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【结 构 式】

【分子编号】14443

【品名】2-chloroacetonitrile; chloroacetonitrile

【CA登记号】107-14-2

【 分 子 式 】C2H2ClN

【 分 子 量 】75.49732

【元素组成】C 31.82% H 2.67% Cl 46.96% N 18.55%
与该中间体有关的原料药合成路线共 17 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1

该中间体在本合成路线中的序号：(H)

The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII), which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII). The dehydrobromination of (VIII) with LiBr in DMF affords (IX), which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X). The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI), which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII). Finally, (XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF, and then with KOH in hot water-methanol. The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII), which is finally hydrolyzed with H2SO4 in acetic acid. The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV), which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV). Finally, this acid is decarboxylated by heating at 150 C.

参考文献 中间体
合成目标
【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 .
【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(H) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(D) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(G) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(F) 35647 diethyl 2-bromomalonate 685-87-0 C7H11BrO4 详情 详情
(E) 40097 diphenyliodonium chloride 1483-72-3 C12H10ClI 详情 详情
(I) 40081 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether 1984-59-4 C7H6Cl2O 详情 详情
(VII) 40088 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone C11H12Cl2O2 详情 详情
(VIII) 40089 2-bromo-1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone C11H11BrCl2O2 详情 详情
(IX) 40090 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-2-propen-1-one C11H10Cl2O2 详情 详情
(X) 40091 6,7-dichloro-5-methoxy-2-methyl-1-indanone C11H10Cl2O2 详情 详情
(XI) 40092 6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone C17H14Cl2O2 详情 详情
(XII) 40093 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone C16H12Cl2O2 详情 详情
(XIII) 40094 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetonitrile C18H13Cl2NO2 详情 详情
(XIV) 40095 diethyl 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonate C23H22Cl2O6 详情 详情
(XV) 40096 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonic acid C19H14Cl2O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

2) By reaction of 4-methoxybenzylamine (I) with diethyl iminocarbonate (A) in water to give diethyl N-(4-methoxybenzyl)iminocarbonate (II), followed by treatment with methylamine in water - ethanol - H2SO4.

参考文献 中间体
合成目标
【1】 Najer, H.; Giudidelli, J.F. (Sanofi-Synthelabo); 2-(2'-Cyclopropylphenoxymethyl)-2-imidazoline and pharmaceutically acceptable salts thereof. DE 2234714; ES 404927; FR 2145423; GB 1386355; US 3803130 .
【2】 Hillier, K.; Castaner, J.; Cirazoline. Drugs Fut 1978, 3, 5, 359.
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) 14754 ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine 107-15-3 C2H8N2 详情 详情
(I) 39809 2-cyclopropylphenol 10292-60-1 C9H10O 详情 详情
(II) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(III) 39810 2-(2-cyclopropylphenoxy)acetonitrile C11H11NO 详情 详情
(IV) 39811 ethyl 2-(2-cyclopropylphenoxy)ethanimidoate C13H17NO2 详情 详情
(V) 17330 2-(chloromethyl)-4,5-dihydro-1H-imidazole C4H7ClN2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(III)

LM-1554 is synthesized by condensation of 2-amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene (I) with chloroacetonitrile (III) in the presence of dry hydrogen chloride gas followed by basification. Alternatively, 2-amino-3-carbamoyl-4,5,6,7-tetrahydrobenzo[b]thiophene (IV) can be condensed with chloroacetonitrile (III) under the above reaction conditions. The condensation of (I) with chloroacetamide (II) in the presence of an equivalent of phosphorus oxychloride in chloroform followed by basification also yields LM-1554.

