CN111072507A - DL-neopentyl glycine intermediate, preparation method thereof and preparation method of derivative based on intermediate - Google Patents

DL-neopentyl glycine intermediate, preparation method thereof and preparation method of derivative based on intermediate Download PDF

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CN111072507A
CN111072507A CN201911322619.3A CN201911322619A CN111072507A CN 111072507 A CN111072507 A CN 111072507A CN 201911322619 A CN201911322619 A CN 201911322619A CN 111072507 A CN111072507 A CN 111072507A
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许玉东
徐飞翔
华理想
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Nanjing Delno Pharmaceutical Technology Co Ltd
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Abstract

The invention relates to the field of amino acid preparation, and particularly relates to a DL-neopentyl glycine intermediate, a preparation method thereof and a preparation method of a derivative based on the intermediate. The preparation method of the DL-neopentyl glycine intermediate comprises acetylation reaction, condensation reaction, hydrolysis reaction, oximation reaction and reduction reaction, and then the corresponding derivative is obtained through acetylation reaction and resolution. The preparation method shortens the reaction time, the reaction is more thorough, the DL-neopentyl glycine preparation method can be obtained through the reaction, two methods for preparing the derivatives D-neopentyl glycine and L-neopentyl glycine are obtained simultaneously, the purity of the prepared product is high, secondary refinement is not needed, the production cost is reduced, and the industrial large-scale production is facilitated.

Description

DL-neopentyl glycine intermediate, preparation method thereof and preparation method of derivative based on intermediate
Technical Field
The invention relates to the field of amino acid preparation, and particularly relates to a DL-neopentyl glycine intermediate, a preparation method thereof and a preparation method of a derivative based on the intermediate.
Background
Amino acids are widely present in the natural world, and there are two isomers of D-type amino acids and L-type amino acids, which exert different physiological actions in the body. L-neopentyl glycine, D-neopentyl glycine, are all off-white to light beige crystalline powders, which are well known as DL-neopentyl glycine derivatives. At present, domestic and foreign documents report few methods for producing DL-neopentyl glycine and DL-neopentyl glycine derivatives, and most of the methods are carried out by adopting a synthesis method, so that the method has the disadvantages of serious environmental pollution, low yield, complicated post-treatment of products and unsuitability for mass production.
Disclosure of Invention
In order to solve the problems, improve the yield and purity of the product, improve the production process of the product, reduce the production cost of the finished product and improve the subsequent maintenance effect of the product, the invention provides a preparation method of a DL-neopentyl glycine intermediate, which comprises the following steps:
(1) acetylation reaction: firstly weighing glycylglycine and acetic anhydride, adding glycylglycine into acetic anhydride solution for dissolving, heating for refluxing, after the reaction is finished, concentrating and drying reaction liquid in vacuum to obtain oily matter, weighing, adding ethyl acetate for dissolving, filtering to remove salt, then concentrating and drying obtained filtrate in vacuum, slowly adding petroleum ether, stirring and pulping while adding the petroleum ether, then carrying out suction filtration, and drying to obtain an intermediate diacetylated glycylglycine;
(2) condensation reaction: taking the intermediate of the diametylated glycylglycine prepared in the step (1), simultaneously weighing pivalaldehyde, potassium carbonate and tetrabutylammonium bromide, adding the diametylated glycylglycine, the potassium carbonate and the tetrabutylammonium bromide into a DMF solution, dropwise adding the pivalaldehyde under the stirring condition, reacting at normal temperature, adding a reaction solution into 1L of deionized water after the reaction is finished, stirring for crystallization, performing suction filtration, and performing vacuum drying to obtain an intermediate of neopentyl diametylated glycylglycine;
(3) adding the intermediate neopentyl diacetylglycylglycine prepared in the step 2 into HCL solution, gradually heating to 105 ℃, clarifying the reaction solution, deepening the color, reacting for a period of time, stirring at low temperature after the reaction is finished, crystallizing, filtering, and drying in vacuum to obtain an intermediate β -keto acid intermediate;
(4) oximation reaction, namely adding the intermediate β -keto acid prepared in the step (3) into a 20% NaOH solution, heating and stirring, clarifying a reaction solution, then cooling the temperature to 40 ℃, dropwise adding hydroxylamine hydrochloride in batches, separating out a large amount of solids in the dropwise adding process, stirring for 30min after the addition is finished, finally cooling the reaction solution to 0 ℃, stirring for 1-2h, carrying out suction filtration, washing crystals with ice water for 2-3 times, and carrying out vacuum drying to obtain an intermediate oxime compound;
(5) reduction reaction: and (3) adding the intermediate oxime compound prepared in the step (4) into a hydrochloric acid solution, stirring, heating to 35 ℃, uniformly stirring, adding reducing agent zinc powder every 30min, and stopping adding the zinc powder after the reaction is finished. Concentrating the reaction liquid to dryness, and crystallizing with ultrapure water to obtain an intermediate DL-neopentyl glycine.
