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【结 构 式】 
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【分子编号】29459 【品名】4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine 【CA登记号】156-41-2 |
【 分 子 式 】C8H10ClN 【 分 子 量 】155.62684 【元素组成】C 61.74% H 6.48% Cl 22.78% N 9% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(I)By condensation of 2-(4-chlorophenyl)ethylamine (I) with thiocarbonyldiimidazole (II) in refluxing acetonitrile.
| 【1】 Zhu, Z.; et al.; N,N'-Di(phenethyl)thiourea liquid-phase combinatorial libraries: Synthesis and apoptosis induction. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 023. |
合成路线3
该中间体在本合成路线中的序号：(II)By condensation of 4-chloro-5-methylthieno[2,3-d]pyrimidine (I) with 2-(4-chlorophenyl)ethylamine (II) by means of diisopropylethylamine (DIEA) in hot DMF.
| 【1】 Katada, J.; Iijima, K.; Muramatsu, M.; Hayashi, M.; Hayashi, Y.; Hattori, M.; Takami, M.; Yasuda, E.; Cytotoxic effects of NSL-1406, a new thienopyrimidine derivative, on leukocytes and osteoclasts. Bioorg Med Chem Lett 1999, 9, 6, 797. |
合成路线4
该中间体在本合成路线中的序号：(IV)Protection of 2'-O-acetyl-6-O-methylerythromycin A (I) with chlorotrimethylsilane afforded the 4''-O-trimethylsilyl derivative (II). Subsequent treatment with carbonyldiimidazole and NaH produced the dehydrated imidazolide (III), which was converted to the cyclic carbamate (V) upon reaction with 4-chlorophenethyl amine (IV). Acid hydrolysis of the cladinose moiety gave alcohol (VI), and further condensation with carbonyldiimidazole yielded imidazolide (VII).
| 【1】 Waid, P.; Dalton, C.R.; Randolph, J.T.; Greer, J.; Nichols, C.J.; Haviv, F.; Mort, N.A.; Sauer, D.R. (Abbott Laboratories Inc.); Macrolide LHRH antagonists. WO 0012522 . |
| 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) | 38154 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[((3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-4-[[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl)oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C40H71NO14 | 详情 | 详情 | |
| (II) | 38155 | (2S,3R,4S,6R)-4-(dimethylamino)-2-[[(3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-14-ethyl-12,13-dihydroxy-7-methoxy-4-([(4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-2,10-dioxooxacyclotetradecanyl]oxy]-6-methyltetrahydro-2H-pyran-3-yl acetate | C43H79NO14Si | 详情 | 详情 | |
| (III) | 38156 | (2R,3S,7R,9R,10R,11R,12S,13R)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-2-ethyl-9-methoxy-12-([(4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxa-4-cyclotetradecen-3-yl 1H-imidazole-1-carboxylate | C47H79N3O14Si | 详情 | 详情 | |
| (IV) | 29459 | 4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine | 156-41-2 | C8H10ClN | 详情 | 详情 |
| (V) | 38157 | (2S,3R,4S,6R)-2-[[(3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-8-([(4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C52H85ClN2O14Si | 详情 | 详情 | |
| (VI) | 38158 | (2S,3R,4S,6R)-2-[[(3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-1-(4-chlorophenethyl)-4-ethyl-8-hydroxy-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl]oxy]-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-3-yl acetate | C41H63ClN2O11 | 详情 | 详情 | |
| (VII) | 38159 | (3aS,4R,7R,8S,9R,10R,11R,13R,15R,15aR)-10-[[(2S,3R,4S,6R)-3-(acetoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy]-1-(4-chlorophenethyl)-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-2,6,14-trioxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-8-yl 1H-imidazole-1-carboxylate | C45H65ClN4O12 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Lorcaserin hydrochloride can be prepared by several different procedures. 4-Chlorophenethylamine (I) is acylated with 2-chloropropionyl chloride (II) in the presence of pyridine in CH2Cl2 to give the chloropropionamide (III), which is cyclized to the benzazepinone (IV) upon heating with AlCl3. Subsequent reduction of (IV) with either BH3 or LiAlH4 in Et2O affords the racemic lorcaserin (V) (1-3). In a related method, chloropropionamide (III) is reduced with borane in THF to yield the chloro amine (VIa), which is then cyclized to benzazepine (V) in the presence of AlCl3 (3). Alternatively, condensation of 4-chlorophenethyl bromide (VII) with 1-amino-2-propanol (VIII) provides the aminoalcohol (IX), which is converted to either the chloro amine (VIa) or the analogous bromo amine (VIb) by treatment with SOCl2 or SOBr2, respectively (3). Optical resolution of tetrahydrobenzazepine (V) either employing chiral HPLC or by crystallization with D-tartaric acid furnishes the target (R)-enantiomer (X) (1-3). This is finally converted to the title hydrochloride salt by treatment with HCl in different solvent systems (4). In a further procedure, after protection of 4-chlorophenethylamine (I) as the corresponding trifluoroacetamide (XI) by means of trifluoroacetic anhydride and pyridine in CH2Cl2, iodination with bis(pyridine)iodonium tetrafluoroborate in the presence of trifluoromethanesulfonic acid furnishes (XII). Subsequent alkylation of trifluoroacetamide (XII) with allyl bromide under phase transfer conditions leads to the iodo olefin (XIII), which undergoes intramolecular Heck cyclization in the presence of Pd(OAc)2 and PPh3 to furnish the methylene benzazepine (XIV). After reduction of (XIV) to the methyl analogue (XV) by catalytic hydrogenation over Pd/C, the N-trifluoroacetyl group is hydrolyzed with NaOH in aqueous MeOH to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (V) (5). Scheme 1.
