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【结 构 式】

【分子编号】11296

【品名】2-Chloroacetyl chloride; Chloroacetic chloride

【CA登记号】79-04-9

【 分 子 式 】C2H2Cl2O

【 分 子 量 】112.94268

【元素组成】C 21.27% H 1.78% Cl 62.78% O 14.17%
与该中间体有关的原料药合成路线共 74 条
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合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of cyclohexylamine (I) with chloroacetyl chloride (II) in water in the presence of sodium hydroxide gives N-cyclohexyl-2-chloro-acetamide (III), which by reaction with piperazine (IV) in water is converted to N-[(N-cyclohexylcarbamoyl)methyl]piperazine (V). This compound is then treated with one equivalent of HCl.

参考文献 中间体
合成目标
【1】 Corvi-Mora, C. (Camillo Corvi SpA); N-Cyclohexyl-piperazino acetamides and propionamides. US 4123530; US 4278796 .
【2】 de Angelis, L.; Esaprazole hydrochloride. Drugs Fut 1986, 11, 4, 263.
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) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 27377 2-chloro-N-cyclohexylacetamide C8H14ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 27378 N-cyclohexyl-2-(1-piperazinyl)acetamide C12H23N3O 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

The reaction of p-chlorobenzaldehyde (I) sodium cyanide and ethyl acetate gives ethyl 4-(p-chlorophenyl)-4-oxobutyrate (II), which is hydrolyzed with KOH to the corresponding free acid (III). The reduction of (III) with Zn and aqueous HCl affords 4-(p-chlorophenyl)butyric acid (IV), which is condensed with heptylamine (B) by means of oxalyl chloride (A) in refluxing benzene to yield N-heptyl-4-(p-chlorophenyl)butyramide (V), which is reduced with diborane in refluxing THF to afford N-heptyl-4-(p-chlorophenyl)butylamine (VI). The acetylation of (VI) with acetyl chloride (C) by means of Na2CO3 in acetone gives N-acetyl-N-heptyl-4-(p-chlorophenyl)butylamine (VII), which is reduced with diborane as before to yield N-ethyl-N-heptyl-4-(p-chlorophenyl)butylamine (VIII). The quaternization of (VIII) with refluxing ethyl bromide (D) gives N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butylammonium bromide (IX), which by elution through a column with Dowex 1-X8, hydroxide form, resin is converted into N,N-diethyl-N-heptyl-4-(p-chlorophenyl)butyl ammonium hydroxide (X). Finally, this compound is salified with diluted aqueous phosphoric acid.

参考文献 中间体
合成目标
【1】 Fukuzawa, S.; et al.; JP 76131883 .
【2】 Muro, T.; et al.; US 4005084 .
【3】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Y-8894. Drugs Fut 1981, 6, 7, 423.
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) 11229 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate 541-41-3 C3H5ClO2 详情 详情
(B) 37495 Maleic acid; (Z)-2-Butenedioic acid 110-16-7 C4H4O4 详情 详情
(I) 37488 1-(benzylamino)-3-[2-(2-thienylmethyl)phenoxy]-2-propanol C21H23NO2S 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 37489 N-benzyl-2-chloro-N-[2-hydroxy-3-[2-(2-thienylmethyl)phenoxy]propyl]acetamide C23H24ClNO3S 详情 详情
(IV) 37490 4-benzyl-6-[[2-(2-thienylmethyl)phenoxy]methyl]-3-morpholinone C23H23NO3S 详情 详情
(V) 37491 4-benzyl-2-[[2-(2-thienylmethyl)phenoxy]methyl]morpholine; (4-benzyl-2-morpholinyl)methyl 2-(2-thienylmethyl)phenyl ether C23H25NO2S 详情 详情
(VI) 37492 ethyl 2-[[2-(2-thienylmethyl)phenoxy]methyl]-4-morpholinecarboxylate C19H23NO4S 详情 详情
(VII) 37493 2-[[2-(2-thienylmethyl)phenoxy]methyl]oxirane; 2-oxiranylmethyl 2-(2-thienylmethyl)phenyl ether C14H14O2S 详情 详情
(VIII) 37494 2-aminoethyl hydrogen sulfate 926-39-6 C2H7NO4S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(A)

The condensation of 1 2-benzenediamine (I) with methyltetrahydro-5-methyl 4-oxo-3-thiophenecarboxylate (II) in toluene using a Dean-Stark trap gives the triyclic system (III), which is dehydrogenated to 4,9-dihydro-3-methyl-10H-thienol[3,4-b][1,5]benzodiazepin-10-one (IV). Treatment of (IV) with chloroacetyl chloride in dioxane in the presence of K2CO3 yields 4-chloroacetyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (V), which is finally reacted with N-methylpiperazine to produce telenzepine, which is isolated as the hydrochloride.

参考文献 中间体
合成目标
【1】 Borner, H.; Haffer, G.; Sauer, G. (Schering AG); Process for the preparation of 2-bromo-8-ergolinyl. DE 3340025; US 4970314 .
【2】 Galvan, M.; Eltze, M.; Figala, V.; TELENZEPINE HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 4, 327.
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) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(A) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 12824 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine 95-54-5 C6H8N2 详情 详情
(II) 11372 Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate C5H9NO2 详情 详情
(II) 22082 methyl (5R)-5-methyl-4-oxotetrahydro-3-thiophenecarboxylate C7H10O3S 详情 详情
(III) 22083 (3R)-3-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C12H12N2OS 详情 详情
(III) 22088 2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl 3-oxobutanoate C16H20Cl2N2O3 详情 详情
(IV) 22084 3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C12H10N2OS 详情 详情
(V) 22085 4-(2-chloroacetyl)-3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C14H11ClN2O2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(D)

Epoxidation of trans-cinnamyl alcohol (A) gives compound (I), which in turn is reacted with sodium 2-ethoxyphenate (B) to give the diol (II). The primary alcoholic group of (II) is reacted with p-nitrobenzoyl chloride to obtain (III), and (IV) is prepared by treatment of (III) with methanesulfonyl chloride. By treatment of (IV) with sodium hydroxide in an aqueous/dioxane solution the epoxide (V) is obtained in high yield, and this reaction causes inversion of configuration at C-2 carbon atom. Treatment of (V) with aqueous methanolic ammonia gives (VI), which in turn is acylated to (VII) with chloroacetyl chloride and cyclized to morpholone (VIII) with potassium tert-butoxide. The reduction to the final compound FCE-20124 is performed with [sodium bis(2-methoxyethoxy)aluminum hydride] (RED-AL) in toluene.

参考文献 中间体
合成目标
【1】 Lazzari, E.; Meroni, M.; Mazzini, G.; Melloni, P.; Della Torre, A.; Configurantional studies on 2[gamma-(2-ethoxyphenoxy)benzyl]morpholine FCE-20124. Tetrahedron 1985, 41, 7, 1393.
【2】 Torre, A.D.; Carniel, G.; Rossi, A.; Melloni, P. (Pharmacia Corp.); Substituted morpholine derivatives and compositions. DE 2901032; FR 2430412; FR 2442839; GB 2014981; JP 54148739; US 4229449 .
【3】 Riva, F.; FCE-20124. Drugs Fut 1985, 10, 11, 905.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(A) 13951 (E)-3-Phenyl-2-propen-1-ol 104-54-1 C9H10O 详情 详情
(B) 29768 sodium 2-ethoxybenzenolate C8H9NaO2 详情 详情
(I) 29767 [(2R,3S)-3-phenyloxiranyl]methanol C9H10O2 详情 详情
(II) 29769 (2S,3S)-3-(2-ethoxyphenoxy)-3-phenyl-1,2-propanediol C17H20O4 详情 详情
(III) 29770 (1S,2S)-1-(2-ethoxyphenoxy)-4-(4-nitrophenyl)-1-phenyl-2-butanol C24H25NO5 详情 详情
(IV) 29771 2-ethoxyphenyl (1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-(4-nitrobenzyloxy)-1-phenylbutyl ether; [[(1S)-1-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]-3-(4-nitrobenzyloxy)propyl]oxy](methyl)dimethylene-lambda(6)-sulfane C27H31NO6S 详情 详情
(V) 29772 2-ethoxyphenyl (S)-2-oxiranyl(phenyl)methyl ether; 2-[(S)-(2-ethoxyphenoxy)(phenyl)methyl]oxirane C17H18O3 详情 详情
(VI) 29773 (1S,2S)-3-amino-1-(2-ethoxyphenoxy)-1-phenyl-2-propanol C17H21NO3 详情 详情
(VII) 29774 1-[3-[(chlorocarbonyl)amino]-2-hydroxy-1-phenylpropoxy]-2-ethoxybenzene C18H20ClNO4 详情 详情
(VIII) 29775 (6R)-6-[(2-ethoxyphenoxy)(phenyl)methyl]-3-morpholinone C19H21NO4 详情 详情
(C) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

The title compound has been synthesized by several procedures. Acylation of 2-benzylaniline (I) by chloroacetyl chloride (II) gave chloroacetamide (III). Subsequent cyclization of amide (III) under Vilsmeier conditions furnished the dibenzoazepine (IV). Nucleophilic substitution of the chlorine atom of (IV) by methylamine led to amine (V). The imine function of (V) was reduced with either LiAlH4 or NaBH4 to the diamine (VI), which was further converted into the fused diketopiperazine (VII) upon heating with diethyl oxalate. The amide groups of (VII) were then reduced by means of borane in THF, yielding the target tetracyclic diamine, which was finally isolated as the corresponding hydrochloride salt

参考文献 中间体
合成目标
【1】 van der Burg, W.J.; et al.; A novel type of substituted piperazine with high antiserotonin potency. J Med Chem 1970, 13, 1, 35.
【2】 van der Burg, W.J.; Delobelle, J.; Polycyclic piperazines. US 3534041 .
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) 62393 2-benzylaniline; 2-benzylphenylamine 28059-64-5 C13H13N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 62394 N-(2-benzylphenyl)-2-chloroacetamide C15H14ClNO 详情 详情
(IV) 62395 6-(chloromethyl)-11H-dibenzo[b,e]azepine 21535-44-4 C15H12ClN 详情 详情
(V) 62396 11H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(11H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine C16H16N2 详情 详情
(VI) 62397 6,11-dihydro-5H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine C16H18N2 详情 详情
(VII) 62398 2-methyl-1,2,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepine-3,4-dione C18H16N2O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

1) The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride by means of triethylamine in dichloromethane gives N-(2,6-dimethylphenyl) chloroacetamide (III), which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV). Finally, this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

参考文献 中间体
合成目标
【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 .
【2】 Prous, J.; Castaner, J.; RANOLAZINE < Rec INN; USAN >. Drugs Fut 1988, 13, 9, 837.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 24102 N-(2,6-dimethylphenyl)-2-(1-piperazinyl)acetamide C14H21N3O 详情 详情
(VI) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

2) The condensation of epoxide (VI) with piperazine (IV) in refluxing isopropanol gives 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine (VII), which is then condensed with chloroacetamide (III) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 .
【2】 Prous, J.; Castaner, J.; RANOLAZINE < Rec INN; USAN >. Drugs Fut 1988, 13, 9, 837.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情
(VII) 24109 1-(2-methoxyphenoxy)-3-(1-piperazinyl)-2-propanol C14H22N2O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The Friedel-Crafts' condensation of 1,3-difluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 yields alpha-chloro-2,4-difluoroacetophenone (III), which is treated with 1,2,4-triazole (IV) and triethylamine in refluxing ethyl acetate giving alpha-(1H-12,4-triazol-1-yl)-2,4-diftuoroacetophenone (V). The reaction of (V) with trimethylsulfoxonium iodide (VI) by means of NaOH in toluene affords 1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole (VII), which is finally treated again with 1,2,4-triazole (IV) and K2CO3 in hot DMF.

参考文献 中间体
合成目标
【1】 Narayanaswami, S.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0096569; ES 523038 .
【2】 Richardson, K. (Pfizer Inc.); Triazoles. GB 2099818; US 4404216 .
【3】 Fromtling, R.A.; Castaner, J.; Serradell, M.N.; Fluconazole. Drugs Fut 1985, 10, 12, 982.
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) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 16321 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone 51336-94-8 C8H5ClF2O 详情 详情
(IV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(V) 15372 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone 863867-75-6 C10H7F2N3O 详情 详情
(VI) 29693 Trimethylsulfoxonium iodide 1774-47-6 C3H9IOS 详情 详情
(VII) 29839 1-[[2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole 86386-76-7 C11H9F2N3O 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).

参考文献 中间体
合成目标
【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 .
【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119.
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) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 11297 2-hydroxyethyl 2-chloroacetate C4H7ClO3 详情 详情
(IV) 11298 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin 81-07-2 C7H5NO3S 详情 详情
(V) 11299 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate C11H11NO6S 详情 详情
(VI) 11300 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C11H11NO6S 详情 详情
(VII) 11301 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C12H13NO6S 详情 详情
(VIII) 11302 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid C10H9NO5S 详情 详情
(IX) 11303 (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride 102-92-1 C9H7ClO 详情 详情
(X) 11304 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride C28H21NO7S 详情 详情
(XI) 11305 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine 504-29-0 C5H6N2 详情 详情
(XII) 11306 Cyclohexanol 108-93-0 C6H12O 详情 详情
(XIII) 11307 cyclohexyl 2-chloroacetate C8H13ClO2 详情 详情
(XIV) 11308 cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate C15H17NO5S 详情 详情
(XV) 11309 cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C15H17NO5S 详情 详情
(XVI) 11310 cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate C16H19NO5S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(A)

Erdosteine (III) can be obtained in a two-step synthesis starting from homocysteine thiolactone (I). (I) is acylated in chloroform with chloroacetyl chloride (A) to the amide (II). Subsequent reaction with thioglycolic acid (B) gives rise to (III).

参考文献 中间体
合成目标
【1】 Gobetti, M.; Pedrazzoli, A.; Bradamante, S.; DL-S-[2-[N-3-(2-Oxotetrahydrothienyl)acetamido]]-thioglycolic acid: A novel mucolytic agent of the class of homocysteine thiolactone derivatives. Farm Sci Ed 1986, 41, 1, 69-79.
【2】 Fregnan, G.B.; Pappalardo, M.; ERDOSTEINE < Rec INN >. Drugs Fut 1990, 15, 9, 887.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(B) 18524 2-sulfanylacetic acid 68-11-1 C2H4O2S 详情 详情
(I) 22495 3-aminodihydro-2(3H)-thiophenone 10593-85-8 C4H7NOS 详情 详情
(II) 31177 2-chloro-N-(2-oxotetrahydro-3-thiophenyl)acetamide 84611-22-3 C6H8ClNO2S 详情 详情

合成路线11

该中间体在本合成路线中的序号：

Synthesis of intermediate (I): 1a) Dimethyl acetonedicarboxylate (IV) is treated with MgCl2 and triethylamine, giving the corresponding magnesium complex (V), which by cyclocondensation with chloroacetyl chloride and thiourea yields methyl 2-(2-aminothiazol-4-yl)-3-hydroxy-4-(methoxycarbonyl)-2-butenoate (VI). The reduction of (VI) with NaBH4 affords dimethyl 2-(2-aminothiazol-4-yl)-3-hydroxyglutarate (VII), which by successive treatments with benzyloxycarbonyl chloride (to protect the amino group), and with mesyl chloride - triethylamine (to dehydrate the OH group) is converted to methyl 2-[2 (benzyloxycarbonylamino)thiazol-4-y]-4-(methoxycarbonyl)-2-butenoate (VIII). The hydrolysis of (VIII) with aqueous NaOH in toluene gives the corresponding diacid (IX), which is selectively esterified with benzyl alcohol in acidic medium yielding (I). 1b) The reaction of methyl 2-(2-aminothiazol-4-yl)acetate (X) with beozyloxycarbonyl chloride and NaHCO3 gives the protected compound (XI), which is condensed with methyl 3-methoxyacrylate (XII) by means of sodium methoxide in DMF to yield dimethyl ester (VIII), already obtained.

参考文献 中间体
合成目标
【1】 Yoshioka, M.; Synthetic studies related to oral beta-lactam antibiotics. Pure Appl Chem 1987, 59, 8, 1041.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10180 Thiourea 62-56-6 CH4N2S 详情 详情
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 22689 (Z)-5-(benzyloxy)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-5-oxo-2-pentenoic acid C23H20N2O6S 详情 详情
(IV) 22692 dimethyl 3-oxopentanedioate 1830-54-2 C7H10O5 详情 详情
(V) 22693 Bis(3-Hydroxy-2-pentenoic acid dimethyl ester) magnesium salt C14H18MgO10 详情 详情
(VI) 22694 dimethyl (E)-2-(2-amino-1,3-thiazol-4-yl)-3-hydroxy-2-pentenedioate C10H12N2O5S 详情 详情
(VII) 22695 dimethyl 2-(2-amino-1,3-thiazol-4-yl)-3-hydroxypentanedioate C10H14N2O5S 详情 详情
(VIII) 22696 dimethyl (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioate C18H18N2O6S 详情 详情
(IX) 22697 (Z)-2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)-2-pentenedioic acid C16H14N2O6S 详情 详情
(X) 22698 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate 64987-16-2 C6H8N2O2S 详情 详情
(XI) 22699 methyl 2-(2-[[(benzyloxy)carbonyl]amino]-1,3-thiazol-4-yl)acetate C14H14N2O4S 详情 详情
(XII) 22700 methyl (E)-3-methoxy-2-propenoate 34846-90-7 C5H8O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

In a related method, the intermediate tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the penta(chloroacetyl) derivative (III). The chloroacetate ester groups are then hydrolyzed under basic conditions to afford the tetra-hydroxy chloroacetamide (IV). Conversion of (IV) to the hydroxy acetamide (V) is accomplished by treatment with sodium acetate and NaOH. Amide (V) is finally alkylated with either chloroetanol (VI) or with ethylene oxide (VII) to furnish the title N-(hydroxyethyl) amide.

参考文献 中间体
合成目标
【1】 Dunn, T.J.; Kneller, M.T.; White, D.H.; Jones, M.M.; Doran, N.O. (Mallinckrodt Medical Inc.); Process for producing ioversol. WO 9640286 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 59326 2-({3-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C24H23Cl5I3N3O11 详情 详情
(IV) 59327 5-[(2-chloroacetyl)amino]-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C16H19ClI3N3O7 详情 详情
(V) 59324 N~1~,N~3~-bis(2,3-dihydroxypropyl)-5-(glycoloylamino)-2,4,6-triiodoisophthalamide C16H20I3N3O8 详情 详情
(VI) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(VII) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

In an alternative procedure, the intermediate amino tetraacetate (I) is acylated by chloroacetyl chloride (II), yielding chloroacetamide (III). The amide N is then alkylated with bromoethyl acetate (IV) to produce (V). Simultaneous hydrolysis of the acetate esters and the chloro group in aqueous sulfuric acid furnishes the title compound.

参考文献 中间体
合成目标
【1】 McCarthy, W.Z.; Kneller, M.T.; Lin, Y.; White, D.H. (Mallinckrodt Medical Inc.); Synthesis of ioversol using chloroacetyl chloride. WO 9301840 .
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) 59322 2-(acetyloxy)-1-({[3-amino-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C22H26I3N3O10 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 59328 2-(acetyloxy)-1-[({3-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)methyl]ethyl acetate C24H27ClI3N3O11 详情 详情
(IV) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(V) 59329 2-(acetyloxy)-1-({[3-[[2-(acetyloxy)ethyl](2-chloroacetyl)amino]-5-({[2,3-bis(acetyloxy)propyl]amino}carbonyl)-2,4,6-triiodobenzoyl]amino}methyl)ethyl acetate C28H33ClI3N3O13 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

Similarly, the tetrahydroxy amine (I) is acylated by chloroacetyl chloride (II) to produce the tetraester amide (III). After amide alkylation with bromoethyl acetate (IV), the resultant penta-ester (V) is hydrolyzed to the title compound using aqueous sulfuric acid.

