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【结 构 式】

【分子编号】10358

【品名】1-Bromo-3-chloropropane

【CA登记号】109-70-6

【 分 子 式 】C3H6BrCl

【 分 子 量 】157.43734

【元素组成】C 22.89% H 3.84% Br 50.75% Cl 22.52%
与该中间体有关的原料药合成路线共 36 条
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合成路线1

该中间体在本合成路线中的序号：(V)

By condensation of 2-(3-methoxyphenyl)tetradecanenitrile (I) [prepared by alkylation of 3-methoxyphenylacetonitrile (III) with 1-bromoundecane (IV) with 1-chloro-4-methyl-6-(3-methoxyphenyl)-4-azahexane (II) (prepared by alkylation of N-methyl-[2-(3-methoxyphenyl)ethylamine (VI) with 1-bromo-3-chloropropane (V)) by means of sodium amide in refluxing toluene.

参考文献 中间体
合成目标
【1】 Ehrmann, O.; et al. (BASF AG); omega-Cyano-1, omega-diphenyl-azaalkiane derivatives, their preparation and drugs containing them. DE 3144150 .
【2】 Castaner, J.; Prous, J.; Anipamil. Drugs Fut 1986, 11, 3, 171.
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) 24059 2-(3-methoxyphenyl)tetradecanenitrile C21H33NO 详情 详情
(II) 24060 3-chloro-N-(3-methoxyphenethyl)-N-methyl-1-propanamine C13H20ClNO 详情 详情
(III) 24061 3-methoxyphenylacetonitrile; 2-(3-methoxyphenyl)acetonitrile 19924-43-7 C9H9NO 详情 详情
(IV) 24062 1-bromododecane 143-15-7 C12H25Br 详情 详情
(V) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VI) 24064 2-(3-methoxyphenyl)-N-methyl-1-ethanamine C10H15NO 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

Compound can be prepared in several different ways, all starting from 3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (I): 1) The condensation of (I) with N-(3-bromopropyl)-N'-(m-chlorophenyl)piperazine (B) by means of NaNH2, NaH or sodium alcoholate in an organic solvent (DMSO, DMF, dioxane, benzene, alcohol, tetralin, etc.). 2) The condensation of (I) with 1-chloro-3-bromopropane (A) by means of sodium alcoholate in alcohol gives 1-(3-chloropropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (II), which is then condensed with an inert solvent by means of HCl acceptor. 3) The condensation of (II) with diethanolamine (C) affords 1-(3-bishydroxyethylaminopropyl)-3,4-diethyl-DELTA2-1,2,4-triazolin-5-one (III), which is then converted into the corresponding dichlorocompound (IV) by means of SOCl2. Finally, (IV) is cyclized with m-chloroaniline (E).

参考文献 中间体
合成目标
【1】 Palazzo, G.; 1-[3-(4-Metrachlorophenyl-1-piperazinyl)propyl]-3,4-diethyl-delta2-1,2,4-triazolin-5-one. DE 2351739; FR 2202702; GB 1438337; US 3857845 .
【2】 de Angelis, L.; Castaner, J.; Etoperidone. Drugs Fut 1977, 2, 3, 164.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(E) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(D) 24273 2-[(2-hydroxyethyl)amino]-1-ethanol 111-42-2 C4H11NO2 详情 详情
(B) 33592 1-(3-bromopropyl)-4-(4-chlorophenyl)piperazine C13H18BrClN2 详情 详情
(I) 33588 4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one 52883-26-8 C6H11N3O 详情 详情
(II) 33589 2-(3-chloropropyl)-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one C9H16ClN3O 详情 详情
(III) 33591 2-[3-[bis(2-hydroxyethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one C13H26N4O3 详情 详情
(IV) 33590 2-[3-[bis(2-chloroethyl)amino]propyl]-4,5-diethyl-2,4-dihydro-3H-1,2,4-triazol-3-one C13H24Cl2N4O 详情 详情
(C) 33593 1-(4-chlorophenyl)piperazine 38869-46-4 C10H13ClN2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The reaction of 3,4-dimethoxyphenylacetic acid (I) with SOCl2 in methylene chloride gives the corresponding acyl chloride (II), which is treated with aminoacetaldehyde dimethylacetal (III) and triethylamine in methylene chloride yielding N-(2,2-diethoxyethyl)-3,4-dimethoxyphenylacetamide (IV). The cyclization of (IV) by means of HCl in acetic acid atfords 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (V), which is alkylated with 1-bromo-3-chloro propane (VI) by means of potassium tert-butoxide in DMSO to give 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (VII). The reaction of (VII) with N-methyl-2-(3,4-dimethoxyphenyl)ethylamine (VIII) at 100 C affords 7,8-dimethoxy-3-[3-[N-methyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-1,3-dihydro-2H-3-benzazepin-2-one (IX), which is finally hydrogenated with H2 over Pd/C in acetic acid.

参考文献 中间体
合成目标
【1】 Reiffen, M.; et al. (Dr. Karl Thomae GmbH); Benzazepines, process for their preparation and their application as pharmaceutical preparations. DE 3119874; EP 0065229; GB 2099425; JP 57193462 .
【2】 Reiffen, M. (Dr. Karl Thomae GmbH); Process for the prepaation of benzazepine derivatives. CA 1207764; DD 215541; DE 3242345 .
【3】 Prous, J.; Castaner, J.; Ul-FS-49. Drugs Fut 1985, 10, 8, 639.
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) 24049 2-(3,4-dimethoxyphenyl)acetic acid 93-40-3 C10H12O4 详情 详情
(II) 20594 2-(3,4-dimethoxyphenyl)acetyl chloride C10H11ClO3 详情 详情
(III) 10331 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal 645-36-3 C6H15NO2 详情 详情
(IV) 24284 N-(2,2-diethoxyethyl)-2-(3,4-dimethoxyphenyl)acetamide C16H25NO5 详情 详情
(V) 24285 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one C12H13NO3 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 18398 1-(tert-butyl) 3-ethyl (3R,4R)-4-phenyl-1,3-piperidinedicarboxylate C19H27NO4 详情 详情
(VIII) 24899 3-(3-chloropropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one C15H18ClNO3 详情 详情
(IX) 24901 3-[3-[(3,4-dimethoxyphenethyl)(methyl)amino]propyl]-7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one C26H34N2O5 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XII)

5) The condensation of 1-chloro-3-bromopropane (XII) with dibutyl phosphonate (XIII) affords dibutyl 3-chloropropylphosphonate (XIV), which by reaction with ethyl N-benzyloxycarbamate (A) is converted into dibutyl 3-(N-benzyloxy-N-ethoxycarbonylamino)propylphosphonate (XV). Finally, this compound is hydrolyzed with HCl in acetic acid to obtain compound (I). 6) The reaction of (XII) with diethyl phosphonate (III) yields diethyl 3-chloropropylphosphonate (XVI), which by condensation with ethyl N-ethoxycarbonyl-oxycarbamate (XVII) is converted into diethyl 3-(N-ethoxycarbonyloxy-N-ethoxycarbonylamino)propylphosphonate (XVIII). Finally, this compound is hydrolyzed with HCl in acetic acid to obtain compound (I).

参考文献 中间体
合成目标
【1】 Kuroda, Y.; et al.; US 4143135 .
【2】 Prous, J.R.; Castaner, J.; FR-31564. Drugs Fut 1980, 5, 5, 239.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 39093 ethyl benzyloxycarbamate C10H13NO3 详情 详情
(I) 39088 3-(hydroxyamino)propylphosphonic acid C3H10NO4P 详情 详情
(III) 12714 diethyl phosphonate; diethyl phosphite 762-04-9 C4H11O3P 详情 详情
(XII) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XIII) 39089 diethyl 3-chloropropylphosphonate C7H16ClO3P 详情 详情
(XIV) 39091 dibutyl 3-chloropropylphosphonate C11H24ClO3P 详情 详情
(XV) 39095 dibutyl 3-[(benzyloxy)(ethoxycarbonyl)amino]propylphosphonate C21H36NO6P 详情 详情
(XVI) 39090 dibutyl phosphonate 1809-19-4 C8H19O3P 详情 详情
(XVII) 39092 1-[([[(ethoxycarbonyl)amino]oxy]carbonyl)oxy]ethane C6H11NO5 详情 详情
(XVIII) 39094 4-ethoxy-8-(ethoxycarbonyl)-4,10-dioxo-3,9,11-trioxa-8-aza-4lambda(5)-phosphatridecane C13H26NO8P 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

Gallopamil is obtained by condensing 2-(3,4,5-trimethoxypheny)-3-methylbutyronitrile (I) with N-(3-chloropropyl)-N-(2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (II) in the presence of bases. Compound (I) can be prepared by reaction of 3,4,5-trimethoxyphenylacetonitrile (III) with isopropyl chloride (IV) by means of NaNH2. Compound (II) is formed from 1-bromo-3-chloropropane (V) and N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine (VI).

