Preparation method of dexamethasone acetate

Abstract

The invention discloses a preparation method of dexamethasone acetate, which adopts dichloromethane as a reaction solvent, can adopt an extraction and separation method, can adopt an extraction and separation method, can adopt an extraction and separation method, can adopt an extraction and separation method, can adopt a new catalyst, can improve the reaction purity from the original 92% to 99%, and can carry out the next reaction without purification and separation. The method is safe and controllable in reaction, high in reaction speed, thorough in reaction and high in reaction purity, due to the fact that an extraction separation method is adopted, the fluoridation purity is greatly improved, impurity points are small and are increased to 98.5% or above from original 94%, fluoride does not need to be separated and is directly refined and decolored, steps are reduced, and compared with a traditional process, separation, drying and intermediate are not needed, and the cost is low. According to the process, the yield is increased by 8%-10%, three wastes are few, clean production is achieved, and a single solvent is adopted and is easy to recover.

Description

Technical Field

[0001] The present invention relates to a chemical preparation method, specifically, a method for preparing dexamethasone acetate. Background Art

[0002]

[0003] In the prior art, the main steps are as follows:

[0004]

[0005] The present invention has the following technical problems:

[0006] 1) In the first step, acetone is used as a solvent, the reaction time is long, the reaction conversion rate is low, only 92%, and the impurity spots are large.

[0007] 2) Solid-liquid separation and drying are required. Energy is wasted. Physical labor is increased.

[0008] 3) The product purity is low and further purification is required to carry out the fluorination reaction.

[0009] 4) The purity of the traditional fluorination reaction is low, only about 94%.

[0010] 5) 40 times of water precipitation is required for the post-treatment, generating a large amount of wastewater and increasing the treatment difficulty. Summary of the Invention

[0011] The present invention makes improvements to the deficiencies of the prior art and provides a synthesis process for dexamethasone acetate. The present invention is achieved through the following technical solutions:

[0012] The present invention discloses a method for preparing dexamethasone acetate, and the reaction formula is as follows:

[0013]

[0014] Among them, compound J is not separated and directly undergoes a "one-pot method". The specific reaction steps are as follows:

[0015] 1) Add 6 - 6.5W of dichloromethane to the reaction kettle, add 1W of raw material I, and stir and cool down to 0 - 10 °C;

[0016] 2) When the temperature reaches 0 - 10 °C, add 0.002 - 0.0025W of diethylamine, and dropwise add 0.2 - 0.3W of acetic anhydride over 0 - 60 minutes;

[0017] 3) After the dropping is completed, keep the temperature at 0 - 10 °C for 3 - 5 hours, and detect the raw material spot. If it is less than 0.2% - 0.3%, it is qualified;

[0018] 4) Add ammonia water with a concentration of 18%, adjust the pH to 5 - 7, let it stand for 30 - 35 minutes, and separate the aqueous layer;

[0019] 5) Cool the reaction solution to -15 to -10 °C, add 0.9 - 0.95 W of DMF, and add dropwise 5 W of 30% - 50% HF aqueous solution over 30 - 90 minutes;

[0020] 6) After the dropwise addition, raise the temperature to -10 to -5 °C, keep the temperature for 3 - 6 hours, and detect the raw material point. A value less than 0.2% - 0.3% is qualified;

[0021] 7) Add dropwise ammonia water with a concentration of 18% - 21%, adjust the pH to 5 - 7, let it stand for 10 - 40 minutes, and separate the aqueous layer;

[0022] 8) Add 2 - 2.5 W of methanol and 1 kg of activated carbon, heat to 55 - 60 °C, keep the temperature for 30 - 40 minutes, filter, first recover the solvent under normal pressure and then under reduced pressure, cool to 0 - 5 °C, keep the temperature for 2 - 4 h, filter with suction, and dry at 45 °C and -0.09 MPa vacuum for 3 - 8 h to obtain the product with a purity ≥ 99.5%, single impurity ≤ 0.2%, water content ≤ 0.2%, and off - white solid.

[0023] As a further improvement, in step 1) of the present invention, the temperature during stirring and cooling is 5 ± 1 °C.

[0024] As a further improvement, in step 2) of the present invention, the time is 30 minutes.

