CN105348123A - Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate - Google Patents
Method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as intermediate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
Abstract
The invention discloses a method for synthesizing Pregabalin by taking gamma-isobutylglutaric anhydride as an intermediate. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and methyl cyanoacetate in an ethanol solvent by taking piperidine as a catalyst; carrying out Michael addition on the condensation product and diethyl malonate in a n-hexane solvent by taking di-n-propylamine as a catalyst; carrying out hydrolyzing decarboxylation on the addition product under the catalysis of strong acid and under the condition of heating; dehydrating the hydrolyzing decarboxylation product in a THF solvent under the catalysis of phosphorus pentoxide and under the condition of heating; enabling the dehydrated hydrolyzing decarboxylation product to subject to ammonolysis reaction with urea; carrying out Hoffman degradation on the ammonolysis reaction product; and finally, carrying out chiral resolution on the Hoffman degradation product by taking (S)-(+)-mandelic acid as a resolving agent. According to the method, isovaleraldehyde and methyl cyanoacetate, which are cheap and are readily available, serve as raw materials and are subjected to Knoevenagel condensation, Michael addition, acid hydrolyzing decarboxylation and dehydrating, so as to obtain the intermediate gamma-isobutylglutaric anhydride; and the gamma-isobutylglutaric anhydride is subjected to ammonolysis, Hoffman degradation and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.
Description
Technical field
The present invention relates to the technical field of lyrica, particularly relate to the method that a kind of γ-isobutylglutaric acid acid anhydride is intermediate synthesis lyrica.
Background technology
Lyrica (Pregbalin), chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is novel γ-aminobutyric acid (GABA) receptor antagonist of Pfizer company research and development.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, its clinical application is further expanded, 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 with the method for γ-isobutylglutaric acid acid anhydride for intermediate synthesis lyrica, the higher and yield of the purity of the refined product obtained through the method.
With the method for γ-isobutylglutaric acid acid anhydride for intermediate synthesis lyrica, comprise the following steps:
(1) be that catalyzer in alcohol solvent in carry out Knoevenagel condensation with methyl cyanoacetate with piperidines by isovaleric aldehyde, obtain 2-cyano group-5-methylhexanoic acid methyl esters (substance A), reaction formula is as follows,
(2) be that catalyzer in normal hexane solvent in carry out Michael addition with diethyl malonate with di-n-propylamine by substance A, obtain 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate (substance B), reaction formula is as follows,
(3) be hydrolyzed substance B under strong acid catalyst decarboxylation in a heated condition, and obtain 5-methyl-3-propyloic caproic acid (substance C), reaction formula is as follows,
(4) dewatered in a heated condition in THF solvent under Vanadium Pentoxide in FLAKES catalysis by substance C, obtain γ-isobutylglutaric acid acid anhydride (material G), reaction formula is as follows,
(5) material G is carried out ammonolysis reaction with urea, obtain the different imide of 3-isobutyl-(material D), reaction formula is as follows,
(6) material D is carried out Hoffman degraded, obtain the racemic modification (material E) of 3-(aminomethyl)-5-methylhexanoic acid, reaction formula is as follows,
(7) be that resolving agent carries out chiral separation by material E with (S)-(+)-amygdalic acid, obtain lyrica (compound F 17-hydroxy-corticosterone), reaction formula is as follows,
As step of the present invention (1), catalyzer piperidines is as a kind of weak base, and the hydrogen ion on the carbon atom that it can be adjacent with the cyano group of methyl cyanoacetate is combined to produce carbanion.Piperidines is as a kind of weak base catalyst, and its reaction conditions is comparatively gentle.The amount of piperidines is 1.5 ~ 2, in the amount of isovaleric aldehyde for 1.Be not particularly limited to the consumption of solvent, the consumption of solvent affects without obvious yield etc.Ethanol contend can be 10 ~ 30ml, in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g.
In Knoevenagel condensation of the present invention, be compared to out concrete restriction not to the amount (mole number) of isovaleric aldehyde and vinyl cyanide.In order to improve the yield of this step reaction, methyl cyanoacetate can be made excessive a little, both amounts can 1:1.05 ~ 1.14, preferably 1:08.The temperature of reaction is advisable with 50 ~ 60 DEG C, is advisable, is less than this reaction times, then the corresponding decline of the yield of this step in this temperature of reaction basis lower reaction times with 4 ~ 8h, but this reaction times unnecessary, and can not yield be improved.
