Preparation method for 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile

Abstract

Disclosed in the present invention is a preparation method for 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile, comprising the following steps: in an organic solvent, under an alkaline condition, enabling compound II and compound III to be subjected to a substitution reaction as shown in the following, wherein R is hydrogen, sulfonyl or p-toluenesulfonyl, and X is F, Cl, or Br. The preparation method of the present invention avoids the use of noble metal as a catalyst, involves low costs, simple operation and high product yield, and is suitable for industrial production.

Description

Preparation method of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile. Background Art

[0002] Crisaborole (English name: Crisaborole), chemically named 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, as shown in Structural Formula 1: is a phosphodiesterase 4 inhibitor developed by Anacor Pharmaceuticals for the topical treatment of atopic dermatitis / atopic dermatitis. The drug is currently available in the United States under the trade name: Eucrisa.

[0003] In the preparation of crisaborole, the substitution of heterocycles and the construction of boron-containing heterocycles are the key to the synthesis route. Currently, the synthesis routes of crisaborole mainly include the following methods:

[0004] Route 1: (Reference: US20070286822)

[0005] This route uses 2-bromo-5-(4-cyanophenoxy)benzoic acid as the key reactant, which is then reduced and then reacted with n-butyl lithium to form a boron-containing heterocycle. However, the method uses n-butyl lithium, a reagent with demanding reaction conditions, which increases process requirements and costs, making it unsuitable for industrial scale-up.

[0006] Route 2: (Reference: WO200911167)

[0007] This route uses 2-bromo-5-hydroxybenzaldehyde as the starting material. After a substitution reaction, the carbon-boron bond is formed in the presence of metallic palladium and chiral ferrocenyl diphosphine. However, this method has several reaction steps and a low final yield (44.8%). Furthermore, the use of two very expensive reagents, palladium and chiral ferrocenyl diphosphine, significantly increases costs, making it unsuitable for industrial production.

[0008] Although the above methods for preparing crisaborole have been reported in the prior art, they all have one or more disadvantages, such as the use of expensive reagents, additional protection and deprotection steps, etc. Therefore, it is very necessary to develop a simple, economical and suitable synthetic route for industrial production. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the defects of existing methods for preparing 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, which require the use of expensive reagents, resulting in high costs and unsuitability for industrialization. The present invention provides a preparation method that is simpler and more economical than the prior art. The preparation method of the present invention avoids the use of precious metals and expensive ligands, is low in cost, simple to operate, and has high product yield and purity, making it suitable for industrial production.

[0010] The present invention relates to a method for preparing crisaborole as shown in Formula I, comprising the following steps: in an organic solvent, under alkaline conditions, subjecting Compound II and Compound III to a substitution reaction as shown below;

[0011] Wherein, R is hydrogen, methylsulfonyl or p-toluenesulfonyl, and X is F, Cl or Br.

[0012] The organic solvent can be an aprotic solvent commonly used in this type of substitution reaction in the art. In the present invention, one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide are particularly preferred, with N-methylpyrrolidone being more preferred. The amount of the organic solvent used can be the amount used in conventional chemical reactions, and the volume-to-mass ratio of the organic solvent to Compound II is preferably 5 to 20 mL / g.

[0013] In the present invention, the base can be an inorganic base and / or an organic base. The inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate, or potassium acetate. The organic base is preferably one or more of morpholine, triethylamine, p-dimethylaminopyridine, and N,N-diisopropylethylamine. The base is more preferably triethylamine. The molar ratio of the base to compound II is preferably (1:1) to (3:1).

[0014] In the present invention, the molar ratio of compound II to compound III is (1:1) to (1:1.5).

[0015] In the present invention, the temperature of the substitution reaction is preferably 50-140°C, more preferably 80-120°C.

[0016] In the present invention, the progress of the substitution reaction can be monitored by conventional means in the art (such as TLC or HPLC), and the substitution reaction time is preferably 2 to 20 hours.

[0017] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0018] After the above substitution reaction is completed, pure compound I can be obtained by simple post-treatment, such as quenching, extraction, washing, drying, concentration, and recrystallization.

[0019] The raw material compound II used in the present invention can be prepared in the laboratory or directly purchased. Unless otherwise specified, the reagents and raw materials used in the present invention are commercially available.

[0020] The positive effects of the present invention are: the preparation method of the present invention avoids the use of precious metals as catalysts, has low cost, is simple to operate, saves costs, has a high product yield and high purity, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0021] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. In the following examples, the test methods without specific conditions are carried out according to conventional methods and conditions, or according to the product specifications.

[0022] Example 1

[0023] Preparation of 5-bromobenzoxaborole (X=Br in general formula II)

[0024] 0.1 mol 2,5-dibromobenzyl alcohol, 0.15 mol triisopropyl borate, 0.4 mol potassium acetate, and 5 mmol bistriphenylphosphine palladium dichloride (3.52) were dissolved in 300 mL DMSO and heated to 120°C for 15 h. The reaction was detected by thin layer chromatography. After the reactant almost disappeared, water was added to quench the reaction. The mixture was added to saturated brine and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel flash chromatography to obtain 20.3 g of 5-bromobenzoxaborole in a yield of 95.2%.

