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【结 构 式】

【分子编号】11907

【品名】Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine

【CA登记号】107-99-3

【 分 子 式 】C4H10ClN

【 分 子 量 】107.58284

【元素组成】C 44.66% H 9.37% Cl 32.95% N 13.02%
与该中间体有关的原料药合成路线共 19 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5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19

合成路线1

该中间体在本合成路线中的序号：(B)

The reaction of 1-(4-methoxyphenyl)-2-phenylethan-1-one (I) with ethyl bromide (A) gave (II) in nearly quantitative yield. Demethoxylation of (II) with pyridine hydrochloride gave (III) in about 70% yield. Treatment of (III) with dimethylaminoethyl chloride (B) gave (IV) in more than 60% yield. Reaction of (IV) with 3'-(2-tetrahydropyranyloxy)phenylmagnesium bromide (C) gave (V) in about 60% yield. Refluxing a solution of (V) in ethanolic hydrochloric acid gave the stereoisomeric E- and Z-mixture (VIa, VIb) of the hydrochloric salt. Fractional crystallization of the mixture in methanol/ether yielded the pure hydrochloric salt of the E-isomer in 48% yield. Conversion of the hydrochloric salt into the free base and treatment of the latter with citric acid yielded the appropriate K-21060E citrate.

参考文献 中间体
合成目标
【1】 Schickaneder, H.; Loser, R.; Grill, H. (Klinge Pharma GmbH); 1,1,2-triphenylbut-1-ene derivatives. DE 3046719; EP 0054168; US 5047431 .
【2】 Loser, R.; Seibel, K.; Janiak, P.-St.; K-21060 E. Drugs Fut 1984, 9, 3, 186.
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) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(A) 30344 1-bromoethane；ethyl bromide 74-96-4 C2H5Br 详情 详情
(VIa) 30350 3-((E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl)phenol C26H29NO2 详情 详情
(VIb) 30351 3-((Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl)phenol C26H29NO2 详情 详情
(I) 30343 1-(4-methoxyphenyl)-2-phenyl-1-ethanone C15H14O2 详情 详情
(II) 30345 1-(4-methoxyphenyl)-2-phenyl-1-butanone C17H18O2 详情 详情
(III) 30346 1-(4-hydroxyphenyl)-2-phenyl-1-butanone C16H16O2 详情 详情
(IV) 30347 1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-butanone 68047-07-4 C20H25NO2 详情 详情
(V) 30349 1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenyl-1-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-butanol C31H39NO4 详情 详情
(C) 30348 bromo[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]magnesium C11H13BrMgO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of 1,4-dihydro-4-phenylcinnoline (I) with methyl p-toluenesulfonate (A) and acetic acid by means of KOH in refluxing toluene gives 1-(N-methyl-N-acetylamino)-3-phenylindole (II), which is hydrolyzed by treatment with refluxing concentrated HCl to afford 1-methylamino-3-phenylindole (III). Finally, this compound is condensed with 2-dimethylaminoethyl chloride (IV) by means of sodium amide in refluxing toluene.

参考文献 中间体
合成目标
【1】 Schatz, F.; et al.; Amino-3-phenylindoles with antidepressant activity. Binodaline hydrochloride and relatd compounds. Arzneim-Forsch Drug Res 1980, 30, 6, 919-923.
【2】 Schatz, F.; et al. (Siegfried AG); N-Amino indole derivatives having pharmacological activity. US 4204998 .
【3】 Hillier, K.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Binodaline. Drugs Fut 1981, 6, 4, 212.
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) 23403 Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate 80-48-8 C8H10O3S 详情 详情
(I) 37421 4-phenyl-1,4-dihydrocinnoline C14H12N2 详情 详情
(II) 37422 N-methyl-N-(3-phenyl-1H-indol-1-yl)acetamide C17H16N2O 详情 详情
(III) 37423 N-methyl-N-(3-phenyl-1H-indol-1-yl)amine; N-methyl-3-phenyl-1H-indol-1-amine C15H14N2 详情 详情
(IV) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

By decomposition of O-beta-(N-methyl-N-carbethoxy)aminoethyl-5H-dibenzo[a,d]cyclohepten-5-one oxime (III) with KOH in carbitol. Compound (III) can be prepared as follows: 5H-ibenzo[a,d]cyclohepten-5-one oxime (I) is treated with beta-dimethylaminoethyl chloride (IV) in sodium methoxide to give O-beta-dimethylaminoethyl-5H-dibenzo[a,d]cyclohepten-5-one oxime (V), which is treated with ethyl chlorocarbonate in anhydrous benzene.

