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【结 构 式】 
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【分子编号】49181 【品名】Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid 【CA登记号】501-52-0 |
【 分 子 式 】C9H10O2 【 分 子 量 】150.1772 【元素组成】C 71.98% H 6.71% O 21.31% |
合成路线1
该中间体在本合成路线中的序号：(X)The CuI-assisted coupling between methyl N-(4-fluorophenyl)carbamate (I) and 1-bromo-4-fluorobenzene (II) produced the N,N-bis(4-fluorophenyl)carbamate (III), which was subsequently hydrolyzed to bis(4-fluorophenyl)amine (IV) using ethanolic KOH. Acylation of diarylamine (IV) with 3-bromopropionyl chloride (V) gave bromopropionamide (VI). This was then condensed with cis-2,6-dimethylpiperazine (VII) to yield the 3-piperazinylpropionamide (VIII). Amide reduction with LiAlH4 provided the triamino compound (IX). Acid chloride (XI), prepared from hydrocinnamic acid (X), was then coupled with piperazine (IX) to furnish amide (XII). The amide function was finally reduced to the corresponding amine by using LiAlH4.
| 【1】 Cao, J.; Husbands, S.M.; Kopajtic, T.; Newman, A.H.; Katz, J.L.; [3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel for the dopamine transporter. Bioorg Med Chem Lett 2001, 11, 24, 3169. |
| 【2】 Ca, J.; Newman, A.H.; Kopajtic, T.; Katz, J.L.; Husbands, S.M.; [3-cis-3,5-Dimethyl-1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amines analogs as novel probes for the dopamine transporter. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 96. |
| 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) | 49174 | methyl 4-fluorophenylcarbamate | C8H8FNO2 | 详情 | 详情 | |
| (II) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (III) | 49175 | methyl bis(4-fluorophenyl)carbamate | C14H11F2NO2 | 详情 | 详情 | |
| (IV) | 49176 | 4-fluoro-N-(4-fluorophenyl)aniline; N,N-bis(4-fluorophenyl)amine | C12H9F2N | 详情 | 详情 | |
| (V) | 49177 | 3-Bromopropionyl chloride; beta-Bromopropionyl chloride | 15486-96-1 | C3H4BrClO | 详情 | 详情 |
| (VI) | 49178 | 3-bromo-N,N-bis(4-fluorophenyl)propanamide | C15H12BrF2NO | 详情 | 详情 | |
| (VII) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (VIII) | 49179 | 3-[(3R,5S)-3,5-dimethylpiperazinyl]-N,N-bis(4-fluorophenyl)propanamide | C21H25F2N3O | 详情 | 详情 | |
| (IX) | 49180 | N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N,N-bis(4-fluorophenyl)amine; N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-4-fluoro-N-(4-fluorophenyl)aniline | C21H27F2N3 | 详情 | 详情 | |
| (X) | 49181 | Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid | 501-52-0 | C9H10O2 | 详情 | 详情 |
| (XI) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (XII) | 49182 | 1-((2R,6S)-4-[3-[bis(4-fluorophenyl)amino]propyl]-2,6-dimethylpiperazinyl)-3-phenyl-1-propanone | C30H35F2N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)Bromochromanone (XVI) was prepared by bromination of 4-chromanone (XV). Subsequent reduction of (XVI) with NaBH4 provided bromohydrin (XVII). Ritter reaction of (XVII) with acetonitrile and sulfuric acid, followed by acidic hydrolysis, led to racemic cis-3-bromo-4-chromanol, which was then resolved by means of (S)-(+)-mandelic acid. The desired (S,S)-isomer (XVIII) was coupled with hydrocinnamic acid (XIX) giving amide (XX). After protection of hydroxy amide (XX) as the acetonide (XXI), the lithium enolate of amide (XXI) was alkylated with allyl bromide (XXII) to furnish the (S)-2-benzyl-4-pentenamide (XXIII) as the main diastereoisomer. Halogenation of (XXIII) with N-iodosuccinimide in H2O-EtOAc afforded iodohydrin (XXIV), which was cyclized to epoxide (XXV) in the presence of NaOMe.
| 【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (XVI) | 56263 | 3-bromo-2,3-dihydro-4H-chromen-4-one | C9H7BrO2 | 详情 | 详情 | |
| (XVII) | 56264 | 3-bromo-4-chromanol | C9H9BrO2 | 详情 | 详情 | |
| (XVIII) | 56265 | (3S,4S)-4-amino-3,4-dihydro-2H-chromen-3-ol | C9H11NO2 | 详情 | 详情 | |
| (XIX) | 49181 | Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid | 501-52-0 | C9H10O2 | 详情 | 详情 |
| (XX) | 56266 | N-[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]-3-phenylpropanamide | C18H19NO3 | 详情 | 详情 | |
| (XXI) | 56267 | 1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-3-phenyl-1-propanone | C21H23NO3 | 详情 | 详情 | |
| (XXII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXIII) | 56268 | (2S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-penten-1-one | C24H27NO3 | 详情 | 详情 | |
| (XXIV) | 56269 | (2R,4S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO4 | 详情 | 详情 | |
| (XXV) | 56270 | (2R)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO4 | 详情 | 详情 |