| 【1】 Smith, B., Smith, J., Schultz, J., Gilson, C. III (Arena Pharmaceuticals, Inc.). Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases. EP 1633720, JP 2007516941, WO 2005003096. |
| 【2】 Smith, B.M., Smtih, J.M., Tsai, J.H. et al. Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity. Bioorg Med Chem Lett 2005, 15(5): 1467-70. |
| 【3】 Burbaum, B.W., Gilson, C.A. III, Aytes, S. et al. (Arena Pharmaceuticals, Inc.). Processes for preparing 3-benzazepines. EP 1636191, JP 2007521269, WO 2005019179. |
| 【4】 Agarwal, R.K., Betts, W.L. III, Henshilwood, J.A., Kiang, Y.-H., Post, N. (Arena Pharmaceuticals, Inc.). Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. WO 2006069363. |
| 【5】 Smith, B., Smith, J. (Arena Pharmaceuticals, Inc.). 5HT2C receptor modulators. EP 1557409, JP 2005527579, JP 2006143751, US 2003225057, US 6953787, WO 2003086306. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIb) | 65408 | 4-Chloro-N-(2-bromopropyl)benzeneethanamine | C11H15BrClN | 详情 | 详情 | |
| (Via) | 65407 | 4-Chloro-N-(2-chloropropyl)benzeneethanamine | 897926-35-1 | C11H15Cl2N | 详情 | 详情 |
| (I) | 29459 | 4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine | 156-41-2 | C8H10ClN | 详情 | 详情 |
| (II) | 12926 | 2-Chloropropanoyl chloride; 2-Chloropropionyl chloride | 7623-09-8 | C3H4Cl2O | 详情 | 详情 |
| (III) | 65404 | 2-chloro-n-(2-(4-chlorophenyl)ethyl)propanamide; 1-((2-(4-chlorophenyl)ethyl)amino)-1-oxo-2-chloropropane | 34164-14-2 | C11H13Cl2NO | 详情 | 详情 |
| (IV) | 65405 | 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one | 824430-77-5 | C11H12ClNO | 详情 | 详情 |
| (V) | 65406 | Lorcaserin A; 8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine | 616201-80-0 | C11H14ClN | 详情 | 详情 |
| (VII) | 65409 | 4-Chlorophenethyl bromide; 1-(2-Bromoethyl)-4-chlorobenzene | 6529-53-9 | C8H8BrCl | 详情 | 详情 |
| (VIII) | 41397 | 1-amino-2-propanol | 78-96-6 | C3H9NO | 详情 | 详情 |
| (IX) | 65410 | 1-[[2-(4-Chlorophenyl)ethyl]amino]-2-hydroxypropane | 847063-13-2 | C11H16ClNO | 详情 | 详情 |
| (X) | 65411 | (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; Lorcaserin | 616202-92-7 | C11H14ClN | 详情 | 详情 |
| (XI) | 65412 | C10H9ClF3NO | 详情 | 详情 | ||
| (XII) | 65413 | C10H8ClF3INO | 详情 | 详情 | ||
| (XIII) | 65414 | C13H12ClF3INO | 详情 | 详情 | ||
| (XIV) | 65415 | C13H11ClF3NO | 详情 | 详情 | ||
| (XV) | 65416 | C13H13ClF3NO | 详情 | 详情 |