CN112094274A - Improved tofacitinib synthesis method and impurity preparation method - Google Patents
Improved tofacitinib synthesis method and impurity preparation method Download PDFInfo
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Abstract
The invention discloses an improved tofacitinib synthesis method and an impurity preparation method. According to the improved tofacitinib synthesis method, the impurity formula A is decomposed into the compound II by controlling the pH value of the reaction liquid, and meanwhile, formic acid in the reaction liquid exists in a salt mode and is easy to remove, so that the reaction yield and the tofacitinib quality are effectively improved. Meanwhile, the invention also provides a synthesis method of the impurity formula A, the impurity formula A can be synthesized by the method, and the quality of tofacitinib is detected and controlled.
Description
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to an improved tofacitinib synthesis method and an impurity preparation method.
Background
Tofacitinib (Tofacitinib), which is chemically named as N-methyl-N- [ (3R,4R) -1-cyanoacetyl-4-methylpiperidin-3-yl ] -7H-pyrrolo [2,3-d ] pyrimidin-4-amine, is a JAK inhibitor developed by feverfew and can effectively inhibit the activity of JAK1 and JAK 3. At present, tofacitinib is widely used for treating rheumatoid arthritis and can be used as an autoimmune disease medicament and an immunosuppressant.
Compound of tofacitinib patent CN1195755C discloses a synthesis method, as shown below.
The reaction route has the advantages of high yield, stable process and easily obtained raw materials. However, the debenzylation reaction needs to be carried out under the condition of hydrogen pressurization, so that the equipment safety requirement is high, the potential safety hazard is large, and the industrial production is not facilitated.
In order to solve the technical defects, patents such as CN105348287 and CN106146517 disclose that formic acid and ammonium formate are used as hydrogen sources to perform debenzylation reduction instead of hydrogen.
The reaction route of CN106146517 is shown in the following.
These solutions using formic acid or ammonium formate, although avoiding the use of hydrogen and reducing the reaction times, introduce drawbacks. Formic acid or ammonium formate is liable to react with the reduction product under heating to form amidated impurities, and the impurities have properties similar to those of tofacitinib and are difficult to remove. Particularly in large-scale production, the process impurities can be obviously increased along with the increase of reaction equivalent, and the quality of the tofacitinib is seriously influenced. In addition, in the subsequent treatment of tofacitinib, tofacitinib is degraded when the alkalinity of the pH is too high or too low, thereby affecting the yield.
Disclosure of Invention
The invention aims to overcome the defects that impurities which are difficult to separate are easily generated and the aftertreatment process can cause degradation of tofacitinib in the prior art, and provides an improved tofacitinib synthesis method and an impurity preparation method.
The technical scheme adopted for realizing the purpose is as follows:
the invention also provides an improved tofacitinib synthesis method, which is characterized by comprising the following steps:
1) reacting the compound I with formic acid or ammonium formate in a solvent under the action of a first catalyst under the heating condition;
2) filtering the reaction liquid obtained in the step 1), adding alkali into the filtrate to adjust the pH value to be alkaline, and after the reaction is completed, washing, extracting and separating liquid to obtain a compound II;
3) reacting the compound II with ethyl cyanoacetate under the action of a second catalyst; after the reaction is completed, washing and extracting with weak alkaline water to obtain a tofacitinib crude product;
preferably, the solvent of step 1) comprises one of methanol, ethanol and propanol. The solvent used may also be other commonly used alcoholic solvents or protic solvents, such as isopropanol, butanol, isoamyl alcohol, and the like.
Preferably, the heating temperature in the step 1) is 60-70 ℃. The temperature of heating needs to be controlled around the reflux temperature of the solvent. When the environment is changed, the heating temperature can be increased or decreased appropriately, for example, 50, 55, 60, 65, 70, 75, 80, 85 ℃.
