CN105348126A - Method for synthesizing Pregabalin by taking chloroacetonitrile and isobutylaldehyde as raw materials - Google Patents
Method for synthesizing Pregabalin by taking chloroacetonitrile and isobutylaldehyde as raw materials Download PDFInfo
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Abstract
The invention discloses a method for synthesizing Pregabalin by taking chloroacetonitrile and isobutylaldehyde as raw materials. The method comprises the steps: carrying out substitution reaction on chloroacetonitrile and trimethyl phosphite in a methanol solvent by taking sodium methoxide as a catalyst; carrying out substitution reaction on the substitution reaction product and 1-ethyl chloroacetate in an ethanol solvent by taking sodium hydroxide as a catalyst; carrying out Wittig-Horner reaction on the substitution reaction product and isobutylaldehyde in a THF solvent by taking sodium hydride as a catalyst; carrying out catalytic hydrogenation by taking Raney nickel as a catalyst; carrying out hydrolysis in a methanol solvent by taking potassium hydroxide as a catalyst, and then, adding acid into hydrolyzate for acid precipitation; and finally, carrying out chiral resolution by taking (S)-mandelic acid as a resolving agent. According to the method, chloroacetonitrile, which is cheap and is readily available, serves as a raw material and is subjected to substitution reaction twice, Wittig-Horner reaction with isobutylaldehyde, catalytic hydrogenation, hydrolyzing acid precipitation 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 a kind of method being Material synthesis lyrica with chloromethyl cyanide, isobutyric aldehyde.
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 method being Material synthesis lyrica with chloromethyl cyanide, isobutyric aldehyde, the higher and yield of the purity of the refined product obtained through the method.
With chloromethyl cyanide, isobutyric aldehyde for a method for Material synthesis lyrica, comprise the following steps:
(1) be that catalyzer in methanol solvate in carry out substitution reaction with trimethyl phosphite with sodium methylate by chloromethyl cyanide, obtain nitrile ethylphosphonic acid dimethyl ester (substance A), reaction formula is as follows,
(2) be that catalyzer in alcohol solvent in carry out substitution reaction with 1-ethyl chloroacetate with sodium hydroxide by substance A, obtain (3-cyano group) ethyl propionate base dimethyl phosphonate (substance B), reaction formula is as follows,
(3) be that catalyzer carries out Wittig-Horner reaction in THF solvent by substance B with isobutyric aldehyde sodium hydride, obtain 3-cyano group-5-methylhexanoic acid ethyl ester (substance C), reaction formula is as follows,
(4) be that catalyzer carries out shortening with Raney's nickel by substance C, obtain the racemic modification (material D) of 3-(aminomethyl)-5-methylhexanoic acid, reaction formula is as follows,
(5) be that catalyzer is hydrolyzed in methanol solvate with potassium hydroxide by material D, then add acid and carry out acid out, obtain the racemic modification (material E) of 3-(aminomethyl)-5-methylhexanoic acid, reaction formula is as follows,
(6) 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), chloromethyl cyanide is S with the substitution reaction of trimethyl phosphite
nthe substitution reaction of 2 mechanism.This reaction mechanism is, the first stage, and the P atom of the methylene radical attack trimethyl phosphite of chloromethyl cyanide generates interior drone salt (phosphorus positive ion and chlorine negative ion formed); Subordinate phase, CH sloughed by this interior drone salt
3cl.
The present invention is compared to out concrete restriction not to the amount (mole number) of chloromethyl cyanide and trimethyl phosphite.In order to improve the yield of this step reaction, chloromethyl cyanide can be made excessive a little, both amounts can 1:1.05 ~ 1.14, preferably 1:08.The temperature of reaction is advisable with 10 ~ 20 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 3 ~ 4h, but this reaction times unnecessary, and can not yield be improved.Preferably, the consumption of sodium methylate is 1.2 ~ 2.4, in the amount of trimethyl phosphite for 1.Methanol usage is 2 ~ 4, in the amount of sodium methylate for 1.
