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【结 构 式】

【分子编号】54241

【品名】(3S)-3-ethoxypyrrolidine; ethyl (3S)pyrrolidinyl ether

【CA登记号】n/a

【 分 子 式 】C6H13NO

【 分 子 量 】115.17536

【元素组成】C 62.57% H 11.38% N 12.16% O 13.89%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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2

该中间体在本合成路线中的序号:(XIII)

The intermediate 3(S)-ethoxypyrrolidine (XIII) has been obtained by alkylation of 1-benzyl-3(S)-hydroxypyrrolidine (XVIII) with ethyl iodide and NaH in THF to give 1-benzyl-3(S)-ethoxypyrrolidine (XIX), which is finally debenzylated with H2 over Pd/C in methanol.

1 Scherschlicht, R.R.; Widmer, U. (F. Hoffmann-La Roche AG); Tricyclic pyridone deriv.. EP 0496274; JP 1992312585; US 5281711; US 5326769 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 54241 (3S)-3-ethoxypyrrolidine; ethyl (3S)pyrrolidinyl ether n/a C6H13NO 详情 详情
(XVIII) 54243 (3S)-1-benzyl-3-pyrrolidinol 101385-90-4 C11H15NO 详情 详情
(XIX) 54244 (3S)-1-benzylpyrrolidinyl ethyl ether; (3S)-1-benzyl-3-ethoxypyrrolidine n/a C13H19NO 详情 详情
Extended Information