参考文献 中间体
合成目标
【1】 Shishoo, C.J.; et al.; Process for the manufacture of pharmacologically active new heterocyclic compounds and salts thereof. IN 151496 .
【2】 Arya, V.P.; LM-1554. Drugs Fut 1985, 10, 2, 123.
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) 28963 ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 4506-71-2 C11H15NO2S 详情 详情
(II) 28964 2-chloroacetamide 79-07-2 C2H4ClNO 详情 详情
(III) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(IV) 28965 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide C9H12N2OS 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XXVII)

The reduction of 2-octyn-1-ol (XII) with bis(2-methoxyethoxy)aluminum hydride in toluene/THF gives 2-octen-1-ol (XIII), which is treated with tert-butyl hydroperoxide, (+)-diethyl L-tartrate and titanium tetraisopropoxide in dichloromethane yielding epoxide (XIV). The latter is reduced with bis(2-ethoxyethoxy)aluminum hydride in toluene/THF, affording the chiral diol (XV). The selective monotosylation of (XV) with TsCl in pyridine provides the primary tosylate (XVI), which is treated with NaI in hot acetone to furnish 1-iodo-3-octanol (XVII). Protection of (XVII) with dihydropyran and pyridine hydrochloride gives the tetrahydropyranyl ether (XVIII), which is condensed with dimethyl methylphosphonate (XIX) by means of BuLi and TEA in THF to yield the phosphonate (XX). Condensation of compound (XX) with 5-methoxy-2,3,3a,4-tetrahydronaphtho[2,3-b]furan-2-one (XXI) by means of BuLi in THF affords the tricyclic adduct (XXII), which is hydrogenated with H2 over Pd/C in ethanol to provide compound (XXIII). Isomerization of (XXIII) with NaOH in refluxing ethanol gives diastereomer (XXIV). The reduction of the carbonyl group of (XXIV) with NaBH4 in methanol, followed by deprotection with HOAc in THF yields compound (XXV). The demethylation of compound (XXV) by means of BuLi and Ph2PH in THF affords the tricyclic phenol (XXVI), which is condensed with 2-chloroacetonitrile (XXVII) by means of K2CO3 in refluxing acetone to provide the precursor (XXVIII). Finally, the cyano group of (XXVIII) is hydrolyzed with KOH in refluxing water.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364.
【2】 Aristoff, P.A. (Pharmacia Corp.); Carbacyclin analogues. EP 0159784; JP 1985208936; US 4683330 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 46559 2-octyn-1-ol C8H14O 详情 详情
(XIII) 46560 (E)-2-octen-1-ol C8H16O 详情 详情
(XIV) 46561 [(2R,3S)-3-pentyloxiranyl]methanol C8H16O2 详情 详情
(XV) 46562 (3S)-1,3-octanediol C8H18O2 详情 详情
(XVI) 46563 (3S)-3-hydroxyoctyl 4-methylbenzenesulfonate C15H24O4S 详情 详情
(XVII) 46564 (3S)-1-iodo-3-octanol C8H17IO 详情 详情
(XVIII) 46565 (1S)-1-(2-iodoethyl)hexyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-(2-iodoethyl)hexyl]oxy]tetrahydro-2H-pyran C13H25IO2 详情 详情
(XIX) 13067 ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate C15H9F2NO4S 详情 详情
(XX) 46566 dimethyl (4S)-4-(tetrahydro-2H-pyran-2-yloxy)nonylphosphonate C16H33O5P 详情 详情
(XXI) 46567 (3aS)-5-methoxy-3a,4-dihydronaphtho[2,3-b]furan-2(3H)-one C13H12O3 详情 详情
(XXII) 46568 (9aS)-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one C27H38O4 详情 详情
(XXIII) 46569 (1S,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one C27H40O4 详情 详情
(XXIV) 46570 (1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one C27H40O4 详情 详情
(XXV) 46571 (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol C22H34O3 详情 详情
(XXVI) 46572 (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalene-2,5-diol C21H32O3 详情 详情
(XXVII) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XXVIII) 46573 2-([(1R,2R,3aS,9aS)-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl]oxy)acetonitrile C23H33NO3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

