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

Abstract

The invention discloses a preparation method of 4-[(1, 3-dihydro-1-hydroxy-2, 1-benzoxaborolan-5-yl) oxy] cyanobenzene, which comprises the following step: in an organic solvent, under an alkaline condition, carrying out substitution reaction on a compound II and a compound III as shown in the specification, thereby obtaining the 4-[(1, 3-dihydro-1-hydroxy-2, 1-benzoxaborolan-5-yl) oxy] cyanobenzene. Wherein R is hydrogen, sulfonyl or p-toluenesulfonyl, and X is F, Cl or Br. The preparation method disclosed by the invention avoids using noble metal as a catalyst, and is low in cost, simple to operate, high in product yield and suitable for industrial production. # imgabs0 #

Description

Technical Field

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

[0002] Crisaborole, with the chemical name 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborole-5-yl)oxy]benzonitrile as shown in Structural Formula 1, is a phosphodiesterase 4 inhibitor developed by Anacor Pharmaceuticals for the topical treatment of allergic dermatitis / atopic dermatitis. This drug has been marketed in the United States (trade name: Eucrisa).

[0003]

[0004] In the preparation process of Crisaborole, the substitution of the heterocycle and the construction of the boron-containing heterocycle are the key to the synthetic route. Currently, the main synthetic routes of Crisaborole are as follows:

[0005] Route 1: (Reference: US20070286822)

[0006]

[0007] This route uses 2-bromo-5-(4-cyanophenoxy)benzoic acid as an important reactant. After reduction, the boron-containing heterocycle is constructed with the participation of n-butyllithium. The disadvantage of this method is that it uses n-butyllithium, a reagent with harsh reaction conditions, which increases the process requirements and cost, and is not suitable for industrial scale-up.

[0008] Route 2: (Reference: WO200911167)

[0009]

[0010] This route uses 2-bromo-5-hydroxybenzaldehyde as a raw material. After a substitution reaction, the construction of the carbon-boron bond is achieved with the participation of palladium metal and chiral ferrocenyl diphosphine. The disadvantages of this method are many reaction steps and a low final yield (44.8%). In addition, due to the use of two very expensive reagents, palladium metal and chiral ferrocenyl diphosphine, the cost is greatly increased, making it difficult to be suitable for industrial production.

[0011] Although the above methods for preparing Crisaborole have been reported in the prior art, they all have one or more disadvantages, such as using expensive reagents and increasing protection and deprotection steps. Therefore, it is very necessary to develop a simple, economical and industrially applicable synthetic route. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to overcome the defect that in the existing method for preparing 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile, expensive reagents need to be used, the cost is very high, and it is not suitable for industrialization. Therefore, a simpler and more economical preparation method compared with the existing technology is provided. The preparation method of the present invention avoids the participation of precious metals and expensive ligands, has a low cost, and is simple in operation, with a high product yield and high purity, and is suitable for industrial production.

[0013] The present invention relates to a method for preparing crisaborole as shown in formula I, which comprises the following steps: in an organic solvent, under alkaline conditions, subjecting compound II and compound III to the substitution reaction shown below.

[0014]

[0015] Among them, R is hydrogen, methanesulfonyl or p-toluenesulfonyl, and X is F, Cl or Br.

[0016] Among them, the organic solvent can be an aprotic solvent commonly used in such substitution reactions in the art. The present invention particularly preferably selects one or more of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, and more preferably N-methylpyrrolidone. The amount of the organic solvent can be the amount used in conventional chemical reactions, and the volume-mass ratio thereof to compound II is preferably 5-20 mL / g.

[0017] 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, and 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)-(3:1).

[0018] In the present invention, the molar ratio of compound II to compound III is (1:1)-(1:1.5).

[0019] In the present invention, the temperature of the substitution reaction is preferably 50-140 °C, and more preferably 80-120 °C.

[0020] 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 2-20 hours.

[0021] On the basis of not violating the common knowledge in this field, the above preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0022] 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.

[0023] The starting compound II used in the present invention can be prepared in the laboratory by itself or purchased directly. Unless otherwise specified, the reagents and raw materials used in the present invention are all commercially available.

[0024] The positive effects of the present invention are as follows: The preparation method of the present invention avoids the use of precious metals as catalysts, has low cost, simple operation, cost savings, high product yield and high purity, and is suitable for industrial scale-up production. Specific Embodiments

[0025] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the examples described herein. The test methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0026] Example 1

[0027] Preparation of 5-bromobenzooxaborole (X = Br in general formula II)

[0028]

[0029] 0.1 mol of 2,5-dibromobenzyl alcohol, 0.15 mol of triisopropyl borate, 0.4 mol of potassium acetate, and 5 mmol of bis(triphenylphosphine)palladium dichloride (3.52 g) were dissolved in 300 mL of DMSO, heated to 120 °C and reacted for 15 h. The reaction was monitored by thin-layer chromatography. After the reactants almost disappeared, the reaction was quenched by adding water. The mixture was added to saturated brine, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography on silica gel to obtain 20.3 g of 5-bromobenzooxaborole with a yield of 95.2%.