参考文献 中间体
合成目标
【1】 McCarthy, W.Z.; Kneller, M.T.; Lin, Y.; White, D.H. (Mallinckrodt Medical Inc.); Synthesis of ioversol using chloroacetyl chloride. WO 9301840 .
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) 59316 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide C14H18I3N3O6 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 59326 2-({3-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-5-[(2-chloroacetyl)amino]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C24H23Cl5I3N3O11 详情 详情
(IV) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(V) 59330 2-({3-[[2-(acetyloxy)ethyl](2-chloroacetyl)amino]-5-[({2,3-bis[(2-chloroacetyl)oxy]propyl}amino)carbonyl]-2,4,6-triiodobenzoyl}amino)-1-{[(2-chloroacetyl)oxy]methyl}ethyl 2-chloroacetate C28H29Cl5I3N3O13 详情 详情

合成路线15

该中间体在本合成路线中的序号：(II)

The Friedel-Crafts condensation of fluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 gives the phenacyl chloride (III), which is cyclized with N-isopropylaniline (IV) by means of ZnCl2 to yield 3-(4-fluorophenyl)-1-isopropyl-1H-indole (V). The condensation of (V) with 3-(N-methyl-N-phenylamino)acrolein (VI) by means of POCl3 in acetonitrile affords 3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrolein (VII), which is further condensed with tert-butyl acetoacetate (VIII) by means of BuLi and NaH in THF to provide 7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6(E)-heptenoic acid tert-butyl ester (IX). The reduction of the ketonic group of (IX) with NaBH4 catalyzed by Et2B-OMe as chelating agent gives the diol (X) with a syn configuration. Finally, the tert-butyl ester group of (X) is hydrolyzed with NaOH in ethanol/water to afford the target fluvastatin sodium.

参考文献 中间体
合成目标
【1】 Repic, O.; et al.; The story of Lescol: From research to production. Org Process Res Dev 2001, 5, 5, 519.
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) 17466 Fluorobenzene 462-06-6 C6H5F 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 11786 2-Chloro-1-(4-fluorophenyl)-1-ethanone; 2-Chloro-4'-fluoroacetophenone 456-04-2 C8H6ClFO 详情 详情
(IV) 27905 N-isopropyl-N-phenylamine 768-52-5 C9H13N 详情 详情
(V) 11788 3-(4-Fluorophenyl)-1-isopropyl-1H-indole 93957-49-4 C17H16FN 详情 详情
(VI) 27906 (E)-3-(methylanilino)-2-propenal C10H11NO 详情 详情
(VII) 11790 (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-2-propenal C20H18FNO 详情 详情
(VIII) 27907 Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate 1694-31-1 C8H14O3 详情 详情
(IX) 27908 tert-butyl (E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoate C28H32FNO4 详情 详情
(X) 27909 tert-butyl (3R,5S,6E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoate C28H34FNO4 详情 详情

合成路线16

该中间体在本合成路线中的序号：(V)

2) The reaction of N-(2,3-epoxypropyl)phthalimide (I) with dibenzylamine (II) at 80 C gives 1-(dibenzylamino)-3-(phthalimido)-2-propanol (III), which is hydrolyzed with refluxing concentrated HCl to afford 1-amino-3-(dibenzylamino)-2-propanol (IV). The acylation of (IV) with chloroacetyl chloride (V) in CHCl3 yields the corresponding chloroacetamide (VI), which is cyclized by means of potassium tert-butoxide in refluxing ethanol to give 6-(dibenzylaminomethyl)morpholin-3-one (VII). The debenzylation of (VII) with H2 over Pd(OH)2/C in ethanol yields 6-(aminomethyl)morpholin-3-one (VIII), which is condensed with 4-(acetamido)-5-chloro-2-ethoxybenzoyl chloride (IX) by means of triethylamine in CHCl3 to afford the monoacetylated derivative of metabolite M-2 (X). Finally, this compound is hydrolyzed with HCl in refluxing ethanol/water to give metabolite M-2. The two final steps of this sequence can also be performed in a single step by condensation of morpholinone (VIII) with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of carbonyldiimidazole (CDI) in THF to afford directly the metabolite M-2 after neutralization with aqueous NH4OH.

参考文献 中间体
合成目标
【1】 Kato, S.; Yoshida, N.; Morie, T.; Synthesis and biological activities of metabolites of mosapride, a new gastroprokinetic agent. Chem Pharm Bull 1995, 43, 4, 699.
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) 12335 2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide 5455-98-1 C11H9NO3 详情 详情
(II) 12361 N,N-Dibenzylamine; Dibenzylamine; N-Benzyl(phenyl)methanamine 103-49-1 C14H15N 详情 详情
(III) 12362 2-[3-(Dibenzylamino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione C25H24N2O3 详情 详情
(IV) 12363 1-Amino-3-(dibenzylamino)-2-propanol C17H22N2O 详情 详情
(V) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VI) 12365 2-Chloro-N-[3-(dibenzylamino)-2-hydroxypropyl]acetamide C19H23ClN2O2 详情 详情
(VII) 12366 6-[(Dibenzylamino)methyl]-3-morpholinone C19H22N2O2 详情 详情
(VIII) 12367 6-(Aminomethyl)-3-morpholinone C5H10N2O2 详情 详情
(IX) 12368 4-(Acetamido)-5-chloro-2-ethoxybenzoyl chloride C11H11Cl2NO3 详情 详情
(X) 12369 4-(Acetamido)-5-chloro-2-ethoxy-N-[(5-oxo-1,4-oxazinan-2-yl)methyl]benzamide C16H20ClN3O5 详情 详情
(XI) 12333 4-Amino-5-chloro-2-ethoxybenzoic acid C9H10ClNO3 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

The methylation of ethyl 2-(hydroxyimino)-3-oxobutyrate (I) with dimethyl sulfate and Na2CO3 in methanol gives ethyl 2-(methoxyimino)-3-oxobutyrate (II), which is brominated with Br2 in CHCl3 yielding ethyl 4-bromo-2-(methoxyimino)-3-oxobutyrate (III). The cyclization of (III) with thiourea (IV) in refluxing ethanol affords ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate (V), which is acylated with chloroacetyl chloride (VI) in DMA to give the corresponding N-chloroacetyl derivative (VII). The hydrolysis of (VII) with KOH in ethanol-water affords 2-(2-chloroacetamidothiazol-4-yl)-2-(methoxyimino)acetic acid (VIII), which is condensed with desacetoxycephalosporanic acid (IX) by means of N-hydroxysuccinimide (NOHS) and dicyclohexylcarbodiimide (DCC) in THF yielding 7beta-[2-(2-chloroacetamidothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]desacetoxycephalosporanic acid (X). The deprotection of (X) with sodium acetate in THF gives the free acid (XI), which is finally esterified with pivaloyloxymethyl bromide (XII) by means of NaHCO3 in ethyl acetate-DMSO.

参考文献 中间体
合成目标
【1】 Ochiai, M.; Morimoto, A.; Matsushita, Y. (Takeda Chemical Industries, Ltd.); Cephalosporin derivatives, process for their preparation and medicines containing them. DE 2715385 .
【2】 Nakao, H.; Sugawara, S. (Sankyo Co., Ltd.); Cephalosporin derivatives for oral administration. DE 3020625 .
【3】 Prous, J.; Castaner, J.; CEFETAMET PIVOXIL < Prop INNM >. Drugs Fut 1989, 14, 5, 420.
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) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate；(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(II) 20854 ethyl 2-(methoxyimino)-3-oxobutanoate C7H11NO4 详情 详情
(III) 10181 ethyl 4-bromo-2-(methoxyimino)-3-oxobutanoate 60845-87-6 C7H10BrNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 10182 Ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate; 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic acid ethyl ester 64485-88-7 C8H11N3O3S 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 20859 ethyl 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetate C10H12ClN3O4S 详情 详情
(VIII) 20860 2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetic acid 64486-18-6 C8H8ClN3O4S 详情 详情
(IX) 20861 (6R,7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; 7-ADCA 22252-43-3 C8H10N2O3S 详情 详情
(X) 20862 (6R,7R)-7-[[2-[2-[(2-chloroacetyl)amino]-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C16H16ClN5O6S2 详情 详情
(XI) 20863 (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H15N5O5S2 详情 详情
(XII) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(A)

Synthesis of the intermediate diazepinone (IV) is accomplished by a one-pot synthesis. Condensation of 2-chloro-3-aminopyridine (I) with the anthranilic ester (II) is effected in the presence of potassium tert-butoxide as a catalyst. The resulting anthranilic amide (III) is cyclized under the influence of catalytic amounts of sulfuric acid. Treatment of (IV) with chloroacetylchloride in toluene yields the corresponding choroacetamide (V). The side chain of AQ-RA 741 is prepared starting from 4-picoline, which is alkylated by reaction with 3-(diethylamino)propylchloride in the presence of n-butyllithium. Hydrogenation of (VIII) using platinum dioxide as a catalyst furnishes the diamine (IX), which is coupled with (V) in the presence of catalytic amounts of sodium iodide in acetone leading to AQ-RA 741 as its free base.

参考文献 中间体
合成目标
【1】 Eberlein, W.; Engel, W.; Trummlitz, G.; Mihm, G.; Mayer, N.; Doods, H. (Dr. Karl Thomae GmbH); Condensed diazepinones, process for their preparation and medicines containing them. AU 8824122; DE 3735895; EP 0312895; JP 1989230580; US 5175158 .
【2】 Eberlein, W.; Doods, H.; Wetzel, B.; AQ-RA-741. Drugs Fut 1990, 15, 8, 786.
【3】 LaMontagne, M.P.; et al.; Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics. J Med Chem 1989, 32, 8, 1728-32.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
(II) 11161 methyl 2-aminobenzoate; Methyl anthranilate 134-20-3 C8H9NO2 详情 详情
(III) 11162 2-Amino-N-(2-chloro-3-pyridinyl)benzamide C12H10ClN3O 详情 详情
(IV) 11163 5,11-Dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one C12H9N3O 详情 详情
(V) 11164 11-(2-Chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one C14H10ClN3O2 详情 详情
(VI) 31150 4-methylpyridine 108-89-4 C6H7N 详情 详情
(VII) 31151 N-(3-chloropropyl)-N,N-diethylamine; 3-chloro-N,N-diethyl-1-propanamine C7H16ClN 详情 详情
(VIII) 31152 N,N-diethyl-N-[4-(4-pyridinyl)butyl]amine; N,N-diethyl-4-(4-pyridinyl)-1-butanamine C13H22N2 详情 详情
(IX) 31153 N,N-diethyl-N-[4-(4-piperidinyl)butyl]amine; N,N-diethyl-4-(4-piperidinyl)-1-butanamine C13H28N2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

The benzoyl-protected ligand (IV) was prepared as follows. Acylation of triglycine (I) with chloroacetyl chloride (II) produced the chloroacetamide (III). Subsequent treatment of chloride (III) with sodium thiobenzoate yielded thioester (IV). The title 99technetium complex was prepared by in situ hydrolysis of the thiobenzoate ester (IV) to mercaptoacetyl triglycine (V) in the presence of a solution of [99mTc]pertechnetate, SnCl2 as the technetium reducing species, and gluconate or tartrate as intermediate Tc complexing agents.

参考文献 中间体
合成目标
【1】 Hung, J.C.; et al.; Rapid preparation and quality control of technetium-99m MAG3(TM). J Nucl Med Technol 1991, 19, 3, 176.
【2】 Reyes-Herrera, L.; et al.; An alkaline kit formulation to obtain [99mTc]MAG3 in high radiochemical yields. J Radioanal Nucl Chem 1995, 199, 6, 507.
【3】 Grummon, G.; et al.; Synthesis, characterization and crystal structures of technetium(V)-oxo complexes useful in nuclear medicine. 1. Complexes of mercaptoacetylglycylglycylglycine (MAG3) and its methyl ester derivative (MAG3OMe). Inorg Chem 1995, 34, 7, 1764.
【4】 Fritzburg, A. (University of Utah); Radiolabeled technetium chelates for use in renal function determinations. EP 0173424 .
【5】 Fritzberg, A.R.; Kasina, S.; Eshima, D.; Johnson, D.L.; Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement. J Nucl Med 1986, 27, 1, 111.
【6】 Brandau, W.; et al.; Technetium-99m labeled renal function and imaging agents. 3. Synthesis of Tc-99m-MAG3 and biodistribution of by-products. Int J Radiat Appl Instrum Part A - Appl Radiat Isotop 1988, 39, 2, 121.
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) 56518 2-({2-[(2-aminoacetyl)amino]acetyl}amino)acetic acid C6H11N3O4 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 56519 2-{[2-({2-[(2-chloroacetyl)amino]acetyl}amino)acetyl]amino}acetic acid C8H12ClN3O5 详情 详情
(IV) 56520 1,4,7,10-tetraoxo-1-phenyl-2-thia-5,8,11-triazatridecan-13-oic acid C15H17N3O6S 详情 详情
(V) 56521 2-{[2-({2-[(2-sulfanylacetyl)amino]acetyl}amino)acetyl]amino}acetic acid C8H13N3O5S 详情 详情

合成路线20

该中间体在本合成路线中的序号：(A)

The acylation of benzoxazolin-2-one (I) with propionic anhydride (II) by means of P2O5 and MsOH gives 6-propionylbenzoxazolin-2-one (III), which is treated with chloroacetyl chloride to yield 7-propionyl-3,4-dihydro-2H-1,4-benzoxazin-3-one (IV). The Mannich condensation of (IV) with CH2O and NH3 followed by methylation with methyl iodide affords the trimethylammonium compound (V), which by reaction with KCN, followed by hydrolysis with HCl gives 3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbonyl)butyric acid (VI). Finally this compound is cyclized with hydrazine to furnish the target pyridazinone.

参考文献 中间体
合成目标
【1】 Bonte, J.P.; Lesier, D.; Lespagnol, C.; et al.; 6-Acyl benzoxazolinones. I. Eur J Med Chem - Chim Ther 1974, 9, 491.
【2】 Kryvenko, M.; Techer, H.; Lavergne, M.; et al.; Electrophilic substitutions of 2H-1,4-benzoxazine-3-one: Acylation and chlorosulfonation. CR Acad Sci Paris Ser C 1970, 270, 19, 1601.
【3】 Lesier, D.; Lespagnol, C.; Bonte, J.P.; et al.; 6-Acyl benzoxazolinones. II. Preparation of some transformation products. Eur J Med Chem - Chim Ther 1974, 9, 497-500.
【4】 Thyes, M.; Lehmann, H.D.; Gries, J.; et al.; 6-Aryl-4,5-dihydro-3(2H)-pyridazinones. A new class of compounds with platelet aggregation inhibiting and hypotensive activities. J Med Chem 1983, 26, 6, 800.
【5】 Moussavi, Z.; Lesieur, D.; Depreux, P.; An aternative synthesis of cardiotonic 6-(3,4-dihydro-3-oxo-1,4[2H]benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-ones. Synth Commun 1991, 21, 2, 271.
【6】 Combs, D.W.; Bemoradan and related pyridazinone cardiotonics. Drugs Fut 1993, 18, 2, 139.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 41299 2-Benzoxazolinone; 2(3H)-benzoxazolone; 1,3-benzoxazol-2(3H)-one 59-49-4 C7H5NO2 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 41300 6-propionyl-1,3-benzoxazol-2(3H)-one C10H9NO3 详情 详情
(IV) 41301 7-propionyl-2H-1,4-benzoxazin-3(4H)-one C11H11NO3 详情 详情
(V) 41302 N,N,N,2-tetramethyl-3-oxo-3-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-1-propanaminium C15H21N2O3 详情 详情
(VI) 41303 3-methyl-4-oxo-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)butyric acid C13H13NO5 详情 详情

合成路线21

该中间体在本合成路线中的序号：

1) The acylation of 2-amino-7-methoxy-1-tetralone (I) with chloroacetyl chloride in ethyl acetate - water by means of NaHCO3 gives the corresponding chloroacetamido derivative (II), which is reduced with NaBH4 in ethanol - CHCl3 to trans-2-(chloroacetamido)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (III). The cyclization of (III) by means of NaH in DMF yields the oxazinone (IV), which is reduced with LiAlH4 in refluxing THF to trans-9-methoxy-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazine (V). The alkylation of (V) with propyl bromide by means of K2CO3 in DMF gives the N-propyl derivative (VI), which is finally demethylated by means of pyridine hydrochloride at 200 C.

参考文献 中间体
合成目标
【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 .
【2】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
19502 Propyl bromide; 1-Bromopropane 106-94-5 C3H7Br 详情 详情
(I) 21376 2-amino-7-methoxy-3,4-dihydro-1(2H)-naphthalenone C11H13NO2 详情 详情
(II) 21377 2-chloro-N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)acetamide C13H14ClNO3 详情 详情
(III) 21378 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide C13H16ClNO3 详情 详情
(IV) 21379 (4aR,10bR)-9-methoxy-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one C13H15NO3 详情 详情
(V) 21380 (4aR,10bR)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C13H17NO2 详情 详情
(VI) 21381 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C16H23NO2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(C)

2) The reaction of 7-methoxy-1-tetralone (VII) with isopentyl nitrite and potassium tert-butoxide in ethanol - ether gives 7-methoxy-2-oxyimino-1-tetralone (VIII), which by reduction with H2 over Pd/C in THF and acylation with propanoyl chloride is converted to 7-methoxy-2-propionamido-1-tetralone (IX). The reduction of (IX) with NaBH4 in ethanol yields the alcohol (X), which by further reduction with LiAlH4 in THF affords trans-7-methoxy-2-(proylamino)-1,2,3,4-tetrahydronaphthalen-1-ol (XI). The cyclization of (XI) with chloroacetyl chloride by means of NaH in THF - acetonitrile gives trans-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth[1,2-b]-1,4-oxazin-3-one (XII), which is reduced with LiAlH4 in THF to compound (VI), already obtained.