参考文献 中间体
合成目标
【1】 Pirola, O.; Rossi, S.; Fanelli, O.; Maggi, R.; O- And N- substituted 5H-dibenzo[a,d]cyclohepten-5-one oximes with thymoleptic acticity. VII. Synthesis and pharmacological properties of the substituted oximes. Farm Sci Ed 1969, 24, 7, 685-703.
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Demexiptiline hydrochloride. Drugs Fut 1982, 7, 1, 19.
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) 31713 5H-dibenzo[a,d]cyclohepten-5-one oxime C15H11NO 详情 详情
(III) 31716 ethyl 2-[(5H-dibenzo[a,d]cyclohepten-5-ylideneamino)oxy]ethyl(methyl)carbamate C21H22N2O3 详情 详情
(IV) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(V) 31715 5H-dibenzo[a,d]cyclohepten-5-one O-[2-(dimethylamino)ethyl]oxime C19H20N2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

Compound can be prepared in two different ways: 1) By condensation of 8-chlorodibenzo[b,f]thiepin-10(11H)-one (I) with 2-dimethylaminoethyl chloride (II) by means of NaH in benzene - DMF at 60 C. 2) By condensation of 8-chloro-10-(2-chloroethoxy)dibenzo[b,f]thiepin (III) with dimethylamine.

参考文献 中间体
合成目标
【1】 Umio, S.; Ueta, I.; JP 7235439 .
【2】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; Zotepine. Drugs Fut 1979, 4, 10, 758.
【3】 Umio, S.; et al. (Fujisawa Pharmaceutical Co., Ltd.); Tricyclic enol ether compounds. DE 1907670; FR 2002064; GB 1247067; NL 6902489; US 3704245 .
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) 33427 8-chlorodibenzo[b,f]thiepin-10(11H)-one C14H9ClOS 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(III) 33428 8-chlorodibenzo[b,f]thiepin-10-yl 2-chloroethyl ether; 2-chloro-11-(2-chloroethoxy)dibenzo[b,f]thiepine C16H12Cl2OS 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

A new synthesis of TA-3090 has been published: The cyclization of 2-amino-5-chlorothiophenol (I) with trans-2,3-epoxy-3-(4-methoxyphenyl)propanoic acid methyl ester (II) by heating at 160 C gives cis-8-chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzo thiazepin-4-one (III), which is submitted to optical resolution with (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride. The (2S-cis)-isomer of (III) is then condensed with 2-(dimethylamino)ethyl chloride (IV) by means of K2CO3 in refluxing acetone - water, yielding (2S-cis)-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphen yl-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (V). Finally, this compound is acetylated with acetic anhydride in refluxing pyridine and converted into the maleate salt.

参考文献 中间体
合成目标
【1】 Inoue, H.; Konda, M.; Hashiyama, T.; et al.; Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities. J Med Chem 1991, 34, 2, 675-87.
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) 11904 2-Amino-5-chlorobenzenethiol; 2-Amino-5-chlorophenylhydrosulfide C6H6ClNS 详情 详情
(II) 11905 methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C11H12O4 详情 详情
(III) 11906 (2S,3S)-8-Chloro-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H14ClNO3S 详情 详情
(IV) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(V) 11908 (2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H23ClN2O3S 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

A new synthesis of racemic TA-3090 has been reported: The condensation of 5-chloro-2-nitrothiophenol (I) with 4-methoxybenzyl chloride (II) by means of sodium ethoxide in ethanol gives the thioether (III), which is reduced with SnCl2 in hot ethanol to afford 4-chloro-2-(4-methoxybenzylthio)aniline (IV). The acylation of (IV) with ethoxalyl chloride (V) by means of NaHCO3 in dichloromethane - water yields the oxamate (VI), which is condensed with 2-(dimethylamino)ethyl chloride (VII) by means of K2CO3 and 18-crown-6 in hot acetonitrile to afford the alkylated oxamate compound (VIII). The cyclization of (VIII) by means of lithium diisopropylamide in THF gives 8-chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiaze pine-3,4(2H,5H)-dione (IX), which is reduced with NaBH4 in aqueous ethanol to cis-8-chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazepin-4-one (X). Finally, this compound is acetylated in the usual manner.