As step of the present invention (2), those skilled in the art knows, in the reaction mechanism of Michael addition, the mesomethylene carbon negative ion of diethyl malonate mainly selects the β position carbon atom (namely to connect the ortho position carbon atom of electron-withdrawing group-CN ,-COOMe carbon potential) being replaced in carbon-carbon double bond.However, in order to the mesomethylene carbon negative ion reducing diethyl malonate is replaced in the α position carbon atom of carbon-carbon double bond and produced by product thus, elite from di-n-propylamine as catalyzer with select normal hexane as solvent.
The temperature of Michael addition is preferably 20 ~ 35 DEG C, and the time of reaction is 2 ~ 4h.The amount of diethyl malonate is 1.02 ~ 1.08, and the amount of di-n-propylamine is 1.5 ~ 2, and both are all 1 calculating with the amount of substance A here.The volume of normal hexane is 30 ~ 60ml, in the total mass of substance A and diethyl malonate for 1g.
As step of the present invention (3), hydrolysis decarboxylation reaction in fact includes the cyano group of first substance B and carboxylate methyl ester, carboxyethyl are hydrolyzed under strong acid catalyst
subsequently, this intermediate is because of containing a propanedioic acid similar structures carbon (namely connect two carboxyls), and very unstable, be heated decarboxylize.Thoroughly generate carboxylic acid to make cyan-hydrolysis and decarboxylation is easily carried out, the temperature that the present invention selects hydrolysis decarboxylation to react is 90 ~ 110 DEG C.Lower than this temperature, cyan-hydrolysis thoroughly generates carboxylic acid and all more difficult generation of decarboxylation; Temperature is too high, easily produces the by product of carboxylic acid anhydride in ring-type.At this temperature, the time of above-mentioned reaction is 6 ~ 10h.
Aforementioned, acid for massfraction be the hydrochloric acid of 30 ~ 37wt%.The amount of acid is 5 ~ 7, in the amount of substance B for 1.React in Glycerol solvents and carry out; The volume ratio of glycerine and water is 10 ~ 20:1.
As step of the present invention (4), Vanadium Pentoxide in FLAKES is reacted by the water produced with substance C intramolecular dehydration and is played the effect of dewatering agent.The present invention is to the consumption that can obtain Vanadium Pentoxide in FLAKES according to chemical reaction metering.In order to obtain the inner-acid anhydride product of higher yields, preferably the amount of Vanadium Pentoxide in FLAKES is 0.4 ~ 2, in the amount of substance C for 1.The temperature of the heating of dehydration reaction is 90 ~ 100 DEG C.Temperature is too high then easily there is intermolecular dehydration side reaction; Temperature is too low, and dehydration reaction is difficult to carry out.Consumption as THF can do conventional adjustment according to actual needs, and such as 5 ~ 10ml, in the quality of substance C for 1g.
As step of the present invention (5), compared to ammoniacal liquor, urea can reduce the temperature required for ammonolysis reaction, thus significantly improves the yield of ammonia solution.The amount of urea is 0.55 ~ 0.60, in the amount of substance C for 1.The temperature of ammonolysis reaction is 30 ~ 40 DEG C, and the time of reaction is 1 ~ 2h.
As step of the present invention (6), reaction conditions, the raw material of Hoffman degraded can refer to known in the art.But the object as yield is considered, the present invention using sodium hydroxide and sodium hypobromite as reactant, and with the amount of material D be the amount of 1 metering sodium bromate for 1.1 ~ 1.4, the amount of sodium hydroxide is 3.5 ~ 4.5.Be understandable that, because sodium hypobromite is more unstable, can adopt sodium hydroxide and the obtained product of bromine reaction when requiring no purifying directly and substrate carry out Hoffman degraded.The temperature of reaction is 65 ~ 75 DEG C, and the time of reaction is 1 ~ 2h.
