CN108424372B - Process for purifying 2, 2, 2-trifluoro-N- [ (S) -4-carbonyltetrahydronaphthalen-1-yl ] -acetamide - Google Patents
Process for purifying 2, 2, 2-trifluoro-N- [ (S) -4-carbonyltetrahydronaphthalen-1-yl ] -acetamide Download PDFInfo
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- CN108424372B CN108424372B CN201810447808.2A CN201810447808A CN108424372B CN 108424372 B CN108424372 B CN 108424372B CN 201810447808 A CN201810447808 A CN 201810447808A CN 108424372 B CN108424372 B CN 108424372B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- C—CHEMISTRY; METALLURGY
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The invention discloses a 2, 2, 2-trifluoro-N- [ (A)S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl]-process for purification of acetamide, compound 1: 2, 2, 2-trifluoro-N- [ (iii)S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]-acetamide is oxidized in one step to form compound 1. The purification comprises the following steps: after the reaction is finished, adding an alcohol solvent for quenching, carrying out suction filtration, and concentrating the filtrate to a certain volume; and (4) carrying out suction filtration, and drying a filter cake to obtain a compound 1. According to the improved process, the alcohol solvent is added after the reaction is finished, so that the quenching reaction of pentahydrate sodium thiosulfate can be replaced, the solubility of the compound 1 in the solution is increased, and the filtering is facilitated. Meanwhile, a crystallization purification method for concentrating the solvent to a certain volume to precipitate solids is adopted, the purity of the product can reach more than 98%, the yield of the product can reach more than 90%, and the purity and the yield of the product are both greatly improved. The purification process is simpler and more convenient to operate, shortens the preparation period, reduces the manufacturing cost, reduces the waste discharge and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a purification process of 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide.
Background
MOR is the target of action of opioid analgesics such as endogenous enkephalin and morphine. An oxacyclic derivative (general formula 1) reported in a patent (WO2017063509) is a receptor agonist of MOR, and the intermediate 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide (compound 1) is one of important structural fragments of the oxacyclic derivative (general formula 1).
The patent (US2014364411) reports that the work-up purification process for the preparation of compound 1 is: after the reaction is finished, adding sodium thiosulfate pentahydrate to quench the reaction solution, concentrating the reaction solution to a certain volume, adding a large amount of water and ethyl acetate to extract the concentrated solution, performing suction filtration, separating out an organic phase, washing with brine, drying the organic phase with anhydrous magnesium sulfate, and finally concentrating the solvent to obtain the compound 1.
The purification process is finally directly concentrated to dryness to obtain the compound 1, the purity of the compound is only about 95 percent, and the process of concentrating to obtain a solid product is not beneficial to the operation of amplification production. Because the purification operation steps are long, the yield is only about 80 percent. The purification condition has low preparation efficiency and high manufacturing cost, generates a large amount of waste and is not suitable for industrial production.
Therefore, it is necessary to find a method for purifying compound 1, which is simple in operation, economical, environmentally friendly and advantageous for industrial production.
Disclosure of Invention
The invention aims to solve the defects of low production efficiency, high cost, serious pollution and unsuitability for industrial production of the existing compound 1 preparation, and provides a purification process of 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide, which comprises the following steps:
(1)2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide, namely the compound 2 is oxidized under the action of potassium permanganate to generate 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide, namely the compound 1;
(2) after the reaction is finished, quenching the mixture by using an alcohol solvent, carrying out suction filtration, concentrating the filtrate to obtain a concentrated solution, carrying out suction filtration, and drying a filter cake to obtain a pure compound 1; the mass ratio of the volume of the concentrated solution to the compound 2 is as follows: 12: 1-13: 1.
The reaction principle of the invention is as follows:
according to the invention, the purification method is redesigned on the basis of the existing method for preparing the compound 1, and the method adds an alcohol solvent after the reaction is finished, so that the quenching reaction of sodium thiosulfate pentahydrate can be replaced, the solubility of the compound 1 in the solution is increased, the filtering is facilitated, the generated waste water and waste gas are less, and the environmental protection is facilitated; the purification method has simple steps and is suitable for industrial application.
