Synthesis method of crisaborole

Abstract

The invention relates to a synthesis method of crisaborole, and belongs to the field of pharmaceutical chemicals. According to the method, 4-(4-bromo-3-(hydroxymethyl) phenoxy) benzyl alcohol is used as an intermediate, and high-purity crisaborole is obtained through coupling and cyclization reactions. The preparation method provided by the invention has the advantages of easily available raw materials, low price, high total yield, simple reaction conditions and operation process, and no need of column chromatography purification in the whole route. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for synthesizing an anti-inflammatory drug, crisaborole. Technical Background

[0002] Crisaboeole is an anti-inflammatory drug developed by Anacro Pharmaceuticals and approved by the FDA in December 2016. Its chemical name is 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, and its molecular formula is C 14 H 10 BNO3, molecular weight is 251.05, its structural formula is as shown in the attached Figure 1 :

[0003] The prior art discloses a variety of preparation methods for crisaborole, but the introduction of boric acid esters is mainly carried out in the following two ways: the first borylation method is to first protect the hydroxyl group of the intermediate 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzyl alcohol, and then react with n-butyl lithium and a borylation agent under deep cold (-78°C) conditions for borylation, which is not conducive to industrial production. (1) Route 1. Patent US2007293457A1 uses MOM to protect the hydroxyl group, and n-butyl lithium and trimethyl borate react for borylation, see attached Figure 2 .

[0004] (2) Route 2. Patent CN101914109B uses 3,4-dihydro-2H-pyran to protect the hydroxyl group, and n-butyl lithium and trimethyl borate are reacted for borylation. Figure 3 .

[0005] The second borylation method first protects the hydroxyl group of the intermediate 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzyl alcohol, and then undergoes palladium-catalyzed coupling borylation. The steps used are close to the final product, and there is palladium residue and the cost is relatively high.

[0006] For example, the synthesis method of crisaborole disclosed in patents WO2018216032; WO2018207216, WO2018224923, see attached Figure 4 .

[0007] In the existing technology, a protecting group needs to be introduced before borylation, which is not in line with the concept of green chemistry. The borylation step is carried out under harsh conditions of ultra-low temperature using an organic lithium reagent, or the introduction of a boronic acid functional group using palladium catalysis faces the problems of palladium residue and high cost. Summary of the invention

[0008] In order to solve the above problems of the prior art, the present invention aims to provide a new method for preparing crisaborole. The method introduces boric acid ester by free radical coupling, has mild reaction conditions and simple operation, and successfully avoids the harsh reaction conditions of introducing protective groups, using metal catalysts and ultra-low temperature. Figure 5 .

[0009] A method for preparing crisaborole impurities, characterized in that it comprises the following steps:

[0010] Step 1: Mix the intermediate 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzyl alcohol (Formula I) with an organic solvent, then add a base or a boronating agent under ultraviolet light, and keep warm for reaction.

[0011] Step 2: After the reaction is completed, the solvent is removed by distillation under reduced pressure, ethyl acetate is added to the residue, stirred and diluted, washed twice with sodium chloride aqueous solution, and the organic phase is collected. The filtrate is concentrated to obtain a brown solid, which is then recrystallized in n-heptane to obtain an off-white solid (compound of formula II).

[0012] Step 3: Mix the compound of formula II and tetrahydrofuran, stir to dissolve, cool to -5-5°C, slowly drop concentrated hydrochloric acid, heat to 40-50°C and stir for 5 hours. Cool to room temperature, add purified water and ethyl acetate, separate the liquids, collect the organic phase, wash the organic phase with saturated sodium bicarbonate solution and sodium chloride solution, collect the organic phase, concentrate, add purified water and n-heptane, stir and crystallize for 2 hours, filter by suction, and collect the filter cake.

[0013] Step 4: Recrystallize the filter cake in methanol, filter with suction, wash the filter cake with n-heptane, collect the filter cake, and dry the filter cake in vacuo at 45° C. for 12 h to obtain the compound of formula III (criborole).

[0014] Furthermore, the organic solvent is selected from acetonitrile, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, preferably methanol or acetonitrile.

[0015] Furthermore, the base is selected from sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, sodium methoxide, potassium methoxide, lithium methoxide, preferably potassium tert-butoxide.

[0016] Furthermore, the wavelength range of the ultraviolet light is 315-190nm.

[0017] Furthermore, the boronating agent is tetrahydroxydiboron or bis(pinacol)diboron.

[0018] Furthermore, the molar ratio of the compound of formula I to the boronating agent is 1:1-1:10; preferably 1:2.

[0019] Furthermore, the reaction temperature of the compound of formula I and the boronating agent is -10 to 110°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Attached Figure 1 The structural formula of crisaborole

[0029] Attached Figure 2 For route 1, patent US2007293457A1 uses MOM to protect the hydroxyl group, and n-butyl lithium and trimethyl borate react to perform borylation.

[0030] Attached Figure 3 For route 2, patent CN101914109B uses 3,4-dihydro-2H-pyran to protect the hydroxyl group, and n-butyl lithium and trimethyl borate are reacted for borylation.

[0031] Attached Figure 4 This is the synthesis method of crisaborole disclosed in patents WO2018216032; WO2018207216 and WO2018224923.