参考文献 中间体
合成目标
【1】 Takeda, M.; Takamura, N.; Oh-ishi, T.; Harada, T.; Morimoto, M.; Inoue, H.; Nagasawa, M.; A new synthetic route to 1,5-benzothiazepines. Synthesis of derivatives of diltiazem. Chem Pharm Bull 1992, 40, 8, 1986.
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) 11909 5-Chloro-2-nitrophenylhydrosulfide; 5-Chloro-2-nitrobenzenethiol C6H4ClNO2S 详情 详情
(II) 11910 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether 824-94-2 C8H9ClO 详情 详情
(III) 11911 4-[[(5-Chloro-2-nitrophenyl)sulfanyl]methyl]phenyl methyl ether; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]-1-nitrobenzene C14H12ClNO3S 详情 详情
(IV) 11912 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]phenylamine; 4-Chloro-2-[(4-methoxybenzyl)sulfanyl]aniline C14H14ClNOS 详情 详情
(V) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(VI) 11914 ethyl 2-[4-chloro-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate C18H18ClNO4S 详情 详情
(VII) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(VIII) 11916 ethyl 2-[4-chloro[2-(dimethylamino)ethyl]-2-[(4-methoxybenzyl)sulfanyl]anilino]-2-oxoacetate C22H27ClN2O4S 详情 详情
(IX) 11917 (2S)-8-Chloro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione C20H21ClN2O3S 详情 详情
(X) 11908 (2S,3S)-8-Chloro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H23ClN2O3S 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

Alkylation of the lactam N of thiazepinone (I) with 2-(dimethylamino)ethyl chloride (II) in the presence of K2CO3 or under phase-transfer conditions gave thiazeinone (III). Subsequent esterification of (III) with acetic anhydride furnished the title compound. Alternatively, diltiazem has been prepared by acetylation of thiazeinone (I) with Ac2O to yield the lactam acetate ester (IV), which is then alkylated with chloride (II) under phase-transfer conditions

参考文献 中间体
合成目标
【1】 Coffen, D.L.; Madan, P.B.; Schwartz, A. (F. Hoffmann-La Roche AG); Process for the preparation of optically pure aminophenylthio- and aminonaphthalenylthio-propanoic acids. EP 0343474 .
【2】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 .
【3】 Murthy, K.; Weeratunga, G.; Burchat, A. (ACIC (Canada) Inc.); Method for the manufacture of benzothiazepine derivs.. WO 9638429 .
【4】 Piselli, F.L.; Boschi, P.; Navoni, C.; A process for the preparation of diltiazem. EP 0594101 .
【5】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 .
【6】 Hytonen, M. (Orion Corporation); Process for the manufacture of diltiazem. EP 0728751; JP 1996253464; US 5644054 .
【7】 Hulshof, L.A.; Kuilman, T.; Process for preparing 1,5-benzothiazepin derivs.. EP 0450705 .
【8】 Manghisi, E.; Cascio, G. (Lusofarmaco); Process for the optical resolution of the dl-alpha-hydroxy-3-(4-methoxyphenyl)-3-(2-aminophenylthio)propionic acid. US 4533748 .
【9】 Simonovitch, H.; Hoffmann, T.; Sassoon, S. (Abic, Ltd.); A process for the preparation of benzothiazepin derivs.. EP 0158303 .
【10】 Hytonen, M. (Orion Corporation); Method for the preparation of pharmaceutically active benzothiazepine derivs.. EP 0702009 .
【11】 Manghisi, E.; Perego, B.; A process for the preparation of diltiazem. WO 9210485 .
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) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(III) 62488 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(IV) 62452 2-(4-methoxyphenyl)-4-oxo-4,5-dihydro-1,5-benzothiazepin-3-yl acetate C18H15NO4S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