Preferably, the alcohol solvent is methanol, ethanol or propanol.
Preferably, the volume ratio of the solvent for quenching to the compound 2 in the step 2 is: 0.1:1 to 50: 1;
the concentration temperature in the preferred step 2 is: 10-60 ℃;
the method has the advantages that the alcohol solvent is added after the reaction is finished, so that the quenching reaction of the sodium thiosulfate pentahydrate can be replaced, the solubility of the compound 1 in the solution is increased, and the filtering is facilitated. Meanwhile, the crystallization purification method for separating out solids by concentrating the solution to a certain volume has the advantages of high purity of over 98 percent, high yield of over 90 percent, high purity and yield, simple and convenient operation, suitability for industrial mass production, low preparation cost, environmental friendliness and the like.
Detailed Description
The invention is further illustrated by the following examples in which:
the starting materials used in the present invention are all commercially available.
Example 1: synthesis of Compound 1
2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]15.0g of (e) -acetamide (compound 2) was dissolved in 300mL of a mixed solvent of acetone and water (V/V ═ 1/1), 15.0g of magnesium sulfate was added, 29.3 g of potassium permanganate was slowly added with stirring, and the reaction was stirred for 2 hours. Adding 500mL of ethanol, continuously stirring for 1h, carrying out suction filtration, and concentrating the filtrate at 10-20 ℃ under reduced pressure to 180-200 mL. Suction filtration, filter cake decompression drying to obtain 14.6g white solid compound 1, yield 92.3%, purity 98.5%. ESI: M/z:258[ M + H ]]+.1H NMR(400MHz，CDCl3):δ8.03-8.05(m，1H)，7.59-7.63(m，1H)， 7.44-7.47(t，1H，J＝7.6Hz)，7.33-7.35(d，1H，J＝7.7Hz),6.73-6.75(m,1H),5.39-5.45 (m，1H)，2.67-2.86(m，2H)，2.43-2.50(m，1H)，2.20-2.29(m，1H)。
Example 2: synthesis of Compound 1
2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]30.0g of (e) -acetamide (compound 2) was dissolved in 600 mL of a mixed solvent of acetone and water (V/V. 1/1), 30.0g of magnesium sulfate was added, 58.6 g of potassium permanganate was slowly added with stirring, and the reaction was stirred for 2 hours. Adding 300mL of propanol, continuously stirring for 1h, carrying out suction filtration, and concentrating the filtrate at 30-40 ℃ under reduced pressure to 360-400 mL. Suction filtration, filter cake decompression drying to obtain 28.8g white solid compound 1, yield 90.7%, purity 98.9%. ESI: M/z:258[ M + H ]]+。
Example 3: synthesis of Compound 1
2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]30.0g of (e) -acetamide (compound 2) was dissolved in 600 mL of a mixed solvent of acetone and water (V/V. 1/1), 30.0g of magnesium sulfate was added, 58.6 g of potassium permanganate was slowly added with stirring, and the reaction was stirred for 2 hours. Adding 1500mL of ethanol, continuously stirring for 1h, performing suction filtration, and concentrating the filtrate at 50-60 ℃ under reduced pressure to obtain a concentrated solution360-400 mL. Suction filtration, filter cake decompression drying to obtain 29.1g white solid compound 1, yield 91.7%, purity 99.1%. ESI: M/z:258[ M + H ]]+。
Example 4: synthesis of Compound 1
2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]1.50Kg of (E) -acetamide (compound 2) was dissolved in 30L of a mixed solvent of acetone and water (V/V-1/1), 1.50Kg of magnesium sulfate was added, 2.93 Kg of potassium permanganate was slowly added with stirring, and the reaction was stirred for 2 hours. Adding 150mL of ethanol, continuously stirring for 1h, carrying out suction filtration, and concentrating the filtrate at 30-40 ℃ under reduced pressure to 18-20L. Suction filtering, and drying the filter cake under reduced pressure to obtain 1.42Kg of off-white solid compound 1 with yield of 89.6% and purity of 98.2%. ESI: M/z:258[ M + H ]]+。
