CN109678737A - A kind of preparation method of Pregabalin - Google Patents
A kind of preparation method of Pregabalin Download PDFInfo
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- CN109678737A CN109678737A CN201910120352.3A CN201910120352A CN109678737A CN 109678737 A CN109678737 A CN 109678737A CN 201910120352 A CN201910120352 A CN 201910120352A CN 109678737 A CN109678737 A CN 109678737A
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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Abstract
The present invention relates to a kind of preparation methods of Pregabalin, the preparation method is the following steps are included: in alkaline solution, (R)-(-) Hoffmann rearrangement reaction is carried out under the action of -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite, after rearrangement reaction, by reaction solution be added acid-organic solvent system in, extraction merging organic phase, then plus alkali carry out alkali analysis, mashing washing, is made the Pregabalin of high-purity.Above-mentioned preparation method has process route simple, and product yield is high, the high advantage of product purity, and can meet pharmaceutical quality standard without recrystallization, is suitble to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of preparation method of Pregabalin.
Background technique
Pregabalin is used to treat the partial epilepsy effect of adult patient, and in June, 2005 is through U.S.'s food and drug pipe
Reason office (FDA) approval listing, increases a variety of new indications, the market demand is larger, becomes global best-selling drugs in March, 2006
One of.
Existing numerous patents report the preparation synthetic method of Pregabalin at present, and patent CN101500985A describes use
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid carries out Hoffmann rearrangement under the action of sodium hydroxide, sodium hypochlorite
Reaction, then through salt acid for adjusting pH, obtain Pregabalin.However, discovery is using above-mentioned special when reappearing to special sharp method
Sharp method, product yield is low, is readily incorporated the unknown impuritie for being difficult to remove, and is unable to satisfy Medicinal crude drug standard.
Patent CN106748850A also reports (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid in hydroxide
It is carried out except Hoffmann rearrangement reaction under the action of sodium, sodium hypochlorite, it also occur that side reaction, generates the impurity X for being difficult to remove
With impurity Y.
Impurity X and impurity Y is difficult in subsequent product purifying as the critical impurities in Pregabalin preparation process
It removes, directly affects the quality standard of product Pregabalin.
In view of the above problems, it is necessary to find a kind of process optimization improved method of Pregabalin.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of Pregabalin.The receipts of product can be improved in the preparation method
Rate and purity, and simple process are suitble to industrialized production.
The present invention solves its technical problem and adopts the following technical solutions to realize.
The present invention provides a kind of preparation method of Pregabalin, comprising the following steps:
In alkaline solution, (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite are subjected to Hough
Graceful rearrangement reaction obtains reaction solution, and reaction solution is added into acid-organic solvent system, extraction merging organic phase, then plus
Alkali carries out alkali analysis, and the Pregabalin of high-purity is made in mashing washing.
The beneficial effects of the present invention are:
The present invention provides a kind of preparation method of Pregabalin, the preparation method in the present invention overcomes current Puri bar
The generally existing yield of woods preparation process is low, and purity is not high, it is difficult to meet the defect of pharmaceutical quality standard.Pass through Hoffmann rearrangement
Reaction prepares Pregabalin, and after rearrangement reaction, the reaction solution after Hoffmann rearrangement reaction is added to acid-organic solvent
In system, adjusts pH to acidity, enter product in organic system at after salt, react the impurity of generation substantially in water phase, then
In organic system plus alkali carries out alkali and analyses free Pregabalin out, only needs simply to be beaten a small amount of inorganic salts of removing after precipitation,
Product can be obtained the Pregabalin of high-purity without recrystallization.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is the liquid phase HPLC map of Pregabalin prepared by the embodiment 10 recorded in CN101500985A,
Fig. 2 is the liquid phase HPLC map of the Pregabalin prepared in the embodiment of the present invention 1.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
A kind of preparation method of Pregabalin provided in an embodiment of the present invention is specifically described below.
The embodiment of the present invention provides a kind of preparation method of Pregabalin, comprising the following steps:
In alkaline solution, (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite are subjected to Hough
Graceful rearrangement reaction obtains reaction solution, and reaction solution is added into acid-organic solvent system, extraction merging organic phase, then plus
Alkali carries out alkali analysis, and the Pregabalin of high-purity is made in mashing washing.