As step of the present invention (7), chiral separation, concrete operations can be, first can will split substrate racemic modification, (S)-(+)-amygdalic acid, alcoholic solvent (such as Virahol, ethanol etc.) heating for dissolving in water, the temperature herein heated can be 40 ~ 60 DEG C.Then, this solution to be cooled to 0 ~ 5 DEG C with crystallize out, be lyrica.The consumption of aforementioned (S)-(+)-amygdalic acid is 1.5 ~ 2, to split the amount of substrate for 1.
The present invention for raw material, through Knoevenagel condensation, Michael addition, acid hydrolysis decarboxylation, dehydration, obtains intermediate γ-isobutylglutaric acid acid anhydride with isovaleric aldehyde that is inexpensive, that be easy to get and methyl cyanoacetate; Again by γ-isobutylglutaric acid acid anhydride ammonia solution, Hoffman degraded and chiral separation, obtain lyrica.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, amount be 1.5 piperidines (amount of isovaleric aldehyde is 1), 10 ethanol (in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g), by this mixture temperature control to 50 DEG C.Slowly instill the methyl cyanoacetate (in the amount of isovaleric aldehyde for 1) that amount is 1.05 equably again, constant temperature to 50 DEG C, make it under constantly stirring to react 8h, filter, distillation, ether is washed, obtain 2-cyano group-5-methylhexanoic acid methyl esters, by this called after compd A.
In reaction vessel, insert above-mentioned substance A, diethyl malonate (with the quality of substance A for 1) that di-n-propylamine (be 1 calculating in the amount of substance A) that amount is 1.5,30ml normal hexane (in the total mass of substance A and diethyl malonate for 1g), amount are 1.02.Temperature control to 20 DEG C, under return stirring, the time of reaction is 4h.Adopt conventional separation means, isolate 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate, by this called after substance B.
In reaction vessel, insert above-mentioned substance B, volume ratio is the G & W of 10:1.Be heated to temperature control to 90 DEG C, under return stirring, slowly instill the hydrochloric acid (amount of hydrochloric acid is 5, in the amount of substance B for 1) that massfraction is 30wt%, the time of question response is 10h.Adopt conventional separation means, isolate 5-methyl-3-propyloic caproic acid, by this called after substance C.
In reaction vessel, insert above-mentioned substance C, be 1 amount in the amount of substance C be the Vanadium Pentoxide in FLAKES of 0.4, appropriate TFH, temperature control to 90 DEG C question response 5h.Conventional separation means is adopted to isolate γ-isobutylglutaric acid acid anhydride, by this called after G.
In reaction vessel, insert above-mentioned substance G, amount be 0.55 urea (in the amount of substance C for 1).Be heated to 30 DEG C, the time of stirring reaction is 1h.Adopt conventional separation means, isolate the different imide of 3-isobutyl-, by this called after material D.
To insert in the amount of material D in reaction vessel be 1 amount is the sodium hydroxide of 4.5 and appropriate water, makes it to dissolve.Time again by solution ice bath to 0 DEG C, admixture quality is the bromine of 1.1 ~ 1.4, and bromine is fully reacted.Be warming up to again 4 DEG C add material D after, ice bath to 0 DEG C more rapidly, stirs for some time.Then warming-in-water to 65 DEG C, makes it to react 2h, adopts conventional separation means to isolate the racemic modification of 3-(aminomethyl)-5-methylhexanoic acid, by this called after material E.
By above-mentioned E, consumption be 1.5 (S)-(+)-amygdalic acid (to split the amount of substrate for 1), Virahol be heated to 40 DEG C and make to be dissolved in the water.Again this solution to be cooled to 0 DEG C with crystallize out, be lyrica.In this example, total recovery is 23.2%, and recording its purity through HPLC is 98.0%.
Embodiment 2
In reaction vessel, insert isovaleric aldehyde, amount be 2 piperidines (amount of isovaleric aldehyde is 1), 30ml ethanol (in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g), by this mixture temperature control to 60 DEG C.Slowly instill the methyl cyanoacetate (in the amount of isovaleric aldehyde for 1) that amount is 1.14 equably again, constant temperature to 60 DEG C, make it under constantly stirring to react 4h, filter, distillation, ether is washed, obtain 2-cyano group-5-methylhexanoic acid methyl esters, by this called after compd A.
