Preparation method of crisaborole intermediate
By extracting and reacting the dibromo derivative solution, a high-purity monobromocriborone intermediate was prepared, solving the problems of low purity and yield in the synthesis of criborone and achieving cost reduction and product quality improvement.
Patent Information
- Application Number
- CN202311249233.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-26
- Publication Date
- 2025-03-28
AI Technical Summary
In the existing technology, the dibromo derivatives generated during the synthesis of creborone lead to a decrease in purity and yield, necessitating an improvement in the purity and yield of creborone intermediates.
The dibromo derivative solution was extracted with an extraction solvent, and then diethyl phosphite and a base were added to react. The mixture was then washed with water and concentrated to obtain a high-purity monobromocriborone intermediate.
It significantly improves the purity and yield of criborone intermediates, reduces production costs, and is simple and safe to operate, making it suitable for industrial production.
Smart Images
Figure CN119707742A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical chemistry, and more specifically relates to a method for preparing a dibrominated product of a key intermediate of crisaborole by debromination. Background Art
[0002] Clisborole is a nonsteroidal phosphodiesterase 4 (PDE-4) inhibitor used for topical treatment of mild to moderate atopic dermatitis in patients over 2 years old. Brominated intermediates are used in the synthesis of crisaborole, which is obtained by bromination reaction, but dibrominated products are produced, which reduces purity and yield.
[0003] Therefore, it is necessary to propose a method for preparing a monobrominated crisaborole intermediate by debromination of a dibrominated product to improve purity and yield and reduce cost. Summary of the invention
[0004] In order to overcome the shortcomings of the prior art, the present invention aims to provide a method for preparing a crisaborole intermediate by debrominating a dibrominated product, so that the by-product dibrominated product can be utilized, significantly improving the utilization rate of the intermediate and thus reducing the cost.
[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:
[0006] A method for preparing a crisaborole inhibitor intermediate I, the method comprising the following steps:
[0007] (1) Intermediate II reacts in an acetonitrile solution to obtain a mixed solution of a monobrominated product (intermediate I) and a dibrominated product (intermediate III), which is then extracted with an extraction solvent to obtain a debrominated raw material;
[0008] (2) mixing the above raw materials with diethyl phosphite and a base, washing with water after the reaction, and concentrating to obtain a high-purity and high-yield crisaborole intermediate I;
[0009] The intermediate II structural formula is The intermediate I structural formula is
[0010] Furthermore, the reactants of intermediate II in acetonitrile solution also include N-bromosuccinimide and azobisisobutyronitrile.
[0011] Furthermore, the reaction temperature of intermediate II in acetonitrile solution is 70-80° C., and the reaction time is 3-8 hours.
[0012] As an alternative, the extraction in step (1) is performed by mixing a saturated saline solution with an extraction solvent and then extracting together.
[0013] Furthermore, the raw material extraction solvent is esters or ethers; preferably ethers; most preferably isopropyl ether.
[0014] Furthermore, the base is any one of potassium carbonate, sodium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, and N-methylmorpholine; preferably potassium carbonate, triethylamine, and N,N-diisopropylethylamine; and most preferably potassium carbonate.
[0015] Furthermore, the molar ratio of the dibromo compound in the raw material to the base in step (2) is 1:1-5; preferably, the molar ratio of the dibromo compound in the raw material to the base is 1:3-5; further preferably, it is 1:4-5.
[0016] Furthermore, the molar ratio of the dibrominated product in the raw material of step (2) to the diethyl phosphite is 1:1.0-2.2; preferably, the molar ratio of the dibrominated product in the raw material to the diethyl phosphite is 1:1.6-2.2; more preferably, it is 1:1.8-2.0.
[0017] Furthermore, the reaction temperature in step (2) is 10-50°C, preferably 20-40°C; more preferably 25-35°C.
[0018] Furthermore, the reaction time of step (2) is 2-10 hours; preferably, the reaction time is 2-6 hours.
[0019] Furthermore, the washing in step (2) is carried out using saturated salt water.
