Preparation method of fluorometholone acetate

Abstract

The invention discloses a preparation method of fluorometholone acetate, which comprises the following steps: step 1, adding acetic acid, acetic anhydride and a catalyst A into a compound (I), heating reaction raw materials to disappear, adding water for extraction reaction, and filtering to obtain a compound (II) fluorometholone diacetate; and 2, adding the compound (II) fluorometholone diacetate into a solvent B, controlling the temperature, adding an alkali C, carrying out heat preservation reaction for 7-10 hours, concentrating the solvent, adding water to precipitate a solid, filtering, drying, and refining to obtain a compound (III) fluorometholone acetate. According to the method, high-purity fluorometholone acetate can be obtained through two-step reaction of esterification and selective hydrolysis, and the cost is relatively low; the process is simple to operate, stable and suitable for large-scale production. The production difficulty of the fluorometholone acetate is reduced, and the requirement on the purity quality of the raw materials is not high. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing fluorometholone acetate. Background Art

[0002] Fluorometholone acetate (NSC 47438) is a synthetic corticosteroid used to treat steroid-responsive eye inflammation. It has a better anti-inflammatory effect than prednisolone acetate when used in eye drops, and it is a long-acting drug with a duration of more than 3 hours. Fluorometholone acetate has a good anti-inflammatory effect and has important applications in ophthalmology. The chemical name of fluorometholone acetate and its structure are as follows:

[0003]

[0004] Fluorometholone acetate is a fluorometholone derivative, and there are few reports on the preparation of fluorometholone as a raw material. In CN101397325A, fluorometholone acetate is synthesized by a one-step method using acetic anhydride and acetic acid. Experimental verification shows that most of the product is fluorometholone diacetate. The selectivity at positions 11 and 17 in the esterification process is poor, and high-yield and high-quality fluorometholone acetate cannot be obtained. In addition, it is found in the experiment that the hydrolysis of fluorometholone diacetate is selective under different alkaline conditions. Therefore, the present invention re-involves a new synthesis route based on the experimental results. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a method for preparing fluorometholone acetate, and the synthetic route is as follows:

[0006]

[0007] The following steps are involved:

[0008] Step 1: Compound (I) fluorometholone undergoes esterification reaction with acetic acid and acetic anhydride to generate compound (II) fluorometholone diacetate;

[0009] Step 2: Compound (II) fluorometholone diacetate is selectively hydrolyzed under alkaline catalytic conditions to generate compound (III) fluorometholone acetate.

[0010] Furthermore, step 1 is specifically as follows: compound (I) is added with solvent acetic acid, then acetic anhydride and catalyst A, the temperature is raised to react until the raw material disappears, water is added to extract and quench the reaction, and the compound (II) fluorometholone diacetate is obtained by filtration.

[0011] Furthermore, in step 1, catalyst A is any one of sulfuric acid, phosphoric acid, and p-toluenesulfonic acid monohydrate.

[0012] Furthermore, in step 1, the molar ratio of compound (I) to catalyst A is 1:0.1 to 1:0.5.

[0013] Furthermore, in step 1, the volume ratio of compound (I) to acetic anhydride is 1:2 to 1:5, preferably 1:2 to 1:2.5.

[0014] Furthermore, in step 1, the volume ratio of compound (I) to acetic acid is 1:3 to 1:5.

[0015] Furthermore, in step 1, the reaction temperature is 60-80°C.

[0016] Furthermore, step 2 is specifically as follows: compound (II) fluorometholone diacetate is added to solvent B, base C is added under temperature control, the reaction is kept warm for 7 to 10 hours, the solvent is concentrated, water is added to precipitate the solid, the solid is filtered and dried, and then purified to obtain compound (III) fluorometholone acetate.

[0017] Furthermore, in step 2, the hydrolysis reaction temperature is 20-45°C.

[0018] Furthermore, in step 2, the volume ratio of compound (II) to solvent B is 1:5 to 1:20.

[0019] Furthermore, in step 2, the molar ratio of compound (II) to base C is 1:0.5 to 1:2.

[0020] Furthermore, in step 2, solvent B is any one of methanol, ethanol and tetrahydrofuran.

[0021] Furthermore, in step 2, base C is any one of sodium methoxide, sodium hydroxide and sodium carbonate.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The present invention can obtain high-purity fluorometholone acetate through two-step reactions of esterification and selective hydrolysis, and the cost is low.

