CN115536524B - Preparation method of 3-isobutyl glutaric acid - Google Patents
Preparation method of 3-isobutyl glutaric acid Download PDFInfo
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- CN115536524B CN115536524B CN202211148183.2A CN202211148183A CN115536524B CN 115536524 B CN115536524 B CN 115536524B CN 202211148183 A CN202211148183 A CN 202211148183A CN 115536524 B CN115536524 B CN 115536524B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- 238000000034 method Methods 0.000 claims abstract description 30
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims abstract description 29
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- RMEIIVVTCGPCHM-UHFFFAOYSA-N 2-(2-methylpropyl)propane-1,1,3,3-tetracarboxylic acid Chemical compound C(CC(C)C)(C(C(=O)O)C(=O)O)C(C(=O)O)C(=O)O RMEIIVVTCGPCHM-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
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- 239000012074 organic phase Substances 0.000 claims 1
- 238000003756 stirring Methods 0.000 abstract description 18
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 abstract description 11
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- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
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- 210000004556 brain Anatomy 0.000 description 7
- 238000009776 industrial production Methods 0.000 description 7
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- 238000006845 Michael addition reaction Methods 0.000 description 6
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- 238000006482 condensation reaction Methods 0.000 description 6
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- 239000002253 acid Substances 0.000 description 5
- 150000001728 carbonyl compounds Chemical class 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- LCPQXKAEQQWPAB-UHFFFAOYSA-N 4-ethoxycarbonyl-7-methyloct-4-enoic acid Chemical compound CCOC(=O)C(CCC(O)=O)=CCC(C)C LCPQXKAEQQWPAB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- -1 (E) -N- (5-methylhex-2-enyl) -benzamide Chemical compound 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- XBRGZVMBYLXWTE-UHFFFAOYSA-N ethyl 5-methylhex-2-enoate Chemical compound CCOC(=O)C=CCC(C)C XBRGZVMBYLXWTE-UHFFFAOYSA-N 0.000 description 3
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- 238000006460 hydrolysis reaction Methods 0.000 description 3
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- 239000000463 material Substances 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
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- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000000911 decarboxylating effect Effects 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- WQVNYCULJRPXJR-UHFFFAOYSA-N 2,4-dicyano-3-(2-methylpropyl)pentanediamide Chemical compound CC(C)CC(C(C#N)C(N)=O)C(C#N)C(N)=O WQVNYCULJRPXJR-UHFFFAOYSA-N 0.000 description 1
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
- BQDIBWCNCPDDPZ-UHFFFAOYSA-N 3-carbamoyl-5-methylhexanoic acid Chemical compound CC(C)CC(C(N)=O)CC(O)=O BQDIBWCNCPDDPZ-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical class NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
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- 229940009697 lyrica Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
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- 239000003444 phase transfer catalyst Substances 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01C—AMMONIA; CYANOGEN; COMPOUNDS THEREOF
- C01C1/00—Ammonia; Compounds thereof
- C01C1/24—Sulfates of ammonium
- C01C1/242—Preparation from ammonia and sulfuric acid or sulfur trioxide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of preparation of pregabalin key intermediates, in particular to a preparation method of 3-isobutyl glutaric acid, which takes cyanoacetamide and isovaleraldehyde as raw materials and prepares the 3-isobutyl glutaric acid by a one-pot method through an improved process of adding ammonium sulfate. The method has the characteristics of simple process, low content of monocarboxyl as a byproduct, less three wastes and the like, solves the problem that the existing process is difficult to stir, and is suitable for industrialized production of 3-isobutyl glutaric acid.
Description
Technical Field
The invention relates to the field of preparation of pregabalin key intermediates, in particular to a preparation method of 3-isobutyl glutaric acid. In particular to a preparation method of 3-isobutyl glutaric acid, which takes cyanoacetamide and isovaleraldehyde as raw materials and is suitable for industrial production by adding ammonium sulfate to improve the process.
Background
Pregabalin, its commercial name is Le Ruika (Lyrica), is a novel gamma-aminobutyric acid analogue, can be used for treating pain caused by postherpetic neuralgia, peripheral neuralgia and diabetic peripheral neuropathy, and has good antiepileptic therapeutic effect.
The preparation method of pregabalin mainly comprises the following four steps:
1. natural chiral library method: l-leucine is used as a starting material, and (3S) -isobutyl lactone is obtained through bromination, esterification, alkylation, hydrolysis and cyclization, and then the target product pregabalin is obtained through iodination, azide, hydrolysis and catalytic hydrogenation.