The esterification of pyridine-2,5-dicarboxylic acid (I) with thionyl chloride/methanol gives the corresponding dimethyl ester (II), which is hydrogenated with H2 over PtO2 in acetic acid yielding piperidine-2,5-dicarboxylic acid dimethyl ester (III), as a mixture of the cis- and trans-isomers. The condensation of (III) with 2-chloroacetonitrile (IV) by means of Na2CO3 in refluxing isobutyl methyl ketone affords the expected 1-(cyanomethyl) derivative (V), which is cyclized by hydrogenation with H2 over RaNi in methanol/ethyl acetate giving racemic cis-1-oxo-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine-7-carboxylic acid methyl ester (VI). The reduction of (VI) with LiAlH4 in refluxing THF yields the corresponding hydroxymethyl derivative (VII), which is condensed with 2-chloropyrimidine by means of Na2CO3 in refluxing water affording racemic cis-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (IX). The reaction of (IX) with methanesulfonyl chloride and triethylamine gives the expected mesylate (X), which is treated with sodium azide in DMF to afford the corresponding azido derivative (XI). The reaction of (XI) with hydrazine in refluxing ethanol gives the racemic cis-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XII), which is submitted to optical resolution by formation of the corresponding salt with (-)-mandelic acid, separation of the diastereomers by crystallization, and decomposition of the desired salt with NaOH to yield (7R,9aS)-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (XIII). Finally, this compound is condensed with succinic anhydride (XIV) in refluxing xylene.

参考文献 中间体
合成目标
【1】 Castaner, J.; Graul, J.; Silvestre, J.S.; Sunepitron Hydrochloride. Drugs Fut 1998, 23, 2, 161.
【2】 Desai, K.A.; Bright, G.M. (Pfizer Inc.); Bis-aza-bicyclic anxiolytic agents and antidepressants. EP 0380217; JP 1990233681; US 5122525; WO 9008144; WO 9008148 .
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) 14440 2,5-pyridinedicarboxylic acid 100-26-5 C7H5NO4 详情 详情
(II) 14441 dimethyl 2,5-pyridinedicarboxylate 881-86-7 C9H9NO4 详情 详情
(III) 14442 dimethyl 2,5-piperidinedicarboxylate C9H15NO4 详情 详情
(IV) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(V) 14444 dimethyl 1-(cyanomethyl)-2,5-piperidinedicarboxylate C11H16N2O4 详情 详情
(VI) 14445 methyl (7S,9aS)-1-oxooctahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate C10H16N2O3 详情 详情
(VII) 14446 (7S,9aS)octahydro-2H-pyrido[1,2-a]pyrazin-7-ylmethanol C9H18N2O 详情 详情
(VIII) 11191 2-Chloropyrimidine 1722-12-9 C4H3ClN2 详情 详情
(IX) 14448 [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanol C13H20N4O 详情 详情
(X) 14449 [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl methanesulfonate C14H22N4O3S 详情 详情
(XI) 14450 [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methyl azide; (7S,9aS)-7-(azidomethyl)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazine C13H19N7 详情 详情
(XII) 63830 [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7S,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine C13H21N5 详情 详情
(XIII) 14451 [(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methylamine; [(7R,9aS)-2-(2-pyrimidinyl)octahydro-2H-pyrido[1,2-a]pyrazin-7-yl]methanamine C13H21N5 详情 详情
(XIV) 11291 Dihydro-2,5-furandione; Succinic anhydride 108-30-5 C4H4O3 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

L-697,661 was prepared via a convergent route: Formylation of 2-pentanone (I) with ethyl formate and sodium methoxide gave the ketoaldehyde sodium salt (II). When a mixture of anhydrous diethyl ether and absolute ethanol, 6:1 v/v, was used as solvent, the desired regioisomer precipitated out of solution. Treatment of ethyl nitroacetate (III) with ethanol saturated with ammonia provided nitroacetamide ammonium salt (IV). The nitroacetamide was then condensed with (II) in an aqueous solution of piperidinium acetate to afford the 3-nitropyridinone (V). Catalytic reduction of (V) provided the 3-aminopyridinone (VI). Treatment of chloroacetonitrile (VII) with hydrogen chloride and absolute ethanol gave ethyl chloroiminoacetate hydrochloride (VIII). Nitration of 2,4-dichlorophenol (IX), followed by catalytic reduction of the resultant product, led to the aminophenol (X). Coupling of (X) with (VIII) yielded the chloromethylbenzoxazole (XI), which was converted to the corresponding iodomethyl derivative (XII). Alkylation of the 3-aminopyridinone (VI) with the iodomethylbenzoxazole (XII) furnished L-697,661.

