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【结 构 式】

【分子编号】19443

【品名】N-methylmethanamine; N,N-dimethylamine

【CA登记号】124-40-3

【 分 子 式 】C2H7N

【 分 子 量 】45.08432

【元素组成】C 53.28% H 15.65% N 31.07%
与该中间体有关的原料药合成路线共 18 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of cyclopentene oxide (I) with dimethylamine (II) gives 2-(dimethylamino)cyclopentanol (III), which is treated with methanesulfonyl chloride and NaH in THF to afford the corresponding methasulfonyl ester (IV). The condensation of (IV) with 3,4-dichloroaniline (V) in THF yields N,N-dimethyl-N'-(3,4-dichlorophenyl)cyclopentane-1,2-diamine (VI), which is acylated with propionic anhydride (A) and treated finally with maleic acid (B).

参考文献 中间体
合成目标
【1】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. BE 0861351; BE 0861355; US 4156015 .
【2】 Szmuszkovicz, J.; Composes alcanoylanilides et leur preparation. BE 0875461 .
【3】 Szmuszkovicz, J.; N-(2-aminocyclopentyl)amides. BE 0867554; DE 2817112; FR 2416882; GB 1581914; JP 54106451; NL 7803442 .
【4】 Szmuszkovicz, J.; Anilide derivatives as antidepressants. US 4128663; US 4148913 .
【5】 Szmuszkovicz, J.; N-(2-Aminocyclopentyl)acylanilides and treating depression. US 4156733; US 4157398 .
【6】 Szmuszkovicz, J.; Kane, M.P.; von Voigtlander, P.F.; A new non-tricyclic antidepressant agent. Synthesis and activity of N-[trans-2-(dimethyamino)cyclopentyl]-N-(3,4-dichlorophenyl)propanamide and related compounds. J Med Chem 1981, 24, 10, 1230-36.
【7】 Owen, R.T.; Serradell, M.N.; Castaner, J.; U-48753 E. Drugs Fut 1984, 9, 11, 846.
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) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(B) 23808 Fumaric acid; (E)-2-butenedioic acid 110-17-8 C4H4O4 详情 详情
(I) 34274 (1R,5S)-6-oxabicyclo[3.1.0]hexane C5H8O 详情 详情
(II) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(III) 34275 (1S,2S)-2-(dimethylamino)cyclopentanol C7H15NO 详情 详情
(IV) 34276 N,N-dimethyl-N-((1S,2S)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)amine; (1S,2S)-N,N-dimethyl-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentanamine C10H21NOS 详情 详情
(V) 23629 3,4-dichloroaniline 95-76-1 C6H5Cl2N 详情 详情
(VI) 34277 N-[(1S,2S)-2-(3,4-dichloroanilino)cyclopentyl]-N,N-dimethylamine; (1S,2S)-N(1)-(3,4-dichlorophenyl)-N(2),N(2)-dimethyl-1,2-cyclopentanediamine C13H18Cl2N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

This compound can be prepared in two different ways: 1) By reaction of cyanuric chloride (I) with dimethylamine (A) in acetone. 2) By reduction of hexamethylolmelamine hexamethyl ether (II) with H2 over Raney-Ni in methanol - water at 100 C and under pressure.

参考文献 中间体
合成目标
【1】 Gunduz, T.; Hexamethylmelamine [2,4,6-tris(dimethylamino)-1,3,5-triazine]. Commun Fac Sci Univ Ankara 1968, 15, 6, 69-73.
【2】 US 3424752 .
【3】 Rutty, C.J.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Hexamethylmelamine. Drugs Fut 1980, 5, 10, 492.
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) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(I) 23813 2,4,6-Trichloro-s-triazine; Cyanuric chloride; Trichlorocyanidine; Tricyanogen chloride; 2,4,6-Trichloro-1,3,5-triazine 108-77-0 C3Cl3N3 详情 详情
(II) 39213 N(2),N(2),N(4),N(4),N(6),N(6)-hexakis(methoxymethyl)-1,3,5-triazine-2,4,6-triamine; N-[4,6-bis[bis(methoxymethyl)amino]-1,3,5-triazin-2-yl]-N,N-bis(methoxymethyl)amine 3089-11-0 C15H30N6O6 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The condensation of 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (I) with phenyl chlorocarbonate (II) in pyridine yields 7-chloro-1,3-dihydro-3-phenoxycarbonyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (III), m.p. 176-8 C, which is then condensed with dimethylamine.