The embodiment of the present invention provides a kind of preparation method of Pregabalin, and the preparation method is the following steps are included: in alkalinity
In solution, (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite are subjected to Hoffmann rearrangement reaction and obtained
Reaction solution is added into acid-organic solvent system reaction solution, extraction merging organic phase, then plus alkali carry out alkali analysis, mashing
The Pregabalin of high-purity is made in washing.The method overcome after traditional Hoffmann rearrangement reaction, direct acid adding is in water
Solid is precipitated in phase, needs to use isopropanol and crystal's system, the impurity for being difficult to remove is contained in product, product purity is low to be lacked
It falls into.The preparation method of Pregabalin provided in an embodiment of the present invention, Pregabalin can meet pharmaceutical quality mark without recrystallization
It is quasi-.The process route of the preparation method is simple, and product yield is high, and product purity is high, is suitble to industrialized production.
In some embodiments, the preparation of Pregabalin is specifically includes the following steps: in alkaline solution, by (R)-
(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite carry out Hoffmann rearrangement reaction and obtain reaction solution, will be anti-
It answers solution to be added into acid-organic solvent system, then adjusts pH, layering for the first time, water layer is extracted with organic solvent, is associated with
Machine phase, then alkali is added into organic phase, pH is adjusted for the second time, until Pregabalin is precipitated, mashing is washed, and the general of high-purity is made
Auspicious Bahrain.
Currently, the separating-purifying of Pregabalin is that after the completion of reaction, solid is precipitated in direct acid adding in water phase, need
Using isopropanol and crystal's system, containing the impurity for being difficult to remove in product, the above method generally has yield low, and purity is not high,
It is difficult to meet pharmaceutical quality standard.
The preparation method of Pregabalin provided in an embodiment of the present invention, the separating-purifying of Pregabalin the following steps are included:
After Hoffmann rearrangement reaction, reaction solution is added into acid-organic solvent system, adjusts pH to acidity, product is laggard at salt
Enter in organic system, react the impurity of generation substantially in water phase, then extraction merging organic phase, into organic phase be added alkali into
The free Pregabalin out of row alkali analysis, only needs simply mashing to remove a small amount of inorganic salts, product is without recrystallizing after precipitation
Obtain the Pregabalin of high-purity.
Specifically, the separating-purifying of the Pregabalin provided in the embodiment of the present invention is the following steps are included: directly by Hough
Reaction solution after graceful rearrangement reaction is added dropwise in acid-organic solvent system, the most Pregabalin in reaction solution and acid
At salt and enter in organic solvent, impurity enters in water layer, to effectively realize the separation of crude product and impurity, hereafter will
Crude product carries out simply post-processing the Pregabalin that can be obtained by high-purity again.It can be seen that in the embodiment of the present invention
Process for separation and purification is overcome well in the preparation process of current Pregabalin, and directly acid adding is analysed in water phase in reaction solution
Solid out, the low defect of solid purity.This be adulterate and swept along a large amount of impurity in the obtained Pregabalin solid of reaction, and
Effectively Pregabalin is separated with impurity not on source, although also using isopropanol and crystal's system, subtractive process is not
Impurity therein can be effectively removed, not only time-consuming and laborious and efficiency is lower, but also the purity of obtained product is still lower, nothing
Method is met the requirements.
In some embodiments, alkaline water is added portionwise in (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid
It in solution, is uniformly mixed to obtain mixed solution, the aqueous solution of sodium hypochlorite is added drop-wise in mixed solution, carry out Huffman
The reaction equation of rearrangement reaction, Hoffmann rearrangement reaction is as follows:
The embodiment of the present invention provides a kind of preparation method of Pregabalin, comprising the following steps: in alkaline aqueous solution,
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid carries out Hoffmann rearrangement reaction under the action of sodium hypochlorite.As it can be seen that
The preparation of Pregabalin in the embodiment of the present invention is related to hoffman degradation reaction, by reaction raw materials (R)-(-) -3- (amino first
Acyl methyl) alkaline solution of -5- methylhexanoic acid and sodium hypochlorite when acting on, sloughs carbonyl and generates primary amine.Its reaction equation is such as
Under:
This reaction process is more complicated, and the reaction mechanism mechanism of reaction is as follows:
Step 1 is amide chloro in R- (-) -3- (carbamoyl methyl) -5- methylhexanoic acid, i.e., hydrogen is taken by chlorine on nitrogen-atoms
In generation, obtains N- chlorinated amide intermediate.
