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Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride

A technology of tiagabine hydrochloride and a synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of easy decomposition, deepening color, low yield of alkylation, etc., and achieves the effects of mild reaction conditions and convenient operation.

Active Publication Date: 2013-04-10
FUZHOU NEPTUNUS FUYAO PHARMA
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0007]In the synthetic route A, the synthetic steps of intermediate 6 are cumbersome, two-step Grignard reaction is required, the source of 3-methylthiophene formaldehyde is difficult and cyclopropyl bromide The price is too high; in the synthesis route B: the synthesis of intermediate 6, the disadvantage is that the source of n-butyllithium is difficult, it is not easy for large-scale industrial production, and extremely low temperature reaction conditions are required
There are also some problems in the remaining steps: as the low yield of alkylation, only 50%
[0015] However, the powder from acidic water is ultra-fine crystal, which is difficult to filter and has high water content. It is difficult to dry when it is lower than 40°C, so the USP It is stipulated that the maximum allowable water content of tiagabine hydrochloride raw materials is 5%
However, the hydrochloric tiagabine hydrochloride is unstable, easy to decompose during storage, and the color deepens
In addition, there is no method that can effectively reduce the impurity content in tiagabine hydrochloride in the prior art

Method used

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  • Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride
  • Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride
  • Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of compound 1 2,2-bis(3-methyl-2-thienyl)tetrahydrofuran

[0035] In anhydrous tetrahydrofuran (10.5 ml), magnesium chips (237 mg, 8.42×10 -3 mol) and 2-bromo3-methylthiophene (1.64 g, 9.27×10 -3 mol) to prepare (3-methyl-2-thienyl)magnesium bromide in THF, cooled to 0 °C with ice water, added ethyl 4-bromobutyrate (0.897 g, 4.60 ×10 -3 mol), control the addition below 10 °C, and then heat up and reflux for 3 h. After the reaction mixture was cooled to 0°C, saturated NH 4 Cl solution (20.0 ml). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (6 ml×2). Combine the organic phases and dilute with anhydrous Na 2 SO 4 Drying. The organic phase was rotary evaporated to obtain the compound 1 : Pale yellow solid, dissolved in a small amount of ethanol, added petroleum ether to precipitate the compound; white crystal (1.11g, yield 91.1%); Mp: 68-72 °C; MS ESI + 265 [M+1] + ; 1 H NMR (CDCl 3): d 2.10 (s, 3H), 2.12...

Embodiment 2

[0037] Compound 4 4-Bromo-1.1-bis(3-methyl-2-thienyl)-1-butene

[0038] compound 1 (1.21 g, 4.58 ×10 -3 mol) with 47.0% HBr (7.26 g, 42.1×10 -3 mol) mixture was stirred and heated at 80 °C for 6 h. After cooling to room temperature, extract with ethyl acetate 10ml ?? 2, combine the organic phases, and successively add water, 1% K 2 CO 3 Aqueous solution and washed to neutral. organic phase with anhydrous Na 2 SO 4 After drying and decolorization with activated carbon, the purple oil was obtained by rotary evaporation, and then purified by column chromatography (silica gel 300-400 mesh, petroleum ether) to obtain the compound 4 : yellow oil (1.31 g, yield 87.5%); MS ESI + : 327 [M+1] + ; IR (KBr): = 3103, 2962, 1443, 1267, 712 cm -1 ; MS ESI + : 328 [M+1] + ; 1 H NMR (CDCl 3 ) d 2.05 (s, 3H), 2.07 (s, 3H), 2.72 (q, J = 7.2 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H), 6.08 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 7.08 (d, J...

Embodiment 3

[0040] Compound 6 ( R )-(-)-N-[4,4-bis(3-methylthiophen-2-yl)-3-butenyl]-3-piperidinecarboxylic acid ethyl ester [tiagabine ethyl ester]

[0041] at room temperature R -Ethyl 3-piperidinecarboxylate (2.27 g, 14.4 × 10 -3 mol), 7 (4.90 g, 14.4 × 10 -3 mol), anhydrous K 2 CO 3 (2.98 g, 21.6×10 -3 mol), KI (120 mg, 7.2×10 -4 mol) and acetone (30 ml) were stirred for 72 hours, filtered to remove inorganic salts, the filtrate was rotary evaporated, and the residue was purified by column chromatography (silica gel 200-300 mesh, petroleum ether: acetone) to obtain the compound 6 : yellow oil (4.28 g, yield 74.3%); [a] D 25 = -24.9° ( c = 1.00, EtOH); IR (KBr): =3104, 2942, 1732, 1446, 712cm -1 ; MS (ESI + ): 404.2 [M+1] + ; 1 H-NMR (500MHz, CDCl 3 ) d: 1.24 (t, J = 7.1 Hz, 3H), 1.41 (ddd, J = 3.5 / 12.7 / 16.2 Hz, 1H), 1.50~1.60 (m, 1H), 1.62~1.75 (m, 1H), 1.87~1.99 (m, 2H), 2.00 (s, 3H), 2.04 (s, 3H ), 2.10~2.17 (m, 1H), 2.26 (q, J = 5.5 Hz, 2H), 2.45~2....

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Abstract

The invention provides a method for synthesizing tiagabine hydrochloride, which has the following synthesizing route. The invention also provides a method for preparing anhydrous tiagabine hydrochloride of medicinal preparation level in a single or mixed organic solvent. An important dithiophene N-alkylated intermediate is prepared by the compact synthesizing method; and the synthesizing route does not need expensive special reagents, is convenient to operate, has mild reaction conditions, and is suitable for expanded preparation. In addition, when the anhydrous tiagabine hydrochloride is prepared by adopting the single or mixed organic solvent, the residual organic solvent is tried to remove so that the anhydrous tiagabine hydrochloride meets the requirement of a medicament preparation.

Description

technical field [0001] The invention relates to a synthesis method of tiagabine hydrochloride and a method for preparing the anhydrous preparation grade thereof. Background technique [0002] ( R )-(-)-N-[4,4-bis(3-methyl-2-thienyl)-1-butyl-3-ene]piperidine-3-carboxylate hydrochloride, its common name is Tiagabine Hydrochloride. USP 5, 010, 090 was the first to report the synthesis of tiagabine hydrochloride and its use as a GABA uptake protein inhibitor. It was first listed in Denmark and France by Novo Nordisk in 1996, and is now listed in many countries around the world. As a new antiepileptic drug with a new mode of action, this drug is an important breakthrough in the treatment of antiepileptic drugs. It has a significant effect on the approximately 30 percent of seizures that are refractory to existing medications. Compared with other antiepileptic drugs, its side effects are mild and there is no drug resistance. Clinical studies have shown that the drug is more s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/14
Inventor 赵学清
Owner FUZHOU NEPTUNUS FUYAO PHARMA
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