A preparation method of 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester

Abstract

The invention discloses a preparation method of 3-methylbenzo[d]oxazole-2(3H)-one-5-boric acid pinacol ester, and belongs to the technical field of organic synthesis. 4-hydroxyphenylboric acid pinacol ester is used as a raw material, first reacted with di-tert-butyl dicarbonate to obtain 4-(tert-butyloxycarbonyloxy)phenylboric acid pinacol ester, then halogenated with a halogenating agent to obtain 4-(tert-butyloxycarbonyloxy)-3-halogen-phenylboric acid pinacol ester, and finally reacted with methylamine under high pressure to obtain 3-methylbenzo[d]oxazole-2(3H)-one-5-boric acid pinacol ester. The process method is simple in operation, convenient in post-processing, avoids the use of palladium catalysts and ligands, improves economic efficiency, and has a total yield of more than 81% and a purity of more than 99%.

Description

Technical Field

[0001] The invention relates to a method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester, belonging to the technical field of organic synthesis. Background Art

[0002] Benzoxazolone derivatives are important intermediates for plant protection agents, pharmaceuticals and dyes. Many benzoxazolone derivatives have been described in therapeutics to have a variety of pharmacological activities, ranging from analgesic and anti-inflammatory compounds to antipsychotics and neuroprotective anticonvulsant compounds.

[0003] 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one, CAS: 1220696-32-1. As an organic building block of benzoxazolone, it can be used to synthesize dipeptidyl peptidase 1 inhibitors, which can be used to treat obstructive airway diseases, bronchiectasis, cystic fibrosis, asthma, emphysema, chronic obstructive pulmonary disease and other diseases.

[0004] In the prior art, there are few studies on the synthesis of 3-methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester. Patent WO2018 / 93569A1 uses 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one as a raw material and reacts with PdCl2(dppf) 2- In the presence of CH2Cl2 catalyst and potassium acetate, it reacts with diboric acid pinacol ester in 1,4-dioxane solvent with a yield of about 60%. 2- CH2Cl2 is expensive, not economical, and not conducive to industrial production. The reaction equation is as follows:

[0005]

[0006] Patent US2015 / 210655A1 uses 4-chloro-2-aminophenol as a raw material, reacts with N,N'-carbonyldiimidazole to obtain chlorzoxazone, and then reacts with iodomethane in the presence of cesium carbonate to obtain 5-chloro-3-methylbenzo[D]oxazol-2(3H)-one, and finally couples with diboric acid pinacol ester under the catalysis of palladium acetate and ligand X-phos to obtain the product with a yield of about 90%. Although the yield is high, the purity and content are lacking, and further purification is required. In addition, palladium acetate and ligand X-phos are expensive and not economical. The reaction equation is as follows:

[0007]

[0008] In view of the shortcomings of the above methods, it is necessary to provide a coupling reaction that does not require expensive palladium catalysts and ligands, and solve the problems of purity and content, improve economic efficiency, and be suitable for industrial-scale production to meet the growing market demand. Summary of the invention

[0009] In order to overcome the above technical defects, the present invention discloses a method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester. 4-hydroxyphenylboric acid pinacol ester is used as a raw material, first reacted with di-tert-butyl dicarbonate to obtain 4-(tert-butyloxycarbonyloxy)phenylboric acid pinacol ester, then reacted with a halogenating agent to obtain 4-(tert-butyloxycarbonyloxy)-3-halogen-phenylboric acid pinacol ester, and finally reacted with methylamine under high pressure to obtain 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester. The process is simple in operation, convenient for post-treatment, avoids the use of palladium catalysts and ligands, improves economic efficiency, and has a total yield of more than 81% and a purity of more than 99%.

[0010] The preparation method of 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester of the present invention comprises the following steps:

[0011]

[0012] The first step: mixing 4-hydroxyphenylboronic acid pinacol ester and DMAP in an organic solvent, adding di-tert-butyl dicarbonate to react, and obtaining 4-(tert-butyloxycarbonyloxy)phenylboronic acid pinacol ester;

[0013] Step 2: dissolving 4-(tert-butoxycarbonyloxy)phenylboronic acid pinacol ester in an organic solvent, adding a halogenating agent to react, and obtaining 4-(tert-butoxycarbonyloxy)-3-chloro / bromo-phenylboronic acid pinacol ester;

[0014] Step 3: In the presence of a catalyst, 4-(tert-butoxycarbonyloxy)-3-chloro / bromo-phenylboronic acid pinacol ester is reacted with methylamine in an autoclave at elevated temperature for ring-closure reaction to obtain 3-methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester.

[0015] Furthermore, in the above technical solution, in the first step, the organic solvent is selected from dichloromethane or 1,2-dichloroethane.