参考文献 中间体
合成目标
【1】 Saari, W.S.; Hoffman, J.M.; Wai, J.S.; et al.; 2-Pyridinone derivatives: A new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors. J Med Chem 1991, 34, 9, 2922.
【2】 Goldmann, M.E.; Wai, J.S.; L-697,661. Drugs Fut 1992, 17, 4, 283.
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) 15048 2-pentanone 107-87-9 C5H10O 详情 详情
(II) 15049 sodium (Z)-2-ethyl-3-oxo-1-buten-1-olate C6H9NaO2 详情 详情
(III) 15050 ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester 626-35-7 C4H7NO4 详情 详情
(IV) 15051 1-Carbamoyl-1-nitromethanide ammonium salt C2H7N3O3 详情 详情
(V) 15052 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone C8H10N2O3 详情 详情
(VI) 15053 3-amino-5-ethyl-6-methyl-2(1H)-pyridinone C8H12N2O 详情 详情
(VII) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(VIII) 15055 1-chloro-2-pentanimine hydrochloride C5H11Cl2N 详情 详情
(IX) 11953 2,5-Dichlorophenol 583-78-8 C6H4Cl2O 详情 详情
(X) 15057 2-amino-3,6-dichlorophenol C6H5Cl2NO 详情 详情
(XI) 15058 4,7-dichloro-2-(chloromethyl)-1,3-benzoxazole C8H4Cl3NO 详情 详情
(XII) 15059 4,7-dichloro-2-(iodomethyl)-1,3-benzoxazole C8H4Cl2INO 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VI)

Benzodioxan-6-amine (I) was protected as the corresponding acetanilide (II), which was subsequently subjected to Friedel-Crafts condensation with chloroacetyl chloride (III) in the presence of ZnCl2, yielding the chloro ketone (IV). Acidic hydrolysis of the acetamide function of (IV) provided amino ketone (V). Alternatively, intermediate (V) was prepared by direct acylation of aniline (I) employing chloroacetonitrile (VI) in the presence of BCl3. The 7-(chloromethyl)camptothecin derivative (VIII) was synthesized through a Friedlander condensation between amino ketone (V) and the known keto lactone (VII). Finally, displacement of the chloride of (VIII) with N-methylpiperazine (IX) gave rise to the title piperazinylmethyl camptothecin.

参考文献 中间体
合成目标
【1】 Luzzio, M.J.; et al.; Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995, 38, 3, 395.
【2】 Luzzio, M.J.; Besterman, J.M.; Evans, M.G.; Myers, P.L. (GlaxoSmithKline plc); Water soluble camptothecin derivs.. EP 0540099; JP 1993222048; JP 2000109475; US 5559235 .
【3】 Sternbach, D.D.; Lackey, K. (GlaxoSmithKline Inc.); Preparation of water soluble camptothecin derivs.. US 5342947 .
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) 54867 1,4-Benzodioxan-6-amine; 3,4-Ethylenedioxyaniline; 6-Amino-1,4-benzodioxane 22013-33-8 C8H9NO2 详情 详情
(II) 54868 N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide C10H11NO3 详情 详情
(III) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(IV) 54869 N-[7-(2-chloroacetyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetamide C12H12ClNO4 详情 详情
(V) 54870 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone C10H10ClNO3 详情 详情
(VI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(VII) 10841 (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione C13H13NO5 详情 详情
(VIII) 54871 (8S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3-dihydro-11H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione C23H19ClN2O6 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XI)

Condensation of 5-methoxy-1,3-dimethyl-2,3-dihydro-1H-indol-2-one (IV) with 2-chloroacetonitrile (XI) by means of a chiral phase transfer catalyst gives 2-(5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-y)-acetonitrile, which is separated into enantiomers by chromatography. Reductocyclization of the (S)-enantiomer (XII) by means of Vitride affords (3aS)-N1-noresermethole (XIII), which is submitted to a reductive methylation to provide esermethole (X). O-demethylation of (X) by means of BBr3 or AlCl3 gives eseroline (II), which is finally condensed with phenyl isocyanate.