参考文献 中间体
合成目标
【1】 Castaner, J.; Bundgaard, H.; Camazepam. Drugs Fut 1976, 1, 10, 458.
【2】 Ferrrari, G.; Casagrande, C.; 1,4-Benzodiazepine derivatives. DE 2142181; ES 394484; FR 2103475; GB 1327930 .
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) 40454 7-chloro-3-hydroxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one 846-50-4 C16H13ClN2O2 详情 详情
(II) 13580 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate 1885-14-9 C7H5ClO2 详情 详情
(III) 40455 7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl phenyl carbonate C23H17ClN2O4 详情 详情
(IV) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情

合成路线4

该中间体在本合成路线中的序号：(IV)

Treatment of 2-oxo-3,3-diphenyl-tetrahydrofuran (I) with HBr(g) yields bromo derivative (II), which is then converted into butyryl chloride derivative (III) by means of thionyl chloride in refluxing chloroform. Reaction of derivative (III) with dimethylamine (IV) in toluene affords dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (V), which is then condensed with 4-(4-chlorophenyl)-4-piperidinol (VI) by means of Na2CO3 and KI in refluxing 4-methyl-2-pentanone to provide N,N-dimethyl butyramide derivative (VII). Finally, the target product is obtained by N-oxidation of the piperidine ring in (VII) by heating with H2O2 in MeOH/methylbenzene or in 4-methyl-2-pentanone.

参考文献 中间体
合成目标
【1】 Cooymans, L.P.; Wals, L. (Janssen Pharmaceutica NV); Novel alpha,alpha-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides. EP 0219898; JP 1987087569; US 4824853; US 4898873 .
【2】 Niemegeers, C.J.E.J.; Janssen, P.A.J.; Stokbroekx, R.A.; Vandenberk, J. (Janssen Pharmaceutica NV); 2,2-Diaryl-4-(4'-aryl-4'-hydroxy-piperidino)-butyramides. US 3714159 .
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) 48324 alpha,alpha-Diphenyl-gamma-butyrolactone; 4-Methoxychalcone; (4-Methoxybenzylidene)acetophenone; Dihydro-3,3-diphenyl-2(3H)-furanone; 4-Hydroxy-2,2-diphenylbutyric acid gamma-lactone; alpha,alpha-Diphenylbutyrolactone 959-33-1 C16H14O2 详情 详情
(II) 48325 4-bromo-2,2-diphenylbutyric acid C16H15BrO2 详情 详情
(III) 48326 4-bromo-2,2-diphenylbutanoyl chloride C16H14BrClO 详情 详情
(IV) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(V) 48327 N-[3,3-diphenyldihydro-2(3H)-furanylidene]-N-methylmethanaminium bromide C18H20BrNO 详情 详情
(VI) 35870 4-(4-chlorophenyl)-4-piperidinol; 4-(4-Chlorophenyl)-4-hydroxypiperidine 39512-49-7 C11H14ClNO 详情 详情
(VII) 48328 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-N,N-dimethyl-2,2-diphenylbutanamide C29H33ClN2O2 详情 详情

合成路线5

该中间体在本合成路线中的序号：

The condensation of ethoxymethylenemalonic acid diethyl ester (XVI) with 2-methoxyaniline (XVII) in hot toluene gives the aminomethylene derivative (XVIII), which is cyclized with POCl3 and polyphosphoric acid (PPA) at 100 C yielding 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XIX), which is hydrolyzed with NaOH in methanol to the corresponding free acid (XX), and treated with refluxing SOCl2 to afford 4-chloro-8-methoxyquinoline-3-carbonyl chloride (XXI). The reaction of (XXI) with dimethylamine gives the corresponding amide (XXII), which is condensed with o-toluidine (VII) in refluxing dioxane yielding the expected secondary amine (XXIII). Finally, this compound is treated with propylmagnesium chloride (XXIV) to afford the target compound.

