Process for the preparation of mometasone furanoate

Abstract

The application belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of mometasone furanoate. The method comprises the following steps: compound A is dissolved in dichloromethane and anhydrous ethanol, then hydrogen chloride is introduced to perform a reaction, and HPLC monitoring is performed until the residual compound A is less than or equal to 0.5%; the obtained reaction solution is distilled at normal pressure until the temperature of the reaction solution is 70-78 DEG C, and then cooling and crystallization are performed to obtain mometasone furanoate. The mometasone furanoate prepared by the method has a HPLC purity of greater than 99.5%, and the yield is as high as 90-98%. Moreover, the method is simple in operation, moderate in reaction temperature, controllable in conditions, short in reaction time, and high in production efficiency, and is more suitable for commercial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing mometasone furoate. Background Technology

[0002] Mometasone furoate (Rupatadine Fumarate), chemically named 9α,21-dichloro-11β,17-dihydroxy-16α-methylpregn-1,4-diene-3,20-dione 17-(2-furoate), with the chemical structure shown in Formula I, was developed by Schering-Plough and is indicated for eczema, neurodermatitis, atopic dermatitis, and pruritus.

[0003]

[0004] I.

[0005] The most crucial step in the preparation of mometasone furoate is the reaction from compound A to generate the target compound. Literature reports that this step occurs in a concentrated hydrochloric acid / glacial acetic acid / dichloromethane system, with the following reaction formula:

[0006] .

[0007] This method involves the reaction of a dichloromethane solution of compound A with concentrated hydrochloric acid in a two-phase reaction. Glacial acetic acid acts as a phase transfer catalyst. Currently reported literature includes US5886200A, US4472393, CN106279340B, CN112110975, CN105566437B, CN105481933B, and CN109206468B. The disadvantages of this method are: firstly, the reaction is heterogeneous and susceptible to many influencing factors, such as stirring speed and method; secondly, the reaction time is long, resulting in numerous byproducts that are difficult to purify; and thirdly, post-processing requires separation, washing, and back-extraction, making the operation complex, generating significant waste liquid, and negatively impacting environmental protection.

[0008] According to the literature, a dichloromethane solution of compound A was mixed with different equivalents of concentrated hydrochloric acid and glacial acetic acid. The reaction was monitored by HPLC. After compound A was ≤5% in the reaction solution, the rate of decrease of compound A became very slow. It took at least 8 hours to react until compound A was ≤0.5%. There were many byproducts (identified by LC-MS, molecular weight was 503.4). The impurity was close to the main peak and was not easy to remove.

[0009] To further demonstrate this, 99.9% pure mometasone furoate was dissolved in dichloromethane, and concentrated hydrochloric acid and glacial acetic acid in the same proportions as in the above reaction were added. The reaction was carried out under the same conditions as above, and the reaction was monitored by HPLC. After 1 hour, about 3% of compound A was generated in the reaction solution. After 3 hours, a new 1.1% impurity (identified by LC-MS with a molecular weight of 503.4) was generated. This indicates that mometasone furoate undergoes a reverse reaction in this system to generate compound A, bringing the reaction to equilibrium. Furthermore, degradation impurities are generated as the reaction time increases.

[0010] Therefore, it is necessary to conduct more in-depth research on mometasone furoate in order to overcome the shortcomings of existing technologies and improve the yield and purity of mometasone furoate. Summary of the Invention

[0011] In view of this, one of the objectives of the present invention is to provide a method for preparing mometasone furoate. The present invention uses dichloromethane and anhydrous ethanol as solvents, which solves the problems of long reaction time, low yield and purity, and easy generation of degradation impurities in the prior art, and provides a new approach for the preparation of mometasone furoate.

[0012] To achieve the above objectives, the present invention adopts the following technical solution:

[0013] A method for preparing mometasone furoate includes the following steps:

[0014] S1: Compound A reacts with hydrogen chloride in a solvent to obtain a reaction solution;

[0015] S2: The reaction solution obtained from S1 was subjected to atmospheric distillation and cooling to crystallize, yielding mometasone furoate.