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】 Greig, N.H.; Pei, X.-F.; Brossi, A.; Phenserine, a novel anticholinesterase related to physostigmine: Total synthesis and biological properties. Aust J Chem 1996, 49, 2, 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
(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
(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
(XI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XII) 58089 2-[(3S)-5-methoxy-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]acetonitrile C13H14N2O2 详情 详情
(XIII) 58090 (3aS,8aR)-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methyl ether; (3aS,8aR)-5-methoxy-3a,8-dimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole C13H18N2O 详情 详情

合成路线9

该中间体在本合成路线中的序号：(XXXI)

Glycidonitrile (XXXII) was prepared by condensation of ketone (XIV) with chloroacetonitrile (XXXI) under Darzens conditions. Epoxide ring opening in (XXXII) by HCl in toluene provided the chlorohydrin (XXXIII). Acetylation of (XXXIII), followed by dehydrohalogenation led to the acetoxy acrylonitrile (XXXIV). Hydrolysis and decarbonylation of (XXXIV) provided an alternative access to the arylpropionic acid (IX)

参考文献 中间体
合成目标
【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 .
【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 62687 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid C14H14O2S 详情 详情
(XIV) 62689 1-[4-(3-methyl-2-thienyl)phenyl]-1-ethanone C13H12OS 详情 详情
(XXXI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XXXII) 62703 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxiranecarbonitrile C15H13NOS 详情 详情
(XXXIII) 62704 3-chloro-2-hydroxy-3-[4-(3-methyl-2-thienyl)phenyl]butanenitrile C15H14ClNOS 详情 详情
(XXXIV) 62705 (Z)-1-cyano-2-[4-(3-methyl-2-thienyl)phenyl]-1-propenyl acetate C17H15NO2S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XI)

Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V). Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C. Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII). Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.

参考文献 中间体
合成目标
【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 .
【2】 Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586.
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) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 42524 5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid C12H12O3 详情 详情
(II) 42525 methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate C13H14O3 详情 详情
(III) 42526 methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate C14H15NO3 详情 详情
(IV) 42527 5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid C13H14O5 详情 详情
(V) 42528 (3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione C13H12O4 详情 详情
(VI) 42529 ethyl 4-(2-methoxyphenyl)butanoate C13H18O3 详情 详情
(VII) 42530 diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate C17H22O6 详情 详情
(VIII) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(IX) 42531 (3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C21H21NO3 详情 详情
(X) 42532 (3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole C13H17NO 详情 详情
(XI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(XII) 42533 (3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione C15H18N2O3 详情 详情
(XIII) 42534 3-hydroxy-2-pyrazinecarboxamide 55321-99-8 C5H5N3O2 详情 详情
(XIV) 42535 3-chloro-2-pyrazinecarbonitrile 55557-52-3 C5H2ClN3 详情 详情
(XV) 42536 3-chloro-2-cyanopyrazin-1-ium-1-olate C5H2ClN3O 详情 详情
(XVI) 23995 ethyl 2-sulfanylacetate 2713-34-0 C4H8O2S 详情 详情
(XVII) 42537 7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate C9H9N3O3S 详情 详情
(XVIII) 42538 ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate C9H8ClN3O2S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IX)

Reduction of morpholinone (I) with L-Selectride in THF at -78 C produced the intermediate lactol (II), which was condensed at low temperature with 3,5-bis(trifluoromethyl)benzoyl chloride (III) to afford acyl acetal (IV). Further reaction with dimethyl titanocene in THF-toluene at 80 C provided enol ether (V). Catalytic hydrogenation of the double bond, with concomitant N-benzyl group hydrogenolysis, yielded a 8:1 mixture of diastereomers, from which the major isomer (VI) was isolated by column chromatography. Alkylation of morpholine (VI) with N-methoxycarbonyl-2-chloroacetamidrazone (VII) (obtained by reaction of chloroacetonitrile (IX) with NaOMe and methyl carbazate in MeOH) in the presence of N-ethyl diisopropylamine (DIEA) in acetonitrile gave the intermediate (VIII), which was finally cyclized to the desired triazolone in refluxing xylene.