参考文献 中间体
合成目标
【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
40593 Sulfurous oxychloride; Thionyl chloride 7719-09-7 Cl2OS 详情 详情
(VII) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(XVI) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(XVII) 25193 2-methoxyphenylamine; 2-methoxyaniline 517-28-2 C7H9NO 详情 详情
(XVIII) 32784 diethyl 2-[(2-methoxyanilino)methylene]malonate C15H19NO5 详情 详情
(XIX) 32785 ethyl 8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C13H13NO4 详情 详情
(XX) 32786 8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C11H9NO4 详情 详情
(XXI) 32787 4-chloro-8-methoxy-3-quinolinecarbonyl chloride C11H7Cl2NO2 详情 详情
(XXII) 32788 4-chloro-8-methoxy-N,N-dimethyl-3-quinolinecarboxamide C13H13ClN2O2 详情 详情
(XXIII) 32789 8-methoxy-N,N-dimethyl-4-(2-toluidino)-3-quinolinecarboxamide C20H21N3O2 详情 详情
(XXIV) 32790 Chloro(propyl)magnesium 2234-82-4 C3H7ClMg 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XII)

3) The condensation of indole (VI) with N,N-diethylchloroacetamide (X) by means of POCl3 gives 3-chloroacetyl-N-methyl-1H-indole-5-methanesulfonamide (XI), which is treated with dimethylamine (XII) in refluxing ethanol to afford the dimethylaminoacetyl derivative (XIII), which is finally reduced with NaBH4 in refluxing propanol.

参考文献 中间体
合成目标
【1】 Oxford, A.W. (Glaxo Group Ltd.); An indole derivative.. GB 2162522 .
【2】 Coates, I.H.; Dowle, M.D. (Glaxo Group Ltd.); Heterocyclic compounds.. FR 2530625; GB 2124210; US 4816470 .
【3】 Humphrey, P.P.A.; Feniuk, W.; Perren, M.J.; Oxford, A.W.; Brittain, R.T.; Prous, J.; Castaner, J.; SUMATRIPTAN SUCCINATE < Prop INNM; BAN >. Drugs Fut 1989, 14, 1, 35.
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) 19441 2-chloro-N,N-diethylacetamide 2315-36-8 C6H12ClNO 详情 详情
(I) 19432 (4-aminophenyl)-N-methylmethanesulfonamide; 4-amino-N-ethylbenzylmethanesulfamide 109903-35-7 C8H12N2O2S 详情 详情
(II) 19433 (4-hydrazinophenyl)-N-methylmethanesulfonamide 88933-16-8 C8H13N3O2S 详情 详情
(III) 19434 2-(phenylsulfanyl)acetaldehyde C8H8OS 详情 详情
(IV) 19435 N-methyl(4-[2-[(E)-2-(phenylsulfanyl)ethylidene]hydrazino]phenyl)methanesulfonamide C16H19N3O2S2 详情 详情
(V) 19436 N-methyl[3-(phenylsulfanyl)-1H-indol-5-yl]methanesulfonamide C16H16N2O2S2 详情 详情
(VI) 19437 1H-indol-5-yl-N-methylmethanesulfonamide C10H12N2O2S 详情 详情
(XI) 19442 [3-(2-chloroacetyl)-1H-indol-5-yl]-N-methylmethanesulfonamide C13H15ClN2O 详情 详情
(XII) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(XIII) 19444 [3-[2-(dimethylamino)acetyl]-1H-indol-5-yl]-N-methylmethanesulfonamide C14H19N3O3S 详情 详情

合成路线7

该中间体在本合成路线中的序号：

The condensation of ethoxymethylenemalonic acid diethyl ester (XXV) with 2-methoxyaniline (XXVI) in hot toluene gives the aminomethylene derivative (XXVII), which is cyclized with POCl3 and polyphosphoric acid (PPA) at 100 C yielding 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XXVIII), which is hydrolyzed with NaOH in methanol to the corresponding free acid (XXIX), and treated with refluxing SOCl2 to afford 4-chloro-8-methoxyquinoline-3-carbonyl chloride (XXX). The reaction of (XXX) with dimethylamine gives the corresponding amide (XXXI), which is condensed with o-toluidine (VIII) in refluxing dioxane yielding the expected secondary amine (XXXII). Finally, this compound is treated with propylmagnesium chloride (XXXIII) to afford the intermediate (XII).

