CN114933524A - Synthesis method of 4-tert-butyl cyclohexyl acetic acid - Google Patents
Synthesis method of 4-tert-butyl cyclohexyl acetic acid Download PDFInfo
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- 239000001257 hydrogen Substances 0.000 claims description 15
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- UEERPCZVXPLDMN-UHFFFAOYSA-N 2-(4-tert-butylcyclohexyl)acetic acid Chemical compound CC(C)(C)C1CCC(CC(O)=O)CC1 UEERPCZVXPLDMN-UHFFFAOYSA-N 0.000 description 1
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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
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention discloses a synthesis method of 4-tert-butyl cyclohexyl acetic acid, which comprises the steps of dissolving 4-tert-butyl phenyl acetic acid in a solvent, adding a catalyst into the solvent, carrying out high-pressure catalytic hydrogenation reaction, filtering the reaction solution after the reaction is finished, carrying out desolventizing concentration, adding the concentrated solution into water to precipitate solids, centrifuging and drying to obtain the refined 4-tert-butyl cyclohexyl acetic acid. The synthesis method provided by the invention adopts 4-tert-butyl phenylacetic acid as a raw material, the raw material is cheap and easy to obtain, the target product can be obtained through one-step catalytic hydrogenation reaction, the synthesis process is efficient and simple, the reaction step is short, the production cost is low, the product yield is high, the product purity is high, ions harmful to subsequent coupling reaction are not contained, and the synthesis method has obvious advantages on the subsequent synthesis of buparvaquone. The reaction conditions in the whole production process are mild, safe and environment-friendly, the equipment conditions are easy to meet, and the industrial production is facilitated.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of 4-tert-butyl cyclohexyl acetic acid.
Background
Theileria is a general term for diseases caused by various types of coke worms of Theileria parasitizing cattle, sheep and other wild animals, and the annular Theileria is the most common. The bovine theileriosis is bovine hemozoiasis caused by theileria annulata and has the characteristics of wide epidemic rate, high morbidity and high mortality rate. After the pathogens are transmitted to the cattle by the ticks, the pathogens parasitize in macrophages, lymphocytes and erythrocytes, and then cause diseases which are mainly characterized by high fever, anemia, emaciation and body surface lymph node swelling, thereby leading to the death of the cattle.
Buparvaquone is a very effective medicament for treating theileria bovis at present, competitively inhibits energy metabolism and mitochondrial respiration of diseased protozoa by blocking Q circulation of cytochrome bc1 complex on mitochondrial inner membrane in diseased protozoa cells, further leads to collapse of mitochondrial inner membrane potential and finally leads to death of parasites, and the chemical formula of buparvaquone is shown as follows:
at present, the global buparvaquone bulk drug is mainly produced in India and mainly imported domestically, and the existing high-efficiency method for industrially producing buparvaquone is realized by the following reaction formula:
4-tert-butyl cyclohexyl acetic acid is used as one of two main raw materials for synthesizing buparvaquone, and directly influences the production cost, scale and subsequent popularization and application of the buparvaquone.
Currently, 4-tert-butylcyclohexylacetic acid is synthesized mainly by the following method:
the method obtains the 4-tert-butyl cyclohexanoic acid through four-step reaction, and has the main defects that: a large amount of phosphorus-containing wastewater is generated in the reaction process, so that the environmental protection pressure is high; the obtained product often contains trace NaCl, and the sodium chloride is easy to cause the catalyst AgNO in the subsequent coupling reaction 3 Inactivating; control experiments showed that the reaction was completely disabled by the addition of 0.05eq. NaCl. Therefore, the process is harsh on the purification of the target product.
Disclosure of Invention
In order to solve the problems of the method, the invention provides a high-efficiency environment-friendly synthesis process which has cheap and easily obtained raw materials and can obtain a target product through one-step catalytic hydrogenation.