In reaction vessel, insert above-mentioned substance A, diethyl malonate (with the quality of substance A for 1) that di-n-propylamine (be 1 calculating in the amount of substance A) that amount is 2,60ml normal hexane (in the total mass of substance A and diethyl malonate for 1g), amount are 1.08.Temperature control to 35 DEG C, under return stirring, the time of reaction is 2h.Adopt conventional separation means, isolate 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate, by this called after substance B.
In reaction vessel, insert above-mentioned substance B, volume ratio is the G & W of 20:1.Be heated to temperature control to 110 DEG C, under return stirring, slowly instill the hydrochloric acid (amount of hydrochloric acid is 7, in the amount of substance B for 1) that massfraction is 37wt%, the time of question response is 6h.Adopt conventional separation means, isolate 5-methyl-3-propyloic caproic acid, by this called after substance C.
In reaction vessel, insert above-mentioned substance C, be 1 amount in the amount of substance C be the Vanadium Pentoxide in FLAKES of 2, appropriate TFH, temperature control to 100 DEG C question response 2h.Conventional separation means is adopted to isolate γ-isobutylglutaric acid acid anhydride, by this called after G.
In reaction vessel, insert above-mentioned substance G, amount be 0.60 urea (in the amount of substance C for 1).Be heated to 40 DEG C, the time of stirring reaction is 1h.Adopt conventional separation means, isolate the different imide of 3-isobutyl-, by this called after material D.
To insert in the amount of material D in reaction vessel be 1 amount is the sodium hydroxide of 5.5 and appropriate water, makes it to dissolve.Time again by solution ice bath to 0 DEG C, admixture quality is the bromine of 1.4, and bromine is fully reacted.Be warming up to again 4 DEG C add material D after, ice bath to 0 DEG C more rapidly, stirs for some time.Then warming-in-water to 75 DEG C, makes it to react 1h, adopts conventional separation means to isolate the racemic modification of 3-(aminomethyl)-5-methylhexanoic acid, by this called after material E.
By above-mentioned E, consumption be 2 (S)-(+)-amygdalic acid (to split the amount of substrate for 1), Virahol be heated to 40 ~ 60 DEG C and make to be dissolved in the water.Again this solution to be cooled to 0 ~ 5 DEG C with crystallize out, be lyrica.In this example, total recovery is 27.4%, and recording its purity through HPLC is 98.3%.
Embodiment 3
In reaction vessel, insert isovaleric aldehyde, amount be 1.75 piperidines (amount of isovaleric aldehyde is 1), 20ml ethanol (in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g), by this mixture temperature control to 55 DEG C.Slowly instill the methyl cyanoacetate (in the amount of isovaleric aldehyde for 1) that amount is 1.10 equably again, constant temperature to 55 DEG C, make it under constantly stirring to react 6h, filter, distillation, ether is washed, obtain 2-cyano group-5-methylhexanoic acid methyl esters, by this called after compd A.
In reaction vessel, insert above-mentioned substance A, diethyl malonate (with the quality of substance A for 1) that di-n-propylamine (be 1 calculating in the amount of substance A) that amount is 1.75,45ml normal hexane (in the total mass of substance A and diethyl malonate for 1g), amount are 1.05.Temperature control to 25 DEG C, under return stirring, the time of reaction is 3h.Adopt conventional separation means, isolate 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate, by this called after substance B.
In reaction vessel, insert above-mentioned substance B, volume ratio is the G & W of 15:1.Be heated to temperature control to 100 DEG C, under return stirring, slowly instill the hydrochloric acid (amount of hydrochloric acid is 6, in the amount of substance B for 1) that massfraction is 35wt%, the time of question response is 8h.Adopt conventional separation means, isolate 5-methyl-3-propyloic caproic acid, by this called after substance C.
In reaction vessel, insert above-mentioned substance C, be 1 amount in the amount of substance C be the Vanadium Pentoxide in FLAKES of 1.2, appropriate TFH, temperature control to 95 DEG C question response 3.5h.Conventional separation means is adopted to isolate γ-isobutylglutaric acid acid anhydride, by this called after G.