Further, in the step (1), the mass ratio of glycylglycine to acetic anhydride is (1-2):2, the temperature raising reflux temperature is 120-.
Further, in the step (2), the ratio of the diacetylglycylglycine to the glycylglycine is calculated according to molar mass: pivalaldehyde: potassium carbonate: tetrabutylammonium bromide: and DMF (20: 20:20:1: 80), and the reaction time at normal temperature is 3-4 h.
Further, in the step (3), the addition amount of the neopentyl diacetyl glycylglycine and the HCL is (1-2): 6, the concentration of HCL is 5-6mol/l, the temperature rise is 95-115 ℃, and the reaction time is 4-6 h.
Further, in the step (4), the β -keto acid, the hydroxylamine hydrochloride and the NaOH solution are added according to the mass ratio of 2 (1-2) to (8-10), the heating and stirring are carried out, the heating temperature is 45-55 ℃, and the stirring time is 1-2 hours.
Further, in the step (5), the dosage of the intermediate oxime compound and hydrochloric acid is 1: (6-8), adding the zinc powder in batches, wherein the adding amount is 40-60g each time, and the detection standard of reaction completion is to detect that the oximate reaction is complete by adopting TCL.
A process for preparing D-neopentyl glycine from a DL-neopentyl glycine intermediate comprising the steps of:
(6) acetylation reaction and resolution: and (3) adding the intermediate DL-neopentyl glycine prepared in the step (5) into 4 times of pure water, stirring, adjusting the pH value by using a NaOH solution with the concentration of 20% at low temperature, dropwise adding an acetic anhydride solution, and stirring at normal temperature. After the reaction is completed, cooling the reaction liquid to below 0 ℃, adjusting the pH value by using concentrated hydrochloric acid, separating out a large amount of white solid, stirring for 1-2h, performing suction filtration, and performing vacuum drying to obtain AC-DL-neopentyl glycine;
(7) preparation of D-neopentyl glycine: and (3) adding the AC-DL-neopentyl glycine prepared in the step (6) into an 8-time aqueous solution, adjusting the pH value by using ammonia water, reacting at 37 ℃, adding D-aminoacylase, stirring, standing for reacting, decoloring the solution by using activated carbon, concentrating to a small volume, performing suction filtration to obtain a product D-neopentyl glycine, and keeping a mother solution.
Further, the mass ratio of DL-neopentyl glycine to water to acetic anhydride is 1:4 (1-2), the pH value regulated by NaOH solution is 7.5-8.5, the dropwise adding acetic anhydride is stirred for 8-9 hours at normal temperature, and the pH value regulated by concentrated hydrochloric acid is 1-2;
in the step (7), the mass ratio of the AC-DL-neopentyl glycine to the water is 1 (6-10), the mass of the D-aminoacylase accounts for 0.02 percent of that of the AC-DL-neopentyl glycine, the pH value is adjusted to be 7.5-8 by the ammonia water, and the standing reaction time is 22-26 h.
