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【结 构 式】 
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【分子编号】20848 【品名】(2R,6S)-2,6-dimethylpiperazine 【CA登记号】 |
【 分 子 式 】C6H14N2 【 分 子 量 】114.19064 【元素组成】C 63.11% H 12.36% N 24.53% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 3-chloropropanol (I) with 2,6-dimethylpiperazine (II) by means of Na2CO3 in refluxing glycol monomethyl ether gives 3-(3,5-dimethyl-1-piperazinyl)propanol (III), which by reaction with refluxing SOCl2 is converted into 3-(3,5-dimethylpiperazinyl)propyl chloride (IV). Finally, this compound is condensed with carbazole (V) by means of NaH in hot DMF; a final treatment with aqueous HCl yields the dihydrochloride.
| 【1】 Harfenist, M.; Jogner, C.T. (Glaxo Wellcome Inc.); Carbazole compounds and medicinal use thereof. DD 147110; EP 0012208; EP 0051321; US 4379160 . |
| 【2】 Blancafort, P.; Hilier, K.; Serradell, M.N.; Castaner, J.; BW-234U. Drugs Fut 1983, 8, 4, 303. |
| 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) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 36062 | 3-[(3R,5S)-3,5-dimethylpiperazinyl]-1-propanol | C9H20N2O | 详情 | 详情 | |
| (IV) | 36063 | (3R,5S)-1-(3-chloropropyl)-3,5-dimethylpiperazine | C9H19ClN2 | 详情 | 详情 | |
| (V) | 36064 | 9H-carbazole | 86-74-8 | C12H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of ethyl pentafluorobenzoylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with cyclopropylamine (II) in ether gives the aminomethylene derivative (III), which is cyclized by means of NaH in THF yielding ethyl 5,6,7,8-tetrafluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (IV). The reaction of (IV) with benzylamine (V) by means of K2CO3 in refluxing acetonitrile affords the benzylamino derivative (VI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol giving ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (VII). The hydrolysis of (VII) with hot H2SO4 yields the free acid (VIII), which is finally condensed with cis-2,6-dimethylpiperazine (IX) in DMF.
| 【1】 Matsumoto, J.; Miyamoto, T.; Egawa, H.; Nakamura, S. (Dainippon Pharm. Co.; Ltd.); Novel quinoline derivatives and processes for preparation thereof. AU 8664277; EP 0221463; JP 87277362 . |
| 【2】 Prous, J.; Castaner, J.; AT-4140. Drugs Fut 1989, 14, 5, 413. |
| 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) | 20840 | ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate | C11H7F5O3 | 详情 | 详情 | |
| (II) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (III) | 20842 | ethyl 2-[(cyclopropylamino)methyl]-3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate | C15H14F5NO3 | 详情 | 详情 | |
| (IV) | 20843 | ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11F4NO3 | 详情 | 详情 | |
| (V) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VI) | 20845 | ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C22H19F3N2O3 | 详情 | 详情 | |
| (VII) | 20846 | ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H13F3N2O3 | 详情 | 详情 | |
| (VIII) | 19819 | 4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid | C17H15NO4S | 详情 | 详情 | |
| (IX) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reaction of pentafluorobenzoylacetic acid ethyl ester (I) with triethyl orthoformate in refluxing acetic anhydride, followed by condensation with cyclopropylamine, gives 2-(pentafluorobenzoyl)-3-(cyclopropylamino)acrylic acid ethyl ester (II), which is cyclized by means of NaH in THF to yield 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III). The hydrolysis of (III) with H2SO4 /HOAc in refluxing water affords the corresponding carboxylic acid (IV), which is finally condensed with cis-2,6-dimethylpiperazine (V) in DMF to provide the target quinolone.