The invention is realized by the following technical scheme:
a synthesis method of 4-tert-butyl cyclohexyl acetic acid is characterized in that 4-tert-butyl phenyl acetic acid is dissolved in a solvent, a catalyst is added into the solvent to carry out high-pressure catalytic hydrogenation reaction, and the chemical reaction formula is as follows:
in certain embodiments, the catalyst is raney nickel or palladium on carbon.
In certain embodiments, the solvent is methanol or ethanol.
In certain embodiments, the amount of catalyst is from 5% to 15% of the amount of 4-tert-butylacetic acid used.
In certain embodiments, the ratio of the amount of solvent to the amount of 4-tert-butylacetic acid is 4 to 10:1 (v/w).
In certain embodiments, the steps of operating are specifically:
dissolving 4-tert-butyl phenylacetic acid in a solvent, adding the solution into a hydrogenation kettle, adding a catalyst into the solution, replacing gas in the solution with nitrogen and hydrogen in sequence, filling hydrogen into the kettle after replacement, stirring, and adjusting the system pressure to 4-8 MPa for reaction.
In certain embodiments, the reaction time is 12 to 20 hours.
In certain embodiments, the reaction pressure is 6 MPa.
In certain embodiments, the reaction time is 16 h.
In some embodiments, after the reaction is completed, the reaction solution is filtered to remove the catalyst, desolventized and concentrated, added into water to precipitate a solid, centrifuged and dried to obtain the purified 4-tert-butylcyclohexylacetic acid.
In certain embodiments, the venting of the pressure in the tank is carried out by a nitrogen displacement step prior to the filtration of the reaction solution from the catalyst.
In certain embodiments, the volume of the concentrate is reduced to 1/5-1/2 of the original volume.
In certain embodiments, the volume ratio of concentrate to water is 1:2 to 10.
In certain embodiments, the drying temperature is 40 to 60 ℃.
In certain embodiments, the drying time is 4 to 8 hours.
The synthesis method of 4-tert-butyl cyclohexyl acetic acid provided by the invention has the following advantages:
(1) the synthesis method provided by the invention adopts 4-tert-butyl phenylacetic acid as a raw material, the raw material is cheap and easy to obtain, the raw material can be directly purchased from the market, the target product can be obtained through one-step catalytic hydrogenation reaction, the synthesis process is efficient and simple, the reaction steps are short, and the production cost is low.
(2) The synthesis method of 4-tert-butyl cyclohexyl acetic acid provided by the invention has the advantages that the product yield is high, the product purity is easy to control, the concentrated solution is added into water to separate out solids, the quality requirement can be met, the product purity is high, ions harmful to subsequent coupling reaction are not contained, and the synthesis method has obvious advantages for the subsequent synthesis of buparvaquone.
(3) The reaction conditions in the whole production process are mild, safe and environment-friendly, no solvent or reagent with high toxicity and pollution is involved, no waste gas, waste liquid or waste residue with high pollution is generated, the equipment conditions are easy to meet, and the industrial production is facilitated.
Drawings
FIG. 1 is a NMR chart of 4-t-butylcyclohexylacetic acid of the present invention.
Detailed Description
The present invention will be described in further detail below with reference to embodiments.
The synthetic route of the scheme is as follows:
example 1
50.00g (0.26mol) of 4-tert-butyl phenylacetic acid is dissolved in 250ml of methanol, the solution is added into a hydrogenation kettle, 5.00g of palladium carbon catalyst is added into the solution, the covering is closed to ensure firm fixation, then 0.3MPa nitrogen gas is substituted for 3 times and 0.3MPa hydrogen gas is substituted for 2 times in sequence, after the substitution is finished, 6MPa hydrogen gas is filled into the kettle, and the stirring is started. And (4) observing the change of the pressure gauge in the process, and supplementing hydrogen to 6MPa when the pressure in the kettle is lower than 4MPa until the pressure in the kettle is basically stable. And after the pressure in the kettle is stable, stopping stirring, standing for 10 minutes, opening an exhaust valve to exhaust the pressure in the kettle, replacing the pressure in the kettle with 0.3MPa nitrogen for 2 times, then exhausting the pressure in the kettle, opening a kettle cover to perform mixing and suction filtration in the kettle, and performing vacuum desolventizing and concentrating on the obtained filtrate to about 100 ml.
