CN115322143A - Preparation method of 4-piperidine formic acid tert-butyl ester hydrochloride - Google Patents
Preparation method of 4-piperidine formic acid tert-butyl ester hydrochloride Download PDFInfo
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- CN115322143A CN115322143A CN202210877302.1A CN202210877302A CN115322143A CN 115322143 A CN115322143 A CN 115322143A CN 202210877302 A CN202210877302 A CN 202210877302A CN 115322143 A CN115322143 A CN 115322143A
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- tert
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- piperidinecarboxylic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- 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
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of 4-tert-butyl piperidine formate hydrochloride, belonging to the field of synthesis of a pharmaceutical intermediate. The method takes 4-piperidinecarboxylic acid as a raw material to synthesize the 4-piperidinecarboxylic acid tert-butyl ester hydrochloride through salt forming reaction and esterification reaction under a pressurized condition. The invention provides a preparation method of 4-tert-butyl piperidine formate hydrochloride, which has the advantages of controllable reaction process, simple operation, high yield and good product purity.
Description
Technical Field
The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of 4-tert-butyl piperidine formate hydrochloride.
Background
4-piperidine carboxylic acid tert-butyl ester hydrochloride, molecular formula: c 10 H 20 ClNO 2 Molecular weight: 221.72, CAS:892493-65-1, having the following chemical formula:
the 4-piperidine carboxylic acid tert-butyl ester hydrochloride is an important intermediate for synthesizing antitumor drugs, urinary system drugs and cardiovascular and cerebrovascular drugs, and two synthetic routes are available at present, wherein in the first route (WO 2015085132), 4-piperidine carboxylic acid is used as a raw material to synthesize N-Cbz-piperidine-4-carboxylic acid, then carboxylic acid is converted into acyl chloride by using an acylating reagent, the acyl chloride reacts with tert-butyl alcohol to obtain N-Cbz-4-piperidine carboxylic acid tert-butyl ester, finally Cbz is removed, and the 4-piperidine carboxylic acid tert-butyl ester hydrochloride is obtained by salifying, and the specific synthetic route is as follows:
the 4-piperidinecarboxylic acid tert-butyl ester hydrochloride is synthesized by 5 steps of reaction by taking 4-piperidinecarboxylic acid as a raw material, the reaction route is long, the total yield is low, acyl chloride and tert-butyl alcohol react in one step, the steric hindrance of tert-butyl alcohol is large, the yield is less than 60%, CBz is used for protecting amine, and then a protecting group is removed, so that the reaction steps are increased, and the total yield is reduced.
Patent JP2009161510 reports a technology of synthesizing tert-butyl 4-piperidinecarboxylate by a one-step method, namely a technology of adding 4-piperidinecarboxylic acid with isobutene under acid catalysis, and then salifying with hydrochloric acid to obtain tert-butyl 4-piperidinecarboxylate hydrochloride, wherein the specific synthetic route is as follows:
the method is a brand new synthetic route, isobutylene is added under acid catalysis, and 4-tert-butyl piperidinecarboxylate is synthesized by a one-step method, but the 4-tert-butyl piperidinecarboxylate is difficult to dissolve in an organic solvent, the reaction belongs to a gas-liquid heterogeneous reaction, the yield is only about 10%, and the purification and industrialization are difficult to realize.
Disclosure of Invention
The invention provides a preparation method of 4-piperidine formic acid tert-butyl ester hydrochloride aiming at the defects in the prior art.
In order to increase the solubility of the 4-piperidinecarboxylic acid, the reaction is carried out under a certain pressure environment. The method comprises the steps of heating 4-piperidinecarboxylic acid serving as a raw material in concentrated hydrochloric acid for 4 hours under a pressurized condition, cooling, adding a solvent, separating out solids, and filtering to obtain 4-piperidinecarboxylic acid hydrochloride; adding 4-piperidinecarboxylic acid hydrochloride into a solvent, adding a catalyst, and dropwise adding Boc 2 O acid anhydride reacts at a certain temperature and pressure to generate 4-piperidine formic acid tert-butyl ester hydrochloride, and the specific synthetic route is as follows:
s1, adding 4-piperidinecarboxylic acid and concentrated hydrochloric acid into an autoclave, introducing nitrogen, maintaining a certain pressure, reacting at 85-90 ℃ for 4 hours, cooling to room temperature, returning to normal pressure, adding a solvent, cooling to precipitate a solid, and filtering to obtain 4-piperidinecarboxylic acid hydrochloride;
s2, adding 4-piperidinecarboxylic acid hydrochloride and a solvent into an autoclave, adding a catalyst, and adding Boc 2 O acid anhydride reacts at certain temperature and pressure to generate 4-piperidine formic acid tert-butyl ester hydrochloride.