A process for preparing L-neopentyl glycine from a DL-neopentyl glycine intermediate comprising the steps of:
(8) preparation of L-neopentyl glycine: and (3) taking the residual mother liquor in the step (7), regulating the pH value with HCL, crystallizing to obtain acetylated-L-neopentyl glycine, adding 8-12 times of HCL for reflux reaction for 10 hours, recovering hydrochloric acid, regulating the pH value with NaOH, and crystallizing to obtain L-neopentyl glycine.
Further, the pH value of HCL is adjusted to be 2.5-4, the reaction reflux time is 8-12h, and the pH value of NaOH is adjusted to be 7.5-8.5.
Has the advantages that:
the preparation method of the invention shortens the reaction time, has more thorough reaction, and is synthesized by taking glycylglycine as the initial raw material through several simple reactions of acetylation, addition, hydrolysis, oximation, reduction, acetylation and resolution. In the preparation process of the product, each part of the product from the intermediate to the product is pure, high in yield, simple to operate, and easy to obtain conditions, so that the waste of raw materials is avoided, and the method is also suitable for industrial large-scale production. The purity of the product is up to 99% and the yield is up to 99.9% by high performance liquid chromatography.
Description of the drawings:
FIG. 1: the invention implements 1 DL-neopentyl glycine intermediate and its derivative preparation schematic diagram;
FIG. 2: the Mass Spectrum (MS) of the DL-neopentyl glycine intermediate prepared in the embodiment 1 of the invention;
FIG. 3: the Mass Spectrum (MS) of the D-neopentyl glycine prepared in the embodiment 1 of the invention;
FIG. 4: the Mass Spectrum (MS) of the L-neopentyl glycine prepared in the embodiment 1 of the invention.
Detailed Description
The invention relates to a test item and a test method thereof, wherein the test item comprises the following steps:
purity: taking a proper amount of prepared product, preparing the prepared product into a 1mg/ml solution by using fluidity, and calculating the purity of the product by peak area by adopting liquid chromatography.
Yield: calculating by the formula:
Figure BDA0002327566660000041
wherein m is1Is the mass of D-neopentyl glycine, m2Is the mass of L-neopentyl glycine, m3Is the mass of DL-neopentyl glycine.
Example 1:
the preparation method of the DL-neopentyl glycine intermediate comprises the following steps:
(1) acetylation reaction: firstly weighing 80g of glycylglycine and 80g of acetic anhydride, adding glycylglycine into an acetic anhydride solution for dissolving, heating to 120 ℃, refluxing for 4h, after the reaction is finished, concentrating and drying the reaction solution in vacuum to obtain 116g of oily matter, adding 232g of ethyl acetate for dissolving, filtering to remove salt, concentrating and drying the obtained filtrate in vacuum, slowly adding 232g of petroleum ether, stirring and pulping while adding the petroleum ether, then carrying out suction filtration and drying to obtain 163g of intermediate diacetylated glycylglycine;
(2) condensation reaction: taking 20g of the intermediate obtained in the step (1), simultaneously weighing 20g of pivalaldehyde, 20g of potassium carbonate and 1g of tetrabutylammonium bromide, adding the diacetyl glycylglycine, the potassium carbonate and the tetrabutylammonium bromide into 80g of DMF (dimethyl formamide) solution, dropwise adding the pivalaldehyde under the stirring condition, reacting for 3 hours at normal temperature, after the reaction is finished, adding the reaction solution into 1L of deionized water, stirring for crystallization, carrying out suction filtration, and carrying out vacuum drying to obtain 36g of the intermediate neopentyl diacetyl glycylglycine;
(3) hydrolysis reaction, namely adding 36g of the intermediate neopentyl diacetylglycylglycine prepared in the step 2 into 216g of HCL solution with the concentration of 5mol/l, gradually heating to 95 ℃, enabling the reaction solution to become clear and dark, reacting for 4 hours, stirring and crystallizing at low temperature after the reaction is finished, performing suction filtration, and performing vacuum drying to obtain 26g of the intermediate β -keto acid intermediate;
(4) oximation reaction, namely adding 26g of intermediate β -keto acid prepared in the step (3) into 208g of 20% NaOH solution, heating to 45 ℃, stirring for 1h, clarifying the reaction solution, then cooling to 40 ℃, dropwise adding 13g of hydroxylamine hydrochloride in batches, separating out a large amount of solids in the dropwise adding process, stirring for 30min after the addition is finished, finally cooling the reaction solution to 0 ℃, stirring for 1h, carrying out suction filtration, washing a crystal with ice water for 2 times, and carrying out vacuum drying to obtain 18g of intermediate oxime;
(5) reduction reaction: and (3) adding 18g of the intermediate oxime compound prepared in the step (4) into 6 times of hydrochloric acid solution, stirring, heating to 35 ℃, uniformly stirring, adding 40g of reducing agent zinc powder every 30min, and stopping adding the zinc powder after the reaction is finished. The reaction solution was concentrated to dryness and crystallized with ultrapure water to obtain 11.3g of intermediate DL-neopentyl glycine.