[0024] 2. The process operation is simple and stable, which is suitable for large-scale production. The production difficulty of fluorometholone acetate is reduced, and the purity and quality requirements of the raw materials are not high. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The compound (II) prepared in Example 1 1 HMNR spectrum;

[0026] Figure 2 The compound (III) prepared in Example 1 1 HMNR spectrum;

[0027] Figure 3 This is the HPLC spectrum of compound (III) prepared in Example 1. DETAILED DESCRIPTION

[0028] The exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided in order to enable a more thorough understanding of the present invention and to be able to fully convey the scope of the present invention to those skilled in the art. It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in conjunction with the embodiments.

[0029] Example 1

[0030] Step 1: Preparation of compound (II)

[0031] 827 g of compound (Ⅰ), 2.5 L of acetic acid, 2 L of acetic anhydride, and 42 g of p-toluenesulfonic acid monohydrate were added to the reaction kettle in sequence. The temperature was initially raised to 60°C and the reaction was carried out for 3 h. After TLC detection showed that the reaction was complete, the temperature was lowered to 20-30°C, diluted in 40 L of ice water, filtered and washed with water until neutral, and dried at 60-70°C under forced air until constant weight to obtain 900 g of light yellow solid compound (Ⅱ).

[0032] The prepared compound (II) 1 The HMNR spectrum is shown in Figure 1 As shown, 1 HNMR(DMSO-d6,400MHz): 6.83(s,1H),6.30(dd,1H),5.95(s,1H)5.25(m,1H),2.82(m,2H),2.66(m,1H),2.30(d ,1H),2.11(s,3H),2.04(s,4H),1.96(s,3H),1.92(m,1H),1.68(m,3H),1.39(s,4H),1.10(m,4H),0.76(s,3H).

[0033] Step 2: Preparation of compound (III)

[0034] 400g of compound (II), 2L of methanol, 0.8L of water, and 73g of sodium carbonate were added to the reactor in sequence, and the temperature was raised to 40-45°C for 10h. When the liquid phase tracking of compound (II) was less than 5%, the reaction was stopped. The sodium carbonate was filtered, and the filter cake was rinsed with methanol. The filtrate was adjusted to pH=7 with hydrochloric acid, and the methanol was concentrated under reduced pressure at 45-50°C, and 4L of water was added. The mixture was filtered, and dried at 70°C. The crude product was refined with acetone and methanol for 3 times to obtain 300g of white solid compound (III).

[0035] The prepared compound (III) 1 The HMNR spectrum is shown in Figure 2 As shown, 1 HNMR(DMSO-d6,400MHz): 7.28(s,1H),6.26(dd,1H),5.92(s,1H),5.39(m,1H),4.20(m,1H),2.79(m,2H),2.50(m,1H), 2.22(d,1H),2.00(s,3H),1.96(s,4H),1.88(m,1H),1.62(m,3H),1.50(s,3H),1.34(m,1H),1.07(m,4H),0.82(s,3H).

[0036] The HPLC spectrum of the prepared compound (III) is as follows Figure 3 As shown, the purity of fluorometholone acetate is 99.6%, fluorometholone and fluorometholone diacetate are both less than 0.1%, and the maximum impurity is 0.20%.

[0037] Example 2

[0038] Step 1: Preparation of compound (II)

[0039] 400 g of compound (I), 2 L of acetic acid, 2 L of acetic anhydride, and 52 g of sulfuric acid were added to the reactor in sequence. The temperature was initially raised to 75 ° C. After TLC detection showed that the reaction was complete, the temperature was lowered to 20-30 ° C, diluted in 20 L of ice water, filtered, washed with water until neutral, and dried at 60-70 ° C to constant weight to obtain 475 g of light yellow solid compound (II).

[0040] Step 2: Preparation of compound (III)

[0041] 200g of compound (II), 4L of ethanol, 0.8L of water, and 12.6g of sodium methoxide were added to the reaction kettle in sequence, and the temperature was raised to 20-30°C for reaction for 7h. When the liquid phase tracking of compound (II) was less than 5%, the reaction was stopped. The filtrate was adjusted to pH=7 with hydrochloric acid, and ethanol was concentrated under reduced pressure at 45-50°C, 2L of water was added, and the mixture was filtered and dried at 70°C. The crude product was refined with acetone and methanol for 3 times to obtain 120g of white solid compound (III).

