CN110698338A - Preparation method of 3- (4-chlorobenzene) glutaric acid - Google Patents
Preparation method of 3- (4-chlorobenzene) glutaric acid Download PDFInfo
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- CN110698338A CN110698338A CN201911166485.0A CN201911166485A CN110698338A CN 110698338 A CN110698338 A CN 110698338A CN 201911166485 A CN201911166485 A CN 201911166485A CN 110698338 A CN110698338 A CN 110698338A
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- C07—ORGANIC CHEMISTRY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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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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Abstract
The invention relates to a preparation method of 3- (4-chlorobenzene) glutaric acid. The preparation method comprises the following steps: (1) reacting the raw material a with the raw material b in the presence of an organic solvent and organic base, and filtering to obtain a solid; (2) reacting the obtained solid with an alkali water solution, and then acidifying to obtain a 3- (4-chlorobenzene) glutaric acid crude product; (3) purifying the obtained crude product by using activated carbon and a purification solvent to obtain a refined product of 3- (4-chlorobenzene) glutaric acid; the purification solvent is at least one of methanol, isopropanol or ethanol. The preparation method can obtain the refined 3- (4-chlorobenzene) glutaric acid with high yield and high purity.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of 3- (4-chlorobenzene) glutaric acid.
Background
Baclofen (Baclofen), the name of chinese is β -4-chloro-phenyl- γ -aminobutyric acid. The molecular formula is as follows: c10H12ClNO2. The baclofen hydrochloride has good curative effect in clinical treatment of hemiplegia caused by cerebrovascular diseases and apoplexy, spasticity caused by spinal cord injury, central spastic paralysis caused by multiple sclerosis and other diseases, and the like. In addition, the traditional Chinese medicine composition also has certain treatment effects on diseases such as central intractable hiccup, neuropathic pain, dysregulated urination, urination dysfunction after spinal cord injury and the like.
The synthesis routes of baclofen are many, and the synthesis of baclofen by taking 3- (4-chlorobenzene) glutaric acid as a key intermediate is one of the routes with the most industrial application prospect. It can synthesize 3- (4-chlorobenzene) glutaric acid from p-chlorobenzyl alcohol (see scheme 1) or p-chlorobenzaldehyde (scheme 2).
However, the synthesis of the synthetic route 1 needs a large amount of potassium permanganate oxidant, and brings great potential safety hazard in the production process. In the synthetic route 2, the intermediate obtained from the reaction A usually needs to be further crystallized and purified and then subjected to the reaction B to obtain relatively pure 3- (4-chlorobenzene) glutaric acid, and then the purified product of the 3- (4-chlorobenzene) glutaric acid can be obtained. The synthetic route has many and complicated steps and difficult post-treatment, and needs to be further improved.
Disclosure of Invention
Based on the above, one of the purposes of the invention is to provide a preparation method of 3- (4-chlorobenzene) glutaric acid. The intermediate of the preparation method can be directly subjected to subsequent reaction without further purification, and finally 3- (4-chlorobenzene) glutaric acid can be synthesized with high yield and high purity.
The specific technical scheme is as follows:
a preparation method of 3- (4-chlorobenzene) glutaric acid comprises the following steps:
(1) reacting the raw material a with the raw material b in the presence of an organic solvent and organic base, and filtering to obtain a solid;
(2) reacting the obtained solid with an alkali water solution, and then acidifying to obtain a 3- (4-chlorobenzene) glutaric acid crude product;
(3) purifying the obtained crude product by using activated carbon and a purification solvent to obtain a refined product of 3- (4-chlorobenzene) glutaric acid;
the purification solvent is at least one of methanol, isopropanol or ethanol.
Compared with the prior art, the invention has the following beneficial effects:
the invention obtains a solid intermediate by the raw materials a and b under the action of an organic solvent and an organic base. The solid intermediate reacts with an aqueous solution of alkali, and then is acidified to obtain a crude product of 3- (4-chlorobenzene) glutaric acid. Furthermore, after the crude 3- (4-chlorobenzene) glutaric acid is purified by activated carbon and a specific purification solvent, a refined 3- (4-chlorobenzene) glutaric acid can be obtained simply, conveniently and in high yield and high purity.
Detailed Description
In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The embodiment provides a preparation method of 3- (4-chlorobenzene) glutaric acid, which comprises the following steps:
(1) reacting the raw material a with the raw material b in the presence of an organic solvent and organic base, and filtering to obtain a solid;
(2) reacting the obtained solid with an alkali water solution, and then acidifying to obtain a 3- (4-chlorobenzene) glutaric acid crude product;
(3) purifying the obtained crude product by using activated carbon and a purification solvent to obtain a refined product of 3- (4-chlorobenzene) glutaric acid;
the purification solvent is at least one of methanol, isopropanol or ethanol.