As step of the present invention (2), this substitution reaction is different from step (1) and occurs on the phosphorus atom, but occurs on the carbon atom between phosphorus atom and cyano group.This carbon atom is subject to the strong sucting electronic effect of cyano group and the phosphorus oxygen base sucting electronic effect slightly weak compared with cyano group, and its hydrogen atom has stronger tendency of leaving away.And its positive electrical polarity of phosphorus atom on phosphoryl is less than this carbon atom, so replace selectivity obviously will be better than phosphorus atom on this carbon atom.However, in order to control the by product produced because phosphorus atom replaces
the consumption of 1-ethyl chloroacetate is too much unsuitable, such as, be preferably 1:1.05 ~ 1.09.The temperature of reaction is 10 ~ 20 DEG C, and the reaction times is 3 ~ 5h.The consumption of sodium hydroxide is 1 ~ 1.6, in the amount of substance A for 1.Ethanol consumption is 3 ~ 5, in the amount of sodium hydroxide for 1.
As step of the present invention (3), the raw material dawn known to those skilled in the art of Wittig-Horner reaction.Its catalyzer, reactant, solvent three consumption all can refer to the consumption of conventional Wittig-Horner.But based on the consideration of yield, the ratio of the amount of substance B and isobutyric aldehyde is 1:1.04 ~ 1.10.The consumption of sodium hydride is 1 ~ 1.6, in the amount of substance B for 1.THF consumption is 4 ~ 8, in the amount of sodium hydride for 1.The temperature of reaction is 0 ~ 10 DEG C, and the reaction times is 4 ~ 8h.
As step of the present invention (4), shortening refers to that hydrogen and double bond generation addition obtain saturated carbon carbon single bond.In the present invention, adopt Raney's nickel as catalyzer, Raney's nickel has stronger catalytic activity, can significantly improve the catalytic conversion of hydrogenation reaction.The consumption of Raney's nickel 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 step of the present invention (5), under this step is included in the catalysis of potassium hydroxide, hydrolysis obtains carboxylate salt, and adopts acid to become acid to separate out from solution to this carboxylate salt.Potassium hydroxide can the degree of facilitation of hydrolysis.The temperature of hydrolysis reaction is 40 ~ 50 DEG C, and the time of hydrolysis reaction is 1 ~ 2h.The consumption of potassium hydroxide is 1.5 ~ 2.5, in the amount of material D for 1.The consumption of methyl alcohol is 1L, in the quality of material D for 60 ~ 80g.Consumption as water can be 2 ~ 4 times of methyl alcohol volume.In acid out process, the consumption of acid is 1 ~ 1.1, with the amount of potassium hydroxide for 1.Acid can list the conventional organic-inorganic acid such as acetic acid, hydrochloric acid, is preferably acetic acid.
As chiral separation of the present invention, 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 with chloromethyl cyanide that is inexpensive, that be easy to get for raw material, through two substitution reactions, react with the Wittig-Horner of isobutyric aldehyde, shortening, hydrolysis acid out 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 trimethyl phosphite, methyl alcohol (in the amount of sodium methylate for 1) that sodium methylate (in the amount of trimethyl phosphite for 1) that consumption is 1.2, consumption are 2, by this mixture temperature control to 10 DEG C.Add the chloromethyl cyanide (in the amount of trimethyl phosphite for 1) that consumption is 1.05 again, constant temperature to 10 DEG C, make it under constantly stirring to react 5h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance A.
In reaction vessel, insert above-mentioned substance A, ethanol (in the amount of sodium hydroxide for 1) that sodium hydroxide (in the amount of substance A for 1) that consumption is 1, consumption are 3, by this mixture temperature control to 10 DEG C.Add the 1-ethyl chloroacetate (in the amount of substance A for 1) that consumption is 1.05 again, constant temperature to 10 DEG C, make it under constantly stirring to react 5h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance B.
In reaction vessel, insert above-mentioned substance B, THF (in the amount of sodium hydride for 1) that sodium hydride (in the amount of substance B for 1) that consumption is 1, consumption are 4, temperature control to 0 DEG C stirs 10 ~ 20min.Adding consumption is again 1.04 isobutyric aldehydes (in the amounts of substance B for 1), and holding temperature is 0 DEG C, stirring reaction 8h.After question response, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance C.
