-2-pyrrolidinone C18H26ClN3O2 详情 详情
Extended Information