参考文献 中间体
合成目标
【1】 Atkins, R.J.; et al.; Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin. Org Process Res Dev 1997, 1, 3, 185.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
40593 Sulfurous oxychloride; Thionyl chloride 7719-09-7 Cl2OS 详情 详情
(VIII) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(XII) 32799 1-[8-methoxy-4-(2-toluidino)-3-quinolinyl]-1-butanone C21H22N2O2 详情 详情
(XXV) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(XXVI) 25193 2-methoxyphenylamine; 2-methoxyaniline 517-28-2 C7H9NO 详情 详情
(XXVII) 32784 diethyl 2-[(2-methoxyanilino)methylene]malonate C15H19NO5 详情 详情
(XXVIII) 32785 ethyl 8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C13H13NO4 详情 详情
(XXIX) 32786 8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C11H9NO4 详情 详情
(XXX) 32787 4-chloro-8-methoxy-3-quinolinecarbonyl chloride C11H7Cl2NO2 详情 详情
(XXXI) 32788 4-chloro-8-methoxy-N,N-dimethyl-3-quinolinecarboxamide C13H13ClN2O2 详情 详情
(XXXII) 32789 8-methoxy-N,N-dimethyl-4-(2-toluidino)-3-quinolinecarboxamide C20H21N3O2 详情 详情
(XXXIII) 32790 Chloro(propyl)magnesium 2234-82-4 C3H7ClMg 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XII)

The synthesis of moxifetin was described according to the following methods: 1) The first synthesis starts from the acid (I), which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper, or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper. The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide. Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III), which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane, generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol). The reaction of (III) with phosphoryl chloride, followed by sodium borohydride in ethanol, also results in the amine (IV). This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C, by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid. 2) A shorter synthesis begins with the aldehyde (VI), obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate. Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV). Even a procedure via intermediates (VII) and (VIII), i.e., without protection of the phenolic hydroxyl, is feasible. Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield. The following reaction with dimethylamine (XII), leading to the hydroxy amide (VIII), proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane. The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran. The moxifetin base is converted by reactions with acids to crystalline salts, viz. hydrobromide and hydrogen maleate.

参考文献 中间体
合成目标
【1】 Nemec, J.; Metysová, J.; Protiva, M.; Bártl, V.; Metys, J.; Neurotropic and psychotropic agents. LXIII. 7-Methoxy-10-(4-methylpiperazino)dibenzo[b,f]thiepin and its 10,11-dihydro derivative. Coll Czech Chem Commun 1973, 38, 2301-6.
【2】 Schneider, B.; Hasek, J.; Jecny, J.; Crystal and molecular structure of 2-dimethylaminomethyl-3'-hydroxydiphenyl sulfide maleate. Coll Czech Chem Commun 1990, 55, 1529-34.
【3】 Jílek, J.; Valchár, M.; Protiva, M.; Metysová, J.; Sindelár, K.; A novel series of potential antidepressants and selective 5-HT uptake inhibitors. XIth Int Symp Med Chem (Sept 2-7, Jerusalem) 1990, 3.
【4】 Pomykacek, J.; Sindelar, K.; Jilek, J.; et al.; Potential antidepressants: 2-(Methoxy- and hydroxy-phenylthio)-benzylamines as selective inhibitors of 5 hydroxytryptamine re-uptake in the brain. Coll Czech Chem Commun 1989, 54, 12, 3294-338.
【5】 Protiva, M.; Moxifetin Hydrogen Maleate. Drugs Fut 1991, 16, 10, 911.
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) 13625 2-[(3-Methoxyphenyl)sulfanyl]benzoic acid C14H12O3S 详情 详情
(II) 13626 2-[(3-Methoxyphenyl)sulfanyl]benzoyl chloride C14H11ClO2S 详情 详情
(III) 13627 2-[(3-Methoxyphenyl)sulfanyl]-N,N-dimethylbenzamide C16H17NO2S 详情 详情
(IV) 13628 N-[2-[(3-Methoxyphenyl)sulfanyl]benzyl]-N,N-dimethylamine; [2-[(3-Methoxyphenyl)sulfanyl]phenyl]-N,N-dimethylmethanamine C16H19NOS 详情 详情
(V) 25746 2-(benzyloxy)-5-chloro-3-[4-(methylsulfonyl)phenyl]pyridine; 4-[2-(benzyloxy)-5-chloro-3-pyridinyl]phenyl methyl sulfone C19H16ClNO3S 详情 详情
(VI) 13630 2-[(3-Methoxyphenyl)sulfanyl]benzaldehyde C14H12O2S 详情 详情
(VII) 13631 2-[(3-Hydroxyphenyl)sulfanyl]benzoic acid C13H10O3S 详情 详情
(VIII) 13632 2-[(3-Hydroxyphenyl)sulfanyl]-N,N-dimethylbenzamide C15H15NO2S 详情 详情
(IX) 37170 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)-2-(hydroxyimino)acetic acid C16H14N2O3 详情 详情
(X) 63792 2-sulfanylbenzoic acid; thiosalicylic acid 147-93-3 C7H6O2S 详情 详情
(XI) 35983 m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether 2398-37-0 C7H7BrO 详情 详情
(XII) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(XIII) 25756 3-methoxybenzenethiol 15570-12-4 C7H8OS 详情 详情
(XIV) 24114 2-chlorobenzaldehyde 89-98-5 C7H5ClO 详情 详情
(XV) 63793 3-sulfanylphenol C6H6OS 详情 详情
(XVI) 37160 2-iodobenzoic acid 88-67-5 C7H5IO2 详情 详情