参考文献 中间体
合成目标
【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211.
【2】 Cowden, C.J.; et al.; A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist. Tetrahedron Lett 2000, 41, 44, 8661.
【4】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 .
【5】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 .
【6】 MacCoss, M.; Hale, J.J.; Mills, S.G.; et al.; Phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. J Med Chem 2000, 43, 6, 1234.
【7】 Dolling, U.H.; Wilson, R.D.; Hands, D.; Cottrell, I.F. (Merck Sharp & Dohme Ltd.); Chemical synthesis of morpholine derivs.. WO 9965900 .
【8】 Cowden, C.J. (Merck Sharp & Dohme Ltd.); Process for the preparation of 1,2,4-triazolin-5-one derivs.. WO 0196315 .
【3】 Hale, J.J.; Mills, S.G.; MacCoss, M.; Finke, P.E.; Cascieri, M.A.; Sadowski, S.; Ber, E.; Chicchi, G.G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N.N.; Tattersall, F.D.; Rupniak, N.M.; Williams, A.R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D.E.; Structural optimization affording 2-(R)-(1-(R)-3,5-bis(trifluoromethyl)phenylethoxy)-3(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J Med Chem 1998, 41, 23, 4607.
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) 18288 (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone C17H16FNO2 详情 详情
(II) 18289 (2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol C17H18FNO2 详情 详情
(III) 18290 3,5-Bis(trifluoromethyl)benzoyl chloride 785-56-8 C9H3ClF6O 详情 详情
(IV) 18291 (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate C26H20F7NO3 详情 详情
(V) 18292 (2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether C27H22F7NO2 详情 详情
(VI) 18293 (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine 171482-05-6 C20H18F7NO2 详情 详情
(VII) 18294 methyl (Z)-2-chloro-1-hydrazinoethylidenecarbamate C4H8ClN3O2 详情 详情
(VIII) 18295 methyl (Z)-2-[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholinyl]-1-hydrazinoethylidenecarbamate C24H25F7N4O4 详情 详情
(IX) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IV)

Alkylation of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (I) at the N-2 with 3-chlorobenzyl chloride (II) in the presence of NaH in DMF yielded the 2-benzyl derivative (III), which was further alkylated with chloroacetonitrile (IV) at the N-4 to provide the title compound.

参考文献 中间体
合成目标
【1】 Arranz, E.; Díaz, J.A.; Ingate, S.T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S.; Novel 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication. J Med Chem 1998, 41, 21, 4109.
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) 27304 1lambda(6)-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C5H4N2O3S2 详情 详情
(II) 20642 1-chloro-3-(chloromethyl)benzene; 3-Chlorobenzyl chloride 620-20-2 C7H6Cl2 详情 详情
(III) 27306 2-(3-chlorobenzyl)-2H-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C12H9ClN2O3S2 详情 详情
(IV) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

Alkylation of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (I) at the N-2 with 3-fluorobenzyl chloride (II) in the presence of NaH in DMF yielded the 2-benzyl derivative (III), which was further alkylated with chloroacetonitrile (IV) at the N-4 to provide the title compound.

参考文献 中间体
合成目标
【1】 Arranz, E.; Díaz, J.A.; Ingate, S.T.; Witvrouw, M.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Vega, S.; Novel 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleoside reverse transcriptase inhibitors that inhibit human immunodeficiency virus type 1 replication. J Med Chem 1998, 41, 21, 4109.
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) 27304 1lambda(6)-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C5H4N2O3S2 详情 详情
(II) 27307 3-fluorobenzyl chloride; 1-(chloromethyl)-3-fluorobenzene 456-42-8 C7H6ClF 详情 详情
(III) 27308 2-(3-fluorobenzyl)-2H-thieno[3,4-e][1,2,4]thiadiazine-1,1,3(2H,4H)-trione C12H9FN2O3S2 详情 详情
(IV) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

The condensation of 1-(4-chlorophenyl)piperazine (I) with 2-chloroacetonitrile (II) gives 2-[4-(4-chlorophenyl)-1-piperazinyl]acetonitrile (III), which is reduced with borane/dimethylsulfide yielding the corresponding primary amine (IV). Finally, (IV) is condensed with 3-methoxybenzoyl chloride.