[0016] Furthermore, in the above technical solution, in the first step, the molar ratio of 4-hydroxyphenylboronic acid pinacol ester, DMAP and di-tert-butyl dicarbonate is 1:0.25-0.35:1.4-1.6.

[0017] Furthermore, in the above technical solution, in the second step, the organic solvent is selected from dichloromethane or acetonitrile.

[0018] Furthermore, in the above technical solution, in the second step, the halogenating agent is selected from N-bromosuccinimide or N-chlorosuccinimide.

[0019] Furthermore, in the above technical solution, in the second step, the molar ratio of the 4-(tert-butoxycarbonyloxy)phenylboronic acid pinacol ester to the halogenating agent is 1:0.98-1.05.

[0020] Furthermore, in the above technical solution, in the third step, the methylamine is selected from a 40% methylamine aqueous solution, and the catalyst is selected from triethylamine or DBU.

[0021] Furthermore, in the above technical solution, in the third step, the reaction temperature is 110-130° C. and the pressure is 13-15 atm.

[0022] Furthermore, in the above technical solution, in the third step, the molar ratio of the 4-(tert-butoxycarbonyloxy)-3-chloro-phenylboronic acid pinacol ester to methylamine is 1:4.5-5.5.

[0023] Advantageous Effects of the Invention

[0024] 1. It avoids the use of palladium catalysts and ligands, reduces costs, improves economic efficiency, and enhances product market competitiveness.

[0025] 2. The route of the present invention is more reasonable and convenient, and the reaction conversion rate is greatly improved through chemical reaction, thereby improving the product yield and improving the product quality. Specific embodiments

[0026] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0027] Synthesis of 3-Methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester

[0028] Example 1

[0029]

[0030] Under nitrogen protection, 110 g (0.5 mol) of 4-hydroxyphenylboronic acid pinacol ester, 18.3 g (0.15 mol) of DMAP and 800 mL of dichloromethane were added to the reaction flask, and a solution of 163.7 g (0.75 mol) of di-tert-butyl dicarbonate / 200 mL of dichloromethane was added dropwise at room temperature. The reaction was allowed to react for 3 hours at room temperature. TLC detected that there was almost no residual raw material. The reaction solution was distilled under reduced pressure to remove dichloromethane, and then 10 V of n-heptane was added, the temperature was raised to 70 ° C, and hot filtration was performed. The filter cake was rinsed with hot n-heptane, and the filtrate was cooled to 10 ° C and stirred overnight. 156.3 g of 4-(tert-butyloxycarbonyloxy)phenylboronic acid pinacol ester was obtained by filtration, HPLC: 98.7%, and the yield was 97.6%. 1 HNMR(400MHz, CDCl3):8.01-7.98(m,2H),7.21-7.18(m,2H),1.51(s,9H),1.12(s,12H).

[0031] Example 2

[0032]

[0033] Under nitrogen protection, 64 g (0.2 mol) of 4-(tert-butoxycarbonyloxy)phenylboronic acid pinacol ester and 500 mL of acetonitrile were added to the reaction bottle, and 35.2 g (0.198 mol) of NBS was added in 8 batches at 15-20° C. (each time with an interval of 10 minutes), followed by reaction at room temperature for 10 hours. TLC detected that there was almost no raw material remaining, 2 g of sodium bisulfite was added and stirred for 1 hour, and the mixture was concentrated under reduced pressure below 35° C. until no liquid flowed to evaporate the acetonitrile, and 450 mL of methyl tert-butyl ether was added to replace it, and the mixture was stirred at room temperature for 0.5 hour, filtered, and the filter cake was rinsed with methyl tert-butyl ether. The filtrate was then washed with sodium bicarbonate aqueous solution and concentrated under reduced pressure, and n-heptane was added. The mixture was slurried at room temperature and filtered to obtain 76.1 g of 4-(tert-butoxycarbonyloxy)-3-bromo-phenylboronic acid pinacol ester, HPLC 97.6%, and a yield of 95.3%. 1 HNMR(400MHz, CDCl3):7.94-7.91(m,2H),7.16(d,2H),1.50(s,9H),1.12(s,12H).