[0016] The solvent is dichloromethane and anhydrous ethanol; the structural formula of mometasone furoate is shown in Formula I, and the structural formula of compound A is shown in Formula II.

[0017] .

[0018] Furthermore, in S1, the reaction temperature is 0℃~10℃.

[0019] Furthermore, in S1, the reaction system pressure is 0 MPa to 0.05 MPa.

[0020] Furthermore, in S1, the volume ratio of the dichloromethane and the anhydrous ethanol to the weight ratio of the compound A is 2~6:4~12:1.

[0021] Furthermore, in S1, the reaction time is 1 hour.

[0022] Furthermore, in S1, HPLC was used to monitor the residue of compound A until it was ≤0.5%.

[0023] Furthermore, once compound A is ≤0.5%, stop the flow of hydrogen chloride; after evacuating for 5 minutes, use pH test paper to check, and close the vacuum when the pH of the reaction solution is ≥5.

[0024] Furthermore, in S2, the reaction solution is distilled at atmospheric pressure until the temperature reaches 70℃~78℃.

[0025] Further, the mixture is heated to remove dichloromethane under normal pressure. Specifically, the heat transfer medium temperature is initially set to 75°C. When the reaction solution temperature reaches 60°C, the heat transfer medium temperature is adjusted to 88°C to continue distillation. Distillation is stopped when the reaction solution temperature reaches 70-78°C.

[0026] Throughout the process, the temperature of the heat transfer medium showed a trend of first decreasing and then increasing.

[0027] Furthermore, in S2, the cooling crystallization includes: cooling the product obtained by atmospheric distillation to 0~20°C and stirring to crystallize for 60 minutes.

[0028] Furthermore, after S2 cooling and crystallization, the product was filtered, washed with anhydrous ethanol, and dried to obtain mometasone furoate.

[0029] As a preferred technical solution, the method includes the following steps:

[0030] S1: After dissolving compound A in dichloromethane and anhydrous ethanol, hydrogen chloride is introduced to carry out the reaction at 0~10℃. HPLC monitoring is performed until the residual value of compound A is ≤0.5%, at which point the hydrogen chloride is introduced to stop. After vacuuming for 0.5 hours, pH paper is used to test the pH value. When the pH value of the reaction solution is ≥5, the vacuum is turned off.

[0031] S2: Distill the reaction solution described in S1 under normal pressure to a reaction solution temperature of 70~78℃, cool it to 0~20℃, stir to precipitate crystals for 60 minutes, filter, wash with anhydrous ethanol, and dry to obtain mometasone furoate.

[0032] The second objective of this invention is to provide a method for the industrial production of mometasone furoate.

[0033] To achieve the above objectives, the present invention adopts the following technical solution:

[0034] A method for the industrial production of mometasone furoate is carried out in a production system, which is sequentially equipped with a production unit, a distillation unit, a filtration unit, a washing unit, and a drying unit. Each production unit is also equipped with a temperature control unit, a pressure control unit, and a hydrogen chloride control unit. All components in the production system are connected via material pipelines. Compound A is dissolved in the production unit by adding dichloromethane and anhydrous ethanol, and hydrogen chloride is introduced through the hydrogen chloride control unit. After the reaction is complete, the mixture is distilled at atmospheric pressure using the distillation unit. Then, the mixture is cooled to crystallize, and the crystals are filtered, washed, and dried using the filtration, washing, and drying units to obtain mometasone furoate. During the reaction, the temperature and pressure are controlled by the temperature control unit and the pressure control unit.

[0035] Furthermore, the production system also includes a first stirring unit, a second stirring unit, and a vacuum equipment control unit; the first stirring unit is connected to the production unit and is used for stirring and dissolving compound A, dichloromethane, and anhydrous ethanol; the vacuum equipment control unit is connected to the production unit and is used to evacuate the system before atmospheric distillation; the distillation unit is connected in sequence to the second stirring unit and the filtration unit; the second stirring unit is used for stirring and crystallization.