A process for the preparation of D-neopentylglycine, based on the DL-neopentylglycine intermediate:
(6) acetylation reaction and resolution: adding 11.3g of the intermediate DL-neopentyl glycine prepared in the step (5) into 4 times of pure water, stirring, adjusting the pH to 7.5 by using a NaOH solution with the concentration of 20% at low temperature, dropwise adding 22.6g of acetic anhydride solution, and stirring for 8 hours at normal temperature. After the reaction is completed, cooling the reaction liquid to below 0 ℃, adjusting the pH to 1 by using concentrated hydrochloric acid, separating out a large amount of white solid, stirring for 1h, filtering, and drying in vacuum to obtain 7.11g of AC-DL-neopentyl glycine;
(7) preparation of D-neopentyl glycine: adding 7.11g of the AC-DL-neopentyl glycine prepared in the step (6) into 8 times of aqueous solution, adjusting the pH value to 7.5 by using ammonia water, reacting at 37 ℃, adding 0.0014g D-aminoacylase, stirring, standing for 22 hours, fully reacting, decoloring the solution with activated carbon, concentrating to a small volume, and performing suction filtration to obtain 6.28g of a product D-neopentyl glycine, wherein the mother solution is reserved.
A process for preparing L-neopentyl glycine from a DL-neopentyl glycine intermediate comprising the steps of:
(8) preparation of L-neopentyl glycine: and (3) taking the residual mother liquor in the step (7), adjusting the pH value of the HCL to 2.5, crystallizing to obtain acetylated-L-neopentyl glycine, adding 10 times of HCL, refluxing for 10 hours, recovering hydrochloric acid, adjusting the pH value to 7.5 by NaOH, and crystallizing to obtain 4.99g of L-neopentyl glycine.
According to the method, the purity of the obtained DL-neopentyl glycine intermediate, L-neopentyl glycine and D-neopentyl glycine is more than 99% as can be seen by nuclear magnetic resonance spectrum, wherein the recovered D-neopentyl glycine is 55.6%, the recovered L-neopentyl glycine is 44.1% and the overall yield is 99.7%.