合成路线9

该中间体在本合成路线中的序号：

2) The condensation of 7-(formamido)-3-(hydroxymethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XV) with trichloromethyl chloroformate and dimethylamine in THF gives the corresponding dimethylcarbamoyloxy derivative (XVI), which is hydrolyzed with trifluoroacetic acid and anisole to the corresponding acid (as Na salt) (XVII). The esterification of (XVII) with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF as before affords the corresponding ester (XVIII), which is deformylated with HCl in methanol/THF to the 7-amino derivative (XIX). The acylation of (XIX) with 4-bromo-3-oxobutyryl bromide (XX) (obtained from diketene (XXI) with Br2) by means of bis(trimethylsilyl)acetamide in dichloromethane affords the 7-(4-bromo-3-oxobutyramido)-derivative (XXII), which is treated with NaNO2 and acetic acid to obtain the hydroxyimino compound (XXIII). Finally, this compound is cyclized with thiourea in dimethylacetamide. 3) The 7-amino cephem derivative (XIX) can also be acylated with 4-chloro-3-oxobutyryl chloride (XXV) (obtained from diketene (XXI) with Cl2) to yield the 7-(4-chloro-3-oxobutyramido)-derivative (XXVI), which is treated with amyl nitrite and acetyl chloride to afford the hydroxyimino compound (XXVII). Finally, this compound is cyclized with thiourea as before.