[0036] The beneficial effects of this invention are as follows:

[0037] 1. The method for preparing mometasone furoate provided by the present invention has a short reaction time, avoids the risk of degradation impurities generated by compound A under hydrochloric acid aqueous solution conditions, reduces extraction and washing operations, and has the characteristics of few by-products, easy purification, and high production efficiency; moreover, the method of the present invention is simple to operate, with moderate reaction temperature and controllable conditions, making it more suitable for commercial production.

[0038] 2. The method for preparing mometasone furoate provided by the present invention has a product yield of up to 90-98%, an HPLC purity of more than 99.5%, and a single impurity of less than 0.10%.

[0039] 3. The solvents or reagents used in this invention are inexpensive and readily available, easy to add, simple to operate, produce little waste liquid, and are environmentally friendly. Attached Figure Description

[0040] Figure 1 The high-performance colorimetric chromatogram of mometasone furoate prepared in Example 1;

[0041] Figure 2 The infrared spectrum of mometasone furoate prepared in Example 1;

[0042] Figure 3 The mass spectrum of mometasone furoate prepared in Example 1;

[0043] Figure 4The 1H NMR spectrum of mometasone furoate prepared in Example 1;

[0044] Figure 5 The image shows the carbon NMR spectrum of mometasone furoate prepared in Example 1. Detailed Implementation

[0045] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0046] Example 1. Preparation of mometasone furoate

[0047] In a 1000ml reaction flask, dichloromethane (200ml), anhydrous ethanol (400ml), and compound A (50g, 0.103mol) were added sequentially. The mixture was stirred and dissolved at room temperature. The reaction solution was cooled to 0-10℃ using a refrigerant, and hydrogen chloride was introduced to maintain the reaction system pressure at 0.02MPa. The reaction was allowed to proceed for 1 hour. HPLC analysis was performed on a sample. Once compound A was ≤0.5%, the hydrogen chloride flow was stopped. After evacuating to a vacuum for 0.5 hours, pH paper was used to test the pH. When the pH of the reaction solution was ≥5, the vacuum was closed.

[0048] The dichloromethane was removed by heating and distillation under normal pressure. The temperature of the heat medium was initially set to 75°C. When the temperature of the reaction solution reached 60°C, the temperature of the heat medium was adjusted to 88°C to continue distillation. When the temperature of the reaction solution reached 75°C, the distillation was stopped.

[0049] The reaction solution was cooled to 0-20°C using a refrigerant, stirred for 60 minutes to allow crystals to precipitate, filtered, washed with anhydrous ethanol, and dried to obtain mometasone furoate (51.7 g). Yield: 96.3%, HPLC purity: 100.0%, chromatogram as shown. Figure 1 As shown, the liquid chromatography integration results are presented in Table 1. IR (KBr): 3434 cm⁻¹ -1 (υ -O-H ), 3129cm -1 (υ -C=C-H ), 2988cm -1 (υ -C-H ), 2947cm -1 (υ -C-H ), 2935cm -1 (υ -C-H ), 2886cm -1 (υ -C-H ), 1724cm -1 (υ -C=O ), 1658cm -1(υ -C=O ), 1613cm -1 (υ -C=C- ), 1564cm -1 (υ -C=C- ), 1468cm -1 (δ -C-H ), 1395cm -1 (δ -C-H ), 1124cm -1 (υ -C-O ), 888cm -1 (γ -C=C- ), 758cm -1 (γ -C=C- ),like Figure 2 As shown. MS-ESI(m / z): [M+H] + is 521.0, [M+Na] + It is 543.0, such as Figure 3 As shown.