参考文献 中间体
合成目标
【1】 Dengel, F. (Knoll AG); Verfahren zur herstellung basisch substituerter phenylacetonitrile. DE 1154810; DE 1158083 .
【2】 Mannhold, R.; Gallopamil Hydrochloride. Drugs Fut 1984, 9, 2, 108.
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) 29985 3-methyl-2-(3,4,5-trimethoxyphenyl)butanenitrile C14H19NO3 详情 详情
(II) 29986 3-chloro-N-(3,4-dimethoxyphenethyl)-N-methyl-1-propanamine; N-(3-chloropropyl)-N-(3,4-dimethoxyphenethyl)-N-methylamine C14H22ClNO2 详情 详情
(III) 29983 2-(3,4,5-trimethoxyphenyl)acetonitrile 13338-63-1 C11H13NO3 详情 详情
(IV) 29984 2-chloropropane 75-29-6 C3H7Cl 详情 详情
(V) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VI) 18938 2-(3,4-dimethoxyphenyl)-N-methyl-1-ethanamine; N-(3,4-dimethoxyphenethyl)-N-methylamine 3490-06-0 C11H17NO2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(IV)

The total synthesis of picumast dihydrochloride has been described: The alkylation of piperazine (I) with 4-chlorobenzyl chloride (II) in ethanol gives 1-(4-chlorobenzyl)piperazine (III), which is alkylated again with 1-bromo-3-chloropropane (IV) by means of triethylamine in a suitable solvent to yield 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (V). Finally, this compound is condensed with 7-hydroxy-3,4-dimethylcoumarin (VI) by means of K2CO3 in refluxing butanone. Compound (VI) is obtained by cyclization of resorcinol (VII) with ethyl 2-methylacetoacetate (VIII) by means of refluxing acetic acid containing HCl.

参考文献 中间体
合成目标
【1】 Witte, E.-C.; Chemical synthesis of picumast dihydrochloride. Arzneim-Forsch Drug Res 1989, 39, 10a, 1309.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 10356 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride 104-83-6 C7H6Cl2 详情 详情
(III) 10357 1-(4-Chlorobenzyl)piperazine; N-(4-Chlorobenzyl)piperazine C11H15ClN2 详情 详情
(IV) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(V) 10359 1-(4-Chlorobenzyl)-4-(3-chloropropyl)piperazine C14H20Cl2N2 详情 详情
(VI) 10360 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one 2107-78-0 C11H10O3 详情 详情
(VII) 10361 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol 108-46-3 C6H6O2 详情 详情
(VIII) 10362 ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate 609-14-3 C7H12O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The condensation of 7-hydroxycarbostyryl (I) with 1-bromo-3-chloropropane (II) by means of KOH in hot isopropranol gives 7-(3-chloropropoxy)carbostyryl (III), which is then allowed to react with 1-(2,3-dimethylpheny)piperazine (IV) by means of NaI and NaHCO3 in hot acetone.

参考文献 中间体
合成目标
【1】 Banno, K.; Fujioka, T.; Nakagawa, K.; Oshiro, Y. (Otsuka Pharmaceutical Co., Ltd.); Pharmaceutically useful carbostyril derivs.. DE 2912105; FR 2421174; US 4734416 .
【2】 Prous, J.; Castaner, J.; OPC-4392. Drugs Fut 1988, 13, 10, 931.
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) 23392 7-hydroxy-4a,8a-dihydro-2(1H)-quinolinone C9H9NO2 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 23394 7-(3-chloropropoxy)-4a,8a-dihydro-2(1H)-quinolinone C12H14ClNO2 详情 详情
(IV) 23395 1-(2,3-dimethylphenyl)piperazine 1013-22-5 C12H18N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The reaction of 1-bromo-3-chloropropane (I) with thiophenol (II) by means of NaOH in refluxing water gives 1-(phenylthio)-3-chloropropane (III), which is condensed with piperazine (IV) by means of NaOH in refluxing ethanol-water yielding 1-(3-phenylthiopropyl)piperazine (V). Finally, this compound is condensed with 7-(2,3-epoxypropyl)theophylline (VI) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Favier, C.; Pinhas, H.; Beranger, S.; Pascal, J.-C. (Roche Bioscience); Piperazine derivatives of theophylline. EP 0033674; GB 2069487; JP 56120683; US 4374835 .
【2】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; Tester-Dalderup, C.; Tazifylline Hydrochloride. Drugs Fut 1987, 12, 11, 1036.
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) 12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 27778 1-[(3-chloropropyl)sulfanyl]benzene C9H11ClS 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 27779 1-[3-(phenylsulfanyl)propyl]piperazine C13H20N2S 详情 详情
(VI) 27780 1,3-dimethyl-7-(2-oxiranylmethyl)-3,7-dihydro-1H-purine-2,6-dione C10H12N4O3 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

Semotiadil fumarate has been obtained by several related ways: 1) The reaction of 2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (I) with 3-chloropropyl bromide (II) by means of NaH in DMF gives 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (III) , which is condensed with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamine (IV) by means of NaI in NaHCO3 in DMF yielding 2-[2-[3-[N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamino]propoxy]-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (V). Finally, this compound is submitted to optical resolution by salification with L-(+)-2-hydroxy-2-phenylacetic acid (VI), fractional crystallization of the resulting salts, elimination of the chiral acid with NaHCO3 and salification with fumaric acid in ethanol. 2) Compound (V) can also be obtained by condensation of benzothiazinone (I) with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine (VII) by means of NaH in DMF. 3) Compound (V) can also be obtained by condensation of 2-[5-methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (VIII) with 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate (IX) by means of triethylamine in ethanol. 4) The optical resolution of the racemic compound (V) can also be performed by chromatography over a column packed with crystalline cellulose triacetate eluted with 95% ethanol.

参考文献 中间体
合成目标
【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229.
【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 .
【3】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905.
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) 12558 2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one C16H15NO3S 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 12560 2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one C19H20BrNO3S 详情 详情
(IV) 12561 2-(1,3-Benzodioxol-5-yloxy)-N-methyl-1-ethanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-methylamine C10H13NO3 详情 详情
(V) 12562 2-(2-[3-[[2-(1,3-Benzodioxol-5-yloxy)ethyl](methyl)amino]propoxy]-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one C29H32N2O6S 详情 详情
(VI) 12563 (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid 17199-29-0 C8H8O3 详情 详情
(VII) 12564 N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-3-bromo-N-methyl-1-propanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine C13H18BrNO3 详情 详情
(VIII) 12565 2-[5-Methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one C20H24N2O3S 详情 详情
(IX) 12566 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate C10H12O6S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VI)

AHR-53338 is synthesized in an overall yield of 62% from ethyl isonipecotate (I): Ethyl isonipecotate (I) is protected with benzyl bromide (II) to give (III), which is then treated with 2.5 moles of 4-fluorophenylmagnesium bromide to give the tertiary alcohol (IV). The benzyl group is removed by catalytic hydrogenolysis to give the secondary piperidine (V). The reaction of 1-bromo-3-chloropropane (VI) with acetovanillone (VII) gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (VIII) in excellent yield. A mixture of (V) and (VIII) in 1-butanol and triethylamine heated at reflux yields AHR-53338 isolated as the mandelic acid salt.

