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【结 构 式】

【分子编号】14061

【品名】Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride

【CA登记号】4023-34-1

【 分 子 式 】C4H5ClO

【 分 子 量 】104.5358

【元素组成】C 45.96% H 4.82% Cl 33.91% O 15.31%
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：(B)

The hydrogenation of 7-acetyl-6,14-endoetheno-6,7,8,14-tetrahydrothebaine (I) with H2 over Pd/C in acetic acid gives the corresponding endo-ethano derivative (II), which by a Grignard reaction with tertbutyl-magnesium chloride (A) in ether-benzene yields 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine (III). The reaction of III with BrCN in CH2Cl2 affords 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-N-cyano-6,7,8,14-tetrahydronorthebaine (IV), which is treated with KOH in ethylene glycol at 170 C to give 7alpha(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine (V). This compound is treated first with cyclopropylcarbonyl chloride (B) in CH2Cl2 containing triethylamine, followed by a reduction with LiAlH4 in refluxing THF yielding N-cyclopropylmethyl-7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro-northebaine (VI). Finally, (VI) is demethylated with KOH in diethylene glycol at 210-220 C.

参考文献 中间体
合成目标
【1】 Bentley, K.W.; Thebaine and Oripavine derivatives. CH 558362; DE 1620206; FR 6395M; GB 1136214 .
【2】 Castaner, J.; Paton, D.M.; Buprenorphine. Drugs Fut 1977, 2, 9, 570.
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) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(A) 15459 tert-butyl(chloro)magnesium 677-22-5 C4H9ClMg 详情 详情
(I) 33912 1-[(1R,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11,18-tetraen-16-yl]-1-ethanone C23H27NO4 详情 详情
(II) 33913 1-[(1S,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-1-ethanone C23H29NO4 详情 详情
(III) 33914 (2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol C27H39NO4 详情 详情
(IV) 33915 (2R)-2-[(1S,2S,6R,14R,15S,16R)-5-cyano-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol C27H36N2O4 详情 详情
(V) 33916 (2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol C26H37NO4 详情 详情
(VI) 33917 (2R)-2-[(1S,2S,6R,14R,15S,16R)-5-(cyclopropylmethyl)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol C30H43NO4 详情 详情

合成路线2

该中间体在本合成路线中的序号：(B)

Compound can be prepared in two different ways both starting from 14-hydroxydihydronormorphinone (I): 1) By reaction of (I) with cyclopropylmethyl bromide (C) in DMF at 70 C. 2) Product (I) is ketalized with ethylene glycol (A) by means of p-toluenesulfonic acid giving the cyclic ketal (II), m.p. 311-3 C; this in turn, is treated with cyclopropyl carbonyl chloride (B) in a mixture of methylene chloride and triethylamine yielding the N,O-dicyclopropylcarbonyl derivative (III), mp 219-20 C. Compound (III) is reduced with LiAlH4, in refluxing THF yielding the ethylene ketal of naltrexone (IV), m.p. 221-2 C, which is finally hydrolyzed with aqueous HCl at 100 C.

参考文献 中间体
合成目标
【1】 Blumberg, H.; et al.; 14-Hydroxydihydronormorphinone derivatives. US 3332950 .
【2】 Blumberg, H.; et al.; Verfahren zur Herstellung von N-substituierten 14-Hydroxydidronormorphinen. CH 493522; DE 1670616; DE 1795707; GB 1119270 .
【3】 Derives de 14-hydroxydihydronormorphinones. FR 6358M .
【4】 Castaner, J.; Roberts, P.J.; Naltrexone. Drugs Fut 1977, 2, 1, 45.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(B) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(I) 33610 (1S,5R,13R,17R)-10,17-dihydroxy-12-oxa-4-azapentacyclo[9.6.1.0(1,13).0(5,17).0(7,18)]octadeca-7(18),8,10-trien-14-one C16H17NO4 详情 详情
(II) 33611 　 C18H21NO5 详情 详情
(III) 33612 　 C26H29NO7 详情 详情
(IV) 33613 　 C22H27NO5 详情 详情
(C) 22277 Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 7051-34-5 C4H7Br 详情 详情

合成路线3

该中间体在本合成路线中的序号：

1-Acetyl-4-piperidone (I) is condensed with 2-chlorocyanoacetophenone in the presence of sulfur and base to give the thiophene (II). Treatment of (II) with 2-bromopropionyl bromide gives the amide (III), which on reaction with ammonia gives the amine (IV). Cyclization of (IV) with acetic acid/pyridine gives the diazepine (V). Reaction of the amide of (V) with phosphorus pentasulfide or Lawesson's reagent produces the thioamide (VI), which is reacted with acetic hydrazide to give the triazole (VII). Basic hydrolysis of the amide of (VII) produces the amine (VIII), which is resolved to give the S-enantiomer (IX). Reaction of (IX) with cyclopropanecarbonyl chloride gives the amide (X).

