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【结 构 式】 
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【分子编号】12453 【品名】ethyl (3R)hexahydro-3-pyridinecarboxylate 【CA登记号】 |
【 分 子 式 】C8H15NO2 【 分 子 量 】157.21264 【元素组成】C 61.12% H 9.62% N 8.91% O 20.35% |
合成路线1
该中间体在本合成路线中的序号：(II)The ethyl ester of 3-piperidinecarboxylic acid (nipecotic acid) (II) is N-alkylated with 4,4-diphenyl-3-butenyl bromide (I). The ethyl ester of N-(4,4-diphenyl-3-butenyl)nipecotic acid thus obtained is then hydrolyzed with HCl to yield the hydrochloride of the free acid.
| 【1】 Fe, A.; et al.; Orally active and potent inhibitors of gamma-aminobutyric acid uptake. J Med Chem 1985, 28, 5, 653. |
| 【2】 Loscher, W.; SK&F-89976-A. Drugs Fut 1986, 11, 1, 36. |
合成路线2
该中间体在本合成路线中的序号：(XII)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3
该中间体在本合成路线中的序号：(VIII)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4
该中间体在本合成路线中的序号：(VIII)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5
该中间体在本合成路线中的序号：(Ib)Racemic ethyl 3-piperidinecarboxylate (Ia, Ib) was resolved with D-(-)-tartaric acid in EtOH to afford the (S)-piperidine tartrate salt (II). After protection of (II) as the N-Boc derivative (III) by treatment with di-tert-butyl dicarbonate and NaOH, reduction of the carboxylate group of (III) by means of LiBH4 provided alcohol (IV). Subsequent coupling of (IV) with 4-bromo-2,6-dimethylphenol (V) under Mitsunobu conditions provided ether (VI). The N-Boc protecting group of (VI) was then cleaved employing trifluoroacetic acid to give piperidine (VII). Finally, Eschweiler-Clarke methylation using formaldehyde and formic acid furnished the corresponding N-methyl piperidine, which was isolated after conversion to the hydrochloride salt.
| 【1】 Kojima, N.; Nishino, C. (Shiseido Co. Ltd.); Benzamide deriv., anti-ulcer drug, and antibacterial drug. EP 0869124; JP 1998279570; US 5891890 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ib) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (Ia),(II) | 35224 | ethyl (3S)-3-piperidinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (III) | 35220 | 1-(tert-butyl) 3-ethyl (3S)-1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (IV) | 35221 | tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (V) | 31142 | 4-bromo-2,6-dimethylphenol | 2374-05-2 | C8H9BrO | 详情 | 详情 |
| (VI) | 35222 | tert-butyl (3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-piperidinecarboxylate | C19H28BrNO3 | 详情 | 详情 | |
| (VII) | 35223 | (3S)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]piperidine; 4-bromo-2,6-dimethylphenyl (3S)piperidinylmethyl ether | C14H20BrNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VII)Reduction of (R)-ethyl nipecotate (VII) with LiAlH4 yields 3-piperidinemethanol (VIII), which is further protected as the N-Boc derivative (IX) by using Boc2O. Treatment of the piperidine alcohol (IX) with p-toluenesulfonyl chloride and pyridine leads to tosylate (X). Condensation of the sodium derivative of 4-methylimidazole (XI) with tosylate (X) gives rise to a mixture of regioisomeric N-alkylated imidazoles, which are chromatographically separated after derivatization with trityl chloride. The desired isomer (XII) is then deprotected under acidic conditions, giving piperidine (XIII). Finally, EDC-mediated coupling between piperidine (XIII) and the piperazinecarboxylic acid (VI) furnishes the title amide.
| 【1】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. EP 1140904; JP 2002533335; WO 0037458 . |
| 【2】 Cooper, A.B.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Kelly, J.M.; Rane, D.F.; Taveras, A.G.; Guzi, T.; Strickland, C.; Chao, J. (Schering Corp.); Farnesyl protein transferase inhibitors. US 6362188 . |
| 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) | 51595 | (2R)-4-[(11S)-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-[(cyclohexyloxy)carbonyl]-2-piperazinecarboxylic acid | C26H30ClN3O4 | 详情 | 详情 | |
| (VII) | 12453 | ethyl (3R)hexahydro-3-pyridinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (VIII) | 57427 | (1S)-2,2-dimethylcyclopropanecarbonyl chloride | C6H9ClO | 详情 | 详情 | |
| (IX) | 35221 | tert-butyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (X) | 57428 | ethyl 3-ethyl-2-pentenoate | C9H16O2 | 详情 | 详情 | |
| (XI) | 51586 | 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (XII) | 58429 | tert-butyl (3S)-3-[(4-methyl-1H-imidazol-1-yl)methyl]-1-piperidinecarboxylate | C15H25N3O2 | 详情 | 详情 | |
| (XIII) | 58430 | (3R)-3-[(4-methyl-1H-imidazol-1-yl)methyl]piperidine | C10H17N3 | 详情 | 详情 |