参考文献 中间体
合成目标
【1】 Yanni, J.M.; Walsh, D.A.; Franzyshen, S.K.; The synthesis and antiallergy activity of 1-[4-[3-. 193rd ACS Natl Meet 1987, Abst MEDI 85.
【2】 Yanni, J.M.; Walsh, D.A.; AHR-5333B. Drugs Fut 1988, 13, 7, 605.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13643 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide 352-13-6 C6H4BrFMg 详情 详情
(B) 28161 2-hydroxy-2-phenylacetic acid 611-72-3 C8H8O3 详情 详情
(I) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 22600 ethyl 1-benzyl-4-piperidinecarboxylate; N-Benzyl-4-carbethoxy piperidine 24228-40-8 C15H21NO2 详情 详情
(IV) 22601 (1-benzyl-4-piperidinyl)[bis(4-fluorophenyl)]methanol C25H25F2NO 详情 详情
(V) 22602 bis(4-fluorophenyl)(4-piperidinyl)methanol 60284-98-2 C18H19F2NO 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(VIII) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XI)

The reaction of piperidine-4-carboxylic acid (I) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (II), which is treated with SOCl2 and acetic anhydride to yield the corresponding acyl chloride (III). The Friedel-Crafts condensation of (III) with refluxing 1,3-difluorobenzene (IV) by means of AlCl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (V), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (VI). The cyclization of (VI) by means of NaH in hot THF/DMF yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (VII), which is treated with HCl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (VIII). Finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) by means of K2CO3 in hot DMF. The intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (IX) with 3-chcloropropyl bromide (X) by means of NaH or K2CO3 in DMF.

参考文献 中间体
合成目标
【1】 Corbett, R.; Bordeau, K.J.; Helsley, G.C.; Szewczak, M.R.; Wilmot, C.A.; Chiang, Y.; Hartman, H.B.; Conway, P.G.; Glamkowski, E.J.; Strupczewski, J.T.; 3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: Antipsychotic profile of iloperidone (HP 873). J Med Chem 1995, 38, 7, 1119-31.
【2】 Strupczewski, J.T.; Helsley, G.C.; Chiang, Y.; Bordeau, K.J. (Aventis Pharmaceuticals, Inc.); N-(Aryloxyalkyl)heteroarylpiperidines and-heteroarylpiperazines, a process for their preparation and their use as medicaments. EP 0402644; JP 1991063263 .
【3】 Strupczewski, J.T.; Helsley, G.C.; Chiang, Y.; Bordeau, K.J.; Glamkowski, E.J. (Aventis Pharmaceuticals, Inc.); Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analgetics. EP 0542136; EP 0612318; EP 0730452; EP 0957102; EP 0959075; EP 0959076; EP 0963984; JP 1995501055; JP 1997511215; US 5364866; US 5776963; WO 9309102; WO 9511680 .
【4】 Mucke, H.A.M.; Castaner, J.; Iloperidone. Drugs Fut 2000, 25, 1, 29.
【5】 Strupczewski, J.T.; Allen, R.C.; Gardner, B.A. (Aventis Pharmaceuticals, Inc.); 3-(4-Piperidyl)-1,2-benzisoxazoles. US 4355037 .
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) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(II) 32031 1-Formyl-4-piperidinecarboxylic acid 84163-42-8 C7H11NO3 详情 详情
(III) 32032 1-formyl-4-piperidinecarbonyl chloride C7H10ClNO2 详情 详情
(IV) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(V) 32033 4-(2,4-difluorobenzoyl)-1-piperidinecarbaldehyde C13H13F2NO2 详情 详情
(VI) 32034 4-[(2,4-difluorophenyl)(hydroxyimino)methyl]-1-piperidinecarbaldehyde C13H14F2N2O2 详情 详情
(VII) 32035 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinecarbaldehyde C13H13FN2O2 详情 详情
(VIII) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情
(IX) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情
(X) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(XI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XXI)

In a different strategy, the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX). Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX). Alternatively, lithiation of 4-picoline (XVII), followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).

参考文献 中间体
合成目标
【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 .
【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 .
【3】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 31150 4-methylpyridine 108-89-4 C6H7N 详情 详情
(XVIII) 42252 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran C8H15BrO2 详情 详情
(XIX) 59549 4-(4-pyridinyl)butyl tetrahydro-2H-pyran-2-yl ether; 4-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]pyridine C14H21NO2 详情 详情
(XX) 59550 4-(4-pyridinyl)-1-butanol C9H13NO 详情 详情
(XXI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXII) 59551 4-(4-chlorobutyl)pyridine C9H12ClN 详情 详情

合成路线13

该中间体在本合成路线中的序号：

The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a: 4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II). Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III), which is then regiospecifically brominated with N-bromosuccinimide to give (IV). A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V), which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).

参考文献 中间体
合成目标
【1】 Schmittling, E.A.; Sawyer, J.S.; Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6. J Org Chem 1993, 58, 3229-30.
【2】 Sawyer, J.S.; Bach, N.J.; Baker, S.R.; et al.; Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 1995, 38, 22, 4411-32.
【3】 Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; et al.; Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists. J Med Chem 1993, 36, 24, 3982-4.
【4】 Sawyer, J.S.; LY-293111 Sodium. Drugs Fut 1996, 21, 6, 610.
【5】 Sawyer, J.S.; Baldwin, R.F.; Saussy, D.L. Jr.; Froelich, L.L.; Jackson, W.T.; Diaryl ether/carboxylic acid derivatives of LY255283: Receptor antagonists of leukotriene B4. Bioorg Med Chem Lett 1993, 3, 10, 1985-90.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
38403 4-fluorophenylboronic acid 1765-93-1 C6H6BFO2 详情 详情
(I) 16208 4'-Benzyloxy-2'-hydroxyacetophenone; 1-[4-(Benzyloxy)-2-hydroxyphenyl]-1-ethanone 29682-12-0 C15H14O3 详情 详情
(II) 16209 1-[4-(benzyloxy)-2-(3-chloropropoxy)phenyl]-1-ethanone C18H19ClO3 详情 详情
(III) 16210 4-(benzyloxy)-2-(3-chloropropoxy)-1-ethylbenzene; benzyl 3-(3-chloropropoxy)-4-ethylphenyl ether C18H21ClO2 详情 详情
(IV) 16211 benzyl 2-bromo-5-(3-chloropropoxy)-4-ethylphenyl ether; 1-(benzyloxy)-2-bromo-5-(3-chloropropoxy)-4-ethylbenzene C18H20BrClO2 详情 详情
(V) 16212 benzyl 4-(3-chloropropoxy)-5-ethyl-4'-fluoro[1,1'-biphenyl]-2-yl ether; 2-(benzyloxy)-4-(3-chloropropoxy)-5-ethyl-4'-fluoro-1,1'-biphenyl C24H24ClFO2 详情 详情
(VI) 16213 benzyl 5-ethyl-4'-fluoro-4-(3-iodopropoxy)[1,1'-biphenyl]-2-yl ether; 2-(benzyloxy)-5-ethyl-4'-fluoro-4-(3-iodopropoxy)-1,1'-biphenyl C24H24FIO2 详情 详情

合成路线14

该中间体在本合成路线中的序号：

The condensation of 2-nitrophenol (I) with 2,2,2-trrifluoroethyl p-toluenesulfonate (II) by means of K2CO3 in DMF gives 2-(2,2,2-trifluoroethoxy) nitrobenzene (III), which isreduced with H2 over PtO2 in ethanol yiedling the aniline (IV). The cyclization of (IV) with bis (2-chloroethyl)amine (V) and K2CO3 affords the piperazine (VI), which is condensed with 1-benzyl-3-(3-chloro-propyl)-5-methylpyrimidine-2,4(1H,3H)-dione (VII) by means of K2CO3 in refluxing acetonitrile to give the benzylated target compound (VIII). Finally, this compound is deprotected by hydrogenation with ammonium formate and Pd/C. The intermediate pyrimidine (VII) has been obtained by benzylation of thymine (IX) with benzyl bromide and K2CO3 to give the 1-benzylthymine (X), which is alkylated with 1-bromo-3-chloropropane and K2CO3 to the target intemediate (VII).