Preferably, the first catalyst in step 2) is a Pd/C catalyst, preferably 10% Pd/C. In another embodiment, the first catalyst may also be Pd (OH)2and/C. In another embodiment, Pd/C or Pd (OH)2The mass fraction of Pd in the/C may be not only 10%, but also 5, 15 or 20%.
Preferably, the alkalinity in the step 2) is pH value of more than or equal to 13, and the alkali is one of sodium hydroxide and potassium hydroxide. When the pH value is 13 or more, it is ensured that most of the impurity of formula A in the reaction solution is decomposed to compound II. In one embodiment, the impurity of formula a may be decomposed to compound II using an acid having a pH of 3 or less, but when an acid is used, formic acid or formate remains in compound II as formic acid, and the reaction with compound II continues in the subsequent reaction.
In one embodiment, the base used may be other compounds or solutions having a basic property, such as lithium hydroxide, calcium hydroxide, and the like.
Preferably, the reaction temperature in the step 2) is 50-65 ℃.
Preferably, the second catalyst in step 3) is DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene).
Further preferably, the pH value of the weakly alkaline water is 8-8.5.
The invention also provides a preparation method of the tofacitinib process impurity, wherein the compound II reacts with formic acid or ammonium formate to obtain an impurity formula A; in another embodiment, it is also possible to prepare the impurity of formula A by reacting compound II with other formates instead of formic acid or ammonium formate. The other formate may be an alkali metal salt or an alkaline earth metal salt of formic acid such as sodium formate, potassium formate, magnesium formate, calcium formate, etc.
When the pH is too high, the impurity formula A tends to decompose. In order to increase the yield of the impurity of the formula A, the pH value of the reaction needs to be controlled within a certain range, so that the impurity of the formula A obtained by the reaction is not decomposed.
Compared with the prior art, the method has the following advantages:
the invention provides an improved synthetic method of tofacitinib. According to the method, the pH value of the reaction liquid is controlled to be alkaline, the impurity formula A is decomposed into the compound II, and meanwhile, formic acid in the reaction liquid exists in a salt mode and is easy to remove, so that the reaction yield and the tofacitinib quality are effectively improved. In addition, the method also improves the post-treatment process of the tofacitinib, so that the degradation amount of the tofacitinib is reduced. The invention also discloses a preparation method of the impurity formula A of the tofacitinib process, and the impurity formula A can be synthesized by the method to detect and control the quality of the tofacitinib.
Drawings
FIG. 1: of the impurity formula A in example 11H-NMR spectrum;
FIG. 2: MS spectrum of impurity formula A in example 1.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be noted that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
The reagents and instruments used in the present invention are commercially available, and some of the reagents were synthesized according to published literature.
Example 1
6.0g of compound I, 1.2g of 10% Pd/C, 48.0g of ammonium formate and 72ml of methanol are added to a reaction flask, heated to 65 ℃ and stirred for 9 hours under constant temperature. After completion of the reaction, the reaction mixture was filtered, extracted with dichloromethane and ethyl acetate, washed with water, and subjected to liquid separation and reduced pressure distillation to obtain 3.0g of a white powdery compound II with a yield of 68.2%.
Adding 3.0g of compound II, 1.4g of ethyl cyanoacetate, 1.2g of DBU and 10ml of n-butyl alcohol into a reaction bottle, heating to 60-65 ℃, and stirring for 8-9 hours under heat preservation. After the reaction is completed, the temperature is reduced to room temperature, water is added, ethyl acetate is used for extraction, and the light yellow tofacitinib crude product 1.6g is obtained after concentration and drying, and the yield is 62.8%.
Separating the impurity in the compound II by using a chromatographic separation method to obtain the impurity formula A, wherein the impurity accounts for 32.6 percent of the weight of the product. The proportion of impurity of formula A in compound II increases with increasing reaction time, the content of impurity of formula A in part of the batch even exceeding 50%. FIG. 1 and FIG. 2 show impurity formula A1H-NMR spectrum and MS spectrum.