Several related procedures utilize racemic intermediates that are resolved in more advanced synthetic steps. The racemic trans-glycidic ester (IX) was prepared by Darzen's condensation between anisaldehyde (VII) and methyl chloroacetate (VIII). Opening of the epoxide group of (IX) with 2-aminothiophenol (X) in hot chlorobenzene in the presence of FeCl3 gave rise to the racemic threo adduct (XI) which, without isolation, was cyclized to the cis-lactam (XII) by addition of methanesulfonic acid and then heating to reflux. Alkylation of the lactam N of (XII) with 2-(dimethylamino)ethyl chloride (II) led to the racemic precursor (XIII). Resolution of (XIII) to provide the (S,S)-isomer (VII) was then accomplished by preferential crystallization of supersaturated solutions of several sulfonate salts of (XIII) upon seeding with the desired enantiomer. Racemic diltiazem (XIV), obtained by acetylation of (XIII), has been resolved via formation of the corresponding diastereoisomeric salts with (S)-naproxen

参考文献 中间体
合成目标
【1】 Gizur, T.; Harsanyi, K.; Fogassy, E.; Studies of the resolution of racemates in the synthesis of diltiazem. J Prakt Chem Chem-Ztg 1994, 336, 7, 628.
【2】 Yamada, S.; Yoshioka, R.; Shibatani, T.; Optical resolution of a 1,5-benzothiazepine derivative,a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation. Chem Pharm Bull 1997, 45, 12, 1922.
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) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(VII) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(VII) 62488 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(VIII) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(IX) 11905 methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate C11H12O4 详情 详情
(X) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(XI) 62439 methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate C17H19NO4S 详情 详情
(XII) 62436 (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO3S 详情 详情
(XIII) 62487 5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C20H24N2O3S 详情 详情
(XIV) 62489 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate C22H26N2O4S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

Selective hydrolysis of the acetate ester of (XXV) using benzylamine in THF led to phenol (XXVI), which was further methylated by means of diazomethane, yielding methyl ether (XXVII). Reduction of the nitro group (XXVII) to the corresponding aniline (XXVIII) was then performed employing ferrous sulfate and ammonium hydroxide. Subsequent saponification of the methyl ester group of (XXVIII) gave amino acid (XXIX). Cyclization of (XXIX) with ethyl chloroformate and triethylamine furnished lactam (XXX). The lactam N of (XXX) was then alkylated by 2-(dimethylamino)ethyl chloride (II) to produce (XXXI). Finally, deprotection of the methoxymethyl group of (XXXI) and concomitant O-acetylation was accomplished by treatment with acetyl chloride and TiCl4

参考文献 中间体
合成目标
【1】 Honma, T.; Igarashi, K. (Shionogi & Co. Ltd.); Process for production of diltiazem hydrochloride. US 4552695 .
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) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(XXV) 62473 methyl (2S,3S)-3-[4-(acetyloxy)phenyl]-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate C20H21NO8S 详情 详情
(XXVI) 62474 methyl (2S,3S)-3-(4-hydroxyphenyl)-2-(methoxymethoxy)-3-[(2-nitrophenyl)sulfanyl]propanoate C18H19NO7S 详情 详情
(XXVII) 62475 methyl (2S,3S)-2-(methoxymethoxy)-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C19H21NO7S 详情 详情
(XXVIII) 62476 methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoate C19H23NO5S 详情 详情
(XXIX) 62477 (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-(methoxymethoxy)-3-(4-methoxyphenyl)propanoic acid C18H21NO5S 详情 详情
(XXX) 62470 (2S,3S)-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C18H19NO4S 详情 详情
(XXXI) 62478 (2S,3S)-5-[2-(dimethylamino)ethyl]-3-(methoxymethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C22H28N2O4S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The racemic precursor threo-hydroxy nitro ester (III), prepared by addition of 2-nitrothiophenol (II) to the racemic trans-glycidate (I), has been optically resolved by enantioselective lipase-catalyzed esterification of the (R,R)-isomer, producing the (R,R)-acetate (IV), while leaving unaltered the target intermediate, the (S,S)-hydroxy nitroester enantiomer (V). The racemic hydroxy nitro ester (III) has also been resolved through formation of the diastereoisomeric salts with L-lysine