参考文献 中间体
合成目标
【1】 1,4-Diazepine deriv. and its pharmaceutical use. AU 8943761; EP 0367110; EP 0606103; EP 0677524; JP 1990256682; US 5221671; US 5304553; US 5382579; US 5409909; US 5438045; US 5468740; US 5482937 .
【2】 Clark, R.S.J.; E6123. Drugs Fut 1991, 16, 4, 310.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12923 3-(2-Chlorophenyl)-3-oxopropanenitrile 40018-25-5 C9H6ClNO 详情 详情
14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(I) 14050 N-Acetyl-4-piperidone; 1-Acetyltetrahydro-4(1H)-pyridinone 32161-06-1 C7H11NO2 详情 详情
(II) 14051 1-[2-Amino-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridin-6(5H)-yl]-1-ethanone C16H15ClN2O2S 详情 详情
(III) 14052 N-[6-Acetyl-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]-2-bromopropanamide C19H18BrClN2O3S 详情 详情
(IV) 14053 N-[6-Acetyl-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]-2-aminopropanamide C19H20ClN3O3S 详情 详情
(V) 14054 8-Acetyl-5-(2-chlorophenyl)-3-methyl-1,3,6,7,8,9-hexahydro-2H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepin-2-one C19H18ClN3O2S 详情 详情
(VI) 14055 5-(2-Chlorophenyl)-8-ethanethioyl-3-methyl-1,3,6,7,8,9-hexahydro-2H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-2-thione C19H18ClN3S3 详情 详情
(VII) 14056 1-[6-(2-Chlorophenyl)-1,4-dimethyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-9(8H)-yl]-1-ethanethione C21H20ClN5S2 详情 详情
(VIII) 14057 6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine C19H18ClN5S 详情 详情
(IX) 14058 (4S)-6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine C19H18ClN5S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(III)

A large-scale production method (kg scale) for E-6123 has been reported: The optical resolution of racemic 6-(2-chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (I), prepared by the previously reported method, by crystallization of its salt with (+)-(D)-dibenzoyltartaric acid in ethanol and treatment with aqueous NaHCO3 gives the corresponding (S)-isomer (II), which is then acylated with cyclopropanecarbonyl chloride (III) and pyridine in dichloromethane.

参考文献 中间体
合成目标
【1】 Miyazawa, S.; Shimomura, N.; Okano, K.; et al.; A practical synthesis of optically active platelet-activating factor antagonist, E6123, and its absolute configuration. Chem Pharm Bull 1992, 40, 2, 521.
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) 14057 6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine C19H18ClN5S 详情 详情
(II) 14058 (4S)-6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine C19H18ClN5S 详情 详情
(III) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

1) Racemic igmesine has been synthesized as follows: Alkylation of 2-phenylbutyric acid (I) with cinnamyl bromide (II) by means of butyllithium in THF gives 2-ethyl-2,5-diphenyl-4-pentenoic acid (III), which is treated with sodium azide and phenyl dichlorophosphate in dichloromethane, yielding the corresponding azide (IV). The Curtius rearrangement of (IV) in refluxing toluene affords the isocyanate (V), which is reduced with LiAlH4/AlCl3 in THF to give N-(1-ethyl-1,4-diphenyl-3-butenyl)-N-metylamine (VI). The acylation of (VI) with cyclopropanecarbonyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding amide (VIII), which is finally reduced with LiAlH4/AlCl3 in THF/ethyl ether.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Igmesine Hydrochloride . Drugs Fut 1999, 24, 2, 133.
【2】 Aubard, G.; Calvet, A.; Gouret, C.; Grouhel, A.; Jacobelli, H.; Junien, J.-L. (Jouveinal SA); Disubstituted benzylamines, process for their preparation, their use as medicament and their synthesis intermediates. EP 0361990; EP 0362001; FR 2636625; US 5034419; US 5089639 .
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) 21130 2-Phenylbutyric acid; alpha-Ethylbenzeneacetic acid 90-27-7 C10H12O2 详情 详情
(II) 21131 1-[(E)-3-bromo-1-propenyl]benzene 4392-24-9 C9H9Br 详情 详情
(III) 21132 (E)-2-ethyl-2,5-diphenyl-4-pentenoic acid C19H20O2 详情 详情
(IV) 21133 (E)-2-ethyl-2,5-diphenyl-4-pentenoyl azide C19H19N3O 详情 详情
(V) 21134 1-[(E)-1-ethyl-1-isocyanato-4-phenyl-3-butenyl]benzene; (E)-1-ethyl-1,4-diphenyl-3-butenyl isocyanate C19H19NO 详情 详情
(VI) 21135 (rac)-[(E)-N-methyl-3,6-diphenyl-5-hexen-3-amine]; (rac)-[N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylamine] C19H23N 详情 详情
(VII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(VIII) 21137 (rac)-[N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylcyclopropanecarboxamide] C23H27NO 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

