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Synthesis method of Gabitril and its racemate and S-configuration

A synthesis method and racemate technology, which are applied in the preparation of ethyl β-piperidinecarboxylate, tiagabine and S-configuration tiagabine, can solve the problems of unsuitability for industrial production and high price, and achieve The effect of convenient operation and mild reaction conditions

Inactive Publication Date: 2006-12-06
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Knud reported its synthetic method in 1993 (J.Med.Chem., 1993,36,1716-1725), but the two synthetic methods that they used have all used the organometallic reagent ( Scheme 1), so it is not suitable for industrial production

Method used

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  • Synthesis method of Gabitril and its racemate and S-configuration
  • Synthesis method of Gabitril and its racemate and S-configuration
  • Synthesis method of Gabitril and its racemate and S-configuration

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Preparation of compound 3

[0018] 2.3 grams (4.9mmol) compound 2 (Br - Ph 3 P + (CH 2 ) 3 Br) was dissolved in dry tetrahydrofuran, and 1.1 g (9.8 mmol) of potassium tert-butoxide was added, heated to reflux under nitrogen protection for 2 hours, and 1.0 g of compound 1 (4.5 mmol) dissolved in 10 ml of tetrahydrofuran was added dropwise. React at 65°C for 3 hours, add 25ml of water after cooling, and extract the reaction solution with ether. The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated and obtained by column chromatography with a yield of 46%. 1 H NMR (CDCl 3 , δppm): 1.45(m, 2H), 1.47(m, 2H), 1.95(s, 3H), 1.97(s, 3H), 6.81(m, 2H), 7.14(m, 2H).MS(EI) : m / z 246 (M + ).

Embodiment 2

[0020] Preparation of Compound 4 (X=Cl)

[0021] 0.42 g (1.7 mmol) of compound 3 was dissolved in 5 ml of dry dioxane, 0.5 ml of 4M hydrochloric acid was added, the reaction solution was stirred at 120°C for 20 minutes, after cooling, 5 ml of water was added, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, concentrated and obtained by column chromatography with a yield of 90%. 1 H NMR (CDCl 3 , δppm): 2.04(s, 3H), 2.05(s, 3H), 2.71(q, 2H, J=6.9), 3.44(t, 2H, J=6.9), 6.06(t, 1H, J=7.2) , 6.78(d, 1H, J=4.8), 6.85(d, 1H, J=5.1), 7.08(d, 1H, J=4.8), 7.23(d, 1H, J=6.0).MS(EI): m / z 282 (M + ).HRMS calcd.for:C 14 h 15 CLS 2 282.8578 (M + +1), found: 282.02755.

Embodiment 3

[0023] Preparation of Compound 6 (R'=C 2 h 5 )

[0024] 0.43 g (1.5 mmol) of compound 4 (X=Cl) was dissolved in 15 ml of acetone, 0.48 ml (3 mmol) of ethyl (R)-β-piperidinecarboxylate 5, 51 mg (0.3 mmol) of potassium iodide, 0.414 g ( 3mmol) of potassium carbonate, stirred at room temperature for 72 hours, stopped the reaction, filtered off the insoluble matter, evaporated the filtrate to dryness, dissolved the residue in 10ml of ethyl acetate, washed with 10ml of 10% tartaric acid aqueous solution, and washed with saturated brine (2×30ml) , dried over anhydrous sodium sulfate, and obtained 0.33 g of product by silica gel column chromatography, with a yield of 55%. 1 HNMR (CDCl 3 )δ: 1.21(3H, m), 1.37~1.72(3H, m), 1.93(2H, m), 2.02(3H, s), 2.05(3H, s), 2.09~2.17(1H, m), 2.34 (2H, m), 2.54(3H, m), 2.73(1H, m), 2.96(1H, m), 4.07~4.15(2H, q, t=7.2Hz), 6.03(1H, t, J=7Hz ), 6.76 (1H, d, J = 4.8Hz), 6.84 (1H, d, J = 4.8Hz), 7.06 (1H, d, J = 4.5Hz), 7.22 (1H, d, J = 4.8Hz).

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Abstract

A process for synthesizing Gabitril used to prepare the medicines for treating epilepsy and the diseases associated with GABA, its recemate, and its S-configuration are disclosed. Its advantage is low cost.

Description

technical field [0001] The invention provides a new synthesis method of Tiagabine, a medicine for treating epilepsy and GABA (γ-Aminobutyric acid) intake-related diseases. The invention also provides the preparation method of racemic tiagabine and S-configuration tiagabine. The invention also provides a preparation method of the optically pure ethyl β-piperidinecarboxylate, which is the raw material needed for synthesizing the above compound. Background technique [0002] [0003] In 1991, Nielsen et al. first reported that tiagabine (Tiagabine) had a good antispasmodic effect, and was also a good inhibitor of GABA (γ-Aminobutyric acid) uptake (Eur.J.pharmacol., 1991, 196 (3) , 257-266). At present, it has been developed as a drug for treating epilepsy and GABA (γ-Aminobutyric acid) intake-related diseases (CN 1225094A, 1999, 8, 4). Knud was equal to 1993 and reported its synthetic method (J.Med.Chem., 1993,36,1716-1725), but the two synthetic methods that they used ha...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/18C07D409/14
Inventor 张建革蒋昌盛闻韧林国强
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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