Example 2
Adding 40g of compound I, 8g of 10% Pd/C, 233g of formic acid and 480ml of methanol into a reaction bottle, heating to 67-70 ℃, and stirring for 4-5 hours under heat preservation. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, 30% aqueous sodium hydroxide solution was added to adjust the pH to 14, and the aqueous phase was washed with ethyl acetate. And then adding methanol into the water phase, and stirring and reacting for 4 hours at 50-60 ℃. After the reaction was completed, dichloromethane was added to extract 3 times, liquid separation was performed, the organic phase was concentrated until no distillate was obtained, and then dried to obtain 24.1g of a white solid powder compound II with a yield of 82.4%. Impurity formula A was not detected.
Adding 20g of compound II, 18.4g of ethyl cyanoacetate, 12.4g of DBU and 100ml of tetrahydrofuran into a reaction bottle, heating to 60-65 ℃, and stirring for 4-5 hours under heat preservation. After the reaction is finished, cooling to room temperature, pouring into a separating funnel, adding water into the funnel, adding ethyl acetate into the funnel, extracting for 3 times, separating, combining organic phases, washing the organic phases with neutral sodium chloride water, drying and then carrying out vacuum spin drying. Finally, the crude product of tofacitinib is obtained by drying, 19.6g is obtained, and the yield is 76.9%.
Example 3
Adding 40g of compound I, 8g of 10% Pd/C, 320g of ammonium formate and 480ml of methanol into a reaction bottle, heating to 67-70 ℃, and stirring for 4-5 hours under heat preservation. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, then 30% aqueous sodium hydroxide solution was added to adjust the pH to 13, and the aqueous phase was washed with ethyl acetate. And then adding methanol into the water phase, and stirring and reacting for 4 hours at the temperature of 55-60 ℃. After the reaction was completed, dichloromethane was added to extract 3 times, followed by liquid separation, concentration of the organic phase until no distillate was obtained, and drying to obtain 22.3g of a white solid powder compound II. The yield thereof was found to be 76.2%. Impurity formula A was not detected.
Adding 20g of compound II, 18.4g of ethyl cyanoacetate, 12.4g of DBU and 100ml of tetrahydrofuran into a reaction bottle, heating to 60-65 ℃, and stirring for 4-5 hours under heat preservation. After the reaction is finished, cooling to room temperature, pouring into a separating funnel, adding water into the funnel, adding ethyl acetate into the funnel, extracting for 3 times, separating, combining organic phases, washing the organic phases with neutral sodium chloride water, drying and then carrying out vacuum spin drying. Finally, the crude product of tofacitinib is obtained after drying, wherein the yield is 73.8 percent.
Example 4
160g of compound I, 32g of 10% Pd/C, 1280g of ammonium formate and 1.9L of methanol are added into a reaction bottle, heated to 60-65 ℃, kept warm and stirred for 4-5 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, 30% aqueous sodium hydroxide solution was added to adjust the pH to 14, and the aqueous phase was washed with ethyl acetate. And then adding methanol into the water phase, and stirring and reacting for 5 hours at the temperature of 60-65 ℃. After the reaction was completed, dichloromethane was added to extract 3 times, followed by liquid separation, concentration of the organic phase until no distillate was obtained, and drying to obtain compound II94.8g as a white solid powder. The yield thereof was found to be 81%. Impurity formula A was not detected.
Adding 80g of compound II, 73.8g of ethyl cyanoacetate, 49.6g of DBU and 400ml of tetrahydrofuran into a reaction bottle, heating to 60-65 ℃, and stirring for 4-5 hours under the condition of heat preservation. After the reaction is finished, cooling to room temperature, pouring into a separating funnel, adding water into the funnel, adding ethyl acetate into the funnel, extracting for 3 times, separating, combining organic phases, washing the organic phases with neutral sodium chloride water, drying and then carrying out vacuum spin drying. Finally, 79.7g of the crude tofacitinib product is obtained after drying, and the yield is 78.2%.
