A process for the preparation of a boronic acid derivative

Abstract

The application discloses a preparation method of a boronic acid derivative and belongs to the field of organic chemistry. The preparation method of the boronic acid derivative adopts alkyl Grignard reagent as an alkali and cooperatively uses a suitable substrate, so that the expensive palladium catalyst is not needed, the reaction time is shortened to 1h, and the yield is improved. In addition, in the quenching reaction process, the temperature is controlled to be 45-100 DEG C, the hydroxyl protecting group can be directly removed in the post-treatment process, and thus the boronic acid derivative with unprotected hydroxyl can be directly obtained in a high yield.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and more specifically to a method for preparing a boric acid derivative. Background Technology

[0002] According to the patents CN113784957A and WO2023028534A1, the following compounds are all important pharmaceutical intermediates.

[0003]

[0004] In the reports of the two patents mentioned above, the preparation methods of compounds 3a and 3b are both based on the reaction of the corresponding iodobenzene compounds with pinacol borate under palladium acetate catalysis. According to the records, the yield under such reaction conditions is 74.7%.

[0005] CN113784957A also reports a method for preparing compound 3'a, which requires using the corresponding iodobenzene as a raw material to first prepare compound 3a, and then deprotecting it in the presence of trifluoroacetic acid to finally obtain compound 3'a. Such steps are rather cumbersome and may cause some loss of product. Summary of the Invention

[0006] The present invention is made to solve the above-mentioned problems, and aims to provide a method for preparing boric acid derivatives that can retain the hydroxyl protecting group, and a one-pot method for preparing boric acid derivatives that simultaneously completes the two-step reaction of adding borate ester or boric acid group and dehydroxyl protection.

[0007] Option A:

[0008] This invention provides a method for preparing a boric acid derivative, comprising the following steps:

[0009] In the presence of alkyl Grignard reagents and solvents, compound 1 reacts with compound 2 to form a reaction solution; after the reaction is complete, a quencher is added and the temperature is controlled for post-treatment and purification to obtain compound 3 and / or compound 3'.

[0010]

[0011] In the formula, PG is a hydroxyl protecting group selected from R3-X-CH2- or R4R4'R4"Si-; R is a C1-C5 alkoxy group; R1 and R2 are independently selected from C1-C5 alkyl groups, or R1 and R2 are bonded to adjacent atoms to form a ring, wherein the ring is a borate ester ring;

[0012] Wherein, X is O or S; R3 is a substituted or unsubstituted C1-C5 straight-chain or branched alkyl group, and the substituent is selected from halogens (F, Cl, Br, I), C1-C5 alkoxy groups, C1-C5 alkylsilyl groups, substituted or unsubstituted phenyl groups; the substituents on the benzene ring are C1-C5 alkyl groups, C1-C5 alkoxy groups, and halogens.

[0013] R4, R4', and R4" are each independently selected from C1-C5 straight-chain or branched alkyl or phenyl groups.

[0014] In one embodiment of the present invention, the PG is preferably R3-X-CH2-, which can be better removed during post-processing compared to silicon-based protecting groups, thereby obtaining compound 3'.

[0015] In one embodiment of the present invention, the PG is specifically selected from any one of trimethylsilyl, triethylsilyl, isopropyl dimethylsilyl, isopropyl diethylsilyl, tert-butyl dimethylsilyl, tert-butyl diphenylsilyl, triisopropylsilyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-methoxyethoxymethyl, meththiomethyl, p-methoxybenzoxymethyl, and 2-(trimethylsilyl)ethoxymethyl.

[0016] In one embodiment of the present invention, compound 2 is selected from any one of the following compounds:

[0017]

[0018] In one embodiment of the present invention, during the post-processing, the temperature is controlled at 45°C-100°C to obtain compound 3'; the temperature is controlled at above 25°C and below 45°C to obtain compound 3' and / or compound 3; and the temperature is controlled at no more than 25°C to obtain compound 3.

[0019] Furthermore, by controlling the temperature at 35℃-40℃, compounds 3' and 3 were obtained.

[0020] In one embodiment of the present invention, the quenching agent is water or an aqueous solution of an inorganic salt with a pH value less than 7. Specifically, a saturated aqueous solution of ammonium chloride can be selected.