2. Asymmetric synthesis: taking (E) -N- (5-methylhex-2-enyl) -benzamide as a raw material, selectively hydrogenating, hydrolyzing to remove the benzamide, and finally hydrogenating under the catalysis of platinum dioxide to obtain pregabalin.
3. Enzyme resolution method: the method comprises the steps of selecting isovaleraldehyde and diethyl malonate as raw materials, carrying out a brain Wen Ge condensation reaction and a 1, 4-Michael addition reaction on the raw materials under the catalysis of organic amine to generate an intermediate, splitting the intermediate by hydrolytic enzyme or lipase, and then carrying out a series of processes such as catalytic hydrogenation and the like to obtain pregabalin.
4. Chemical resolution method: 3-carbamoyl-5-methylhexanoic acid is obtained from 3-isobutylglutaric acid, and the substance can be firstly degraded into 3-aminomethyl-5-methylhexanoic acid, then resolved by (S) -mandelic acid, and degraded into the target product pregabalin.
In the existing industrial production, most of pregabalin adopts a chemical resolution method, and in the chemical resolution method, 3-isobutyl glutaric acid is an important intermediate, so that improvement of the preparation process of 3-isobutyl glutaric acid has important significance for the industrial production of pregabalin.
The existing preparation method of 3-isobutyl glutaric acid takes isovaleraldehyde and carbonyl compound containing active hydrogen as raw materials, and the 3-isobutyl glutaric acid is obtained by brain Wen Ge condensation reaction, 1, 4-Michael addition reaction, acidic hydrolysis, decarboxylation under concentrated acid and extraction.
You Haifeng et al propose that diethyl malonate is used as a carbonyl compound containing active hydrogen under alkaline catalysis, and is subjected to condensation reaction with isovaleraldehyde and dehydration reaction with brain Wen Ge to obtain ethyl 2-carboxyethyl-5-methyl-2-hexenoate. And then heating and decarboxylating to obtain the 5-methyl-2-hexenoic acid ethyl ester, and then carrying out Michael addition on the 5-methyl-2-hexenoic acid ethyl ester and diethyl malonate. Finally, carrying out acidic hydrolysis, decarboxylating under concentrated acid, and extracting to obtain the 3-isobutyl glutaric acid. Because the addition steric hindrance is large when the 2-carboxyethyl-5-methyl-2-hexenoic acid ethyl ester is directly added with diethyl malonate, the reaction is difficult to complete. So the route is subjected to condensation and dehydration reaction by brain Wen Ge to obtain the 2-carboxyethyl-5-methyl-2-hexenoic acid ethyl ester, and then the 2-carboxyethyl-5-methyl-2-hexenoic acid ethyl ester is not directly added with diethyl malonate, but is subjected to decarboxylation to generate the 5-methyl-2-hexenoic acid ethyl ester with smaller steric hindrance, and then is subjected to Michael addition with the diethyl malonate. The method requires purification and separation of intermediates, multiple replacement of reaction solvents and catalyst systems, complicated operation steps and great increase of three wastes, and is not suitable for industrial production.
Zhang Jing et al propose that ethyl cyanoacetate is used as a carbonyl compound containing active hydrogen under basic catalysis, and is subjected to condensation reaction with isovaleraldehyde by brain Wen Ge, and then is subjected to Michael addition with diethyl malonate to obtain ethyl 2-cyano-4-carboxyethyl-3-isobutyl glutarate. Then acidic hydrolysis, decarboxylation under concentrated acid, extraction to obtain 3-isobutyl glutaric acid. The method uses the carbonyl compounds of two active hydrogen of ethyl cyanoacetate and diethyl malonate, so that the content of monocarboxyl byproducts in the product is high, and meanwhile, the reaction time of the method is long, and the operation is complicated.