[0020] Compared with the prior art, the present invention has the following beneficial effects:
[0021] The present invention provides a method for preparing a crisaborole intermediate. By adding ethers and water to extract a reaction liquid, drying to obtain a dibrominated reaction raw material, and then adding an appropriate amount of alkali and diethyl phosphite to react for a certain period of time, a high-purity monobrominated crisaborole intermediate can be obtained. The present invention converts the byproduct dibrominated product into a crisaborole intermediate, improves purity and yield, reduces cost, is simple and safe to operate, and is suitable for production scale-up. DETAILED DESCRIPTION
[0022] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.
[0023] Example 1
[0024] The synthetic route of I in the formula is shown below (1):
[0025]
[0026] When synthesizing I, III will be produced and it is difficult to purify. The preparation method of the mixed solution raw material (hereinafter referred to as raw material) of the monobrominated product (intermediate I) and the dibrominated product (intermediate III) is as follows:
[0027] Add 5.76 g (20 mmol) II, 4.46 g (25 mmol) N-bromosuccinimide (NBS), 0.032 g (2 mmol) azobisisobutyronitrile (AIBN), and 58 ml acetonitrile to a reaction bottle, raise the temperature to 80°C, and keep warm for 8 hours. When the reaction is completed, cool to 30°C, add 170 ml saturated saline solution and 58 ml ethyl acetate, stir, stand and separate, and dry over anhydrous sodium sulfate to obtain a mixed solution of monobrominated and dibrominated products.
[0028] The amount of substance III is calculated according to the formula = the amount of feed of II / the molecular weight of II*the proportion of III in the liquid phase.
[0029] According to the present invention, a method for debrominating the above-mentioned solution containing a dibrominated byproduct is provided:
[0030] The above raw materials were detected by HPLC: II accounted for 1.23%, I accounted for 84.86%, and III accounted for 12.92% (2.58mmol). 1.42g (10.33mmol) potassium carbonate and 0.64g (4.65mmol) diethyl phosphite were added to the solution, and the mixture was kept at 30°C for 4 hours. 100ml saturated brine was added to the reaction solution and stirred for 30 minutes. The mixture was allowed to stand for separation, and the organic phase was concentrated to obtain a solid. HPLC detection: II accounted for 0.97%, I accounted for 76.72%, and III accounted for 9.19%.
[0031] Example 2
[0032] Add 57.6 g (0.2 mol) of II, 44.6 g (0.25 mol) of NBS, 0.32 g (0.002 mol) of AIBN, and 580 ml of acetonitrile to the reaction bottle, raise the temperature to 80 ° C, and keep warm for 8 hours. When the reaction is completed, cool to 0 ° C, add 1.7 L of saturated saline solution and 580 ml of isopropyl ether, stir, stand and separate, and dry over anhydrous sodium sulfate to obtain a raw material containing a dibrominated by-product.
[0033] According to the present invention, a method for debrominating the above-mentioned solution containing a dibrominated byproduct is provided:
[0034] Take 1 / 6 of the above raw material containing dibromo byproducts, and detect by HPLC: II, accounting for 0.86%, I accounting for 84.36%, III accounting for 13.82% (4.60mmol). Add 2.55g (18.42mmol) potassium carbonate and 1.14g (8.29mmol) diethyl phosphite to the solution, keep warm at 30°C for 4 hours, add 100ml saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.90%, I accounts for 97.65%, and III accounts for 0.14%.
[0035] Example 3
[0036] Take 1 / 6 of the raw material containing the dibromo by-product in Example 2, and detect by HPLC: II accounts for 0.86%, I accounts for 84.36%, and III accounts for 13.82% (4.60mmol). Add 2.55g (18.42mmol) potassium carbonate and 1.14g (8.29mmol) diethyl phosphite to the solution, keep warm at 50°C for 4 hours, add 100ml saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.88%, I accounts for 95.52%, and III accounts for 1.14%.
