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【结 构 式】 
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【分子编号】12443 【品名】2-Bromo-3-methylthiophene 【CA登记号】14282-76-9 |
【 分 子 式 】C5H5BrS 【 分 子 量 】177.0647 【元素组成】C 33.92% H 2.85% Br 45.13% S 18.11% |
合成路线1
该中间体在本合成路线中的序号：(II)The synthesis of 5-hydroxytiagabine, a metabolite of tiagabine in humans, has been undertaken to confirm that it is present entirely as (E)- and (Z)-isomers of the tautomeric 5-oxo form: The bromination of 3-methylthiophene (I) with N-bromosuccinimide gives 2-bromo-3-methylthiophene (II), which is chlorinated with N-chlorosuccinimide to yield 2-bromo-5-chloro-3-methylthiophene (III). The reaction of (III) with Mg affords 5-chloro-3-methylthien-2-ylmagnesium bromide (IV), which is condensed with 3-methylthiophene-2-carboxaldehyde (V) (obtained from (II) by reaction with magnesium and dimethylformamide) to give the bisthienylmethanol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) yields the bisthienyl ketone (VII), which is treated with sodium methoxide to afford the bis(2-thienyl)ketone (VIII). The Grignard reaction of (VIII) with cyclopropylmagnesium bromide (IX) gives the trisubstituted methanol (X), which is submitted to ring opening with trimethylsilyl bromide to afford the thiophenone (XI) as a mixture of the (E)- and (Z)-isomers. The condensation of (XI) with piperidine-3(R)-carboxylic acid ethyl ester (XII) by means of K2CO3 gives 1-[4-(3-methyl-5-oxo-2,5-dihydrothien-2-ylidene)-4-(3-methyl-2-thienyl) butyl]piperidine-3(R)-carboxylic acid ethyl ester (XIII) (also as a mixture of (E)- and (Z)-isomers). Finally, this compound is hydrolyzed to the free acid in HCl medium.
| 【1】 Thogersen, H.; Chorghade, M.S.; Lee, E.C.; Andersen, K.E.; Sorensen, P.O.; Lundt, B.F.; Begtrup, M.; Lau, J.; Petersen, H.; The synthesis of novel GABA uptake inhibitors. 2. Synthesis of 5-hdroxytiagabine, a human metabolite of the GABA reuptake inhibitor tiagabine. Tetrahedron 1994, 50, 29, 8699. |
| 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) | 12442 | 3-Methylthiophene | 616-44-4 | C5H6S | 详情 | 详情 |
| (II) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (III) | 12444 | 2-Bromo-5-chloro-3-methylthiophene | C5H4BrClS | 详情 | 详情 | |
| (IV) | 12445 | Bromo(5-chloro-3-methyl-2-thienyl)magnesium | C5H4BrClMgS | 详情 | 详情 | |
| (V) | 12446 | 3-Methyl-2-thiophenecarboxaldehyde; 3-Methyl-2-thiophenecarbaldehyde | 5834-16-2 | C6H6OS | 详情 | 详情 |
| (VI) | 12447 | (5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol | C11H11ClOS2 | 详情 | 详情 | |
| (VII) | 12448 | (5-Chloro-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone | C11H9ClOS2 | 详情 | 详情 | |
| (VIII) | 12449 | (5-Methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanone | C12H12O2S2 | 详情 | 详情 | |
| (IX) | 12450 | Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide | 23719-80-4 | C3H5BrMg | 详情 | 详情 |
| (X) | 12451 | Cyclopropyl(5-methoxy-3-methyl-2-thienyl)(3-methyl-2-thienyl)methanol | C15H18O2S2 | 详情 | 详情 | |
| (XI) | 12452 | 5-[(E)-4-Bromo-1-(3-methyl-2-thienyl)butylidene]-4-methyl-2(5H)-thiophenone | C14H15BrOS2 | 详情 | 详情 | |
| (XII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (XIII) | 12454 | ethyl (3R)-1-[4-[3-methyl-5-oxo-2(5H)-thiophenylidene]-4-(3-methyl-2-thienyl)butyl]hexahydro-3-pyridinecarboxylate | C22H29NO3S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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3
该中间体在本合成路线中的序号：(V)Treatment of 2-(trityloxy)ethanol (I) with bromoacetic acid (II) and n-BuLi in THF affords ethoxyacetic acid derivative (III), which is then converted into ethyl ester (IV) by means of EtOH and DCC in CH2Cl2 in the presence of 4-pyrrolidinopyridine. Reaction of (IV) with Grignard reagent, prepared from 2-bromo-3-methylthiophene (V) and Mg turnings in THF, provides compound (VI), which is then converted into the corresponding tosylate derivative (VII) by treatment with BuLi and p-toluenesulfonyl chloride (p-TsCl) in toluene. Reaction of (VII) with (R)-ethyl nipecotate (VIII) and K2CO3 yields ethyl ester (IX), which is finally hydrolyzed with aqueous NaOH in EtOH followed by treatment with diluted HCl.
| 【1】 Knutsen, L.J.S.; Andersen, K.E.; Lau, J.; et al.; Synthesis of novel GABA uptake inhibitors. 3. Diaryloximine and diarylvinyl ether derivatives of nipecotic acid and guvacine as anticonvulsant agents. J Med Chem 1999, 42, 18, 3447. |
| 【2】 Knutsen, L.J.S.; Jorgensen, A.S.; Andersen, K.E.; Sonnewald, U. (Novo Nordisk A/S); Novel N-substd. azaheterocyclic carboxylic acids. EP 0374801; JP 1990223551; US 5071859; US 5214057 . |
| 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) | 42978 | 2-(trityloxy)-1-ethanol | C21H20O2 | 详情 | 详情 | |
| (II) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (III) | 42979 | 2-[2-(trityloxy)ethoxy]acetic acid | C23H22O4 | 详情 | 详情 | |
| (IV) | 42980 | ethyl 2-[2-(trityloxy)ethoxy]acetate | C25H26O4 | 详情 | 详情 | |
| (V) | 12443 | 2-Bromo-3-methylthiophene | 14282-76-9 | C5H5BrS | 详情 | 详情 |
| (VI) | 42981 | 2-[[2,2-bis(3-methyl-2-thienyl)vinyl]oxy]-1-ethanol | C14H16O2S2 | 详情 | 详情 | |
| (VII) | 42982 | 2-[[2,2-bis(3-methyl-2-thienyl)vinyl]oxy]ethyl 4-methylbenzenesulfonate | C21H22O4S3 | 详情 | 详情 | |
| (VIII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (IX) | 42983 | ethyl (3R)-1-(2-[[2,2-bis(3-methyl-2-thienyl)vinyl]oxy]ethyl)-3-piperidinecarboxylate | C22H29NO3S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)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 |