The solvent in the step S1 is one or more of acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butyl alcohol and dimethyl sulfoxide, preferably methanol, and the amount of the solvent is 3 times of the mass of 4-piperidinecarboxylic acid; the pressure is 0.3-0.5MPa;
the solvent in the step S2 is the mixture of tetrahydrofuran, water, acetonitrile and water, 1, 4-dioxane and water, acetone and water, the volume ratio of the organic solvent to the water is 1; the catalyst is one of 4-dimethylamino pyridine and 4-pyrrolidinyl pyridine, and is preferably 4-dimethylamino pyridine; the reaction temperature is 50-60 ℃; the reaction pressure is 0.2-0.4MPa.
The invention has the beneficial effects that:
(1) The reaction is carried out under certain pressure, so that the solubility of the 4-piperidinecarboxylic acid and the 4-piperidinecarboxylic acid hydrochloride is increased, and the reaction time is greatly shortened;
(2) The reaction route section can synthesize the 4-tert-butyl piperidine formate by only 2 steps of reaction;
(3) The product has good purity and high yield, the total yield of the two-step reaction is 80 percent, and the product purity is more than 99 percent.
Detailed Description
Example 1:
adding 4-piperidinecarboxylic acid (2 kg) into a 10L high-pressure reaction kettle, adding concentrated hydrochloric acid (2 kg), introducing nitrogen, maintaining the pressure of the reaction system at 0.5MPa, reacting at 90 ℃ for 4h, cooling to room temperature of 20-25 ℃, recovering normal pressure, adding methanol (3 kg), cooling to 5-10 ℃, and precipitating a solid. Filtration and washing of the filter cake with methanol (1 kg) and drying gave a white solid with a yield of 95%.
Adding 4-piperidinecarboxylic acid hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) into a 10L high-pressure reaction kettle, introducing nitrogen, maintaining the pressure of a reaction system at 0.4MPa and the temperature of 60 ℃ for reaction for 2h, cooling to the room temperature of 20-25 ℃, recovering the normal pressure, continuously cooling to 5-10 ℃, precipitating solids, filtering, washing a filter cake with ethyl acetate (3 kg) for 1 hour, filtering, and drying to obtain white solids, wherein the yield is 84% and the purity is 99%.
Example 2:
adding 4-piperidinecarboxylic acid (2 kg) into a 10L high-pressure reaction kettle, adding concentrated hydrochloric acid (2 kg), introducing nitrogen, maintaining the pressure of a reaction system at 0.3MPa, reacting at 85 ℃ for 4h, cooling to room temperature of 20-25 ℃, recovering normal pressure, adding acetone (3 kg), cooling to 5-10 ℃, and precipitating a solid. Filtration and washing of the filter cake with acetone (1 kg) and drying gave a white solid in 93% yield.
Adding 4-piperidinecarboxylic acid hydrochloride (1 kg), acetone (2 kg), water (2 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) into a 10L high-pressure reaction kettle, introducing nitrogen, maintaining the pressure of a reaction system at 0.2MPa, reacting at 50 ℃ for 2h, cooling to room temperature of 20-25 ℃, recovering normal pressure, continuously cooling to 5-10 ℃, separating out solids, filtering, washing a filter cake with ethyl acetate (3 kg) for 1 hour, filtering, and drying to obtain a white solid, wherein the yield is 80.2%, and the purity is 99%.
Example 3:
adding 4-piperidinecarboxylic acid (2 kg) into a 10L high-pressure reaction kettle, adding concentrated hydrochloric acid (2 kg), introducing nitrogen, maintaining the pressure of the reaction system at 0.4MPa, reacting at 90 ℃ for 4h, cooling to room temperature of 20-25 ℃, recovering normal pressure, adding dimethyl sulfoxide (3 kg), cooling to 5-10 ℃, and precipitating a solid. Filtration and washing of the filter cake with dimethyl sulfoxide (1 kg) and drying gave a white solid with a yield of 95%.
Adding 4-piperidinecarboxylic acid hydrochloride (1 kg), tetrahydrofuran (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-pyrrolidinyl pyridine (45 g) into a 10L high-pressure reaction kettle, introducing nitrogen, maintaining the pressure of a reaction system at 0.3MPa, reacting at 60 ℃ for 2h, cooling to room temperature of 20-25 ℃, recovering normal pressure, continuously cooling to 5-10 ℃, separating out solids, filtering, washing a filter cake with ethyl acetate (3 kg) for 1 hour, filtering, and drying to obtain a white solid, wherein the yield is 82.5% and the purity is 99%.
Example 4:
adding 4-piperidinecarboxylic acid (2 kg) into a 10L normal-pressure reaction kettle, adding concentrated hydrochloric acid (2 kg), reacting for 4h at 90 ℃, cooling to room temperature of 20-25 ℃, recovering normal pressure, adding methanol (3 kg), cooling to 5-10 ℃, and precipitating a solid. Filtration and washing of the filter cake with methanol (1 kg) and drying gave a white solid in 73% yield.
Adding 4-piperidinecarboxylic acid hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg), boc anhydride (1.4 kg) and 4-dimethylaminopyridine (40 g) into a 10L reaction kettle, reacting at 60 ℃ for 2h, cooling to room temperature of 20-25 ℃, continuously cooling to 5-10 ℃, separating out a solid, filtering, washing a filter cake with ethyl acetate (3 kg) for 1 hour, filtering, and drying to obtain a white solid, wherein the yield is 48% and the purity is 98%.