| 【1】 Matsumoto, J.-I.; Miyamoto, T.; Egawa, H.; Nakamura, S. (Dainippon Pharmaceutical Co., Ltd.); Quinoline derivs., pharmaceutical compsn. and method of use. EP 0242789; US 4886810 . |
| 【2】 Miyamoto, T.; Matsumoto, J.; Chiba, K.; et al.; Synthesis and structure-activity relationships of 5-substituted 6,8-difluoroquinolones, including sparfloxacin, a new quinolone antibacterial agent with improved potency. J Med Chem 1990, 33, 6, 1645. |
| 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) | 20840 | ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate | C11H7F5O3 | 详情 | 详情 | |
| (II) | 55231 | ethyl (Z)-3-(cyclopropylamino)-2-(2,3,4,5,6-pentafluorobenzoyl)-2-propenoate | C15H12F5NO3 | 详情 | 详情 | |
| (III) | 20843 | ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C15H11F4NO3 | 详情 | 详情 | |
| (IV) | 55232 | 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C13H7F4NO3 | 详情 | 详情 | |
| (V) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Alkylation of diphenylamine (I) with THP-protected 3-bromopropanol (II) using NaH in 15-crown-5 yields tertiary amine (III), which is then deprotected with HOAc/H2O to provide (IV). Alcohol (IV) is treated with PPh3 and CBr4 to afford alkyl bromide (V), which is then converted into amine (VII) by reaction with 2,6-dimethylpiperazine (VI) in DMF/H2O in the presence of K2CO3. Finally, (VII) is acylated with 3-phenylpropionyl chloride (VIII) and reduced with LAH.
| 【1】 Vilner, B.J.; Husbands, S.M.; Bowen, W.D.; Newman, A.H.; Kopajtic, T.; Izenwasser, S.; Katz, J.L.; Structure-activity relationships at the monoamine transporters and sigma receptors for a novel series of 9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole (rimcazole) analogues. J Med Chem 1999, 42, 21, 4446. |
| 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) | 42251 | Diphenylamine; N-phenylaniline; N,N-diphenylamine | 122-39-4 | C12H11N | 详情 | 详情 |
| (II) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (III) | 42253 | N-phenyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]aniline; N,N-diphenyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]amine | C20H25NO2 | 详情 | 详情 | |
| (IV) | 42254 | 3-(diphenylamino)-1-propanol | C15H17NO | 详情 | 详情 | |
| (V) | 42255 | N-(3-bromopropyl)-N-phenylaniline; N-(3-bromopropyl)-N,N-diphenylamine | C15H16BrN | 详情 | 详情 | |
| (VI) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (VII) | 42256 | N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N,N-diphenylamine; N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N-phenylaniline | C21H29N3 | 详情 | 详情 | |
| (VIII) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)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6
该中间体在本合成路线中的序号：(XII)Vilsmeier-Haack formylation of ethyl 4-methylpyrrole-2-carboxylate (IX) using POCl3 in DMF furnished the pyrrole aldehyde (X). Subsequent basic hydrolysis of the ethyl ester group of (X) gave 5-formyl-4-methylpyrrole-2-carboxylic acid (XI), which was further coupled to cis-2,6-dimethylpiperazine (XII) producing amide (XIII). The title compound was finally prepared by aldol condensation between the pyrrole aldehyde (XIII) and lactam (VIII) in the presence of piperidine.
| 【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 60852 | 4-(3-chloro-4-fluoroanilino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C12H8ClFN4O | 详情 | 详情 | |
| (IX) | 60049 | ethyl 4-methyl-1H-pyrrole-2-carboxylate | C8H11NO2 | 详情 | 详情 | |
| (X) | 60050 | ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate | C9H11NO3 | 详情 | 详情 | |
| (XI) | 60051 | 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid | C7H7NO3 | 详情 | 详情 | |
| (XII) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (XIII) | 60853 | 5-{[(3R,5S)-3,5-dimethylpiperazinyl]carbonyl}-3-methyl-1H-pyrrole-2-carbaldehyde | C13H19N3O2 | 详情 | 详情 |