参考文献 中间体
合成目标
【1】 Kanerva, L.T.; Sundholm, O.; Lipase catalysis in the resolution of racemic intermediates of diltiazem synthesis in organic solvents. J Chem Soc - Perkins Trans I 1993, 13, 1385.
【2】 Senuma, M.; Shibazaki, M.; Nishimoto, S.; Shibata,K.; Okamura, K.; Date, T.; The practical resolution of (2RS,3RS)-2-hydroxy-3-(4-methoxyphenyl)-3-(2-nitrophenylthio)propionic acid, a key intermediate for diltiazem, with L-lysine. Chem Pharm Bull 1989, 37, 12, 3204.
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) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(II) 62460 2-nitrobenzenethiol; 2-nitrophenylhydrosulfide C6H5NO2S 详情 详情
(III) 62471 methyl 2-hydroxy-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C17H17NO6S 详情 详情
(IV) 62472 methyl (2R,3R)-2-(acetyloxy)-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C19H19NO7S 详情 详情
(V) 63417 methyl (2S,3S)-2-hydroxy-3-(4-methoxyphenyl)-3-[(2-nitrophenyl)sulfanyl]propanoate C17H17NO6S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(III)

Grignard addition of phenylmagnesium bromide to (+)-camphor (I) yielded the endo-alcohol (II), which was reacted with 1-dimethylamino-2-chloroethane (III) to give the base corresponding to EGYT-3886. EGYT-3886 is the 2-(E)-butenedioate salt (1:1).

参考文献 中间体
合成目标
【1】 Budai, Z.; Magdanyi, L.; Lay, A.; Mezei, T.; Grasser, K.; Petocz, L.; Kosoczky, I. (Egis Pharmaceuticals Ltd.); Basic ethers and pharmaceutical compsns. containing the same. US 4342762 .
【2】 Berényi, E.; Baskó, G.; Fekete, M.; Nógrádi, M.; EGYT-3886. Drugs Fut 1990, 15, 12, 1174.
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) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
(I) 28296 1-[4-(difluoromethoxy)phenyl]-2-phenyl-1-ethanone C15H12F2O2 详情 详情
(II) 31225 1,7,7-trimethyl-2-phenylbicyclo[2.2.1]heptan-2-ol C16H22O 详情 详情
(III) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

The condensation of 4-hydroxybenzaldehyde (I) with 2-(dimethylamino)ethyl chloride (II) by means of K2CO3 in hot isopropyl ether yields 4-[2-(dimethylamino)ethoxy]benzaldehyde (III), which is treated with hydroxylamine hydrochloride in refluxing ethanol to afford the corresponding oxime (IV). The hydrogenation of (IV) with H2 over RaNi in methanolic ammonia yields 4-[2-(dimethylamino)ethoxy]benzylamine (V), which is finally condensed with 3,4-dimethoxybenzoyl chloride (VI) (obtain303ed from the corresponding acid (VII) with SOCl2) in toluene.