Example 2:
the preparation method of the DL-neopentyl glycine intermediate comprises the following steps:
(1) acetylation reaction: firstly weighing 80g of glycylglycine and 160g of acetic anhydride, adding glycylglycine into an acetic anhydride solution for dissolving, heating to 130 ℃, refluxing for 5 hours, after the reaction is finished, concentrating and drying the reaction solution in vacuum to obtain 108g of oily matter, adding 108g of ethyl acetate for dissolving, filtering to remove salt, concentrating and drying the obtained filtrate in vacuum, slowly adding 108g of petroleum ether, stirring and pulping while adding the petroleum ether, then carrying out suction filtration and drying to obtain 151g of intermediate diacetyl glycylglycine;
(2) condensation reaction: taking 30g of the intermediate obtained in the step (1), simultaneously weighing 30g of pivalaldehyde, 30g of potassium carbonate and 1.5g of tetrabutylammonium bromide, adding the diacetyl glycylglycine, the potassium carbonate and the tetrabutylammonium bromide into 120g of DMF solution, dropwise adding the pivalaldehyde under the stirring condition, reacting for 4 hours at normal temperature, after the reaction is finished, adding the reaction solution into 1L of deionized water, stirring and crystallizing, performing suction filtration, and performing vacuum drying to obtain 46g of the intermediate neopentyl diacetyl glycylglycine;
(3) hydrolysis reaction, namely adding 46g of the intermediate neopentyl diacetylglycylglycine prepared in the step 2 into 138g of HCL solution with the concentration of 6mol/l, gradually heating to 115 ℃, enabling the reaction solution to become clear and dark, reacting for 6h, stirring and crystallizing at low temperature after the reaction is finished, performing suction filtration, and performing vacuum drying to obtain 37g of the intermediate β -keto acid intermediate;
(4) oximation reaction, namely adding 37g of intermediate β -keto acid prepared in the step (3) into 185g of 20% NaOH solution, heating to 55 ℃, stirring for 1.5h, clarifying the reaction solution, then cooling to 40 ℃, dropwise adding 37g of hydroxylamine hydrochloride in batches, separating out a large amount of solids in the dropwise adding process, stirring for 30min after the dropwise adding is finished, finally cooling the reaction solution to 0 ℃, stirring for 2h, performing suction filtration, washing crystals for 3 times by using ice water, and performing vacuum drying to obtain 25g of intermediate oximation;
(5) reduction reaction: adding 25g of the intermediate oxime compound prepared in the step (4) into 8 times of hydrochloric acid solution, stirring, heating to 35 ℃, uniformly stirring, adding 50g of reducing agent zinc powder every 30min, and stopping adding the zinc powder after the reaction is finished. The reaction solution was concentrated to dryness and crystallized with ultrapure water to obtain 15.5g of intermediate DL-neopentyl glycine.
A process for the preparation of D-neopentylglycine, based on the DL-neopentylglycine intermediate:
(6) acetylation reaction and resolution: adding 15.5g of the intermediate DL-neopentyl glycine prepared in the step (5) into 6 times of pure water, stirring, adjusting the pH to 8.5 by using a NaOH solution with the concentration of 20% at low temperature, dropwise adding 15.5g of acetic anhydride solution, and stirring for 9 hours at normal temperature. After the reaction is completed, cooling the reaction liquid to below 0 ℃, adjusting the pH to 2 by using concentrated hydrochloric acid, separating out a large amount of white solid, stirring for 1h, filtering, and drying in vacuum to obtain 10.37g of AC-DL-neopentyl glycine;
(7) preparation of D-neopentyl glycine: and (3) adding 10.37g of the AC-DL-neopentyl glycine prepared in the step (6) into 6 times of aqueous solution, adjusting the pH value to 8 by using ammonia water, reacting at 37 ℃, adding 0.0021g D-aminoacylase, stirring, standing for 26 hours, fully reacting, decoloring the solution with activated carbon, concentrating to a small volume, and performing suction filtration to obtain 8.38g of a product D-neopentyl glycine, wherein the mother solution is reserved.
A process for preparing L-neopentyl glycine from a DL-neopentyl glycine intermediate comprising the steps of:
(8) preparation of L-neopentyl glycine: and (3) taking the residual mother liquor in the step (7), adjusting the pH value of the HCL to be 4, crystallizing to obtain acetylated-L-neopentyl glycine, adding 8 times of HCL, refluxing for 12 hours, recovering hydrochloric acid, adjusting the pH value to be 8.5 by NaOH, and crystallizing to obtain 7.01g of L-neopentyl glycine.
According to the method, the purity of the obtained DL-neopentyl glycine intermediate, L-neopentyl glycine and D-neopentyl glycine is more than 99% as can be seen by nuclear magnetic resonance spectrum, wherein the recovered D-neopentyl glycine is 54.06%, the recovered L-neopentyl glycine is 45.23% and the overall yield is 99.29% in the prepared DL-neopentyl glycine intermediate.