The concentrate was slowly poured into about 250ml of water with stirring to precipitate a large amount of white solid, stirring was continued for 0.5 hour, filtration was carried out, and the resulting filter cake was air-dried at 50 ℃ for about 8 hours to constant weight to obtain 50.93g of white solid with a yield of 98.8%.
Example 2
50.00g (0.26mol) of 4-tert-butyl phenylacetic acid is dissolved in 250ml of methanol, the solution is added into a hydrogenation kettle, 15.00g of Raney nickel is added into the solution, the covering is closed to ensure firm fixation, then 0.3MPa nitrogen is substituted for 3 times and 0.3MPa hydrogen is substituted for 2 times in sequence, after the substitution is finished, 6MPa hydrogen is filled into the kettle, and the stirring is started. And (4) observing the change of the pressure gauge in the process, and supplementing hydrogen to 6MPa when the pressure in the kettle is lower than 4MPa until the pressure in the kettle is basically stable. And after the pressure in the kettle is stable, stopping stirring, standing for 10 minutes, opening an exhaust valve to exhaust the pressure in the kettle, replacing the pressure in the kettle with 0.3MPa nitrogen for 2 times, then exhausting the pressure in the kettle, opening a kettle cover to mix and pump-filter the pressure in the kettle, and performing vacuum desolventizing and concentrating on the obtained filtrate to about 100 ml.
The concentrate was slowly poured into about 250ml of water with stirring to precipitate a large amount of white solid, stirring was continued for 0.5 hour, filtration was carried out, and the resulting filter cake was air-dried at 50 ℃ for about 8 hours to a constant weight to obtain 50.18g of white solid in a yield of 97.3%.
Compared with the palladium-carbon catalyst in the embodiment 1, the product yield obtained by using Raney nickel as the catalyst is equivalent, and no obvious difference exists, and the Raney nickel is preferably used as the catalyst in consideration of the cost of the Raney nickel and the palladium-carbon catalyst.
Example 3
50.00g (0.26mol) of 4-tert-butyl phenylacetic acid is dissolved in 250ml of ethanol, the solution is added into a hydrogenation kettle, 15.00g of Raney nickel is added into the solution, the covering is closed to ensure firm fixation, then 0.3MPa nitrogen is substituted for 3 times and 0.3MPa hydrogen is substituted for 2 times in sequence, after the substitution is finished, 6MPa hydrogen is filled into the kettle, and the stirring is started. And (4) observing the change of the pressure gauge in the process, and supplementing hydrogen to 6MPa when the pressure in the kettle is lower than 4MPa until the pressure in the kettle is basically stable. And after the pressure in the kettle is stable, stopping stirring, standing for 10 minutes, opening an exhaust valve to exhaust the pressure in the kettle, replacing the pressure in the kettle with 0.3MPa nitrogen for 2 times, then exhausting the pressure in the kettle, opening a kettle cover to perform mixing and suction filtration in the kettle, and performing vacuum desolventizing and concentrating on the obtained filtrate to about 100 ml.
The concentrate was slowly poured into about 250ml of water with stirring to precipitate a large amount of white solid, stirring was continued for 0.5 hour, filtration was carried out, and the resulting filter cake was air-dried at 50 ℃ for about 8 hours to constant weight to obtain 49.92g of white solid in 96.8% yield.
Compared with the methanol solvent in the embodiment 2, the ethanol catalyst has the advantages that the product yield is equivalent, no obvious difference exists, and the ethanol catalyst is preferably used in consideration of the cost of the ethanol catalyst and the methanol catalyst.