Example 5
Adding 9.0kg of compound I, 1.8kg of 10% Pd/C, 72.0kg of ammonium formate and 90kg of methanol into a reaction kettle, heating to 60-70 ℃, and stirring for 3-5 hours under heat preservation. And after the reaction is completed, cooling to 0-10 ℃, filtering, washing a filter cake with methanol, and collecting filtrate. And (3) adjusting the pH value of the filtrate to 13 by using 30% liquid alkali, heating to 60-65 ℃ under stirring, then cooling, adding dichloromethane for multiple times of extraction, and collecting an organic layer. The organic layer was washed with deionized water several times, and dried by distillation under reduced pressure to give 4.61kg of Compound II in a yield of 70%. Impurity formula A was not detected.
Adding 4.0kg of compound II, 3.7kg of ethyl cyanoacetate, 2.5kg of DBU and 18.0kg of tetrahydrofuran into a reaction kettle, and heating to 60-65 ℃ for reaction for 4-5 h. And cooling to room temperature after the reaction is completed, separating and extracting with ethyl acetate, washing the organic layer with water with the pH value of 7-8.5, and distilling the organic layer under reduced pressure after liquid separation until no distillate exists. Then drying to obtain 3.82kg of the tofacitinib crude product with the yield of 75 percent.
Example 6
To reaction flask X, 10mg of impurity formula A and 5ml of methanol were added, and 30% aqueous sodium hydroxide solution was added to adjust the pH to 13, followed by stirring at room temperature for 2 hours.
To reaction flask Y, 10mg of impurity formula A and 5ml of methanol were added, and 2N HCl solution was added to adjust pH to 3, followed by stirring at room temperature for 2 hours.
To reaction flask Z, 10mg of impurity formula A and 5ml of methanol were added, and 30% aqueous sodium hydroxide solution was added to adjust the pH to 12, followed by stirring at room temperature for 2 hours.
The content of impurity of formula A in reaction flask X, Y, Z was then determined by HPLC.
In another embodiment, the sodium hydroxide and HCl solutions used may be exchanged for other acid-base solutions.
The results of the experiment are shown in table 1.
TABLE 1
| Batch number | Number of reaction flask | Reaction time (h) | HPLC detection of remaining amount of impurity formula A (%) |
| 121203 | |
2 | Not detected out |
| 121204 | |
2 | 86.2 |
| 121205 | |
2 | 1.6％ |
As can be seen from the above table, when the pH of the solution is 13 or more, the impurity of formula A can be removed effectively.
Example 7
Adding 3.0g of compound II, 2.1g of ethyl cyanoacetate, 1.8g of DBU and 15ml of tetrahydrofuran into a 25ml reaction bottle, heating to 60-65 ℃, and keeping the temperature and stirring. After the reaction, the temperature is reduced to room temperature, the mixture is poured into a 250ml separating funnel, water with different pH values is added into the funnel, ethyl acetate is added for extraction and separation for multiple times, and organic phases are combined. Concentrating until no distillate drips out to obtain the tofacitinib.
The results of the experiment are shown in table 2.
TABLE 2
| Batch number | pH value | Compound II content (%) HPLC |
| 170106-2 | 8.5 | 0.505％ |
| 170106-3 | 9 | 0.612％ |
| 170112-4 | 7～8.5 | 0.321％ |
As can be seen from the above table, when the pH value is 7-8.5, the content of the compound II is low, and the purity of the tofacitinib crude product is high.
Finally, it should be noted that the above examples, using specific embodiments and experiments, have described the invention in detail, but it will be apparent to those skilled in the art that on the basis of the present invention, modifications or improvements can be made thereto without departing from the spirit of the invention. Thus, such modifications and improvements do not depart from the spirit of the invention and are intended to be included within the scope of the invention as claimed.