Zdenko Hamersak and Zhou Bugao propose that cyanoacetamide is used as a carbonyl compound containing active hydrogen to undergo condensation reaction with isovaleraldehyde through brain Wen Ge under alkaline catalysis. And after dehydration, the mixture is Michael added with cyanoacetamide to obtain 2, 4-dicyano-3-isobutyl glutaramide. Then acidic hydrolysis is carried out, decarboxylation is carried out under concentrated acid, and 3-isobutyl glutaric acid is obtained by extraction. The route of the preparation method comprises a series of reactions of condensation, dehydration, michael addition, acid hydrolysis and decarboxylation under concentrated acid of the brain Wen Ge, wherein the reaction can be completed by adopting a one-pot method, and the reaction solvent is water, so that the route is convenient to operate, saves energy consumption, generates less three wastes and is beneficial to industrial production. However, this route has a problem that a large amount of white solid appears in the reaction liquid after the reaction (condensation, dehydration and addition) starts, the solid absorbs or encapsulates the solvent water and the reaction liquid, the whole reaction material becomes a paste, the stirring cannot sufficiently mix the reaction material, and the reaction cannot be completed rapidly and sufficiently. Therefore, although the reaction itself has low activation energy and can be carried out in an ice-water bath, even if the reaction is carried out for more than 30 hours, the reaction is insufficient, and the monocarboxyl compound still exists in the product, so that the yield and purity are reduced and the requirement of the content of the medical intermediate cannot be met.
To solve this problem, the reaction is sufficiently completed in order to improve the reaction, thereby allowing the reaction materials to be sufficiently mixed. Zdenko Hamersak et al resort to the addition of a solvent, and when the reaction gives a large amount of white solid, resulting in poor flowability and difficulty in stirring, methylene chloride was added to change its flowability. And Zhou Bugao, when a large amount of paste is produced in the reaction and is difficult to stir, the reaction is heated to 70-80 ℃ until the reaction liquid is clear and well stirred. Since the paste is almost insoluble in the solvent, the addition of the solvent does not really solve the stirring problem, and the addition of the solvent affects both the subsequent hydrolysis and decarboxylation reactions, which results in problems of difficulty in increasing the reaction temperature and insufficient reaction, and the final yield is only 74%. And after the temperature is raised, side reactions are increased, and reaction byproducts are greatly increased, so that the yield and purity of the 3-isobutyl glutarate are difficult to be improved.
CN 106278931A reports a process for the preparation of 3-isobutylglutaric acid monoamide using isovaleraldehyde and cyanoacetamide as starting materials, wherein a phase transfer catalyst is used when cyanoacetamide is reacted with isovaleraldehyde in a solvent to prepare 2, 4-dicyano-3-isobutylglutaric acid diamide. Experiments show that the reaction generates a large amount of white solid, so that the fluidity is poor, the stirring is difficult, the solid is sticky and can not be filtered out, and the content of monocarboxyl compounds is high after the direct acid hydrolysis.
From the analysis of the existing preparation route of 3-isobutyl glutaric acid, the existing preparation method of 3-isobutyl glutaric acid has the problems of complicated steps, more three wastes or long reaction time, high impurity content of monocarboxyl matters, viscous reaction system and difficult stirring.
Disclosure of Invention
The invention aims to overcome the defects of the existing preparation method of 3-isobutyl glutaric acid in the background art, and provides a novel preparation method of 3-isobutyl glutaric acid, which has the advantages of simple process, low content of impurity monocarboxylic compounds, less three wastes and suitability for industrial production.
The invention mainly uses cyanoacetamide and isovaleraldehyde as raw materials, and adopts a route shown as a formula 1.
The method specifically comprises the following steps:
(1) 2, 4-dicyano-3-isobutyl glutaramide is prepared by the reaction of cyanoacetamide and isovaleraldehyde in a solvent in the presence of ammonium sulfate under the catalysis of alkali;
wherein the reaction temperature is 0-35 ℃, the reaction time is 8-25 h, and the molar ratio of cyanoacetamide to isovaleraldehyde is 2.0-3.0.
The alkaline catalyst is organic base and inorganic base such as morpholine, and the solvent is one or a mixture of more of water, dimethylbenzene, toluene and benzene.
Preferably, the reaction temperature is 10-20 ℃, the reaction time is 10-14 h, the molar ratio of cyanoacetamide to isovaleraldehyde is 2.0-2.2, and the solvent is water.
(2) Adding sulfuric acid to the step (1), and hydrolyzing 2, 4-dicyano-3-isobutyl glutaramide to generate 2, 4-dicarboxy-3-isobutyl glutaramide;
(3) Decarboxylation of 2, 4-dicarboxy-3-isobutylglutaric acid to produce 3-isobutylglutaric acid;
In the steps (2) and (3), the reaction temperature is 70-140 ℃.