In some embodiments, in step (3), the mass ratio of the crude product to the activated carbon is: 200-400: 1.
in some of the embodiments, in step (1), the organic base is at least one selected from diethylamine, piperidine and pyridine, preferably pyridine.
In some of these embodiments, in step (2), the base that reacts with the solid is selected from an alkali metal base or an alkaline earth metal base.
In some of these embodiments, the alkali metal base is selected from at least one of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, and lithium hydroxide, preferably potassium hydroxide.
In some of the embodiments, in step (1), the organic solvent is selected from at least one of acetonitrile, acetone, ethyl acetate, and ethanol.
In some embodiments, in step (1), the molar ratio of feedstock a to feedstock b is 1: 2-4, preferably 2-3.
In some of these embodiments, the temperature of the reaction in step (1) is from 25 to 50 ℃, preferably from 25 to 35 ℃.
In some of these embodiments, the reaction time in step (1) is 4h to 10h, preferably 5 to 7 h.
In some embodiments, in step (2), the concentration of the alkali in the aqueous solution of the alkali is 5% to 20% by mass.
In some of these embodiments, the step of purifying in step (3) comprises: mixing the crude product, activated carbon and a purification solvent, heating, filtering after the crude product is dissolved, and crystallizing the obtained filtrate.
In some of these embodiments, the temperature of the devitrification is 0-10 ℃.
In some of these embodiments, the temperature of the heating is 50-60 ℃.
The present invention will be described in further detail with reference to specific examples.
Example 1: preparation method of 3- (4-chlorobenzene) glutaric acid
The method comprises the following steps:
(1) 800g of raw material a, 1700g of raw material b, 3.0L of ethanol and 173g of piperidine are added into a three-necked bottle, and the mixture reacts for 6 hours at the temperature of 30-45 ℃. And (3) carrying out suction filtration on the system, adding a filter cake into 800ml of 10% potassium hydroxide aqueous solution for hydrolysis, and adding 200ml of hydrochloric acid after the reaction is finished to obtain 970g of crude 3- (4-chlorobenzene) glutaric acid with the purity (HPLC) of 95.7%.
(2) Adding the crude product (600g) and activated carbon (2 g) into methanol (1.2 kg), heating to 50-60 ℃ to dissolve the solid, removing the activated carbon by suction filtration, cooling the filtrate to 5 ℃ for crystallization for 1h, suction filtration, and drying under reduced pressure at 50 ℃ to obtain refined white crystal (575 g), the yield is 97.6%, the purity (HPLC) is 99.8%, and the maximum single impurity is 0.03%.
Example 2: preparation method of 3- (4-chlorobenzene) glutaric acid
This example differs from example 1 in that: the purification solvent methanol in example 1 was replaced with isopropanol.
The method comprises the following steps:
(1) 600g of crude 3- (4-chlorobenzene) glutaric acid prepared in example 1 was taken.
(2) Adding the crude product (600g) and activated carbon (2 g) into isopropanol (1.2 kg), heating to 50-60 ℃ to dissolve the solid, removing the activated carbon by suction filtration, cooling the filtrate to 5 ℃ for crystallization for 1h, suction filtration, and drying under reduced pressure at 50 ℃ to obtain refined white crystal (572 g), wherein the yield is 95.3%, the purity (HPLC) is 99.7%, and the maximum single impurity content is 0.04%.
EXAMPLE 33 preparation of (4-chlorobenzene) glutaric acid
This example differs from example 1 in that: the purification solvent methanol in example 1 was replaced with ethanol.
The method comprises the following steps:
(1) 600g of crude 3- (4-chlorobenzene) glutaric acid prepared in example 1 was taken.
(2) Adding the crude product (600g) and activated carbon (2 g) into ethanol (1.2 kg), heating to 50-60 ℃ to dissolve the solid, removing the activated carbon by suction filtration, cooling the filtrate to 5 ℃ for crystallization for 1h, suction filtration, and drying under reduced pressure at 50 ℃ to obtain a refined product of white crystals (550 g), the yield is 91.7%, the purity (HPLC) is 99.4%, and the maximum single impurity content is 0.02%.
EXAMPLE 43 preparation of (4-chlorobenzene) glutaric acid
The method comprises the following steps:
(1) 600g of crude 3- (4-chlorobenzene) glutaric acid prepared in example 1 was taken.
(2) Adding the crude product (600g) and activated carbon (1 g) into methanol (1.2 kg), heating to 50-60 ℃ to dissolve the solid, removing the activated carbon by suction filtration, cooling the filtrate to 0-10 ℃ for crystallization for 1h, suction filtration, and drying under reduced pressure at 50 ℃ to obtain refined white crystal (570 g), wherein the yield is 95%, the purity (HPLC) is 99.8%, and the maximum single impurity content is 0.03%.
