CN110981851A - Preparation method of canagliflozin impurity - Google Patents
Preparation method of canagliflozin impurity Download PDFInfo
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- CN110981851A CN110981851A CN201911351198.7A CN201911351198A CN110981851A CN 110981851 A CN110981851 A CN 110981851A CN 201911351198 A CN201911351198 A CN 201911351198A CN 110981851 A CN110981851 A CN 110981851A
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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Abstract
The invention provides a preparation method of canagliflozin impurities, which comprises the following steps: under the protection of inert gas, dissolving 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene in a solvent, dropwise adding an n-butyllithium solution at a reaction temperature, introducing dry CO2 gas into the reaction system, heating to room temperature for reacting for 2 hours, adding a saturated ammonium chloride solution into the reaction system, and extracting, drying, concentrating and purifying to obtain a canagliflozin impurity (formula II); the reaction temperature does not exceed-40 ℃. The technical scheme of the invention has the advantages of cheap and easily obtained raw materials, simple operation and post-treatment, mild reaction conditions, stable process, high yield and good reproducibility; the technical scheme makes up the blank that the preparation method is not available at home and abroad, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of canagliflozin impurities.
Background
Canagliflozin (formula I), the chemical name of which is (1S) -1, 5-dehydro-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol, is a sodium-glucose co-transporter 2(SGLT2) inhibitor developed by Mitsubishi corporation and Qiangsheng corporation of Japan, and reduces the blood glucose concentration by inhibiting SGLT2 so that glucose in renal tubules cannot be smoothly reabsorbed into the blood and excreted with urine. The medicine is approved by the FDA in US for marketing at 29 days 3 and 3 months in 2013, and is under the trade name of Invokana, and is used for treating adult type 2 diabetes.
Currently, most of the methods for synthesizing canagliflozin adopt 2- (4-fluorophenyl) -5- [ (5-halo-2-methylphenyl) methyl ] thiophene as a starting material, and the reaction conditions required in the first coupling reaction are strict, such as no water and no oxygen, but the canagliflozin impurities can be generated in the process of scale-up production: 3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylbenzoic acid (formula II).
The adverse reaction of the medicine in the clinical use process is related to the pharmacological activity of the raw material medicine and the impurities in the medicine. Canagliflozin impurity (formula II) is one of the impurities that may be produced during the production or degradation of canagliflozin, and is chemically named 3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylbenzoic acid. At present, no synthesis report of the compound exists at home and abroad.
The research on impurities in medicines is an important content of the research on the quality of medicines, and the research and control on impurities are one of key factors for ensuring the quality of medicines and ensuring the safety of medicines. The canagliflozin impurity (formula II) is one of the important impurities of canagliflozin, has great significance for the product of the canagliflozin by deep research on the canagliflozin impurity, can make up the blank that the preparation method is not available in China for the synthetic research on the canagliflozin impurity (formula II), and provides convenience for pharmaceutical enterprises to develop the variety.
Disclosure of Invention
Aiming at the technical problems, the invention discloses a preparation method of canagliflozin impurities, which is obtained by adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene and carbon dioxide by a one-step method and has simple operation and post-treatment.
In contrast, the technical scheme adopted by the invention is as follows:
a method for preparing canagliflozin impurities, comprising:
under the protection of inert gas, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Dissolving thiophene in solvent, dripping n-butyl lithium solution at reaction temperature, and adding dried CO2Introducing gas into the reaction system, raising the temperature to room temperature for reaction for 2 hours, adding a saturated ammonium chloride solution into the reaction system, and extracting, drying, concentrating and purifying to obtain canagliflozin impurities (formula II); the reaction temperature does not exceed-40 ℃. The reaction formula is shown as follows:
the technical scheme adopts a one-step method, the canagliflozin impurity (formula II) is obtained by adding 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene and carbon dioxide, the raw materials are cheap and easy to obtain, the operation and the post-treatment are simple, the reaction condition is mild, the process is stable, the yield is high, and the reproducibility is good.
In a further improvement of the invention, the ratio of the amount of the substance added to the n-butyllithium solution to the amount of the substance of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene is 1.0 to 1.6: 1.
