CN105130832A - Process for synthesizing pregabalin - Google Patents

Process for synthesizing pregabalin Download PDF

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Publication number
CN105130832A
CN105130832A CN201510602324.7A CN201510602324A CN105130832A CN 105130832 A CN105130832 A CN 105130832A CN 201510602324 A CN201510602324 A CN 201510602324A CN 105130832 A CN105130832 A CN 105130832A
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China
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methyl
synthesis
acid
reaction mixture
water
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CN201510602324.7A
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Chinese (zh)
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何金蓉
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成都艾比科生物科技有限公司
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Priority to CN201510602324.7A priority Critical patent/CN105130832A/en
Publication of CN105130832A publication Critical patent/CN105130832A/en

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Abstract

The invention discloses a process for synthesizing pregabalin. According to a synthesis route in the process, isovaleraldehyde and propane diacid are condensed for esterification; under the catalytic action of tetramethyl guanidine, a Michael addition is performed with nitromethane; a palladium-carbon catalyst of which the mass fraction is 10% is adopted in glacial acetic acid for reduction and hydrogenation; a raceme (+/-)-1 is obtained by directly performing hydrolysis in a hydrochloric acid solution without separation, and can be split to obtain (S)-1. The process provided by the invention is available, a few of reaction steps are taken, process conditions are mild, and the total yield is greatly improved on the basis of the prior art.

Description

A kind of synthesis technique of lyrica

Technical field

The present invention relates to synthesis technology field, specifically refers to a kind of synthesis technique of lyrica .

Background technology

Lyrica [pregabalin, (S) .1] chemistry by name (S) 3_ aminomethyl one Jue methylhexanoic acid [(3S)-3 one aminomethyl-5 mono-methylhex-anoicacid], it is aminobutyric acid (GABA) receptor antagonist developed by Pfizer Inc., obtain European Union's approval in July, 2004 and in Britain's Initial Public Offering, help epilepsy therapy medicine as the attached of partial seizure patient.Compare with the gabapentin used clinically (gabapentin), the anticonvulsant action of this product is stronger, and untoward reaction is less, have dosage low, take number of times few, have the advantages such as angst resistance effect concurrently, the regeneration product of gabapentin, wide market.

Lyrica is chipal compounds, and its S type isomer has pharmacologically active.One of current synthesis technique be (+) one norephedrine be that chiral auxiliary(reagent) carries out asymmetric synthesis, condition is harsh, and cost is high; Two of synthesis technique is with diethyl malonate and isovaleric aldehyde for starting raw material, needs the potassium cyanide using severe toxicity; Synthesis technique three with isovaleric aldehyde, Malonamide nitrile or ethyl cyanoacetate for raw material, through intermediate 3 one isobutylglutaric acid, finally obtain target compound, route is longer, complicated operation, improve, but total recovery is lower, is only 61% to its technique.

Summary of the invention

The object of the invention is to: the synthesis technique that a kind of lyrica is provided.

The present invention is achieved through the following technical solutions: a kind of synthesis technique of lyrica, comprises the following steps:

(1) 5-methyl-2-hexenoic acid is synthesized;

(2) 5-methyl-2-hexenoic acid ethyl ester is synthesized;

(3) 5-methyl-3-nitre methylhexanoic acid ethyl ester is synthesized;

(4) the own ester of 5-methyl-3-Aminomethyl caproic acid is synthesized;

(5) 5-methyl-3-Aminomethyl caproic acid is synthesized.

Further, the synthetic method of described step (1) 5-methyl-2-caproic acid is get 30g propanedioic acid and be dissolved in 50ml anhydrous pyridine, icy salt solution water-bath is cooled to 0 DEG C, the isovaleric aldehyde newly steamed by 28ml slowly adds in above-mentioned solution under vigorous stirring, and 30min dropwises, and forms yellow slurry.Remove cryosel water-bath, reaction mixture nature body, to room temperature, continues to stir 12h, by TLC monitoring reaction.Reaction mixture becomes colorless settled solution, is heated to 60 DEG C, keeps 5h, has CO2 gas slow release, be warming up to 90 DEG C, continues 2h, treats that CO2 release is complete, is poured into by reaction mixture in 100ml water, separate upper organic phase, be dissolved in 100ml ethyl acetate.Organic phase 140ml6.0mol/l hydrochloric acid soln and 100ml water washing, add anhydrous sodium sulfate drying.Steam except ethyl acetate with Rotary Evaporators, residue rectifying, collects 82 DEG C, 133pa cut.

Further, in described step (2), the method for synthesis 5-methyl-2-hexenoic acid ethyl ester is: in 100mI there-necked flask, add 19g compound 4,35mL ethanol, the 0.7mL vitriol oil, backflow is spent the night, add 120ml water, by extracted with diethyl ether, the diethyl ether solution of merging, respectively with saturated sodium hydrogen carbonate solution, water washing, adds anhydrous Na 2S04 dry.