Example 3:
the preparation method of the DL-neopentyl glycine intermediate comprises the following steps:
(1) acetylation reaction: firstly weighing 80g of glycylglycine and 80g of acetic anhydride, adding glycylglycine into an acetic anhydride solution for dissolving, heating to 140 ℃, refluxing for 6 hours, after the reaction is finished, concentrating and drying the reaction solution in vacuum to obtain 112g of oily matter, adding 112g of ethyl acetate for dissolving, filtering to remove salt, concentrating and drying the obtained filtrate in vacuum, slowly adding 112g of petroleum ether, stirring and pulping while adding the petroleum ether, then carrying out suction filtration and drying to obtain 143g of intermediate diacetylated glycylglycine;
(2) condensation reaction: taking 40g of the intermediate obtained in the step (1), simultaneously weighing 40g of pivalaldehyde, 40g of potassium carbonate and 2g of tetrabutylammonium bromide, adding the diacetyl glycylglycine, the potassium carbonate and the tetrabutylammonium bromide into 160g of DMF solution, dropwise adding the pivalaldehyde under the stirring condition, reacting for 3.5 hours at normal temperature, after the reaction is finished, adding the reaction solution into 1L of deionized water, stirring and crystallizing, performing suction filtration, and performing vacuum drying to obtain 41g of the intermediate neopentyl diacetyl glycylglycine;
(3) hydrolysis reaction, namely adding 41g of the intermediate neopentyl diacetylglycylglycine prepared in the step 2 into 246g of HCL solution with the concentration of 5mol/l, gradually heating to 105 ℃, enabling the reaction solution to become clear and dark, reacting for 5h, stirring and crystallizing at low temperature after the reaction is finished, performing suction filtration, and performing vacuum drying to obtain 29g of the intermediate β -keto acid intermediate;
(4) oximation reaction, namely adding 29g of the intermediate β -keto acid prepared in the step (3) into 145g of a 20% NaOH solution, heating to 50 ℃, stirring for 2h, cooling the reaction solution to 40 ℃, dropwise adding 14.5g of hydroxylamine hydrochloride in batches, separating out a large amount of solids in the dropwise adding process, stirring for 30min after the dropwise adding is finished, cooling the reaction solution to 0 ℃, stirring for 1.5h, performing suction filtration, washing crystals for 2 times with ice water, and performing vacuum drying to obtain 23g of an intermediate oximate;
(5) reduction reaction: adding 23g of the intermediate oxime compound prepared in the step (4) into 7 times of hydrochloric acid solution, stirring, heating to 35 ℃, uniformly stirring, adding 60g of reducing agent zinc powder every 30min, and stopping adding the zinc powder after the reaction is finished. The reaction solution was concentrated to dryness and crystallized with ultrapure water to obtain 16.7g of intermediate DL-neopentyl glycine.
A process for the preparation of D-neopentylglycine, based on the DL-neopentylglycine intermediate:
(6) acetylation reaction and resolution: adding 16.7g of the intermediate DL-neopentyl glycine prepared in the step (5) into 4 times of pure water, stirring, adjusting the pH to 8 by using a NaOH solution with the concentration of 20% at low temperature, dropwise adding 33.4g of acetic anhydride solution, and stirring for 8.5 hours at normal temperature. After the reaction is completed, cooling the reaction liquid to below 0 ℃, adjusting the pH to 2 by using concentrated hydrochloric acid, separating out a large amount of white solid, stirring for 1h, filtering, and drying in vacuum to obtain 11.3g of AC-DL-neopentyl glycine;
(7) preparation of D-neopentyl glycine: and (3) adding 11.3g of the AC-DL-neopentyl glycine prepared in the step (6) into 10 times of aqueous solution, adjusting the pH value to 7.5 by using ammonia water, reacting at 37 ℃, adding 0.002 0.0022g D-aminoacylase, stirring, standing for 24 hours, fully reacting, decoloring the solution with activated carbon, concentrating to a small volume, and performing suction filtration to obtain 9.77g of a product D-neopentyl glycine, wherein the mother solution is reserved.
