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【结 构 式】 
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【分子编号】11953 【品名】2,5-Dichlorophenol 【CA登记号】583-78-8 |
【 分 子 式 】C6H4Cl2O 【 分 子 量 】163.00256 【元素组成】C 44.21% H 2.47% Cl 43.5% O 9.82% |
合成路线1
该中间体在本合成路线中的序号：(I)Compound can be prepared in three different ways: 1) Condensation of 2,5-dichlorophenol (I) with epichlorohydrin (A) by means of NaOH in water to give 1-(2,5-dichlorophenoxy)-2,3-epoxypropane (II), which is then condensed again with tert-butylamine in refluxing ethanol. Finally, HCl in ethanol is added. 2) Condensation of (I) with epichlorohydrin (A) by means of pyridine gives 1-(2,5-dichlorophenoxy)-3-chloro-2-propanol (III), which is then condensed with tert-butylamine as before. 3) Condensation of (I) with 1-(tertbutylamino)-2,3-epoxypropane (B) or with 1-(tertbutylamino)-3-chloro-2-propanol (C) by means of NaOH in refluxing ethanol.
| 【1】 Hajos, A.; et al.; Aminopropanol derivative. DE 2213044; FR 2130284; GB 1337921; NL 7203323 . |
| 【2】 Castaner, J.; Sumgurbey, K.; GYKI-41099. Drugs Fut 1978, 3, 4, 295. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 33503 | N-(tert-butyl)-N-(2-oxiranylmethyl)amine; 2-methyl-N-(2-oxiranylmethyl)-2-propanamine | C7H15NO | 详情 | 详情 | |
| (I) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (II) | 33501 | 2,5-dichlorophenyl 2-oxiranylmethyl ether; 2-[(2,5-dichlorophenoxy)methyl]oxirane | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 33502 | 1-chloro-3-(2,5-dichlorophenoxy)-2-propanol | C9H9Cl3O2 | 详情 | 详情 | |
| (C) | 31720 | 1-(tert-butylamino)-3-chloro-2-propanol | C7H16ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.
| 【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597. |
| 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) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11955 | (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone | C13H8Cl2O2 | 详情 | 详情 | |
| (IV) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (VII) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (VIII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (IX) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (X) | 11962 | (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone | C13H9ClO3 | 详情 | 详情 | |
| (XI) | 11963 | 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H21ClO7S2 | 详情 | 详情 | |
| (XII) | 11964 | 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H22ClNO7S2 | 详情 | 详情 | |
| (XIII) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XIV) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XV) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)L-697,661 was prepared via a convergent route: Formylation of 2-pentanone (I) with ethyl formate and sodium methoxide gave the ketoaldehyde sodium salt (II). When a mixture of anhydrous diethyl ether and absolute ethanol, 6:1 v/v, was used as solvent, the desired regioisomer precipitated out of solution. Treatment of ethyl nitroacetate (III) with ethanol saturated with ammonia provided nitroacetamide ammonium salt (IV). The nitroacetamide was then condensed with (II) in an aqueous solution of piperidinium acetate to afford the 3-nitropyridinone (V). Catalytic reduction of (V) provided the 3-aminopyridinone (VI). Treatment of chloroacetonitrile (VII) with hydrogen chloride and absolute ethanol gave ethyl chloroiminoacetate hydrochloride (VIII). Nitration of 2,4-dichlorophenol (IX), followed by catalytic reduction of the resultant product, led to the aminophenol (X). Coupling of (X) with (VIII) yielded the chloromethylbenzoxazole (XI), which was converted to the corresponding iodomethyl derivative (XII). Alkylation of the 3-aminopyridinone (VI) with the iodomethylbenzoxazole (XII) furnished L-697,661.
| 【1】 Saari, W.S.; Hoffman, J.M.; Wai, J.S.; et al.; 2-Pyridinone derivatives: A new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors. J Med Chem 1991, 34, 9, 2922. |
| 【2】 Goldmann, M.E.; Wai, J.S.; L-697,661. Drugs Fut 1992, 17, 4, 283. |
| 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) | 15048 | 2-pentanone | 107-87-9 | C5H10O | 详情 | 详情 |
| (II) | 15049 | sodium (Z)-2-ethyl-3-oxo-1-buten-1-olate | C6H9NaO2 | 详情 | 详情 | |
| (III) | 15050 | ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester | 626-35-7 | C4H7NO4 | 详情 | 详情 |
| (IV) | 15051 | 1-Carbamoyl-1-nitromethanide ammonium salt | C2H7N3O3 | 详情 | 详情 | |
| (V) | 15052 | 5-ethyl-6-methyl-3-nitro-2(1H)-pyridinone | C8H10N2O3 | 详情 | 详情 | |
| (VI) | 15053 | 3-amino-5-ethyl-6-methyl-2(1H)-pyridinone | C8H12N2O | 详情 | 详情 | |
| (VII) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (VIII) | 15055 | 1-chloro-2-pentanimine hydrochloride | C5H11Cl2N | 详情 | 详情 | |
| (IX) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (X) | 15057 | 2-amino-3,6-dichlorophenol | C6H5Cl2NO | 详情 | 详情 | |
| (XI) | 15058 | 4,7-dichloro-2-(chloromethyl)-1,3-benzoxazole | C8H4Cl3NO | 详情 | 详情 | |
| (XII) | 15059 | 4,7-dichloro-2-(iodomethyl)-1,3-benzoxazole | C8H4Cl2INO | 详情 | 详情 |