参考文献 中间体
合成目标
【1】 Jones, J.H.; McClure, D.E.; Grenda, V.J. (Merck & Co., Inc.); Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them. EP 0080115 .
【2】 Williams, M.; Jones, J.H.; Randall, W.C.; Clineschmidt, B.V.; Martin, G.E.; Lumma, P.K.; Hirshfield, J.M.; Anderson, P.S.; McClure, D.E.; Lundell, G.F.; Baldwin, J.J.; Smith, G.; Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists. J Med Chem 1984, 27, 12, 1607.
【3】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951.
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) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(A) 21382 1-nitropentane 1002-16-0 C5H11NO2 详情 详情
(VI) 21381 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C16H23NO2 详情 详情
(VII) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(VIII) 21386 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime C11H11NO3 详情 详情
(IX) 21387 N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide C14H17NO3 详情 详情
(X) 21388 N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO3 详情 详情
(XI) 21389 (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol C14H21NO2 详情 详情
(XII) 21390 (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one C16H21NO3 详情 详情
(C) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情

合成路线23

该中间体在本合成路线中的序号：(C)

3) The acylation of D-aspartic acid (I) with methyl chloroformate and NaOH in water yields N-(methoxycarbonyl)-D-aspartic acid (II), which is anhydrized with oxalyl chloride and DMF in isopropyl acetate giving the corresponding anhydride (III). The Friedel-Craft's condensation of (III) with 2-chloroanisole (IV) by means of AlCl3 in nitromethane - dichloromethane affords 3-(3-chloro-4-methoxybenzoyl)-N-(methoxycarbonyl)-D-alanine (V), which is reduced with H2 over Pd/C in aqueous acetic acid to the substituted amino acid (VI). The reaction of (VI) with PCl5 or oxalyl chloride yields the corresponding acyl chloride (VII), which is cyclized by means of FeCl3 in nitromethane-dichloromethane affording 7-methoxy-2(R)-(methoxycarbonylamino)-1-tetralone (VIII). The reduction of (VIII) with sodium bis(methoxyethoxy) aluminum hydride (BMAlH) in toluene gives the trans-aminoalcohol (IX), which is deprotected by treatment with NaOH in methanol - water yielding (2R-trans)-2-amino-1-hydroxy-7-methoxytetraline (X). The acylation of (X) with propionyl anhydride in methanol - water affords the amide (XI), which is reduced with BH3-dimethyl sulfide giving [2(R)-trans]-1-hydroxy-7-methoxy-2-(propylamino)tetraline (XII). The acylation of (XII) with chloroacetyl chloride in toluene - aqueous Na2CO3 affords the chloroacetamide (XIII), which is cyclized by means of NaOH and tetrabutylammonium chloride to give [4a(R)-trans]-9-methoxy-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphth [1,2-b]-1,4-oxazin-3-one (XIV). The reduction of (XIV) with BMAlH as before gives the methylated product (XV), which is finally demethylated with BBr3 and cyclohexene in dichloromethane.

参考文献 中间体
合成目标
【1】 Melillo, D.G.; Mathre, D.J.; Larsen, R.D. (Merck & Co., Inc.); Chiral synthesis of (+)-trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-propyl-4H-naphth(1,2-b)- 1,4-oxazine. EP 0251547 .
【2】 Prous, J.; Castaner, J.; NAXAGOLIDE HYDROCHLORIDE < Prop INNM; USAN >. Drugs Fut 1989, 14, 10, 951.
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) 21391 D-aspartic acid; (2R)-2-aminobutanedioic acid 1783-96-6 C4H7NO4 详情 详情
(II) 21392 (2R)-2-[(methoxycarbonyl)amino]butanedioic acid C6H9NO6 详情 详情
(III) 21393 methyl (3R)-2,5-dioxotetrahydro-3-furanylcarbamate C6H7NO5 详情 详情
(IV) 21394 1-chloro-2-methoxybenzene 766-51-8 C7H7ClO 详情 详情
(V) 21395 (2R)-4-(3-chloro-4-methoxyphenyl)-2-[(methoxycarbonyl)amino]-4-oxobutyric acid C13H14ClNO6 详情 详情
(VI) 21396 (2R)-2-[(methoxycarbonyl)amino]-4-(4-methoxyphenyl)butyric acid C13H17NO5 详情 详情
(VII) 21397 methyl (1R)-1-(chlorocarbonyl)-3-(4-methoxyphenyl)propylcarbamate C13H16ClNO4 详情 详情
(VIII) 21398 methyl (2R)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate C13H15NO4 详情 详情
(IX) 21399 methyl (1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate C13H17NO4 详情 详情
(X) 21400 (1R,2R)-2-amino-7-methoxy-1,2,3,4-tetrahydro-1-naphthalenol C11H15NO2 详情 详情
(XI) 21388 N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO3 详情 详情
(XII) 21389 (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol C14H21NO2 详情 详情
(XIII) 21403 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylacetamide C16H22ClNO3 详情 详情
(XIV) 21390 (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one C16H21NO3 详情 详情
(XV) 21381 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C16H23NO2 详情 详情
(C) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XI)

The syntheses of remacemide [13C]-, [14C]-, [2H]-,and [3H]-labeled in several different positions have been described: The Friedel Crafts condensation of benzene with acetyl chloride (II) by means of AlCl3 in CS2 gives acetophenone (III), which by a Grignard condensation with benzylmagnesium chloride (IV) in THF yields 1,2-diphenyl-3-propanol (V). Reaction of (V) with NaCN and sulfuric acid in acetic acid affords the formamide (VI), which is hydrolyzed with refluxing aqueous HCl to give the amine (VII). The condensation of (VII) with N-Boc-glycine (VIII) and DCC or with the N-Boc-glycine mixed anhydride (IX) and TEA in dichloromethane yields the protected glycinamide (X), which is finally deprotected with HCl in refluxing methanol. Alternatively, condensation of amine (VII) with chloroacetyl chloride (XI) by means of pyridine in dichloromethane provides the chloroacetamide (XII), which is finally treated with ammonia in ethanol/dichloromethane. In this reaction sequence, the use of [carbonyl-14C]-acetophenone (III), [13C6]-benzene (I), [13C2]-acetyl chloride (II), the [1-13C]-glycines (VIII) and (IX) or the [2-3H]-glycine (VIII) as starting materials affords remacemide labeled in the corresponding positions. [2H or 3H]-remacemide labeled in 2,6-positions of the 1-phenyl ring is obtained by submitting the amine (VII) to isotopic exchange with 2H2O/RhCl3, 2H2/Iridium complex, or 3H2/Iridium complex.

参考文献 中间体
合成目标
【1】 Dawson, G.E.; Coombs, M.E.; Fedorchuk, M.; et al.; Preparation of remacemide hydrochloride labelled with carbon-14, carbon-13, deuterium and tritium. J Label Compd Radiopharm 2000, 43, 6, 533.
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) 13364 Benzene 71-43-2 C6H6 详情 详情
(II) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(III) 10317 Acetophenone 98-86-2 C8H8O 详情 详情
(IV) 18327 benzyl(chloro)magnesium 6921-34-2 C7H7ClMg 详情 详情
(V) 41763 1,2-diphenyl-2-propanol 5342-87-0 C15H16O 详情 详情
(VI) 41764 1-methyl-1,2-diphenylethylformamide C16H17NO 详情 详情
(VII) 41765 1-methyl-1,2-diphenylethylamine; 1,2-diphenyl-2-propanamine C15H17N 详情 详情
(VIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(IX) 41766 [(tert-butoxycarbonyl)amino]acetic 1,1-dimethylpropionic anhydride C12H21NO5 详情 详情
(X) 41767 tert-butyl 2-[(1-methyl-1,2-diphenylethyl)amino]-2-oxoethylcarbamate C22H28N2O3 详情 详情
(XI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XII) 41768 2-chloro-N-(1-methyl-1,2-diphenylethyl)acetamide C17H18ClNO 详情 详情

合成路线25

该中间体在本合成路线中的序号：(IV)

The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II), which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III). The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 - water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V), which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI). Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII), which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII). Finally, this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.

参考文献 中间体
合成目标
【1】 Tahara, T.; Kawakita, T.; Yasumoto, M.; Fukuda, T. (Welfide Corporation); Benzoxazine cpds. and pharmaceutical use thereof. EP 0313393; JP 1989207290; JP 1990005415; US 4892872 .
【2】 Prous, J.; Castaner, J.; Azasetron Hydrochloride. Drugs Fut 1993, 18, 3, 206.
【3】 Kawakita, T.; Tahara, T.; Kuroita, T.; Yasumoto, M.; Sano, M.; Fukuda, T.; Inaba, K.; Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists. Chem Pharm Bull 1992, 40, 3, 624-30.
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) 13714 Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate 4068-78-4 C8H7ClO3 详情 详情
(II) 13715 Methyl 5-chloro-2-hydroxy-3-nitrobenzoate C8H6ClNO5 详情 详情
(III) 13716 Methyl 3-amino-5-chloro-2-hydroxybenzoate C8H8ClNO3 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 13718 Methyl 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate C10H8ClNO4 详情 详情
(VI) 13719 Methyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate C11H10ClNO4 详情 详情
(VII) 13720 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid C10H8ClNO4 详情 详情
(VIII) 13721 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carbonyl chloride C10H7Cl2NO3 详情 详情
(IX) 13722 1-Azabicyclo[2.2.2]oct-3-ylamine; 3-Quinuclidinamine; 3-Aminoquinuclidin 6238-14-8 C7H14N2 详情 详情

合成路线26

该中间体在本合成路线中的序号：(VII)

Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.

参考文献 中间体
合成目标
【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084.
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) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(II) 34050 methyl pentanimidoate C6H13NO 详情 详情
(III) 34051 2-butyl-3,5-dihydro-4H-imidazol-4-one C7H12N2O 详情 详情
(IV) 34052 2-butyl-5-chloro-1H-imidazole C7H11ClN2 详情 详情
(V) 34053 N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine C10H16ClN3 详情 详情
(VI) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IX) 14576 pentanimidamide 109-51-3 C5H12N2 详情 详情
(X) 34054 2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one C10H17N3O 详情 详情
(XI) 13925 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 83857-96-9 C8H11ClN2O 详情 详情
(XII) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XIII) 34055 2-(pentanimidoylamino)acetic acid C7H14N2O2 详情 详情
(XIV) 13921 Pentanenitrile; n-Valeronitrile 110-59-8 C5H9N 详情 详情

合成路线27

该中间体在本合成路线中的序号：(III)

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28

该中间体在本合成路线中的序号：(II)

The Friedel Crafts condensation of 6-chloroindolin-2-one (I) with 14C labeled 2-chloroacetyl chloride (II) by means of AlCl3 in CS2 gives 6-chloro-5-(2-chloroacetyl)indolin-2-one (III), which is reduced with trimethylsilane in TFA to yield the labeled chloroethyl derivative (IV). Finally, this compound is condensed with 3-(1-piperazinyl)-1,2-benzoisothiazole (V) by means of Na2CO3 in refluxing water to provide the target radiolabeled compound.

参考文献 中间体
合成目标
【1】 Howard, H.R.; Shenk, K.D.; Smolarek, T.A.; Marx, M.H.; Windels, J.H.; Roth, R.W.; Synthesis of H-3- and C-14-labelled CP-88,059: A potent atypical antipsychotic agent. J Label Compd Radiopharm 1994, 34, 2, 117.
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) 16275 6-chloro-1,3-dihydro-2H-indol-2-one 56341-37-8 C8H6ClNO 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 62883 2-chloroacetyl chloride C2Cl2O 详情 详情
(III) 16276 6-chloro-5-(2-chloroacetyl)-1,3-dihydro-2H-indol-2-one C10H7Cl2NO2 详情 详情
(III) 62884 6-chloro-5-(2-chloroacetyl)-1,3-dihydro-2H-indol-2-one C10H5Cl2NO2 详情 详情
(IV) 16277 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one- C10H9Cl2NO 详情 详情
(IV) 62885 6-Chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one C10H7Cl2NO 详情 详情
(V) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情

合成路线29

该中间体在本合成路线中的序号：(V)

The synthesis of the intermediate (chlorophenyl)piperazinone (VIII) has been reported by two procedures. The hydrochloride salt prepared from 3-chloroaniline (I) was treated with 2-oxazolidinone (II) at 160 C to produce the aryl ethylenediamine (III), which was subsequently protected as the N-Boc derivative (IV). Acylation of aniline (IV) with chloroacetyl chloride (V) gave the chloroacetamide (VI). This was then cyclized to the piperazinone (VII) by treatment with K2CO3 in hot DMF. Further acid deprotection of the Boc group of (VII) afforded the intermediate (VIII).

参考文献 中间体
合成目标
【1】 Anthony, N.J.; Ciccarone, T.M.; Gomez, R.P.; Hutchinson, J.H.; Williams, T.M.; Dinsmore, C.J.; Stokker, G.E. (Merck & Co., Inc.); Inhibitors of farnesyl-protein transferase. EP 0820445; JP 1998511098; US 5856326; WO 9630343 .
【2】 Williams, T.M.; Dinsmore, C.J.; Hutchinson, J.H. (Merck & Co., Inc.); Inhibitors of prenyl-protein transferase. EP 1014984; WO 9909985 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(II) 21456 1,3-oxazolidin-2-one 497-25-6 C3H5NO2 详情 详情
(III) 37091 　 C7H5Cl2FNO2P 详情 详情
(IV) 47286 tert-butyl 2-(3-chloroanilino)ethylcarbamate C13H19ClN2O2 详情 详情
(V) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VI) 47287 tert-butyl 2-[3-chloro(2-chloroacetyl)anilino]ethylcarbamate C15H20Cl2N2O3 详情 详情
(VII) 47288 tert-butyl 4-(3-chlorophenyl)-3-oxo-1-piperazinecarboxylate C15H19ClN2O3 详情 详情
(VIII) 47289 1-(3-chlorophenyl)-2-piperazinone C10H11ClN2O 详情 详情

合成路线30

该中间体在本合成路线中的序号：(V)

In an alternative procedure, 3-chloroaniline (I) was acylated with chloroacetyl chloride (V) to produce chloroacetamide (IX). Displacement of the chloride group of (IX) with ethanolamine (X) gave rise to the amide alcohol (XI), which was then cyclized to the piperazinone (VIII) under Mitsunobu conditions.

参考文献 中间体
合成目标
【1】 Cowen, J.A.; Askin, D.; McWilliams, J.C.; Maligres, P.E.; McCauley, J.A. (Merck & Co., Inc.); Process for making farnesyl-protein transferase inhibitors. WO 0001691 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(V) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 47289 1-(3-chlorophenyl)-2-piperazinone C10H11ClN2O 详情 详情
(IX) 47290 2-chloro-N-(3-chlorophenyl)acetamide C8H7Cl2NO 详情 详情
(X) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(XI) 47291 N-(3-chlorophenyl)-2-[(2-hydroxyethyl)amino]acetamide C10H13ClN2O2 详情 详情

合成路线31

该中间体在本合成路线中的序号：(IV)

Cyclization of D-tryptophan methyl ester (I) with piperonal (II) by means of TFA in dichloromethane gives, after separation of the undesired trans-isomer by flash chromatography, the (1R,3R-cis)-pyrido-indole derivative (III). The acylation of (III) with chloroacetyl chloride (IV) and NaHCO3 in chloroform yields the chloroacetyl derivative (V), which is finally cyclized with methylamine in methanol.

参考文献 中间体
合成目标
【1】 Daugan, A.; Grondin, P.; Ruault, C.; et al.; The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem 2003, 46, 21, 4533.
【2】 Martin, L.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; IC-351. Drugs Fut 2001, 26, 1, 15.
【3】 Daugan, A.C.-M. (Icos Corp.); Tetracyclic derivs., process of preparation and use. EP 0740668; JP 1997508113; US 5859006; US 6025494; US 6127542; WO 9519978 .
【4】 Daugan, A.C.-M. (Icos Corp.); Use of cGMP-phosphodiesterase inhibitors to treat impotence. JP 1999509221; US 6140329; WO 9703675 .
【5】 Gellibert, F.; Daugan, A.C.-M. (Icos Corp.); Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use. US 6143746 .
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) 20416 methyl (2R)-2-amino-3-(1H-indol-3-yl)propanoate C12H14N2O2 详情 详情
(II) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(III) 43790 methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate C20H18N2O4 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 43791 methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylate C22H19ClN2O5 详情 详情

合成路线32

该中间体在本合成路线中的序号：(VI)

The protection of the 3-(2-aminoethyl)-1H-indol-5-ol (I) with di-tert-butyl dicarbonate gives the corresponding carbamate (II), which is condensed with the chloroacetyl piperazine (III) (obtained by reaction of 4-(1-piperazinyl) benzonitrile (IV) with chloroacetyl chloride (V) by means of CaCO3) using K2CO3 and KI in refluxing 2-butanone to yield the protected target compound (V). Finally, this compound is deprotected with TFA in toluene.

参考文献 中间体
合成目标
【1】 Halazy, S.; Perez, M.; Briley, M.; Pauwels, P. (Pierre Fabre Medicament); Indole-derived azylpiperazines as ligands for 5HT1-like receptors 5HT1B and 5HT1D. EP 0729455; FR 2712591; JP 1997505072; US 5726177; WO 9514004 .
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) 26317 3-(2-Aminoethyl)-5-hydroxyindole; 5-Hydroxytryptamine; 3-(2-Aminoethyl)-1H-indol-5-ol 50-67-9 C10H12N2O 详情 详情
(II) 26321 tert-butyl 2-(5-hydroxy-1H-indol-3-yl)ethylcarbamate C15H20N2O3 详情 详情
(III) 26319 4-(1-piperazinyl)benzonitrile C11H13N3 详情 详情
(IV) 26320 4-[4-(2-chloroacetyl)-1-piperazinyl]benzonitrile C13H14ClN3O 详情 详情
(V) 26322 tert-butyl 2-(5-[2-[4-(4-cyanophenyl)-1-piperazinyl]-2-oxoethoxy]-1H-indol-3-yl)ethylcarbamate C28H33N5O4 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情

合成路线33

该中间体在本合成路线中的序号：(V)

3-Hydroxy-4-nitrobenzaldehyde (I) was treated with 1,3-propanediol (II) in the presence of p-toluenesulfonic acid to afford the corresponding acetal (III). Catalytic hydrogenation of the nitro group of (III) over Raney-Ni gave aniline (IV), which was then acylated with chloroacetyl chloride (V) in the presence of NaHCO3 to the chloroacetamide (VI). The acetal function of (VI) was hydrolyzed with HCl in aqueous MeOH, and subsequent cyclization of the chloroacetamide (VII) using K2CO3 in acetonitrile produced the formylbenzoxazinone (VIII). The target compound was then prepared by reductive condensation of aldehyde (VIII) with N-(4-chlorophenyl)piperazine (IX) in the presence of sodium triacetoxyborohydride and AcOH.

参考文献 中间体
合成目标
【1】 Brink, W.A.; Wustrow, D.J.; Belliotti, T.R.; et al.; A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: Discovery of a potential atypical antipsychotic agent. J Med Chem 1999, 42, 25, 5181.
【2】 Belliotti, T.; Wise, L.D.; Wustrow, D.J. (Pfizer Inc.); Benzoxazinone dopamine D4 receptor antagonists. EP 0906294; WO 9745419 .
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) 21032 3-hydroxy-4-nitrobenzaldehyde C7H5NO4 详情 详情
(III) 21034 5-(1,3-dioxan-2-yl)-2-nitrophenol C10H11NO5 详情 详情
(IV) 21035 (rac)-2-amino-5-(1,3-dioxan-2-yl)phenol C10H13NO3 详情 详情
(V) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VI) 21037 2-chloro-N-[4-(1,3-dioxan-2-yl)-2-hydroxyphenyl]acetamide C12H14ClNO4 详情 详情
(VII) 21038 2-chloro-N-(4-formyl-2-hydroxyphenyl)acetamide C9H8ClNO3 详情 详情
(VIII) 21039 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carbaldehyde C9H7NO3 详情 详情

合成路线34

该中间体在本合成路线中的序号：(VII)

The reaction of N-(tert-butoxycarbonyl)-L-norleucine (I) with N,O-dimethylhydroxylamine (II) by means of EDC, HOBT and TEA in DMF gives the methoxyamide (III), which is reduced with LiAlH4 to the corresponding aldehyde (IV). The reductocondensation of (IV) with 3-(trifluoromethoxy)aniline (V) by means of NaBH(OAc)3 affords the secondary amine (VI), which is acylated with chloroacetyl chloride (VII) and NaHCO3 to the chloroacetamide (VIII). The cyclization of (VIII) by means of Cs2CO3 in DMF gives the piperazinone (IX), which is finally reductocondensed with 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) by means of NaBH(OAc)3. The intermediate 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) has been obtained as follows: The tritylation of 1H-imidazole-4-methanol (XI) with trityl chloride and TEA in DMF gives the corresponding 1-trityl derivative (XII), which is acetylated with Ac2O and pyridine yielding the acetate (XIII). The condensation of (XIII) with 4-(bromomethyl)benzonitrile (XIV) in hot ethyl acetate affords 4-(5-acetoxyimidazol-1-ylmethyl)benzonitrile (XV), which is hydrolyzed with LiOH in THF/water providing the carbinol (XVI). Finally, this alcohol is oxidized to the target aldehyde (X) by means of SO3 and pyridine in DMSO.