[0025] As a further improvement, in step 3) of the present invention, the holding time is 4 h.

[0026] As a further improvement, in step 4) of the present invention, the pH is 6.

[0027] As a further improvement, in step 5) of the present invention, the HF aqueous solution is 40% and the dropwise addition time is 60 minutes.

[0028] As a further improvement, the holding reaction time in step 6) of the present invention is 4 h. 8. According to the method of claim 7, in step 7), adjust the pH to 6 and the standing time is 30 minutes.

[0029] As a further improvement, the drying time in step 8) of the present invention is 4 h.

[0030] The beneficial effects of the present invention are as follows:

[0031] 1) Using dichloromethane as the reaction solvent, the extraction and separation method can be adopted, and the original two - step separation is combined into one step after the reaction is completed.

[0032] 2) A new catalyst is adopted, and the reaction purity is increased from the original 92% to 99%. Without purification and separation, the next-step reaction can be carried out. The reaction is safe, controllable, with a fast reaction speed, complete reaction, and high reaction purity.

[0033] 3) Due to the adoption of the extraction and separation method, the purity of the fluorination reaction is greatly improved, and the impurity points are small, increasing from the original 94% to more than 98.5%.

[0034] 4) The fluoride does not need to be separated and is directly refined and decolorized, reducing the steps.

[0035] 5) Compared with the traditional process, separation, drying, and intermediates are not required, reducing the solvent consumption. The yield of this process is increased by 8%-10%, the cost is reduced by about 10% per kilogram, and at the same time, the labor intensity is reduced. The purity of the finished product reaches more than 99.5%, meeting the Chinese Pharmacopoeia: CP2020 and the United States Pharmacopoeia: USP-NF2024.

[0036] 6) There is less three wastes, achieving clean production.

[0037] 7) A single solvent is adopted, which is easy to recycle.

[0038] 8) The stirring temperature is 5±1°C, and the raw material points are significantly reduced, which is more conducive to the reaction proceeding in the positive direction.

[0039] 9) When the HF aqueous solution is 40%, after the concentration increases, it is conducive to the reaction proceeding in the positive direction.

[0040] 10) When the pH is adjusted to 6, the chromaticity of the product is significantly improved. Specific implementation manners

[0041] The technical solutions of the present invention will be further described below through specific examples:

[0042] The reagents are purchased from commercial sources and used after passing the inspection.

[0043] In order to make the technical problems, technical solutions, and beneficial effects solved by the present invention clearer, the following will further describe the present invention in combination with specific examples. The specific examples given are the preferred examples of the present invention.

[0044] Example 1-1: Preparation of 8DM acetate

[0045]

[0046] 1) Add 6.5W dichloromethane to the reaction kettle, add 1W of raw material I, and stir and cool down to 5±1°C

[0047] 2) When the temperature reaches 5 ± 1 °C, add 0.0025 W of diethylamine, and dropwise add 0.3 W of acetic anhydride over 30 minutes;

[0048] 3) After the dropwise addition, maintain the temperature at 5 ± 1 °C for 4 hours, and detect the raw material point. If it is less than 0.5%, it is qualified;

[0049] 4) Dropwise add ammonia water with a concentration of 18%, adjust the pH to 6, let it stand for 30 minutes, and separate the aqueous layer;

[0050] Example 1-2: Preparation of Dexamethasone Acetate

[0051]

[0052] 5) Cool the reaction solution to -15 to -10 °C, add 0.95 W of DMF, and dropwise add 5 W of 40% HF aqueous solution over 60 minutes;

[0053] 6) After the dropwise addition, raise the temperature to -10 to -5 °C, maintain the reaction for 4 hours, and detect the raw material point. If it is less than 0.5%, it is qualified;

[0054] 7) Dropwise add ammonia water with a concentration of 18%, adjust the pH to 6, let it stand for 30 minutes, and separate the aqueous layer;

[0055] 8) Add 2 W of methanol and 1 kg of activated carbon, heat to 55 - 60 °C, maintain the temperature for 30 - 40 minutes, filter, first recover the solvent under normal pressure and then under reduced pressure, cool to 0 - 5 °C, maintain the temperature for 2 - 4 h, filter by suction, dry at 45 °C under vacuum (-0.09 MPa) for 4 h, and obtain 0.95 W of off-white solid. The weight yield is 95%, the purity is ≥ 99.5%, the single impurity is ≤ 0.2%, the water content is ≤ 0.2%,.....