2) Igmesine has been synthesized as follows: Hydrolysis of the previously described isocyanate (V) with HCl in refluxing THF/water gives the corresponding amine (IX), which is submitted to optical resolution with L-(-)tartaric acid, yielding the (+)-isomer (+)-(IX). The acylation of (+)-(IX) with formic acid and carbonyldiimidazole (CDI) affords the expected formamide (+)-(X), which is reduced with AlAl3/LiAlH4 in THF/ethyl ether, giving (-)-N-(1-ethyl-1,4-diphenyl-3-butenyl)-N-metylamine (-)-(VI). The condensation of (-)-(VI) with cyclopropanecarbonyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding amide (+)-(VIII), which is finally reduced with AlCl3/LiAlH4 in THF/ethyl ether.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Igmesine Hydrochloride . Drugs Fut 1999, 24, 2, 133.
【2】 Aubard, G.; Calvet, A.; Gouret, C.; Grouhel, A.; Jacobelli, H.; Junien, J.-L. (Jouveinal SA); Disubstituted benzylamines, process for their preparation, their use as medicament and their synthesis intermediates. EP 0361990; EP 0362001; FR 2636625; US 5034419; US 5089639 .
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) 64672 (E)-1-ethyl-1,4-diphenyl-3-butenylamine; (E)-3,6-diphenyl-5-hexen-3-amine C18H21N 详情 详情
(+)-(X) 64673 (E)-1-ethyl-1,4-diphenyl-3-butenylformamide C19H21NO 详情 详情
(-)-(VI) 64674 (E)-N-methyl-3,6-diphenyl-5-hexen-3-amine; N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylamine C19H23N 详情 详情
(+)-(VIII) 64675 N-[(E)-1-ethyl-1,4-diphenyl-3-butenyl]-N-methylcyclopropanecarboxamide C23H27NO 详情 详情
(V) 21134 1-[(E)-1-ethyl-1-isocyanato-4-phenyl-3-butenyl]benzene; (E)-1-ethyl-1,4-diphenyl-3-butenyl isocyanate C19H19NO 详情 详情
(VII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(IX) 21138 (rac)-(E)-3,6-diphenyl-5-hexen-3-amine; (rac)-[(E)-1-ethyl-1,4-diphenyl-3-butenylamine] C18H21N 详情 详情

合成路线7

该中间体在本合成路线中的序号：(XXVII)

6) Mass labeled saprisartan has been obtained as follows: The Wittig condensation of cyclopropylcarbonyl chloride (XXVII) with ethoxycarbonylmethylene triphenylphosphorane (XXVIII) by means of bis(trimethylsilyl)acetamide in dichloromethane gives 3-cyclopropyl-3-oxo-2-(triphenylphosphoranylidene)propionic acid ethyl ester (XXIX), which is oxidized with potassium peroxymonosulfate to the dicarbonyl compound (XXX). The cyclization of (XXX) with [all-13C]-propionaldehyde (XXXI) (obtained by hydrogenation of the corresponding acyl chloride (XXXII) with H2 over Pd/C in THF containing 2,6-lutidine) and [15N]-ammonium acetate by means of triethylamine in THF yields 4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIII). The condensation of (XXXIII) with the benzofuran (XXI) (already described in Scheme 2) by means of K2CO3 in dimethylacetamide affords 1-[3-bromo-2-(2-nitrophenyl)benzofuran-5-ylmethyl]-4-cyclopropyl-2-[1,2-13C]-ethyl-[1,3-15N,2-13C]imidazole-5-carboxylic acid ethyl ester (XXXIV), which is finally treated sequentially with Fe and acetic acid to reduce the nitro group, with trifluoromethanesulfonic anhydride to acylate the amino group, with NaOH to hydrolyze the ester group, and with carbonyldiimidazole and ammonia to generate the amide group, thus obtaining mass labeled saprisartan. This sequence has already been described in Scheme 19090802a for the unlabeled compound.