参考文献 中间体
合成目标
【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 19106 2-nitrophenol 88-75-5 C6H5NO3 详情 详情
(II) 29561 2,2,2-trifluoroethyl 4-methylbenzenesulfonate 433-06-7 C9H9F3O3S 详情 详情
(III) 29562 2-nitrophenyl 2,2,2-trifluoroethyl ether; 1-nitro-2-(2,2,2-trifluoroethoxy)benzene C8H6F3NO3 详情 详情
(IV) 29563 2-(2,2,2-trifluoroethoxy)aniline; 2-(2,2,2-trifluoroethoxy)phenylamine C8H8F3NO 详情 详情
(V) 21583 2-chloro-N-(2-chloroethyl)-1-ethanamine; Bis(2-chloroethyl)amine; 1,1'-iminobis(2-chloroethane); N,N-bis(2-chloroethyl)amine 821-48-7 C4H9Cl2N 详情 详情
(VI) 29564 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether C12H15F3N2O 详情 详情
(VII) 29565 1-benzyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C15H17ClN2O2 详情 详情
(VIII) 29566 1-benzyl-5-methyl-3-(3-[4-[2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl]propyl)-2,4(1H,3H)-pyrimidinedione C27H31F3N4O3 详情 详情
(IX) 12204 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine 65-71-4 C5H6N2O2 详情 详情
(X) 29567 1-benzyl-5-methyl-2,4(1H,3H)-pyrimidinedione C12H12N2O2 详情 详情

合成路线15

该中间体在本合成路线中的序号：

In a related procedure, dihydroxybenzoyl indole (X) was selectively alkylated at 4-hydroxyl group with alpha-bromo-p-xylene (IV) to provide ether (XI). Further alkylation of (XI) with 1-bromo-3-chloropropane gave (XII). Then, halogen displacement in (XII) by piperazine (VI) furnished the precursor ethyl ester (IX), which was finally hydrolyzed to the target carboxylic acid as above.

参考文献 中间体
合成目标
【1】 Sato, H.; et al.; Dual-acting agents with alpha1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory activities. Synthesis and evaluation of arylpiperazine derivatives. Bioorg Med Chem Lett 1999, 9, 11, 1553.
【2】 Yoshida, K.; Kurimoto, T.; Takei, M.; Sato, H. (Zeria Pharmaceutical Co., Ltd.); Indole deriv. and medicine containing the same. EP 0753511; US 5760040; WO 9526955 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 24623 1-(bromomethyl)-4-methylbenzene 104-81-4 C8H9Br 详情 详情
(VI) 23055 ethyl 2-(1-piperazinyl)phenyl ether; 1-(2-ethoxyphenyl)piperazine C12H18N2O 详情 详情
(IX) 26126 ethyl 4-(3-[3-[3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy]-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate C44H51N3O6 详情 详情
(X) 26127 ethyl 4-[3-(3,4-dihydroxybenzoyl)-1H-indol-1-yl]butanoate C21H21NO5 详情 详情
(XI) 26128 ethyl 4-(3-[3-hydroxy-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate C29H29NO5 详情 详情
(XII) 26129 ethyl 4-(3-[3-(3-chloropropoxy)-4-[(4-methylbenzyl)oxy]benzoyl]-1H-indol-1-yl)butanoate C32H34ClNO5 详情 详情

合成路线16

该中间体在本合成路线中的序号：(X)

5-Methyluracil (VII) was protected with SEM-Cl (VIII) to yield the 1-SEM derivative (IX), which was subsequently alkylated with 1-bromo-3-chloropropane (X) under phase-transfer conditions to provide chloride (XI). Alkylation of piperazine (VI) with chloride (XI) in the presence of NaI and K2CO3 furnished adduct (XII). The title compound was then obtained by deprotection of (XII) upon treatment with tetrabutylammonium fluoride in THF.

参考文献 中间体
合成目标
【1】 Bantle, G.W.; Elworthy, T.R.; Guzman, A.; Jaime-Figueroa, S.; Lopez-Tapia, F.J.; Morgans, D.J. Jr.; Perez-Medrano, A.; Pfister, J.R.; Sjogren, E.B.; Talamas, F.X. (F. Hoffmann-La Roche AG); Pyrimidinedione, pyrimidinetrione, triazinedione, tetrahydroquinazolinedione derivs. as alpha1-adrenergic receptor antagonists. EP 0748800; JP 1997100269 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 54367 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether C12H14F4N2O 详情 详情
(VII) 12204 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine 65-71-4 C5H6N2O2 详情 详情
(VIII) 27243 [2-(chloromethoxy)ethyl](trimethyl)silane 76513-69-4 C6H15ClOSi 详情 详情
(IX) 54368 5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione C11H20N2O3Si 详情 详情
(X) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XI) 54369 3-(3-chloropropyl)-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione C14H25ClN2O3Si 详情 详情
(XII) 54370 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]-1-piperazinyl}propyl)-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,4(1H,3H)-pyrimidinedione C26H38F4N4O4Si 详情 详情

合成路线17

该中间体在本合成路线中的序号：(X)

In a different protection strategy, sulfonylation of 5-methyluracil (VII) by means of p-toluenesulfonyl chloride under Schotten-Baumann conditions furnished the 1-tosyl derivative (XIII). This was condensed with 1-bromo-3-chloropropane (X), yielding chloride (XIV). Removal of the tosyl protecting group of (XIV) by hydrolysis with H2SO4 afforded 3-(3-chloropropyl)-5-methyluracil (XV). Finally, alkylation of piperazine (VI) with chloride (XV) led to the title compound.

参考文献 中间体
合成目标
【1】 Chapman, R.C.; Perkins, J. (F. Hoffmann-La Roche AG); Process for manufacturing alpha1L-adrenoceptor antagonists. EP 0949250 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 54367 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine; 5-fluoro-2-(1-piperazinyl)phenyl 2,2,2-trifluoroethyl ether C12H14F4N2O 详情 详情
(VII) 12204 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine 65-71-4 C5H6N2O2 详情 详情
(X) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XIII) 54371 5-methyl-1-[(4-methylphenyl)sulfonyl]-2,4(1H,3H)-pyrimidinedione C12H12N2O4S 详情 详情
(XIV) 54372 3-(3-chloropropyl)-5-methyl-1-[(4-methylphenyl)sulfonyl]-2,4(1H,3H)-pyrimidinedione C15H17ClN2O4S 详情 详情
(XV) 54373 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione C8H11ClN2O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XXXV)

In a further method, the lithium acetylide of 2-(propargyloxy)tetrahydropyran (XXXIV) was alkylated with 1-bromo-3-chloropropane (XXXV) to afford chloride (XXXVI). Displacement of the Cl atom of (XXXVI) with NaCN yielded nitrile (XXXVII), which was further hydrolyzed to carboxylic acid (XXXVIII) under basic conditions. Esterification of (XXXVIII) with concomitant tetrahydropyranyl group cleavage in ethanolic H2SO4 gave hydroxy ester (XXXIX). Conversion of (XXXIX) to the corresponding mesylate, followed by treatment with KI, provided ethyl 7-iodo-5-heptynoate (XL). (R)-(+)-nopinone (XXVI) was then alkylated with the propargyl iodide (XL) in the presence of LDA to afford (XLI). Conversion of (XLI) to oxime (XLII), followed by reduction with TiCl3 and BH3•t-BuNH2, provided amino ester (XLIII). Then, partial hydrogenation of the triple bond of (XLIII) over Lindlar catalyst furnished the precursor aminoalkene ester (XLIV).

参考文献 中间体
合成目标
【1】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVI) 60678 (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one C9H14O 详情 详情
(XXXIV) 43835 2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-(2-propynyloxy)tetrahydro-2H-pyran 6089-04-9 C8H12O2 详情 详情
(XXXV) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXXVI) 60680 2-[(6-chloro-2-hexynyl)oxy]tetrahydro-2H-pyran; 6-chloro-2-hexynyl tetrahydro-2H-pyran-2-yl ether C11H17ClO2 详情 详情
(XXXVII) 60681 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynenitrile C12H17NO2 详情 详情
(XXXVIII) 60682 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynoic acid C12H18O4 详情 详情
(XXXIX) 60683 ethyl 7-hydroxy-5-heptynoate C9H14O3 详情 详情
(XL) 60684 ethyl 7-iodo-5-heptynoate C9H13IO2 详情 详情
(XLI) 60685 ethyl 7-[(1R,3R,5R)-6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl]-5-heptynoate C18H26O3 详情 详情
(XLII) 60686 ethyl 7-[(1R,3R,5R)-2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate C18H27NO3 详情 详情
(XLIII) 60687 ethyl 7-[(1R,2R,3R,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate C18H29NO2 详情 详情
(XLIV) 60688 ethyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate C18H31NO2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(B)

4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound).