In reaction vessel, insert above-mentioned substance G, amount be 0.57 urea (in the amount of substance C for 1).Be heated to 35 DEG C, the time of stirring reaction is 1.5h.Adopt conventional separation means, isolate the different imide of 3-isobutyl-, by this called after material D.
To insert in the amount of material D in reaction vessel be 1 amount is the sodium hydroxide of 5 and appropriate water, makes it to dissolve.Time again by solution ice bath to 0 DEG C, admixture quality is the bromine of 1.25, and bromine is fully reacted.Be warming up to again 4 DEG C add material D after, ice bath to 0 DEG C more rapidly, stirs for some time.Then warming-in-water to 70 DEG C, makes it to react 1.5h, adopts conventional separation means to isolate the racemic modification of 3-(aminomethyl)-5-methylhexanoic acid, by this called after material E.
By above-mentioned E, consumption be 1.7 (S)-(+)-amygdalic acid (to split the amount of substrate for 1), Virahol be heated to 40 ~ 60 DEG C and make to be dissolved in the water.Again this solution to be cooled to 0 ~ 5 DEG C with crystallize out, be lyrica.In this example, total recovery is 28.7%, and recording its purity through HPLC is 98.9%.
Embodiment 4
In reaction vessel, insert isovaleric aldehyde, amount be 1.8 piperidines (amount of isovaleric aldehyde is 1), 20ml ethanol (in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g), by this mixture temperature control to 55 DEG C.Slowly instill the methyl cyanoacetate (in the amount of isovaleric aldehyde for 1) that amount is 1.10 equably again, constant temperature to 55 DEG C, make it under constantly stirring to react 6h, filter, distillation, ether is washed, obtain 2-cyano group-5-methylhexanoic acid methyl esters, by this called after compd A.
In reaction vessel, insert above-mentioned substance A, diethyl malonate (with the quality of substance A for 1) that di-n-propylamine (be 1 calculating in the amount of substance A) that amount is 1.8,50ml normal hexane (in the total mass of substance A and diethyl malonate for 1g), amount are 1.06.Temperature control to 25 DEG C, under return stirring, the time of reaction is 3h.Adopt conventional separation means, isolate 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate, by this called after substance B.
In reaction vessel, insert above-mentioned substance B, volume ratio is the G & W of 15:1.Be heated to temperature control to 100 DEG C, under return stirring, slowly instill the hydrochloric acid (amount of hydrochloric acid is 6, in the amount of substance B for 1) that massfraction is 30 ~ 37wt%, the time of question response is 6h.Adopt conventional separation means, isolate 5-methyl-3-propyloic caproic acid, by this called after substance C.
In reaction vessel, insert above-mentioned substance C, be 1 amount in the amount of substance C be the Vanadium Pentoxide in FLAKES of 0.5, appropriate TFH, temperature control to 95 DEG C question response 3h.Conventional separation means is adopted to isolate γ-isobutylglutaric acid acid anhydride, by this called after G.
In reaction vessel, insert above-mentioned substance G, amount be 0.58 urea (in the amount of substance C for 1).Be heated to 30 DEG C, the time of stirring reaction is 1h.Adopt conventional separation means, isolate the different imide of 3-isobutyl-, by this called after material D.
To insert in the amount of material D in reaction vessel be 1 amount is the sodium hydroxide of 5 and appropriate water, makes it to dissolve.Time again by solution ice bath to 0 DEG C, admixture quality is the bromine of 1.2, and bromine is fully reacted.Be warming up to again 4 DEG C add material D after, ice bath to 0 DEG C more rapidly, stirs for some time.Then warming-in-water to 71 DEG C, makes it to react 1.5h, adopts conventional separation means to isolate the racemic modification of 3-(aminomethyl)-5-methylhexanoic acid, by this called after material E.
By above-mentioned E, consumption be 1.8 (S)-(+)-amygdalic acid (to split the amount of substrate for 1), Virahol be heated to 40 ~ 60 DEG C and make to be dissolved in the water.Again this solution to be cooled to 0 ~ 5 DEG C with crystallize out, be lyrica.In this example, total recovery is 30.3%, and recording its purity through HPLC is 99.1%.