Step 2 is under alkali effect, and dehydrochlorination, obtaining the nitrogen-atoms of an electron deficient, (nitrogen-atoms outermost layer only has
Six electronics) intermediate acyl group nitrence.Acyl group nitrence is very unstable, is easy to happen rearrangement.
Step 3 is that alkyl is transferred on the nitrogen-atoms of electron deficient with pair of electrons, generates isocyanates, and isocyanates exists
Alkaline aqueous solution high temperature sloughs carbon dioxide and generates primary amine.
It can be seen that hoffman degradation reaction process is extremely complex, and since the reaction is apparent exothermic reaction, hold
It is also easy to produce other side reactions and impurity, the separating step of the temperature and crude product in reaction process need to be controlled, it is high-purity to obtain
The Pregabalin of degree.
In the preparation process of the Pregabalin provided in the embodiment of the present invention, since Hoffmann rearrangement reaction heat release is obvious,
And entire reaction process is extremely complex, in order to reduce the generation of side reaction, reduces the impurity content in product, control is added suitable
Sequence are as follows: (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid is added portionwise in alkaline aqueous solution, is uniformly mixed
To mixed solution, the aqueous solution of sodium hypochlorite is added drop-wise in mixed solution.It was reacted by controlling addition sequence and can control
Temperature in journey is conducive to the progress of rearrangement reaction, reduces the generation of side reaction and the generation of impurity.
In some embodiments, Hoffmann rearrangement reaction includes:
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid is added portionwise in alkaline aqueous solution, is stirred
It is even to obtain mixed solution, the aqueous solution of sodium hypochlorite is added drop-wise in mixed solution, 0.5-1h, hypochlorous acid are reacted at 0-10 DEG C
After the aqueous solution of sodium is added dropwise, then it is warming up to 65-80 DEG C, the reaction was continued 1-2h.
In some embodiments, the alkali in alkaline aqueous solution and (R)-(-) -3- (carbamoyl methyl) -5- methyl oneself
Acid dosage molar ratio be 3.5-5.5:1, preferably 3.5-4.5:1,
The molar ratio for having dosage of sodium hypochlorite and (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid is 1.5-
1.1:1 preferably 1.1:1.
In some embodiments, the alkali in alkaline aqueous solution is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide,
The mass fraction of alkaline aqueous solution is 20-30%, and the mass fraction of aqueous sodium hypochlorite solution is 5-15%.
In the preparation process of Pregabalin in the embodiment of the present invention, the dosage of strict control aqueous sodium hypochlorite solution can
To control the extent of reaction and reaction process of the Pregabalin in entire reaction process.
In some embodiments, organic phase includes obtained organic solvent layer and the water layer obtained after layering after layering
Extract layer, it is preferred that the extraction times of water layer are 3-4 times.
In the preparation process of the Pregabalin provided in the embodiment of the present invention, the reaction that will be obtained after Hoffmann rearrangement reaction
Liquid is added into acid-organic solvent system, can since for acid by organic solvent diluting, the acidity of system is mild uniform in the system
So that the most Pregabalin and acid in reaction solution at salt and enter in organic solvent, impurity enters in water layer, has simultaneously
A small amount of Pregabalin can also enter in water layer.Therefore, after first time adjusts pH, layering obtains organic solvent layer and water
Water layer recycling organic solvent carries out the organic solvent extract layer that water layer is obtained by extraction by layer, merges and obtains after above-mentioned layering
The extract layer of the water layer obtained after organic solvent layer and layering, it is preferred that in the extractant and acid-organic solvent system of water layer
Organic solvent it is identical or different, the extraction times of water layer are 3-4 times, to guarantee that the Pregabalin dissolved in water layer is all extracted
It gets in organic solvent, alkali then is added into the organic phase after merging, second of adjusting pH, at this point, in organic solvent
The salt of Pregabalin is separated out by alkali, only needs simply to be beaten a small amount of inorganic salts of removing after precipitation, product is without recrystallization
It can get the Pregabalin of high-purity.