参考文献 中间体
合成目标
【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(A) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(I) 19349 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine 7144-05-0 C6H14N2 详情 详情
(II) 19351 N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine C13H18N2 详情 详情
(III) 21110 benzylhydrosulfide; phenylmethanethiol 100-53-8 C7H8S 详情 详情
(IV) 21111 benzyl(3-chloropropyl)dioxo-lambda(6)-sulfane; benzyl 3-chloropropyl sulfone C10H13ClO2S 详情 详情
(V) 21112 [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methylamine; [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methanamine C16H26N2O2S 详情 详情
(VI) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

Alkylation of phenothiazine (I) with 1-bromo-3-chloropropane (II) in the presence of NaH in DMF at room temperature afforded chloropropyl compound (III), and then reaction of this compound with 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (IV) and K2CO3 in refluxing dioxan yielded the title compound.

参考文献 中间体
合成目标
【1】 Bright, C.; Brown, T.J.; Cox, P.; Halley, F.; Lockey, P.; McLay,, I.M.; Moore, U.; Porter, B.; Williams, R.J.; Identification of a non peptidic RANTES antagonist. Bioorg Med Chem Lett 1998, 8, 7, 771-774.
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) 18114 N,N-dimethyl-10H-phenothiazine-2-sulfonamide 1090-78-4 C14H14N2O2S2 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 18115 10-(3-chloropropyl)-N,N-dimethyl-10H-phenothiazine-2-sulfonamide C17H19ClN2O2S2 详情 详情
(IV) 18116 1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1021-25-6 C13H17N3O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(V)

7-Hydroxy-3-methylcoumarin (III) was obtained by Perkin reaction of 2,4-dihydroxybenzaldehyde (I) and propionic anhydride (II) in the presence of sodium propionate in pyridine. Alkylation of N-phenylpiperazine (IV) with 1-bromo-3-chloropropane (V) and NaOH in acetone provided the chloropropyl compond (VI), which was finally condensed with coumarin (III) using NaH in DMF.

参考文献 中间体
合成目标
【1】 Antonello, C.; et al.; Synthesis and characterization of new methylpsoralens as potential photochemotherapeutic agents. Farmaco 1994, 49, 4, 277.
【2】 Teran, C.; Santana, L.; Uriarte, E.; Fall, Y.; Unelius, L.; Tolf, B.R.; Phenylpiperazine derivatives with strong affinity for 5HT1A, D2A and D3 receptors. Bioorg Med Chem Lett 1998, 8, 24, 3567.
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) 20094 2,4-dihydroxybenzaldehyde 95-01-2 C7H6O3 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 20096 7-hydroxy-3-methyl-2H-chromen-2-one C10H8O3 详情 详情
(IV) 10756 N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine 92-54-6 C10H14N2 详情 详情
(V) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VI) 20099 1-(3-chloropropyl)-4-phenylpiperazine C13H19ClN2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(II)

2',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with 1-bromo-3-chloropropane (II) in the presence of K2CO3 in refluxing acetone to yield the 4'-(3-chloropropyl)ether (III). Further condensation of (III) with Vilsmeier reagent, followed by aqueous work up, provided the 3-formylchromenone (IV), which was subsequently reduced with sodium borohydride in CHCl3-EtOH at 0 C to give the (hydroxymethyl)chromenone (V). Finally, alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI) with chloride (V) in the presence of K2CO3 and KI in refluxing acetonitrile yielded the title compound, which was isolated as the hydrochloride salt from methanol.

参考文献 中间体
合成目标
【1】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.
【2】 Bolos, J.; et al.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. J Med Chem 1996, 39, 15, 2962.
【3】 Bolós, J.; Anglada, L.; Gubert, S.; Planas, J.M.; Agut, J.; Princep, M.; De la Fuente, N.; Sacristan, A.; Ortiz, J.A.; 7-[3-(1-Piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymethyl)chromen-4-one (abaperidone, FI-8602). J Med Chem 1998, 41, 27, 5402.
【4】 Foguet, R.; Anglada, L.; Bolós, J.; Ortiz, J.; Sacristán, A.; Castellò, J.M. (Ferrer Internacional SA); 4-(6-Fluoro-1, 2-benzisoxazolyl)-1-piperidinyl-propoxy-chromen-4-one derivs., their preparation and their use in the treatment of psychosis, schizophrenia and anxiety. EP 0765323; ES 2101646; ES 2103237; JP 1998501557; US 5736558; WO 9632389 .
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) 13961 Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone 89-84-9 C8H8O3 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 26820 1-[4-(3-chloropropoxy)-2-hydroxyphenyl]-1-ethanone C11H13ClO3 详情 详情
(IV) 26821 7-(3-chloropropoxy)-4-oxo-4H-chromene-3-carbaldehyde C13H11ClO4 详情 详情
(V) 26822 7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one C13H13ClO4 详情 详情
(VI) 17910 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole C12H13FN2O 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

Methyl 2,4-dihydroxybenzoate (VII) was selectively protected as the 4-benzyl ether (VIII) with benzyl bromide in the presence of potassium carbonate. Condensation with sodium (methylsulfinyl)methyde provided the corresponding methylsulfinyl ketone (IX). This was condensed with two equivalents of formaldehyde to yield (X). Subsequent pyrolysis of the sulfoxide group furnished chromenone (XI). Deprotection of the benzyl ether was achieved by treatment with boron trichloride, and the resulting 7-hydroxychromenone (XII) was then alkylated with 1-bromo-3-chloropropane (II) to give 7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one (V).

参考文献 中间体
合成目标
【1】 Nieto, J.; Bolos, J.; Unpublished results .
【2】 Princep, M.; Guglietta, A.; Bolos, J.; Abaperidone Hydrochloride. Drugs Fut 2001, 26, 4, 335.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(V) 26822 7-(3-chloropropoxy)-3-(hydroxymethyl)-4H-chromen-4-one C13H13ClO4 详情 详情
(VII) 16623 methyl 2,4-dihydroxybenzoate 2150-47-2 C8H8O4 详情 详情
(VIII) 46606 methyl 4-(benzyloxy)-2-hydroxybenzoate C15H14O4 详情 详情
(IX) 46607 1-[4-(benzyloxy)-2-hydroxyphenyl]-2-(methylsulfinyl)-1-ethanone C16H16O4S 详情 详情
(X) 46608 7-(benzyloxy)-3-(hydroxymethyl)-3-(methylsulfinyl)-2,3-dihydro-4H-chromen-4-one C18H18O5S 详情 详情
(XI) 46609 7-(benzyloxy)-3-(hydroxymethyl)-4H-chromen-4-one C17H14O4 详情 详情
(XII) 46610 7-hydroxy-3-(hydroxymethyl)-4H-chromen-4-one C10H8O4 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VIII)

The reaction of 3-chloroaniline (I) with ethanolamine (II) by means of 47% HBr by heating at 170 C gives N-(3-chlorophenyl)ethylenediamine (III), which is condensed with ethyl 2-bromopropionate (IV) by means of triethylamine in refluxing toluene yielding the alanine derivative (V). The cyclization of (V) with refluxing 2N HCl affords the piperazinone (VI), which is reduced with LiAlH4 in ethyl ether providing 1-(3-chlorophenyl)-3-methylpiperazine (VII). The alkylation of (VII) with 1-bromo-3-chloropropane (VIII) by means of NaOH in acetone/water gives 4-(3-chlorophenyl)-1-(3-chloropropyl)-2-methylpiperazine (IX), which is condensed with the sodium salt of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (X) in refluxing xylene/isobutanol yielding the target compound as a racemic mixture (XI). Finally, this compound is submitted to optical resolution with L-(+)-tartaric acid (XII).

