CN1288145C

CN1288145C - Synthesis method of Gabitril and its racemate and S-configuration

Info

Publication number: CN1288145C
Application number: CN 200410089084
Authority: CN
Inventors: 张建革; 蒋昌盛; 闻韧; 林国强
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2004-12-03
Filing date: 2004-12-03
Publication date: 2006-12-06
Anticipated expiration: 2024-12-03
Also published as: CN1651426A

Abstract

The invention provides a new synthesis method of tiagabine, a medicine for treating epilepsy and diseases related to GABA intake. X, X', X"=Br, Cl, I; X, X', X" are the same or different groups R'=C _n H _2n+1 , n=1～5; Ph is phenyl in the present invention The preparation method of racemic tiagabine and S-configuration tiagabine is provided. The synthesis route proposed by the invention does not need expensive special reagents, is convenient to operate, has mild reaction conditions, and is suitable for enlarged preparation.

Description

The synthetic method of tiagabine and raceme thereof and S-configuration

Technical field

The invention provides the novel synthesis of the diseases related medicine tiagabine (Tiagabine) of a kind of treatment epilepsy and GABA (γ-Aminobutyric acid) picked-up.The present invention provides the preparation method of the tiagabine and the S-configuration tiagabine of racemization simultaneously.The present invention also provides the preparation method of the required optically pure β-piperidine ethyl formate of raw material of synthetic above-claimed cpd.

Background technology

Nielsen in 1991 etc. have reported that at first tiagabine (Tiagabine) has good spasmolytic effect, simultaneously still the fine inhibitor of GABA (γ-Aminobutyric acid) picked-up (Eur.J.pharmacol., 1991,196 (3), 257-266).At present it has been developed into treatment epilepsy and GABA (the diseases related medicine (CN 1225094A, 1999,8,4) of picked-up of γ-Aminobutyricacid).Knud equals to report in 1993 its synthetic method (J.Med.Chem., 1993,36,1716-1725), but two kinds of synthetic methods of their usefulness have all been used the responsive especially and expensive organometallic reagent (Scheme 1) to air, therefore are unsuitable for suitability for industrialized production.

Summary of the invention

The invention provides the precursor of a kind of tiagabine and raceme thereof and S-configuration.

The present invention also provide a kind of synthetic tiagabine and raceme and S-configuration thereof with and the method for precursor.

The precursor of tiagabine provided by the invention and raceme thereof and S-configuration, its structural formula is as follows:

The method of synthetic tiagabine provided by the invention is expressed as follows with reaction formula

X, X ', X "=Br, Cl, I; X, X ', X " are identical or different group

R '=C _nH _2n+1, n=1～5; Ph is a phenyl

Specifically, the reaction conditions of recommending is that (preparation recommends to see Tetrahedron lett. with compound 2,2003,44,4547-4550) be dissolved in organic solvent for example methylene dichloride, trichloromethane, 1, in 2-ethylene dichloride, tetrahydrofuran (THF), ether, acetonitrile, dioxane benzene or the toluene etc., add 1～2 normal alkali, described alkali can be C _nH _2n+1OM (n=1～5, M=Na, K), potassium hydroxide, sodium hydroxide or salt of wormwood; After the reflux 1～2 hour, add compound 1 (recommend, 1993,36,1716-1725 method) with reference to J.Med.Chem., in 0～110 ℃ of reaction reacted in 1～24 hour compound 3 (with reference to Tetrahedron lett., 2003,44,4547-4550).Compound 3 is dissolved in organic solvent and for example the open loop of methylene radical cyclopropane ring can be got compound 4 in tetrahydrofuran (THF), dioxane or the acetonitrile etc. (recommend with reference to Tetrahedron under the effect of acid, 2004,60, the 2057-2059 method), described acid is hydrochloric acid, Hydrogen bromide or hydroiodic acid HI for example, and reaction is recommended in 0～50 ℃ of reaction 1～10 hour.Compound 4 is dissolved in organic solvent such as acetone, acetonitrile or the tetrahydrofuran (THF) etc., under the effect of salt of wormwood, pyridine or triethylamine and potassiumiodide, reacted 10～72 hours at 0-50 ℃ with compound 5, get compound 6, be that 1-3 can get target compound tiagabine (Tiagabine) with hcl acidifying to PH again after compound 6 hydrolysis, hydrolysis can be to be dissolved in potassium hydroxide or the sodium hydroxide hydrolysis of using 1-15N in the ethanol.

Replace (R)-β-piperidine ethyl formate 5 with the β-piperidine ethyl formate of racemization and (S)-β-piperidine ethyl formate, utilize aforesaid method can get the tiagabine and the S-configuration tiagabine of racemization respectively.Be about to the compound 5 ' of the corresponding racemization of compound 5 usefulness in the previous reaction formula

Or compound

Replace, obtain the compound 6 ' of corresponding racemization

Or compound

The synthetic route that the present invention proposes need not expensive special reagent, and is easy to operate, and the reaction conditions gentleness is suitable for enlarging preparation.

Embodiment

To help further to understand the present invention by following embodiment, but not limit content of the present invention.

