CN105085290A - Method for synthesizing pregabalin - Google Patents
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Abstract
The invention discloses a synthesis method of pregabalin. The synthesis method comprises the following steps: carrying out addition elimination reaction on isovaleraldehyde and diethyl malonate in a solvent composed of DMSO (dimethyl sulfoxide) and carbon tetrachloride by using vanadium tetrachloride as a catalyst; carrying out Michael addition on the product obtained in the first step in an alkaline alcohol solvent; carrying out hydrogenation reaction on the product obtained in the second step with hydrogen gas by using a carbon-supported Pd catalyst; carrying out hydrolysis reaction on the product obtained in the third step in hydrochloric acid; and carrying out chiral resolution on the product obtained in the fourth step in an alcohol-water mixed solvent by using L-malic acid as a resolving agent. The cheap and accessible isovaleraldehyde used as the raw material is subjected to addition elimination, Michael addition, hydrogenation reaction, hydrolysis and chiral resolution to obtain the pregabalin. The method has the advantages of simple reaction route and higher yield of each step, thereby ensuring the total yield and purity of the final pregabalin.
Description
Technical field
The present invention relates to the technical field of lyrica, particularly relate to a kind of method of synthesizing lyrica.
Background technology
Lyrica (Pregbalin), chemical name is (S)-3-aminomethyl one 5 monomethyl caproic acid, is that Pfizer company grinds
Novel Y mono-aminobutyric acid (GABA) receptor antagonist sent out.In July, 2004 goes on the market with trade(brand)name Lyrica through European Union's approval first, is used for the treatment of the insane carbuncle outbreak of part of adult patients.In June, 2005 goes on the market in the U.S. through FDA Food and Drug Administration (FDA) approval.In March, 2006, add new indication, be used for the treatment of generalized anxiety disorder and sociability anxiety disorder, within 2009, get permission again to be used for the treatment of Spinal injury, wound, multiple sclerosis, diabetic neuropathy pain and indomethacin neuralgia, make it clinical
Application is further expanded, and becomes one of global best-selling drugs.Its structure is as shown in Equation 1:
Chinese patent CN101555240A discloses a kind of preparation method of lyrica, after the method adopts heteroge-neous catalyst hydrogenation 3-cyano group-5-methyl-oneself-3-olefin(e) acid ethyl ester prepares 3-amino methyl 1 monomethyl acetic acid, split by (S)-amygdalic acid again, obtain (S)-lyrica.The raw material sources that the method adopts are more difficult, and lyrica total recovery is not high, and the purity of product is lower.
Summary of the invention
In view of this, the invention provides a kind of synthetic method of lyrica, the higher and yield of the purity of the refined product obtained through this synthetic method.
A purification process for lyrica, comprises the following steps:
1) be catalyzer by isovaleric aldehyde and diethyl malonate with vanadium tetrachloride, in the solvent be made up of DMSO and tetracol phenixin, carry out addition elimination reaction in 5 ~ 10 DEG C, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester (compd A), reaction formula is as follows
(2) described 2-propyloic-5-methyl-2-hexenoic acid ethyl ester is carried out Michael addition with cyanic acid in the alcoholic solvent of alkali, obtain 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester (compd B), reaction formula is as follows,
(3) described ester is carried out hydrogenation reaction with carbon load P d for catalyzer with hydrogen, obtain 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim (Compound C), reaction formula is as follows,
(4) be hydrolyzed described 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim reaction in acid condition, and obtain oneself racemic modification (Compound D) of 3-(aminomethyl)-5-methyl, reaction formula is as follows,
(5) racemic modification of described 3-(aminomethyl)-5-methylhexanoic acid take L MALIC ACID as resolving agent, in the mixed solvent of alcohol and water, carries out chiral separation, and obtain lyrica (compd E), reaction formula is as follows,
As addition elimination reaction step of the present invention, the course of its reaction is that first the methylene radical of diethyl malonate is seized hydrogen ion by vanadium tetrachloride, produces the carbanion of methylene radical.By the carbonyl of this carbanion as nucleophilic reagent attack isovaleric aldehyde, thus complete the course of addition; Second step, the hydrogen generation elimination reaction on the hydroxyl on adduct and ortho position carbon.Due to the carbon atom adjacent with hydroxyl, one is be positioned on the ortho position of carbonyl carbon, and another is positioned at the methylene radical on diethyl malonate, and in the elimination reaction stage, there is the product that two kinds are selected cancellation, thus this reaction exists certain byproduct.In the present invention, use vanadium tetrachloride as catalyzer, can greatly improve elimination reaction course obtain with the selectivity of the methylene product hydrogen elimination products on diethyl malonate, ensure that the yield of this step reaction.Preferably, the consumption of vanadium tetrachloride is 0.8 ~ 4%, is 100 calculating with the total mass of ring ethyl ketone and diethyl malonate.