In some embodiments, acid is selected from least one of inorganic acid and organic acid, preferably sulfuric acid, hydrochloric acid, phosphorus
Acid, at least one of formic acid and acetic acid,
Alcohol of the organic solvent selected from C4, the aliphatic ketone of C1-C6, at least one of ethyl acetate and toluene, preferably just
Butanol, isobutanol, butanone, at least one of ethyl acetate and toluene.
Preferably, first time pH is adjusted to 2-7, and more preferable pH is adjusted to 2-5.
In some embodiments, after layering is specifically includes the following steps: reaction solution is added dropwise, temperature is controlled
Within 25 DEG C, after adjusting pH for the first time, 25 DEG C -30 DEG C are warming up to, stratification.
By the reaction mechanism mechanism of reaction above-mentioned it can be seen that hoffman degradation reaction process is extremely complex, intermediate isocyanic acid is formed
Ester, energy and water, alcohol, the reaction of many kinds of substance such as amine are easy to cause side reaction, occur being difficult to purify impurity, product generally has receipts
Rate is low, and purity is low, is unable to satisfy Medicinal crude drug standard.
Reaction solution in the preparation process of the Pregabalin provided in the embodiment of the present invention, after Hoffmann rearrangement reaction
In, directly reaction solution is added dropwise in acid-organic solvent system.The temperature in control adition process is needed during being added dropwise, in order to avoid
New side reaction and impurity are generated, after being added dropwise, temperature is controlled within 25 DEG C, after adjusting pH for the first time, is warming up to
25 DEG C -30 DEG C (if temperature continues to increase, may cause the precipitation of Pregabalin), stratification at above-mentioned temperature can make water
Layer and organic solvent layer are sufficiently separated, i.e., at entering in organic solvent after salt, impurity enters in water layer product Pregabalin, real
Efficiently separating for crude product and impurity is showed.
In some embodiments, for alkali analysis alkali be selected from least one of organic base and inorganic base, preferably three
Ethamine, ammonium hydroxide, sodium hydroxide, potassium hydroxide, at least one of potassium carbonate and sodium bicarbonate,
Preferably, pH to 6-8 is adjusted second, more preferably to 7-8.
In some embodiments, alkali analysis and mashing washing are specifically includes the following steps: alkali is added into organic phase, and second
Secondary adjusting pH is continuously heating to 75-85 DEG C, reacts 0.5-1h, and filters pressing is cooled to 0-10 DEG C, and time 3-5h is precipitated, is centrifuged, washes
It washs, solid is beaten using purified water, dry after centrifugation.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
32kg (0.8mol) sodium hydroxide is added to stirring and dissolving in 80L water, 0-10 DEG C is down to, 40kg is added portionwise
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid controls 0-10 DEG C, finishes stirring 10min, liquor natrii hypochloritis is added dropwise
(9.7%164kg) controls 0-10 DEG C of temperature, finishes insulation reaction 30min, be to slowly warm up to 80 DEG C of 1h, it is standby to be cooled to room temperature
With.
80L butanone and sulfuric acid 50L are added in reaction kettle and are cooled to 15 DEG C or so, above-mentioned spare reaction solution, control is added dropwise
Within 25 DEG C of system, sulfuric acid tune pH=2 is finished, is warming up to 25 DEG C -30 DEG C, static layering, water layer is extracted with 40L*3 butanone, is merged
(combined organic layer includes 80L butanone and 40L*3 butanone) is warming up to 85 DEG C of stirrings with ammonium hydroxide tune pH=8 after organic layer
10min, filters pressing are cooled to 0-10 DEG C, 3h, centrifugation, with 40ml ethanol washing, solid is beaten with 40L purified water into crystallization kettle
1h, centrifugation, 80 DEG C of heated-air drying 2h obtain Pregabalin 33kg, yield 97.1%, purity 99.99%.
