CN102964263A - Process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid - Google Patents
Process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid Download PDFInfo
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Abstract
The invention relates to a process for preparing (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid. The process comprises the steps: (1) preparing 3-isobutylglutaric acid, namely, reacting cyanoacetamide with isovaleric aldehyde in the presence of a catalyst, and then adding concentrated sulfuric acid for reaction to obtain 3-isobutylglutaric acid; (2) reacting 3-isobutylglutaric acid with acetic anhydride to obtain 3-isobutylglutaric anhydride; and (3) reacting 3-isobutylglutaric anhydride with ammonia to produce (+/-)-3-(Carbamoymethyl)-5-methylhexanoic acid. According to the process, the raw materials adopted by the process are available, the operation is simple, the yield of each reaction is higher than 80 percent, the total yield of the target product is high, and the cost is low.
Description
Technical field
The present invention relates to the preparation method of a kind of (±)-3-(carbamyl)-5-methylhexanoic acid.
Background technology
Carbamyl)-the 5-methylhexanoic acid is the important intermediate of lyrica (Pregabalin).In the prior art, a kind of method of preparation R-3-(carbamyl)-5-methylhexanoic acid is that chemistry splits (±)-3-(carbamyl)-5-methylhexanoic acid.Have not yet to see the Chinese patent report about the preparation method of (±)-3-(carbamyl)-5-methylhexanoic acid.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, provides a kind of yield high, and cost is low, is suitable for the preparation method of (±)-3-(carbamyl) of suitability for industrialized production-5-methylhexanoic acid.
For solving above technical problem, the present invention takes following technical scheme:
The preparation method of a kind of (±)-3-(carbamyl)-5-methylhexanoic acid, it comprises the steps:
(1), the preparation of 3-isobutylglutaric acid: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator and voltage stabilizing dropping funnel, add Malonamide nitrile, water, catalyzer (DMF), be cooled to 5 ~ 15 ℃, stir and add isovaleric aldehyde, 5 ~ 15 ℃ of reactions 7 ~ 9 hours, insulation is finished, cooling, drip 98wt% sulfuric acid, interior temperature control is at 30 ~ 50 ℃, and time for adding 2 ~ 3 hours drips, 30 ~ 50 ℃ of insulations 2.5 ~ 3.5 hours, then slowly be warmed up to 70 ~ 80 ℃, insulation reaction is 0.5 ~ 1.5 hour again, then is warmed up to backflow, temperature is at 100 ~ 110 ℃, back flow reaction 2.5 ~ 3.5 hours, then normal pressure steams water to 130 ~ 135 ℃ of interior temperature, stops steaming water, and under this temperature back flow reaction 2.5 ~ 3.5 hours, reaction is cooled to 50 ~ 60 ℃ after finishing, and adds toluene, at 50 ~ 60 ℃, stirred 0.5 ~ 1 hour, static layering, organic layer enters Nong Shrink Fu, decompression steams toluene, treat that temperature reaches 120-130 ℃, toluene steams to the greatest extent, cooling, namely get the 3-isobutylglutaric acid, wherein: Malonamide nitrile, the molar ratio of isovaleric aldehyde and sulfuric acid is 2.05 ~ 3:1:5 ~ 8;
(2), the preparation of 3-isobutyl-valeric anhydride: in the reaction vessel that reflux exchanger, thermometer, agitator are housed, add 3-isobutylglutaric acid and aceticanhydride, temperature rising reflux, kept back flow reaction 2 ~ 4 hours, then steam a part of acetic acid and aceticanhydride, stop after making interior temperature reach 100-120 ℃ the distillation and under 115 ~ 120 ℃, insulation reaction 3 ~ 6 hours, reaction finishes, cooling treats that temperature is down to below 80 ℃, opens vacuum, underpressure distillation gets 3-isobutyl-valeric anhydride, and wherein: the molar ratio of 3-isobutylglutaric acid and aceticanhydride is 1:1.2 ~ 2;
(3); the preparation of (±)-3-(carbamyl)-5-methylhexanoic acid: in the reaction vessel that thermometer and agitator are housed; add solvent methyl tertiary butyl ether and water; open stirring; below 5 ℃, drip 3-isobutyl-valeric anhydride and ammoniacal liquor, temperature is less than 0 ℃ in the control; after dripping off; control temperature-5 ℃ ~ 0 ℃, insulation reaction 3 ~ 6 hours, static layering; it is the hydrochloric acid of 20wt% ~ 30wt% that water layer drips concentration; temperature control is below 10 ℃, reaches 1 ~ 2, discharging to pH; filter; get the thick wet product of (±)-3-(carbamyl)-5-methylhexanoic acid, wherein, the molar ratio of 3-isobutyl-valeric anhydride and ammonia is 1:2 ~ 3.
Further, described method also comprises the step that the thick wet product of (±)-3-(carbamyl)-5-methylhexanoic acid are made with extra care.