[0050] 1 1H-NMR (H+ NMR), (400 MHz, DMSO) δ 8.05 (s, 1H), 7.34–7.31 (d, 1H), 7.26 (s, 1H), 6.74 (s, 1H), 6.27–6.24 (d, 1H), 6.01 (s, 1H), 5.65 (d, 1H), 4.46 (s, 1H), 4.29 (s, 2H), 2.76–2.74 (m, 2H), 2.67–2.66 (m, 1H), 2.38–2.35 (m, 1H), 2.25–2.12 (d, 2H), 1.91–1.83 (d, 2H), 1.62 (s, 3H), 1.54 (m, 2H), 1.32 (s, 3H), 1.31 (s, 1H), 1.22 (s, 3H), as shown Figure 4 As shown. 13 C-NMR (carbon nuclear magnetic resonance) (100 MHz, CDCl3) δ 197.68, 185.63, 166.81, 158.46, 152.94, 149.23, 143.87, 129.12, 124.56, 120.34, 113.14, 95.18, 85.62, 74.00, 49.99, 48.38, 46.70, 43.73, 36.35, 34.36, 34.09, 30.29, 27.91, 24.83, 23.27, 20.16, 17.92, as shown. Figure 5 As shown.

[0051] Table 1

[0052] 1 24.672 Mometasone furoate 465.985 931.247 100.00 1.08 na 15572 sum 100.00

[0053] Example 2. Preparation of mometasone furoate

[0054] In a 250ml reaction flask, dichloromethane (60ml), anhydrous ethanol (120ml), and compound A (10g, 0.0206mol) were added sequentially. After dissolving by stirring at room temperature, the reaction solution was cooled to 0℃~10℃ using a cooling medium. Hydrogen chloride was then introduced to maintain the reaction system pressure at 0.01MPa. The reaction was allowed to proceed for 1 hour, and a sample was taken for HPLC analysis. The results showed that compound A < 0.5%, at which point the hydrogen chloride introduction was stopped. After evacuating under vacuum for 0.5 hours, the pH was tested with pH paper. When the pH of the reaction solution was ≥ 5, the vacuum was turned off. The dichloromethane was then removed by heating. The heating medium temperature was initially set to 75℃. When the reaction solution temperature reached 60℃, the heating medium temperature was adjusted to 88℃ to continue distillation. Distillation was stopped when the reaction solution temperature reached 78℃. The reaction solution was cooled to 0-20°C using a refrigerant, stirred and crystallized for 60 minutes, filtered, washed with anhydrous ethanol, and dried to obtain mometasone furoate (51.5 g), with a yield of 95.9% and an HPLC purity of 99.8%.

[0055] Example 3. Preparation of mometasone furoate

[0056] In a 250 ml reaction flask, dichloromethane (60 ml), anhydrous ethanol (120 ml), and compound A (10 g, 0.0206 mol) were added sequentially. After dissolving by stirring at room temperature, the reaction solution was cooled to 0-10°C using a refrigerant. Hydrogen chloride was then introduced to maintain the reaction system pressure at 0.01 MPa. The reaction was allowed to proceed for 1 hour. HPLC analysis was performed on a sample; if compound A was < 0.5%, the hydrogen chloride flow was stopped. After evacuating under vacuum for 0.5 hours, pH paper was used to test the pH. When the pH of the reaction solution was ≥ 5, the vacuum was closed. Dichloromethane was removed by heating. The heating medium temperature was initially set to 75°C. When the reaction solution temperature reached 60°C, the heating medium temperature was adjusted to 88°C to continue distillation. Distillation was stopped when the reaction solution temperature reached 70°C. The reaction solution was cooled to 0-20°C using a refrigerant, stirred, and crystallized for 60 minutes. The crystals were filtered, washed with anhydrous ethanol, and dried to obtain mometasone furoate (49.9 g), with a yield of 92.9% and an HPLC purity of 99.9%.

[0057] Comparative Example 1. Preparation of mometasone furoate

[0058] In a 100ml reaction flask, dichloromethane (20ml), anhydrous ethanol (40ml), and compound A (5g, 0.0103mol) were added sequentially. The mixture was stirred and dissolved at room temperature. The reaction solution was cooled to -10℃ to -5℃ using a refrigerant. Hydrogen chloride was introduced to maintain the pressure of the reaction system at 0.03MPa. After 1 hour of reaction, HPLC showed that 5% of compound A was not completely reacted.