参考文献 中间体
合成目标
【1】 Negi, S.; et al.; Studies on orally active cephalosporins. I. Synthesis and structure-activity relationships of new 3-substituted carbamoyloxymethyl cephalosporins. J Antibiot 1994, 47, 12, 1507-25.
【2】 Fromtling, R.A.; Castaner, J.; E-1101. Drugs Fut 1995, 20, 8, 766.
【3】 Negi, S.; Yamanaka, M.; Katsu, K.; Sugiyama, I.; Komatu, Y.; Kamata, A.; Tsuruoka, A.; Machida, Y. (Eisai Co., Ltd.); 7-Acyl-3-(substd. carbamoyloxy)cephem cpds., use thereof and process for their preparation. EP 0484966; EP 0761671; JP 1992178392; JP 1992282388; JP 1993311173; JP 1993311174; JP 1994092969; JP 1998067784; US 5559225; US 5587473; US 5604217 .
【4】 Negi, S.; Yamanaka, M.; Sugiyama, I.; et al.; E1101, a new oral cephalosporin: I. Synthesis and structure-activity relations of 3-substituted carbamoyloxymethyl cephems. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 894.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
42918 Chloroformic acid trichloromethyl ester; di-Phosgene; Chloroformic Acid, Trichloromethyl Ester; Trichloromethyl chloroformate; Diphosgene 503-38-8 C2Cl4O2 详情 详情
(XIV) 15685 1-iodoethyl isopropyl carbonate C6H11IO3 详情 详情
(XV) 15686 benzhydryl 7-(formylamino)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O5S 详情 详情
(XVI) 64676 diphenylmethyl 3-({[(dimethylamino)carbonyl]oxy}methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C25H25N3O6S 详情 详情
(XVII) 15687 7-(Formamido)-3-(N,N-dimethylcarbamoyloxy)-3-cephem-4-carboxylic acid sodium salt C12H14N3NaO6S 详情 详情
(XVIII) 15689 1-[(isopropoxycarbonyl)oxy]ethyl 3-([[(dimethylamino)carbonyl]oxy]methyl)-7-(formylamino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H25N3O9S 详情 详情
(XIX) 15690 1-[(isopropoxycarbonyl)oxy]ethyl 7-amino-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H25N3O8S 详情 详情
(XX) 15691 4-bromo-3-oxobutanoyl bromide C4H4Br2O2 详情 详情
(XXI) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(XXII) 15693 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-bromo-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28BrN3O10S 详情 详情
(XXIII) 64677 1-({[(1-methylethyl)oxy]carbonyl}oxy)ethyl 7-{[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino}-3-({[(dimethylamino)carbonyl]oxy}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27BrN4O11S 详情 详情
(XXIV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(XXV) 15696 4-chloro-3-oxobutanoyl chloride C4H4Cl2O2 详情 详情
(XXVI) 15697 1-[(isopropoxycarbonyl)oxy]ethyl 7-[(4-chloro-3-oxobutanoyl)amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H28ClN3O10S 详情 详情
(XXVII) 15698 1-[(isopropoxycarbonyl)oxy]ethyl 7-[[4-chloro-2-(hydroxyimino)-3-oxobutanoyl]amino]-3-([[(dimethylamino)carbonyl]oxy]methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C21H27ClN4O11S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(B)

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with allyl magnesium bromide (A) in ethyl ether gives 5-hydroxy-5-allyldibenzo[a,d]cyclohepta-1,4,6-triene (II), which is dehydrated with acetic anhydride and acetyl chloride at 90 C yielding 5-propenylidenedibenzo[a,d]cyclohepta-1,4,6-triene (III). Finally, this compound is treated with phenylmagnesium bromide and dimethylamine (B) at 80 C.

参考文献 中间体
合成目标
【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【2】 Schmitt, G. (F. Hoffmann-La Roche AG); A process for the manufacture of tricyclic amines. BE 0636000; CH 385191; DE 1468006; FR 1366413; GB 990105 .
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) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(B) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(I) 29151 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone 2222-33-5 C15H10O 详情 详情
(II) 40125 5-allyl-5H-dibenzo[a,d]cyclohepten-5-ol C18H16O 详情 详情
(III) 40126 5-(2-propenylidene)-5H-dibenzo[a,d]cycloheptene C18H14 详情 详情

合成路线11

该中间体在本合成路线中的序号：(B)

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with cyclopropyl magnesium bromide (D) in THF gives 5-hydroxy-5-cyclopropyldibenzo[a,d]cyclohepta-1,4,6-triene (V), which is then treated with HBr in acetic acid to yield 5-(3-bromopropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VI). Finally, (VI) is treated with dimethylamine (B) in benzene at 95 C. The hydroxycompound (V), obtained as before, is treated with HClO4 in dioxane to yield 5-(3-hydroxypropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VII), which is then treated with p-toluenesulfonyl chloride in pyridine to afford the tosyl derivate (VIII). Finally, (VIII) is treated with dimethylamine (B) in benzene at 100 C.

参考文献 中间体
合成目标
【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【2】 Hoffsommer, R.D. Jr.; et al.; Nouveaux derives de dibenzocycloheptenes et leur preparation. BE 0631012 .
【3】 Wendler, N.L.; Dibenzocycloheptenes. BE 0633316 .
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) 12450 Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide 23719-80-4 C3H5BrMg 详情 详情
(B) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(I) 29151 5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone 2222-33-5 C15H10O 详情 详情
(V) 40129 5-cyclopropyl-5H-dibenzo[a,d]cyclohepten-5-ol C18H16O 详情 详情
(VI) 40130 5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene C18H15Br 详情 详情
(VII) 40131 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propanol C18H16O 详情 详情
(VIII) 40132 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl 4-methylbenzenesulfonate C25H22O3S 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