[0056] Example 2-1: Preparation of 8DM Acetate

[0057]

[0058] 1) Add 6 W of dichloromethane to the reaction kettle, add 1 W of raw material I, and stir and cool to 5 ± 1 °C;

[0059] 2) When the temperature reaches 5 ± 1 °C, add 0.002 W of diethylamine, and dropwise add 0.2 W of acetic anhydride over 30 minutes;

[0060] 3) After the dropwise addition, maintain the temperature at 5 ± 1 °C for 4 hours, and detect the raw material point. If it is less than 0.5%, it is qualified;

[0061] 4) Dropwise add ammonia water with a concentration of 18%, adjust the pH to 6, let it stand for 30 minutes, and separate the aqueous layer;

[0062] Example 2-2: Preparation of Dexamethasone Acetate

[0063]

[0064] 5) Cool the reaction solution to -15 to -10 °C, add 0.9 W of DMF, and dropwise add 5 W of 40% HF aqueous solution over 60 minutes;

[0065] 6) After the dropwise addition, heat up to -10 to -5 °C, keep the temperature for 4 hours, and detect the raw material point. A value less than 0.5% is considered qualified;

[0066] 7) Dropwise add ammonia water with a concentration of 18% W, adjust the pH to 6, let it stand for 30 minutes, and separate the aqueous layer;

[0067] 8) Add 2.5 W of methanol and 1 kg of activated carbon, heat to 55 - 60 °C, keep the temperature for 30 - 40 minutes, filter, first recover the solvent under normal pressure and then under reduced pressure, cool to 0 - 5 °C, keep the temperature for 2 - 4 h, carry out suction filtration, and dry at 45 °C under vacuum (-0.09 MPa) for 4 h to obtain the product, 0.93 W, off-white solid, weight yield: 9.3%, purity ≥ 99.5%, single impurity ≤ 0.2%, water content ≤ 0.2%.

[0068] Setting of comparative examples

[0069] Change the temperature of 5 ± 1 °C in Example 1 to the following values respectively, and the other technical features are the same as those in Example 1.

[0070] Temperature Raw material residue Evaluation 3℃ 0.6％ Unqualified 4℃ 0.4％ Qualified 5℃ 0.36％ Qualified 6℃ 0.3％ Qualified 7℃ 0.62％ Unqualified 8℃ 0.65％ Unqualified

[0071] A total of 18 batches of experiments were carried out for the dropwise addition temperature. At least three batches were verified for each temperature point. HPLC was used for tracking and detection. It was found that when the temperature was set at 3 °C, 7 °C, and 8 °C, the average raw material points were 0.6%, 0.62%, and 0.65% respectively, all of which did not meet the requirements. Only at 5 ± 1 °C did it meet the quality requirements. It can be seen that the temperature of 5 ± 1 °C is the optimal reaction condition.

[0072] Change the dropwise addition reaction time of 30 minutes in step 2) of Example 1 to the following values, and the other technical features are the same as those in Example 1.

[0073] Dropping time Raw material residue Evaluation 10 minutes 2.6％ Unqualified 20 minutes 0.8％ Unqualified 30 minutes 0.36％ Qualified 40 minutes 0.56％ Unqualified 50 minutes 0.62％ Unqualified 60 minutes 0.65％ Unqualified

[0074] A total of 18 batches of experiments were carried out for the dropwise addition time. There were three batches each for 10 minutes, 20 minutes, 40 minutes, 50 minutes, and 60 minutes. HPLC was used for tracking and detection. The average raw material points were 2.6%, 0.8%, 0.56%, 0.62%, and 0.65% respectively. All the impurity points did not meet the quality requirements. Only when detected at 30 minutes, the raw material point was 0.36%. It can be seen that the dropwise addition time of 30 minutes is the optimal reaction condition.

[0075] Change the heat preservation time in step 3) of Example 1 from 4 h to the following values, and the other technical features are the same as those in Example 1.