Following table 1 is the peak table of Pregabalin prepared by the embodiment 10 recorded in CN101500985A:
1 peak table of table
<peak table>
PDA Ch1 210nm
| Peak number | Chemical combination name | Retention time | Area | Area % | Highly |
| 1 | Pregabalin | 7.987 | 3898243 | 99.134 | 335556 |
| 2 | 12.750 | 23218 | 0.590 | 1466 | |
| 3 | 33.528 | 3780 | 0.096 | 448 | |
| 4 | 34.773 | 5345 | 0.136 | 780 | |
| 5 | 39.579 | 1721 | 0.044 | 158 | |
| It amounts to | 3932308 | 100.000 | 33848 |
Following table 2 is the peak table of the Pregabalin prepared in the embodiment of the present invention 1:
2 peak table of table
<peak table>
PDA Ch1 210nm
| Peak number | Chemical combination name | Retention time | Area | Highly | Concentration |
| 1 | Pregabalin | 7.990 | 4669852 | 394296 | 0.000 |
| It amounts to | 4669852 | 394296 |
Referring to Fig. 1 and Fig. 2, Fig. 1 is the liquid phase of Pregabalin prepared by the embodiment 10 recorded in CN101500985A
HPLC map, Fig. 2 are the liquid phase HPLC maps of the Pregabalin prepared in the embodiment of the present invention 1.
It further include 4 other compounds in addition to the peak comprising Pregabalin in peak table 1 it can be seen from table 1 and Fig. 1
Peak, and occupy biggish peak area, illustrates that the purity of compound is lower, only 99.1% or so, and can be seen by table 2 and Fig. 2
It out, only include the peak of Pregabalin in peak table 2, the peak without containing other substances illustrates the general of the preparation in the embodiment of the present invention 1
The purity of auspicious Bahrain is very high, reaches 99.99%, is fully able to meet Medicinal crude drug standard.
Embodiment 2
32kg (0.8mol) sodium hydroxide is added to stirring and dissolving in 80L water, 0 DEG C is down to, 40kg (R)-is added portionwise
(-) -3- (carbamoyl methyl) -5- methylhexanoic acid controls 0-10 DEG C, finishes stirring 10min, liquor natrii hypochloritis is added dropwise
(9.7%164kg) controls 0-10 DEG C of temperature, finishes insulation reaction 30min, be to slowly warm up to 80 DEG C of 1h, it is standby to be cooled to room temperature
With.
80L toluene and sulfuric acid are added in reaction kettle and are cooled to 15 DEG C or so, above-mentioned spare reaction solution, control 25 is added dropwise
Within DEG C, sulfuric acid tune pH=3 is finished, is warming up to 25 DEG C -30 DEG C, static layering, water layer is extracted with 40L*3 toluene, is merged organic
(combined organic layer includes 80L toluene and 40L*3 toluene) is warming up to 85 DEG C of stirring 10min with ammonium hydroxide tune pH=7.5 after layer,
Filters pressing is cooled to 0-10 DEG C, 4h into crystallization kettle, and centrifugation, with 40ml ethanol washing, solid is beaten 1h with 40L purified water, from
The heart, 50 DEG C of heated-air drying 3h obtain Pregabalin 31kg, yield 95.1%, purity 99.99%.
Embodiment 3
32kg (0.8mol) sodium hydroxide is added to stirring and dissolving in 80L water, 0-10 DEG C is down to, 40kg is added portionwise
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid controls 0-10 DEG C, finishes stirring 10min, liquor natrii hypochloritis is added dropwise
(9.7%164kg) controls 0-10 DEG C of temperature, finishes insulation reaction 30min, be to slowly warm up to 75 DEG C of 1h, it is standby to be cooled to room temperature
With.