In withstand voltage reactor, insert above-claimed cpd C, quality be 4% with Raney's nickel 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 3-(aminomethyl)-5-methylhexanoic acid ethyl ester, by this called after material D.
In reaction vessel, insert above-mentioned substance D, consumption be 1L methyl alcohol (in the quality of material D for 60g), 2 times of volumes in methyl alcohol water, 4/5ths massfraction be 10 ~ 30% aqueous sodium hydroxide solution (the total amount of potassium hydroxide be 1.5 times to the amount of material D).Temperature control to 40 DEG C, progressively instills remaining aqueous sodium hydroxide solution.2h to be hydrolyzed to, adds the Glacial acetic acid of 1 amount, then stirs with crystallize out.This crystal is dried, obtains 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 56.6%, and recording its purity through HPLC is 98.0%.
Embodiment 2
In reaction vessel, insert trimethyl phosphite, methyl alcohol (in the amount of sodium methylate for 1) that sodium methylate (in the amount of trimethyl phosphite for 1) that consumption is 2.4, consumption are 4, by this mixture temperature control to 20 DEG C.Add the chloromethyl cyanide (in the amount of trimethyl phosphite for 1) that consumption is 1.14 again, constant temperature to 20 DEG C, make it under constantly stirring to react 3h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance A.
In reaction vessel, insert above-mentioned substance A, ethanol (in the amount of sodium hydroxide for 1) that sodium hydroxide (in the amount of substance A for 1) that consumption is 1.6, consumption are 5, by this mixture temperature control to 20 DEG C.Add the 1-ethyl chloroacetate (in the amount of substance A for 1) that consumption is 1.14 again, constant temperature to 20 DEG C, make it under constantly stirring to react 3h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance B.
In reaction vessel, insert above-mentioned substance B, THF (in the amount of sodium hydride for 1) that sodium hydride (in the amount of substance B for 1) that consumption is 1.6, consumption are 8, temperature control to 10 DEG C stirs 10 ~ 20min.Adding consumption is again 1.10 isobutyric aldehydes (in the amounts of substance B for 1), and holding temperature is 10 DEG C, stirring reaction 4h.After question response, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance C.
In withstand voltage reactor, insert above-claimed cpd C, quality be 8% with Raney's nickel catalyst (in the quality of substance C for 100%), the pressure regulating pressurizing device is 16bar, temperature, for being 90 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 3-(aminomethyl)-5-methylhexanoic acid ethyl ester, by this called after material D.
In reaction vessel, insert above-mentioned substance D, consumption be 1L methyl alcohol (in the quality of material D for 80g), 2 times of volumes in methyl alcohol water, 4/5ths massfraction be 10 ~ 30% aqueous sodium hydroxide solution (the total amount of potassium hydroxide be 2.5 times to the amount of material D).Temperature control to 40 DEG C, progressively instills remaining aqueous sodium hydroxide solution.2h to be hydrolyzed to, adds the Glacial acetic acid of 1.1 amounts, then stirs with crystallize out.This crystal is dried, obtains 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 57.7%, and recording its purity through HPLC is 98.3%.
Embodiment 3
In reaction vessel, insert trimethyl phosphite, methyl alcohol (in the amount of sodium methylate for 1) that sodium methylate (in the amount of trimethyl phosphite for 1) that consumption is 1.8, consumption are 3, by this mixture temperature control to 15 DEG C.Add the chloromethyl cyanide (in the amount of trimethyl phosphite for 1) that consumption is 1.10 again, constant temperature to 15 DEG C, make it under constantly stirring to react 4h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance A.
In reaction vessel, insert above-mentioned substance A, ethanol (in the amount of sodium hydroxide for 1) that sodium hydroxide (in the amount of substance A for 1) that consumption is 1.3, consumption are 4, by this mixture temperature control to 15 DEG C.Add the 1-ethyl chloroacetate (in the amount of substance A for 1) that consumption is 1.10 again, constant temperature to 15 DEG C, make it under constantly stirring to react 4h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance B.