[0021] In one embodiment of the present invention, the alkyl Grignard reagent is alkyl magnesium chloride; specifically, isopropyl magnesium chloride may be selected.

[0022] In one embodiment of the present invention, the solvent may be tetrahydrofuran.

[0023] In one embodiment of the present invention, the molar ratio of compound 1 to compound 2 is 1:(1.8-2.2).

[0024] In one embodiment of the present invention, the molar ratio of compound 1 to the alkyl Grignard reagent is 1:(1.2-1.8).

[0025] In one embodiment of the present invention, the molar volume ratio of compound 1 to solvent is 1 mmol: (2-5) mL.

[0026] In one embodiment of the present invention, the method for preparing the boric acid derivative specifically includes:

[0027] An alkyl Grignard reagent was dispersed in a portion of the solvent and the temperature was controlled at -10℃ to -5℃. Then, another portion of the solvent was added to disperse the solution prepared by compound 1. While maintaining the temperature, compound 2 was added and the reaction was carried out at -30℃ to -25℃ to form a reaction solution. After the reaction was completed, a quencher was added and the temperature was controlled for post-treatment and purification to obtain compound 3 and / or compound 3'.

[0028] In the presence of an alkyl Grignard reagent and a solvent, compound 1 reacts with compound 2 to form a reaction solution; after the reaction is complete, a quencher is added and the temperature is controlled for post-treatment and purification to obtain compound 3 and / or compound 3'.

[0029] In one embodiment of the present invention, the reaction formula for the preparation method of compound 1 is as follows:

[0030]

[0031] Includes the following steps:

[0032] a. At least in the presence of a reducing agent, compound 4 is converted into compound 5;

[0033] b. In the presence of an iodine reagent, compound 5 is converted into compound 6;

[0034] c. Compound 6 is converted into the corresponding diazonium salt and then hydrolyzed to obtain compound 7;

[0035] d. Compound 7 reacts with a hydroxyl protecting agent to give compound 1.

[0036] In one embodiment of the present invention, in step a, compound 4 is converted into compound 5 in the presence of a reducing agent, a catalyst, and a reaction solvent; the reducing agent is hydrazine or hydrated hydrazine, and the catalyst is Raney copper.

[0037] In one embodiment of the present invention, in step a, the molar ratio of compound 4 to the reducing agent is 1:(1.8-2.2).

[0038] In one embodiment of the present invention, in step a, the mass ratio of compound 4 to the catalyst is 1:(0.08-0.2).

[0039] In one embodiment of the present invention, in step a, the reaction solvent is ethanol.

[0040] In one embodiment of the present invention, in step a, the molar volume ratio of compound 4 to the reaction solvent is 1 mmol:(2-5) mL.

[0041] In one embodiment of the present invention, the iodizing agent in step b is ICl.

[0042] In one embodiment of the present invention, step b includes the following process: reacting ICl with compound 5 in the presence of a solvent and a base reagent to obtain compound 6; wherein the solvent is R. a COOH, R a Selected from H or C1-C5 alkyl groups; the base reagent is R. c COOX, R c Selected from H or C1-C5 alkyl groups, where X is K or Na.

[0043] In one embodiment of the present invention, the molar ratio of compound 5 to ICl is 1:(0.9-1.1).

[0044] In one embodiment of the present invention, the molar ratio of compound 5 to the base reagent is 1:(0-1.1). Further, the molar ratio of compound 5 to the base reagent is 1:(0.9-1.1).

[0045] In one embodiment of the present invention, the molar volume ratio of compound 5 to solvent is 1 mmol:(2-5) mL.

[0046] In one embodiment of the present invention, step b specifically includes:

[0047] Dispersions of compound 5 and ICl were prepared separately. The compound 5 dispersion and the ICl dispersion were mixed to form a mixture. An alkaline reagent was added to the mixture and the mixture was stirred to react.

[0048] In one embodiment of the present invention, the concentration of the dispersion of compound 5 is 0.5-0.6 mmol / mL.

[0049] In one embodiment of the present invention, the concentration of the ICl dispersion is 1.0-1.5 mmol / mL.