Further, the method of described step (3) synthesis 5-methyl-3-nitre methylhexanoic acid ethyl ester is: with in the 50mL round-bottomed flask of magnetic stir bar, add 5g compound 5,9ml Nitromethane 99Min., 0.8mL1,1,3,3-tetramethyl guanidine, reaction mixture reacts completely in stirred at ambient temperature 15h, TLC monitoring, solvent removed by vacuum, resistates, by silica gel chromatography, collects Rf0.26 part, solvent removed by vacuum.

Further, the method of the own ester of described step (4) synthesis 5-methyl-3-Aminomethyl caproic acid is: 5g compound 6 is dissolved in 80mL Glacial acetic acid, adds the Pd-C that 0.5g massfraction is 10%, uses the air in nitrogen replacement reaction solution under vacuo, continuous 3 times, then connect upper hydrogen balloon, stirred at ambient temperature 12h, TLC monitoring reacts completely, reaction mixture passes through diatomite filtration, removing Pd-C catalyst, concentrated filtrate, obtains tawny liquid.

Further, the method of described step (5) synthesis 5-methyl-3-Aminomethyl caproic acid is: upwards walk the hydrochloric acid 80mL adding 6mol/L in obtained compound 7, reflux 4h, vacuum hydro-extraction, 80g ion exchange resin column (Dowex50W × 8), first wash with water, the pH to effluent liquid is 7.0, then elutes wanted product with the ammoniacal liquor of 0.5molll-1.

The present invention compared with prior art, has the following advantages and beneficial effect:

Synthetic route of the present invention is by isovaleric aldehyde and propanedioic acid condensation, esterification, under tetramethyl guanidine catalysis, Michael addition is carried out with Nitromethane 99Min., adopt massfraction be 10% palladium one charcoal make catalyzer and reduce hydrogenation in glacial acetic acid, without separation, directly in hydrochloric acid soln, hydrolysis obtains racemic modification (±) 1, splits (S) 1.This method is former to be easy to get, and reactions steps is few, and processing condition are gentle, and total recovery for improve a lot on prior art basis.

Embodiment

Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.

Embodiment 1:

Synthesis 5-methyl-2-hexenoic acid: get 30g propanedioic acid and be dissolved in 50ml anhydrous pyridine, icy salt solution water-bath is cooled to 0 DEG C, and the isovaleric aldehyde newly steamed by 28ml slowly adds in above-mentioned solution under vigorous stirring, and 30min dropwises, and forms yellow slurry.Remove cryosel water-bath, reaction mixture nature body, to room temperature, continues to stir 12h, by TLC monitoring reaction.Reaction mixture becomes colorless settled solution, is heated to 60 DEG C, keeps 5h, has CO2 gas slow release, be warming up to 90 DEG C, continues 2h, treats that CO2 release is complete, is poured into by reaction mixture in 100ml water, separate upper organic phase, be dissolved in 100ml ethyl acetate.Organic phase 140ml6.0mol/l hydrochloric acid soln and 100ml water washing, add anhydrous sodium sulfate drying.Steam except ethyl acetate with Rotary Evaporators, residue rectifying, collect 82 DEG C, 133pa cut, obtains 27.84g compound 4, yield 83.0%.

Synthesis 5-methyl-2-hexenoic acid ethyl ester: in 100mI there-necked flask, add 19g compound 4,35mL ethanol, the 0.7mL vitriol oil, backflow is spent the night, add 120ml water, by extracted with diethyl ether, the diethyl ether solution of merging, respectively with saturated sodium hydrogen carbonate solution, water washing, adds anhydrous Na 2s0 4dry.Rectifying, collects 90-93 DEG C, 933pa cut, obtains colourless liquid 5,21.25g, yield 92.0%.

Synthesis 5-methyl-3-nitre methylhexanoic acid ethyl ester: with in the 50mL round-bottomed flask of magnetic stir bar, add 5g compound 5,9ml Nitromethane 99Min., 0.8mL1,1,3,3-tetramethyl guanidine, reaction mixture is in stirred at ambient temperature 15h, TLC monitoring reacts completely, solvent removed by vacuum, and resistates passes through silica gel chromatography, collect Rf0.26 part, solvent removed by vacuum.Obtain colourless liquid (6) 6.40g, yield 92.2%.

The own ester of synthesis 5-methyl-3-Aminomethyl caproic acid: 5g compound 6 is dissolved in 80mL Glacial acetic acid, add the Pd-C that 0.5g massfraction is 10%, use the air in nitrogen replacement reaction solution under vacuo, continuous 3 times, then connect upper hydrogen balloon, stirred at ambient temperature 12h, TLC monitoring reacts completely, and reaction mixture, by diatomite filtration, removes Pd-C catalyzer, concentrated filtrate, obtains tawny liquid.

Synthesis 5-methyl-3-Aminomethyl caproic acid: upwards walk the hydrochloric acid 80mL adding 6mol/L in obtained compound 7, reflux 4h, vacuum hydro-extraction, 80g ion exchange resin column (Dowex50W × 8), first wash with water, pH to effluent liquid is 7.0, then elutes wanted product with the ammoniacal liquor of 0.5moll/l, and elutriant is through vacuum hydro-extraction.Obtain white clumpy solid.Add this solid of triturated under ether, filter, vacuum-drying at 30 DEG C, obtains white powder 2.93g, yield 80.1%.