[0042] Example 3

[0043] Step 1: Preparation of compound (II)

[0044] 400 g of compound (I), 1.3 L of acetic acid, 0.8 L of acetic anhydride, and 30 g of phosphoric acid were added to the reaction kettle in sequence, and the temperature was initially raised to 80 ° C. After TLC detection showed that the reaction was complete, the temperature was lowered to 20-30 ° C, diluted in 20 L of ice water, filtered, washed with water until neutral, and dried at 60-70 ° C to constant weight to obtain 440 g of light yellow solid compound (II).

[0045] Step 2: Preparation of compound (III)

[0046] 200g of compound (II), 2L of tetrahydrofuran, 0.8L of water, and 34.7g of sodium hydroxide were added to the reaction kettle in sequence, and the temperature was raised to 30-40°C for 8h. When the liquid phase tracking of compound (II) was less than 5%, the reaction was stopped. The filtrate was adjusted to pH=7 with hydrochloric acid, ethanol was concentrated under reduced pressure at 45-50°C, 2L of water was added, filtered, and dried at 70°C. The crude product was refined 3 times with acetone and methanol to obtain 100g of white solid compound (III).

[0047] The present invention has been described in detail above through embodiments, but the contents described are only exemplary embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The protection scope of the present invention is defined by the claims. Anyone who utilizes the technical solution described in the present invention, or a technician in the field, inspired by the technical solution of the present invention, designs a similar technical solution within the essence and protection scope of the present invention to achieve the above technical effects, or makes equal changes and improvements to the scope of application, etc., shall still fall within the scope of protection covered by the patent of the present invention.

Claims

1. A method for preparing fluorometholone acetate, characterized in that, The synthetic route is as follows: The following steps are involved: Step 1: Compound (I) fluorometholone undergoes esterification reaction with acetic acid and acetic anhydride to generate compound (II) fluorometholone diacetate; Step 2: Compound (II) fluorometholone diacetate is selectively hydrolyzed under alkaline catalytic conditions to generate compound (III) fluorometholone acetate.

2. The method for preparing fluorometholone acetate according to claim 1, wherein: Step 1 is specifically as follows: Compound (I) is added with acetic acid as a solvent, and then acetic anhydride and catalyst A are added, the temperature is raised to react until the raw materials disappear, water is added to extract and quench the reaction, and the compound (II) fluorometholone diacetate is obtained by filtration.

3. The method for preparing fluorometholone acetate according to claim 2, wherein: In step 1, the catalyst A is any one of sulfuric acid, phosphoric acid, and p-toluenesulfonic acid monohydrate.

4. The method for preparing fluorometholone acetate according to claim 2, wherein: In step 1, the molar ratio of compound (I) to catalyst A is 1:0.1 to 1:0.5, the volume ratio of compound (I) to acetic anhydride is 1:2 to 1:5, and the volume ratio of compound (I) to acetic acid is 1:3 to 1:

5.

5. The method for preparing fluorometholone acetate according to claim 2, wherein: In step 1, the temperature of the reaction is raised to 60-80°C.

6. The method for preparing fluorometholone acetate according to claim 1, characterized in that: Step 2 is specifically as follows: Compound (II) fluorometholone diacetate is added to solvent B, base C is added under temperature control, the reaction is kept warm for 7 to 10 hours, the solvent is concentrated, water is added to precipitate the solid, the solid is filtered and dried, and then purified to obtain compound (III) fluorometholone acetate.

7. The method for preparing fluorometholone acetate according to claim 8, characterized in that: In step 2, the hydrolysis reaction temperature is 20-45°C.

8. The method for preparing fluorometholone acetate according to claim 6, characterized in that: In step 2, the volume ratio of compound (II) to solvent B is 1:5 to 1:20; the molar ratio of compound (II) to base C is 1:0.5 to 1:

2.

9. The method for preparing fluorometholone acetate according to claim 6, characterized in that: In step 2, solvent B is any one of methanol, ethanol and tetrahydrofuran.

10. The method for preparing fluorometholone acetate according to claim 6, wherein in step 2, the base C is any one of sodium methoxide, sodium hydroxide, and sodium carbonate.

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