参考文献 中间体
合成目标
【1】 Castaner, J.; Mealy, N.; Itopride Hydrochloride. Drugs Fut 1995, 20, 12, 1220.
【2】 Ogawa, N.; Yasuda, S.; Kato, H.; Sakaguchi, J.; Iwanaga, Y.; Ito, Y.; Nishino, H.; Synthesis, gastrointestinal prokinetic activity and structure-activity relationships of novel N-[[2-(dialkylamino)ethoxy]benzyl]benzamide derivatives. Chem Pharm Bull 1992, 40, 1, 202-11.
【3】 Itoh, Y.; Kato, H.; Koshinaka, E.; Ogawa, N.; Nishino, H.; Sakaguchi, J. (Hokuriku Seiyaku Co., Ltd.); Amide cpds., process for preparing the same, and compsn. for activating gastric motor function containing the same. AU 8821862; EP 0306827; JP 1989066153; JP 1989079144; JP 1989085960; JP 1989093568; US 4983633 .
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) 13433 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde 123-08-0 C7H6O2 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(III) 13435 4-[2-(Dimethylamino)ethoxy]benzaldehyde C11H15NO2 详情 详情
(IV) 13436 4-[2-(Dimethylamino)ethoxy]benzaldehyde oxime C11H16N2O2 详情 详情
(V) 13437 2-[4-(Aminomethyl)phenoxy]-N,N-dimethyl-1-ethanamine; N-[2-[4-(Aminomethyl)phenoxy]ethyl]-N,N-dimethylamine C11H18N2O 详情 详情
(VI) 13438 3,4-Dimethoxybenzoyl chloride 3535-37-3 C9H9ClO3 详情 详情
(VII) 13439 3,4-Dimethoxybenzoic acid 93-07-2 C9H10O4 详情 详情

合成路线13

该中间体在本合成路线中的序号：(V)

Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloro-N,N-dimethylethyl-amine (V) by means of NaNH2 in toluene gives 3-[2-(di-methylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (VI), which is reduced with Vitride (sodium bis(2-methoxyethoxy)aluminum dihydride) in toluene to yield the secondary alcohol (VII). Optical resolution of (VII) by means of (+)-2,3-di-O-(p-toluoyl)tartaric acid provides the (2S,3S)-diastereomer (VIII), which by reaction with methyl iodide in ethyl ether affords the ammonium salt (IX). Cyclization of compound (IX) by means of methylamine in acetonitrile provides esermethole (X), the methyl ether of eseroline, which is demethylated by means of BBr3 in dichloromethane to give eseroline (II). Finally, eseroline is condensed with phenyl isocyanate (VIII) by means of Na in ethyl ether.

参考文献 中间体
合成目标
【1】 Castañer, J.; Sorbera, L.A.; Phenserine Tartrate. Drugs Fut 2003, 28, 1, 18.
【2】 Brossi, A.; Bi, S.; Greig, N.H.; Pei, X.-F.; 125. Total synthesis of racemic and optically active compounds related to physostigmine and ring-C heteroanalogues from 3-[2'-(dimethylamino)ethyl]-2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indol-2-ol. Helv Chim Acta 1994, 77, 5, 1412.
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) 20365 (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-ol C13H18N2O 详情 详情
(III) 11289 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate 103-71-9 C7H5NO 详情 详情
(IV) 58084 5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one C11H13NO2 详情 详情
(V) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(VI) 58085 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-1,3-dihydro-2H-indol-2-one C15H22N2O2 详情 详情
(VII) 58086 3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2-indolinol C15H24N2O2 详情 详情
(VIII) 58087 (2S,3S)-3-[2-(dimethylamino)ethyl]-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-ol C15H24N2O2 详情 详情
(IX) 36822 2-[(2S,3S)-2-hydroxy-5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-3-yl]-N,N,N-trimethyl-1-ethanaminium iodide C16H27IN2O2 详情 详情
(X) 58088 (3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole C14H20N2O 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

Condensation of 2-(dimethylamino)ethyl chloride hydrochloride (I) with methylamine gave trimethyl ethylenediamine (II), which was coupled with 3,4-dichlorophenylacetic acid (III) in the presence of DCC to afford amide (IV). Subsequent reduction of (IV) with aluminum hydride in THF provided the title diamine.

参考文献 中间体
合成目标
【1】 de Costa, B.R.; et al.; Synthesis, characterization, and biological evaluation of a novel class of N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamines: Structural requirements and binding affinity at the sigma receptor. J Med Chem 1992, 35, 1, 38.
【2】 De Costa, B.R.; Radesca, L.; Bowen, W.; Long, J.; Walker, J.M.; Rice, K.C.; Gray, N.M.; Contreras, P.C. (Pharmacia Corp.); N-(Arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine derivs. for CNS disorders. EP 0518216; WO 9222279 .
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) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(II) 15778 N-[2-(dimethylamino)ethyl]-N-methylamine; N,N,N'-trimethyl-1,2-ethanediamine; N(1),N(1),N(2)-trimethyl-1,2-ethanediamine 142-25-6 C5H14N2 详情 详情
(III) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(IV) 30415 2-(3,4-dichlorophenyl)-N-[2-(dimethylamino)ethyl]-N-methylacetamide C13H18Cl2N2O 详情 详情