参考文献 中间体
合成目标
【1】 Carr, R.M.; Cable, K.M.; Newman, J.J.; Sutherland, D.R.; Synthesis of isotopically labelled angiotensin II antagonist GR138950X. J Label Compd Radiopharm 1996, 38, 5, 453.
【2】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Saprisartan. Drugs Fut 1996, 21, 11, 1129.
【3】 Ross, B.C.; Middlemiss, D.; Scopes, D.I.C.; Jack, T.I.M.; Cardwell, K.S.; Dowle, M.D.; Judd, D.B.; Watson, S.P. (Glaxo Wellcome plc); 1H-Imidazol-1-yl-methyl benzofuran derivs. with the imidazolyl moiety being substd. by a cycloalkyl group. EP 0514198; JP 1994211846; US 5498722; WO 9220674 .
【4】 Judd, D.B.; Dowle, M.D.; Middlemiss, D.; et al.; Bromobenzofuran-based non-peptide antagonists of angiotensin II: GR138950, a potent antihypertensive agent with high oral bioavailability. J Med Chem 1994, 37, 19, 3108-20.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 15956 3-bromo-5-(bromomethyl)-2-(2-nitrophenyl)-1-benzofuran C15H9Br2NO3 详情 详情
(XXVII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XXVIII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(XXIX) 15964 ethyl 3-cyclopropyl-3-oxo-2-(triphenyl-lambda(5)-phosphanylidene)propanoate C26H25O3P 详情 详情
(XXX) 15965 ethyl 3-cyclopropyl-2,3-dioxopropanoate C8H10O4 详情 详情
(XXXI) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(XXXI) 45291 propionaldehyde C3H6O 详情 详情
(XXXII) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(XXXII) 45290 propanoyl chloride C3H5ClO 详情 详情
(XXXIII) 15944 ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C11H16N2O2 详情 详情
(XXXIII) 15968 ethyl 4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C11H16N2O2 详情 详情
(XXXIV) 15957 ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C26H24BrN3O5 详情 详情
(XXXIV) 15969 ethyl 1-[[3-bromo-2-(2-nitrophenyl)-1-benzofuran-5-yl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxylate C26H24BrN3O5 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XIII)

4) The Friedel-Crafts condensation of cyclopropylcarbonyl chloride (XIII) with 2-methyl-2-phenylpropionic acid ethyl ester (XIV) gives 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropionic acid ethyl ester (XV), which by reaction with dry HCl in hot acetonitrile yields the 4-chlorobutyryl derivative (XVI). The condensation of (XVI) with the piperidine (VI) by means of KHCO3 affords the omega-piperidylbutyrophenone (XVII), which is reduced with NaBH4 in methanol to give the dihydroxy ester (XVIII). Finally, this compound is saponified with NaOH in refluxing methanol. 5) The chlorobutyryl derivative (XVI) can also be obtained by direct Friedel-Crafts condensation of propionic ester (XIV) with 4-chlorobutyryl chloride (IV) by means of AlCl3 as before.

参考文献 中间体
合成目标
【1】 Graul, A.; Castañer, J.; Fexofenadine Hydrochloride. Drugs Fut 1996, 21, 10, 1017.
【2】 Krauss, R.C.; Strom, R.M.; Scortichini, C.L.; Kruper, W.J.; Wolf, R.A.; Carr, A.A.; Rudisill, D.E.; Panzone, G.; Hay, D.A.; Wu, W.W. (Merrell Pharmaceuticals, Inc.); Novel intermediates for the preparation of antihistaminic 4-diphenylmethyl/diphenylmethoxy piperidine derivs. WO 9500480 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 11265 4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride 4635-59-0 C4H6Cl2O 详情 详情
(VI) 17178 diphenyl(4-piperidinyl)methanol; alpha,alpha-Diphenyl-4-piperidinomethanol; Azacyclonol 115-46-8 C18H21NO 详情 详情
(XIII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XIV) 17609 ethyl 2-methyl-2-phenylpropanoate C12H16O2 详情 详情
(XV) 17610 ethyl 2-[4-(cyclopropylcarbonyl)phenyl]-2-methylpropanoate C16H20O3 详情 详情
(XVI) 17611 ethyl 2-[4-(4-chlorobutanoyl)phenyl]-2-methylpropanoate C16H21ClO3 详情 详情
(XVII) 17612 ethyl 2-[4-(4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butanoyl)phenyl]-2-methylpropanoate C34H41NO4 详情 详情
(XVIII) 17613 ethyl 2-[4-(1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidinyl]butyl)phenyl]-2-methylpropanoate C34H43NO4 详情 详情

