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【结 构 式】 
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【分子编号】31228 【品名】p-toluidine; 4-methylphenylamine 【CA登记号】106-49-0 |
【 分 子 式 】C7H9N 【 分 子 量 】107.1552 【元素组成】C 78.46% H 8.47% N 13.07% |
合成路线1
该中间体在本合成路线中的序号：(I)Chloroacetylation of p-toluidine (I) gives N-chloroacetyl-p-toluidine (II), which by reaction with 3-methyl-4-chlorophenol in refluxing acetone - K2CO3 is converted into 2-(4-chloro-3-methylphenoxy)-N-(p-tolyl)acetamide (III). The reaction of (III) with Lawesson's reagent in boiling toluene affords the thioamide (IV), which is methylated with methyl iodide in refluxing acetone - K2CO3 and the resulting 5-methyl ether without any further purification is finally subjected in situ to cyclocondensation by treating with ethylcarbazate in refluxing DMF to give IDPH-85184 in an overall yield of 40%.
| 【1】 Scheibye, S.; Pedersen, B.S.; Lawesson, S.U.; Bull Soc Chim Belg 1978, 87, 229. |
| 【2】 Arya, V.P.; IDPH-85184. Drugs Fut 1990, 15, 12, 1178. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 31230 | 4-chloro-3-methylphenol | 59-50-7 | C7H7ClO | 详情 | 详情 | |
| (I) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (II) | 31229 | 2-chloro-N-(4-methylphenyl)acetamide | C9H10ClNO | 详情 | 详情 | |
| (III) | 31231 | 2-(4-chloro-3-methylphenoxy)-N-(4-methylphenyl)acetamide | C16H16ClNO2 | 详情 | 详情 | |
| (IV) | 31232 | 2-(4-chloro-3-methylphenoxy)-N-(4-methylphenyl)ethanethioamide | C16H16ClNOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The required 2-amino-5-methylthiophenol (III) was obtained by basic hydrolysis of the aminobenzothiazole (II), which was prepared from p-toluidine (I) and in situ generated thiocyanogen. Reaction of thiophenol (III) with the arylglycidic ester (IV) produced the racemic threo-amino ester (V). After basic hydrolysis of the ester group of (V), the resultant amino acid was resolved by means of D-(4-hydroxyphenyl)glycine methyl ester. The required amino acid enantiomer (VI) was then cyclized to lactam (VII) by heating in xylene with azeotropic removal of water. N-alkylation of benzothiazepinone (VII) with 2-(dimethylamino)ethyl chloride (VIII) provided (IX). The secondary alcohol of (IX) was esterified with acetic anhydride, and the resultant compound was finally isolated as the corresponding maleate salt.
| 【1】 Inoue, H.; Konda, M.; Hashiyama, T.; Otsuka, H.; Watanabe, A.; Gaino, M.; Takahashi, K.; Date, T.; Okamura, K.; Takeda, M.; Narita, H.; Murata, S.; Odawara, A.; Sasaki, H.; Nagao, T.; Synthesis and biological evaluation of alkyl, alkoxy, alkylthio, or amino-substituted 2,3-dihydro-1, 5-benzothiazepin-4(5H)-ones. Chem Pharm Bull 1997, 45, 6, 1008. |
| 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) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (II) | 59776 | 6-methyl-1,3-benzothiazol-2-ylamine; 6-methyl-1,3-benzothiazol-2-amine | C8H8N2S | 详情 | 详情 | |
| (III) | 59777 | 2-amino-5-methylbenzenethiol; 2-amino-5-methylphenylhydrosulfide | C7H9NS | 详情 | 详情 | |
| (IV) | 59778 | methyl (2S,3S)-3-(4-methylphenyl)-2-oxiranecarboxylate | C11H12O3 | 详情 | 详情 | |
| (V) | 59779 | methyl (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoate | C18H21NO3S | 详情 | 详情 | |
| (VI) | 59780 | (2R,3R)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-hydroxy-3-(4-methylphenyl)propanoic acid | C17H19NO3S | 详情 | 详情 | |
| (VII) | 59781 | (2R,3R)-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C17H17NO2S | 详情 | 详情 | |
| (VIII) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
| (IX) | 59782 | (2R,3R)-5-[2-(dimethylamino)ethyl]-3-hydroxy-8-methyl-2-(4-methylphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C21H26N2O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Acylation of p-toluidine (I) with 3-chloropropionyl chloride afforded the beta-chloroamide (II), which was cyclized to dihydroquinolinone (III) by treatment with AlCl3 at 120 C. After protection of the N atom of (III) as the tert-butyl carbamate (IV), reduction of the 2-oxo group by NaBH4 in ethanol at -25 C, followed by acidic quench with ethanolic HCl, afforded the N-Boc-2-ethoxy derivative (V). The tandem Mannich-Michael cyclization of the alpha-ethoxycarbamate (V) with the (silyloxy)diene (VII) (derived from 1-penten-3-one (VI) in the presence of trimethylsilyl triflate) furnished the benzoquinolizinone (VIII) as a mixture of diastereoisomers. Finally, oxidation of this mixture with mercuric acetate afforded the desired delta-4 unsaturated compound.