The steps (1), (2) and (3) adopt a one-pot method;
the steps (2) and (3) are sequentially carried out or are carried out in a temperature section at the same time;
(4) Extracting the reaction liquid in the step (3) by using a solvent, and desolventizing and crystallizing the organic solvent phase to obtain a product 3-isobutyl glutaric acid;
the solvent is one of xylene, toluene and benzene or a mixed solvent of several solvents.
(5) And (4) neutralizing by introducing ammonia gas into the water, and crystallizing to obtain ammonium sulfate.
The ammonium sulfate obtained in the step (5) can be used in the step (1) in a mechanically-used way, and can be further refined into a commercially-available product.
The beneficial effects are that: the method is suitable for preparing 3-isobutyl glutaric acid by taking cyanoacetamide and isovaleraldehyde as raw materials. The technical proposal solves the difficult problem of difficult stirring in the prior proposal, has the characteristics of simple process, low content of single carboxyl compound serving as a byproduct, less three wastes and the like, and can realize industrial production.
Description of the drawings:
FIG. 1 is a chromatogram of 3-isobutylglutaric acid prepared in example 7.
FIG. 2 is a chromatogram of 3-isobutylglutaric acid prepared in example 8.
Detailed Description
The present application is illustrated below with reference to specific examples, which are given by way of example only and are not to be construed as limiting the overall scope of the application. All the features of the application are the same or similar, and the application is simply changed or replaced.
Example 1
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 14g of cyanoacetamide, 0.25g of morpholine and 11.5g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 0-10 ℃. 6.5g of isovaleraldehyde solution (100% concentration) is slowly added dropwise, and the reaction is continued for 12h after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. Adding 0.55mol of concentrated sulfuric acid dropwise under stirring, and reacting for 3h at 20-30 ℃ after the dripping is finished. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 100-110 ℃ for decarboxylation for 7h. After the reaction, cooling to 80 ℃, adding xylene for extraction, decompressing and evaporating most of the xylene from the extract phase, and cooling to separate out a product, wherein the yield is 85.4%.
Example 2
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 28g of cyanoacetamide, 0.5g of morpholine and 23g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 10-20 ℃. 13g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 12 hours after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. 1.1mol of concentrated sulfuric acid is added dropwise under stirring, and the reaction is carried out for 3 hours at 20-30 ℃ after the completion of the dripping. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 110-120 ℃ for decarboxylation for 7h. After the reaction, cooling to 80 ℃, adding toluene for extraction, decompressing and evaporating most toluene from the extract phase, and cooling to separate out a product, wherein the yield is 89.4%.
Example 3
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 28g of cyanoacetamide, 0.5g of morpholine and 23g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 20-35 ℃.13 g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 8 hours after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. 1.1mol of concentrated sulfuric acid is added dropwise under stirring, and the reaction is carried out for 3 hours at 20-30 ℃ after the completion of the dripping. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 120-130 ℃ for decarboxylation for 7h. After the reaction, cooling to 80 ℃, adding toluene for extraction, decompressing and evaporating most toluene from the extract phase, and cooling to separate out a product, wherein the yield is 87.3%.
Example 4
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 14g of cyanoacetamide, 0.25g of morpholine and 11.5g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled at 20-35 ℃. 6.5g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 16h after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. Adding 0.55mol of concentrated sulfuric acid dropwise under stirring, and reacting for 5h at 20-30 ℃ after the dripping is finished. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 130-140 ℃ for decarboxylation for 10h. After the reaction, cooling to 80 ℃, adding xylene for extraction, decompressing and evaporating most of the xylene from the extract phase, and cooling to separate out a product, wherein the yield is 87.7%.
Example 5
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 14g of cyanoacetamide, 0.25g of morpholine and 11.5g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 10-20 ℃. 6.5g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 25h after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. Adding 0.55mol of concentrated sulfuric acid dropwise under stirring, and reacting for 5h at 20-30 ℃ after the dripping is finished. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 120-130 ℃ for decarboxylation for 10h. After the reaction, cooling to 80 ℃, adding xylene for extraction, decompressing and evaporating most of the xylene from the extract phase, and cooling to separate out a product, wherein the yield is 89.5%.
Example 6
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 28g of cyanoacetamide, 0.5g of morpholine and 23g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 0-10 ℃.13 g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 25h after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. 1.1mol of concentrated sulfuric acid is added dropwise under stirring, and the reaction is carried out for 3 hours at 20-30 ℃ after the completion of the dripping. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 110-120 ℃ for decarboxylation for 7h. After the reaction, cooling to 80 ℃, adding toluene for extraction, decompressing and evaporating most toluene from the extract phase, and cooling to separate out a product, wherein the yield is 90.6%.