合成路线9

该中间体在本合成路线中的序号：(I)

The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of (IV) with 3-hydroxy-4,5-dimethoxybenzaldehyde (V) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (VI), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol. (1)

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castañer, J.; Rabasseda, X.; Iclaprim. Drugs Fut 2004, 29, 3, 220.
【2】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 .
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) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(II) 27189 trimethyl[2-(trimethylsilyl)ethynyl]silane 14630-40-1 C8H18Si2 详情 详情
(III) 27190 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one C9H14OSi 详情 详情
(IV) 27191 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol C9H16OSi 详情 详情
(V) 27192 3-hydroxy-4,5-dimethoxybenzaldehyde C9H10O4 详情 详情
(VI) 27193 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzaldehyde C18H24O4Si 详情 详情
(VII) 27194 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde C15H16O4 详情 详情
(VIII) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IX) 27196 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile C24H24N2O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 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 reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of propynol (IV) with 3-hydroxy-4,5-dimethoxybenzoic acid methyl ester (XI) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (XII), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylic acid methyl ester (XIII). Finally, this compound is reduced with NaAlH2(OCH2CH2)2 and morpholine in toluene to give the previously described 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol.

参考文献 中间体
合成目标
【1】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 .
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) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(II) 27189 trimethyl[2-(trimethylsilyl)ethynyl]silane 14630-40-1 C8H18Si2 详情 详情
(III) 27190 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one C9H14OSi 详情 详情
(IV) 27191 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol C9H16OSi 详情 详情
(VII) 27194 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde C15H16O4 详情 详情
(VIII) 27195 3-anilinopropanenitrile 1075-76-9 C9H10N2 详情 详情
(IX) 27196 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile C24H24N2O3 详情 详情
(X) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(XI) 27197 methyl 3-hydroxy-4,5-dimethoxybenzoate C10H12O5 详情 详情
(XII) 27198 methyl 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzoate C19H26O5Si 详情 详情
(XIII) 27199 methyl 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylate C16H18O5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(X)

The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acylation of (IX) at C-10 hydroxyl group with cyclopropanecarbonyl chloride (X) in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.

参考文献 中间体
合成目标
【1】 Lin, S.; et al.; Syntheses and biological activity of advanced second-generation taxoids. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 315.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 21735 tert-butyl (2R,3R)-2-(difluoromethyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate C18H33F2NO4Si 详情 详情
(VIII) 10467 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 32981-86-5 C29H36O10 详情 详情
(IX) 21737 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C35H50O10Si 详情 详情
(X) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XI) 21783 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-12-[(cyclopropylcarbonyl)oxy]-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C39H54O11Si 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VII)

Esterification of 4-fluoro-3-nitrobenzoic acid (I) with MeOH in the presence of SOCl2 provided the methyl ester (II). Subsequent displacement of the fluoro group with the imidazolyl piperidine (III) gave adduct (IV), which was further protected as the N-trityl derivative (V) using triphenylmethyl chloride and N-methylmorpholine. Catalytic hydrogenation of the nitro group of (V) over Raney-Ni produced aniline (VI), which was acylated with cyclopropanecarbonyl chloride (VII) to furnish amide (VIII). After basic hydrolysis of the methyl ester group of (VIII), the resultant carboxylic acid (IX) was coupled with N,N-dimethyl ethanediamine (X) using PyBOP to yield amide (XI). Finally, acidic treatment of (XI) with HOAc removed the N-trityl protecting group.

参考文献 中间体
合成目标
【1】 Hoornaert, C.; Rouannet, V.; Dellac, G.; Daumas, M.; Adler, M.-A.; Cremer, G. (Sanofi-Synthelabo); 4-[(1H-Imidazol-4-yl)piperidin-1-yl]anilide derivs., their preparation and application in therapy. EP 0991639; WO 9900379 .
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) 46937 4-fluoro-3-nitrobenzoic acid 453-71-4 C7H4FNO4 详情 详情
(II) 46938 methyl 4-fluoro-3-nitrobenzoate C8H6FNO4 详情 详情
(III) 46939 4-(5-methyl-1H-imidazol-4-yl)piperidine C9H15N3 详情 详情
(IV) 46940 methyl 4-[4-(5-methyl-1H-imidazol-4-yl)-1-piperidinyl]-3-nitrobenzoate C17H20N4O4 详情 详情
(V) 46945 methyl 4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]-3-nitrobenzoate C36H34N4O4 详情 详情
(VI) 46941 methyl 3-amino-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoate C36H36N4O2 详情 详情
(VII) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(VIII) 46942 methyl 3-[(cyclopropylcarbonyl)amino]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoate C40H40N4O3 详情 详情
(IX) 46943 3-[(cyclopropylcarbonyl)amino]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzoic acid C39H38N4O3 详情 详情
(X) 14881 N-(2-aminoethyl)-N,N-dimethylamine; N(1),N(1)-dimethyl-1,2-ethanediamine; 2-Dimethylaminoethylamine 108-00-9 C4H12N2 详情 详情
(XI) 46944 3-[(cyclopropylcarbonyl)amino]-N-[2-(dimethylamino)ethyl]-4-[4-(5-methyl-1-trityl-1H-imidazol-4-yl)-1-piperidinyl]benzamide C43H48N6O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