80L n-butanol and hydrochloric acid are added in reaction kettle and are cooled to 15 DEG C or so, above-mentioned spare reaction solution, control is added dropwise
Within 25 DEG C, hydrochloric acid tune pH=4 is finished, is warming up to 25 DEG C -30 DEG C, static layering, water layer 40L*3 extracting n-butyl alcohol merges
(combined organic layer includes 80L n-butanol and 40L*3 n-butanol) is warming up to 85 DEG C of stirrings with ammonium hydroxide tune pH=7 after organic layer
10min, filters pressing are cooled to 0-10 DEG C, 5h into crystallization kettle, and centrifugation is washed, solid is beaten with 40L purified water with 40ml isopropanol
1h, centrifugation are starched, 50 DEG C of heated-air drying 3h obtain Pregabalin 32.2kg, yield 97.7%, purity 99.99%.
Embodiment 4
32kg (0.8mol) sodium hydroxide is added to stirring and dissolving in 80L water, 0-10 DEG C is down to, 40kg is added portionwise
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid controls 0-10 DEG C, finishes stirring 10min, liquor natrii hypochloritis is added dropwise
(9.7%153kg) controls 0-10 DEG C of temperature, finishes insulation reaction 30min, be to slowly warm up to 65 DEG C of 1h, it is standby to be cooled to room temperature
With.
80L ethyl acetate and formic acid are added in reaction kettle and are cooled to 15 DEG C or so, above-mentioned spare reaction solution, control is added dropwise
Within 25 DEG C of system, formic acid tune pH=5 is finished, is warming up to 25 DEG C -30 DEG C, static layering, water layer 40L*3 extracting n-butyl alcohol closes
And (combined organic layer includes 80L ethyl acetate and 40L*3 n-butanol) is warming up to 85 DEG C with ammonium hydroxide tune pH=7 after organic layer
10min is stirred, filters pressing is cooled to 0-10 DEG C, 3h into crystallization kettle, and centrifugation is washed, solid is purified with 40L with 40ml isopropanol
Water is beaten 1h, centrifugation, and 50 DEG C of heated-air drying 3h obtain Pregabalin 29.8kg, yield 94.6%, purity 99.99%.
To sum up, the present invention provides a kind of preparation method of Pregabalin, and the preparation method is the following steps are included: (R)-(-)-
3- (carbamoyl methyl) -5- methylhexanoic acid carries out Hoffmann rearrangement reaction under the action of sodium hydroxide, sodium hypochlorite, resets
After reaction, reaction solution is added into acid-organic solvent system, merges organic phase and adds alkali to carry out alkali analysis, mashing again later
Washing is made the Pregabalin of high-purity, and can meet pharmaceutical quality standard without recrystallization.Meanwhile by embodiment 1-4
Test as can be seen that the Pregabalin of this method preparation high income, purity 99.99% is fully able to meet medical raw
Expect medicine standard.The preparation method has process route simple, and product yield is high, and product purity is high, is suitble to industrialized production.
Compared with the prior art, the embodiment of the present invention has following effective effect:
1, the separation of current Pregabalin is etc. that after reaction, solid is precipitated in direct acid adding in water phase, and solid needs
Isopropanol and crystal's system are used, contains the impurity for being difficult to remove in product, the prior art generally has yield low, and purity is not
It is high, it is difficult to meet pharmaceutical quality standard.
2, the separating-purifying of the Pregabalin in the embodiment of the present invention is after the completion of reaction, to add directly into reaction system
Enter acid-organic solvent system, adjust pH to acidity, product enters in organic system at after salt, reacts the impurity of generation substantially in water
Xiang Zhong, then alkali analyses free Pregabalin, only needs simply to be beaten a small amount of inorganic salts of removing after precipitation, product is without recrystallization
It can be obtained the Pregabalin of high-purity.
3, the preparation of the Pregabalin in the embodiment of the present invention has reaction condition mild, and reaction yield is high, product purity
Height, product can complete fulfillment pharmaceutical quality standard, be suitble to industrialized production.
Embodiments described above is a part of the embodiment of the present invention, instead of all the embodiments.Reality of the invention
The detailed description for applying example is not intended to limit the range of claimed invention, but is merely representative of selected implementation of the invention
Example.Based on the embodiments of the present invention, obtained by those of ordinary skill in the art without making creative efforts
Every other embodiment, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Pregabalin, which comprises the following steps:
In alkaline solution, (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite are subjected to Huffman weight
Row's reaction obtains reaction solution, the reaction solution is added into acid-organic solvent system, extraction merging organic phase, then plus
Alkali carries out alkali analysis, and the Pregabalin of high-purity is made in mashing washing.