合成路线15

该中间体在本合成路线中的序号：(VIII)

The required 2-amino-5-methylthiophenol (III) was obtained by basic hydrolysis of the aminobenzothiazole (II), which was prepared from p-toluidine (I) and in situ generated thiocyanogen. Reaction of thiophenol (III) with the arylglycidic ester (IV) produced the racemic threo-amino ester (V). After basic hydrolysis of the ester group of (V), the resultant amino acid was resolved by means of D-(4-hydroxyphenyl)glycine methyl ester. The required amino acid enantiomer (VI) was then cyclized to lactam (VII) by heating in xylene with azeotropic removal of water. N-alkylation of benzothiazepinone (VII) with 2-(dimethylamino)ethyl chloride (VIII) provided (IX). The secondary alcohol of (IX) was esterified with acetic anhydride, and the resultant compound was finally isolated as the corresponding maleate salt.

参考文献 中间体
合成目标
【1】 Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Watanabe, A.; Gaino, M.; Takahashi, K.; Date, T.; Okamura, K.; Takeda, M.; Narita, H.; Murata, S.; Odawara, A.; Sasaki, H.; Nagao, T.; Synthesis and biological evaluation of alkyl, alkoxy, alkylthio, or amino-substituted 2,3-dihydro-1, 5-benzothiazepin-4(5H)-ones. Chem Pharm Bull 1997, 45, 6, 1008.
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) 31228 p-toluidine; 4-methylphenylamine 106-49-0 C7H9N 详情 详情
(II) 59776 6-methyl-1,3-benzothiazol-2-ylamine; 6-methyl-1,3-benzothiazol-2-amine C8H8N2S 详情 详情
(III) 59777 2-amino-5-methylbenzenethiol; 2-amino-5-methylphenylhydrosulfide C7H9NS 详情 详情
(IV) 59778 methyl (2S,3S)-3-(4-methylphenyl)-2-oxiranecarboxylate C11H12O3 详情 详情
(V) 59779 methyl (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoate C18H21NO3S 详情 详情
(VI) 59780 (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoic acid C17H19NO3S 详情 详情
(VII) 59781 (2R,3R)-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C17H17NO2S 详情 详情
(VIII) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(IX) 59782 (2R,3R)-5-[2-(dimethylamino)ethyl]-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C21H26N2O2S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

Title compound was obtained by alkylation of 5-ethoxy-10,11-dihydrodibenzocycloheptane (I) with N,N-dimethylaminoethyl chloride (II) in the presence of potassium amide in liquid ammonia.

参考文献 中间体
合成目标
【1】 Ting, P.C.; Solomon, D.L.; Friary, R.J.; Villani, F.J.; Piwinski, J.J.; Lee, J.F.; Seidl, V.A.; Jakway, J.P.; Vashi, D.B. (Schering Corp.); Tricyclic derivs., pharmaceutical compsns. containing them. EP 0733035; JP 1997500656; US 5538986; WO 9515939 .
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) 25753 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl ethyl ether; 5-ethoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene C17H18O 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

This compound can be obtained in two differents ways: 1) By oxidation of 2-(2,5-dihydroxyphenyl)-4-dimethylaminobutylamine (I) to give bufotenine in a 45% yield. 2) By alkylation of 2,5-dimethoxybenzyl cyanide (II) with beta-dimethylaminoethyl chloride (A) using sodamide. The product (III) is hydrogenated over Raney-Ni inducing partial cyclization and then demethylation with hydrogen bromide and oxidized with potassium ferricyanide in the cold to yield bufotenine.