Example 5: synthesis of Compound 1
2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalen-1-yl]1.50Kg of (E) -acetamide (compound 2) was dissolved in 30L of a mixed solvent of acetone and water (V/V-1/1), 1.50Kg of magnesium sulfate was added, 2.93 Kg of potassium permanganate was slowly added with stirring, and the reaction was stirred for 2 hours. Adding 15L of ethanol, continuously stirring for 1 hour, carrying out suction filtration, and concentrating the filtrate at 30-40 ℃ under reduced pressure to 18-20L. Suction filtering, and drying the filter cake under reduced pressure to obtain 1.43Kg of off-white solid compound 1 with yield of 90.9% and purity of 99.0%. ESI: M/z:258[ M + H ]]+。
Claims (3)
1. A process for the purification of 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -acetamide comprising the steps of:
(1) oxidizing 2, 2, 2-trifluoro-N- [ (S) -1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide, namely compound 2, under the action of potassium permanganate to generate 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalene-1-yl ] -acetamide, namely compound 1 reaction liquid;
(2) after the reaction is finished, quenching the mixture by using ethanol or propanol, carrying out suction filtration, concentrating the filtrate to obtain a concentrated solution, carrying out suction filtration, and drying a filter cake to obtain a finished product of the compound 1; the mass ratio of the volume of the concentrated solution to the compound 2 is 12: 1-13: 1.
2. the process for the purification of 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -acetamide according to claim 1, wherein: the volume ratio of the solvent quenched in the step (2) to the compound 2 is as follows: 0.1:1 to 50: 1.
3. The process for the purification of 2, 2, 2-trifluoro-N- [ (S) -4-carbonyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl ] -acetamide according to claim 1, wherein: the concentration temperature in the step (2) is as follows: 10 to 60 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103974953A (en) * | 2011-12-09 | 2014-08-06 | 奇斯药制品公司 | Kinase inhibitors |
| CN103987708A (en) * | 2011-12-09 | 2014-08-13 | 奇斯药制品公司 | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphtalen-1-yl urea and uses thereof in the treatment of diseases of the respiratory tract and other diseases |
| CN104039787A (en) * | 2011-12-09 | 2014-09-10 | 奇斯药制品公司 | Kinase inhibitors |
| CN105308046A (en) * | 2013-06-06 | 2016-02-03 | 奇斯药制品公司 | Kinase inhibitors |
| CN105308044A (en) * | 2013-06-06 | 2016-02-03 | 奇斯药制品公司 | Derivatives of [1, 2, 4]-triazolo-[4, 3-A]-pyridine as p38 MAP kinase inhibitors |
| CN105377847A (en) * | 2013-06-06 | 2016-03-02 | 奇斯药制品公司 | Kinase inhibitors |
| WO2017063509A1 (en) * | 2015-10-15 | 2017-04-20 | 江苏恒瑞医药股份有限公司 | Oxa spiro derivative, preparation method therefor, and applications thereof in medicines |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103974953A (en) * | 2011-12-09 | 2014-08-06 | 奇斯药制品公司 | Kinase inhibitors |
| CN103987708A (en) * | 2011-12-09 | 2014-08-13 | 奇斯药制品公司 | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphtalen-1-yl urea and uses thereof in the treatment of diseases of the respiratory tract and other diseases |
| CN104039787A (en) * | 2011-12-09 | 2014-09-10 | 奇斯药制品公司 | Kinase inhibitors |
| CN105308046A (en) * | 2013-06-06 | 2016-02-03 | 奇斯药制品公司 | Kinase inhibitors |
| CN105308044A (en) * | 2013-06-06 | 2016-02-03 | 奇斯药制品公司 | Derivatives of [1, 2, 4]-triazolo-[4, 3-A]-pyridine as p38 MAP kinase inhibitors |
| CN105377847A (en) * | 2013-06-06 | 2016-03-02 | 奇斯药制品公司 | Kinase inhibitors |
| WO2017063509A1 (en) * | 2015-10-15 | 2017-04-20 | 江苏恒瑞医药股份有限公司 | Oxa spiro derivative, preparation method therefor, and applications thereof in medicines |
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