As a further improvement of the invention, the n-butyllithium solution is an n-hexane solution or a toluene solution with n-butyllithium concentration of 1.0-2.5M.
As a further improvement of the invention, the ratio of the added volume of the solvent to the mass of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene is V: and M is 5-20: 1.
As a further improvement of the invention, the solvent is any one of anhydrous tetrahydrofuran, anhydrous toluene and anhydrous 1, 4-dioxane.
As a further improvement of the invention, the reaction temperature is-78 ℃ to-40 ℃.
As a further improvement of the invention, the inert gas is any one of dry nitrogen and argon.
As a further development of the invention, the CO is2The gas is introduced for 1 to 10 hours.
Compared with the prior art, the invention has the beneficial effects that:
the technical scheme of the invention adopts 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene and carbon dioxide to perform addition reaction to obtain the canagliflozin impurity (formula II), and the raw materials are cheap and easy to obtain, the operation and the post-treatment are simple, the reaction condition is mild, the process is stable, the yield is high, and the reproducibility is good; the technical scheme makes up the blank that the preparation method is not available at home and abroad, can also reduce the cost of developing the medicine by pharmaceutical enterprises, and has very good industrial application prospect.
Drawings
FIG. 1 is a MS spectrum of canagliflozin impurity (formula II) of example 1 of the present invention.
FIG. 2 is a 1HNMR spectrum of canagliflozin impurity (formula II) of example 1 of the present invention.
FIG. 3 is an HPLC chromatogram of the canagliflozin impurity (formula II) of example 1 of the present invention.
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
The canagliflozin impurity (formula II) is prepared by the following steps:
under the protection of nitrogen, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Thiophene (4.08g, 10mmol, 1.0eq) was dissolved in anhydrous tetrahydrofuran (32mL), a 2.5M n-butyllithium n-hexane solution (6mL, 15mmol, 1.5eq) was slowly added dropwise at-78 deg.C, and the dried CO was added2Introducing gas into the reaction system for 8 hours, raising the temperature to room temperature for reaction for 2 hours, and then introducing the reaction systemAdding saturated ammonium chloride solution, extracting with dichloromethane, drying with anhydrous sodium sulfate, concentrating, and purifying with silica gel column to obtain 2.81g of canagliflozin impurity (formula II), with yield of 86.1% and HPLC purity of 98.55%.
MS(m/z)：325.1(M-H)-；
1H NMR(400MHz,CDCl3)：δ7.97(s,1H),7.92(d,J＝8Hz，1H),7.46-7.49(m,2H),7.29(d,J＝8Hz，1H),7.00-7.04(m,3H),6.67(d,J＝4Hz，1H),4.18(s,2H),2.40(s,2H)。
MS spectrogram of the obtained canagliflozin impurity (formula II) and1the HNMR spectra are shown in FIG. 1 and FIG. 2, respectively.
HPLC (high performance liquid chromatography) detection is carried out on the canagliflozin impurity (formula II) prepared above, an HPLC spectrogram is shown in figure 3, and the test conditions are as follows:
a chromatographic column: h & E C18A31 SPS 100-104.6X 250mm, 10 μm
Mobile phase:
a: acetonitrile; b: 0.1% phosphoric acid aqueous solution
Mobile phase ratio: a, B is 70: 30
Column temperature: 35 deg.C
Detection wavelength: 215nm
Flow rate: 1.0mL/min
Time: 25.00 min.
Example 2
The preparation method and the test method of canagliflozin in the embodiment are mainly the same as those in the embodiment 1, and the difference is that the method specifically comprises the following steps:
under the protection of nitrogen, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Thiophene (4.08g, 10mmol, 1.0eq) was dissolved in anhydrous tetrahydrofuran (20mL), a 1.0M n-butyllithium n-hexane solution (10mL, 10mmol, 1.0eq) was slowly added dropwise at-40 deg.C, and the dried CO was added2After the gas was introduced into the reaction system for 1 hour, the temperature was raised to room temperature and the reaction was carried out for 2 hours, and then a saturated ammonium chloride solution was added to the reaction system, followed by extraction with methylene chloride, drying over anhydrous sodium sulfate, concentration and purification with a silica gel column to obtain 2.44g of canagliflozin impurity (formula ii), yield 74.8% and HPLC purity 98.10%.