A process for preparing L-neopentyl glycine from a DL-neopentyl glycine intermediate comprising the steps of:
(8) preparation of L-neopentyl glycine: and (3) taking the residual mother liquor in the step (7), adjusting the pH value of the HCL to be 3, crystallizing to obtain acetylated-L-neopentyl glycine, adding 10 times of HCL, refluxing for 10 hours, recovering hydrochloric acid, adjusting the pH value to be 8 by NaOH, and crystallizing to obtain 6.88g of L-neopentyl glycine.
According to the method, the purity of the obtained DL-neopentyl glycine intermediate, L-neopentyl glycine and D-neopentyl glycine is more than 99% as can be seen by nuclear magnetic resonance spectrum, and the recovered L-neopentyl glycine reaches 58.5%, the recovered D-neopentyl glycine reaches 41.2% and the overall yield reaches 99.7%.
The examples show that the overall yield of the L-neopentyl glycine and the D-neopentyl glycine prepared by the chemical resolution method is more than 99%, and the purity of the DL-neopentyl glycine intermediate, the L-neopentyl glycine and the D-neopentyl glycine is more than 99% as shown by nuclear magnetic resonance spectra, so that the product purity is high and the yield is high.
The above description is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto. Any person skilled in the art should be able to substitute or change the technical solution of the present invention and its inventive concept within the technical scope of the present invention.

Claims (10)

1. A preparation method of a DL-neopentyl glycine intermediate is characterized by comprising the following steps:
(1) acetylation reaction: firstly weighing glycylglycine and acetic anhydride, adding glycylglycine into acetic anhydride solution for dissolving, heating for refluxing, after the reaction is finished, concentrating and drying reaction liquid in vacuum to obtain oily matter, weighing, adding ethyl acetate for dissolving, filtering to remove salt, then concentrating and drying obtained filtrate in vacuum, slowly adding petroleum ether, stirring and pulping while adding the petroleum ether, then carrying out suction filtration, and drying to obtain an intermediate diacetylated glycylglycine;
(2) condensation reaction: taking the intermediate of the diametylated glycylglycine prepared in the step (1), simultaneously weighing pivalaldehyde, potassium carbonate and tetrabutylammonium bromide, adding the diametylated glycylglycine, the potassium carbonate and the tetrabutylammonium bromide into a DMF solution, dropwise adding the pivalaldehyde under the stirring condition, reacting at normal temperature, adding a reaction solution into 1L of deionized water after the reaction is finished, stirring for crystallization, performing suction filtration, and performing vacuum drying to obtain an intermediate of neopentyl diametylated glycylglycine;
(3) adding the intermediate neopentyl diacetylglycylglycine prepared in the step 2 into HCL solution, gradually heating to 105 ℃, clarifying the reaction solution, deepening the color, reacting for a period of time, stirring at low temperature after the reaction is finished, crystallizing, filtering, and drying in vacuum to obtain an intermediate β -keto acid intermediate;
(4) oximation reaction, namely adding the intermediate β -keto acid prepared in the step (3) into a 20% NaOH solution, heating and stirring, clarifying a reaction solution, then cooling the temperature to 40 ℃, dropwise adding hydroxylamine hydrochloride in batches, separating out a large amount of solids in the dropwise adding process, stirring for 30min after the addition is finished, finally cooling the reaction solution to 0 ℃, stirring for 1-2h, carrying out suction filtration, washing crystals with ice water for 2-3 times, and carrying out vacuum drying to obtain an intermediate oxime compound;
(5) reduction reaction: and (3) adding the intermediate oxime compound prepared in the step (4) into a hydrochloric acid solution, stirring, heating to 35 ℃, uniformly stirring, adding reducing agent zinc powder every 30min, and stopping adding the zinc powder after the reaction is finished. Concentrating the reaction liquid to dryness, and crystallizing with ultrapure water to obtain an intermediate DL-neopentyl glycine.