[0076] Heat preservation time Raw material residue Evaluation 1h 0.6％ Unqualified 2h 0.58％ Unqualified 3h 0.56％ Unqualified 4h 0.2％ Qualified 5h 0.32％ Unqualified 6h 0.31％ Unqualified

[0077] A total of 18 batches of heat preservation time experiments were carried out, with three batches for 1 h, 2 h, 3 h, 4 h, 5 h, and 6 h respectively. HPLC was used for tracking and detection. The raw material impurity points were as follows: 0.6% for 1 h, 0.58% for 2 h, 0.56% for 3 h, 0.32% for 5 h, and 0.31% for 6 h. The impurity points were relatively large. The raw material points at 5 h and 6 h were qualified, but other impurities were generated. It can be seen that the optimal heat preservation time is 4 h.

[0078] Change the pH in step 4) of Example 1 from 6 to the following values, and the other technical features are the same as those in Example 1.

[0079]

[0080]

[0081] A total of 9 batches of experiments were carried out to adjust the pH. Three batches were made at pH 5. After statistics, the product chromaticity was yellowish. Three batches were made at pH 7, and the product chromaticity was also yellowish, both of which were unqualified. Three batches were made at pH 6, and the chromaticity was normal. It can be seen that pH = 6 is the best pH.

[0082] Change the dropping of 40% HF aqueous solution with 5 W in step 5) of Example 1 to the following values, and the other technical features are the same as those in Example 1.

[0083] HF aqueous solution Raw material residue Evaluation 30％ 1.6％ Unqualified 40％ 0.32.％ Qualified 50％ 0.33％ Qualified

[0084] A total of 9 batches of experiments were carried out on the concentration of HF aqueous solution. HPLC was used for tracking and detection. It was found that when the concentration of HF aqueous solution was 30%, the average of the three batches of raw material points was: the impurity point was 1.6%, which did not meet the quality requirements. When the concentration of HF aqueous solution was 50%, new impurities were generated. It can be seen that 40% HF aqueous solution is the optimal reaction concentration.

[0085] Change the dropping time in step 5) of Example 1 from 60 minutes to the following values, and the other technical features are the same as those in Example 1.

[0086] Dropping time Raw material residue Evaluation 30 minutes 2.6％ Unqualified 60 minutes 0.3％ Qualified 90 minutes 0.32％ Qualified

[0087] A total of 9 batches of experiments were conducted on the dropping time, and HPLC was used for tracking detection. When the dropping time was 30 minutes, three batches of experiments were carried out, and the average impurity points were 2.6%. When the dropping time was 90 minutes, three batches of experiments were carried out, and the average impurity points were 0.32%, both of which did not meet the requirements. When the dropping time was 60 minutes, three batches of experiments were carried out, and the average impurity points were 0.30%, which met the quality requirements. It can be seen that the dropping time of 60 minutes is the optimal time.

[0088] Change the heat preservation reaction in step 6) of Example 1 for 4 hours to the following values, and the other technical features are the same as those in Example 1.

[0089]

[0090]

[0091] A total of 12 batches of experiments were conducted on the heat preservation time. Three batches of experiments were carried out at 3h, 4h, 5h, and 6h respectively. By HPLC tracking detection, the raw material points were too large at 3h, 5h, and 6h, not meeting the quality requirements. Only when the heat preservation time was 4h, the impurity points were 0.28%, meeting the quality requirements. It can be seen that the heat preservation time of 4h is the optimal time.

[0092] Change the pH in step 7) of Example 1 from 6 to the following values, and the other technical features are the same as those in Example 1. Adjust the pH to 6, let it stand for 30 minutes, and separate the aqueous layer;

[0093] PH Material color Evaluation 5 Off-white Unqualified 6 White Qualified 7 Light yellow Qualified

[0094] A total of 9 batches of experiments were conducted on adjusting the pH. Three batches of experiments were carried out at pH 5. After statistics, the color of the product was yellowish. Three batches of experiments were carried out at pH 7, and the color of the product was light yellow. Three batches of experiments were carried out at pH 6, and the color was normal. It can be seen that pH = 6 is the best pH.

[0095] Change the standing time in step 7) of Example 1 from 30 minutes to the following values, and the other technical features are the same as those in Example 1.