参考文献 中间体
合成目标
【1】 Giannangeli, M.; Gazzolla, N.; Luparini, M.R.; Magnani, M.; Mabilia, M.; Picconi, G.; Tomaselli, M.; Baiocchi, L.; Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and alpha1 receptor binding affinity. J Med Chem 1999, 42, 3, 336.
【2】 Baiocchi, L.; Cioli, V. (Angelini Group); Pharmacologically active enantiomers. EP 0707587; JP 1996512036; WO 9501354 .
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) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(II) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(III) 34091 N(1)-(3-chlorophenyl)-1,2-ethanediamine; N-(2-aminoethyl)-N-(3-chlorophenyl)amine C8H11ClN2 详情 详情
(IV) 19460 ethyl 2-bromopropanoate; 2-Bromopropionic acid ethyl ester 535-11-5 C5H9BrO2 详情 详情
(V) 28373 ethyl 2-[[2-(3-chloroanilino)ethyl]amino]propanoate C13H19ClN2O2 详情 详情
(VI) 28374 1-(3-chlorophenyl)-3-methyl-2-piperazinone C11H13ClN2O 详情 详情
(VII) 28375 1-(3-chlorophenyl)-3-methylpiperazine C11H15ClN2 详情 详情
(VIII) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IX) 28376 4-(3-chlorophenyl)-1-(3-chloropropyl)-2-methylpiperazine C14H20Cl2N2 详情 详情
(X) 28377 [3-oxo[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl]sodium C6H4N3NaO 详情 详情
(XI) 28378 2-[3-[4-(3-chlorophenyl)-2-methyl-1-piperazinyl]propyl][1,2,4]triazolo[4,3-a]pyridin-3(2H)-one C20H24ClN5O 详情 详情
(XII) 28379 (2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid 87-69-4 C4H6O6 详情 详情

合成路线25

该中间体在本合成路线中的序号：(V)

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26

该中间体在本合成路线中的序号：(VI)

The condensation of 1-methylpyrole-3-carboxylic acid (I) with beta-alanine benzyl ester (II) by means of diethyl phosphorocyanidate (PCA) in DMF gives the corresponding amide (III), which is debenzylated with H2 over Pd/C in THF yielding the substituted beta-alanine (IV). The cyclization of (IV) by means of polyphosphoric acid (PPA) at 100 C affords the pyrroloazepine (V), which is alkylated with 1-bromo-3-chloropropane (VI) and potassium tert-butoxide in THF giving the 3-chloropropyl derivative (VII). The condensation of (VII) with 1-(4-fluorophenyl)piperazine (VIII) by means of K2CO3 and NaI in refluxing acetonitrile yields the expected addition product (IX), which is selectively reduced at the 8-position with NaBH4 in ethanol affording the 8-hydroxy derivative (X) as a racemic mixture. Finally, this compound is submitted to optical resolution by chiral chromatography providing the target chiral compound.

参考文献 中间体
合成目标
【1】 Shibata, M.; Ogata, A.; Hayashi, Y.; Kamei, T.; Mizuno, A.; Shimamoto, T.; Takiguchi, C.; Inomata, N.; Nakanishi, K.; Oka, N.; Synthesis and serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkyl-substituted pyrrolo [3,2-c]azepines and related compounds. Chem Pharm Bull 2000, 48, 5, 623.
【2】 Mizuno, A.; Shibata, M.; Iwamori, T.; Shimamoto, T.; Nakanishi, K.; Inomata, N. (Suntory Ltd.); Pyrroloazepine derivs.. EP 0807632; US 5962448; WO 9720845 .
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) 30193 1-methyl-1H-pyrrole-3-carboxylic acid C6H7NO2 详情 详情
(II) 30194 benzyl 3-aminopropanoate 27019-47-2 C10H13NO2 详情 详情
(III) 30195 benzyl 3-[[(1-methyl-1H-pyrrol-3-yl)carbonyl]amino]propanoate C16H18N2O3 详情 详情
(IV) 30196 N-[(1-methyl-1H-pyrrol-3-yl)carbonyl]-beta-alanine C9H12N2O3 详情 详情
(V) 30197 1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione C9H10N2O2 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 30198 5-(3-chloropropyl)-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione C12H15ClN2O2 详情 详情
(VIII) 12143 1-(4-Fluorophenyl)piperazine 2252-63-3 C10H13FN2 详情 详情
(IX) 30199 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-1-methyl-6,7-dihydropyrrolo[3,2-c]azepine-4,8(1H,5H)-dione C22H27FN4O2 详情 详情
(X) 30200 5-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-8-hydroxy-1-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one C22H29FN4O2 详情 详情

合成路线27

该中间体在本合成路线中的序号：(VI)

The known imidazoindenopyrazinone (I) was converted to oxime (II) by treatment with isoamyl nitrite and NaH. Subsequent reduction of oxime (II) by means of zinc and AcOH produced acetamide (III), which was hydrolyzed to amine (IV) upon refluxing in 2 N HCl. After protection of amine (IV) as the N-Boc derivative (V), alkylation with 1-bromo-3-chloropropane (VI) in the presence of NaH gave rise to the spiro derivative (VII). Deprotection of the Boc group of (VII) to give amine (VIII) was effected by treatment with trifluoroacetic acid. Finally, Eschweiler-Clarke reductive alkylation of (VIII) with formaldehyde and formic acid furnished the desired N-methyl derivative.

参考文献 中间体
合成目标
【1】 Jimonet, P.; Boireau, A.; Chevé, M.; et al.; Spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives are mixed AMPA and NMDA glycine-site antagonists active in vivo. Bioorg Med Chem Lett 1999, 9, 20, 2921.
【2】 Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.; Genevois-Borella, A.; Jimonet, P.; Mignani, S.; Ribeill, Y. (Aventis Pharma SA); Spiro[heterocycle-imidazo[1,2-a]indeno[1, 2-e]pyrazine]-4'-ones, preparation thereof and drugs containing same. JP 1998508311; US 5777114; WO 9614318 .
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) 39726 5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one C13H9N3O 详情 详情
(II) 42829 4H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4,10(5H)-dione 10-oxime C13H8N4O2 详情 详情
(III) 42830 N-(4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)acetamide C15H12N4O2 详情 详情
(IV) 42831 10-amino-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one C13H10N4O 详情 详情
(V) 42832 tert-butyl 4-oxo-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-ylcarbamate C18H18N4O3 详情 详情
(VI) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(VII) 42833 　 C21H22N4O3 详情 详情
(VIII) 42834 　 C16H14N4O 详情 详情

合成路线28

该中间体在本合成路线中的序号：(II)

The title compound was synthesized by two related methods. 2-Pyrrolidone (I) was alkylated with 1-bromo-3-chloropropane (II) using either sodium or potassium metal or potassium tert-butoxide as the base. The resultant N-(3-chloropropyl)pyrrolidone (III) was then condensed with 1-(4-fluorophenyl)piperazine (IV) in the presence of NaI and Na2CO3 to produce the desired disubstituted piperazine. Alternatively, the title compound was prepared from the known N-(3-chloropropyl)-N'-(4-fluorophenyl)piperazine (V) by condensation with 2-pyrrolidone (I) in the presence of sodium metal in hot xylene.

参考文献 中间体
合成目标
【2】 Jain, S.; Sinha, N.; Saxena, A.K.; Anand, N.; Saxena, R.M.; Dubey, M.P.; Patnaik, G.K.; Ray, M. (Council of Scientific and Industrial Research); Methods for preparing 1-[4-arylpiperazin-1-yl]-3-[2-oxopyrrolidin/piperidin-1-yl]propanes. US 6084097 .
【1】 Jain, S.; Sinha, N.; Saxena, A.K.; Anand, N.; Saxena, R.M.; Dubey, M.P.; Patnaik, G.K.; Ray, M. (Council of Scientific and Industrial Research); 1-[4-Arylpiperazin-1-yl]-3-[2-oxopyrrolidin/piperidin-1-yl]propanes and their use in medical treatments. US 6150367 .
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) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 52874 1-(3-chloropropyl)-2-pyrrolidinone C7H12ClNO 详情 详情
(IV) 12143 1-(4-Fluorophenyl)piperazine 2252-63-3 C10H13FN2 详情 详情
(V) 27397 2-Pyrrolidinone 616-45-5 C4H7NO 详情 详情
(VI) 45622 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine C13H18ClFN2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(III)

This compound can be prepared by three different related ways: 1) By condensation of 1-methoxy-2-aminoindane (I) with 3-bromopropyl diethylamine (II) by means of sodium amide in refluxing toluene (1). 2) The reaction of (I) with 1-chloro-3-bromopropane (III) by heating at 100 C gives the corresponding N-(3-chloropropyl) derivative (IV), which is then condensed with diethylamine by means of NaI in refluxing ethanol (2). 3) By condensation of 1-methoxy-2-indanyl methanesulfonate (V) with N-(diethylaminopropyl)aniline (VI) in refluxing ethanol (2).