参考文献 中间体
合成目标
【1】 Bergman, J.M.; Brashear, K.; Williams, T.M.; et al.; N-Arylpiperazinone inhibitors of farnesyltransferase: Discovery and biological activity. J Med Chem 1999, 42, 19, 3779.
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) 20398 (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid C11H21NO4 详情 详情
(II) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(III) 38382 tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]pentylcarbamate C13H26N2O4 详情 详情
(IV) 38383 tert-butyl (1S)-1-formylpentylcarbamate C11H21NO3 详情 详情
(V) 38384 3-(trifluoromethoxy)phenylamine; 3-(trifluoromethoxy)aniline 1535-73-5 C7H6F3NO 详情 详情
(VI) 38385 tert-butyl (1S)-1-[[3-(trifluoromethoxy)anilino]methyl]pentylcarbamate C18H27F3N2O3 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 38386 tert-butyl (1S)-1-[[(2-chloroacetyl)-3-(trifluoromethoxy)anilino]methyl]pentylcarbamate C20H28ClF3N2O4 详情 详情
(IX) 38387 tert-butyl (2S)-2-butyl-5-oxo-4-[3-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate C20H27F3N2O4 详情 详情
(X) 38388 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile C12H9N3O 详情 详情
(XI) 38393 1H-imidazol-4-ylmethanol C4H6N2O 详情 详情
(XII) 38392 (1-trityl-1H-imidazol-4-yl)methanol C23H20N2O 详情 详情
(XIII) 38391 (1-trityl-1H-imidazol-4-yl)methyl acetate C25H22N2O2 详情 详情
(XIV) 14200 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile 17201-43-3 C8H6BrN 详情 详情
(XV) 38390 [1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate C14H13N3O2 详情 详情
(XVI) 38389 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile C12H11N3O 详情 详情

合成路线35

该中间体在本合成路线中的序号：(VI)

Friedel-Crafts acylation of thioanisole (I) with isobutyryl chloride (II) in the presence of AlCl3 gave ketone (III), which was hydroxylated with NaOH and a phase-transfer agent in CCl4-toluene to provide hydroxyketone (IV). Subsequent oxidation of the sulfide group employing Oxone(tm) gave rise to sulfone (V) (1). Further esterification of (V) with chloroacetyl chloride (VI) and pyridine yielded chloroacetate ester (VII), which was cyclized to the epoxy lactone (VIII) by treatment with DBU in acetonitrile. Finally, epoxide opening with the potassium salt of 5-bromo-2-hydroxypyridine (IX) produced the title (pyridyloxy)furanone.

参考文献 中间体
合成目标
【1】 Chan, C.C.; Lau, C.K.; Brideau, C.; et al.; Synthesis and biological evaluation of 3-heteroaryloxy-4-phenyl-2(5H)-furanones as selective COX-2 inhibitors. Bioorg Med Chem Lett 1999, 9, 22, 3187.
【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 .
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) 19272 methyl phenyl sulfide; 1-(methylsulfanyl)benzene 100-68-5 C7H8S 详情 详情
(II) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(III) 36573 2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone C11H14OS 详情 详情
(IV) 36574 2-hydroxy-2-methyl-1-[4-(methylsulfanyl)phenyl]-1-propanone C11H14O2S 详情 详情
(V) 36575 2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-propanone C11H14O4S 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 36576 1,1-dimethyl-2-[4-(methylsulfonyl)phenyl]-2-oxoethyl 2-chloroacetate C13H15ClO5S 详情 详情
(VIII) 36577 4,4-dimethyl-5-[4-(methylsulfonyl)phenyl]-3,6-dioxabicyclo[3.1.0]hexan-2-one C13H14O5S 详情 详情
(IX) 36578 potassium 5-bromo-2-pyridinolate C5H3BrKNO 详情 详情

合成路线36

该中间体在本合成路线中的序号：(III)

Treatment of (R)-1-aminoindan (I) with trifluoroacetic anhydride in toluene affords trifluoroacetyl derivative (II), which is condensed with chloroacetyl chloride (III) by means of AlCl3 in 1,2-dichloroethane to provide compound (IV). Oxidation of chloroacetyl derivative (IV) with 3-chloroperoxybenzoic acid (mCPBA) and TFA in CH2Cl2 allows formation of chloroacetoxy (V), which is converted into the hydroxy form (VI) by heating in hot methanol/H2O in the presence of K2CO3. N-Protection of (VI) is then performed by treatment with di-t-butyl dicarbonate and Et3N in THF to furnish Boc derivative (VII), which is then converted into derivative (IX) by O-acylation with N-Me, N-Et carbamoyl chloride (VIII) by means of NaH in acetonitrile. Removal of the Boc group of (IX) by treatment with HCl (gas) in dioxane gives hydrochloride (X), which is finally N-alkylated with propargyl bromide (XI) by means of K2CO3 in acetonitrile to yield the desired product.

参考文献 中间体
合成目标
【1】 Youdim, M.B.H.; Herzig, Y.; Sterling, J.; Goren, T.; Chorev, M. (Technion - Israel Institute of Technology; Teva Pharmaceutical Industries Ltd.; Yissum Research Development Co.); Aminoindan derivs.. EP 0966435; JP 2001506269; WO 9827055 .
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) 14863 (1R)-2,3-Dihydro-1H-inden-1-ylamine; (R)-(-)-1-Aminoindan; (1R)-2,3-Dihydro-1H-inden-1-amine 10277-74-4 C9H11N 详情 详情
(II) 46687 N-[(1R)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide C11H10F3NO 详情 详情
(III) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(IV) 46688 N-[(1R)-6-(2-chloroacetyl)-2,3-dihydro-1H-inden-1-yl]-2,2,2-trifluoroacetamide C13H11ClF3NO2 详情 详情
(V) 46689 (3R)-3-[(2,2,2-trifluoroacetyl)amino]-2,3-dihydro-1H-inden-5-yl 1lambda(3)-dichlorane-1-carboxylate C12H10Cl2F3NO3 详情 详情
(VI) 46690 (3R)-3-amino-2,3-dihydro-1H-inden-5-ol C9H11NO 详情 详情
(VII) 46691 tert-butyl (1R)-6-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate C14H19NO3 详情 详情
(VIII) 46692 1,2-dimethyl-1-hydrazinecarbonyl chloride C3H7ClN2O 详情 详情
(IX) 46693 (3R)-3-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate C17H25N3O4 详情 详情
(X) 46694 (3R)-3-amino-2,3-dihydro-1H-inden-5-yl 1,2-dimethyl-1-hydrazinecarboxylate C12H17N3O2 详情 详情
(XI) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情

合成路线37

该中间体在本合成路线中的序号：(X)

The condensation of 3-(4-morpholinylmethyl)-2H-1-benzopyran-8-ol (VI) with 2(R)-(p-toluenesulfonyloxymethyl)-4-(triphenylmethyl)morpholine (XVI) by means of K2CO3 in DMF gives the protected target compound (XVII), which is finally deprotected with acetic acid and salified with methanesulfonic acid. The intermediates benzopyran (VI) and morpholine (XVI) have been obtained as follows: Benzopyran (VI): The reaction of 8-methoxy-4H-1-benzopyran-3-carboxylic acid (I) with SOCl2 in refluxing toluene gives the acyl chloride (II), which is condensed with morpholine (III) in dioxane yielding the methanone (IV). The reaction of (IV) with BBr3 in dichloromethane affords the 1-(8-hydroxy-2H-1-benzopyran-3-yl)-1-(4-morpholinyl)methanone (V), which is reduced with LiAlH4 in THF giving the desired intermediate benzopyran (VI). Morpholine (XVI): The reaction of benzyl (S)-glycicyl ether (VII) with benzylamine (VIII) gives 1-(benzylamino)-3-(benzyloxy)-2(R)-propanol (IX), which is cyclized with chloroacetyl chloride (X) and triethylamine in dichloromethane yielding the morpholinone (XI). The reduction of (XI) with LiAlH4 in ethyl ether affords the fully protected morpholine (XII), which is debenzylated with H2 over Pd/C in ethanol giving 2(R)-(hydroxyethyl)morpholine (XIII). The reaction of (XIII) with trityl chloride (XIV) and TEA in dichloromethane yields the N-tritylmorpholine (XV), which is finally tosylated with tosyl chloridde and pyridine affording the desired intermediate morpholine (XVI).

参考文献 中间体
合成目标
【1】 Berg, S.; et al.; (R)-(+)-2[[[3-(Morpholinomethyl)-2H-chromen-8-yl]oxy]methyl]morpholine methanesulfonate: A new selective rat 5-hydroxytryptamine1B receptor antagonist. J Med Chem 1998, 41, 11, 1934.
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) 28621 8-methoxy-2H-chromene-3-carboxylic acid 57543-59-6 C11H10O4 详情 详情
(II) 28622 8-methoxy-2H-chromene-3-carbonyl chloride C11H9ClO3 详情 详情
(III) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(IV) 28623 (8-methoxy-2H-chromen-3-yl)(4-morpholinyl)methanone C15H17NO4 详情 详情
(V) 28624 (8-hydroxy-2H-chromen-3-yl)(4-morpholinyl)methanone C14H15NO4 详情 详情
(VI) 28625 3-(4-morpholinylmethyl)-2H-chromen-8-ol C14H17NO3 详情 详情
(VII) 22645 (1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-1-naphthalenyl (2S)-2-methylbutanoate; Lovastatin 75330-75-5 C24H36O5 详情 详情
(VIII) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(IX) 28626 (2S)-1-(benzylamino)-3-(benzyloxy)-2-propanol C17H21NO2 详情 详情
(X) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XI) 28627 (6R)-4-benzyl-6-[(benzyloxy)methyl]-3-morpholinone C19H21NO3 详情 详情
(XII) 28628 benzyl [(2R)-4-benzylmorpholinyl]methyl ether C19H23NO2 详情 详情
(XIII) 12353 (2R)-1,4-Oxazinan-2-ylmethanol C5H11NO2 详情 详情
(XIV) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(XV) 28629 [(2R)-4-tritylmorpholinyl]methanol C24H25NO2 详情 详情
(XVI) 28631 [(2R)-4-tritylmorpholinyl]methyl 4-methylbenzenesulfonate C31H31NO4S 详情 详情
(XVII) 28632 (2R)-2-([[3-(4-morpholinylmethyl)-2H-chromen-8-yl]oxy]methyl)-4-tritylmorpholine C38H40N2O4 详情 详情

合成路线38

该中间体在本合成路线中的序号：(IX)

The reduction of the ester function of (I) with LiAlH4 in THF gives (II). O-demethylation of (II) with EtSNa in DMF yields alcohol (III), which is then cyclized by Mitsunobu reaction with DEAD·Ph3P in THF to yield (IV). Displacement of the Br of (IV) by means of Zn(CN)2 and Pd(PPh3)4 in DMF affords cyano derivative (V), which is then converted into (VI) after debenzylation by treatment with HCl/EtOH and H2 over Pd/C. Finally (VI) is coupled with aldehyde (VII) by reductive amination in 1,2-dichloroethane in presence of NaBH(OAc)3.Alternatively the final product can be obtained by reaction of (VI) with chloro derivative (X) in CH3CN in presence of K2CO3 and KI. (X) can be obtained by acylation of acetanilide (VIII) with chloride (A) in 1,2-dichloroethane in presence of AlCl3 followed by treatment with TFA and Et3SiH.

参考文献 中间体
合成目标
【1】 Audinot, V.; Dubuffet, T.; Newman-Tancredi, A.; Cussac, D.; Millan, M.J.; Lavielle, G.; Loutz, A.; Novel benzopyrano[3,4-c]pyrrole derivatives as potent and selective dopamine D3 receptor antagonists. Bioorg Med Chem Lett 1999, 9, 14, 2059.
【2】 Lejeune, F.; Hautefaye, P.; Millan, M.; Dubuffet, T.; Lavielle, G. (ADIR et Cie.); Chromene derivs., process for their preparation and pharmaceutical compsns. containing them. EP 0887350; JP 1999071376; US 6090837 .
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) 33760 methyl (3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)-3-pyrrolidinecarboxylate C20H22BrNO3 详情 详情
(II) 33761 [(3R,4S)-1-benzyl-4-(5-bromo-2-methoxyphenyl)pyrrolidinyl]methanol C19H22BrNO2 详情 详情
(III) 33762 2-[(3S,4R)-1-benzyl-4-(hydroxymethyl)pyrrolidinyl]-4-bromophenol C18H20BrNO2 详情 详情
(IV) 41665 (3aS,9bR)-2-benzyl-8-bromo-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole C18H18BrNO 详情 详情
(V) 41666 (3aS,9bR)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile C19H18N2O 详情 详情
(VI) 41667 (3aS,9bR)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile C12H12N2O 详情 详情
(VII) 41662 N-[4-(2-oxoethyl)phenyl]acetamide C10H11NO2 详情 详情
(VIII) 10194 N-Phenylacetamide; Acetanilide 103-84-4 C8H9NO 详情 详情
(IX) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(X) 41663 N-[4-(2-chloroacetyl)phenyl]acetamide C10H10ClNO2 详情 详情
(XI) 41664 N-[4-(2-chloroethyl)phenyl]acetamide C10H12ClNO 详情 详情

合成路线39

该中间体在本合成路线中的序号：(II)

Treatment of an excess of indole (I) with chloroacetyl chloride (II) in the presence of AlCl3 under Friedel-Crafts conditions produced the trimer intermediate (III), which was cyclized and acylated to yield the title indolyl quinoline.

参考文献 中间体
合成目标
【1】 Chakrabarti, G.; et al.; Indolylquinoline derivatives are cytotoxic to Leishmania donovani promastigotes and amastigotes in vitro and are effective in treating murine visceral leishmaniasis. J Antimicrob Chemother 1999, 43, 3, 359.
【2】 Mahato, S.B.; et al.; Synthesis of indolylquinolines under Friedel-Crafts reaction conditions. Tetrahedron 1994, 50, 36, 10803.
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) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 29273 N-(1H-indol-2-yl)-N-[2-[(E)-2-(1H-indol-3-yl)ethenyl]phenyl]amine C24H19N3 详情 详情

合成路线40

该中间体在本合成路线中的序号：(IV)

A new synthetic route has been reported. 4-Amino-1-benzylpiperidine (I) was protected as the t-butyl carbamate (II) using Boc2O, and the N-benzyl group was subsequently removed by transfer hydrogenolysis, yielding 4-(t-butoxycarbonylamino)piperidine (III). Butyl chloroacetate (V), prepared by treatment of chloroacetyl chloride (IV) with n-butanol, was then condensed with piperidine (III) to afford (VI). After acidic cleavage of the Boc protecting group of (VI), the resultant amino piperidine (VII) was acylated with the mixed anhydride (VIII) to provide the target amide.

参考文献 中间体
合成目标
【1】 Sakaguchi, J.; et al.; An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224). Chem Pharm Bull 2001, 49, 6, 788.
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) 34808 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 50541-93-0 C12H18N2 详情 详情
(II) 56563 tert-butyl 1-benzyl-4-piperidinylcarbamate C17H26N2O2 详情 详情
(III) 41601 tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine 73874-95-0 C10H20N2O2 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 14595 n-Butyl Chloroacetate; butyl 2-chloroacetate 590-02-3 C6H11ClO2 详情 详情
(VI) 51930 butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate C16H30N2O4 详情 详情
(VII) 51931 butyl 2-(4-amino-1-piperidinyl)acetate C11H22N2O2 详情 详情
(VIII) 29299 4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride C10H10ClNO5 详情 详情

合成路线41

该中间体在本合成路线中的序号：(VI)

Nitrosation of 7-methoxy-2-tetralone (I) using isoamyl nitrite and potassium tert-butoxide provided the oximino ketone (II). Catalytic hydrogenation of the oxime function of (II) in the presence of propionic anhydride gave rise to the propionamide (III). Ketone reduction by means of NaBH4 produced a mixture of cis- and trans-hydroxy amides from which the pure trans-isomer (IV) was isolated after two recrystallizations from EtOAc. The amide function of (IV) was subsequently reduced with LiAlH-4 to the N-propyl amine (V). Acylation of amino alcohol (V) with chloroacetyl chloride (VI) afforded the corresponding chloroacetamido alcohol (VII), which was further cyclized to compound (VIII) upon treatment with NaH. The lactam carbonyl group of (VIII) was then reduced with borane-dimethyl sulfide complex to the cyclic amine (IX). Methyl ether cleavage in (IX) to produce phenol (X) was then achieved by heating with pyridine hydrochloride (1). Phenol (X) was converted to the aryl triflate (XI) by treatment with trifluoromethanesulfonic anhydride. Displacement of the triflate group of (XI) with zinc cyanide in the presence of Pd catalyst furnished nitrile (XII). Partial hydrolysis of the nitrile (XII) under basic conditions produced the corresponding racemic amide. The title dextro-enantiomer was then isolated by preparative chiral HPLC.

参考文献 中间体
合成目标
【2】 Millan, M.; Lejeune, F.; Peglion, J.-L.; Harmange, J.-C. (ADIR et Cie.); Disubstd. trans-3,4,4a,5,6,10b-hexahydro-2H-napht(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical compsns. containing them. CA 2246482; EP 0899267; FR 2767825; JP 1999130759; US 6025356 .
【1】 Peglion, J.-L.; et al.; Discovery of S32504. A preferential agonist at dopamine D3 vs. D2 receptors possessing antiparkinsonian and antidepressant properties. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 208.
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) 21385 7-methoxy-3,4-dihydro-1(2H)-naphthalenone 6836-19-7 C11H12O2 详情 详情
(II) 21386 7-methoxy-3,4-dihydro-1,2-naphthalenedione 2-oxime C11H11NO3 详情 详情
(III) 21387 N-(7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl)propanamide C14H17NO3 详情 详情
(IV) 21388 N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide C14H19NO3 详情 详情
(V) 21389 (1R,2R)-7-methoxy-2-(propylamino)-1,2,3,4-tetrahydro-1-naphthalenol C14H21NO2 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 21403 2-chloro-N-[(1R,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylacetamide C16H22ClNO3 详情 详情
(VIII) 21390 (4aR,10bR)-9-methoxy-4-propyl-4a,5,6,10b-tetrahydro-2H-naphtho[1,2-b][1,4]oxazin-3(4H)-one C16H21NO3 详情 详情
(IX) 21381 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl methyl ether C16H23NO2 详情 详情
(X) 51579 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol C15H21NO2 详情 详情
(XI) 51580 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-yl trifluoromethanesulfonate C16H20F3NO4S 详情 详情
(XII) 51581 (4aR,10bR)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine-9-carbonitrile C16H20N2O 详情 详情

合成路线42

该中间体在本合成路线中的序号：(VII)

The acylation of 3-aminobenzoic acid with acetic anhydride in ethyl acetate gives the corresponding acetamide (II), which is treated with SOCl2 in refluxing ethyl acetate yielding 3-(trifluoroacetamido)benzoyl chloride (III). The reaction of (III) with urea (IV) in toluene at 100 C gives the acylated urea (V), which is deprotected with butylamine in refluxing methanol to afford N-(3-aminobenzoyl)urea (VI). The acylation of (VI) with chloroacetyl chloride (VII) in dimethylacetamide provides the corresponding amide (VIII), which is finally treated with NaI in dimethylacetamide.