The present invention is compared to out concrete restriction not to the amount (mole number) of isovaleric aldehyde and diethyl malonate.In order to improve the yield of this step reaction, diethyl malonate can be made excessive a little, both amounts can 1:1.05 ~ 1.14, preferably 1:08.Be advisable with 6 ~ 12h in this temperature of reaction basis lower reaction times, be less than this reaction times, then the corresponding decline of the yield of this step, but this reaction times unnecessary, and can not yield be improved.In the present invention, the mixed solvent of DMSO and tetracol phenixin, as aprotic solvent, weakens the hydrogen ion of the methylene radical on diethyl malonate and the binding ability of carbon atom, and hydrogen atom can be sloughed smoothly.
As Michael reaction of the present invention, the principle of its reaction, by those skilled in the art are understood, does not repeat them here.Michael reaction temperature of the present invention such as can be 20 ~ 35 DEG C, on the basis of this temperature, the reaction times can be chosen as 2 ~ 4h.The consumption of cyanic acid in theory with the substrate of addition etc. mole, but cyanic acid is as nucleophilic reagent, based on the yield that this step is reacted, cyanic acid can be made excessive a little, and both amount can 1.02 ~ 1.08, are preferably 1:1.05.As for, the place alcoholic solvent of this step reaction, with C
1~ C
4alcohol, such as ethanol, Virahol, methyl alcohol etc.As for alkali, mineral alkali can be adopted, such as sodium hydroxide, potassium hydroxide etc.
Aforementioned, hydrogenation reaction, refers to that hydrogen and double bond generation addition obtain saturated carbon carbon single bond.This hydrogenation reaction comprises two sub-step of reaction: the first stage, and cyano group hydrogenation generates methylamino-; Subordinate phase, there is intramolecular dehydration reaction in methylamino-and a group-4 ethyl formate, generates the five membered lactams rings with rock steady structure.In the present invention, adopt Pd as catalyzer, Pd has stronger catalytic activity, can significantly improve the catalytic conversion of hydrogenation reaction.The consumption of Pd is advisable with 4 ~ 8%, in the quality of 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester for 100%.Preferably, the temperature of hydrogenation reaction is 90 ~ 120 DEG C.Correspondingly, the pressure of reaction is 10 ~ 16bar (1bar is 100Kpa).The flow of hydrogen does not limit, and can adopt the hydroxyl flow that this area shortening is conventional, or makes conventional selection according to actual.
As hydrolysis reaction of the present invention, comprise two son reactions of open loop depickling and salify.Open loop depickling, its reaction mechanism is that first the lactan five-ring of 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim is hydrolyzed and open loop, obtains intermediate that is amino and carboxyl.Then this carboxy intermediate sloughs the carboxyl on middle-COOEt.Ring-opening reaction is reversible reaction, particularly under the prerequisite of being heated, reacts towards counter movement.Thus, the temperature of reaction should at low temperature, such as 15 ~ 30 DEG C; Correspondingly, the time 0.5 ~ 1h of reaction.In the son reaction of open loop depickling, hydrochloric acid is only as providing hydrionic acid catalyst; In salt-forming stage, it forms salt as reactant with amino.In order to ensure the transformation efficiency of open loop depickling reaction, the amount of acid is preferred mode with excessive.Such as, the amount of hydrochloric acid with 1.01 ~ 1.1, in the amount of 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim be 1 for.Concrete restriction is not done in acid, such as, can be hydrochloric acid, sulfuric acid, nitric acid etc.