2. the preparation method of Pregabalin according to claim 1, which is characterized in that specifically includes the following steps: in alkalinity
In solution, (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid and sodium hypochlorite are subjected to Hoffmann rearrangement reaction and obtained
The reaction solution is added into acid-organic solvent system reaction solution, then adjusts pH for the first time, layering, water layer is with having
Solvent extraction, merges organic phase, then alkali is added into the organic phase, and second of adjusting pH is beaten until Pregabalin is precipitated
Pulp-water is washed, and the Pregabalin of high-purity is made.
3. the preparation method of Pregabalin according to claim 2, which is characterized in that the Hoffmann rearrangement reaction include with
Lower step:
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid is added portionwise in alkaline aqueous solution, is uniformly mixed
To mixed solution, the aqueous solution of sodium hypochlorite is added drop-wise in the mixed solution, carries out Hoffmann rearrangement reaction, the Hough
The reaction equation of graceful rearrangement reaction is as follows:
4. the preparation method of Pregabalin according to claim 3, which is characterized in that the Hoffmann rearrangement reaction includes:
(R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid is added portionwise in alkaline aqueous solution, is uniformly mixed
To mixed solution, the aqueous solution of sodium hypochlorite is added drop-wise in the mixed solution, 0.5-1h is reacted at 0-10 DEG C, it is described secondary
After the aqueous solution of sodium chlorate is added dropwise, then it is warming up to 65-80 DEG C, the reaction was continued 1-2h.
5. the preparation method of Pregabalin according to claim 3, which is characterized in that alkali and institute in the alkaline aqueous solution
State (R)-(-) -3- (carbamoyl methyl) -5- methylhexanoic acid molar ratio be 3.5-5.5:1, preferably 3.5-4.5:1,
The molar ratio of the sodium hypochlorite and (R)-(-) -3- (the carbamoyl methyl) -5- methylhexanoic acid is 1.5-1.1:1,
Preferably 1.1:1,
Alkali in the alkaline aqueous solution is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide, the alkaline aqueous solution
Mass fraction is 20-30%,
The mass fraction of the aqueous sodium hypochlorite solution is 5-15%.
6. the preparation method of Pregabalin according to claim 2, which is characterized in that after the organic phase includes the layering
The extract layer of obtained organic solvent layer and the water layer obtained after the layering, it is preferred that the extraction times of water layer are 3-4 times.
7. the preparation method of Pregabalin according to claim 2, which is characterized in that described sour selected from inorganic acid and organic
At least one of acid, preferably sulfuric acid, hydrochloric acid, phosphoric acid, at least one of formic acid and acetic acid,
Alcohol of the organic solvent selected from C4, the aliphatic ketone of C1-C6, at least one of ethyl acetate and toluene, preferably just
Butanol, isobutanol, butanone, at least one of ethyl acetate and toluene,
Preferably, pH to 2-7 is adjusted for the first time, more preferably adjusts pH to 2-5.
8. the preparation method of Pregabalin according to claim 2, which is characterized in that the layering specifically includes following step
It is rapid: after the reaction solution is added dropwise, control temperature within 25 DEG C, for the first time adjust pH after, be warming up to 25 DEG C-
30 DEG C, stratification.
9. the preparation method of Pregabalin according to claim 2, which is characterized in that the alkali for alkali analysis is selected from organic
At least one of alkali and inorganic base, preferably triethylamine, ammonium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate and sodium bicarbonate
At least one of,
Preferably, it adjusts pH to 6-8 second, more preferably adjusts pH to 7-8.
10. the preparation method of Pregabalin according to claim 2, which is characterized in that the alkali analysis and mashing washing are specific
The following steps are included: alkali is added into the organic phase, second of adjusting pH is continuously heating to 75-85 DEG C, reacts 0.5-1h,
Filters pressing is cooled to 0-10 DEG C, time 3-5h is precipitated, centrifugation, washing, solid is beaten using purified water, dry after centrifugation.
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