参考文献 中间体
合成目标
【1】 Bekesi, J.G.; Holland, J.F.; Jiang, J.-D.; Ma, L.; Roboz, J.; Deng, L.; Weisz, I.; Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas. Anti-Cancer Drug Des 1998, 13, 7, 735.
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) 26638 3-Aminobenzoic acid 99-05-8 C7H7NO2 详情 详情
(II) 26639 3-[(2,2,2-trifluoroacetyl)amino]benzoic acid C9H6F3NO3 详情 详情
(III) 26640 3-[(2,2,2-trifluoroacetyl)amino]benzoyl chloride C9H5ClF3NO2 详情 详情
(IV) 19310 urea 57-13-6 CH4N2O 详情 详情
(V) 26641 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2,2,2-trifluoroacetamide C10H8F3N3O3 详情 详情
(VI) 26642 N-(3-aminobenzoyl)urea C8H9N3O2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 26643 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2-chloroacetamide C10H10ClN3O3 详情 详情

合成路线43

该中间体在本合成路线中的序号：(VI)

The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia/THF/ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene/THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH/THF to provide N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V). The acylation of (V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160?C to afford 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol/water and acidified with 1N HCl. Alternatively, the intermediate N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V) can also be obtained by condensation of 2-chloro-N-(4-methylphenyl)acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).

参考文献 中间体
合成目标
【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Lumiracoxib. Drugs Fut 2002, 27, 8, 740.
【2】 Xu, D.; Allmendinger, T.; Acemoglu, M.; Calienni, J.V.; Cercus, J.; Loiseleur, O.; Sedelmeier, G. (Novartis AG; Novartis-Erfindungen VmbH); Process for phenylacetic acid derivs.. WO 0123346 .
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) 53835 1-Methoxy-4-methylbenzene; 4-Methylanisole; Methyl P-Tolyl Ether; p-Cresyl methyl ether; 4-Methoxytoluene 104-93-8 C8H10O 详情 详情
(II) 53836 1-methoxy-4-methyl-1,4-cyclohexadiene; methyl 4-methyl-1,4-cyclohexadien-1-yl ether n/a C8H12O 详情 详情
(III) 53837 2-Chloro-6-fluoroaniline 363-51-9 C6H5ClFN 详情 详情
(IV) 53838 N-(2-chloro-6-fluorophenyl)-N-(4-methyl-2-cyclohexen-1-ylidene)amine; 2-chloro-6-fluoro-N-(4-methyl-2-cyclohexen-1-ylidene)aniline n/a C13H13ClFN 详情 详情
(V) 53839 2-chloro-6-fluoro-N-(4-methylphenyl)aniline; N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine n/a C13H11ClFN 详情 详情
(VI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VII) 53840 2-chloro-N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)acetamide n/a C15H12Cl2FNO 详情 详情
(VIII) 53841 1-(2-chloro-6-fluorophenyl)-5-methyl-1,3-dihydro-2H-indol-2-one n/a C15H11ClFNO 详情 详情
(IX) 31229 2-chloro-N-(4-methylphenyl)acetamide C9H10ClNO 详情 详情
(X) 53842 2-chloro-6-fluorophenol 2040-90-6 C6H4ClFO 详情 详情
(XI) 53843 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide n/a C15H13ClFNO2 详情 详情

合成路线44

该中间体在本合成路线中的序号：

Reaction of 3-fluoroaniline (I) with formic acid gave formanilide (II), which was reduced by means of LiAlH4 to afford 3-fluoro-N-methylaniline (III). Further alkylation of (III) with benzyl chloride provided the tertiary amine (IV). Vilsmeier-Haack formylation of (IV) with POCl3 and DMF yielded aldehyde (V), which was condensed with nitroethane in the presence of ammonium acetate to give the 2-nitropropene derivative (VI). After reduction of (VI) to the amine (VII) with LiAlH4, condensation with chloroacetyl chloride afforded chloracetamide (VIII). Subsequent displacement of the chlorine of (VIII) with dibenzylamine yielded the tertiary amine (IX). Finally, hydrogenolytic debenzylation of (IX) in the presence of Pd/C furnished the title compound.

参考文献 中间体
合成目标
【1】 Larsson, L.-G.; Florvall, L.; Ross, S.B.; Fagervall, I.; Prodrugs of neuron-selective monoamine oxidase inhibitors: Amino acid derivatives of 1-(4-aminophenyl)-2-aminopropanes. Eur J Med Chem 1999, 34, 2, 137.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
12117 Nitroethane; 1-Nitroethane 79-24-3 C2H5NO2 详情 详情
19171 1-(Chloromethyl)benzene; Benzyl chloride 100-44-7 C7H7Cl 详情 详情
(I) 20697 3-fluoroaniline; 3-fluorophenylamine 372-19-0 C6H6FN 详情 详情
(II) 29575 3-fluorophenylformamide C7H6FNO 详情 详情
(III) 20700 3-fluoro-N-methylaniline; N-(3-fluorophenyl)-N-methylamine C7H8FN 详情 详情
(IV) 29576 N-benzyl-3-fluoro-N-methylaniline; N-benzyl-N-(3-fluorophenyl)-N-methylamine C14H14FN 详情 详情
(V) 29577 4-[benzyl(methyl)amino]-2-fluorobenzaldehyde C15H14FNO 详情 详情
(VI) 29578 N-benzyl-N-[3-fluoro-4-[(E)-2-nitro-1-propenyl]phenyl]-N-methylamine; N-benzyl-3-fluoro-N-methyl-4-[(E)-2-nitro-1-propenyl]aniline C17H17FN2O2 详情 详情
(VII) 29579 N-[4-(2-aminopropyl)-3-fluorophenyl]-N-benzyl-N-methylamine; 4-(2-aminopropyl)-N-benzyl-3-fluoro-N-methylaniline C17H21FN2 详情 详情
(VIII) 29580 N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-chloroacetamide C19H22ClFN2O 详情 详情
(IX) 29581 N-(2-[4-[benzyl(methyl)amino]-2-fluorophenyl]-1-methylethyl)-2-(dibenzylamino)acetamide C33H36FN3O 详情 详情

合成路线45

该中间体在本合成路线中的序号：(IV)

In an alternative method, ring opening of epoxide (I) with benzylamine produced aminoalcohol (III). Subsequent coupling of (III) with chloroacetyl chloride (IV) yielded chloroacetamide (V), which was cyclized to the morpholinone (VI) upon treatment with NaOMe in MeOH. Reduction of the lactam function of (VI) with LiAlH4 gave the N-benzyl morpholine (VII). Finally, the N-benzyl group of (VII) was cleaved by hydrogenolysis using Pearlman's catalyst.

参考文献 中间体
合成目标
【1】 Corral, C.; Lissavetzky, J.; Sánchez-Mateo, C.C.; Darias, V.; Expósito-Orta, M.A.; Martín-Conde, J.A.; Manzanares, I.; Synthesis and preliminary pharmacological evaluation of thiophene analogues of viloxazine as potential antidepressant drugs. Bioorg Med Chem 1999, 7, 7, 1349.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(I) 34727 4-ethoxy-3-thienyl 2-oxiranylmethyl ether; 2-[[(4-ethoxy-3-thienyl)oxy]methyl]oxirane C9H12O3S 详情 详情
(III) 34729 1-(benzylamino)-3-[(4-ethoxy-3-thienyl)oxy]-2-propanol C16H21NO3S 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 34730 N-benzyl-2-chloro-N-[3-[(4-ethoxy-3-thienyl)oxy]-2-hydroxypropyl]acetamide C18H22ClNO4S 详情 详情
(VI) 34731 4-benzyl-6-[[(4-ethoxy-3-thienyl)oxy]methyl]-3-morpholinone C18H21NO4S 详情 详情
(VII) 34732 4-benzyl-2-[[(4-ethoxy-3-thienyl)oxy]methyl]morpholine; 4-[(4-benzyl-2-morpholinyl)methoxy]-3-thienyl ethyl ether C18H23NO3S 详情 详情

合成路线46

该中间体在本合成路线中的序号：(II)

Benzoxazinone (IV) was prepared by condensation of 2-amino-5-nitrophenol (I) with either chloroacetyl chloride (II) in the presence of NaHCO3 or ethyl bromoacetate (III) in the presence of KF. Subsequent N-alkylation of (IV) with iodomethane provided (V). After reduction of the nitro group of (V) to amine (VI) by hydrogenation over Pd/C, condensation with benzyl chloroformate afforded carbamate (VII). The chiral oxazolidinone (IX) was obtained by reaction of (VII) with (-)-(R)-glycidyl butyrate (VIII) in the presence of butyllithium in THF at low temperature. Conversion of (IX) to mesylate, followed by displacement with NaN3 gave azide (X). Amine (XI) was then obtained by either hydrogenation of (X) over Pd/C or by reduction with trimethyl phosphite. Finally, reaction of (XI) with acetyl chloride and triethylamine provided the title acetamide.

参考文献 中间体
合成目标
【1】 Haebich, D.; Haerter, M.; Bartel, S.; Riedl, B.; Stolle, A.; Raddatz, S.; Kroll, H.P.; Guarnieri, W.; Endermann, R.; Wild, H.; Rosentreter, U.; Ruppelt, M.; Synthesis and antibacterial activity of novel heteroaryl oxazolidinones: II. Benzoxazinone- and benzthiazinone-oxazolidinones. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F566.
【2】 Shridhar, D.R.; et al.; A facile synthesis of 2-alkyl(aryl)-6- and -7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazines. Synthesis 1982, 986.
【3】 Endermann, R.; Habich, D.; Ruppelt, M.; Raddatz, S.; Rosentreter, U.; Riedl, B.; Bartel, S.; Wild, H.; Stolle, A.; Guarnieri, W.; Kroll, H.-P. (Bayer AG); Novel bicyclene-substd. oxazolidinones. DE 19802239; WO 9937641 .
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) 33067 2-amino-5-nitrophenol 121-88-0 C6H6N2O3 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(IV) 33068 7-nitro-2H-1,4-benzoxazin-3(4H)-one C8H6N2O4 详情 详情
(V) 33069 4-methyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one C9H8N2O4 详情 详情
(VI) 33070 7-amino-4-methyl-2H-1,4-benzoxazin-3(4H)-one C9H10N2O2 详情 详情
(VII) 33071 benzyl 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-ylcarbamate C17H16N2O4 详情 详情
(VIII) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(IX) 33072 7-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H14N2O5 详情 详情
(X) 33073 7-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H13N5O4 详情 详情
(XI) 33074 7-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-4-methyl-2H-1,4-benzoxazin-3(4H)-one C13H15N3O4 详情 详情

合成路线47

该中间体在本合成路线中的序号：(XII)

The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.

参考文献 中间体
合成目标
【1】 Darrow, J.W.; Maynard, G.D.; Horvath, R.F. (Neurogen Corp.); Aminoalkyl substd. 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivs.. EP 1068207; US 6147085; WO 9951600 .
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) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(II) 44979 2-hydroxycyclohexanone 533-60-8 C6H10O2 详情 详情
(III) 44980 2-(mesitylamino)-1-cyclohexen-1-ol C15H21NO 详情 详情
(IV) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(V) 44981 2-amino-1-mesityl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile C18H21N3 详情 详情
(VI) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VII) 44982 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-amine C21H25N3 详情 详情
(VIII) 44983 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine C21H21N3 详情 详情
(IX) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(X) 44984 N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)-2-methylpropanamide C25H27N3O 详情 详情
(XI) 44985 N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine C25H29N3 详情 详情
(XII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XIII) 44986 2-chloro-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)acetamide C27H30ClN3O 详情 详情
(XIV) 44987 N-(2-chloroethyl)-N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-(2-chloroethyl)-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine C27H32ClN3 详情 详情

合成路线48

该中间体在本合成路线中的序号：(II)

Reaction of indole (I) with chloroacetyl chloride (II) in the presence of pyridine in toluene afforded the chloro ketone (III). This was then treated with sodium azide in aqueous acetone to furnish the azido ketone (IV). Hydrogenation of (IV) over Pd/C in the presence of a catalytic amount of HOAc gave rise to 3,5-bisindolyl pyrazine (V). Finally, N-methylation of the indole rings with iodomethane and K2CO3 yielded the title compound.

参考文献 中间体
合成目标
【1】 Jiang, B.; Gu, X.-H.; Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid. Bioorg Med Chem 2000, 8, 2, 363.
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) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 46764 2-chloro-1-(1H-indol-3-yl)-1-ethanone C10H8ClNO 详情 详情
(IV) 46765 2-azido-1-(1H-indol-3-yl)-1-ethanone C10H8N4O 详情 详情
(V) 46766 3-[5-(1H-indol-3-yl)-2-pyrazinyl]-1H-indole C20H14N4 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

Reaction of indole (I) with chloroacetyl chloride (II) in the presence of pyridine in toluene afforded the chloro ketone (III). This was then treated with sodium azide in aqueous acetone to furnish the azido ketone (IV). Hydrogenation of (IV) over Pd/C in the presence of HCl gave the amino ketone (V). The intermediate 3-indolylglyoxylic chloride (VI) was obtained by acylation of indole (I) with oxalyl chloride in CH2Cl2. Subsequent condensation between acid chloride (VI) and amino ketone (V) produced amide (VII). This was finally cyclized to the desired bisindolyl pyrazinone by treatment with ammonia in a pressure vessel.

参考文献 中间体
合成目标
【1】 Jiang, B.; Gu, X.-H.; Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid. Bioorg Med Chem 2000, 8, 2, 363.
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) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 46764 2-chloro-1-(1H-indol-3-yl)-1-ethanone C10H8ClNO 详情 详情
(IV) 46765 2-azido-1-(1H-indol-3-yl)-1-ethanone C10H8N4O 详情 详情
(V) 46767 2-amino-1-(1H-indol-3-yl)-1-ethanone C10H10N2O 详情 详情
(VI) 13476 Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride 22980-09-2 C10H6ClNO2 详情 详情
(VII) 46768 2-(1H-indol-3-yl)-N-[2-(1H-indol-3-yl)-2-oxoethyl]-2-oxoacetamide C20H15N3O3 详情 详情

合成路线50

该中间体在本合成路线中的序号：(IV)

The reaction of adamantan-1-amine (I) with HNO3 and H2SO4 gives 3-nitroadamantan-1-amine (II), which is hydrolyzed with KOH in hot water to yield 3-hydroxyadamantan-1-amine (III). On the other hand, the reaction of chloroacetyl chloride (IV) with L-prolinamide (V) by means of K2CO3 in THF gives 1-(chloroacetyl)-L-prolinamide (VI), which is treated with trifluoroacetic anhydride in THF to yield the corresponding nitrile (VII). Finally 3-hydroxyadamantan-1-amine (III) is condensed with the 1-(chloroacetyl)-L-prolinenitrile (VII) by means of K2CO3 in dichloromethane to afford the target adamantane derivative.

参考文献 中间体
合成目标
【1】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. EP 1137635; JP 2002531547; US 6166063; WO 0034241 .
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) 60231 tricyclo[3.3.1.1~3,7~]dec-1-ylamine; tricyclo[3.3.1.1~3,7~]decan-1-amine C10H17N 详情 详情
(II) 60232 3-nitrotricyclo[3.3.1.1~3,7~]dec-1-ylamine; 3-nitrotricyclo[3.3.1.1~3,7~]decan-1-amine C10H16N2O2 详情 详情
(III) 60233 3-aminotricyclo[3.3.1.1~3,7~]decan-1-ol C10H17NO 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 36137 (2S)-2-pyrrolidinecarboxamide;L-prolinamide 7531-52-4 C5H10N2O 详情 详情
(VI) 60234 1-(2-chloroacetyl)-2-pyrrolidinecarboxamide C7H11ClN2O2 详情 详情
(VII) 60235 1-(2-chloroacetyl)-2-pyrrolidinecarbonitrile C7H9ClN2O 详情 详情

合成路线51

该中间体在本合成路线中的序号：(VII)

N-Protection of L-Dopa (I) by means of Boc2O and Et3N in H2O-dioxane yields Boc derivative (II), which is then benzylated by reaction with benzyl bromide (III) and K2CO3 in refluxing acetone to provide (IV). Benzyl ester moiety of (IV) is saponified by treatment with NaOH in H2O-dioxane to give carboxylic acid (V), and deprotection of the amino group by means of TFA in CH2Cl2 furnishes trifluoroacetate salt (VI). Acylation of the amine group of (VI) with chloroacetyl chloride (VII) in NaOH yields N-chloroacetyl derivative (VIII), which is cyclized by heating in DMF in the presence of Et3N to afford morpholinedione (IX). Hydrogenation of (IX) over Pd/C in HCl/EtOH provides debenzylated derivative (X), which is finally converted into the desired compound by selective acylation with pivaloyl chloride (XI) in TFA.

参考文献 中间体
合成目标
【1】 Gingolani, G.M.; et al.; Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-Dopa. Bioorg Med Chem Lett 2000, 10, 12, 1385.
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) 15272 (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa 59-92-7 C9H11NO4 详情 详情
(II) 15273 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid C14H19NO6 详情 详情
(III) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(IV) 46700 phenyl (3S)-4-[3,4-bis(benzyloxy)phenyl]-3-[(tert-butoxycarbonyl)amino]butanoate C35H37NO6 详情 详情
(V) 46701 (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid C28H31NO6 详情 详情
(VI) 46702 (2S)-2-amino-3-[3,4-bis(benzyloxy)phenyl]propionic acid C23H23NO4 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 46703 (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(2-chloroacetyl)amino]propionic acid C25H24ClNO5 详情 详情
(IX) 46704 (3S)-3-[3,4-bis(benzyloxy)benzyl]-2,5-morpholinedione C25H23NO5 详情 详情
(X) 46705 (3S)-3-(3,4-dihydroxybenzyl)-2,5-morpholinedione C11H11NO5 详情 详情
(XI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情

合成路线52

该中间体在本合成路线中的序号：(IV)

Condensation of L-alaninol (I) with benzaldehyde produced imine (II), which was further reduced to the N-benzyl amine (III) by means of NaBH4. Subsequent acylation of N-benzyl alaninol (III) with chloroacetyl chloride (IV) provided the chloroacetamide (V). This was subjected to intramolecular cyclization in the presence of NaH to afford morpholinone (VI). Lactam (VI) reduction employing LiAlH4 furnished the substituted morpholine (VII). The N-benzyl group of (VII) was then removed by hydrogenation in the presence of Pd/C, yielding (S)-3-methylmorpholine (VIII).