[0032] Attached Figure 5 The invention relates to a method for preparing the crisaborole impurity. DETAILED DESCRIPTION

[0020] In order to make the technical solutions and beneficial effects of the present invention more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0021] Example 1

[0022] Under nitrogen protection, add the compound of formula I (10.0g, 32.88mmol) and acetonitrile (100ml) to the reaction bottle, reduce the temperature to 15℃, add B2pin2 (16.64g, 65.54mmol) under ultraviolet light irradiation with a wavelength of 254nm, and keep the reaction for 24h. After the reaction is completed, remove the solvent by vacuum distillation, add ethyl acetate (300ml) to the concentrate to dilute, and then wash twice with saturated sodium chloride (2×100ml). Collect the organic phase and concentrate under reduced pressure. Add 100ml of n-heptane to the concentrate and stir for 10h, filter, collect the filter cake, and vacuum dry (-0.08MPa, 50℃) for 4h to obtain 9.6g of compound of formula II with a yield of 84.2%.

[0023] Add the compound of formula II (7.0 g, 18.0 mmol) and 50 ml of tetrahydrofuran into the reaction bottle, stir to dissolve, cool to -5-5°C, slowly drop concentrated hydrochloric acid, raise the temperature to 40-50°C, and stir for 5 h. After the reaction, cool to room temperature, add 50ml purified water and 50ml ethyl acetate, separate the liquids, extract the aqueous phase with 50ml ethyl acetate, combine the organic phases, wash with 50ml saturated sodium bicarbonate solution and 50ml sodium chloride solution respectively, collect the organic phase, add 7.0g anhydrous sodium sulfate and dry for 2h, filter, collect the filtrate, concentrate the filtrate, add 25ml purified water and 15ml n-heptane and stir for 2h, solid precipitates, filter, wash the filter cake with 10mL n-heptane, collect the filter cake, dissolve 4g (16mmol) of the filter cake in 60ml methanol, heat to reflux until the solid is dissolved, slowly reduce to 0-10℃ for crystallization, filter, wash the filter cake with 10ml n-heptane, collect the filter cake, and dry the filter cake at 45℃ in vacuo for 12h to obtain 3.2g of criborol, with a yield of 64.0%. 1 H NMR (500MHz, CDCl3) δ7.81 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.13-7.02 (m, 4H), 5.12 (s, 2H).

[0024] Example 2

[0025] Under nitrogen protection, add the compound of formula I (10.0g, 32.88mmol), methanol (100ml), potassium tert-butoxide (7.4g, 65.76mmol) to the reaction bottle, reduce the temperature to 0℃, add B2pin2 (16.64g, 65.54mmol), and keep warm for 24h. After the reaction is completed, remove the solvent by vacuum distillation, add ethyl acetate (300ml) to the concentrate to dilute, and then wash twice with saturated sodium chloride (2×100ml). Collect the organic phase and concentrate under reduced pressure. Add 100ml of n-heptane to the concentrate and stir for 10h, filter, collect the filter cake, and vacuum dry (-0.08MPa, 50℃) for 4h to obtain 9.1g of compound of formula II with a yield of 79.1%.

[0026] Add the compound of formula II (7.0 g, 18.0 mmol) and 50 ml of tetrahydrofuran into the reaction bottle, stir to dissolve, cool to -5-5°C, slowly drop concentrated hydrochloric acid, raise the temperature to 40-50°C, and stir for 5 h. After the reaction, cool to room temperature, add 50ml purified water and 50ml ethyl acetate, separate the liquids, extract the aqueous phase with 50ml ethyl acetate, combine the organic phases, wash with 50mL saturated sodium bicarbonate solution and 50ml sodium chloride solution respectively, collect the organic phase, add 7.0g anhydrous sodium sulfate and dry for 2h, filter, collect the filtrate, concentrate the filtrate, add 25ml purified water and 15ml n-heptane and stir for 2h, solid precipitates, filter, wash the filter cake with 10ml n-heptane, collect the filter cake, dissolve 4g (16mmol) of the filter cake in 60ml methanol, heat to reflux until the solid is dissolved, slowly reduce to 0-10℃ for crystallization, filter, wash the filter cake with 10ml n-heptane, collect the filter cake, and dry the filter cake at 45℃ in vacuo for 12h to obtain 3.3g of criborol with a yield of 73.8%. 1 H NMR (500MHz, CDCl3) δ7.81 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.13-7.02 (m, 4H), 5.12 (s, 2H).

Claims

1. The present invention provides a method for preparing crisaborole, characterized in that: The method comprises the following steps: Step 1: The compound of formula I is coupled with a boronating agent under ultraviolet light irradiation or the action of a base to obtain a compound of formula II; Step 2: Compound II is reacted with acid to convert it into crisaborole of formula III 。 2. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: The solvent used in step 1 is one or a mixed solvent of two or more of acetonitrile, methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol.

3. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: The base used in step 1 is one or more of sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, potassium tert-butoxide, and sodium tert-butoxide.

4. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: The reaction temperature in step 1 is -10 to 120°C.

5. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: The wavelength range of the ultraviolet light in step 1 is 315-190 nm.

6. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: The boronating agent in step 1 is tetrahydroxydiboron or bis(pinacol)diboron.

7. The method for preparing crisaborole of structural formula III according to claim 1, characterized in that: In step 1, the molar ratio of the compound of formula I to the boronation reagent is 1:1-1:10, preferably 1:2.

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