| 【1】 Machetti, F.; Scarpi, D.; Guarna, A.; Occhiato, E.G.; Benzo[c]quinolizin-3-ones: A novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1. J Med Chem 2000, 43, 20, 3718. |
| 【2】 Guarna, A.; Serio, M. (Applied Research Systems ARS Holdings NV); Benzo[c]quinolizine derivs., their preparation and use as 5alpha-reductases inhibitors. EP 0880520; JP 2000504680; WO 9729107 . |
| 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) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (II) | 43925 | 3-chloro-N-(4-methylphenyl)propanamide | C10H12ClNO | 详情 | 详情 | |
| (III) | 43926 | 6-methyl-3,4-dihydro-2(1H)-quinolinone | C10H11NO | 详情 | 详情 | |
| (IV) | 43927 | tert-butyl 6-methyl-2-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate | C15H19NO3 | 详情 | 详情 | |
| (V) | 43928 | tert-butyl 2-ethoxy-6-methyl-3,4-dihydro-1(2H)-quinolinecarboxylate | C17H25NO3 | 详情 | 详情 | |
| (VI) | 43930 | 1-penten-3-one | 1629-58-9 | C5H8O | 详情 | 详情 |
| (VII) | 43929 | trimethylsilyl (Z)-1-vinyl-1-propenyl ether; trimethyl[[(Z)-1-vinyl-1-propenyl]oxy]silane | C8H16OSi | 详情 | 详情 | |
| (VIII) | 43931 | 4,8-dimethyl-1,2,4,4a,5,6-hexahydro-3H-pyrido[1,2-a]quinolin-3-one | C15H19NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)In an alternative method, 2-thiobarbituric acid (XIII) is alkylated with 1-iodopropane and NaOH in N-methylpyrrolidone to afford the 2-(propylsulfanyl)pyrimidine (XIV). Diazotization of p-toluidine (XV) with NaNO2 and HCl, followed by coupling of the intermediate diazonium salt with pyrimidine (XIV) in the presence of NaOAc, produces the diazo adduct (XVI). After chlorination of (XVI) with POCl3, reductive cleavage of the diazo compound (XVII) with H2 and Pt/C gives 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine (XVIII). Subsequent condensation of (XVIII) with the cyclopentylamino compound (XIX) in ethanolic triethylamine at 120 °C in a pressure vessel provides the diaminopyrimidine (XX), which is further converted to the azapurine (XXI) by treatment with NaNO2 in acetic acid. Then, substitution of chloride (XXI) with 2-(3,4-difluorophenyl)cyclopropylamine (X) in the presence of triethylamine in acetonitrile affords the acetonide (XII), which is finally hydrolyzed to the title compound as in the above method (3). Scheme 2.
| 【3】 Larsson, U., Magnusson, M., Musil, T., Palmgren, A. (AstraZeneca AB). Triazolo pyrimidine compounds. CA 2408914, EP 1299390, JP 2003535093, US 2003148888, US 2006041132, US 2007049755, US 7067663, WO 0192263. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 65451 | (1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine | 1006614-49-8 | C9H9F2N | 详情 | 详情 |
| (XII) | 65453 | 2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol | 274693-26-4 | C26H32F2N6O4S | 详情 | 详情 |
| (XIII) | 25623 | 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol | 504-17-6 | C4H4N2O2S | 详情 | 详情 |
| (XIV) | 65454 | 6-Hydroxy-2-(Propylsulfanyl)-4(3H)-Pyrimidinone | 145783-12-6 | C7H10N2O2S | 详情 | 详情 |
| (XV) | 31228 | p-toluidine; 4-methylphenylamine | 106-49-0 | C7H9N | 详情 | 详情 |
| (XVI) | 65455 | C14H16N4O2S | 详情 | 详情 | ||
| (XVII) | 65456 | C14H14Cl2N4S | 详情 | 详情 | ||
| (XVIII) | 65457 | 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine | 145783-15-9 | C7H9Cl2N3S | 详情 | 详情 |
| (XIX) | 65458 | 2-[[(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol | 274693-55-9 | C10H19NO4 | 详情 | 详情 |
| (XX) | 65459 | 2-[[(3aR,4S,6R,6aS)-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol | 376608-74-1 | C17H27ClN4O4S | 详情 | 详情 |
| (XXI) | 65460 | 2-[[(3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol | 376608-75-2 | C17H24ClN5O4S | 详情 | 详情 |