Malonic acid monoethyl ester (I) is converted into beta-ketoester (III) by formation of the corresponding trimethylsilyl ester with TMSCl and pyridine in ether followed by deprotonation with n-BuLi and acylation with cyclopropanecarbonyl chloride (II) in DME. Treatment of (III) with refluxing N,N-dimethylformamide dimethyl acetal (IV) affords enamine (V). Quinoline-5-amine (VI) is first subjected to diazotation by treatment with NaNO2 in H2O/HCl, reduced with SnCl2.2H2O in HCl and isolated as the corresponding dihydrochloride salt (VII) by treatment with HCl. Condensation of enamine (V) with hydrazine (VII) in the presence of Et3N in refluxing EtOH yields pyrazole ester (VIII), which is converted into acylguanidine (X) either by direct heating with guanidine (IX) in EtOH or by first transformation into the corresponding carboxylic acid (XI) by saponification with NaOH in refluxing MeOH, followed by treatment with refluxing thionyl chloride and reaction with guanidine hydrochloride (XII) under Schotten-Baumann conditions in refluxing THF/NaOH. Finally, treatment of the free base (X) with HCl in THF allows isolation of the corresponding monohydrochloride-monohydrate salt .

参考文献 中间体
合成目标
【1】 Wester, R.T.; Allen, M.C.; Guzman-Perez, A.; et al.; Discovery of zoniporide: A potent and selective sodium-hydrogen exchanger type 1 (NHE-1) inhibitor with high aqueous solubility. Bioorg Med Chem Lett 2001, 11, 6, 803.
【2】 Guzman-Perez, A.; Ruggeri, R.B.; Wester, R.T.; Hamanaka, E.S.; Mularski, C.J. (Pfizer Inc.); N-[(Substd. five-membered di- or triaza diunsaturated ring)carbonyl] guanidine derivs. for the treatment of ischemia. EP 1056729; WO 9943663 .
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),(XII) 14790 Guanidine 113-00-8 CH5N3 详情 详情
(I) 15086 3-ethoxy-3-oxopropionic acid 1071-46-1 C5H8O4 详情 详情
(II) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(III) 15949 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate 24922-02-9 C8H12O3 详情 详情
(IV) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(V) 48913 ethyl (Z)-3-amino-2-(cyclopropylcarbonyl)-2-propenoate C9H13NO3 详情 详情
(VI) 26799 5-Aminoquinoline; 5-quinolinamine 611-34-7 C9H8N2 详情 详情
(VII) 48914 5-hydrazinoquinoline C9H9N3 详情 详情
(VIII) 48915 ethyl 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylate C18H17N3O2 详情 详情
(X) 48917 N''-[[5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazol-4-yl]carbonyl]guanidine C17H16N6O 详情 详情
(XI) 48916 5-cyclopropyl-1-(5-quinolinyl)-1H-pyrazole-4-carboxylic acid C16H13N3O2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

Paclitaxel (I) was sequentially protected at the 2'-O with tert-butyldimethylsilyl chloride and imidazole and then at the 7-O with triethylsilyl chloride to afford the bis-silyl derivative (II). Selective hydrolysis of the benzoate ester group of (II) using Triton B provided (III). The vicinal 1,2-diol group of (III) was protected as the cyclic carbonate (IV) by treatment with either triphosgene or carbonyldiimidazole. The remaining free hydroxyl group of (IV) at position 4 was then acylated with cyclopropanecarbonyl chloride (V) in the presence of lithium hexamethyldisilazide to furnish the corresponding ester (VI). Subsequent deprotection of the cyclic carbonate ester of (VI) was achieved by selective hydrolysis with LiOH to afford diol (VII). Regioselective acylation of (VII) on the 2-hydroxyl with 2,4-difluorobenzoic acid (VIII) and DCC produced ester (IX). The final desilylation step was performed by treatment with HF-pyridine.