The reaction of 6-(2,6-difluorobenzyl)-2-(methylsulfanyl)pyrimidin-4(3H)-one (I) with dimethylamine (II) gives the target aminopyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
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) 51832 6-(2,6-difluorobenzyl)-2-(methylsulfanyl)-4(3H)-pyrimidinone C12H10F2N2OS 详情 详情
(II) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VII)

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14

该中间体在本合成路线中的序号：(XI)

The methylation of 6-chloro-1H-indole-2-carboxylic acid ethyl ester (I) with NaH and Me-I in DMF gives the 1-methylindole derivative (II), which is condensed with 2-chloro-2-oxoacetic acid ethyl ester (III) by means of TiCl4 in dichloroethane to yield 6-chloro-2-[2-(ethoxycarbonyl)-1-methyl-1H-indol-3-yl]-2-oxoacetic acid ethyl ester (IV). The cyclization of (IV) with phenylhydrazine (V) in refluxing acetic acid affords the 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylic acid ethyl ester (VI). The reduction of the ester group of (VI) by means of NaBH4 in refluxing THF/methanol affords the hydroxymethyl derivative (VII), which is oxidized with MnO2 in refluxing dichloromethane to provide the corresponding carbaldehyde (VIII). The reaction of (VIII) with p-Toluenesulfonylmethyl isocyanide (TosMIC) and potassium tert-butoxide in dimethoxyethane gives the acetonitrile derivative (IX), which is hydrolyzed with HCl in refluxing methanol to yield the acetate ester derivative (X). Finally, this compound is treated with dimethylamine and trimethylaluminum in toluene to afford the target dimethylacetamide derivative.

参考文献 中间体
合成目标
【1】 Bartsch, R.; Sevrin, M.; Froissant, J.; Evanno, Y.; Dubois, L.; Marguet, F.; Gille, C. (Sanofi-Synthélabo); 4-Oxo-3,5-dihydro-4H-pyridazino[4,5-b]-indole-1-acetamide derivs., their preparation and their application in therapy. EP 1000063; FR 2766823; JP 2001512122; US 6262045; WO 9906406 .
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) 55771 ethyl 6-chloro-1H-indole-2-carboxylate C11H10ClNO2 详情 详情
(II) 55772 ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate C12H12ClNO2 详情 详情
(III) 11043 Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride 4755-77-5 C4H5ClO3 详情 详情
(IV) 55773 ethyl 6-chloro-3-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-indole-2-carboxylate C16H16ClNO5 详情 详情
(V) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(VI) 55774 ethyl 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carboxylate C20H16ClN3O3 详情 详情
(VII) 55775 7-chloro-1-(hydroxymethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one C18H14ClN3O2 详情 详情
(VIII) 55776 7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indole-1-carbaldehyde C18H12ClN3O2 详情 详情
(IX) 55777 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetonitrile C19H13ClN4O 详情 详情
(X) 55778 methyl 2-(7-chloro-5-methyl-4-oxo-3-phenyl-4,5-dihydro-3H-pyridazino[4,5-b]indol-1-yl)acetate C20H16ClN3O3 详情 详情
(XI) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情

合成路线15

该中间体在本合成路线中的序号：(A)

The condensation of 3-pyridincarboxaldehyde (I) with diethyl malonate (II) by means of piperidine in refluxing benzene gives diethyl (3-pyridyl)methylenemalonate (III), which by reaction with dimethylamine (A) in ether is converted into diethyl alpha-dimethylamino-(3-pyridyl)methylmalonate (IV). The reduction of (IV) with LiAlH4 in THF affords 2-[alpha-dimethylamino-(3-pyridyl)methyl]-1,3-propanediol (V), which is finally cyclized with paraformaldehyde by means of boron trifluoride ethearate in acetonitrile. (1-3)

参考文献 中间体
合成目标
【1】 Booher, R.N. (Eli Lilly and Company); US 3905987 .
【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Doxpicomine hydrochloride. Drugs Fut 1981, 6, 9, 548.
【3】 Booher, R.N.; et al.; Various 5-substituted and 2,5-disubstituted 1,3-dioxanes, a new class of analgesic agents. J Med Chem 1977, 20, 7, 885.
【4】 Booher, R.N. (Eli Lilly and Company); US 3962269 .
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) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(I) 12849 Nicotinaldehyde; 3-Pyridinecarboxaldehyde 500-22-1 C6H5NO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 60974 diethyl 2-(3-pyridinylmethylene)malonate C13H15NO4 详情 详情
(IV) 60975 diethyl 2-[(dimethylamino)(3-pyridinyl)methyl]malonate C15H22N2O4 详情 详情
(V) 60976 2-[(dimethylamino)(3-pyridinyl)methyl]-1,3-propanediol C11H18N2O2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VII)