Example 4
50.00g (0.26mol) of 4-tert-butyl phenylacetic acid is dissolved in 250ml of ethanol, the solution is added into a hydrogenation kettle, 15.00g (10% w/w) of Raney nickel is added into the solution, the covering is closed, the fixation is ensured to be firm, then, nitrogen gas with 0.3MPa is used for replacing for 3 times and hydrogen gas with 0.3MPa is used for replacing for 2 times in sequence, hydrogen gas with 6MPa is filled into the kettle after the replacement is finished, and the stirring is started. And (4) observing the change of the pressure gauge in the process, and supplementing hydrogen to 6MPa when the pressure in the kettle is lower than 4MPa until the pressure in the kettle is basically stable. And after the pressure in the kettle is stable, stopping stirring, standing for 10 minutes, opening an exhaust valve to exhaust the pressure in the kettle, replacing the pressure in the kettle with 0.3MPa nitrogen for 2 times, then exhausting the pressure in the kettle, opening a kettle cover to mix and pump-filter the pressure in the kettle, and performing vacuum desolventizing and concentrating on the obtained filtrate to about 100 ml.
The concentrate was slowly poured into about 500ml of water with stirring to precipitate a large amount of white solid, stirring was continued for 0.5 hour, filtration was carried out, and the resulting filter cake was air-dried at 50 ℃ for about 8 hours to a constant weight to obtain 50.44g of a white solid in a yield of 97.8%.
Compared with example 3, the product yield is equivalent without obvious difference by increasing the amount of water to be used by 10 times (v/w) of 4-tert-butylbenzoic acid, and the post-treatment is preferably carried out by using the amount of water to be used by 5 times (v/w) of 4-tert-butylbenzoic acid in consideration of the amount of waste liquid generated.
Example 5
3.00kg (15.60mol) of 4-tert-butylacetic acid are dissolved in 14L of methanol and approximately 5L of the solution are pumped into a 20L hydrogenation vessel. Adding 0.30kg of the mixture into 1L of methanol, pumping the mixture into a hydrogenation kettle, quickly pumping the residual 4-tert-butyl phenylacetic acid methanol solution into the hydrogenation kettle after the pumping is finished, closing a valve, then sequentially performing nitrogen replacement for 3 times at 0.3MPa and hydrogen replacement for 2 times at 0.3MPa, filling hydrogen at 6MPa into the kettle after the replacement is finished, and starting stirring. And (4) observing the change of the pressure gauge in the process, and supplementing hydrogen to 6MPa when the pressure in the kettle is lower than 4MPa until the pressure in the kettle is basically stable. After the pressure in the kettle is stabilized, stopping stirring, opening an exhaust valve to exhaust the pressure in the kettle, replacing the pressure with 0.3MPa nitrogen for 2 times, then exhausting the pressure in the kettle, putting the mixture in the kettle into a filter-pressing tank for filter-pressing, and performing vacuum desolventizing concentration on the obtained filtrate to about 6L.
The concentrate was slowly poured into about 15L of water with stirring to precipitate a large amount of white solid, stirring was continued for 0.5 hour, centrifugation was carried out, and the resulting solid was air-dried at 50 ℃ for about 6 hours to a constant weight to give 3.04kg of white solid in 98.4% yield.
In summary, the following steps: the synthesis method provided by the invention adopts 4-tert-butyl phenylacetic acid as a raw material, the raw material is cheap and easy to obtain, the target product can be obtained through one-step catalytic hydrogenation reaction, the synthesis process is efficient and simple, the reaction step is short, the production cost is low, the product yield is high, the product purity is high, ions harmful to subsequent coupling reaction are not contained, and the synthesis method has obvious advantages for the subsequent synthesis of buparvaquone. The whole production process has mild reaction conditions, safety, environmental protection and easy satisfaction of equipment conditions, and is beneficial to industrial production.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these should be considered as within the scope of the present invention.
Claims (10)
1. A synthesis method of 4-tert-butyl cyclohexyl acetic acid is characterized in that 4-tert-butyl phenyl acetic acid is dissolved in a solvent, a catalyst is added into the solvent, and high-pressure catalytic hydrogenation reaction is carried out, wherein the chemical reaction formula is as follows:
2. the synthesis method according to claim 1, wherein the catalyst is Raney nickel or palladium on carbon, and the solvent is methanol or ethanol.