Embodiment 1

The preparation of compound 3

2.3 gram (4.9mmol) compound 2 (Br ^-Ph ₃P ⁺(CH ₂) ₃Br) be dissolved in the exsiccant tetrahydrofuran (THF); add 1.1 gram (9.8mmol) potassium tert.-butoxides; reflux is 2 hours under the nitrogen protection; dropping is dissolved in 1.0 in the 10ml tetrahydrofuran (THF) and digests compound 1 (4.5mmol); add the back in 65 ℃ of reactions 3 hours; the cooling back adds 25ml water, reaction solution extracted with diethyl ether.The organic phase washing, anhydrous sodium sulfate drying concentrates the back column chromatography and gets productive rate 46%. ¹H?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

The preparation of compound 4 (X=Cl)

0.42 gram (1.7mmol) compound 3 is dissolved in the dry dioxane of 5ml, adds 0.5ml 4M hydrochloric acid, reaction solution stirred 20 minutes at 120 ℃, and the cooling back adds 5ml water, mixed solution dichloromethane extraction.The extraction liquid washing, anhydrous sodium sulfate drying concentrates the back column chromatography and gets productive rate 90%. ¹H?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 ₁₄H ₁₅ClS ₂?282.8578(M ⁺+1)，found：282.02755.

Embodiment 3

The preparation of compound 6 (R '=C ₂H ₅)

0.43 gram (1.5mmol) compound 4 (X=Cl) is dissolved in 15 milliliters of acetone, add 0.48 milliliter (3mmol) (R)-β-piperidine ethyl formate 5,51 milligrams of (0.3mmol) potassiumiodides, 0.414 gram (3mmol) salt of wormwood, stirring at room 72 hours, stopped reaction, the filtering insolubles, evaporate to dryness filtrate, resistates are dissolved in 10 milliliters of ethyl acetate, wash with 10 milliliter of 10% aqueous tartaric acid solution, saturated common salt washing (2 * 30ml), anhydrous sodium sulfate drying, silica gel column chromatography get 0.33 gram product, productive rate 55%. ¹HNMR(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)。

Embodiment 4

The preparation of amorphous Tiagabine

Digest compound 6 with 0.79 and be dissolved in 8 milliliters of dehydrated alcohols, drip the aqueous sodium hydroxide solution of 0.33 milliliter of 12N, stirring at room 48 hours, stopped reaction, the ice bath cooling transfers to 1～2 with 4N hydrochloric acid with pH value, uses dichloromethane extraction, organic phase saturated common salt washing (2 * 30ml), anhydrous sodium sulfate drying boils off solvent, is separated out by solid, use ethanol: methylene dichloride: the mixed solvent recrystallization of ether=1: 0.1: 4 gets 0.6 gram straight product, productive rate 75%.The gained crystal is dissolved in 30 ml waters, and freeze-drying gets amorphous powder. ¹HNMR(CD ₃OD)δ：1.29～2.20(4H，m)，2.40(3H，s)，2.42(3H，s)，2.64～3.01(5H，m)，3.22(2H，m)，3.50(1H，m)，3.67(1H，m)，6.00(1H，m)，6.59～6.65(2H，m)，6.77～6.85(2H，m)；ESI-MS(m/z)：377[M-Cl+H] ⁺；[α] _D ²⁰＝-9.1(c＝1，H ₂O)。

Claims

1. the precursor of a tiagabine and raceme and S-configuration is characterized in that structural formula is as follows:

2. the synthetic method of the compound of claim 1 is characterized in that comprising the steps:

The compound that makes general formula 1 with

Reaction,

In the formula, X, X ' represent Cl, Br or I.

3. synthetic method according to claim 2, it is characterized in that described step is that 1～2 normal compound 2 is dissolved in the organic solvent, add 1～2 normal alkali, after the reflux 1～2 hour, add the described compound 1 of 1 normal claim 2 that is dissolved in the above-mentioned solvent, in 0～110 ℃ of reaction 1～24 hour, described compound 2 was

X, X ' are as described in the claim 2.

4. the purposes of the described compound of claim 1 is characterized in that being used for synthetic tiagabine and raceme and S-configuration.

5. purposes according to claim 4 is characterized in that comprising the steps:

1) the described compound 3 of claim 1 gets compound 4 after open loop under the effect of acid,

In the formula, X " represent Cl, Br or I;

2) make the compound of general formula 4, with the compound reaction of following formula 5 ', R ' represents C ₁～C ₅Alkyl,

3) compound of the resulting general formula 6 ' of conversion is the compound as the bottom right formula;

6. purposes according to claim 4 is characterized in that comprising the steps:

In the formula, X " represent Cl, Br or I;

2) make the compound of general formula 4, with the compound reaction of following formula 5, R ' represents C ₁～C ₅Alkyl,

3) compound of the resulting general formula 6 of conversion is the compound as the bottom right formula;

7. purposes according to claim 6, it is characterized in that the described method for preparing compound 4 by compound 3 is that compound 3 is dissolved in the organic solvent, under the effect of the acid of 1～6N,, the open loop of methylene radical cyclopropane ring is got compound 4 in 0～50 ℃ of reaction 1～10 hour.

8. purposes according to claim 6, it is characterized in that the described method for preparing compound 6 by compound 4 is that compound 4 is dissolved in the organic solvent, under the effect of salt of wormwood, pyridine or triethylamine and potassiumiodide, reacted 10～72 hours at 0～50 ℃, get compound 6 with compound 5.

9. according to claim 7 or 8 described purposes, it is characterized in that described organic solvent is methylene dichloride, trichloromethane, 1,2-ethylene dichloride, tetrahydrofuran (THF), ether, acetonitrile, dioxane, acetone, benzene or toluene.

10. purposes according to claim 6 is characterized in that the described method for preparing tiagabine by compound 6 is that compound 6 is dissolved in the ethanol potassium hydroxide or sodium hydroxide hydrolysis with 1～15N, again with hcl acidifying to PH be 1～2 target compound.