参考文献 中间体
合成目标
【1】 Jackson, A.H.; Harley-Mason, J.; A new synthesis of bufotenine. Chem Ind 1952, 954.
【2】 Amoros-Marin, L.; Carlin, R.B.; 2,4,6-Tri-p-chlorophenylpyridine. A by-product of a Fischer indole transformation. J Am Chem Soc 1959, 81, 730-733.
【3】 Wallis, D.I.; Nash. H.L.; Bufotenine. Drugs Fut 1981, 6, 11, 671.
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) 39015 2-(2,5-dimethoxyphenyl)acetonitrile 18086-24-3 C10H11NO2 详情 详情
(I) 39014 2-[1-(aminomethyl)-3-(dimethylamino)propyl]-1,4-benzenediol C12H20N2O2 详情 详情
(II) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(III) 39016 2-(2,5-dimethoxyphenyl)-4-(dimethylamino)butanenitrile C14H20N2O2 详情 详情
(IV) 39017 N-[4-amino-3-(2,5-dimethoxyphenyl)butyl]-N,N-dimethylamine; 2-(2,5-dimethoxyphenyl)-N(4),N(4)-dimethyl-1,4-butanediamine C14H24N2O2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(IV)

The condensation between benzamidoxime (I) and methyl salicylate (II) in the presence of NaOEt under microwave irradiation generated oxadiazole (III). Subsequent alkylation of the hydroxyl group of (III) with dimethylaminoethyl chloride and NaH in dioxan produced the target aminoethyl ether, which was finally isolated as the corresponding hydrochloride salt.

参考文献 中间体
合成目标
【1】 Brenner, M.; Maier, R.; Wienrich, M.; Weiser, T.; Palluk, R.; Bechtel, W.-D.; Sagrada, A.; Ensinger, H.; Pschorn, U.; Cesana, R. (Boehringer Ingelheim GmbH); Oxadiazoles, processes for their preparation and their use as medicaments. DE 19643037; EP 0934288; JP 2000505089; WO 9817652 .
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) 20438 N'-hydroxybenzenecarboximidamide 613-92-3 C7H8N2O 详情 详情
(II) 15754 methyl salicylate 119-36-8 C8H8O3 详情 详情
(III) 32225 3,4,5-trimethoxybenzoic acid 118-41-2 C10H12O5 详情 详情
(IV) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情

合成路线19

该中间体在本合成路线中的序号：(V)

Lithiation of N-methylpyrazole (I) by means of n-butyllithium, followed by addition to 2-thiophenecarboxaldehyde (II), afforded carbinol (III). This compound was alternatively obtained by sodium borohydride reduction of diheteroaryl ketone (IV). Condensation of alcohol (III) with either 2-(dimethylamino)ethyl chloride (IV) in the presence of NaOH or 2-(dimethylamino)ethanol (VI) under catalysis of H2SO4 furnished ether (VII). This compound was finally converted to the title citrate salt by treatment with citric acid in EtOH.

参考文献 中间体
合成目标
【1】 Frigola-Constansa, J.; Andaluz-Mataro, B.; Merce-Vidal, R. (Laboratorios del Dr. Esteve, SA); Thienylazolylalcoxyethanamines, their preparation and their application as medicaments. WO 9952525 .
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) 44234 1-methyl-1H-pyrazole; N-Methylpyrazole 930-36-9 C4H6N2 详情 详情
(II) 30732 2-thiophenecarbaldehyde; Thiophene-2-carboxaldehyde 98-03-3 C5H4OS 详情 详情
(III) 44235 (1-methyl-1H-pyrazol-5-yl)(2-thienyl)methanol C9H10N2OS 详情 详情
(IV) 44236 (1-methyl-1H-pyrazol-5-yl)(2-thienyl)methanone C9H8N2OS 详情 详情
(V) 11907 Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine 107-99-3 C4H10ClN 详情 详情
(VI) 44237 2-(dimethylamino)-1-ethanol 108-01-0 C4H11NO 详情 详情
(VII) 44238 N,N-dimethyl-2-[(1-methyl-1H-pyrazol-5-yl)(2-thienyl)methoxy]-1-ethanamine; N,N-dimethyl-N-[2-[(1-methyl-1H-pyrazol-5-yl)(2-thienyl)methoxy]ethyl]amine C13H19N3OS 详情 详情
Extended Information