参考文献 中间体
合成目标
【1】 Powers, J.P. (Tularik Inc.); Arylsulfonic acid salts of pyrimidine-based antiviral agents. US 6410726; WO 0151485 .
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) 14341 L-Alaninol; (2S)-2-Amino-1-propanol; L-(+)-Alaninol 2749-11-3 C3H9NO 详情 详情
(II) 55056 (2S)-2-{[(E)-phenylmethylidene]amino}-1-propanol C10H13NO 详情 详情
(III) 55057 (2S)-2-(benzylamino)-1-propanol C10H15NO 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 55058 N-benzyl-2-chloro-N-[(1S)-2-hydroxy-1-methylethyl]acetamide C12H16ClNO2 详情 详情
(VI) 55059 (5S)-4-benzyl-5-methyl-3-morpholinone C12H15NO2 详情 详情
(VII) 55060 (3S)-4-benzyl-3-methylmorpholine C12H17NO 详情 详情
(VIII) 55061 (3S)-3-methylmorpholine C5H11NO 详情 详情

合成路线53

该中间体在本合成路线中的序号：(VII)

The protection of the NH group of N-[3(S)-(dibenzylamino)-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine (I) with Boc2O and TEA in THF gives the carbamate (II), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to yield the primary amine (III). The condensation of (III) with N-(benzyloxycarbonyl)-L-tert-leucine (IV) by means of EDC, HOBT and NMM in DMF affords the leucinamide (V), which is deprotected with H2 and Pd/C in methanol, providing the intermediate (VI). The acylation of the free amino group of (VI) with chloroacetyl chloride (VII) and KHCO3 in ethyl acetate/water gives the chloroacetamide (VIII), which is treated with HCl in ethyl acetate/dioxane in order to eliminate the Boc protecting group and yield the secondary amine (IX). The reaction of (IX) with 3-nitrophenylsulfonyl chloride (X) and K2CO3 in THF/water gives the sulfonamide (XI), which is treated with 3-fluorobenzylamine (XII) in refluxing THF to afford the glycyl-tert-leucyl derivative (XIII). Finally, the reduction of the nitro group of (XIII) with H2 over Pd/C in methanol provides the target 3-aminophenylsulfonamide.

参考文献 中间体
合成目标
【1】 Kaltenbach, R.F.; Trainor, G.L. (DuPont Pharmaceuticals Co.); Bis-amino acid sulfonamides containing N-terminally A substd. benzyl group as HIV protease inhibitors. EP 1140983; WO 0042060 .
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) 48825 (2R,3S)-N(3),N(3)-dibenzyl-N(1)-isobutyl-2-methyl-4-phenyl-1,3-butanediamine; N,N-dibenzyl-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]amine C29H38N2 详情 详情
(II) 48826 tert-butyl (2R,3S)-3-(dibenzylamino)-2-methyl-4-phenylbutyl(isobutyl)carbamate C34H46N2O2 详情 详情
(III) 48827 tert-butyl (2R,3S)-3-amino-2-methyl-4-phenylbutyl(isobutyl)carbamate C20H34N2O2 详情 详情
(IV) 48828 (2S)-2-[[(benzyloxy)carbonyl]amino]-3,3-dimethylbutyric acid C14H19NO4 详情 详情
(V) 48829 benzyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(isobutyl)amino]-2-methylpropyl]amino)carbonyl]-2,2-dimethylpropylcarbamate C34H51N3O5 详情 详情
(VI) 48830 tert-butyl (2R,3S)-3-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-2-methyl-4-phenylbutyl(isobutyl)carbamate C26H45N3O3 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 48831 tert-butyl (2R,3S)-3-([(2S)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanoyl]amino)-2-methyl-4-phenylbutyl(isobutyl)carbamate C28H46ClN3O4 详情 详情
(IX) 48832 (2S)-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide C23H38ClN3O2 详情 详情
(X) 41948 3-nitrobenzenesulfonyl chloride 121-51-7 C6H4ClNO4S 详情 详情
(XI) 48833 (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(3-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide C29H41ClN4O6S 详情 详情
(XII) 48834 3-Fluorobenzylamine 100-82-3 C7H8FN 详情 详情
(XIII) 48835 (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(3-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-([2-[(3-fluorobenzyl)amino]acetyl]amino)-3,3-dimethylbutanamide C36H48FN5O6S 详情 详情

合成路线54

该中间体在本合成路线中的序号：(VII)

The protection of the NH group of N-[3(S)-(dibenzylamino)-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine (I) with Boc2O and TEA in THF gives the carbamate (II), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to yield the primary amine (III). The condensation of (III) with N-(benzyloxycarbonyl)-L-tert-leucine (IV) by means of EDC, HOBT and NMM in DMF affords the leucinamide (V), which is deprotected with H2 and Pd/C in methanol, providing the intermediate (VI). The acylation of the free amino group of (VI) with chloroacetyl chloride (VII) and KHCO3 in ethyl acetate/water gives the chloroacetamide (VIII), which is treated with HCl in ethyl acetate/dioxane in order to eliminate the Boc protecting group and yield the secondary amine (IX). The reaction of (IX) with 4-nitrophenylsulfonyl chloride (X) and K2CO3 in THF/water gives the sulfonamide (XI), which is treated with 3-fluorobenzylamine (XII) in refluxing THF to afford the glycyl-tert-leucyl derivative (XIII). Finally, the reduction of the nitro group of (XIII) with H2 over Pd/C in methanol provides the target 4-aminophenylsulfonamide.

参考文献 中间体
合成目标
【1】 Kaltenbach, R.F.; Trainor, G.L. (DuPont Pharmaceuticals Co.); Bis-amino acid sulfonamides containing N-terminally A substd. benzyl group as HIV protease inhibitors. EP 1140983; WO 0042060 .
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) 48825 (2R,3S)-N(3),N(3)-dibenzyl-N(1)-isobutyl-2-methyl-4-phenyl-1,3-butanediamine; N,N-dibenzyl-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]amine C29H38N2 详情 详情
(II) 48826 tert-butyl (2R,3S)-3-(dibenzylamino)-2-methyl-4-phenylbutyl(isobutyl)carbamate C34H46N2O2 详情 详情
(III) 48827 tert-butyl (2R,3S)-3-amino-2-methyl-4-phenylbutyl(isobutyl)carbamate C20H34N2O2 详情 详情
(IV) 48828 (2S)-2-[[(benzyloxy)carbonyl]amino]-3,3-dimethylbutyric acid C14H19NO4 详情 详情
(V) 48829 benzyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(isobutyl)amino]-2-methylpropyl]amino)carbonyl]-2,2-dimethylpropylcarbamate C34H51N3O5 详情 详情
(VI) 48830 tert-butyl (2R,3S)-3-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-2-methyl-4-phenylbutyl(isobutyl)carbamate C26H45N3O3 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 48831 tert-butyl (2R,3S)-3-([(2S)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanoyl]amino)-2-methyl-4-phenylbutyl(isobutyl)carbamate C28H46ClN3O4 详情 详情
(IX) 48832 (2S)-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide C23H38ClN3O2 详情 详情
(X) 15809 4-nitrobenzenesulfonyl chloride 98-74-8 C6H4ClNO4S 详情 详情
(XI) 48836 (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide C29H41ClN4O6S 详情 详情
(XII) 48834 3-Fluorobenzylamine 100-82-3 C7H8FN 详情 详情
(XIII) 48837 (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-([2-[(3-fluorobenzyl)amino]acetyl]amino)-3,3-dimethylbutanamide C36H48FN5O6S 详情 详情

合成路线55

该中间体在本合成路线中的序号：(II)

The pyrrolidine intermediate (VII) has been obtained as follows: The acylation of N-Boc-pyrrolidine-3(R)-amine (I) with chloroacetyl chloride (II) and TEA in dichloromethane gives the acetamide (III), which by treatment with ammonia in methanol/water yields the glycinamide (IV). The reaction of (IV) with protected S-methylisothiourea (V) in methanol affords the protected guanidine (VI). The N-Boc deprotection of (VI) by means of HCl in ethyl acetate/acetonitrile affords the target pyrrolidine intermediate (VII).

参考文献 中间体
合成目标
【1】 Kanno, O.; Shibayama, T.; Ohya, S.; Shimoji, Y.; Kuwahara, S.; Ishikawa, K.; Kojima, K.; Kawamoto, I.; R-115685, a novel parenteral carbapenem: Synthesis and structure-activity relationships. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1229.
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) 53603 tert-butyl (3S)-3-amino-1-pyrrolidinecarboxylate n/a C9H18N2O2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 53604 tert-butyl (3S)-3-[(2-chloroacetyl)amino]-1-pyrrolidinecarboxylate n/a C11H19ClN2O3 详情 详情
(IV) 53605 tert-butyl (3S)-3-[(2-aminoacetyl)amino]-1-pyrrolidinecarboxylate n/a C11H21N3O3 详情 详情
(V) 53606 1-({[imino(methylsulfanyl)methyl]amino}carbonyl)-4-nitrobenzene n/a C9H9N3O3S 详情 详情
(VI) 53607 tert-butyl (3S)-3-{[2-({imino[(4-nitrobenzoyl)amino]methyl}amino)acetyl]amino}-1-pyrrolidinecarboxylate n/a C19H26N6O6 详情 详情
(VII) 53608 2-({imino[(4-nitrobenzoyl)amino]methyl}amino)-N-[(3S)pyrrolidinyl]acetamide n/a C14H18N6O4 详情 详情

合成路线56

该中间体在本合成路线中的序号：(II)

Compound can be prepared in two related ways: 1) The acylation of 2,6-dimethylaniline (I) with chloroacetyl chloride (II) in acetic acid gives omega-chloro-2,6-dimethylacetanilide (III), which is then condensed with disodium salt of iminodiacetic acid (IV) in refluxing ethanol-water. 2) The reaction of (III) with ammonia in ethanol gives omega-amino-2,6-dimethylacetanilide (V), which is finally treated with chloroacetic acid (A) and NaOH in refluxing 95% ethanol.

参考文献 中间体
合成目标
【1】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Paton, D.M.; Lidofenin. Drugs Fut 1979, 4, 5, 342.
【2】 Callery, P.S.; et al.; Tissue distribution of technetium-99m and carbon-14 labeled N-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid. J Med Chem 1976, 19, 7, 962-964.
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) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(I) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 39492 2-[(carboxymethyl)amino]acetic acid 142-73-4 C4H7NO4 详情 详情
(V) 39493 2-amino-N-(2,6-dimethylphenyl)acetamide C10H14N2O 详情 详情

合成路线57

该中间体在本合成路线中的序号：(B)

By cyclization of 2-(N-methyl-2-aminoacetamido)-3-(o-chlorophenyl)-5-ethylthiophene (II) in pyridine - benzol - acetic acid. The starting thiophene (II) can also be obtained in two different ways both starting from the 2-methylamino-3-(o-chlorobenzoyl)-5-ethylthiophene (I): (a) The thiophene (I) is condensed with chloroacetyl chloride giving 2-(N-methylchloroacetamido)-3-(o-chlorobenzoyl)-5-ethylthiophene (III), which by treatment with NaI gives the corresponding iodoacetamido derivative (IV). This compound reacts with NaN3 giving the corresponding azide (V), which finally reacts with HBr affording the thiophene (II). (b) The reaction of the thiophene (I) with N-carbobenzoxyglycyl chloride gives the carbobenzoxy derivative (VI) which is then hydrolyzed with HBr to give (II).

参考文献 中间体
合成目标
【1】 Castaner, J.; Chartterjee, S.S.; Clotiazepan. Drugs Fut 1976, 1, 8, 363.
【2】 Nakanishi, M.; et al. (Yoshitomi Pharmaceutical Industries Ltd.); DE 2107356 .
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 60743 (2-chlorophenyl)[5-ethyl-2-(methylamino)-3-thienyl]methanone C14H14ClNOS 详情 详情
(II) 60748 2-amino-N-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-N-methylacetamide C16H17ClN2O2S 详情 详情
(III) 60744 2-chloro-N-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-N-methylacetamide C16H15Cl2NO2S 详情 详情
(IV) 60745 N-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-2-iodo-N-methylacetamide C16H15ClINO2S 详情 详情
(V) 65181 2-azido-N-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-N-methylacetamide C16H15ClN4O2S 详情 详情
(VI) 60747 benzyl 2-[[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl](methyl)amino]-2-oxoethylcarbamate C24H23ClN2O4S 详情 详情
(C) 60746 benzyl 2-chloro-2-oxoethylcarbamate C10H10ClNO3 详情 详情

合成路线58

该中间体在本合成路线中的序号：(II)

3-Chloroaniline (I) was acylated with chloroacetyl chloride (II) in isopropyl acetate. The resulting chloroacetanilide (III) was condensed with ethanolamine (IV) to yield the (hydroxyethyl)glycinamide (V). Cyclization of (V) to produce the piperazinone (VI) was then effected by treatment with di-tert-butyl azodicarboxylate and tributylphosphine.

参考文献 中间体
合成目标
【1】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25239 3-chloroaniline; 3-chlorophenylamine 108-42-9 C6H6ClN 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 47290 2-chloro-N-(3-chlorophenyl)acetamide C8H7Cl2NO 详情 详情
(IV) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(V) 47291 N-(3-chlorophenyl)-2-[(2-hydroxyethyl)amino]acetamide C10H13ClN2O2 详情 详情
(VI) 47289 1-(3-chlorophenyl)-2-piperazinone C10H11ClN2O 详情 详情

合成路线59

该中间体在本合成路线中的序号：(V)

Treatment of 9-fluorenone (I) with H2SO4 and sodium azide furnishes phenanthridinone derivative (II), which is then nitrated by means of HNO3 in HOAc to provide compound (III). Reduction of the nitro moiety of (III) by means of Fe and NH4Cl in DMF affords amino derivative (IV), which is then acylated with chloroacetyl chloride (V) in ethyl acetate in the presence of NaHCO3 or pyridine/DMF to yield chloroacetamide derivative (VI). Finally, the target compound can be obtained by condensation of (VI) with dimethyl amine (VII) in DMF/MeOH followed by treatment with HCl/Et2O in MeOH. Alternatively, the desired product can be synthesized as follows: Treatment of 2-amino-9-fluorenone (VIII) with chloroacetyl chloride (V) in AcOEt and NaHCO3 gives chloroacetamide (IX), which is then subjected to reaction with dimethyl amine (VII) in DMF/MeOH to provide dimethylacetamide (X). Reaction of (X) with H2SO4 and sodium azide, followed by treatment with HCl/Et2O in MeOH, affords a mixture of regioisomers from which the desired compound is isolated.

参考文献 中间体
合成目标
【1】 Southan, G.; Jagtap, P.; Szabo, C.; Salzman, A. (Inotek Corporation); Substd. phenanthridinones and methods of use thereof. US 6277990 .
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) 48902 9-Fluorenone; fluorenone 486-25-9 C13H8O 详情 详情
(II) 48903 6(5H)-Phenanthridinone; Phenanthridinone 1015-89-0 C13H9NO 详情 详情
(III) 48904 2-Nitro-6(5H)-phenanthridinone C13H8N2O3 详情 详情
(IV) 48905 2-amino-6(5H)-phenanthridinone C13H10N2O 详情 详情
(V) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VI) 48906 2-chloro-N-(6-oxo-5,6-dihydro-2-phenanthridinyl)acetamide C15H11ClN2O2 详情 详情
(VII) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(VIII) 48907 3-Amino-9-fluorenone C13H9NO 详情 详情
(IX) 48908 2-chloro-N-(9-oxo-9H-fluoren-3-yl)acetamide C15H10ClNO2 详情 详情
(X) 48909 2-(dimethylamino)-N-(9-oxo-9H-fluoren-3-yl)acetamide C17H16N2O2 详情 详情

合成路线60

该中间体在本合成路线中的序号：(IX)

The lithium derivative (II), prepared from p-bromo-alpha-methylbenzylamine (I), was added to piperonal (III) to obtain the diaryl carbinol (IV), which was further deoxygenated to (V) using triethylsilane and trifluoroacetic acid. Basic hydrolysis of the trifluoroacetamide function of (V) provided amine (VI). This was then alkylated with the chiral triflate (VII) to afford amino ester (VIII). Subsequent acylation of amine (VIII) with chloroacetyl chloride (IX), followed by cyclization of the resulting chloroacetamide (X) with ammonia, led to the diketopiperazine (XI). Reduction of the carbonyl groups of (XI), followed by reductive amination of the resulting piperazine (XII) with N-Boc-4-piperidinone (XIII), gave the piperidinyl piperazine (XIV). After acidic Boc group cleavage of (XIV), the resulting piperidine (XV) was finally condensed with 2,6-dimethylbenzoic acid (XVI) to yield the target benzamide.

参考文献 中间体
合成目标
【1】 Tagat, J.R.; et al.; Piperazine-based CCR5 antagonists as HIV-1 inhibitors. I: 2(S)-methyl piperazine as a key pharmacophore element. Bioorg Med Chem Lett 2001, 11, 16, 2143.
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) 50550 N-[(1S)-1-(4-bromophenyl)ethyl]-2,2,2-trifluoroacetamide C10H9BrF3NO 详情 详情
(II) 50551 　 C10H8F3Li2NO 详情 详情
(III) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(IV) 50552 N-((1S)-1-[4-[1,3-benzodioxol-5-yl(hydroxy)methyl]phenyl]ethyl)-2,2,2-trifluoroacetamide C18H16F3NO4 详情 详情
(V) 50553 N-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2,2,2-trifluoroacetamide C18H16F3NO3 详情 详情
(VI) 50554 (1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]-1-ethanamine; (1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethylamine C16H17NO2 详情 详情
(VII) 50555 ethyl (2R)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate C6H9F3O5S 详情 详情
(VIII) 50556 ethyl (2S)-2-([(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]amino)propanoate C21H25NO4 详情 详情
(IX) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(X) 50557 ethyl (2S)-2-[[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl](2-chloroacetyl)amino]propanoate C23H26ClNO5 详情 详情
(XI) 50558 (6S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-6-methyl-2,5-piperazinedione C21H22N2O4 详情 详情
(XII) 50559 (2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methylpiperazine C21H26N2O2 详情 详情
(XIII) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(XIV) 50560 tert-butyl 4-((3S)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-3-methylpiperazinyl)-1-piperidinecarboxylate C31H43N3O4 详情 详情
(XV) 50561 (2S)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylmethyl)phenyl]ethyl]-2-methyl-4-(4-piperidinyl)piperazine C26H35N3O2 详情 详情
(XVI) 50562 m-Xylylic acid; 2,6-Dimethylbenzoic acid; m-Xylene-2-carboxylic acid 632-46-2 C9H10O2 详情 详情

合成路线61

该中间体在本合成路线中的序号：(IV)

The reductocondensation of N-Boc-piperidin-4-one (I) with 3,4-dichloroaniline (II) by means of NaHB(OAc)3 in dichloroethane gives the secondary amine (III), which is acylated with chloroacetyl chloride (IV) by means of K2CO3 in dichloromethane to yield the chloroacetamide (V). The reaction of (V) with 3,5-dimethylphenol (VI) by means of Cs2CO3 in acetonitrile affords the aryl ether (VII), which is finally Boc deprotected with TFA in dichloromethane to provide the title trisubstituted acetamide.