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 (8)
1., with the method for γ-isobutylglutaric acid acid anhydride for intermediate synthesis lyrica, it is characterized in that, comprise the following steps:
(1) be that catalyzer in alcohol solvent in carry out Knoevenagel condensation with methyl cyanoacetate with piperidines by isovaleric aldehyde, obtain 2-cyano group-5-methylhexanoic acid methyl esters (substance A), reaction formula is as follows,
(2) be that catalyzer in normal hexane solvent in carry out Michael addition with diethyl malonate with di-n-propylamine by substance A, obtain 5-methyl-3-cyanoethyl-3-Methoxyacetyl-2-propyloic ethyl hexanoate (substance B), reaction formula is as follows,
(3) be hydrolyzed substance B under strong acid catalyst decarboxylation in a heated condition, and obtain 5-methyl-3-propyloic caproic acid (substance C), reaction formula is as follows,
(4) substance C is dewatered in a heated condition under Vanadium Pentoxide in FLAKES catalysis in THF solvent, obtain γ-isobutylglutaric acid acid anhydride (material G, reaction formula is as follows,
(5) material G is carried out ammonolysis reaction with urea, obtain the different imide of 3-isobutyl-(material D), reaction formula is as follows,
(6) material D is carried out Hoffman degraded, obtain the racemic modification (material E) of 3-(aminomethyl)-5-methylhexanoic acid, reaction formula is as follows,
(7) be that resolving agent carries out chiral separation by material E with (S)-(+)-amygdalic acid, obtain lyrica (compound F 17-hydroxy-corticosterone), 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 isovaleric aldehyde and methyl cyanoacetate is 1:1.05 ~ 1.14;
Preferably, the temperature of reaction is 50 ~ 60 DEG C, and the reaction times is 4 ~ 8h;
Preferably, the amount of piperidines is 1.5 ~ 2, in the amount of isovaleric aldehyde for 1;
Preferably, ethanol contend is 10 ~ 30ml, in the total mass of isovaleric aldehyde and methyl cyanoacetate for 1g.
3. synthetic method according to claim 1, is characterized in that, in step (2):
The temperature of reaction is 20 ~ 35 DEG C, and the time of reaction is 2 ~ 4h.
Preferably, the amount of diethyl malonate is 1.02 ~ 1.08, is 1 calculating with the amount of substance A;
Preferably, the amount of di-n-propylamine is 1.5 ~ 2, in the amount of substance A for 1;
Preferably, the volume of described normal hexane is 30 ~ 60ml, in the total mass of substance A and diethyl malonate for 1g.
4. synthetic method according to claim 1, is characterized in that, in step (3):
The temperature of hydrolysis decarboxylation reaction is 90 ~ 110 DEG C, and the time of reaction is 6 ~ 10h;
Preferably, the amount of acid is 5 ~ 7, in the amount of substance B for 1.
Preferably, react in Glycerol solvents and carry out; The volume ratio of glycerine and water is 10 ~ 20:1;
Preferably, acid for massfraction be the hydrochloric acid of 30 ~ 37wt%.
5. synthetic method according to claim 1, is characterized in that, in step (4):
The temperature of heating is 90 ~ 100 DEG C;
Preferably, the amount of Vanadium Pentoxide in FLAKES is 0.4 ~ 2, in the amount of substance C for 1.
6. synthetic method according to claim 1, is characterized in that, in step (5):
The amount of urea is 0.55 ~ 0.60, in the amount of material G for 1;
Preferably, the temperature of ammonolysis reaction is 30 ~ 40 DEG C, and the time of reaction is 1 ~ 2h.
7. synthetic method according to claim 1, is characterized in that, in step (6):
Reaction is carried out in the condition adding sodium hydroxide and sodium hypobromite;
Preferably, the amount of sodium hypobromite is 1.1 ~ 1.4, in the amount of material D for 1;
Preferably, the amount of sodium hydroxide is 3.5 ~ 4.5, in the amount of material D for 1;
Preferably, the temperature of reaction is 65 ~ 75 DEG C, and the time of reaction is 1 ~ 2h.
8. synthetic method according to claim 1, is characterized in that, in step (7):
The consumption of described (S)-(+)-amygdalic acid is 1.5 ~ 2, in the amount of material E for 1.
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