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【结 构 式】 
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【分子编号】48639 【品名】4-(Trifluoromethyl)phenylboronic acid 【CA登记号】 |
【 分 子 式 】C7H6BF3O2 【 分 子 量 】189.9296496 【元素组成】C 44.27% H 3.18% B 5.69% F 30.01% O 16.85% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Suzuki coupling between 4-bromobenzaldehyde (XII) and 4-trifluoromethylbenzeneboronic acid (XIII) produced the biphenyl compound (XIV). The reductive amination of aldehyde (XIV) with N,N-diethyl ethylenediamine (XV) gave diamine (XVI) (1). This was finally coupled with the intermediate carboxylic acid (XI) to afford the title amide.
| 【1】 Smith, S.A.; Inhibition of lipoprotein-associated phospholipase A2 - A novel approach for the treatment of atherosclerosis. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst . |
| 【2】 Ife, R.J.; Leach, C.A.; Smith, S.A.; Pinto, I.L.; Hickey, D.M.B.; Fenwick, A.E. (GlaxoSmithKline plc); Pyrimidinone cpds.. EP 1175408; WO 0066567 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 53050 | 2-[2-[(4-fluorobenzyl)sulfanyl]-5-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-oxo-1(4H)-pyrimidinyl]acetic acid | n/a | C18H17FN4O3S | 详情 | 详情 |
| (XII) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (XIII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XIV) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
| (XV) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (XVI) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)The mercaptoimidazole (IX) was prepared by condensation between 4-bromobenzylamine (VII), 1,3-dihydroxyacetone (VIII) and potassium thiocyanate. Oxidative desulfuration of (IX) with hydrogen peroxide in acidic medium yielded imidazole (X). The biphenyl derivative (XII) was obtained by Suzuki coupling of aryl bromide (X) with 4-(trifluoromethyl)benzeneboronic acid (XI). Subsequent oxidation of the alcohol group of (XII) under Swern conditions gave aldehyde (XIII). Finally, reductive coupling of aldehyde (XIII) with piperazinone (VI) in the presence of sodium triacetoxyborohydride furnished the title compound.
| 【2】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 . |
| 【1】 Kohl, N.E.; Nguyen, D.N.; Lobell, R.B.; Williams, T.M.; Heimbrook, D.C.; Buser, C.A.; Huber, H.E.; Stump, C.A.; Graham, S.L.; Potent inhibitors of farnesyltransferase and geranylgeranyltransferase. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 56. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 | |
| (VII) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VIII) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (IX) | 48637 | [1-(4-bromobenzyl)-2-sulfanyl-1H-imidazol-5-yl]methanol | C11H11BrN2OS | 详情 | 详情 | |
| (X) | 48638 | [1-(4-bromobenzyl)-1H-imidazol-5-yl]methanol | C11H11BrN2O | 详情 | 详情 | |
| (XI) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XII) | 48640 | (1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol | C18H15F3N2O | 详情 | 详情 | |
| (XIII) | 48641 | 1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carbaldehyde | C18H13F3N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Suzuki coupling between 4-bromobenzaldehyde (XI) and 4-trifluoromethylbenzeneboronic acid (XII) affords the biphenylyl aldehyde (XIII). This is then reductively aminated with N,N-diethylethylenediamine (XIV) and NaBH4 to produce diamine (XV) (1,3). Finally, coupling between amine (XV) and carboxylic acid (VIII) leads to the title carboxamide
| 【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067. |
| 【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 . |
| 【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 . |
| 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) | 63494 | 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid | C16H15FN2O3S | 详情 | 详情 | |
| (XI) | 22231 | 4-Bromobenzaldehyde | 1122-91-4 | C7H5BrO | 详情 | 详情 |
| (XII) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XIII) | 53051 | 4-[4-(trifluoromethyl)phenyl]benzaldehyde | n/a | C14H9F3O | 详情 | 详情 |
| (XIV) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (XV) | 53052 | N-[2-(diethylamino)ethyl]-N-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}amine; N~1~,N~1~-diethyl-N~2~-{[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl}-1,2-ethanediamine | n/a | C20H25F3N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Substitution of 1-chloro-2-methoxy-4-nitrobenzene (I) with 2-(diethylamino)ethanol (II) gives rise to ether (III). Subsequent nitro group reduction in (III) by catalytic hydrogenation affords aniline (IV). Condensation of amine (IV) with triethyl orthoformate, followed by reduction of the resultant formimidate (V) with NaBH4 leads to the N-methyl amine (VI). This is acylated by 4-bromobenzoyl chloride (VII) to furnish the bromobenzamide (VIII). Finally, Suzuki coupling of bromide (VIII) with 4-trifluoromethylphenylboronic acid (IX) produces the title biphenyl compound
| 【1】 Stemp, G.; Johnson, C.N.; Jones, M.; O'Toole, C.A.; Thewlis, K.M.; Witty, D. (GlaxoSmithKline plc); Carboxamide cpds. and their use as antagonists of a human 11CBy receptor. EP 1305304; WO 0210146 . |
| 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) | 60896 | 1-chloro-2-methoxy-4-nitrobenzene; 2-chloro-5-nitrophenyl methyl ether | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 16183 | Diethylaminoethanol; 2-(diethylamino)-1-ethanol | 100-37-8 | C6H15NO | 详情 | 详情 |
| (III) | 60897 | N,N-diethyl-2-(2-methoxy-4-nitrophenoxy)-1-ethanamine; N,N-diethyl-N-[2-(2-methoxy-4-nitrophenoxy)ethyl]amine | C13H20N2O4 | 详情 | 详情 | |
| (IV) | 60898 | N-[2-(4-amino-2-methoxyphenoxy)ethyl]-N,N-diethylamine; 4-[2-(diethylamino)ethoxy]-3-methoxyaniline | C13H22N2O2 | 详情 | 详情 | |
| (V) | 60899 | ethyl 4-[2-(diethylamino)ethoxy]-3-methoxyphenyliminoformate | C16H26N2O3 | 详情 | 详情 | |
| (VI) | 60900 | N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylamine; 4-[2-(diethylamino)ethoxy]-3-methoxy-N-methylaniline | C14H24N2O2 | 详情 | 详情 | |
| (VII) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
| (VIII) | 60901 | 4-bromo-N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylbenzamide | C21H27BrN2O3 | 详情 | 详情 | |
| (IX) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 |