2. The method as claimed in claim 1, wherein in the step (1), the mass ratio of glycylglycine to acetic anhydride is (1-2):2, the temperature-rising reflux temperature is 120-.
3. The process for preparing a DL-neopentyl glycine intermediate as claimed in claim 1, wherein in the step (2), the ratio of the diacetylglycylglycine: pivalaldehyde: potassium carbonate: tetrabutylammonium bromide: and DMF (20: 20:20:1: 80), and the reaction time at normal temperature is 3-4 h.
4. The process for preparing DL-neopentyl glycine intermediate as claimed in claim 1, wherein in the step (3), the neopentyl bis acetylated glycylglycine and HCL are added in the amount of (1-2): 6, the concentration of HCL is 5-6mol/l, the temperature rise is 95-115 ℃, and the reaction time is 4-6 h.
5. The method for preparing DL-neopentyl glycine intermediate as claimed in claim 1, wherein in step (4), the β -keto acid, hydroxylamine hydrochloride and NaOH solution are added in the mass ratio of 2 (1-2) to (8-10), the heating temperature is 45-55 ℃, and the stirring time is 1-2 h.
6. The process for preparing a DL-neopentyl glycine intermediate as claimed in claim 1, wherein in the step (5), the intermediate oxime compound and hydrochloric acid are used in the mass ratio of 1: (6-8), adding the zinc powder in batches, wherein the adding amount is 40-60g each time, and the detection standard of reaction completion is to detect that the oximate reaction is complete by adopting TCL.
7. A process for the preparation of D-neopentylglycine, an intermediate prepared according to claims 1-6, comprising the steps of:
(6) acetylation reaction and resolution: adding the intermediate DL-neopentyl glycine prepared in the step (5) into 4 times of pure water, stirring, adjusting the pH value by using a NaOH solution with the concentration of 20% at low temperature, dropwise adding an acetic anhydride solution, stirring at normal temperature, cooling the reaction liquid to below 0 ℃ after the reaction is completed, adjusting the pH value by using concentrated hydrochloric acid, separating out a large amount of white solids, stirring for 1-2h, carrying out suction filtration, and carrying out vacuum drying to obtain AC-DL-neopentyl glycine;
(7) preparation of D-neopentyl glycine: and (3) adding the AC-DL-neopentyl glycine prepared in the step (6) into 6-10 times of aqueous solution, adjusting the pH value by using ammonia water, reacting at 37 ℃, adding D-aminoacylase, stirring, standing for reacting, decoloring the solution by using activated carbon, concentrating to a small volume, performing suction filtration to obtain a product D-neopentyl glycine, and keeping mother liquor.
8. The method for preparing D-neopentyl glycine as claimed in claim 7, characterized in that in step (6), the mass ratio of DL-neopentyl glycine to water to acetic anhydride is 1:4 (1-2), the pH value adjusted by NaOH solution is 7.5-8.5, the dropwise adding acetic anhydride is stirred for 8-9h at normal temperature, and the pH value adjusted by concentrated hydrochloric acid is 1-2;
in the step (7), the mass ratio of the AC-DL-neopentyl glycine to the water is 1 (6-10), the mass of the D-aminoacylase accounts for 0.02 percent of that of the AC-DL-neopentyl glycine, the pH value is adjusted to be 7.5-8 by the ammonia water, and the standing reaction time is 22-26 h.
9. A process for the preparation of L-neopentyl glycine, an intermediate prepared according to claims 1 to 8, comprising the steps of:
(8) preparation of L-neopentyl glycine: and (3) taking the residual mother liquor in the step (7), regulating the pH value with HCL, crystallizing to obtain acetylated-L-neopentyl glycine, adding 8-12 times of HCL for reflux reaction for 10 hours, recovering hydrochloric acid, regulating the pH value with NaOH, and crystallizing to obtain L-neopentyl glycine.
10. The method for preparing L-neopentyl glycine as claimed in claim 9, characterized in that in step (8), said HCL is adjusted to pH 2.5-4, said reaction reflux time is 8-12h, said NaOH is adjusted to pH 7.5-8.5.
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