参考文献 中间体
合成目标
【1】 (A. Christiaens SA); .
【2】 Vanhoof, P.; De Ridder, R. (A. Christiaens SA); CA 1068239; CH 617663; DD 123598; ZA 7607468 .
【3】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Thorpe, P.J..; Moxaprindine. Drugs Fut 1981, 6, 6, 354.
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) 60986 1-methoxy-N-phenyl-2-indanamine; N-(1-methoxy-2,3-dihydro-1H-inden-2-yl)-N-phenylamine C16H17NO 详情 详情
(II) 60989 3-bromo-N,N-diethyl-1-propanamine; N-(3-bromopropyl)-N,N-diethylamine C7H16BrN 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 60987 N-(3-chloropropyl)-1-methoxy-N-phenyl-2-indanamine; N-(3-chloropropyl)-N-(1-methoxy-2,3-dihydro-1H-inden-2-yl)-N-phenylamine C19H22ClNO 详情 详情
(V) 60988 1-methoxy-2,3-dihydro-1H-inden-2-yl methanesulfonate C11H14O4S 详情 详情
(VI) 60990 N-(3-anilinopropyl)-N,N-diethylamine; N~1~,N~1~-diethyl-N~3~-phenyl-1,3-propanediamine C13H22N2 详情 详情

合成路线30

该中间体在本合成路线中的序号：(II)

Alkylation of 4-cyano-4'-hydroxybiphenyl (I) with 1-bromo-3-chloropropane (II) yields the chloropropyl ether (III). This is then condensed with the mono-protected homopiperazine (IV) to furnish (V). Removal of the N-Boc group of (V) to afford amine (VI) is then accomplished by treatment with trifluoroacetic acid in CH2Cl2. Amine (VI) is subsequently coupled with N-Boc-D-thiazolylalanine (VII) in the presence of EDC/DMAP producing amide (VIII). (1,2)

参考文献 中间体
合成目标
【1】 Curtis, M.P.; Dwight, W.; Fox, G.B.; Esbenshade, T.A.; Pan, J-B.; Bennani, Y.L.; Hancock, A.A.; Faghih, R.; A-320436: Potent human non-imidazole histamine H3 receptor antagonist. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 240.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
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) 48735 4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile 19812-93-2 C13H9NO 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 57817 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carbonitrile C16H14ClNO 详情 详情
(IV) 54079 tert-Butyl 1-homopiperazine carboxylate n/a C10H20N2O2 详情 详情
(V) 64053 1,1-dimethylethyl 4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepane-1-carboxylate C26H33N3O3 详情 详情
(VI) 64054 4'-{[3-(1,4-diazepan-1-yl)propyl]oxy}[1,1'-biphenyl]-4-carbonitrile C21H25N3O 详情 详情
(VII) 12882 (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid C11H16N2O4S 详情 详情
(VIII) 64055 1,1-dimethylethyl 2-(4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate C32H39N5O4S 详情 详情

合成路线31

该中间体在本合成路线中的序号：(III)

Intramolecular cyclization of p-hydroxy-4-chlorobutyrophenone (I) under alkaline conditions yields cyclopropyl(4-hydroxyphenyl) ketone (II). The phenolic hydroxyl group is then alkylated by 1-bromo-3-chloropropane (III) to furnish the chloropropyl ether (IV). Subsequent condensation of alkyl chloride (IV) with piperazine (V) gives rise to the N-substituted piperazine (VI). This is then coupled with N-Boc-L-alanine (VII) in the presence of EDC/DMAP to afford amide (VIII) (1, 2). After acidic cleavage of the N-Boc protecting group, the resultant monosubstituted piperazine (IX) is acylated by furanoyl chloride (X) to furnish the target furamide derivative

参考文献 中间体
合成目标
【1】 Black, L.A.; Faghih, R.; Liu, H.; et al.; Acyl-D-alanine amides: Selective histamine H3 receptor antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 323.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .
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) 62995 　 C10H11ClO2 详情 详情
(II) 27425 cyclopropyl(4-hydroxyphenyl)methanone C10H10O2 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 62988 5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine C11H8BrN5 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 62996 　 C17H24N2O2 详情 详情
(VII) 15859 Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 7764-95-6 C8H15NO4 详情 详情
(VIII) 63042 　 C28H23ClN2O2 详情 详情
(IX) 63043 　 C17H15ClN2O2 详情 详情
(X) 26093 2-Furoyl chloride 527-69-5 C5H3ClO2 详情 详情

合成路线32

该中间体在本合成路线中的序号：(III)

Cyclization of 4-chloro-4'-hydroxybutyrophenone (I) in the presence of 50% aqueous NaOH produces cyclopropyl (4-hydroxyphenyl) ketone (II). This is then alkylated with 1-bromo-3-chloropropane (III) to afford the chloropropyl ether (IV). Chloride displacement in (IV) with an excess of piperazine (V) in the presence of KI and K2CO3 furnishes the monosubstituted piperazine (VI). Subsequent coupling of piperazine (VI) with N-Boc-L-alanine (VII) leads to amide (VIII). Finally, Boc group cleavage in (VIII) employing trifluoroacetic acid yields the title compound (1-3).

参考文献 中间体
合成目标
【1】 Faghih, R.; Dwight, W.; Black, L.; Liu, H.; Gentles, R.; Phelan, K.; Esbenshade, T.A.; Ireland, L.; Miller, T.R.; Kang, C.-H.; Krueger, K.M.; Fox, G.B.; Hancock; Bennani, Y.L.; Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: Binding preference for D-amino acids motifs. Bioorg Med Chem Lett 2002, 12, 15, 2035.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .
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) 62995 　 C10H11ClO2 详情 详情
(II) 27425 cyclopropyl(4-hydroxyphenyl)methanone C10H10O2 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 62998 [4-(3-chloropropoxy)phenyl](cyclopropyl)methanone C13H15ClO2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 62996 　 C17H24N2O2 详情 详情
(VII) 15859 Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 7764-95-6 C8H15NO4 详情 详情
(VIII) 64059 tert-butyl (1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethylcarbamate C25H37N3O5 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The condensation of 4-hydroxy-3-methoxybenzoic acid ethyl ester (I) with 3-chloropropyl bromide (II) by means of K2CO3 in refluxing DMF gives the 4(3-chloropropoxy)-3-methoxybenzoic acid ethyl ester (III), which is nitrated by means of HNO3 and AcOH to yield the 2-nitro derivative (IV). The condensation of (IV) with piperidine (V) by means of K2CO3 in hot toluene affords 5-methoxy-2-nitro-4-[3-(1-piperidinyl)propoxy]benzoic acid ethyl ester (VI), which is reduced by means of Pd/C and HCO2K in ethanol/water to provide the 2-amino derivative (VII). The cyclization of (VII) with formamide and ammonium formate at 135 C gives the quinazoline (VIII), which is treated with SOCl2 in refluxing toluene to yield the chloro derivative (IX). Finally this compound is condensed with the piperazinecarboxamide (X) by means of K2CO3 in hot DMF/toluene to afford the target CT-53518.