[0059] Comparative Example 2. Preparation of Mometasone Furoate

[0060] In a 100ml reaction flask, dichloromethane (20ml), anhydrous ethanol (40ml), and compound A (5g, 0.0103mol) were added sequentially. After stirring and dissolving at room temperature, the reaction solution was cooled to 20℃~30℃ using a coolant. Hydrogen chloride was then introduced to maintain the pressure of the reaction system at 0.03MPa. The reaction was carried out for 1 hour. HPLC showed that compound A had completely reacted, but the impurities were relatively large.

[0061] Comparative Example 3. Preparation of Mometasone Furoate

[0062] In a 250 ml reaction flask, dichloromethane (60 ml), methanol (120 ml), and compound A (10 g, 0.0206 mol) were added sequentially. After dissolving by stirring at room temperature, the reaction solution was cooled to 0-10°C using a refrigerant. Hydrogen chloride was then introduced to maintain the reaction system pressure at 0.01 MPa. The reaction was allowed to proceed for 1 hour. HPLC analysis was performed on a sample; if compound A was < 0.5%, the hydrogen chloride flow was stopped. After evacuating under vacuum for 0.5 hours, pH paper was used to test the pH. Once the pH of the reaction solution was ≥ 5, the vacuum was closed. Dichloromethane was removed by heating. The heating medium temperature was initially set to 55°C. When the reaction solution temperature reached 40°C and became pasty, 20 ml of methanol was added. The reaction solution was cooled to 0-20°C using a refrigerant, stirred, and allowed to crystallize for 60 minutes. The mixture was filtered, washed with methanol, and dried to obtain mometasone furoate (41.9 g), with a yield of 78.0% and an HPLC purity of 99.1%.

[0063] The above experiments show that compound A can react completely using a mixture of dichloromethane and methanol or a mixture of dichloromethane and ethanol as the reaction solvent, while maintaining the reaction temperature between 0°C and 10°C. However, if a mixture of dichloromethane and methanol is used as the reaction solvent, methanol, due to its low boiling point, is easily distilled off along with the dichloromethane during distillation. Patent US5886200A discloses a method for purifying mometasone furoate using dichloromethane and methanol, which involves concentrating dichloromethane under reduced pressure and adding methanol for distillation. However, the concentration endpoint cannot be controlled, making it unsuitable for large-scale production. Replacing methanol with ethanol, due to the significant difference in boiling points between ethanol and dichloromethane, allows for easy separation and removal of dichloromethane through atmospheric distillation. The distillation endpoint can be determined by controlling the reaction temperature, resulting in a stable, controllable process that is also simple to operate.

[0064] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing mometasone furoate, characterized in that, Includes the following steps: S1: Compound A is dissolved in dichloromethane and anhydrous ethanol, and hydrogen chloride is introduced into the solution at 0~10℃ to carry out the reaction. S2: The reaction solution obtained from S1 is distilled under normal pressure until the temperature of the reaction solution is 70℃~78℃, and then cooled to crystallize, to obtain mometasone furoate; The structural formula of mometasone furoate is shown in Formula I, and the structural formula of compound A is shown in Formula II. 。 2. The method according to claim 1, characterized in that, In S1, the reaction system pressure is 0 MPa to 0.05 MPa.

3. The method according to claim 1, characterized in that, In S1, the volume ratio of the dichloromethane and the anhydrous ethanol to the weight ratio of compound A is 2~6:4~12:

1.

4. The method according to claim 1, characterized in that, In S1, the reaction time is 1 hour.

5. The method according to claim 1, characterized in that, In S1, HPLC was used to monitor the residual amount of compound A to ≤0.5%.

6. The method according to claim 1, characterized in that, In S2, the cooling crystallization includes: cooling the product obtained by atmospheric distillation to 0~20℃ and stirring to crystallize for 60 minutes.

7. The method according to claim 1, characterized in that, After S2 cooling and crystallization, the product was filtered, washed with anhydrous ethanol, and dried to obtain mometasone furoate.

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