3. The synthesis method according to claim 2, wherein the amount of the catalyst is 5-15% of the amount of 4-tert-butyl phenylacetic acid, and the ratio of the amount of the solvent to the amount of the 4-tert-butyl phenylacetic acid is 4-10: 1 (v/w).
4. The synthesis method according to claim 1, characterized by the specific operating steps of:
dissolving 4-tert-butyl phenylacetic acid in a solvent, adding the solution into a hydrogenation kettle, adding a catalyst into the solution, replacing gas in the solution with nitrogen and hydrogen in sequence, filling hydrogen into the kettle after replacement, stirring, and adjusting the system pressure to 4-8 MPa for reaction.
5. The synthesis method according to claim 4, wherein the reaction time is 12-20 h.
6. The synthesis method according to claim 5, characterized in that the reaction pressure is 6MPa and the reaction time is 16 h.
7. The synthesis method according to any one of claims 1 to 6, wherein after completion of the reaction, the reaction mixture is subjected to filtration to remove the catalyst, concentration by desolventization, precipitation of a solid by adding water, centrifugation and drying to obtain purified 4-tert-butylcyclohexylacetic acid.
8. The synthesis method according to claim 7, characterized in that before the reaction solution is filtered to remove the catalyst, a nitrogen replacement step is further included, and the pressure in the kettle is evacuated.
9. The method as claimed in claim 7, wherein the volume of the concentrated solution is reduced to 1/5-1/2 of the original volume, and the volume ratio of the concentrated solution to water is 1: 2-10.
10. The synthesis method according to claim 7, wherein the drying temperature is 40-60 ℃ and the drying time is 4-8 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4485116A (en) * | 1981-10-16 | 1984-11-27 | Hudson Alan T | Antiprotozoal compounds |
| US6127427A (en) * | 1995-11-23 | 2000-10-03 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| CN1443747A (en) * | 2003-04-16 | 2003-09-24 | 西安瑞联近代电子材料有限责任公司 | Method for synthesizing 4-alkyl cyclohexyl acetic acid |
| US20040209858A1 (en) * | 2002-10-22 | 2004-10-21 | Bennani Youssef L. | Cycloalkylamides and their therapeutic applications |
| CN105418363A (en) * | 2015-11-02 | 2016-03-23 | 山东川成医药股份有限公司 | Synthetic method for 4-tertiary butyl cyclohexaneacetic acid |
| CN110240548A (en) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | A kind of preparation method of Cariliprazine intermediate |
-
2021
- 2021-12-30 CN CN202111650247.4A patent/CN114276231A/en active Pending
-
2022
- 2022-05-26 CN CN202210588776.4A patent/CN114933524A/en not_active Withdrawn
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| US6127427A (en) * | 1995-11-23 | 2000-10-03 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| US20040209858A1 (en) * | 2002-10-22 | 2004-10-21 | Bennani Youssef L. | Cycloalkylamides and their therapeutic applications |
| CN1443747A (en) * | 2003-04-16 | 2003-09-24 | 西安瑞联近代电子材料有限责任公司 | Method for synthesizing 4-alkyl cyclohexyl acetic acid |
| CN105418363A (en) * | 2015-11-02 | 2016-03-23 | 山东川成医药股份有限公司 | Synthetic method for 4-tertiary butyl cyclohexaneacetic acid |
| CN110240548A (en) * | 2018-03-09 | 2019-09-17 | 上虞京新药业有限公司 | A kind of preparation method of Cariliprazine intermediate |
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| J.A. ANDERSON ET AL: "Aqueous phase hydrogenation of substituted phenyls over carbon nanofibre and activated carbon supported Pd", 《JOURNAL OF CATALYSIS》, vol. 270, pages 9 - 15, XP026916175, DOI: 10.1016/j.jcat.2009.11.028 * |
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