According to a concrete aspect, described process for purification is: after the product methylate tertbutyl ether heating for dissolving that will slightly wet, minute water adds decolorizing with activated carbon, filters, and crystallisation by cooling filters, and oven dry gets product.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
The raw material that operational path of the present invention is taked is easy to get, and is simple to operate, and the yield of each step reaction all is higher than 80%, and the target product total recovery is high, and cost is low.
Embodiment
The present invention will be further described in detail below in conjunction with specific embodiment.
The preparation of embodiment 1 3-isobutylglutaric acid
Reflux exchanger is being housed, thermometer, in the four-hole boiling flask of agitator and voltage stabilizing dropping funnel, add Malonamide nitrile 18.5g (0.22mol), water 50g, catalyzer (DMF) 0.5g is cooled to 5 ~ 15 ℃, stirs to add isovaleric aldehyde 8.6g (0.1mol), 5 ~ 15 ℃ of reactions 8 hours, insulation is finished, and cooling drips 98% sulfuric acid 70g (0.7mol), interior temperature control is at 30 ~ 50 ℃, time for adding 2 ~ 3 hours dripped, 30 ~ 50 ℃ of insulations 3 hours, then slowly be warmed up to 70 ~ 80 ℃, insulation reaction is 1 hour again, then is warmed up to backflow, and temperature is at 100 ~ 110 ℃, back flow reaction 3 hours, then normal pressure steams water to 130 ~ 135 ℃ of interior temperature, stops steaming water, and under this temperature back flow reaction 3 hours, after reaction finishes, be cooled to 50 ~ 60 ℃, add toluene 50ml, at 50 ~ 60 ℃, stirred 0.5 ~ 1 hour, static layering, water is abandoned it, enters the three wastes and processes.Organic layer enters Nong Shrink Fu, and decompression steams toluene and treats that temperature reaches 120-130 ℃, and toluene steams and cools off to the greatest extent to get 3-isobutylglutaric acid 19g, HPLC content 90.5%, yield 〉=86%.
The preparation of embodiment 2 3-isobutyl-valeric anhydrides
In the four-hole boiling flask that reflux exchanger, thermometer, agitator are housed, add 3-isobutylglutaric acid pentanedioic acid 37.6g (0.2mol) and aceticanhydride 30.6g (0.3mol), temperature rising reflux kept back flow reaction 3 hours.Then steam a part of acetic acid and aceticanhydride, stop distillation after making interior temperature reach 100 ~ 120 ℃ and at 120 ℃, insulation reaction 4 hours.Reaction finishes, and cooling makes below the temperature to 80 ℃, opens vacuum, begins decompression and steams low boiling, and the beginning underpressure distillation gets 3-isobutyl-valeric anhydride 32g, HPLC content 98.5%, yield 〉=90%.
The preparation of embodiment 3 (±)-3-(carbamyl)-5-methylhexanoic acid
In the four-hole boiling flask that thermometer, agitator are housed, add methyl tertiary butyl ether 25ml and water 50ml, open and be stirred in below 5 ℃ 3-isobutyl-valeric anhydride 17g (0.1mol) and ammoniacal liquor 22g(0.25mol that dropping prepares according to embodiment 2 methods), temperature is less than 0 ℃, after dripping off, pH=9, then control is-5 ~ 0 ℃, insulation reaction 4 hours, pH is constant, static 0.5 hour, layering, water layer adds water 50ml, drip 30wt% hydrochloric acid, temperature is controlled less than 10 ℃, pH=1 ~ 2, discharging, filter, get slightly wet product 28g.These slightly wet product are made with extra care; method is as follows: after slightly wet product add 280g methyl tertiary butyl ether heating for dissolving with 28g; divide water; add the 3g decolorizing with activated carbon, filter crystallisation by cooling; filter; oven dry namely obtains (±)-3-(carbamyl)-5-methylhexanoic acid finished product 15g, HPLC content 99.8%, yield: 〉=80%.