In reaction vessel, insert above-mentioned substance B, THF (in the amount of sodium hydride for 1) that sodium hydride (in the amount of substance B for 1) that consumption is 1.3, consumption are 6, temperature control to 5 DEG C stirs 10 ~ 20min.Adding consumption is again 1.07 isobutyric aldehydes (in the amounts of substance B for 1), and holding temperature is 5 DEG C, stirring reaction 6h.After question response, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance C.
In withstand voltage reactor, insert above-claimed cpd C, quality be 6% with Raney's nickel 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 12h, stopped reaction.Said mixture is added in ethanol, filters solid.Liquid phase is distilled ethanol, obtains 3-(aminomethyl)-5-methylhexanoic acid ethyl ester, by this called after material D.
In reaction vessel, insert above-mentioned substance D, consumption be 1L methyl alcohol (in the quality of material D for 60 ~ 80g), 2 times of volumes in methyl alcohol water, 4/5ths massfraction be 10 ~ 30% aqueous sodium hydroxide solution (the total amount of potassium hydroxide be 2 times to the amount of material D).Temperature control to 45 DEG C, progressively instills remaining aqueous sodium hydroxide solution.1.5h to be hydrolyzed to, adds the Glacial acetic acid of 1.05 amounts, then stirs with crystallize out.This crystal is dried, obtains 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 59.7%, and recording its purity through HPLC is 98.9%.Embodiment 4
In reaction vessel, insert trimethyl phosphite, methyl alcohol (in the amount of sodium methylate for 1) that sodium methylate (in the amount of trimethyl phosphite for 1) that consumption is 2, consumption are 3, by this mixture temperature control to 15 DEG C.Add the chloromethyl cyanide (in the amount of trimethyl phosphite for 1) that consumption is 1.10 again, constant temperature to 15 DEG C, make it under constantly stirring to react 3h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance A.
In reaction vessel, insert above-mentioned substance A, ethanol (in the amount of sodium hydroxide for 1) that sodium hydroxide (in the amount of substance A for 1) that consumption is 1.2, consumption are 4, by this mixture temperature control to 15 DEG C.Add the 1-ethyl chloroacetate (in the amount of substance A for 1) that consumption is 1.10 again, constant temperature to 15 DEG C, make it under constantly stirring to react 3h.After reaction terminates, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance B.
In reaction vessel, insert above-mentioned substance B, THF (in the amount of sodium hydride for 1) that sodium hydride (in the amount of substance B for 1) that consumption is 1.5, consumption are 6, temperature control to 0 DEG C stirs 10 ~ 20min.Adding consumption is again 1.04 ~ 1.10 isobutyric aldehydes (in the amounts of substance B for 1), and holding temperature is 0 DEG C, stirring reaction 5h.After question response, with the cancellation of the 0.1MHCl aqueous solution, layering, collected organic layer.Aqueous phase toluene extracts once, merges organic layer, anhydrous sodium sulfate drying.Filter, filtrate concentrates, and (moving phase of column chromatography is sherwood oil to column chromatography for separation: ethyl acetate=2:1).By this called after substance C.
In withstand voltage reactor, insert above-claimed cpd C, quality be 6% with Raney's nickel 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 3-(aminomethyl)-5-methylhexanoic acid ethyl ester, by this called after material D.