参考文献 中间体
合成目标
【1】 Johnston, K.A.; Kingston, D.G.I.; Chordia, M.D.; Fairchild, C.R.; Kadow, J.F.; Long, B.H.; Yuan, H.; Jagtap, P.G.; Synthesis and bioactivity of 2,4-diacyl analogues of paclitaxel. Bioorg Med Chem 2001, 9, 1, 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) 48197 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,4,9-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C45H49NO13 详情 详情
(II) 48198 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-1,4-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C57H77NO13Si2 详情 详情
(III) 48199 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,2,4-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoate C50H73NO12Si2 详情 详情
(IV) 48200 (1S,5S,6R,7S,10R,12S,13S,15R,18S)-15-(acetoxy)-7-hydroxy-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-18-yl (2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoate C51H71NO13Si2 详情 详情
(V) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(VI) 48201 (1S,5S,6R,10R,12S,13S,15R,18S)-15-(acetoxy)-18-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-7-yl cyclopropanecarboxylate C55H75NO14Si2 详情 详情
(VII) 48202 (1S,2S,3R,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-1,2-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-4-yl cyclopropanecarboxylate C54H77NO13Si2 详情 详情
(VIII) 35123 2,4-difluorobenzoic acid 1583-58-0 C7H4F2O2 详情 详情
(IX) 48203 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylpropanoyl)oxy]-4-[(cyclopropylcarbonyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl 2,4-difluorobenzoate C61H79F2NO14Si2 详情 详情

合成路线15

该中间体在本合成路线中的序号：(III)

The chlorination of cyclohexane-1,3-dione (I) with chloramine T in acetonitrile gives 2-chlorocyclohexane-1,3-dione (II), which is finally condensed with cyclopropanecarbonyl chloride (III) by means of potassium tert-butoxide in THF to yield the target cyclohexenyl ester.

参考文献 中间体
合成目标
【1】 Wu, C.-S.; Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y.; Lin, S.-W.; Lin, Y.-L.; SAR studies of 3-cyclopropanecarbonyloxy-2-cyclohexen-1-one as inhibitors of 4-hydroxyphenylpyruvate dioxygenase. Bioorg Med Chem 2002, 10, 3, 685.
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) 11244 1,3-Cyclohexanedione 504-02-9 C6H8O2 详情 详情
(II) 54418 2-chloro-1,3-cyclohexanedione C6H7ClO2 详情 详情
(III) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情

合成路线16

该中间体在本合成路线中的序号：(X)

Reaction of 2-carboxybenzaldehye (I) with dimethyl phosphite in the presence of MeONa in MeOH affords the isobenzofuranylphosphonate (II), which is condensed with 2-fluoro-5-formylbenzonitrile (III) by means of triethylamine in THF to give the benzylidene-isobenzofuranone (IV). Basic hydrolysis of the nitrile group of compound (IV) followed by treatment with hydrazine hydrate leads to the phthalazinone-carboxylic acid (V) (1-3), which can also be obtained by treatment of isobenzofuranone (IV) first with hydrazine hydrate in THF, followed by hydrolysis of the resulting phthalazinone nitrile (VI) with aqueous NaOH (2). Coupling of carboxylic acid (V) with N-Boc-piperazine (VII) by means of HBTU and DIEA in dimethylacetamide yields the Boc-protected amide (VIII), which is then deprotected to compound (IX) by treatment with HCl in EtOH or MeOH. Finally, piperazine-phthalazinone (IX) is acylated with cyclopropanecarbonyl chloride (X) in the presence of triethylamine or DIEA in CH2Cl2 (1, 2). Alternatively, condensation of piperazine (XI) with cyclopropanecarbonyl chloride (X) in AcOH solution gives N-(cyclopropylcarbonyl)piperazine (XII) (2), which is then coupled with the phthalazinone-carboxylic acid (V) by means of HBTU and DIEA in acetonitrile or dimethylacetamide (2, 3). Scheme 1.