[0025] Example 2

[0026] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0027] 0.06 mol of 4-hydroxybenzonitrile was dissolved in 100 mL of N-methylpyrrolidone. 0.1 mol of triethylamine was slowly added and stirred thoroughly. Then, 0.05 mol of 5-bromo-1,2-benzoxaborolane was added. The temperature was raised to 80°C and refluxed for 6 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 11.6 g of a white solid with 98% purity, a yield of 92.1%.

[0028] 1 H-NMR (400 MHz, d 6 -DMSO) δ (ppm): 9.41 (s, 1H), 7.82 (d, J = 9.1Hz, 2H), 7.31 (d, J = 8.1Hz, 1H), 7.13 ( d,J=2.5Hz,1H), 7.10(d,J=8.9Hz,2H), 7.05(dd,J=8.1,2.5Hz,1H), 4.98(s,2H).

[0029] Example 3

[0030] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0031] 0.06 mol of 4-hydroxybenzonitrile was dissolved in 100 mL of N,N-dimethylformamide. 0.1 mol of triethylamine was slowly added and stirred thoroughly. Then, 0.05 mol of 5-bromo-1,2-benzoxaborolane was added. The temperature was raised to 100°C and refluxed for 6 hours. The reaction solution was cooled to room temperature and adjusted to neutrality with an appropriate amount of dilute hydrochloric acid. Ethyl acetate was then added for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 11.3 g of a white solid with 98% purity, a yield of 89.7%.

[0032] Example 4

[0033] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0034] 0.06 mol of 4-hydroxybenzonitrile was dissolved in 100 mL of N-methylpyrrolidone, and 0.1 mol of potassium carbonate was slowly added. After stirring, 0.05 mol of 5-fluoro-1,2-benzoxaborolane was added, and the temperature was raised to 90°C and refluxed for 8 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 10.8 g of a white solid with 98% purity, a yield of 86.1%.

[0035] Example 5

[0036] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0037] 0.06 mol of 4-hydroxybenzonitrile was dissolved in 100 mL of N-methylpyrrolidone, and 0.1 mol of p-dimethylaminopyridine was slowly added. After stirring, 0.05 mol of 5-bromo-1,2-benzoxaborolane was added, and the temperature was raised to 110°C and refluxed for 8 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 10.7 g of a white solid with 98% purity, a yield of 85.4%.

[0038] Example 6

[0039] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0040] 0.06 mol of 4-hydroxybenzonitrile was dissolved in 100 mL of dimethyl sulfoxide, and 0.1 mol of morpholine was slowly added. After stirring, 0.05 mol of 5-chloro-1,2-benzoxaborolane was added. The temperature was raised to 90°C and refluxed for 10 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 10.5 g of a white solid with 98% purity, a yield of 83.8%.

[0041] Example 7

[0042] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0043] 0.06 mol of 4-methylsulfonylbenzonitrile was dissolved in 100 mL of N-methylpyrrolidone. 0.125 mol of triethylamine was slowly added and stirred thoroughly. Then, 0.05 mol of 5-bromo-1,2-benzoxaborolane was added. The temperature was raised to 110°C and refluxed for 15 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 11.1 g of a white solid with 98% purity, a yield of 88.5%.

[0044] Example 10

[0045] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0046] 0.06 mol of 4-(p-Toluenesulfonyl)benzonitrile was dissolved in 100 mL of N-methylpyrrolidone. 0.125 mol of triethylamine was slowly added and stirred thoroughly. Then, 0.05 mol of 5-bromo-1,2-benzoxaborolane was added. The temperature was raised to 110°C and refluxed for 12 hours. The reaction solution was cooled to room temperature, adjusted to neutrality with an appropriate amount of dilute hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel flash chromatography to obtain 11.3 g of a white solid with 98% purity, a yield of 89.9%.

Claims

1. A method for preparing 4-[(1,3-dihydroxy-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, characterized in that comprising the following steps: in an organic solvent, under basic conditions, subject compound II and compound III to the nucleophilic substitution reaction as shown below, Among them, R is hydrogen, C1-C4 aliphatic hydrocarbon group, methylsulfonyl group or p-toluenesulfonyl group, and X is F, Cl, Br.

2. The preparation method according to claim 1, characterized in that: The organic solvent is one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

3. The preparation method according to claim 1, characterized in that: The base is an inorganic base and / or an organic base. The inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium acetate or potassium acetate. The organic base is one or more of morpholine, triethylamine, p-dimethylaminopyridine or N,N-diisopropylethylamine.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the base to Compound II is (1:1) to (3:1).

5. The preparation method according to claim 1, characterized in that: The temperature of the substitution reaction is 50 - 140 °C.

6. The preparation method according to claim 1, wherein: The molar ratio of Compound II to Compound III is (1:1) to (1:1.5).

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