Example 5:
adding 4-piperidinecarboxylic acid hydrochloride (1 kg), acetonitrile (2 kg), water (1 kg) and Boc anhydride (1.4 kg) into a 10L high-pressure reaction kettle, introducing nitrogen, maintaining the pressure of a reaction system at 0.4MPa, reacting at 60 ℃ for 2h, cooling to room temperature of 20-25 ℃, recovering normal pressure, continuously cooling to 5-10 ℃, precipitating solids, filtering, washing a filter cake with ethyl acetate (3 kg) for 1 hour, filtering, and drying to obtain white solids, wherein the yield is 42.8% and the purity is 88%.
Example 6:
adding 4-piperidinecarboxylic acid (100 g) into a 1L high-pressure reaction kettle, adding 1, 4-dioxane (300 g) and concentrated sulfuric acid (10 g), introducing isobutene, maintaining the pressure at 0.5MPa and the temperature at 50 ℃ for reaction for 3 hours, and performing sampling central control analysis to obtain a 4-piperidinecarboxylic acid conversion rate of 9%.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (7)
1. The preparation method of 4-piperidine formic acid tert-butyl ester hydrochloride is characterized in that the synthetic route of the preparation method is as follows:
s1, adding 4-piperidinecarboxylic acid and concentrated hydrochloric acid into an autoclave, introducing nitrogen, maintaining the reaction pressure, reacting at 85-90 ℃, cooling to room temperature, returning to normal pressure, adding a solvent, cooling to precipitate a solid, and filtering to obtain 4-piperidinecarboxylic acid hydrochloride;
s2, adding 4-piperidinecarboxylic acid hydrochloride and a solvent into an autoclave, adding a catalyst, and adding Boc 2 And O, maintaining the reaction temperature and the reaction pressure to generate the 4-piperidine carboxylic acid tert-butyl ester hydrochloride.
2. The method for preparing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the solvent in step S1 is one or more selected from acetone, tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol, and dimethyl sulfoxide, and the amount of the solvent is 3 times the mass of 4-piperidinecarboxylic acid.
3. The process for producing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the reaction pressure in the step S1 is 0.3 to 0.5MPa.
4. The method for preparing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the solvent in the step S2 is a mixture of tetrahydrofuran, water, acetonitrile and water, 1, 4-dioxane and water, acetone and water, and the volume ratio of the solvent to the water is 1.
5. The method for preparing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the catalyst in the step S2 is one of 4-dimethylaminopyridine and 4-pyrrolidinylpyridine.
6. The process for producing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the reaction temperature in the step S2 is 50 to 60 ℃.
7. The process for producing tert-butyl 4-piperidinecarboxylate hydrochloride according to claim 1, wherein the reaction pressure in the step S2 is 0.2 to 0.4MPa.
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| CN202210877302.1A CN115322143B (en) | 2022-07-21 | 2022-07-21 | Preparation method of 4-tert-butyl piperidine formate hydrochloride |
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| CN202210877302.1A CN115322143B (en) | 2022-07-21 | 2022-07-21 | Preparation method of 4-tert-butyl piperidine formate hydrochloride |
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| CN115322143B CN115322143B (en) | 2023-07-14 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035777A (en) * | 2004-10-01 | 2007-09-12 | P.安杰莱蒂分子生物学研究所 | Modulators of hcv replication |
| US20120064181A1 (en) * | 2009-03-23 | 2012-03-15 | Burgey Christopher S | P2X3 Receptor Antagonists for Treatment of Pain |
| CN107501275A (en) * | 2012-12-07 | 2017-12-22 | 沃泰克斯药物股份有限公司 | It can be used as the compound of ATR kinase inhibitors |
| CN108239021A (en) * | 2016-12-27 | 2018-07-03 | 浙江九洲药物科技有限公司 | A kind of trifluoromethylation technique of pyridine bromide and its derivative |
| CN114423751A (en) * | 2020-01-22 | 2022-04-29 | 北京加科思新药研发有限公司 | Novel heterocyclic compounds useful as selective AURORA a inhibitors |
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- 2022-07-21 CN CN202210877302.1A patent/CN115322143B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101035777A (en) * | 2004-10-01 | 2007-09-12 | P.安杰莱蒂分子生物学研究所 | Modulators of hcv replication |
| US20120064181A1 (en) * | 2009-03-23 | 2012-03-15 | Burgey Christopher S | P2X3 Receptor Antagonists for Treatment of Pain |
| CN107501275A (en) * | 2012-12-07 | 2017-12-22 | 沃泰克斯药物股份有限公司 | It can be used as the compound of ATR kinase inhibitors |
| CN108239021A (en) * | 2016-12-27 | 2018-07-03 | 浙江九洲药物科技有限公司 | A kind of trifluoromethylation technique of pyridine bromide and its derivative |
| CN114423751A (en) * | 2020-01-22 | 2022-04-29 | 北京加科思新药研发有限公司 | Novel heterocyclic compounds useful as selective AURORA a inhibitors |
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