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【结 构 式】 
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【分子编号】31457 【品名】N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine 【CA登记号】1188-33-6 |
【 分 子 式 】C7H17NO2 【 分 子 量 】147.21752 【元素组成】C 57.11% H 11.64% N 9.51% O 21.74% |
合成路线1
该中间体在本合成路线中的序号：(B)The reaction of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-thione (I) with glycine (A) by means of Na2CO3 in refluxing ethanol-water gives 2-carboxymethylamino-7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine (II), which is cyclized by means of dicyclohexylcarbodiimide in methylene chloride to afford 8-nitro-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2-a][1,4]benzodiazepin-1-one (III). The reaction of (III) with dimethylformamide diethylacetal (B) by means of triethylamine in benzene yields 8-nitro-2-(dimethylaminomethylene)-6-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one (IV), which is treated with N-methylpiperazine (C) in refluxing toluene to produce 8-nitro-(2-chlorophenyl)-2-(N-methylpiperazin-1-ylmethylene)-1,2-dihydro-1H,4H-imidazo [1,2-a][1,4]benzodiazepin-1-one (V). This compound is finally treated with methanesulfonic acid.
| 【1】 Taylor, J.B.; Harrison D.R.; 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones. US 4044142 . |
| 【2】 Ager, J.R.; et al.; Central nervous system activity of a novel class of annelated 1,4-benzodiazwpines, aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-ones. J Med Chem 1977, 20, 8, 1035-41. |
| 【3】 Thorpe, P.J.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RU-31,158. Drugs Fut 1980, 5, 3, 144. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40922 | N,N'-dicyclohexylurea | 2387-23-7 | C13H24N2O | 详情 | 详情 | |
| (A) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (B) | 31457 | N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine | 1188-33-6 | C7H17NO2 | 详情 | 详情 |
| (I) | 32632 | 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-thione | C15H10ClN3O2S | 详情 | 详情 | |
| (II) | 32633 | 2-[[5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-yl]amino]acetic acid | C17H13ClN4O4 | 详情 | 详情 | |
| (III) | 30373 | 6-(2-chlorophenyl)-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one | C17H11ClN4O3 | 详情 | 详情 | |
| (IV) | 32634 | 6-(2-chlorophenyl)-2-[(Z)-(dimethylamino)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one | C20H16ClN5O3 | 详情 | 详情 | |
| (V) | 30375 | 6-(2-chlorophenyl)-2-[(Z)-(4-methyl-1-piperazinyl)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one | C23H21ClN6O3 | 详情 | 详情 | |
| (C) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)A new process for the production of venlafaxine has been reported: Esterification of 2-(4-methoxyphenyl)-acetic acid (I) with ethanol and sulfuric acid gives the corresponding ethyl ester (II), which is condensed with ethyl formate by means of NaH to yield 2-formyl-3-(4-methoxyphenyl)acetic acid ethyl ester (III). Reaction of (III) with dimethylamine and K2CO3 in EtOH affords 3-(dimethylamino)-2-(4-methoxyphenyl)acrylic acid ethyl ester (IV), which is reduced with either NaBH4, LiAlH4 or H2 over Pd/C or Pt/C in ethanol to provide the corresponding propionic ester (V). Finally, this compound is cyclized with the bismagnesiane (VI) in THF. Alternatively, acrylic ester (IV) can be obtained directly by condensation of acetate (II) with dimethylformamide diethylacetal (VII) at 135 C. Alternatively, propionic ester (V) can be obtained by condensation of acetate (II) with N,N-dimethylmethylene-iminium iodide (VIII) by means of LDA in THF/heptane/ ethylbenzene.