It can be prepared in several different way (Scheme 31229302a): 1) The nitrosation of 2-[3-(dimethylamino)propylamino]-5-methylbenzophenone (I) with NaNO2 and HCl in chloroform gives the corresponding N-nitroso compound (II), which is cyclized by reaction with Zn in acetic acid. 2) By reaction of 1-(3-methylaminopropyl)-5-methyl-3-phenyl-1H-indazole (III) with formaldehyde and NaBH4 in methanol. 3) The reaction of 3-phenyl-5-methyl-1H-indazole (IV) with 1,3-dibromopropane (V) by means of NaH in DMF gives 1-(3-bromopropyl)-5-methyl-3-phenyl-1H-indazole (VI), which is then condensed with dimethylamine (VII). 4) By reaction of (IV) with 1-(dimethylamino)-3-bromopropane (VIII) by means of NaOH in a mixture of toluene and water.

参考文献 中间体
合成目标
【1】 Fujimura, Y.; et al. (Cubist Pharmaceuticals, Inc.); JP 76125281 .
【2】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); DE 2503815; FR 2259601; GB 1489280; JP 75106958; JP 75145244; JP 75148335; JP 7663172; US 3994890 .
【3】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7659861 .
【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Paton, D.M.; FS-32. Drugs Fut 1979, 4, 8, 583.
【5】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7714765 .
【6】 Fujimura, Y.; et al. (Chugai Pharmaceutical Co. Ltd.); JP 7714766 .
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) 61119 (2-{[3-(dimethylamino)propyl]amino}-5-methylphenyl)(phenyl)methanone C19H24N2O 详情 详情
(II) 61120 　 C19H23N3O2 详情 详情
(III) 61123 N-methyl-3-(5-methyl-3-phenyl-1H-indazol-1-yl)-1-propanamine; N-methyl-N-[3-(5-methyl-3-phenyl-1H-indazol-1-yl)propyl]amine C18H21N3 详情 详情
(IV) 34172 5-methyl-3-phenyl-1H-indazole C14H12N2 详情 详情
(V) 12581 1,3-Dibromopropane 109-64-8 C3H6Br2 详情 详情
(VI) 61121 1-(3-bromopropyl)-5-methyl-3-phenyl-1H-indazole C17H17BrN2 详情 详情
(VII) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
(VIII) 61122 3-bromo-N,N-dimethyl-1-propanamine; N-(3-bromopropyl)-N,N-dimethylamine C5H12BrN 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

The reaction of 6-(2,6-difluorobenzyl)-5-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (I) with dimethylamine (II) gives the target aminopyrimidinone.

参考文献 中间体
合成目标
【1】 Artico, M.; Selected non-nucleoside reverse transcriptase inhibitors (NNRTIs): the DABOs family. Drugs Fut 2002, 27, 2, 159.
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) 51828 6-(2,6-difluorobenzyl)-5-methyl-2-(methylsulfanyl)-4(3H)-pyrimidinone C13H12F2N2OS 详情 详情
(II) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

By reaction of 2,4-dichloromethylamino-s-triazine (I) with dimethylamine (II) in refluxing water.

参考文献 中间体
合成目标
【1】 Cabanillas, F.; Pentamethylmelamine Hydrochloride. Drugs Fut 1979, 4, 6, 434.
【2】 Borkovec, A.B.; De Milo, A.B.; Positive opinion for Humira label extension in E.U.. J Med Chem 1967, 10, 457.
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) 61095 4,6-dichloro-N-methyl-1,3,5-triazin-2-amine; N-(4,6-dichloro-1,3,5-triazin-2-yl)-N-methylamine C4H4Cl2N4 详情 详情
(II) 19443 N-methylmethanamine; N,N-dimethylamine 124-40-3 C2H7N 详情 详情
Extended Information