As chiral separation of the present invention, preferably, chiral separation specifically comprises: be dissolved in resolution solvent at 30 ~ 40 DEG C by the racemic modification of L MALIC ACID and 3-(aminomethyl)-5-methylhexanoic acid, then at 0 ~ 5 DEG C crystallization, obtain lyrica salt.Herein, the amount of resolving agent is 0.6 ~ 0.8, is 1 calculating with the amount of racemic modification.Resolution solvent can be adopted after crystallization to wash.What deserves to be explained is, chiral separation can operate repeatedly, based on improving the purity split.
The present invention for raw material, through addition cancellation, Michael addition, hydrogenation reaction, hydrolysis and chiral separation, obtains lyrica with isovaleric aldehyde that is inexpensive, that be easy to get.This reaction scheme is simple, and its yield often walking reaction is all higher, ensure that total recovery and the purity of final lyrica thus.
Embodiment
Technical scheme of the present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
In reaction vessel, insert isovaleric aldehyde, the vanadium tetrachloride (in the total mass of isovaleric aldehyde and diethyl malonate for 100%) of 0.8%, the DMSO of 2 volumes and tetracol phenixin mixed solvent (in the volume of cyclohexanone for 1), this mixture is cooled to-5 DEG C.Add the diethyl malonate (in the amount of isovaleric aldehyde for 1) of 1.05 amounts again, constant temperature to 5 DEG C, make it under constantly stirring to react 12h, filter, distillation, ether is washed, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester, by this called after compd A.
In the reactor of high pressure, insert above-claimed cpd A, quality be 3 ethanol (in the quality of compd A for 1), regulate temperature to 20 DEG C, slowly instill amount be 1.02 HCN (in the amount of compd A for 1).After question response 4h, be cooled to 10 DEG C and filter out solid.By solid washing twice, adopt methyl alcohol: water is that the mixed solution of 3:2 carries out recrystallization, obtains 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester, by this called after compd B.
In withstand voltage reactor, insert above-claimed cpd B, quality be 4% with carbon Pt-supported catalyst (in the quality of compd B for 100%), the pressure regulating pressurizing device is 9bar, temperature, for being 80 DEG C, first passing into nitrogen and removes oxygen, then pass into hydrogen and react.The time of question response is after 18h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim, by this called after Compound C.
Insert in reaction vessel above-claimed cpd C under cooled conditions admixture quality be the hydrochloric acid dilute hydrochloric acid of 1, regulate the temperature to 15 DEG C of mixed solution, stir and make it hydrolysis reaction.The time of question response is after 1h, stopped reaction.Filter out solid, by washing with alcohol, obtain oneself racemic modification of 3-(aminomethyl)-5-methyl, by this called after material D.
The L MALIC ACID (be 1 calculating with the amount of material D) that above-mentioned substance D and amount are 0.6 is inserted in reaction vessel, 1h is stirred at 50 DEG C, make it to be dissolved in the solvent of second alcohol and water, crystallization 2h at 0 DEG C again, suction filtration goes out crystallization, repeat this operation 3 to 5 times, obtain lyrica salt.In this example, total recovery is 33.2%, and recording its purity through HPLC is 97.0%.
Embodiment 2
In reaction vessel, insert isovaleric aldehyde, the vanadium tetrachloride (in the total mass of isovaleric aldehyde and diethyl malonate for 100%) of 4%, the DMSO of 10 volumes and tetracol phenixin mixed solvent (in the volume of isovaleric aldehyde for 1), this mixture is cooled to 10 DEG C.Add the diethyl malonate (in the amount of isovaleric aldehyde for 1) of 1.14 amounts again, constant temperature to 10 DEG C, make it under constantly stirring to react 6h, filter, distillation, ether is washed, obtain 1,1-cyclohexyl allenolic acid diethyl ester, by this called after compd A.
In the reactor of high pressure, insert above-claimed cpd A, quality be 10 methyl alcohol (in the quality of compd A for 1), regulate temperature to 35 DEG C, slowly instill amount be 1.08 HCN (in the amount of compd A for 1).After question response 2h, be cooled to 10 DEG C and filter out solid.By solid washing twice, adopt methyl alcohol: water is that the mixed solution of 3:2 carries out recrystallization, obtains 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester, by this called after compd B.
In withstand voltage reactor, insert above-claimed cpd B, quality be 8% with carbon Pt-supported catalyst (in the quality of compd B for 100%), the pressure regulating pressurizing device is 16bar, temperature, for being 120 DEG C, first passing into nitrogen and removes oxygen, then pass into hydrogen and react.The time of question response is after 10h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim, by this called after Compound C.