| 【1】 Camps Garcia, P.; Bosch i Llado, J.; Onrubia Miguel, M.C.; Arnalot i Aguilar, C.; Soldevila Madrid, N. (Medichem SA); Venlafaxine production process. WO 0107397 . |
| 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) | 34793 | 2-(4-methoxyphenyl)acetic acid; p-Methoxyphenyl formate; Homoanisic acid; p-Methyl benzyl formate; 4-methoxyphenylacetic acid; 4-methoxybenzeneacetic acid; p-methoxyphenylacetic acid | 104-01-8 | C9H10O3 | 详情 | 详情 |
| (II) | 48550 | 4-methoxyphenylacetic acid ethyl ester; Ethyl 4-methoxyphenylacetate; Homoanisic acid ethyl ester | 14062-18-1 | C11H14O3 | 详情 | 详情 |
| (III) | 48551 | ethyl 2-(4-methoxyphenyl)-3-oxopropanoate | C12H14O4 | 详情 | 详情 | |
| (IV) | 48552 | ethyl (E)-3-(dimethylamino)-2-(4-methoxyphenyl)-2-propenoate | C14H19NO3 | 详情 | 详情 | |
| (V) | 48553 | ethyl 3-(dimethylamino)-2-(4-methoxyphenyl)propanoate | C14H21NO3 | 详情 | 详情 | |
| (VI) | 48554 | Pentamethylenebis(magnesium bromide); Pentane-1,5-di(magnesium bromide) | C5H10Br2Mg2 | 详情 | 详情 | |
| (VII) | 31457 | N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine | 1188-33-6 | C7H17NO2 | 详情 | 详情 |
| (VIII) | 48555 | Eschenmoser's salt; N,N-Dimethylmethyleneimmonium chloride; N,N-Dimethylmethyleneimmonium iodide | C3H8IN | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)The acylation of 2-(4-chlorophenyl)ethylamine (I) with Ac2O in toluene gives the acetamide (II), which is cyclized with oxalyl chloride (III) in dichloromethane to yield the oxazolidinedione (IV). The cyclization of (IV) by means of FeCl3 in dichloromethane affords the oxazolo-isoquinoline (V), which is hydrolyzed with hot H2SO4 in methanol or AcOH to provide 7-chloro-1-methyl-3,4-dihydroisoquinoline (VI). The cyclization of (VI) with 3-(dimethylamino)-2-phenylacrylic acid ethyl ester (VII) in hot AcOH gives the benzoquinolizine (VIII), which is brominated with NBS in hot AcOH to yield the 1-bromo compound (IX). Finally, this compound is condensed with 3(S)-ethoxypyrrolidine (XIII) and carbon monoxide by means of Pd(OAc)2 dppp in hot acetonitrile to furnish the target acyl pyrrolidine compound. Alternatively, bromocompound (IX) is condensed with CO by means of Pd(OAc)2 dppp in hot DMSO to give the carboxylic acid (XI), which is treated with oxalyl chloride and DMAP in hot ethyl acetate to yield the corresponding acyl chloride (XII). Finally, this compound is condensed with 3(S)-ethoxypyrrolidine (XIII) by means of TEA in toluene. In a further method, the bromocompound (IX) is condensed with CO by means of Pd(OAc)2 dppp in hot methanol to yield the methyl ester (X), which is hydrolyzed with KOH in methanol/water to the already reported carboxylic acid (XI). A third method is also reported: The condensation of carboxylic acid (XI) with 3(S)-hydroxypyrrolidine (XIV) by means of NMM and HBTU in DMF gives the corresponding acyl pyrrolidine (XV), which is finally alkylated with ethyl iodide and KOH in DMF. The intermediate 3-(dimethylamino)-2-phenylacrylic acid ethyl ester (VII) has been obtained by condensation of 2-phenylacetic acid ethyl ester (XVI) with dimethylformamide diethylacetal (XVII) at 150 C.