Above-described embodiment only is explanation technical conceive of the present invention and characteristics; its purpose is to allow the personage who is familiar with technique can understand content of the present invention and according to this enforcement; can not limit protection scope of the present invention with this; all equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (3)
1. the preparation method of one kind (±)-3-(carbamyl)-5-methylhexanoic acid is characterized in that: comprise the steps:
(1), the preparation of 3-isobutylglutaric acid: reflux exchanger is being housed, thermometer, in the reaction vessel of agitator and voltage stabilizing dropping funnel, add Malonamide nitrile, water, catalyzer (DMF), be cooled to 5 ~ 15 ℃, stir and add isovaleric aldehyde, 5 ~ 15 ℃ of reactions 7 ~ 9 hours, insulation is finished, cooling, drip 98wt% sulfuric acid, interior temperature control is at 30 ~ 50 ℃, and time for adding 2 ~ 3 hours drips, 30 ~ 50 ℃ of insulations 2.5 ~ 3.5 hours, then slowly be warmed up to 70 ~ 80 ℃, insulation reaction is 0.5 ~ 1.5 hour again, then is warmed up to backflow, temperature is at 100 ~ 110 ℃, back flow reaction 2.5 ~ 3.5 hours, then normal pressure steams water to 130 ~ 135 ℃ of interior temperature, stops steaming water, and under this temperature back flow reaction 2.5 ~ 3.5 hours, reaction is cooled to 50 ~ 60 ℃ after finishing, and adds toluene, at 50 ~ 60 ℃, stirred 0.5 ~ 1 hour, static layering, organic layer enters Nong Shrink Fu, decompression steams toluene, treat that temperature reaches 120-130 ℃, toluene steams to the greatest extent, cooling, namely get the 3-isobutylglutaric acid, wherein: Malonamide nitrile, the molar ratio of isovaleric aldehyde and sulfuric acid is 2.05 ~ 3:1:5 ~ 8;
(2), the preparation of 3-isobutyl-valeric anhydride: in the reaction vessel that reflux exchanger, thermometer, agitator are housed, add 3-isobutylglutaric acid and aceticanhydride, temperature rising reflux, kept back flow reaction 2 ~ 4 hours, then steam a part of acetic acid and aceticanhydride, stop after making interior temperature reach 100-120 ℃ the distillation and under 115 ~ 120 ℃, insulation reaction 3 ~ 6 hours, reaction finishes, cooling treats that temperature is down to below 80 ℃, opens vacuum, underpressure distillation gets 3-isobutyl-valeric anhydride, and wherein: the molar ratio of 3-isobutylglutaric acid and aceticanhydride is 1:1.2 ~ 2;
(3); the preparation of (±)-3-(carbamyl)-5-methylhexanoic acid: in the reaction vessel that thermometer and agitator are housed; add solvent methyl tertiary butyl ether and water; open stirring; below 5 ℃, drip 3-isobutyl-valeric anhydride and ammoniacal liquor, temperature is less than 0 ℃ in the control; after dripping off; control temperature-5 ℃ ~ 0 ℃, insulation reaction 3 ~ 6 hours, static layering; it is the hydrochloric acid of 20wt% ~ 30wt% that water layer drips concentration; temperature control is below 10 ℃, reaches 1 ~ 2, discharging to pH; filter; get the thick wet product of (±)-3-(carbamyl)-5-methylhexanoic acid, wherein, the molar ratio of 3-isobutyl-valeric anhydride and ammonia is 1:2 ~ 3.
2. the preparation method of (±) according to claim 1-3-(carbamyl)-5-methylhexanoic acid is characterized in that: described method also comprises the step that the thick wet product of (±)-3-(carbamyl)-5-methylhexanoic acid are made with extra care.
3. the preparation method of (±) according to claim 2-3-(carbamyl)-5-methylhexanoic acid; it is characterized in that: described process for purification is: after the product methylate tertbutyl ether heating for dissolving that will slightly wet; divide water; add decolorizing with activated carbon; filter; crystallisation by cooling filters, and oven dry gets product.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175276A (en) * | 2015-07-25 | 2015-12-23 | 安徽东凯生物科技有限公司 | Synthetic method for optically pure(R)-3-carbamyl methyl-5-methyl caproic acid |
| CN105348123A (en) * | 2015-11-26 | 2016-02-24 | 太仓运通生物化工有限公司 | Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate |
| CN108912082A (en) * | 2018-07-23 | 2018-11-30 | 湖北宇阳药业有限公司 | A kind of preparation method of pregabalin intermediate |
| CN108912004A (en) * | 2018-08-01 | 2018-11-30 | 宏冠生物药业有限公司 | A kind of synthetic method of pregabalin intermediate |
| CN115536524A (en) * | 2022-09-20 | 2022-12-30 | 常州大学 | Preparation method of 3-isobutyl glutaric acid |
| CN116143743A (en) * | 2023-01-08 | 2023-05-23 | 太仓市茜泾化工有限公司 | Preparation process and preparation device of 3-isobutyl glutaric anhydride |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105175276A (en) * | 2015-07-25 | 2015-12-23 | 安徽东凯生物科技有限公司 | Synthetic method for optically pure(R)-3-carbamyl methyl-5-methyl caproic acid |
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| CN108912082A (en) * | 2018-07-23 | 2018-11-30 | 湖北宇阳药业有限公司 | A kind of preparation method of pregabalin intermediate |
| CN108912004A (en) * | 2018-08-01 | 2018-11-30 | 宏冠生物药业有限公司 | A kind of synthetic method of pregabalin intermediate |
| CN108912004B (en) * | 2018-08-01 | 2021-05-07 | 宏冠生物药业有限公司 | Synthetic method of pregabalin intermediate |
| CN115536524A (en) * | 2022-09-20 | 2022-12-30 | 常州大学 | Preparation method of 3-isobutyl glutaric acid |
| CN115536524B (en) * | 2022-09-20 | 2024-05-28 | 常州大学 | A kind of preparation method of 3-isobutylglutaric acid |
| CN116143743A (en) * | 2023-01-08 | 2023-05-23 | 太仓市茜泾化工有限公司 | Preparation process and preparation device of 3-isobutyl glutaric anhydride |
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