Example 3
The preparation method and the test method of canagliflozin in the embodiment are mainly the same as those in the embodiment 1, and the difference is that the method specifically comprises the following steps:
under the protection of argon, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Thiophene (4.08g, 10mmol, 1.0eq) was dissolved in anhydrous toluene (80mL), 2.5M n-butyllithium solution in toluene (6mL, 15mmol, 1.5eq) was slowly added dropwise at-78 deg.C, and the dried CO was added2After gas is introduced into the reaction system for 10 hours, the temperature is raised to room temperature for reaction for 2 hours, saturated ammonium chloride solution is added into the reaction system, and then the mixture is extracted by dichloromethane, dried by anhydrous sodium sulfate, concentrated and purified by a silica gel column to obtain 2.51g of canagliflozin impurity (formula II), the yield is 78.9 percent, and the HPLC purity is 98.22 percent.
Example 4
The preparation method and the test method of canagliflozin in the embodiment are mainly the same as those in the embodiment 1, and the difference is that the method specifically comprises the following steps:
under the protection of argon, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Thiophene (4.08g, 10mmol, 1.0eq) was dissolved in anhydrous 1, 4-dioxane (32mL), a 1.5M n-butyllithium toluene solution (8mL, 12mmol, 1.2eq) was slowly added dropwise at-60 deg.C, and the dried CO was added2After the gas was introduced into the reaction system for 5 hours, the reaction system was further warmed to room temperature for 2 hours, and then a saturated ammonium chloride solution was added to the reaction system, followed by extraction with methylene chloride, drying over anhydrous sodium sulfate, concentration and purification with a silica gel column to obtain 2.73g of canagliflozin impurity (formula ii), yield 83.6%, HPLC purity 98.22%.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
Claims (8)
1. A preparation method of canagliflozin impurity is characterized by comprising the following steps:
under the protection of inert gas, 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl]Dissolving thiophene in solvent, dripping n-butyl lithium solution at reaction temperature, and adding dried CO2Introducing gas into the reaction system, raising the temperature to room temperature for reaction for 2 hours, adding a saturated ammonium chloride solution into the reaction system, and extracting, drying, concentrating and purifying to obtain a canagliflozin impurity shown in the following formula; the reaction temperature is not more than-40 ℃;
2. the method for preparing canagliflozin impurity according to claim 1, characterized in that: the ratio of the amount of the substance added to the n-butyllithium solution to the amount of the substance of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene is 1.0-1.6: 1.
3. The method for preparing canagliflozin impurity according to claim 2, characterized in that: the n-butyllithium solution is n-hexane solution or toluene solution with n-butyllithium concentration of 1.0-2.5M.
4. The method for preparing canagliflozin impurity according to claim 1, characterized in that: the ratio of the added volume of the solvent to the mass of 2- (4-fluorophenyl) -5- [ (5-iodo-2-methylphenyl) methyl ] thiophene is V: and M is 5-20: 1.
5. The method for preparing canagliflozin impurity according to claim 4, characterized in that: the solvent is any one of anhydrous tetrahydrofuran, anhydrous toluene and anhydrous 1, 4-dioxane.
6. The method for preparing canagliflozin impurity according to claim 1, characterized in that: the reaction temperature is-78 ℃ to-40 ℃.
7. The method for preparing canagliflozin impurity according to claim 1, characterized in that: the inert gas is any one of dry nitrogen and argon.
8. The method for preparing canagliflozin impurity according to any one of claims 1 to 7, characterized in that: the CO is2The gas is introduced for 1 to 10 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
| CN115260151A (en) * | 2022-09-02 | 2022-11-01 | 上海予君生物科技发展有限公司 | Synthesis process of canagliflozin impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | Novel compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
| CN115260151A (en) * | 2022-09-02 | 2022-11-01 | 上海予君生物科技发展有限公司 | Synthesis process of canagliflozin impurity |
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