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【结 构 式】 
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【药物名称】Lirequinil, Ro-41-3696 【化学名称】10-Chloro-1-[3(S)-ethoxypyrrolidin-1-ylcarbonyl]-3-phenyl-6,7-dihydro-4H-benzo[a]quinolizin-4-one 【CA登记号】143943-73-1 【 分 子 式 】C26H25ClN2O3 【 分 子 量 】448.95375 |
【开发单位】Roche (Originator) 【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, GABA(A) BZ Site Receptor Partial Agonists |
合成路线1
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
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 . |