Claims (10)
1. An improved synthetic method of tofacitinib is characterized by comprising the following steps:
1) reacting the compound I with formic acid or ammonium formate in a solvent under the action of a first catalyst under the heating condition;
2) filtering the reaction liquid obtained in the step 1), adding alkali into the filtrate to adjust the pH value to be alkaline, and after the reaction is completed, washing, extracting and separating liquid to obtain a compound II;
3) reacting the compound II with ethyl cyanoacetate under the action of a second catalyst; after the reaction is completed, washing and extracting with weak alkaline water to obtain a tofacitinib crude product;
2. the synthesis method of claim 1, wherein the solvent of step 1) comprises one of methanol, ethanol and propanol.
3. The synthesis method according to claim 1, wherein the heating temperature in the step 1) is 60-70 ℃.
4. The synthesis method according to claim 1, wherein the first catalyst in step 1) is a Pd/C catalyst, preferably 10% Pd/C.
5. The synthesis method of claim 1, wherein the alkalinity in step 2) is pH value of 13 or more, and the alkali comprises one of sodium hydroxide and potassium hydroxide.
6. The synthesis method according to claim 1, wherein the reaction temperature in the step 2) is 50-65 ℃.
7. The method of claim 1, wherein the second catalyst in step 3) is DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene).
8. The synthesis method of claim 1, wherein the pH value of the weak alkaline water in the step 3) is 7-8.5.
9. The synthesis method of claim 8, wherein the pH value of the weak alkaline water in the step 3) is 8-8.5.
10. A preparation method of tofacitinib process impurities is characterized in that a compound II reacts with formic acid or ammonium formate to obtain an impurity formula A;
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146517A (en) * | 2016-06-20 | 2016-11-23 | 山东大学 | A kind of citric acid expelling pathogens by strengthening vital QI is for the synthetic method of Buddhist nun |
| CN109776547A (en) * | 2019-03-22 | 2019-05-21 | 北京新领先医药科技发展有限公司 | Preparation method of tofacitinib citrate |
| WO2019182322A1 (en) * | 2018-03-20 | 2019-09-26 | 삼진제약주식회사 | Novel salt, manufacturing method therefor, and pharmaceutical composition comprising same |
| CN110343113A (en) * | 2019-08-07 | 2019-10-18 | 山东鲁抗医药股份有限公司 | Preparation method of tofacitinib intermediate |
| CN111265668A (en) * | 2019-06-09 | 2020-06-12 | 黄泳华 | Composition comprising a histamine release-promoting substance and an inhibitory compound |
| CN111588724A (en) * | 2020-06-06 | 2020-08-28 | 黄泳华 | Use of pyrrolopyrimidine derivatives in the treatment of Janus kinase mediated diseases |
-
2020
- 2020-09-08 CN CN202010933890.7A patent/CN112094274A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146517A (en) * | 2016-06-20 | 2016-11-23 | 山东大学 | A kind of citric acid expelling pathogens by strengthening vital QI is for the synthetic method of Buddhist nun |
| WO2019182322A1 (en) * | 2018-03-20 | 2019-09-26 | 삼진제약주식회사 | Novel salt, manufacturing method therefor, and pharmaceutical composition comprising same |
| CN109776547A (en) * | 2019-03-22 | 2019-05-21 | 北京新领先医药科技发展有限公司 | Preparation method of tofacitinib citrate |
| CN111265668A (en) * | 2019-06-09 | 2020-06-12 | 黄泳华 | Composition comprising a histamine release-promoting substance and an inhibitory compound |
| CN110343113A (en) * | 2019-08-07 | 2019-10-18 | 山东鲁抗医药股份有限公司 | Preparation method of tofacitinib intermediate |
| CN111588724A (en) * | 2020-06-06 | 2020-08-28 | 黄泳华 | Use of pyrrolopyrimidine derivatives in the treatment of Janus kinase mediated diseases |
Non-Patent Citations (2)
| Title |
|---|
| CHIEYEON CHOUGH ET AL.: "Design, synthesis and evaluation of (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor", 《MED. CHEM. COMMUN.》 * |
| 吕佳徽: "枸橼酸托法替尼的工艺优化及质量研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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