Comparative example 13 preparation of (4-chlorobenzene) glutaric acid
This comparative example differs from example 1 in that: activated carbon is not used in the purification process of the step (2).
The method comprises the following steps:
(1) 600g of crude 3- (4-chlorobenzene) glutaric acid prepared in example 1 was taken.
(2) Adding the crude product (600g) into 1.2kg of methanol, heating to 50-60 ℃ to dissolve the solid, carrying out suction filtration on the filtrate, cooling to 0-10 ℃ for crystallization for 1h, carrying out suction filtration, and drying under reduced pressure at 50 ℃ to obtain a crystallized refined product 563g, wherein the yield is 93%, the purity (HPLC) is 98.1%, and the maximum single impurity content is 0.12%.
Comparative example 23- (4-Chlorobenzene) glutaric acid production method
The method comprises the following steps:
(1) 600g of the crude product prepared in example 1 were taken.
(2) Adding the crude product (600g) and activated carbon (2 g) into water (1.2 kg), heating to 50-60 ℃ to dissolve the solid, removing the activated carbon by suction filtration, cooling the filtrate to 5 ℃ to crystallize for 1h, suction filtration, and drying to obtain a refined product (420 g), wherein the yield is 70%, the purity (HPLC) is 98.3%, and the maximum single impurity content is 0.2%.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (13)
1. A preparation method of 3- (4-chlorobenzene) glutaric acid is characterized by comprising the following steps:
(1) reacting the raw material a with the raw material b in the presence of an organic solvent and organic base, and filtering to obtain a solid;
(2) reacting the obtained solid with an alkali water solution, and then acidifying to obtain a 3- (4-chlorobenzene) glutaric acid crude product;
(3) purifying the obtained crude product by using activated carbon and a purification solvent to obtain a refined product of 3- (4-chlorobenzene) glutaric acid;
the purification solvent is at least one of methanol, isopropanol or ethanol.
2. The preparation method according to claim 1, wherein in the step (3), the mass ratio of the crude product to the activated carbon is as follows: 200-400: 1.
3. the method of claim 1, wherein the step of purifying in step (3) comprises: mixing the crude product, activated carbon and a purification solvent, heating, filtering after the crude product is dissolved, and crystallizing the obtained filtrate.
4. The production method according to claim 3, wherein the temperature of the crystallization is 0 to 10 ℃.
5. The method according to claim 3, wherein the heating temperature is 50 to 60 ℃.
6. The method according to claim 1, wherein in the step (1), the organic base is at least one selected from the group consisting of diethylamine, piperidine and pyridine.
7. The process according to claim 1, wherein in the step (2), the base to be reacted with the solid is selected from an alkali metal base or an alkaline earth metal base.
8. The method according to claim 7, wherein the alkali metal base is at least one selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, and lithium hydroxide.
9. The production method according to any one of claims 1 to 8, wherein in the step (1), the molar ratio of the raw material a to the raw material b is 1: 2-4.
10. The production method according to any one of claims 1 to 8, wherein the temperature of the reaction in step (1) is 25 to 50 ℃.
11. The production method according to any one of claims 1 to 8, wherein in the step (1), the organic solvent is at least one selected from the group consisting of acetonitrile, acetone, ethyl acetate and ethanol.
12. The production method according to any one of claims 1 to 8, wherein the reaction time in step (1) is 4 to 10 hours.
13. The production method according to any one of claims 1 to 8, wherein in the step (2), the concentration by mass of the alkali in the aqueous solution of the alkali is 5% to 20%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242219A (en) * | 2012-02-13 | 2013-08-14 | 江苏恩华药业股份有限公司 | 2,6-diketone-piperazine (piperidine) type derivative and application thereof |
| CN106187794A (en) * | 2016-07-12 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of green industrialized production method of baclofen |
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- 2019-11-25 CN CN201911166485.0A patent/CN110698338A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242219A (en) * | 2012-02-13 | 2013-08-14 | 江苏恩华药业股份有限公司 | 2,6-diketone-piperazine (piperidine) type derivative and application thereof |
| CN106187794A (en) * | 2016-07-12 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of green industrialized production method of baclofen |
Non-Patent Citations (3)
| Title |
|---|
| ALI SABERI: "A facile and efficient synthesis of Baclofen", 《IRANIAN CHEMICAL COMMUNICATION》 * |
| LIN-JIE YAN: "Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides", 《CHEMCATCHEM》 * |
| 熊前程等: "《有机化学》", 31 August 2018 * |
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