参考文献 中间体
合成目标
【1】 Martin, N.M.B., Smith, G.C.M., Jackson, S.P. et al. (KuDOS Pharmaceuticals Ltd.; Maybridge Ltd.). Phthalazinone derivatives. CA 2517629, EP 1633724, GB 2415430, JP 2006519837, JP 2008001718, US 2005059663, US 2006149059, US 2008200469, US 7449464, WO 2004080976.
【2】 Menear, K.A., Ottridge, A.P., Londesbrough, D.J. et al. (KuDOS Pharmaceuticals Ltd.). Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one. US 2008146575, WO 2008047082.
【3】 Menear, K.A., Adcock, C., Boulter, R. et al. 4-[3-(4-Cyclopropanecarbonyl piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly (ADP-ribose) polymerase-1. J Med Chem 2008, 51(20): 6581-91.
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) 65828 3-hydroxy-2-benzofuran-1(3H)-one 　 C8H6O3 详情 详情
(II) 65829 Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate; (3-Oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester 61260-15-9 C10H11O5P 详情 详情
(III) 65830 3-Cyano-4-fluorobenzaldehyde; 2-Fluoro-5-formylbenzonitrile 218301-22-5 C8H4FNO 详情 详情
(IV) 65831 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile 763114-25-6 C16H8FNO2 详情 详情
(V) 65832 2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid 763114-26-7 C16H11FN2O3 详情 详情
(VI) 65833 　 　 C16H10FN3O 详情 详情
(VII) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(VIII) 65834 　 　 C25H27FN4O4 详情 详情
(IX) 65835 1-[5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine 763111-47-3 C20H19FN4O2 详情 详情
(X) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XII) 65836 1-(Cyclopropylcarbonyl)piperazine 59878-57-8 C8H14N2O 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

Condensation of 2-amino-6-bromopyridine (I) with ethoxycarbonyl isothiocyanate (II) in CH2Cl2 gives 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl) thiourea (III), which by cyclization with hydroxylamine hydrochloride (IV) in the presence of DIEA in EtOH/MeOH yields 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine (V). N-Acylation of amine (V) with cyclopropanecarbonyl chloride (VI) using Et3N in acetonitrile, and subsequent treatment with methanolic ammonia, results in the carboxamide (VII) . Suzuki coupling of compound (VII) with 4-(hydroxymethyl)phenylboronic acid (VIII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C, followed by bromination with PBr3 in CHCl3, affords the benzyl bromide intermediate (IX), which is finally condensed with thiomorpholine-1,1-dioxide (X) using DIEA in CH2Cl2/MeOH .
Alternatively, condensation of (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (XI) with thiomorpholine 1,1-dioxide (X) by means of DIEA in CH2Cl2/MeOH gives intermediate (XII), which finally undergoes Suzuki coupling with aryl bromide (VII) in the presence of PdCl2(dppf) and K2CO3 in dioxane/H2O at 90 °C .

参考文献 中间体
合成目标
【1】 Menet, C.J.M., Smits, K.K. (Galapagos NV). 5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-yl carboxamides as JAK inhibitors. CN 102482273, EP 2445911, JP 2012530766, KR 2012107919, US 201331319, US 8088764, WO 2010149769.
【2】 Menet, C.J.M., Smits, K.K. (Galapagos NV). Novel compound useful for the treatment of degenerative and inflammatory diseases. US 2012142678, US 8563545.
【3】 Van ‘t Klooster, G.A.E., Brys, R.C.X., Van Rompaey, L.J.C., Namour, F.S. (Galapagos NV). Aminotriazolopyridine for use in the treatment of inflammation, and pharmaceutical composition thereof. US 2013345209, WO 2013189771.
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) 41341 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine 19798-81-3 C5H5BrN2 详情 详情
(II) 25964 1-[(isothiocyanatocarbonyl)oxy]ethane 16182-04-0 C4H5NO2S 详情 详情
(III) 67818 1-(6-bromopyridin-2-yl)-3-(ethoxycarbonyl)thiourea 　 C9H10BrN3O2S 详情 详情
(IV) 65957 Hydroxylamine hydrochloride; Hydroxylammonium chloride; Oxammonium hydrochloride 5470-11-1 H3NO.HCl 详情 详情
(V) 67819 2-amino-5-bromo[1,2,4]triazolo[1,5-a]pyridine 　 C6H5BrN4 详情 详情
(VI) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(VII) 67820 N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide 　 C10H9BrN4O 详情 详情
(VIII) 67821 4-(hydroxymethyl)phenylboronic acid 59016-93-2 C7H9BO3 详情 详情
(IX) 67822 N-(5-(4-(bromomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide 　 C17H15BrN4O 详情 详情
(X) 67823 thiomorpholine-1,1-dioxide 39093-93-1 C4H9NO2S 详情 详情
(XI) 67824 (4-bromomethylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane 138500-85-3 C13H18BBrO2 详情 详情
(XII) 67825 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine 1,1-dioxide 　 C17H26BNO4S 详情 详情
Extended Information