| 【1】 Spurr, P.R.; An expedient route to the tricyclic pyridone derivative Ro 41-3696 a novel non-benzodiazepine sleep inducer. Tetrahedron Lett 1995, 36, 16, 2745. |
| 【2】 Scherschlicht, R.R.; Widmer, U. (F. Hoffmann-La Roche AG); Tricyclic pyridone deriv.. EP 0496274; JP 1992312585; US 5281711; US 5326769 . |
| 【3】 Spurr, P. (F. Hoffmann-La Roche AG); Process for the preparation of a benzo(a)quinolizinone deriv.. EP 0650966 . |
| 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) | 29459 | 4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine | 156-41-2 | C8H10ClN | 详情 | 详情 |
| (II) | 54231 | N-[2(4-chlorophenyl)ethyl]acetamide | 88422-94-0 | C10H12ClNO | 详情 | 详情 |
| (III) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (IV) | 54232 | 2-chloro-3-(4-chlorophenethyl)-2-methyl-1,3-oxazolidine-4,5-dione | n/a | C12H11Cl2NO3 | 详情 | 详情 |
| (V) | 54233 | 9-chloro-10b-methyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione | n/a | C12H10ClNO3 | 详情 | 详情 |
| (VI) | 54234 | 7-chloro-1-methyl-3,4-dihydroisoquinoline | n/a | C10H10ClN | 详情 | 详情 |
| (VII) | 54235 | ethyl (Z)-3-(dimethylamino)-2-phenyl-2-propenoate | n/a | C13H17NO2 | 详情 | 详情 |
| (VIII) | 54236 | 10-chloro-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-4-one | n/a | C19H14ClNO | 详情 | 详情 |
| (IX) | 54237 | 1-bromo-10-chloro-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-4-one | n/a | C19H13BrClNO | 详情 | 详情 |
| (X) | 54238 | methyl 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carboxylate | n/a | C21H16ClNO3 | 详情 | 详情 |
| (XI) | 54239 | 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carboxylic acid | n/a | C20H14ClNO3 | 详情 | 详情 |
| (XII) | 54240 | 10-chloro-4-oxo-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbonyl chloride | n/a | C20H13Cl2NO2 | 详情 | 详情 |
| (XIII) | 54241 | (3S)-3-ethoxypyrrolidine; ethyl (3S)pyrrolidinyl ether | n/a | C6H13NO | 详情 | 详情 |
| (XIV) | 38841 | (3R)-3-pyrrolidinol | C4H9NO | 详情 | 详情 | |
| (XV) | 54242 | 10-chloro-1-{[(3S)-3-hydroxypyrrolidinyl]carbonyl}-3-phenyl-6,7-dihydro-4H-pyrido[2,1-a]isoquinolin-4-one | n/a | C24H21ClN2O3 | 详情 | 详情 |
| (XVI) | 21045 | ethyl 2-phenylacetate | 101-97-3 | C10H12O2 | 详情 | 详情 |
| (XVII) | 31457 | N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine | 1188-33-6 | C7H17NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Reaction of 2-chloro-5-acetylpyridine (I) with refluxing dimethylformamide diethylacetal (II) afforded the enaminoketone (III). Subsequent condensation of (III) with 3,4,5-trimethoxyphenylguanidinium nitrate (IV) in the presence of NaOH gave rise to the pyridinyl pyrimidine (V). Finally, displacement of the halogen atom of (V) with (S)-2-ethylpiperazine (VI) yielded the title compound.
| 【1】 Davis, P.; Hutchings, M.; Moffat, D.; et al.; 4-Pyridin-5-yl-2-(3,4,5-trimethoxyphenylamino)pyrimidines: Potent and selective inhibitors of ZAP 70. Bioorg Med Chem Lett 1999, 9, 23, 3351. |
| 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) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (II) | 31457 | N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine | 1188-33-6 | C7H17NO2 | 详情 | 详情 |
| (III) | 31458 | (E)-1-(6-chloro-3-pyridinyl)-3-(dimethylamino)-2-propen-1-one | C10H11ClN2O | 详情 | 详情 | |
| (IV) | 31459 | N-(3,4,5-Trimethoxyphenyl)guanidinium nitrate | C10H16N4O6 | 详情 | 详情 | |
| (V) | 31460 | N-[4-(6-chloro-3-pyridinyl)-2-pyrimidinyl]-N-(3,4,5-trimethoxyphenyl)amine; 4-(6-chloro-3-pyridinyl)-N-(3,4,5-trimethoxyphenyl)-2-pyrimidinamine | C18H17ClN4O3 | 详情 | 详情 | |
| (VI) | 31461 | (2S)-2-ethylpiperazine | C6H14N2 | 详情 | 详情 |