[0037] Example 4
[0038] Take 1 / 6 of the raw material containing the dibromo byproduct in Example 2, and detect by HPLC: II accounts for 0.86%, I accounts for 84.36%, and III accounts for 13.82% (4.60mmol). Add 1.86g (18.42mmol) of triethylamine and 1.14g (8.29mmol) of diethyl phosphite to the solution, keep warm at 30°C for 4 hours, add 100ml of saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.83%, I accounts for 94.28%, and III accounts for 2.14%.
[0039] Example 5
[0040] Take 1 / 6 of the raw material containing the dibromo by-product in Example 2, and detect by HPLC: II accounts for 0.86%, I accounts for 84.36%, and III accounts for 13.82% (4.60mmol). Add 1.95g (18.42mmol) of sodium carbonate and 1.14g (8.29mmol) of diethyl phosphite to the solution, keep warm at 30°C for 4 hours, add 100ml of saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.90%, I accounts for 85.65%, and III accounts for 13.14%.
[0041] Example 6
[0042] Take 1 / 6 of the raw material containing the dibromo by-product in Example 2, and detect by HPLC: II accounts for 0.86%, I accounts for 84.36%, and III accounts for 13.82% (4.60mmol). Add 1.23g (9.21mmol) potassium carbonate and 1.14g (8.29mmol) diethyl phosphite to the solution, keep warm at 30°C for 4 hours, add 100ml saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.90%, II accounts for 89.35%, and III accounts for 8.74%.
[0043] Example 7
[0044] Take 1 / 6 of the raw material containing the dibromo by-product in Example 2, and detect by HPLC: II accounts for 0.86%, I accounts for 84.36%, and III accounts for 13.82% (4.60mmol). Add 2.55g (18.42mmol) potassium carbonate and 0.89g (6.45mmol) diethyl phosphite to the solution, keep warm at 30°C for 4 hours, add 100ml saturated brine to the reaction solution and stir for 30 minutes, let stand and separate, concentrate the organic phase, and obtain a solid. HPLC detection: II accounts for 0.90%, I accounts for 91.65%, and III accounts for 7.14%.
[0045] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing a crisaborole inhibitor intermediate I, characterized in that: The method comprises the following steps: (1) intermediate II is reacted in an acetonitrile solution to obtain a mixed solution of monobrominated product and dibrominated product, which is then extracted with an extraction solvent to obtain a debrominated raw material; (2) Mixing the raw material of step (1) with diethyl phosphite and a base, washing with water after the reaction, and concentrating to obtain a high-purity and high-yield crisaborole intermediate I, wherein the intermediate II has the structural formula: The intermediate I structural formula is 2. The preparation method according to claim 1, characterized in that: The reactants of intermediate II in acetonitrile solution also include N-bromosuccinimide and azobisisobutyronitrile.
3. The preparation method according to claim 1, characterized in that: The reaction temperature of intermediate II in acetonitrile solution is 70-80° C., and the reaction time is 3-8 hours.
4. The preparation method according to claim 1, characterized in that: The raw material extraction solvent is esters or ethers; preferably ethers; most preferably isopropyl ether.
5. The preparation method according to claim 1, characterized in that: The base is any one of potassium carbonate, sodium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine and N-methylmorpholine; preferably potassium carbonate, triethylamine and N,N-diisopropylethylamine; most preferably potassium carbonate.
6. The preparation method according to claim 1, characterized in that: The molar ratio of the dibromo compound in the raw material to the base in step (2) is 1:1-5; preferably, the molar ratio of the dibromo compound in the raw material to the base is 1:3-5; more preferably, it is 1:4-5.
7. The preparation method according to claim 1, characterized in that: The molar ratio of the dibrominated product in the raw material of step (2) to the diethyl phosphite is 1:1.0-2.2; preferably, the molar ratio of the dibrominated product in the raw material to the diethyl phosphite is 1:1.6-2.2; more preferably, it is 1:1.8-2.
0.
8. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 10-50°C, preferably 20-40°C; more preferably 25-35°C.
9. The preparation method according to claim 1, characterized in that: The reaction time of step (2) is 2-10 hours; preferably, the reaction time is 2-6 hours.