[0096] Standing time Layering phenomenon Evaluation 10 minutes Unclear Unqualified 20 minutes Relatively clear Unqualified 30 minutes Clear Qualified 40 minutes Clear Qualified

[0097] A total of 12 batches of experiments were conducted on the standing time. There were 3 batches at each time point. At 10 minutes and 20 minutes, the layering was not clear visually. At 40 minutes, the layering was clear, but there was material precipitation. It can be seen that the standing time of 30 minutes is the optimal time.

[0098] Change the drying time in step 8) of Example 1 from 4 hours to the following values, and the other technical features are the same as those in Example 1.

[0099]

[0100]

[0101] 24 samples were taken for drying time tracking, with three samples in each time period. The moisture content was detected respectively. The samples were all unqualified at 1h, 2h, and 3h. The moisture content was detected at 5h, 6h, 7h, and 8h and was qualified, but the chromaticity was unqualified. It can be seen that the drying time of 4h is the optimal drying time.

[0102] The above description of the embodiments is to enable those of ordinary skill in the art to understand and apply the present invention. It is obvious that those who are familiar with the technology in this field can easily make various modifications to the above embodiments and apply the general principles described herein to other embodiments without creative labor. Therefore, the present invention is not limited to the above embodiments, and the improvements and modifications made by those skilled in the art to the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A preparation method of dexamethasone acetate, characterized in that, The reaction formula is as follows: Among them, compound J is not separated and directly undergoes a "one-pot method". The specific reaction steps are as follows: 1) Add 6 - 6.5W of dichloromethane into the reaction kettle, add 1W of raw material I, and stir to cool down to 0 - 10°C; 2) When the temperature reaches 0 - 10°C, add 0.002 - 0.0025W of diethylamine, and dropwise add 0.2 - 0.3W of acetic anhydride over 0 - 60 minutes; 3) After the dropwise addition, keep the temperature at 0 - 10°C for 3 - 5 hours, and detect the raw material point. If it is less than 0.2% - 0.3%, it is qualified; 4) Dropwise add ammonia water with a concentration of 18%, adjust the pH to 5 - 7, let it stand for 30 - 35 minutes, and separate the water layer; 5) Cool the reaction solution to -15 ~ -10°C, add 0.9 - 0.95W of DMF, and dropwise add 5W of 30% - 50% HF aqueous solution over 30 - 90 minutes; 6) After the dropwise addition, raise the temperature to -10 ~ -5°C, keep the temperature for reaction for 3 - 6 hours, and detect the raw material point. If it is less than 0.2% - 0.3%, it is qualified; 7) Dropwise add ammonia water with a concentration of 18% - 21%, adjust the pH to 5 - 7, let it stand for 10 - 40 minutes, and separate the water layer; 8) Add 2 - 2.5W of methanol and 1kg of activated carbon, heat to 55 - 60°C, keep the temperature for 30 - 40 minutes, filter, first recover the solvent under normal pressure and then under reduced pressure, cool down to 0 - 5°C, keep the temperature for 2 - 4h, filter by suction, and dry at 45°C under -0.09MPa vacuum for 3 - 8h to obtain the product with a purity ≥ 99.5%, single impurity ≤ 0.2%, water content ≤ 0.2%, and it is a light - colored solid.

2. The method according to claim 1, wherein In the step 1) described above, the temperature for stirring and cooling is 5 ± 1°C.

3. The method according to claim 2, wherein In the step 2) described above, the time is 30 minutes.

4. The method according to claim 3, wherein In the step 3) described above, the holding time is 4h.

5. The method according to claim 1 or 2 or 3 or 4, characterized in that, In the step 4) described above, the pH is 6.

6. The method according to claim 5, characterized in that In the step 5) described above, the HF aqueous solution is 40%, and the dropwise addition time is 60 minutes.

7. The method according to claim 6, wherein In the step 6) described above, the holding time for the reaction is 4h.

8. The method according to claim 7, characterized in that In the step 7) described above, adjust the pH to 6, and the standing time is 30 minutes.

9. The method according to claim 6 or 7, characterized in that, In the step 8) described above, the drying time is 4h.

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