参考文献 中间体
合成目标
【1】 Pirlot, N.; Balançon, L.; Berton, O.; Genicot, C.; Lamberty, Y.; Quéré, L.; Pasau, P.; Lallemand, B.; Talaga, P.; Ryckmans, T.; First dual NK1 antagonists-serotonin reuptake inhibitors: Synthesis and SAR of a new class of potential antidepressants. Bioorg Med Chem Lett 2002, 12, 2, 261.
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) 18620 tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone 79099-07-3 C10H17NO3 详情 详情
(II) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(III) 54455 tert-butyl 4-(3,4-dichloroanilino)-1-piperidinecarboxylate C16H22Cl2N2O2 详情 详情
(IV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(V) 54456 tert-butyl 4-[3,4-dichloro(2-chloroacetyl)anilino]-1-piperidinecarboxylate C18H23Cl3N2O3 详情 详情
(VI) 46786 3,5-dimethylphenol 108-68-9 C8H10O 详情 详情
(VII) 54457 tert-butyl 4-{3,4-dichloro[2-(3,5-dimethylphenoxy)acetyl]anilino}-1-piperidinecarboxylate C26H32Cl2N2O4 详情 详情

合成路线62

该中间体在本合成路线中的序号：(I)

The title compound is prepared by solid phase synthesis employing a Rink amide resin. Acylation of the resin with chloroacetyl chloride (I) affords the chloroacetyl resin (II). Subsequent chloride displacement with s-butylamine (III) provides the aminoacid-bound resin (IV). A new acylation of (IV) with chloroacetyl chloride (I) yields the chloroacetamide (V), which is then displaced by cyclopropylamine (VI), yielding the dipeptide derivative (VII). Then, a further coupling of (VII) with acid chloride (I), followed by displacement of the resultant chloroacetamide resin (VIII) with N-(2-aminoethyl)pyrrolidine (IX) gives rise to the tripeptide resin (X). Finally, cleavage of the dipeptide amide from the solid support is accomplished by treatment with trifluoroacetic acid in CH2Cl2

参考文献 中间体
合成目标
【1】 Montoliu, C.; et al.; Prevention of in vivo excitotoxicity by a family of trialkylglycines, a novel class of neuroprotectants. J. Pharm. Exp. Ther. 2002, 301, 1, 29.
【2】 Felipo Orts, V.; Montoliu Felix, C.; Ferrer Montiel, A.; Planells Cases, R.; Merino Fernandez, J.M.; Perez Paya, E.; Sanchez Baeza, F.; Humet, M.; Messeguer Peypoch, A. (DiverDrugs SL); N-Alkylglycine trimeres capable of protecting neurons against excitotoxic aggressions and compsns. containing said trimeres. WO 0228885 .
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 28964 2-chloroacetamide 79-07-2 C2H4ClNO 详情 详情
(III) 61462 sec-butyl amine; 2-Butanamine, (+-)-; 2-Aminobutane; 2-Butylamine; 2-Butanamine; 2-aminobutane base; butafume; deccotane; frucote; Butanamine; Methylpropylamine; SEC-BUTYLAMINE; (+/-)-sec-Butylamine; (+/-)-2-Aminobutane; Sec-Aminobutane; Sec-Butylamine; 2-Aminobutan; (+/-)-2-Butylamine; sec-Butylamine; Butylamine (sec); SBA; METHYL-n-PROPYLAMINE; (+/-)-2-Aminobutane 13952-84-6 C4H11N 详情 详情
(IV) 61463 2-(sec-butylamino)acetamide C6H14N2O 详情 详情
(V) 61464 2-[sec-butyl(2-chloroacetyl)amino]acetamide C8H15ClN2O2 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VII) 61465 2-{sec-butyl[2-(cyclopropylamino)acetyl]amino}acetamide C11H21N3O2 详情 详情
(VIII) 61466 2-(sec-butyl{2-[(2-chloroacetyl)(cyclopropyl)amino]acetyl}amino)acetamide C13H22ClN3O3 详情 详情
(IX) 18161 2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine 7154-73-6 C6H14N2 详情 详情
(X) 61467 2-(sec-butyl{2-[cyclopropyl(2-{[2-(1-pyrrolidinyl)ethyl]amino}acetyl)amino]acetyl}amino)acetamide C19H35N5O3 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

Acylation of aniline (I) with chloroacetyl chloride (II) in cold CH2Cl2 provides 2-chloro-N-phenylacetamide (III). Then, condensation of (III) with 4-aminoquinaldine (IV) in the presence of NaH in an inert atmosphere furnishes the title compound

参考文献 中间体
合成目标
【1】 Sahu, N.P.; et al.; Synthesis of a novel quinoline derivative, 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide- A potential antileishmanial agent. Bioorg. Med. Chem. 2002, 10, 6, 1687.
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) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 60932 2-chloro-N-phenylacetamide C8H8ClNO 详情 详情
(IV) 61469 4-Aminoquinaldine; 4-Amino-2-methylquinoline; 4-Amino-2-Methylquinoline; 4-Aminoquinaldine; 4-Amino-2-methylchinolin 6628-04-2 C10H10N2 详情 详情

合成路线64

该中间体在本合成路线中的序号：(I)

Chloroacetyl chloride (I) is condensed with bis(trimethylsilyl)acetylene (II) in the presence of AlCl3 to provide 1-chloro-4-(trimethylsilyl)-3-butyn-2-one (III). Cyclization of chloro ketone (III) with thioacetamide (IV) affords the ethynylthiazole derivative (V). Finally, palladium-catalyzed coupling of (V) with 3-bromopyridine (VI) gives rise to the target diarylacetylene.

参考文献 中间体
合成目标
【1】 Cosford, N.D.P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N.D.; Anderson, J.; Bristow, L.; Brodkin, J..; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M.A.; 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]- pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 2003, 46, 2, 204.
【2】 McDonald, I.A.; Munoz, B.; Vernier, J.-M.; Cosford, N.D.P.; Varney, M.A.; Hess, S.D.; Bleicher, L.S.; Cube, R.V.; Schweiger, E.J. (Merck & Co., Inc.); Heterocyclic cpds. and methods of use thereof. JP 2003508390; WO 0116121 .
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 27189 trimethyl[2-(trimethylsilyl)ethynyl]silane 14630-40-1 C8H18Si2 详情 详情
(III) 63351 1-chloro-4-(trimethylsilyl)-3-butyn-2-one C7H11ClOSi 详情 详情
(IV) 19170 ethanethioamide 62-55-5 C2H5NS 详情 详情
(V) 63352 2-methyl-4-[2-(trimethylsilyl)ethynyl]-1,3-thiazole C9H13NSSi 详情 详情
(VI) 13265 3-Bromopyridine 626-55-1 C5H4BrN 详情 详情

合成路线65

该中间体在本合成路线中的序号：(XXV)

In an alternative route to intermediate (III), ortho-metalation of 1,2-difluorobenzene (XXIV) with n-hexyllithium in THF followed by sequential addition of ZnCl2, CuCl and then chloroacetyl chloride (XXV) gives 2-chloro-2’,3’-difluoroacetophenone (XXVI). Subsequent condensation of chloroketone (XXVI) with vinylmagnesium bromide followed by cyclization of the resulting chlorohydrin (XXVII) under alkaline conditions yields epoxide (XXVIII). This is then coupled with diethyl acetamidomalonate (XXIX) in the presence of Pd(OAc)2 and 1,2-bis(diphenylphosphino)ethane (dppe) to generate the allyl alcohol adduct (XXX), which after conversion to the corresponding mesylate (XXXI) is reacted with 2,2,2-trifluoroethylamine (XXXII) in dimethylacetamide to furnish the allylic amine (XXXIII). Decarbethoxylation of malonate (XXXIII) by heating with LiCl in moist dimethylacetamide provides the N-acetyl aminoester (XXXIV). Then, cyclization of (XXXIV) by means of trifluoroacetic acid in hot toluene gives the azepinone derivative (XXXV). After acidic hydrolysis of acetamide (XXXV), the resulting racemic amine is resolved utilizing (-)-O,O’-di-p-toluoyl-L-tartaric acid (DTTA) in the presence of a trace amount of 5-nitrosalicylaldehyde to provide the (S)-amine ditoluoyltartrate salt (XXXVI). Finally, liberation of the tartrate salt (XXXVI) with HCl in isopropanol and simultaneous hydrogenation of the azepine double bond in the presence of Pd/BaSO4 provides the trans-perhydroazepinone (III) (2-5). Scheme 3.

参考文献 中间体
合成目标
【2】 Palucki, M., Davies, I., Steinhuebel, D., Rosen, J. (Merck & Co., Inc.). Process for the preparation of caprolactam CGRP antagonist intermediate. WO 2007120589.
【3】 McLaughlin, M., Palucki, M., Marcantonio, K. (Merck & Co., Inc.). Process for the preparation of pyridine heterocycle CGRP antagonist intermediate. WO 2007120590.
【4】 Belyk, K., Rivera, N. (Merck & Co., Inc.). Process for the preparation of CGRP antagonist. WO 2007120591.
【5】 Belyk, K. (Merck & Co., Inc.). CGRP antagonist salt. WO 2007120592.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 65556 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine 　 C14H15F5N2O 详情 详情
(XXIV) 65570 1,2-Difluorobenzene 367-11-3 C6H4F2 详情 详情
(XXV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XXVI) 65571 2-Chloro-2',3'-difluoroacetophenone 　 C8H5ClF2O 详情 详情
(XXVII) 65572 　 　 C10H9ClF2O 详情 详情
(XXVIII) 65573 　 　 C10H8F2O 详情 详情
(XXIX) 16710 Diethyl 2-(acetamido)malonate; Diethyl acetamidomalonate 1068-90-2 C9H15NO5 详情 详情
(XXX) 65574 　 　 C19H23F2NO6 详情 详情
(XXXI) 65575 　 　 C20H25F2NO8S 详情 详情
(XXXII) 42542 2,2,2-trifluoroethylamine; 2,2,2-trifluoro-1-ethanamine 753-90-2 C2H4F3N 详情 详情
(XXXIII) 65576 　 　 C21H25F5N2O5 详情 详情
(XXXIV) 65577 　 　 C18H21F5N2O3 详情 详情
(XXXV) 65578 　 　 C16H15F5N2O2 详情 详情
(XXXVI) 65579 　 　 C14H13F5N2O.C20H18O8 详情 详情

合成路线66

该中间体在本合成路线中的序号：(XXXIV)

The pyrrolo-oxazine fragments, the free base (II) or the Boc-protected (V) can be synthesized as follows. Butene-1,4-diol (XXIV) is subjected to either of the two following alternative procedures: 1) treatment with mesyl chloride in the presence of Et3N in CH2Cl2 and subsequent reaction with tosylamine, NaOH and tetrabutylammonium hydrogensulfate (TBAHS) in toluene/water at 40 °C (1, 2); or 2) chlorination with thionyl chloride followed by treatment with tosylamide by means of NaH in DMF (3) to afford 1-tosyl-2,5-dihydro-1H-pyrrole (XXV). Compound (XXV) is then epoxidated with meta-chloroperbenzoic acid (mCPBA) in refluxing dichloromethane to yield cis-N-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane (XXVI) (1-3). Desymmetrization of intermediate (XXVI) is carried out by condensation with ethanolamine (XXVII) in refluxing dichloromethane to yield the racemic N-alkylated pyrrolidine derivative rac-(XXVIII), which by reaction with tosyl chloride in pyridine/THF at –10 °C affords the tosylate rac-(XXIX). Cyclization of the racemic (XXIX) by means of NaOH in THF/methanol at 0-3 °C gives the racemic pyrrolo-oxazine rac-(XXX), from which the desired enantiomer (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (XXX) is separated by chiral chromatography. Finally, compound (XXX) is detosylated by means of HBr/AcOH and anisole at 60 °C and the resulting dihydrobromide salt (XXXI) is treated with potassium hydroxide in isopropanol to afford the free base intermediate (II) (1). Scheme 3.
In an improved method for intermediate (II), compound (XXVI) is desymmetrized by coupling with (R)-phenylethylamine (XXXII) in water (2, 3), resulting in a mixture of diastereomers that is resolved by crystallization (2) or chromatography (3). The desired isomer (XXXIII) is N-acylated with chloroacetyl chloride (XXXIV) by means of triethylamine (2) or DIEA in THF (3) to afford the N-chloroacetyl amine (XXXV), which then cyclizes in the presence of sodium hydroxide (2) or potassium tert-butoxide in dichloromethane (3). The resulting bicyclic lactam (XXXVI) is reduced with LiAlH4 in THF (3) or NaBH4 in the presence of BF3.THF complex (2) to give the pyrrolooxazine derivative (XXXVII) (2, 3), which is detosylated by treatment with HCl and subsequently with NaOH, yielding the free amine (XXXVIII). Finally, compound (XXXVIII) is subjected to hydrogenolysis over Pd/C in methanol to afford the target (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (II) (2). Scheme 3.
The Boc-protected compound (V) is obtained by subjecting N-alkylated derivative (XXXVII) to hydrogenolysis over Pd/C in methanol followed by treatment with tert-butoxycarbonyl anhydride in dichloromethane. The resulting fully protected intermediate (XXXIX) is finally detosylated with sodium naphthalenide (3). Scheme 3.

参考文献 中间体
合成目标
【1】 Matzke, M., Petersen, U., Schenke, T. et al. (Bayer Healthcare AG). Use of 7-(2-oxa-5,8-diazabicyclo[4.3.0]non-8-yl)-quinolone carboxylic acid and naphthyridon carboxylic acid derivatives for the treatment of Helicobacter pylori infections and associated gastroduodenal diseases. CA 2274894, DE 19652239, EP 0946176, JP 200351781, JP 2000514825, US 6133260, US 6432948, WO 1998026779.
【2】 Wohlert, S.E., Jaetsch, T., Gallenkamp, B. et al. New fluoroquinolone finafloxacin HCI (FIN): Route of synthesis, physicochemical characteristics and activity under neutral and acid conditions. 48th Annu Intersci Conf Antimicrob Agents Chemother (ICAAC) Infect Dis Soc Am (IDSA) Annu Meet (Oct 25-28, Washington, D.C.) 2008, Abst F1-2036.
【3】 Hong, J., Zhang, Z., Lei, H. et al. A novel approach to finafloxacin hydrochloride (BAY35-3377). Tetrahedron Lett 2009, 50(21): 2525-8.
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) 65947 (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine 　 C6H12N2O 详情 详情
(V) 65950 　 　 C11H20N2O3 详情 详情
(XXIV) 36965 (Z)-2-butene-1,4-diol 6117-80-2 C4H8O2 详情 详情
(XXV) 65968 1-(Toluene-4-sulfonyl)-2,5-dihydro-1H-pyrrole; 1-(p-Tolylsulfonyl)-3-pyrroline; 1-(4-Methylphenylsulfonyl)-2,5-dihydropyrrole; 2,5-Dihydro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole 16851-72-2 C11H13NO2S 详情 详情
(XXVI) 65969 3-Tosyl-6-oxa-3-azabicyclo[3.1.0]hexane 159555-66-5 C11H13NO3S 详情 详情
(XXVII) 10259 Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol 141-43-5 C2H7NO 详情 详情
(XXVIII) 65970 2,5-Dihydro-3-hydroxy-4-[(2-hydroxyethyl)amino]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole 　 C13H20NO4S 详情 详情
(XXIX) 65971 　 　 C20H26NO6S2 详情 详情
(XXX) 65972 　 　 C20H24N2O5S2 详情 详情
(XXXI) 65973 (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine dihydrobromide 　 C6H12N2O.2HBr 详情 详情
(XXXII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(XXXIII) 65974 　 　 C19H24N2O3S 详情 详情
(XXXIV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XXXV) 65975 　 　 C21H25ClN2O4S 详情 详情
(XXXVI) 65976 　 　 C21H24N2O4S 详情 详情
(XXXVII) 65977 　 　　 C21H26N2O3S 详情 详情
(XXXVIII) 65978 　 　 C14H20N2O 详情 详情
(XXXIX) 65979 　 　 C18H26N2O5S 详情 详情

合成路线67

该中间体在本合成路线中的序号：(VII)

Protection of pyrrolidine (I) with Boc2O in MTBE provides the corresponding N-Boc derivative (II) , which after metalation with sec-BuLi in THF and quenching with B(OMe)3 gives N-Boc-boroproline (III) . Condensation of racemic boronic acid (III) with (+)-pinanediol (IV) in isopropyl acetate or MTBE affords the boronate ester (V) as a diastereomeric mixture. After deprotection by removing the Boc group with HCl in i-PrOH or Et2O , the 2(R)-boroproline pinanediol ester hydrochloride (VI) diastereomer is separated by recrystallization from i-PrOH (1-3). Acylation of compound (VI) with 2-chloroacetyl chloride (VII) in the presence of NMM in CH2Cl2 provides the 2-chloroacetamide (VIII), which is then condensed with 3(R)-amino-1-Boc-pyrrolidine (IX) by means of K2CO3 in THF to give the glycinamide derivative (X). Finally, simultaneous hydrolysis of the N-Boc and boronate ester groups in compound (X) using phenylboronic acid in H2O/hexane provides dutogliptin free base (XI) .
Alternatively, coupling of the 2(R)-boroproline derivative (VI) with either the diprotected N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) via activation as the corresponding mixed anhydride with isobutyl chloroformate and NMM in 2-MeTHF , or by means of EDC, HOBt and NMM in CH2Cl2 , or also with the dicyclohexylamine salt (XIII) in the presence of EDC, HOBt and NMM , affords amide (XIV), which is deprotected by catalytic hydrogenolysis over Pd/C in MeOH to give diamine (XV). Finally, diamine (XV) undergoes boronate ester cleavage by means of phenylboronic acid in the presence of L-tartaric acid in H2O/MTBE to afford dutogliptin tartrate .

参考文献 中间体
合成目标
【1】 Wu, Z.P., Campbell, D.A., Cherrington, J.M. (Phenomix Corp.). Solid citrate and tartrate salts of DPP-IV inhibitors. EP 2061474, JP 2010502610, WO 2008027273.
【2】 Campbell, D.A., Winn, D. (Phenomix Corp.). Heterocyclic boronic acid compounds. CA 2545311, EP 1689757, EP 1743676, EP 1997533, JP 2007512254, JP 2009007377, US 2007060547, WO 2005047297.
【3】 Campbell, D.A., Winn, D.T., Betancort, J.M. (Phenomix Corp.). Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV. US 2006264400, US 7317109.
【4】 Campbell, D.A., Winn, D.T. (Phenomix Corp.). Methods of preparing heterocyclic boronic acids and derivatives thereof. EP 1919485, JP 2009503077, US 2008300413, WO2007016356.
【5】 Wu, Z.-P. (Phenomix Corp.). A crystalline synthetic intermediate for preparation of a DPP-IV inhibitor and method of purification thereof. EP 2175727, WO 2009009751.
【6】 Campbell, D.A., Leitao, E.P.T., Wu, Z.-P., Wang, P. (Phenomix Corp.). Methods and intermediates for synthesis of selective DPP-IV inhibitors. EP 2173709, WO 2008109681.
【7】 Wang, P. (Phenomix Corp.). A crystalline synthetic intermediate for pyrrolidin-3-yl-glycylaminoalkylboronates. WO 2009094462.
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) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(II) 16439 tert-butyl 1-pyrrolidinecarboxylate 86953-79-9 C9H17NO2 详情 详情
(III) 63002 1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid 149682-75-7 C9H18BNO4 详情 详情
(IV) 63005 (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol 18680-27-8 C10H18O2 详情 详情
(V) 63006 tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate C19H32BNO4 详情 详情
(VI) 63007 (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine 205116-75-2 C14H24BNO2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 65981 　 　 C16H25BClNO3 详情 详情
(IX) 65982 (3R)-(+)-1-Boc-3-aminopyrrolidine; (3R)-(+)-N-Boc-3-aminopyrrolidine; (3R)-(+)-N-tert-Butoxycarbonyl-3-aminopyrrolidine 147081-49-0 C9H18N2O2 详情 详情
(X) 65983 　 　 C25H42BN3O5 详情 详情
(XI) 65984 [(2R)-1-[[(3R)-3-Pyrrolidinylamino]acetyl]-2-pyrrolidinyl]-boronic acid; Dutogliptin 852329-66-9 C10H20BN3O3 详情 详情
(XII) 65985 　 　 C21H24N2O6 详情 详情
(XIII) 65986 　 　 C21H24N2O6.C12H23N 详情 详情
(XIV) 65987 　 　 C35H44BN3O7 详情 详情
(XV) 65988 　 　 C20H34BN3O3 详情 详情

合成路线68

该中间体在本合成路线中的序号：(III)

Two main strategies have been used to synthesize SQ-109, including a solid-phase approach (1), which was later adapted for solutionphase synthesis (2). In the solid-phase strategy, Rink acid resin is activated at room temperature using triphenylphosphine and hexachloroethane in THF. The activated resin is then loaded with a solution of EtN(i-Pr)2 and (2E)-3,7-dimethylocta-2,6-dien-1-amine (geranylamine, I) in dichloroethane for 8 hours at 45 °C, followed by 6-8 hours at room temperature. The resulting geranylamine-attached resin (II) is then loaded with pyridine and chloroacetyl chloride (III) in THF for 8 hours at 45 °C, followed by 6-8 hours at room temperature to give resin-attached N-geranyl-a-chloroacetamide (IV), which is loaded with EtN(i-Pr)2 and a suspension of 2-adamantamine hydrochloride (V) in DMF at 70-75°C for 16 hours to give resin-attached N-geranyl-N’-(2-adamantyl)glycinamide (VI). Glycinamide (VI) is then reduced in anhydrous THF by adding Red-Al in toluene and stirring for 4 hours at room temperature to yield resin-attached N-geranyl-N’-(2-adamantyl)ethane-1,2-diamine (VII). In the last step, the resin is loaded with TFA and dichloromethane followed by the addition of MeOH to cleave the resin-linked product before filtration. The filtrate is collected and dried to give the trifluoroacetate salt of N-geranyl-N’-(2-adamanthyl)ethane-1,2-diamine (SQ-109), which is further purified by HPLC to give the diacetate salt (3). Scheme 1.