In reaction vessel, insert above-mentioned substance D, consumption be 1L methyl alcohol (in the quality of material D for 60 ~ 80g), 2 times of volumes in methyl alcohol water, 4/5ths massfraction be 10 ~ 30% aqueous sodium hydroxide solution (the total amount of potassium hydroxide be 2 times to the amount of material D).Temperature control to 45 DEG C, progressively instills remaining aqueous sodium hydroxide solution.1h to be hydrolyzed to, adds the Glacial acetic acid of 1.05 amounts, then stirs with crystallize out.This crystal is dried, obtains 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 61.3%, 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 (7)
1. with chloromethyl cyanide, isobutyric aldehyde for a method for Material synthesis lyrica, it is characterized in that, comprise the following steps:
(1) be that catalyzer in methanol solvate in carry out substitution reaction with trimethyl phosphite with sodium methylate by chloromethyl cyanide, obtain nitrile ethylphosphonic acid dimethyl ester (substance A), reaction formula is as follows,
(2) be that catalyzer in alcohol solvent in carry out substitution reaction with 1-ethyl chloroacetate with sodium hydroxide by substance A, obtain (3-cyano group) ethyl propionate base dimethyl phosphonate (substance B), reaction formula is as follows,
(3) be that catalyzer carries out Wittig-Horner reaction in THF solvent by substance B with isobutyric aldehyde sodium hydride, obtain 3-cyano group-5-methylhexanoic acid ethyl ester (substance C), reaction formula is as follows,
(4) be that catalyzer carries out shortening with Raney's nickel by substance C, obtain 3-(aminomethyl)-5-methylhexanoic acid ethyl ester (material D), reaction formula is as follows,
(5) be that catalyzer is hydrolyzed in methanol solvate with potassium hydroxide by material D, then add acid and carry out acid out, obtain the racemic modification (material E) of 3-(aminomethyl)-5-methylhexanoic acid, reaction formula is as follows,
(6) 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 trimethyl phosphite and chloromethyl cyanide is 1:1.05 ~ 1.14;
Preferably, the temperature of reaction is 10 ~ 20 DEG C, and the reaction times is 3 ~ 5h;
Preferably, the consumption of sodium methylate is 1.2 ~ 2.4, in the amount of trimethyl phosphite for 1;
Preferably, methanol usage is 2 ~ 4, in the amount of sodium methylate for 1.
3. synthetic method according to claim 1, is characterized in that, in step (2):
The ratio of the amount of 1-ethyl chloroacetate and substance A is 1:1.05 ~ 1.09;
Preferably, the temperature of reaction is 10 ~ 20 DEG C, and the reaction times is 3 ~ 5h;
Preferably, the consumption of sodium hydroxide is 1 ~ 1.6, in the amount of substance A for 1;
Preferably, ethanol consumption is 3 ~ 5, in the amount of sodium hydroxide for 1.
4. synthetic method according to claim 1, is characterized in that, in step (3):
The ratio of the amount of substance B and isobutyric aldehyde is 1:1.04 ~ 1.10;
Preferably, the temperature of reaction is 0 ~ 10 DEG C, and the reaction times is 4 ~ 8h;
Preferably, the consumption of sodium hydride is 1 ~ 1.6, in the amount of substance B for 1;
Preferably, THF consumption is 4 ~ 8, in the amount of sodium hydride for 1.
5. synthetic method according to claim 1, is characterized in that, in step (4):
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 Raney's nickel is 4 ~ 8%, in the quality of substance C for 100%.
6. synthetic method according to claim 1, is characterized in that, in step (5):
The temperature of described hydrolysis reaction is 40 ~ 50 DEG C, and the time of hydrolysis reaction is 1 ~ 2h;
Preferably, the consumption of described potassium hydroxide is 1.5 ~ 2.5, in the amount of material D for 1;
Preferably, the consumption of described methyl alcohol is 1L, in the quality of material D for 60 ~ 80g;
Preferably, the consumption of described acid is 1 ~ 1.1, with the amount of potassium hydroxide for 1.
7. synthetic method according to claim 1, is characterized in that, in step (6):
The consumption of described (S)-amygdalic acid is 1.5 ~ 2, in the amount of material E for 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH045295A (en) * | 1990-04-24 | 1992-01-09 | Mitsubishi Kasei Corp | Production of phosphonates |
| CN102464594A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of intermediate compound of pregabalin |
-
2015
- 2015-11-26 CN CN201510845683.5A patent/CN105348126A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH045295A (en) * | 1990-04-24 | 1992-01-09 | Mitsubishi Kasei Corp | Production of phosphonates |
| CN102464594A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of intermediate compound of pregabalin |
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| Title |
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| 张桂森等: "普瑞巴林的合成", 《CHINESE JOURNAL OF PHARMACEUTICALS》 * |
| 杨健等: "普瑞巴林的合成", 《高校化学工程学报》 * |
| 陈敖等: "新药普瑞巴林的合成", 《精细与专用化学品第》 * |
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