Example 7
1.5G of ammonium sulfate is dissolved in 10mL of water to obtain an ammonium sulfate aqueous solution; 14g of cyanoacetamide, 0.25g of morpholine and 11.5g of ammonium sulfate aqueous solution are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel, and the temperature is controlled to be 10-20 ℃. 6.5g of isovaleraldehyde solution is slowly added dropwise, and the reaction is continued for 12 hours after the completion of the dropwise addition. After the reaction is finished, the temperature is raised to 15-30 ℃. Adding 0.55mol of concentrated sulfuric acid dropwise under stirring, and reacting for 3h at 20-30 ℃ after the dripping is finished. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 120-130 ℃ for decarboxylation for 7h. After the reaction is finished, cooling to 80 ℃, adding dimethylbenzene for extraction, decompressing and distilling the extract phase to remove most dimethylbenzene, cooling and separating out a product, wherein the yield is 91.8% and the purity of the recrystallized product is 99.7% as shown in figure 1 of the specification.
Example 8
14G of cyanoacetamide, 0.25g of morpholine, 0.2g of dodecyl trimethyl ammonium chloride and a temperature of 10-20 ℃ are sequentially added into a 250mL four-necked flask equipped with a stirrer, a thermometer and a constant pressure dropping funnel. Slowly dropwise adding 6.5g of isovaleraldehyde solution, after 1 hour, keeping the temperature for reaction for 10 hours, and then generating a large amount of viscous solids which are separated by stirring blades, wherein the stirring blades cannot drive the solids, and continuing the reaction for 32 hours. Heating to 15-30 ℃, dropwise adding 0.55mol of concentrated sulfuric acid under stirring, and reacting for 3h at 20-30 ℃ after the dropwise adding is finished. Then heating to 110-120 ℃ for reflux for 6h, then removing part of water at normal pressure, and controlling the temperature to be 120-130 ℃ for decarboxylation for 7h. After the reaction is finished, cooling to 80 ℃, adding dimethylbenzene for extraction, decompressing and distilling an extract phase to remove most dimethylbenzene, cooling and separating out a product, wherein the chromatographic analysis is shown in a figure 2 of the specification, and the product has more monocarboxyl impurities and 75% of product yield.
Claims (8)
1. A preparation method of 3-isobutyl glutaric acid, which is characterized by comprising the following steps:
(1) In the presence of ammonium sulfate and under the catalysis of alkali, cyanoacetamide reacts with isovaleraldehyde in a solvent to prepare 2, 4-dicyano-3-isobutyl glutaramide;
(2) Adding sulfuric acid to the step (1), and hydrolyzing 2, 4-dicyano-3-isobutyl glutaramide to generate 2, 4-dicarboxy-3-isobutyl glutaramide;
(3) Decarboxylation of 2, 4-dicarboxy-3-isobutylglutaric acid to produce 3-isobutylglutaric acid;
(4) Extracting the reaction liquid in the step (3) by using a solvent, and removing the solvent from the organic phase and crystallizing to obtain a product 3-isobutyl glutaric acid;
(5) And (4) neutralizing by introducing ammonia gas into the water, and crystallizing to obtain ammonium sulfate.
2. The method for preparing 3-isobutylglutaric acid as set forth in claim 1, wherein said steps (1), (2) and (3) are carried out by one pot method.
3. The process for producing 3-isobutylglutaric acid as claimed in claim 1, wherein the reaction temperature in the step (1) is 0 to 35 ℃ and the reaction time is 8 to 25 h.
4. The process for producing 3-isobutylglutaric acid as claimed in claim 1, wherein the molar ratio of cyanoacetamide to isovaleraldehyde in the step (1) is 2.0 to 3.0.
5. The method for preparing 3-isobutylglutaric acid as set forth in claim 1, wherein the basic catalyst in the step (1) is morpholine, and the solvent is one or a mixture of several of water, xylene, toluene and benzene.
6. The process for producing 3-isobutylglutaric acid as set forth in claim 1, wherein the reaction temperature in steps (2) and (3) is 70 to 140 ℃.
7. The method for preparing 3-isobutylglutaric acid as set forth in claim 1, wherein the solvent in the step (4) is one or a mixture of several of xylene, toluene and benzene.
8. The method for producing 3-isobutylglutaric acid as claimed in claim 1, wherein the ammonium sulfate obtained in the step (5) is used in the step (1).
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