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【结 构 式】 
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【分子编号】36973 【品名】bromo(3-methyl-2-thienyl)magnesium 【CA登记号】 |
【 分 子 式 】C5H5BrMgS 【 分 子 量 】201.3697 【元素组成】C 29.82% H 2.5% Br 39.68% Mg 12.07% S 15.92% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound has been obtained by two different ways: 1) The Grignard condensation of 3-methylthiophene-2-carbaldehyde (I) with 3-methylthiophen-2-ylmagnesium bromide (II) in ethyl ether gives the carbinol (III), which is oxidized with MnO2 in dichloromethane yielding the corresponding ketone (IV). A new Grignard condensation of (IV) with cyclopropylmagnesium bromide (V) in THF affords the carbinol (VI), which is dehydrated with simultaneous cyclopropane ring opening by means of HBr or TMS-Br in acetic acid giving 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).The condensation of (VII) with piperidine-2(R)-carboxylic acid ethyl ester (VIII) by means of K2CO3 and KI in acetone yields the ethyl ester (IX) of the target compound, which is finally hydrolyzed with NaOH in ethanol. 2) The reaction of 2-bromo-3-methylthiophene (X) with BuLi in ethyl ether gives the corresponding lithium derivative (XI), which is condensed with ethyl 4-bromobutyrate (XII) in the same solvent to afford the previously reported 4,4-bis(3-methyl-2-thienyl)-3-butenyl bromide (VII).
| 【1】 Braestrup, C.; Gronvald, F.C. (Novo Nordisk A/S); Amino acid derivs.. AU 8661336; EP 0236342; ES 8800927; JP 1987503172; US 5010090; WO 8700171 . |
| 【2】 Andersen, K.E.; et al.; The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4, 4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate. J Med Chem 1993, 36, 12, 1716. |
| 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) | 12446 | 3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde | 5834-16-2 | C6H6OS | 详情 | 详情 |
| (II) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (III) | 36974 | bis(3-methyl-2-thienyl)methanol | C11H12OS2 | 详情 | 详情 | |
| (IV) | 36975 | bis(3-methyl-2-thienyl)methanone | C11H10OS2 | 详情 | 详情 | |
| (V) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (VI) | 36976 | cyclopropyl[bis(3-methyl-2-thienyl)]methanol | C14H16OS2 | 详情 | 详情 | |
| (VII) | 36977 | 2-[4-bromo-1-(3-methyl-2-thienyl)-1-butenyl]-3-methylthiophene | C14H15BrS2 | 详情 | 详情 | |
| (VIII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (IX) | 36978 | ethyl (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate | C22H29NO2S2 | 详情 | 详情 | |
| (X) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (XI) | 36979 | (3-methyl-2-thienyl)lithium | C5H5LiS | 详情 | 详情 | |
| (XII) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III), which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol. Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V). After oxidation of aldehyde (V) with sodium chlorite, the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH. Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)). The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 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) | 51497 | 4'-Iodoacetophenone; 4-Iodoacetophenone; 1-(4-Iodophenyl)ethanone | 13329-40-3 | C8H7IO | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 62683 | methyl 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylate | C11H11IO3 | 详情 | 详情 | |
| (IV) | 62684 | 3-(4-iodophenyl)-3-methyl-2-oxiranecarboxylic acid | C10H9IO3 | 详情 | 详情 | |
| (V) | 62685 | 2-(4-iodophenyl)propanal | C9H9IO | 详情 | 详情 | |
| (VI) | 62686 | C18H16I2O4Zn | 详情 | 详情 | ||
| (VII) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (VIII) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (IX) | 62687 | 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid | C14H14O2S | 详情 | 详情 | |