参考文献 中间体
合成目标
【1】 Berardi, F.; Perrone, R.; Tortorella, V.; Leopoldo, M.; Colabufo, N.A.; A structure-affinity relationship study on derivatives of N-[2-[4-(chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a high-affinity and selective D4 receptor ligand. J Med Chem 2000, 43, 2, 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
(I) 33593 1-(4-chlorophenyl)piperazine 38869-46-4 C10H13ClN2 详情 详情
(II) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(III) 36530 2-[4-(4-chlorophenyl)-1-piperazinyl]acetonitrile C12H14ClN3 详情 详情
(IV) 28561 2-[4-(4-chlorophenyl)-1-piperazinyl]-1-ethanamine C12H18ClN3 详情 详情
(V) 16760 3-methoxybenzoyl chloride 1711-05-3 C8H7ClO2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(A)

Compound can be prepared in two different ways: 1) The cyclization of 1,2-cyclohexanedione mono-p-tolylhydrazone (I) by means of formic acid in DMF gives 1,2,3,4-tetrahydro-6-methylcarbazole-1-one (II), which by condensation with chloroacetonitrile (A) by means of sodium ethoxide in dioxane is converted into 1,2,3,4-tetrahydro-6-methyl-9-cyanomethylcarbazole-1-one (III). Finally, this compound is submitted to a reductive cyclization with H2 over Raney-Ni in methanol at 30 atm. and 50 C. 2) The carbazolone (II) can also be condensed with 2-bromoacetaldehyde dibutylacetal (B) by means of sodium ethoxide to afford 1,2,3,4-tetrahydro-6-methyl-9-(beta,beta-dibutoxyethyl)carbazole-1-one (IV), which is cyclized with ammonium acetate in acetic acid yielding 1,2,5,6-tetrahydromethylpyrazino[3,2,1-j,k]-4H-carbazole (V). Finally, this compound is reduced with H2 over Pd/C.

参考文献 中间体
合成目标
【1】 Blancafort, P.; Castañer, J.; Thorpe, P.J.; Serradell, M.N.; Pirlindole. Drugs Fut 1980, 5, 1, 39.
【2】 Shvedov, V.I.; et al.; Synhtesis of 1,10-trimethylenepyrazino[1,2-a]indoles. Khim Farm Zh 1967, 1, 3, 25-30.
【3】 Mashkovskii, M.D.; et al.; New antidepressive preparation pyrozindole. Khim Farm Zh 1974, 8, 3, 60-63.
【4】 Mashkovskii, M.D.; et al.; GB 1340528 .
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) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(I) 39030 1,2-cyclohexanedione 1-[N-(4-methylphenyl)hydrazone] C13H16N2O 详情 详情
(II) 39031 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one C13H13NO 详情 详情
(III) 39032 2-(6-methyl-1-oxo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)acetonitrile C15H14N2O 详情 详情
(IV) 39033 1-(2-bromo-1-butoxyethoxy)butane; 2-bromo-1-butoxyethyl butyl ether C10H21BrO2 详情 详情
(V) 39034 9-(2,2-dibutoxyethyl)-6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one C23H33NO3 详情 详情
(VI) 39035 8-methyl-2,4,5,6-tetrahydro-1H-pyrazino[3,2,1-jk]carbazole C15H16N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The reaction of 8-chloro-3,4,5,6-tetrahydro-2H-1,6-benzothiazocine (I) with chloroacetonitrile (II) by means of Na2CO3 at 90 C gives 8-chloro-6-cyanomethyl-3,4,5,6-tetrahydro-2H-1,6-benzothiazocine (III), which is cyclized with N-isopropylethylenediamine (IV) by heating at 110 C with some CS2