[0030] Example 2

[0031] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0032]

[0033] Dissolve 0.06 mol of 4-hydroxybenzonitrile in 100 mL of N-methylpyrrolidone, slowly add 0.1 mol of triethylamine, and after stirring evenly, add 0.05 mol of 5-bromo-1,2-benzoxaborole. Heat the temperature to 80 °C and reflux for 6 hours. Cool the reaction solution to room temperature, adjust it to neutral with appropriate dilute hydrochloric acid, extract it 3 times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 11.6 g of a white solid with a purity of 98%, and the yield is 92.1%.

[0034] 1 H-NMR(400MHz, 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).

[0035] Example 3

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

[0037]

[0038] Dissolve 0.06 mol of 4-hydroxybenzonitrile in 100 mL of N,N-dimethylformamide, slowly add 0.1 mol of triethylamine, and after stirring evenly, add 0.05 mol of 5-bromo-1,2-benzoxaborole. Heat the temperature to 100 °C and reflux for 6 hours. Cool the reaction solution to room temperature, adjust it to neutral with appropriate dilute hydrochloric acid, extract it 3 times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 11.3 g of a white solid with a purity of 98%, and the yield is 89.7%.

[0039] Example 4

[0040] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0041]

[0042] Dissolve 0.06 mol of 4-hydroxybenzonitrile in 100 mL of N-methylpyrrolidone, slowly add 0.1 mol of potassium carbonate, after stirring evenly, add 0.05 mol of 5-fluoro-1,2-benzoxaborole, heat up to 90 °C, and reflux for 8 hours. Cool the reaction solution to room temperature, add appropriate amount of dilute hydrochloric acid to adjust to neutrality, extract with ethyl acetate for 3 times, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 10.8 g of a white solid with a purity of 98%, and the yield is 86.1%.

[0043] Example 5

[0044] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0045]

[0046] Dissolve 0.06 mol of 4-hydroxybenzonitrile in 100 mL of N-methylpyrrolidone, slowly add 0.1 mol of 4-dimethylaminopyridine, after stirring evenly, add 0.05 mol of 5-bromo-1,2-benzoxaborole, heat up to 110 °C, and reflux for 8 hours. Cool the reaction solution to room temperature, add appropriate amount of dilute hydrochloric acid to adjust to neutrality, extract with ethyl acetate for 3 times, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 10.7 g of a white solid with a purity of 98%, and the yield is 85.4%.

[0047] Example 6

[0048] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0049]

[0050] Dissolve 0.06 mol of 4-hydroxybenzonitrile in 100 mL of dimethyl sulfoxide, slowly add 0.1 mol of morpholine, after stirring evenly, add 0.05 mol of 5-chloro-1,2-benzoxaborole, heat up to 90 °C, and reflux for 10 hours. Cool the reaction solution to room temperature, add appropriate amount of dilute hydrochloric acid to adjust to neutrality, extract with ethyl acetate for 3 times, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 10.5 g of a white solid with a purity of 98%, and the yield is 83.8%.

[0051] Example 7

[0052] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-5-yl)oxy]benzonitrile (Compound I)

[0053]

[0054] Dissolve 0.06 mol of 4-methylsulfonylbenzonitrile in 100 mL of N-methylpyrrolidone. Slowly add 0.125 mol of triethylamine. After stirring evenly, add 0.05 mol of 5-bromo-1,2-benzoxaborole. Heat the temperature to 110 °C and reflux for 15 hours. Cool the reaction solution to room temperature, add an appropriate amount of dilute hydrochloric acid to adjust it to neutral, extract it 3 times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 11.1 g of a white solid with a purity of 98%, and the yield is 88.5%.

[0055] Example 10

[0056] Preparation of 4-[(1,3-dihydro-1-hydroxy-2,1-benzoxaborole-5-yl)oxy]benzonitrile (Compound I)

[0057]

[0058] Dissolve 0.06 mol of 4-(p-toluenesulfonyl)benzonitrile in 100 mL of N-methylpyrrolidone. Slowly add 0.125 mol of triethylamine. After stirring evenly, add 0.05 mol of 5-bromo-1,2-benzoxaborole. Heat the temperature to 110 °C and reflux for 12 hours. Cool the reaction solution to room temperature, add an appropriate amount of dilute hydrochloric acid to adjust it to neutral, extract it 3 times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, concentrate, and purify the crude product by flash silica gel chromatography to obtain 11.3 g of a white solid with a purity of 98%, and the yield is 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, wherein, R is hydrogen, a C1-C4 aliphatic hydrocarbon group, a mesyl group or a tosyl group, and X is F, Cl or 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, characterized in that: The molar ratio of compound II to compound III is (1:1) to (1:1.5).

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