Insert in reaction vessel above-claimed cpd C under cooled conditions admixture quality be the hydrochloric acid dilute hydrochloric acid of 2, regulate the temperature to 30 DEG C of mixed solution, stir and make it hydrolysis reaction.The time of question response is after 0.5h, stopped reaction.Filter out solid, by washing with alcohol, obtain oneself racemic modification of 3-(aminomethyl)-5-methyl, by this called after Compound D.
The L MALIC ACID (be 1 calculating with the amount of material D) that above-mentioned substance D and amount are 0.6 is being inserted in reaction vessel, 1h is stirred at 50 DEG C, make it to be dissolved in the solvent of second alcohol and water, crystallization 2h at 0 DEG C again, suction filtration goes out crystallization, repeat this operation 3 to 5 times, obtain lyrica salt.In this example, total recovery is 34.6%, and recording its purity through HPLC is 97.4%.
Embodiment 3
In reaction vessel, insert isovaleric aldehyde, the vanadium tetrachloride (in the total mass of isovaleric aldehyde and diethyl malonate for 100%) of 2.4%, the DMSO of 6 volumes and tetracol phenixin mixed solvent (in the volume of isovaleric aldehyde for 1), this mixture is cooled to 7 DEG C.Add the diethyl malonate (in the amount of isovaleric aldehyde for 1) of 1.095 amounts again, constant temperature to 7 DEG C, make it under constantly stirring to react 9h, filter, distillation, ether is washed, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester, by this called after compd A.
In the reactor of high pressure, insert above-claimed cpd A, quality be 6 ethanol (in the quality of compd A for 1), regulate temperature to 28 DEG C, slowly instill amount be 1.06 HCN (in the amount of compd A for 1).After question response 3h, be cooled to 10 DEG C and filter out solid.By solid washing twice, adopt methyl alcohol: water is that the mixed solution of 3:2 carries out recrystallization, obtains 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester, by this called after compd B.
In withstand voltage reactor, insert above-claimed cpd B, quality be 6% with carbon Pt-supported catalyst (in the quality of compd B for 100%), the pressure regulating pressurizing device is 13bar, temperature, for being 105 DEG C, first passing into nitrogen and removes oxygen, then pass into hydrogen and react.The time of question response is after 14h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim, by this called after Compound C.
Insert in reaction vessel above-claimed cpd C under cooled conditions admixture quality be the hydrochloric acid dilute hydrochloric acid of 1.5, regulate the temperature to 23 DEG C of mixed solution, stir and make it hydrolysis reaction.The time of question response is after 25min, stopped reaction.Filter out solid, by washing with alcohol, obtain oneself racemic modification of 3-(aminomethyl)-5-methyl, by this called after Compound D.
The L MALIC ACID (be 1 calculating with the amount of material D) that above-mentioned substance D and amount are 0.6 is inserted in reaction vessel, 1h is stirred at 50 DEG C, make it to be dissolved in the solvent of second alcohol and water, crystallization 2h at 0 DEG C again, suction filtration goes out crystallization, repeat this operation 3 to 5 times, obtain lyrica salt.In this example, total recovery is 35.8%, and recording its purity through HPLC is 97.9%.
Embodiment 4
Insert in reaction vessel isovaleric aldehyde, 2% vanadium tetrachloride (in the total mass of isovaleric aldehyde and diethyl malonate for 100%), the DMSO of 2 ~ 10 volumes and the mixed solvent (in the volume of isovaleric aldehyde for 1) of tetracol phenixin, this mixture is cooled to-5 ~ 5 DEG C.Add the diethyl malonate (in the amount of isovaleric aldehyde for 1) of 1.10 amounts again, constant temperature to 0 DEG C, make it under constantly stirring to react 12h, filter, distillation, ether is washed, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester, by this called after compd A.
In the reactor of high pressure, insert above-claimed cpd A, quality be 3 ~ 10 ethanol (in the quality of compd A for 1), regulate temperature to 28 DEG C, slowly instill amount be 1.06 HCN (in the amount of compd A for 1).After question response 4h, be cooled to 10 DEG C and filter out solid.By solid washing twice, adopt methyl alcohol: water is that the mixed solution of 3:2 carries out recrystallization, obtains 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester, by this called after compd B.