The above is only preferred embodiment of the present invention, and not do any pro forma restriction to the present invention, every any simple modification, equivalent variations done above embodiment according to technical spirit of the present invention, all falls within protection scope of the present invention.

Claims (6)

1. a synthesis technique for lyrica, is characterized in that, comprises the following steps:
(1) 5-methyl-2-hexenoic acid is synthesized;
(2) 5-methyl-2-hexenoic acid ethyl ester is synthesized;
(3) 5-methyl-3-nitre methylhexanoic acid ethyl ester is synthesized;
(4) the own ester of 5-methyl-3-Aminomethyl caproic acid is synthesized;
(5) 5-methyl-3-Aminomethyl caproic acid is synthesized.
2. the synthesis technique of a kind of lyrica according to claim 1, it is characterized in that: the synthetic method of described step (1) 5-methyl-2-caproic acid is, getting 30g propanedioic acid is dissolved in 50ml anhydrous pyridine, icy salt solution water-bath is cooled to 0 DEG C, the isovaleric aldehyde newly steamed by 28ml slowly adds in above-mentioned solution under vigorous stirring, 30min dropwises, form yellow slurry, remove cryosel water-bath, reaction mixture nature body is to room temperature, continue to stir 12h, by TLC monitoring reaction, reaction mixture becomes colorless settled solution, be heated to 60 DEG C, keep 5h, there is CO2 gas slow release, be warming up to 90 DEG C, continue 2h, treat that CO2 release is complete, reaction mixture is poured in 100ml water, separate upper organic phase, be dissolved in 100ml ethyl acetate, organic phase 140ml6.0mol/l hydrochloric acid soln and 100ml water washing, add anhydrous sodium sulfate drying, steam except ethyl acetate with Rotary Evaporators, residue rectifying, collect 82 DEG C, 133pa cut.
3. the synthesis technique of a kind of lyrica according to claim 2, it is characterized in that: in described step (2), the method for synthesis 5-methyl-2-hexenoic acid ethyl ester is: in 100mI there-necked flask, add 19g compound 4,35mL ethanol, the 0.7mL vitriol oil, backflow is spent the night, add 120ml water, by extracted with diethyl ether, the diethyl ether solution of merging, respectively with saturated sodium hydrogen carbonate solution, water washing, adds anhydrous Na 2S04 dry.
4. the synthesis technique of a kind of lyrica according to claim 2, it is characterized in that: the method for described step (3) synthesis 5-methyl-3-nitre methylhexanoic acid ethyl ester is: with in the 50mL round-bottomed flask of magnetic stir bar, add 5g compound 5,9ml Nitromethane 99Min., 0.8mL1,1,3,3-tetramethyl guanidine, reaction mixture reacts completely in stirred at ambient temperature 15h, TLC monitoring, solvent removed by vacuum, resistates, by silica gel chromatography, collects Rf0.26 part, solvent removed by vacuum.
5. the synthesis technique of a kind of lyrica according to claim 2, it is characterized in that: the method for the own ester of described step (4) synthesis 5-methyl-3-Aminomethyl caproic acid is: 5g compound 6 is dissolved in 80mL Glacial acetic acid, add the Pd-C that 0.5g massfraction is 10%, use the air in nitrogen replacement reaction solution under vacuo, continuous 3 times, then upper hydrogen balloon is connected, stirred at ambient temperature 12h, TLC monitoring reacts completely, reaction mixture passes through diatomite filtration, removing Pd-C catalyst, concentrated filtrate, obtains tawny liquid.
6. the synthesis technique of a kind of lyrica according to claim 2, it is characterized in that: the method for described step (5) synthesis 5-methyl-3-Aminomethyl caproic acid is: upwards walk the hydrochloric acid 80mL adding 6mol/L in obtained compound 7, reflux 4h, vacuum hydro-extraction, 80g ion exchange resin column (Dowex50W × 8), first wash with water, the pH to effluent liquid is 7.0, then elutes wanted product with the ammoniacal liquor of 0.5molll-1.
CN201510602324.7A 2015-09-21 2015-09-21 Process for synthesizing pregabalin CN105130832A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011016052A2 (en) * 2009-08-03 2011-02-10 Helvetica Industries (P) Limited Process for preparing pregabalin
CN103159636A (en) * 2013-04-05 2013-06-19 李兴惠 Aminomethyl caproic acid derivative and use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011016052A2 (en) * 2009-08-03 2011-02-10 Helvetica Industries (P) Limited Process for preparing pregabalin
CN103159636A (en) * 2013-04-05 2013-06-19 李兴惠 Aminomethyl caproic acid derivative and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
李秀峰等: "抗惊厥药物普瑞巴林的合成工艺改进", 《中国医药化学杂志》 *

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