参考文献 中间体
合成目标
【1】 Lee, R.E., Protopopova, M., Crooks, E., Slayden, R.A., Terrot, M., Barry, C.E. 3rd. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem 2003, 5(2): 172-87.
【2】 Tahlan, K., Wilson, R., Kastrinsky, D.B. et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2012, 56(4): 1797-809.
【3】 Protopopova, M.N., Lee, R.E., Slayden, R.A., Barry, C.E.I., Bogatcheva, E., Einck, L. (US Department of Health & Human Services; Sequella, Inc.). Anti tubercular drug: Compositions and methods. JP 2005526129, US 2003236225, US 2004019117, US 2004033986, US 6951961, US 8268894, WO 2003096989.
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) 66057 Geranylamine; Trans-3,7-Dimethyl-2,6-Octadien-1-ylamine, Trans-3,7-Dimethyl-2,6-Octadienyl Amine 6246-48-6 C10H19N 详情 详情
(II) 66058 Geranylamine-attached resin 　 　 详情 详情
(III) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(IV) 66059 Resin-attached N-geranyl-α-chloroacetamide 　 　 详情 详情
(V) 66060 2-Adamantanamine hydrochloride; 2-Aminoadamantane hydrochloride; Tricyclo[3.3.1.1(3.7)]dec-2-ylamine hydrochloride 10523-68-9 C10H17N.HCl 详情 详情
(VI) 66061 Resin-attached N-geranyl-N’-(2-adamantyl)glycinamide 　 　 详情 详情
(VII) 66062 Resin-attached N-geranyl-N’-(2-adamantyl)ethane-1,2-diamine 　 　 详情 详情

合成路线69

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Venkataraman S, RAO UVB, Muwa V, et al. 2006. Process for the preparation of highly pure zipnsidone hydrochloride. US 2006089502
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
（VI） 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(I) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 16275 6-chloro-1,3-dihydro-2H-indol-2-one 56341-37-8 C8H6ClNO 详情 详情
(III) 16276 6-chloro-5-(2-chloroacetyl)-1,3-dihydro-2H-indol-2-one C10H7Cl2NO2 详情 详情
(IV) 16277 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one- C10H9Cl2NO 详情 详情
(V) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情

合成路线70

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Kieczykowski GR, Jobson RB, Melillo DG, et aL. 1995. Preparation of (4-amino-l-hydroxybuqdidene) bisphosphonic acicl sodium salt, MK-217 (alendmnate sodium): an improved procedure for the preparation of l-hydroxy-l,l-bisphosphonic acids. J Org Chem, 60 (25): 8310～8312
【2】 Patel VM, Chitturi TR, Thennati R 2005. A process for the preparation of 2-(imidazol-l-yl)-l-hydroxyethane-l,l-diphosphoruc acid. W0 2005066188
【3】 Zhu J．Zhou YJ, Lu JG, et al. 2003. Synthesis of zoledroruc acid. 中国新药杂志．12 (1):39～40
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) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 66984 benzyl 2-(1H-imidazol-1-yl)acetate 　 C12H12N2O2 详情 详情
(IV) 66982 2-(1H-Imidazol-1-yl)acetic acid 22884-10-2 C5H6N2O2 详情 详情

合成路线71

该中间体在本合成路线中的序号：(XVI)

Friedel-Crafts acylation of 1-(phenylsulfonyl)pyrrole (XV) with chloroacetyl chloride (XVI) by means of AlCl3 in CH2Cl2 gives 2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone (XVII), which by condensation with sodium N-tosyl formamide (XVIII) (obtained by treatment of tosylamide (XIX) with NaOMe in MeOH to afford sodium tosylamide (XX), which is then formylated with HCOOEt in MeOH) using Bu4NBr in THF at 60 °C affords the corresponding keto amide (XXI). Decarbonylation of intermediate (XXI) by means of H2SO4 in MeOH at 60 °C followed by protection of the keto group with (CH2OH)2 using HC(OMe)3 produces acetal (XXII). Pictet-Spengler cyclization of protected amine (XXII) with (HCHO)n in the presence of TFA in CH2Cl2 affords the 1,5,6,7-tetrahydro-4H-pyrrolo[2,3-c]pyridin-4-one derivative (XXIII) , which by O-methylation with HC(OMe)3 using MsOH and CMNOOH in MeOH yields the enol ether (XXIV). Redox elimination of the tosyl group in compound (XXIV) by means of Na2S2O3 and Et3N gives the pyrrolo[2,3-c]pyridine derivative (XXV) , which can also be prepared by treatment of N-protected amine (XXIII) with HC(OMe)3 in the presence of MsOH or Tf2O and CMNOOH or AIBN . Oxidation of intermediate (XXV) with H2O2 using MeReO3 or phthalic anhydride in CH2Cl2 results in the pyridine-N-oxide (XXVI). Bromination of compound (XXVI) with PyBroP and K3PO4 in trifluorotoluene, followed by treatment with NaOH in i-PrOH at 80 °C yields the bromopyridine (XXVII), which by Friedel-Crafts C-3-acylation with methyl oxalyl chloride (VI) using AlCl3 in CH2Cl2/MeNO2 at 0 °C produces the keto ester (XXVIII). Hydrolysis of the methyl ester (XXVIII) with aqueous NaOH and subsequent treatment with HBr affords (7-bromo-4-methoxypyrrolo[2,3-c]pyridin-3-yl)(oxo)acetic acid hydrobromide salt (XXIX) .

参考文献 中间体
合成目标
【1】 Ueda, Y., Connolly, T.P., Kadow, J.F. et al. (Bristol-Myers Squibb Co.). Prodrugs of piperazine and substituted piperidine antiviral agents. CN 101941990; US 7745625; EP 1725569; JP 2007529519; US 2005209246; WO 2005090367.
【3】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038709.
【4】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038710.
【5】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038711.
【6】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038712.
【7】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038716.
【8】 Eastgate, M.D., Bultman, M.S., Chen, K. et al. (Bristol-Myers Squibb Co.). Methods for the preparation of HIV attachment inhibitor piperazine prodrug compound. US 2015038717.
【2】 Chen, K., Risatti, C., Bultman, M. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J Org Chem 2014, 79(18): 8757-67.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 26971 2-methoxy-2-oxoacetyl chloride 5781-53-3 C3H3ClO3 详情 详情
(XV) 67610 1-(phenylsulfonyl)pyrrole;N-(Benzenesulfonyl)pyrrole;N-Phenylsulfonylpyrrole;1-(Benzenesulfonyl)-1H-pyrrole 16851-82-4 C10H9NO2S 详情 详情
(XVI) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XVII) 67611 2-chloro-1-[1-(phenylsulfonyl)pyrrol-3-yl]ethanone 　 C12H10ClNO3S 详情 详情
(XVIII) 67612 sodium N-tosyl formamide 　 C8H8NNaO3S 详情 详情
(XIX) 59937 4-methylbenzenesulfonamide 70-55-3 C7H9NO2S 详情 详情
(XX) 67613 sodium tosylamide 　 C7H8NNaO2S 详情 详情
(XXI) 67614 N-(2-oxo-2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)ethyl)-N-tosylformamide 　 C20H18N2O6S2 详情 详情
(XXII) 67615 4-methyl-N-((2-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)-1,3-dioxolan-2-yl)methyl)benzenesulfonamide 　 C21H22N2O6S2 详情 详情
(XXIII) 67616 1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4(5H)-one 　 C20H18N2O5S2 详情 详情
(XXIV) 67617 4-methoxy-1-(phenylsulfonyl)-6-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine 　 C21H20N2O5S2 详情 详情
(XXV) 67618 4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine 　 C14H12N2O3S 详情 详情
(XXVI) 67619 4-methoxy-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide 　 C14H12N2O4S 详情 详情
(XXVII) 67620 7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine hydrochloride hydrate 　 C8H7BrN2O.HCl.H2O 详情 详情
(XXVIII) 67621 methyl 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate 　 C11H9BrN2O4 详情 详情
(XXIX) 67622 2-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid hydrobromide 　 C10H7BrN2O4.HBr 详情 详情

合成路线72

该中间体在本合成路线中的序号：(XV)

Selective O-protection of 2,5-dihydroxyacetophenone (XI) with benzyl bromide by means of K2Co3 in acetone or methylisobutylketone yields 2’-hydroxy-5’-benzyloxyacetophenone (XII) , which is then nitrated with fuming Hno3 in AcoH to give the 3’-nitroacetophenone derivative (XIII) . Reduction of the nitro group in compound (XIII) by catalytic hydrogenation over Rh/C in MeoH or Pto2 in 2-MeTHF (4, 5) provides the corresponding aniline (XIV) , which finally undergoes cyclization with chloroacetyl chloride (XV) in the presence of K2Co3 in refluxing acetonitrile or 2-MeTHF .

参考文献 中间体
合成目标
【1】 Bouyssou, T., Hoenke, C., Rudolf, K. et al. Discovery of olodaterol, a novel inhaled b2-adrenoceptor agonist with a 24 h bronchodilatory efficacy. Bioorg Med Chem Lett 2010, 20(4): 1410-4.
【2】 Konetzki, I., Lustenberger, P., Sieger, P. (Boehringer Ingelheim Pharma GmbH & Co. KG). Novel enantiomerically pure beta-agonists, method for the production and the use thereof in the form of a drug. EP 1789405, JP 2007537196, US 2005267106, US 2007027148, US 7220742, US 7491719, US 2009137578, US 8034809, Wo 2005111005.
【3】 Krueger, T., Ries, U., Schnaubelt, J., Rall, W., Leuter, Z.A., Duran, A., Soyka, R. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 1917253, JP 2009504708, US 201114859, Wo 2007020227.
【4】 Rodriguez Dehli, J.M., Hagenkoetter, R., Schul, M., Stange, C. (Boehringer Ingelheim Pharma GmbH & Co. KG). Method for producing betamimetics. EP 2125759, JP 2010516739, US 2010022770, Wo 2008090193.
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) 68012 8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one 　 C17H15NO4 详情 详情
(XI) 38479 1-(2,5-dihydroxyphenyl)-1-ethanone 490-78-8 C8H8O3 详情 详情
(XII) 20133 1-[5-(benzyloxy)-2-hydroxyphenyl]-1-ethanone C15H14O3 详情 详情
(XIII) 68024 1-(5-(benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone 　 C15H13NO5 详情 详情
(XIV) 68025 1-(3-amino-5-(benzyloxy)-2-hydroxyphenyl)ethanone 　 C15H15NO3 详情 详情
(XV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情

合成路线73

该中间体在本合成路线中的序号：(XIV)

Amination of 2-phenylethyl bromide (XII) with methylamine in THF gives N-methylphenethylamine (XIII) , which upon N-acylation with chloroacetyl chloride (XIV) in the presence of NaHCO3 in CH2Cl2 or methyl t-butyl ether yields the chloroacetamide derivative (XV) . Cyclization of intermediate (XV) by Friedel-Crafts alkylation by means of AlCl3 in 1,2-dichlorobenzene at 165 °C gives 3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (XVI) . Alternatively, compound (XVI) can be obtained from 2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (XVII) by N-methylation with methyl iodide by means of NaH in DMF . Treatment of lactam (XVI) with isoamyl nitrite (i-AmONO) in the presence of NaHMDS or LiHMDS in THF yields the 1-hydroxyiminobenzazepinone (XVIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C or with H2 over Raney-Ni in the presence of NH3 in EtOH at 100 °C .
Alternatively, phenylacetyl chloride (XIX) is condensed with N-(2,2-dimethoxyethyl)-N-methylamine (XX) by means of NaHCO3 in methyl t-butyl ether/H2O to furnish the phenylacetamide derivative (XXI), which upon cyclization in the presence of H2SO4 at 110 °C affords the benzazepin-2-one derivative (XXII). Treatment of intermediate (XXII) with i-AmONO in the presence of LiHMDS in THF gives the hydroxyimino derivative (XXIII), which is finally hydrogenated with H2 over Pd/C in the presence of HCl in EtOH at 50 °C .

参考文献 中间体
合成目标
【1】 Koenig, T.M., Nissen, J.S., Mitchell, D. (Eli Lilly and Company). Lactam compound. EP 1345955, JP 2005538031, WO 2002040508.
【2】 Audia, J.E., John, V., Latimer, L.H., Tung, J.S., Nissen, J.S., Thorsett, E.D., McDaniel, S.L. (Eli Lilly and Company; Elan Pharmaceuticals, Inc.). Lactam compound. JP 2004517090, WO 2002047671.
【3】 Koenig, T.M., Audia, J.E., Mitchell, D., Aikins, J.A., Buccilli, L.A., Engel,G.L., McDaniel, S.L. (Eli Lilly and Company). Lactam compound. CA 2425497, EP 1353910, JP 2004521084, WO 2002040451.
【4】 Audia, J.E., Diseroad, B.A., Varghese, J. et al. (Eli Lilly and Company).Lactam compound. US 2007299053, US 7468365.
【5】 Mitchell, D., Hay, L.A., Koenig, T.M., McDaniel, S., Nissen, J.S., Audia, J.E.Classical and dynamic resolution of 1-amino-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one. Tetrahedron Asymmetry 2005, 16(23): 3814-9.
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) 69307 1-amino-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H14N2O 详情 详情
(XII) 20730 1-(2-bromoethyl)benzene；1-Bromo-2-phenylethane;(2-Bromoethyl)benzene;Phenethyl bromide 103-63-9 C8H9Br 详情 详情
(XIII) 69316 N-methyl-2-phenylethanamine；N-Phenethylmethylamine;N-methylphenethylamine 589-08-2 C9H13N 详情 详情
(XIV) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XV) 69317 2-chloro-N-methyl-N-phenethylacetamide C11H14ClNO 详情 详情
(XVI) 69318 3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one；3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 73644-95-8 C11H13NO 详情 详情
(XVII) 69319 4,5-Dihydro-1H-benzo[d]azepin-2(3H)-one;1,3,4,5-Tetrahydrobenzo[d]azepin-2-one;1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one;2,3,4,5-tetrahydro-1H-3-benzazepin-2-one 15987-50-5 C10H11NO 详情 详情
(XVIII) 69320 (E)-1-(hydroxyimino)-3-methyl-4,5-dihydro-1H-benzo[d]azepin-2(3H)-one C11H12N2O2 详情 详情
(XIX) 25890 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride 103-80-0 C8H7ClO 详情 详情
(XX) 36650 2,2-dimethoxy-N-methyl-1-ethanamine;1,1-Dimethoxy-2-(methylamino)-ethane;Methylaminoacetaldehyde dimethyl acetal;N-(2,2-dimethoxyethyl)-N-methylamine 122-07-6 C5H13NO2 详情 详情
(XXI) 69321 N-(2,2-dimethoxyethyl)-N-methyl-2-phenylacetamide C13H19NO3 详情 详情
(XXII) 69322 3-methyl-1H-benzo[d]azepin-2(3H)-one C11H11NO 详情 详情
(XXIII) 69323 (E)-1-(hydroxyimino)-3-methyl-1H-benzo[d]azepin-2(3H)-one C11H10N2O2 详情 详情

合成路线74

该中间体在本合成路线中的序号：(XVII)

Condensation of N-Boc-L-leucine (X) with L-phenylalanine methyl ester (XI) in the presence of DIEA, HOBt and BOP in DMF gives the protected dipeptide (XII). Dipeptide (XII) is then deprotected by means of TFA in CH2Cl2 to yield L-Leu-L-Phe-OMe trifluoroacetate salt (XIII), which without isolation is then condensed with N-Boc-Lhomophenylalanine (XIV) in the presence of DIEA, HOBt and BOP in acetonitrile to yield the protected tripeptide (XV) . Then, N-deprotection of peptide (XV) by means of TFA in CH2Cl2 gives tripeptide (XVI), which is finally coupled with chloroacetyl chloride (XVII) in the presence of DIEA in DMF .

参考文献 中间体
合成目标
【1】 Phiasivongsa, P., Sehl, L.C., Fuller, W.D., Laidig, G.J. (Proteolix, Inc.). Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides. WO 2009045497.
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) 69390 (R)-methyl 2-((S)-2-((R)-2-(2-chloroacetamido)-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate C28H36ClN3O5 详情 详情
(X) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine C11H21NO4 详情 详情
(XI) 12324 methyl (2R)-2-amino-3-phenylpropanoate 21685-51-8 C10H13NO2 详情 详情
(XII) 69398 L-Phenylalanine,N-[(1,1-dimethylethoxy)carbonyl]-L-leucyl-, methyl ester;tert-butyloxycarbonyl-leucylphenylalanine methyl ester;(R)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-phenylpropanoate 5874-73-7 C21H32N2O5 详情 详情
(XIII) 69399 (R)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate;L-Leu-L-Phe-OMe trifluoroacetate salt C16H24N2O3.C2HF3O2 详情 详情
(XIV) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(XV) 69400 (6S,9S,12R)-methyl 12-benzyl-9-isobutyl-2,2-dimethyl-4,7,10-trioxo-6-phenethyl-3-oxa-5,8,11-triazatridecan-13-oate C31H43N3O6 详情 详情
(XVI) 69401 (R)-methyl 2-((S)-2-((R)-2-amino-4-phenylbutanamido)-4-methylpentanamido)-3-phenylpropanoate 2,2,2-trifluoroacetate C26H35N3O4.C2HF3O2 详情 详情
(XVII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
Extended Information