[0034] Example 3

[0035]

[0036] Under nitrogen protection, 64 g (0.2 molq) of 4-(tert-butoxycarbonyloxy)phenylboronic acid pinacol ester and 500 mL of acetonitrile were added to the reaction flask, and 26.4 g (0.198 mol) of NCS was added in 11 batches at 15-20°C (10 minutes interval between each batch), followed by reaction at room temperature for 16 hours. TLC detected that there was almost no raw material remaining, 2 g of sodium bisulfite was added and stirred for 1 hour, and the mixture was concentrated under reduced pressure below 35°C until no liquid flowed to evaporate acetonitrile, and 450 mL of methyl tert-butyl ether was added for replacement, and the mixture was stirred at room temperature for 0.5 hour, filtered, and the filter cake was rinsed with methyl tert-butyl ether. The filtrate was then washed with sodium bicarbonate aqueous solution and concentrated under reduced pressure, and n-heptane was added. The mixture was slurried at room temperature and filtered to obtain 68.7 g of 4-(tert-butoxycarbonyloxy)-3-chloro-phenylboronic acid pinacol ester, HPLC: 95.6%, yield 96.8%. 1 HNMR(400MHz, CDCl3):7.85-7.82(m,2H),7.16(d,2H),1.49(s,9H),1.11(s,12H).

[0037] Example 4

[0038]

[0039] Under nitrogen protection, 20 g (0.05 mol) of 4-(tert-butoxycarbonyloxy)-3-bromo-phenylboronic acid pinacol ester, 21.4 g (0.275 mol) of 40% methylamine and 0.5 g of triethylamine were mixed in a 100 mL autoclave, heated to 120-125° C., reacted for 6 hours, cooled to room temperature, replaced with nitrogen, concentrated under reduced pressure at room temperature to evaporate a large amount of methylamine, extracted with methyl tert-butyl ether, and the organic phase was washed once with 18% citric acid aqueous solution and water, respectively, concentrated under reduced pressure, added with n-heptane for pulping, and filtered to obtain 12.2 g of 3-methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester, HPLC 99.8%, yield 88.7%. 1 HNMR(400MHz, CDCl3):7.65-7.62(m,1H),7.40(s,1H),7.21(d,1H),3.43(s,3H),1.37(s,12H).

[0040] Example 5

[0041]

[0042] Under nitrogen protection, 17.7 g (0.05 mol) of 4-(tert-butoxycarbonyloxy)-3-chloro-phenylboronic acid pinacol ester, 19.4 g (0.25 mol) of 40% methylamine and 0.8 g of DBU were mixed in an autoclave, heated to 130-135° C., reacted for 10 hours, cooled to room temperature, replaced with nitrogen, concentrated under reduced pressure at room temperature to evaporate a large amount of methylamine, extracted with methyl tert-butyl ether, and the organic phase was washed once with 18% citric acid aqueous solution and water, respectively. The organic phase was concentrated under reduced pressure, added with n-heptane for pulping, and filtered to obtain 11.9 g of 3-methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester, HPLC 99.6%, yield 86.7%.

[0043] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester, characterized in that: The steps include: Where: X = Cl, Br; The first step: mixing 4-hydroxyphenylboronic acid pinacol ester and DMAP in an organic solvent, adding di-tert-butyl dicarbonate to react, and obtaining 4-(tert-butyloxycarbonyloxy)phenylboronic acid pinacol ester; The second step: dissolving 4-(tert-butoxycarbonyloxy)phenylboronic acid pinacol ester in an organic solvent, adding a halogenating agent to react, and obtaining 4-(tert-butoxycarbonyloxy)-3-chloro / bromo-phenylboronic acid pinacol ester; the halogenating agent is selected from N-bromosuccinimide or N-chlorosuccinimide; The third step: subjecting 4-(tert-butoxycarbonyloxy)-3-chloro / bromo-phenylboronic acid pinacol ester to a ring-closure reaction with methylamine in the presence of a catalyst by heating in an autoclave to obtain 3-methylbenzo[d]oxazol-2(3H)-one-5-boronic acid pinacol ester; the methylamine is selected from a 40% methylamine aqueous solution, and the catalyst is selected from triethylamine or DBU; the ring-closure reaction temperature is 110-130° C., and the pressure is 13-15 atm.

2. The method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester according to claim 1, characterized in that: In the first step, the organic solvent is selected from dichloromethane or 1,2-dichloroethane.

3. The method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester according to claim 1, characterized in that: In the first step, the molar ratio of 4-hydroxyphenylboronic acid pinacol ester, DMAP and di-tert-butyl dicarbonate is 1:0.25-0.35:1.4-1.

6.

4. The method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester according to claim 1, characterized in that: In the second step, the organic solvent is selected from dichloromethane or acetonitrile.

5. The method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester according to claim 1, characterized in that: In the second step, the molar ratio of the 4-(tert-butyloxycarbonyloxy)phenylboronic acid pinacol ester to the halogenating agent is 1:0.98-1.

05.

6. The method for preparing 3-methylbenzo[d]oxazol-2(3H)-one-5-boric acid pinacol ester according to claim 1, characterized in that: In the third step, the molar ratio of the 4-(tert-butyloxycarbonyloxy)-3-chloro-phenylboronic acid pinacol ester to methylamine is 1:4.5-5.5.

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