参考文献 中间体
合成目标
【1】 Pandey, A.; et al.; Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. J Med Chem 2002, 45, 17, 3772.
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) 57016 3-Methoxy-4-hydroxybenzoic acid ethyl ester; 4-Hydroxy-3-methoxybenzoic acid ethyl ester; Ethyl 4-hydroxy-3-methoxybenzoate; Ethyl vanillate; Ethyl-3-Methoxy-4-Hydroxybenzoate; Vanillic acid ethyl ester 617-05-0 C10H12O4 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 57017 ethyl 4-(3-chloropropoxy)-3-methoxybenzoate C13H17ClO4 详情 详情
(IV) 57018 ethyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate C13H16ClNO6 详情 详情
(V) 10158 Piperidine 110-89-4 C5H11N 详情 详情
(VI) 57019 ethyl 5-methoxy-2-nitro-4-[3-(1-piperidinyl)propoxy]benzoate C18H26N2O6 详情 详情
(VII) 57020 ethyl 2-amino-5-methoxy-4-[3-(1-piperidinyl)propoxy]benzoate C18H28N2O4 详情 详情
(VIII) 57021 6-methoxy-7-[3-(1-piperidinyl)propoxy]-4-quinazolinol C17H23N3O3 详情 详情
(IX) 57022 4-chloro-6-methoxy-7-[3-(1-piperidinyl)propoxy]quinazoline; 4-chloro-6-methoxy-7-quinazolinyl 3-(1-piperidinyl)propyl ether C17H22ClN3O2 详情 详情
(X) 57023 N-(4-isopropoxyphenyl)-1-piperazinecarboxamide C14H21N3O2 详情 详情

合成路线34

该中间体在本合成路线中的序号：(III)

Fischer esterification of 4'-hydroxybiphenyl-4-carboxylic acid (I) with H2SO4/MeOH provides ester (II). The phenolic hydroxyl group is then alkylated with 1-bromo-3-chloropropane (III) in the presence of K2CO3 to furnish the chloropropyl ether (IV). Saponification of methyl ester (IV) with LiOH leads to carboxylic acid (V), which is further activated as the corresponding acid chloride (VI) upon heating in SOCl2. Acid chloride (VI) is subsequently coupled with morpholine (VII) to yield amide (VIII). Finally, alkyl chloride (VIII) is displaced with (R,R)-2,5-dimethylpyrrolidine (IX) in the presence of K2CO3 and KI to furnish the title compound.

参考文献 中间体
合成目标
【1】 Faghih, R.; Bennani, Y.L. (Abbott Laboratories Inc.); Aminoalkoxybiphenyl carboxamides as histamine-3 receptor ligands and their therapeutic applications. US 6316475; WO 0240461 .
【2】 Faghih, R.; Bennani, Y.; Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications. US 2002111340 .
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) 63280 4'-hydroxy[1,1'-biphenyl]-4-carboxylic acid C13H10O3 详情 详情
(II) 63281 methyl 4'-hydroxy[1,1'-biphenyl]-4-carboxylate C14H12O3 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 63282 methyl 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carboxylate C17H17ClO3 详情 详情
(V) 63283 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carboxylic acid C16H15ClO3 详情 详情
(VI) 63284 4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carbonyl chloride C16H14Cl2O2 详情 详情
(VII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(VIII) 63285 [4'-(3-chloropropoxy)[1,1'-biphenyl]-4-yl](4-morpholinyl)methanone C20H22ClNO3 详情 详情
(IX) 63286 (2R,5R)-2,5-dimethylpyrrolidine C6H13N 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XX)

Reaction of 2-nitrovanillin (III) with NH4OH and I2 in H2O/THF yields nitrile (XVIII), which is then condensed with 4-(3-chloropropyl)morpholine hydrochloride (XII) —prepared by alkylation of morpholine (XIX) with 1-bromo-3-chloropropane (XX) in toluene at 84 °C— by means of Cs2CO3 in DMF at 75 °C to give the morpholinopropyl ether (XXI). Reduction of the nitro group in compound (XXI) with Fe and AcOH affords amine (XXII), which by cyclization with ethylenediamine (VII) and sulfur at 100 °C produces the imidazoline derivative (XXIII). Finally, aminoimidazoline (XXIII) is then subjected to ring closure with cyanogen bromide (IX) in the presence of Et3N in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Hentemann, M., Wood, J., Scott, W. et al. (Bayer Pharmaceuticals Corp.). Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. EP 2096919, JP 2010511718, US 2011083984, US 8466283, US 201326113, WO 2008070150.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 68129 2-nitrovanillin；4-Hydroxy-3-methoxy-2-nitrobenzaldehyde 　 C8H7NO5 详情 详情
(VII) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(IX) 28017 cyanic bromide；cyanogen bromide 506-68-3 CBrN 详情 详情
(XII) 18691 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine 7357-67-7 C7H14ClNO 详情 详情
(XIII) 68137 7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine 　 C18H25N5O3 详情 详情
(XVIII) 68140 4-hydroxy-3-methoxy-2-nitrobenzonitrile 　 C8H6N2O4 详情 详情
(XIX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XX) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXI) 66434 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile 675126-26-8 C15H19N3O5 详情 详情
(XXII) 66435 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile 675126-27-9 C15H21N3O3 详情 详情
(XXIII) 68141 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholinopropoxy)aniline 　 C17H26N4O3 详情 详情

合成路线36

该中间体在本合成路线中的序号：(XXIII)

Alkylation of 4’-hydroxy-3’-methoxyacetophenone (XVII) with benzyl bromide by means of K2CO3 in DMF gives benzyl ether (XVIII), which is reacted with fuming HNO3 and concentrated H2SO4 in cold CH2Cl2 to afford 4’-benzyloxy-5’-methoxy-2’-nitroacetophenone (XIX). After reduction of the nitro group of compound (XIX) using iron powder and ammonium formate in refluxing H2O/toluene, the resulting 2-aminoacetophenone derivative (XX) cyclizes with ethyl formate (XXI) in the presence of NaOEt in DME, providing 7-benzyloxy-6-methoxy-4-quinolinol (XXII). Finally, quinolinol (XXII) is treated with trifluoromethanesulfonyl chloride in the presence of DMAP and 2,6-lutidine in cold CH2Cl2 .

参考文献 中间体
合成目标
【1】 Deschamps, N.M., Martin, M.T., Monteith, M.J., Zhou, X. (GlaxoSmithKline Inc.). Preparation of a quinolinyloxydiphenylcyclopropanedicarboxamide. US 2010081805, WO 010036831.
【2】 Wilson, J., Zuberi, S., Naganathan, S., Goldman, E., Kanter, J. (Exelixis, Inc.). Methods of preparing quinoline derivatives. WO 2010056960.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIVa) 22605 4-(3-Chloropropoxy)-3-Methoxyacetophenone;3-(4-Acetyl-2-methoxyphenoxy)propyl chloride;1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone;1-[4-(3-chloropropoxy)-3-methoxyphenyl]-1-ethanone 58113-30-7 C12H15ClO3 详情 详情
(XXIVb) 69115 1-(4-(3-bromopropoxy)-3-methoxyphenyl)ethanone 　 C12H15BrO3 详情 详情
(XXVa) 69117 1-(4-(3-chloropropoxy)-5-methoxy-2-nitrophenyl)ethanone 　 C12H14ClNO5 详情 详情
(XXVb) 69116 1-(4-(3-bromopropoxy)-5-methoxy-2-nitrophenyl)ethanone C12H14BrNO5 详情 详情
(VI) 69105 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline;4-(3-((4-chloro-6-methoxyquinolin-7-yl)oxy)propyl)morpholine 　 C17H21ClN2O3 详情 详情
(XVII) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(XXI) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(XXIII) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(XXVI) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XXVII) 69118 1-(5-methoxy-4-(3-morpholinopropoxy)-2-nitrophenyl)ethanone 　 C16H22N2O6 详情 详情
(XXVIII) 56891 1,3-propanediol cyclic sulfate;1,3,2-dioxathiane 2,2-dioxide;1,3-Propylene sulfate 1073-05-8 C3H6O4S 详情 详情
(XXIX) 69119 4’-(morpholinopropoxy)acetophenone;1-(3-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone 　 C16H23NO4 详情 详情
(XXX) 69120 1-(2-amino-5-methoxy-4-(3-morpholinopropoxy)phenyl)ethanone 　 C16H24N2O4 详情 详情
(XXXI) 69121 6-methoxy-7-(3-morpholinopropoxy)quinolin-4-ol 　 C17H22N2O4 详情 详情
(XXXII) 20360 methyl(phenyl)formamide;N-Methylformanilide;N-Formyl-N-methylaniline;Methylphenylformamide;N-methyl-N-phenylformamide;N-Methyl-N-formylaniline;N-Formyl-N-methylaniline 93-61-8 C8H9NO 详情 详情
Extended Information