In withstand voltage reactor, insert above-claimed cpd B, quality be 6% with carbon Pt-supported catalyst (in the quality of compd B for 100%), the pressure regulating pressurizing device is 12bar, temperature, for being 100 DEG C, first passing into nitrogen and removes oxygen, then pass into hydrogen and react.The time of question response is after 18h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim, by this called after Compound C.
Insert in reaction vessel above-claimed cpd C under cooled conditions admixture quality be the hydrochloric acid dilute hydrochloric acid of 1.5, regulate the temperature to 23 DEG C of mixed solution, stir and make it hydrolysis reaction.The time of question response is after 1h, stopped reaction.Filter out solid, by washing with alcohol, obtain oneself racemic modification of 3-(aminomethyl)-5-methyl, by this called after Compound D.
The L MALIC ACID (be 1 calculating with the amount of material D) that above-mentioned substance D and amount are 0.6 is inserted in reaction vessel, 1h is stirred at 50 DEG C, make it to be dissolved in the solvent of second alcohol and water, crystallization 2h at 0 DEG C again, suction filtration goes out crystallization, repeat this operation 3 to 5 times, obtain lyrica salt.In this example, total recovery is 35.3%, and recording its purity through HPLC is 97.7%.
Embodiment 5
Insert in reaction vessel isovaleric aldehyde, 2% vanadium tetrachloride (in the total mass of cyclohexanone and diethyl malonate for 100%), the DMSO of 5 volumes and the mixed solvent (in the volume of cyclohexanone for 1) of tetracol phenixin, this mixture is cooled to-5 ~ 5 DEG C.Add the diethyl malonate (in the amount of cyclohexanone for 1) of 1.08 amounts again, constant temperature to 0 DEG C, make it under constantly stirring to react 9h, filter, distillation, ether is washed, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester, by this called after compd A.
In the reactor of high pressure, insert above-claimed cpd A, quality be 5 ethanol (in the quality of compd A for 1), regulate temperature to 25 DEG C, slowly instill amount be 1.06 HCN (in the amount of compd A for 1).After question response 3h, be cooled to 10 DEG C and filter out solid.By solid washing twice, adopt methyl alcohol: water is that the mixed solution of 3:2 carries out recrystallization, obtains 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester, by this called after compd B.
In withstand voltage reactor, insert above-claimed cpd B, quality be 5% with carbon Pt-supported catalyst (in the quality of compd B for 100%), the pressure regulating pressurizing device is 12bar, temperature, for being 100 DEG C, first passing into nitrogen and removes oxygen, then pass into hydrogen and react.The time of question response is after 15h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim, by this called after Compound C.
Insert in reaction vessel above-claimed cpd C under cooled conditions admixture quality be the hydrochloric acid dilute hydrochloric acid of 1.3, regulate the temperature to 25 DEG C of mixed solution, stir and make it hydrolysis reaction.The time of question response is after 40min, stopped reaction.Filter out solid, by washing with alcohol, obtain oneself racemic modification of 3-(aminomethyl)-5-methyl, by this called after Compound D.
The L MALIC ACID (be 1 calculating with the amount of material D) that above-mentioned substance D and amount are 0.6 is inserted in reaction vessel, 1h is stirred at 50 DEG C, make it to be dissolved in the solvent of second alcohol and water, crystallization 2h at 0 DEG C again, suction filtration goes out crystallization, repeat this operation 3 to 5 times, obtain lyrica salt.In this example, total recovery is 36.3%, and recording its purity through HPLC is 98.2%.
Because the numerical range of each processing parameter involved in the present invention can not all embody in the above-described embodiments, as long as but those skilled in the art can imagine any numerical value fallen in this numerical range above-mentioned completely all can implement the present invention, certainly also comprise the arbitrary combination of occurrence in some numerical ranges.Herein, for the consideration of length, eliminate the embodiment providing occurrence in certain one or more numerical range, this should not be considered as the insufficient disclosure of technical scheme of the present invention.