| (X) | 10717 | methyl (2S)-2-amino-2-phenylethanoate | C9H11NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)2-(4-Iodophenyl)-2-methyloxirane (XLV) was obtained by addition of dimethylsulfonium methylide to 4-iodoacetophenone (I). Rearrangement of epoxide (XLV) in the presence of molecular sieves led to aldehyde (V), which was protected as the dimethyl acetal (XLVI) upon treatment with trimethyl orthoformate. Palladium-catalyzed condensation of the Grignard reagent (VIII) with aryl iodide (XLVI) furnished the biaryl adduct (XLVII). This was subsequently hydrolyzed to the key aldehyde (XVII) employing AcOH
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 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) | 51497 | 4'-Iodoacetophenone; 4-Iodoacetophenone; 1-(4-Iodophenyl)ethanone | 13329-40-3 | C8H7IO | 详情 | 详情 |
| (V) | 62685 | 2-(4-iodophenyl)propanal | C9H9IO | 详情 | 详情 | |
| (VIII) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (XVII) | 62692 | 2-[4-(3-methyl-2-thienyl)phenyl]propanal | C14H14OS | 详情 | 详情 | |
| (XLV) | 62715 | 2-(4-iodophenyl)-2-methyloxirane | C9H9IO | 详情 | 详情 | |
| (XLVI) | 62716 | 1-(2,2-dimethoxy-1-methylethyl)-4-iodobenzene; 2-(4-iodophenyl)-1-methoxypropyl methyl ether | C11H15IO2 | 详情 | 详情 | |
| (XLVII) | 62717 | 1-methoxy-2-[4-(3-methyl-2-thienyl)phenyl]propyl methyl ether; 2-[4-(2,2-dimethoxy-1-methylethyl)phenyl]-3-methylthiophene | C16H20O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)The iodophenyl propionic acid (XLVIII) was protected as the oxazoline (LII) via activation as the corresponding acid chloride (XLIX), which was condensed with 2-amino-2-methylpropanol (L) to yield amide (LI). Subsequent cyclization of hydroxy amide (LI) by treatment with phosphorus oxychloride led to oxazoline (LII). Palladium coupling between aryl iodide (LII) and the Grignard reagent (VIII) provided the biaryl adduct (LIII). The oxazoline (LIII) was then hydrolyzed to (IX) with sulfuric acid and AcOH
| 【2】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |
| 【1】 Kodama, T.; Nakabayashi, M.; Watanabe, I.; Hirano, Y.; Abe, N.; Tanaka, K.; Arai, H. (Toyama Chemical Co., Ltd.); 2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid derivs. and its non-toxic salts. DE 2850485; JP 1981049376 . |
| 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) | 36973 | bromo(3-methyl-2-thienyl)magnesium | C5H5BrMgS | 详情 | 详情 | |
| (IX) | 62687 | 2-[4-(3-methyl-2-thienyl)phenyl]propanoic acid | C14H14O2S | 详情 | 详情 | |
| (XLVIII) | 62718 | 2-(4-iodophenyl)propanoic acid | C9H9IO2 | 详情 | 详情 | |
| (XLIX) | 62719 | 2-(4-iodophenyl)propanoyl chloride | C9H8ClIO | 详情 | 详情 | |
| (L) | 21513 | 2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol | 124-68-5 | C4H11NO | 详情 | 详情 |
| (LI) | 62720 | N-(2-hydroxy-1,1-dimethylethyl)-2-(4-iodophenyl)propanamide | C13H18INO2 | 详情 | 详情 | |
| (LII) | 62721 | 2-[1-(4-iodophenyl)ethyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole | C13H16INO | 详情 | 详情 | |
| (LIII) | 62722 | 4,4-dimethyl-2-{1-[4-(3-methyl-2-thienyl)phenyl]ethyl}-4,5-dihydro-1,3-oxazole | C18H21NOS | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)In an asymmetric synthesis of the title compound, aldehyde (V) was oxidized with sodium chlorite to afford the corresponding racemic acid, which was resolved via formation of the diastereoisomeric salts with cinchonidine. The target (R)-2-(4-iodophenyl)propionic acid (LIV) was then converted to the zinc salt and subsequently coupled to 3-methyl-2-thienylmagnesium bromide (VIII) in the presence of palladium catalyst to provide the desired chiral arylpropionic acid
| 【1】 Arai, H.; Tanaka, K.; Watanabe, I.; Kodama, T.; Hirano, H.; Abe, N.; Nakabayashi, M. (Toyama Chemical Co., Ltd.); Novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid and pharmaceutically acceptable salt thereof and method for treating symptoms of inflammation and pain. US 4230719 . |