参考文献 中间体
合成目标
【1】 Zivkovic, D. (UCB (Union Chimique-Chemisque Bedrijven) S.A.); BE 727977; CA 897161; DE 1905525; GB 1191963; JP 7213912; NL 6901745; US 366927 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Koch, H.; Dazolicine. Drugs Fut 1981, 6, 9, 540.
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) 60977 8-chloro-3,4,5,6-tetrahydro-2H-1,6-benzothiazocine C10H12ClNS 详情 详情
(II) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(III) 60978 2-(8-chloro-2,3,4,5-tetrahydro-6H-1,6-benzothiazocin-6-yl)acetonitrile C12H13ClN2S 详情 详情
(IV) 50979 (8R,9S,13S,14S)-3-(benzyloxy)-16-[(Z)-hydroxymethylidene]-13-methyl-7,8,9,11,12,13,14,15-octahydro-6H-cyclopenta[a]phenanthren-17-one C26H28O3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

BI-1356 can be synthesized as follows. Cyclization of 2-aminoacetophenone (I) with chloroacetonitrile (II) in the presence of HCl in dioxane gives 2-(chloromethyl)-4-methylquinazoline (III) (1), which can also be prepared by reaction of 2-(chloromethyl)-4-methylquinazoline-3-oxide (IV) with PCl3 in refluxing chloroform (2). Coupling of the quinazoline derivative (III) with 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (V) –prepared by treatment of 8-bromo-3-methylxanthine (VI) with butyn-2-yl bromide (VII) in the presence of TEA or DIEA in DMF (3)–, in the presence of Na2CO3 or K2CO3 provides 1-(4-methylquinazolin-2-ylmethyl)-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (VIII). Condensation of bromoxanthine (VIII) with (R)-3-(phthalimido)piperidine D-tartrate (IX) affords the adduct (X), which is deprotected by heating with 2-aminoethanol in either toluene at 85 ºC or in THF at 65 ºC (1). Scheme 1.
The title compound can also be prepared by coupling of the bromoxanthine (VIII) with 3(R)-(tert-butoxycarbonylamino)piperidine (XI) by means of K2CO3 in DMF to give the N-protected piperidine derivative (XII), which is deprotected with TFA in CH2Cl2 (2, 3). Scheme 1.

参考文献 中间体
合成目标
【1】 Pfrengle, W., Pachur, T., Nicola, T., Duran, A. (Boehringer Ingelheim Corp.). Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)xanthines. US 2006142310.
【2】 Himmelsbach, F., Langkopf, E., Eckhardt, M., Mark, M. Maier, R., Lotz, R.R.H., Tadayyon, M. (Boehringer Ingelheim Corp.). 8-[3-Amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions. US 2004097510.
【3】 Eckhardt, M., Langkopf, E., Mark, M. et al. 8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem 2007, 50(26): 6450-3.
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) 65634 2-Aminoacetophenone;2'-Aminoacetophenone; o-Aminoacetophenone; 1-(2-Aminophenyl)ethanone 551-93-9 C8H9NO 详情 详情
(II) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(III) 65635 2-(Chloromethyl)-4-methylquinazoline 109113-72-6 C10H9ClN2 详情 详情
(IV) 65636 　 　 C10H9ClN2O 详情 详情
(V) 65637 　 　 C10H11BrN4O2 详情 详情
(VI) 65638 　 　 C6H7BrN4O2 详情 详情
(VII) 29428 1-bromo-2-butyne 3355-28-0 C4H5Br 详情 详情
(VIII) 65639 　 　 C20H19BrN6O2 详情 详情
(IX) 65640 　 　 C14H14N2O2.C4H4O6 详情 详情
(X) 65641 　 　 C33H32N8O4 详情 详情
(XI) 65642 (R)-3-(Boc-Amino)piperidine; (R)-(+)-3-tert-Butoxycarbonylaminopiperidine 309956-78-3 C10H20N2O2 详情 详情
(XII) 65643 　 　 C30H38N8O4 详情 详情
Extended Information