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【结 构 式】 
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【分子编号】14019 【品名】p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol 【CA登记号】104-10-9 |
【 分 子 式 】C8H11NO 【 分 子 量 】137.18148 【元素组成】C 70.04% H 8.08% N 10.21% O 11.66% |
合成路线1
该中间体在本合成路线中的序号：(I)Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.
| 【1】 Ashimori, A.; Ono, T.; Inoue, Y.; Fukaya, C. (Welfide Corporation); Dihydropyridine derivs. and pharmaceutical compsns. Thereof. EP 0257616; JP 1988099042; JP 1988225356; US 4886819 . |
| 【2】 (Welfide Corporation); Use of dihydropyridines in cardiotonic pharmaceutical compsns. EP 0109039; US 4543354 . |
| 【3】 Kido, H.; Uchida, T.; Fukaya, C.; Yokoyama, K.; Uchida, Y. (Welfide Corporation); Dihydropyridine derivs. for the treatment of angiospasm. EP 0379737; JP 1990180826 . |
| 【4】 Ono, T.; Ashimori, A.; Inoue, Y.; Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives. Chem Pharm Bull 1991, 39, 1, 91-9. |
| 【5】 Ohe, K.; Tanaka, M.; Yokoyama, K.; Uchida, T.; Fukaya, C.; Watanabe, M.; Ohtaki, Y.; Ashimori, A.; Kagitani, M.; Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicrboxylate hydrochloride. Chem Pharm Bull 1991, 39, 1, 108-11. |
| 【6】 Castaner, J.; Mealy, N.; Prous, J.; AE0047. Drugs Fut 1994, 19, 7, 627. |
| 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) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 14020 | N,N-Bis(2-chloroethyl)amine hydrochloride; 2-Chloro-N-(2-chloroethyl)-1-ethanamine hydrochloride | C4H10Cl3N | 详情 | 详情 | |
| (III) | 14021 | 2-(4-Piperazinophenyl)-1-ethanol | C12H18N2O | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 14023 | 2-[4-(4-Benzhydrylpiperazino)phenyl]-1-ethanol | C25H28N2O | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 14025 | 4-(4-benzhydrylpiperazino)phenethyl 3-oxobutanoate | C29H32N2O3 | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 14028 | 4-(4-benzhydryl-1-piperazinyl)phenethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C36H35N3O5 | 详情 | 详情 | |
| (XI) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XII) | 14030 | 3-(2-cyanoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H19N3O6 | 详情 | 详情 | |
| (XIII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)2-Amino-6-bromopyridine (II) was prepared by reaction of 2,6-dibromopyridine (I) with ammonium hydroxide in a pressure bomb at 170 C. The amino group of (III) was subsequently blocked as the pyrrole derivative (IV) by condensation with 2,5-hexanedione (III). Diazotization of p-aminophenyl ethanol (V) followed by treatment with KI gave iodo derivative (VI). Subsequent reaction of (VI) with SOCl2 provided chloride (VII). Arylpyridine (VIII) was obtained by lithiation of bromopyridine (IV) with BuLi, followed by conversion to the corresponding organozinc compound with ZnCl2 and palladium-catalyzed coupling with iodide (VII). Pyrrole ring cleavage in (VIII) upon treatment with hydroxylamine furnished aminopyridine (IX). Subsequent condensation with N-Boc-piperazine (X) provided adduct (XI). After acid cleavage of the Boc group of (XI), alkylation of the resulting piperazine with phenacyl chloride (XII) yielded the title compound. Alternatively, the title compound was obtained by condensation of chloride (IX) with N-phenacylpiperazine (XIII).
| 【1】 Qian, W.; Lowe, J.A.; Volkmann, R.A.; et al.; A new class of selective and potent inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem Lett 1999, 9, 17, 2569. |
| 【2】 Lowe, J.A. III; Whittle, P.J. (Pfizer Inc.); 6-Phenylpyridyl-2-amine derivs.. EP 0891332; JP 1999510513; WO 9736871 . |
| 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) | 10159 | 2,6-Dibromopyridine | 626-05-1 | C5H3Br2N | 详情 | 详情 |
| (II) | 41341 | 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine | 19798-81-3 | C5H5BrN2 | 详情 | 详情 |
| (III) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
| (IV) | 41342 | 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C11H11BrN2 | 详情 | 详情 | |
| (V) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (VI) | 30973 | 2-(4-iodophenyl)-1-ethanol | C8H9IO | 详情 | 详情 | |
| (VII) | 41343 | 1-(2-chloroethyl)-4-iodobenzene | C8H8ClI | 详情 | 详情 | |
| (VIII) | 41344 | 2-[4-(2-chloroethyl)phenyl]-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C19H19ClN2 | 详情 | 详情 | |
| (IX) | 41345 | 6-[4-(2-chloroethyl)phenyl]-2-pyridinamine; 6-[4-(2-chloroethyl)phenyl]-2-pyridinylamine | C13H13ClN2 | 详情 | 详情 | |
| (X) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XI) | 41346 | tert-butyl 4-[4-(6-amino-2-pyridinyl)phenethyl]-1-piperazinecarboxylate | C22H30N4O2 | 详情 | 详情 | |
| (XII) | 38669 | 2-chloro-1-phenyl-1-ethanone | 532-27-4 | C8H7ClO | 详情 | 详情 |
| (XIII) | 41347 | 1-phenyl-2-(1-piperazinyl)-1-ethanone | C12H16N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation of 2-(4-aminophenyl)ethanol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives 2-[4-(2-hydroxyethyl)phenylamino]acetic acid ethyl ester (III), which is chlorinated with t-butyl hypochlorite in dichloromethane to yield the 2,6-dichlorophenyl derivative (IV). The bromination of (IV) by means of PPh3 and CBr4 in dichloromethane affords the 2-bromoethyl derivative (V), which is condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-1-propanol (VI) by means of DIEA in hot DMF to provide the ethyl ester precursor (VII). Finally, this compound is hydrolyzed with aq. 1N NaOH to give the target N-phenylglycine derivative.
| 【1】 Tanaka, N.; Mukaiyama, H.; Akahane, M.; Miyata, H.; Akahane, S.; Muranaka, H.; Hirabayashi, A.; Tamai, T.; Discovery of novel N-phenylglycine derivatives as potent and selective beta3-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence. J Med Chem 2001, 44, 9, 1436. |
| 【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Phenylaminoalkylcarboxylic acid derivs. and medicinal compsns. containing the same. EP 1043308; WO 9931045 . |
| 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) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 55795 | ethyl 2-[4-(2-hydroxyethyl)anilino]acetate | C12H17NO3 | 详情 | 详情 | |
| (IV) | 55796 | ethyl 2-[2,6-dichloro-4-(2-hydroxyethyl)anilino]acetate | C12H15Cl2NO3 | 详情 | 详情 | |
| (V) | 55797 | ethyl 2-[4-(2-bromoethyl)-2,6-dichloroanilino]acetate | C12H14BrCl2NO2 | 详情 | 详情 | |
| (VI) | 46836 | 4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol | C9H13NO2 | 详情 | 详情 | |
| (VII) | 55798 | ethyl 2-[2,6-dichloro-4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)anilino]acetate | C21H26Cl2N2O4 | 详情 | 详情 |