Applicant states, the present invention illustrates detailed process equipment and process flow process of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned detailed process equipment and process flow process, namely do not mean that the present invention must rely on above-mentioned detailed process equipment and process flow process and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of ancillary component, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (7)
1. a synthetic method for lyrica, is characterized in that, comprises the following steps:
(1) be catalyzer by isovaleric aldehyde and diethyl malonate with vanadium tetrachloride, in the solvent be made up of DMSO and tetracol phenixin, carry out addition elimination reaction in 5 ~ 10 DEG C, obtain 2-propyloic-5-methyl-2-hexenoic acid ethyl ester (compd A), reaction formula is as follows
(2) described 2-propyloic-5-methyl-2-hexenoic acid ethyl ester is carried out Michael addition with cyanic acid in the alcoholic solvent of alkali, obtain 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester (compd B), reaction formula is as follows,
(3) described ester is carried out hydrogenation reaction with carbon load P d for catalyzer with hydrogen, obtain 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim (Compound C), reaction formula is as follows,
(4) be hydrolyzed described 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim reaction in acid condition, and obtain oneself racemic modification (material D) of 3-(aminomethyl)-5-methyl, reaction formula is as follows,
(5) racemic modification of described 3-(aminomethyl)-5-methylhexanoic acid take L MALIC ACID as resolving agent, in the mixed solvent of alcohol and water, carries out chiral separation, and obtain lyrica (compd E), reaction formula is as follows,
2. synthetic method according to claim 1, is characterized in that, in step (1):
The ratio of the amount of described ring ethyl ketone and diethyl malonate is 1:1.05 ~ 1.14;
Preferably, the temperature of described addition cancellation is the reaction times is 6 ~ 12h;
Preferably, the consumption of described vanadium tetrachloride is 0.8 ~ 4%, is 100 calculating with the total mass of ring ethyl ketone and diethyl malonate.
3. synthetic method according to claim 1, is characterized in that, in step (2):
The temperature of described Michael reaction is 20 ~ 35 DEG C, and the time of reaction is 2 ~ 4h.
Preferably, the consumption of described cyanic acid is 1.02 ~ 1.08, is 1 calculating with the amount of 1,1-cyclohexyl allenolic acid diethyl ester;
Preferably, described alcoholic solvent is C
1~ C
4alcohol.
4. synthetic method according to claim 1, is characterized in that, in step (3):
The temperature of described hydrogenation reaction is 90 ~ 120 DEG C, and the time pressure of reaction is 10 ~ 16bar;
Preferably, the consumption of described Pd is 4 ~ 8%, in the quality of 2-propyloic-3-cyano group-5-methylhexanoic acid ethyl ester for 100%.
5. synthetic method according to claim 1, is characterized in that, in step (4):
The temperature of described hydrolysis reaction is 15 ~ 30 DEG C, and the time of hydrolysis reaction is 0.5 ~ 1h;
Preferably, the amount of described acid is 1.01 ~ 1.1, is 1 calculating with the amount of 4-isobutyl--3-formyl oxyethyl group-2-carbonyl-ring Valerolactim.
6. synthetic method according to claim 1, it is characterized in that, described in step (5), chiral separation is specially: be dissolved in resolution solvent by the racemic modification of L MALIC ACID and 3-(aminomethyl)-5-methylhexanoic acid at 30 ~ 40 DEG C, crystallization at 0 ~ 5 DEG C, obtains lyrica salt again.
7. synthetic method according to claim 1, is characterized in that, the amount of described resolving agent is 0.6 ~ 0.8, is 1 calculating with the amount of racemic modification.
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| CN105348124A (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 oxopyrrolidine as intermediate |
| CN105463037A (en) * | 2015-11-26 | 2016-04-06 | 太仓运通生物化工有限公司 | Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate |
| CN108997128A (en) * | 2018-08-03 | 2018-12-14 | 浙江工业大学 | A kind of preparation method of pregabalin intermediate 3- nitre methyl -5- methylhexanoic acid ethyl ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105463037A (en) * | 2015-11-26 | 2016-04-06 | 太仓运通生物化工有限公司 | Method for synthesizing pregabalin with isobutyl butanedinitrile as intermediate |
| CN108997128A (en) * | 2018-08-03 | 2018-12-14 | 浙江工业大学 | A kind of preparation method of pregabalin intermediate 3- nitre methyl -5- methylhexanoic acid ethyl ester |
| CN108997128B (en) * | 2018-08-03 | 2021-02-02 | 浙江工业大学 | Preparation method of pregabalin intermediate 3-nitromethyl-5-ethyl methylhexanoate |
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