[0050] In one embodiment of the present invention, the volume ratio of the compound 5 dispersion and the ICl dispersion is 2:1.

[0051] In one embodiment of the present invention, after the reaction is completed, thiosulfate is added to quench the reaction, the solvent is removed, water and extractant are added, extraction is performed, the organic phase is collected, concentrated and dried to obtain compound 6.

[0052] In one embodiment of the present invention, the extractant is ethyl acetate, and the mass ratio of water to extractant is 1:(0.9-1.1).

[0053] In one embodiment of the present invention, step c specifically includes: adding compound 6 to an aqueous sulfuric acid solution, then adding an aqueous sodium nitrite solution dropwise, mixing and reacting, and then adding uric acid to form a reaction solution; adding the reaction solution dropwise to a preheated quenching solution, and after the addition is complete, cooling to room temperature, adding an extractant for extraction, collecting the organic phase, and concentrating.

[0054] In one embodiment of the present invention, the quenching solution is an aqueous solution of 20 wt% sulfuric acid.

[0055] In one embodiment of the present invention, step d specifically includes: dispersing compound 7 and a base reagent in an organic solvent, controlling the temperature at 10-15°C, and then adding a hydroxyl protecting agent to carry out the reaction.

[0056] In one embodiment of the present invention, the hydroxyl protecting agent is PG-Cl or PG-Br; PG is a hydroxyl protecting group, as defined above.

[0057] Option B:

[0058] The present invention provides a method for preparing a boric acid derivative, comprising the following steps:

[0059] In the presence of alkyl magnesium chloride and a solvent, compound 1 reacts with compound 2 to form a reaction solution. The solution is then post-treated and purified under conditions insufficient to remove the hydroxyl protecting agent to obtain compound 3.

[0060]

[0061] In the formula, PG is a hydroxyl protecting group, as defined above; R is a C1-C5 alkoxy group; R1 and R2 are independently selected from C1-C5 alkyl groups, or R1 and R2 are bonded to adjacent atoms to form a ring, wherein the ring is a borate ester ring.

[0062] In one embodiment of the present invention, the condition that is insufficient to remove the hydroxyl protectant is that a quencher is added to the reaction solution, and the temperature of the reaction solution is controlled below 25°C during the quenching process.

[0063] In one embodiment of the present invention, the temperature may be specifically selected as 0-25°C, more preferably 20-25°C.

[0064] Option C:

[0065] The present invention provides a method for preparing a boric acid derivative, comprising the following steps:

[0066] In the presence of alkyl magnesium chloride and solvent, compound 1 reacts with compound 2 to form a reaction solution. A quencher is added to the reaction solution, and the temperature of the reaction solution is controlled at 45℃-100℃ during the quenching process. After purification, compound 3' is obtained.

[0067]

[0068] In the formula, PG is a hydroxyl protecting group, as defined above; R is a C1-C5 alkoxy group; R1 and R2 are independently selected from C1-C5 alkyl groups, or R1 and R2 are bonded to adjacent atoms to form a ring, wherein the ring is a borate ester ring.

[0069] In one embodiment of the present invention, the temperature is further controlled at 45°C-50°C.

[0070] The role and effect of invention

[0071] According to the method for preparing boric acid derivatives of the present invention, since an alkyl Grignard reagent is used as a base, the present invention not only eliminates the need for expensive palladium catalysts, but also reduces the reaction time to 1 hour and improves the yield.

[0072] Furthermore, because the temperature is controlled at 45-100℃ during the quenching reaction, acid-sensitive hydroxyl protecting groups, represented by ethoxymethyl groups, can be directly removed during the post-processing, thereby obtaining hydroxyl-unprotected boric acid derivatives in high yield. Attached Figure Description

[0073] Figure 1 This is the liquid phase spectrum of compound 5a obtained in Example 1 of the present invention, wherein the retention time of 6.058 min corresponds to compound 5a;

[0074] Figure 2 This is the liquid chromatography spectrum of the sample obtained in Comparative Example 1 of the present invention, wherein a retention time of 6.072 min corresponds to compound 5a, a retention time of 8.020 min corresponds to compound 4a, and a retention time of 11.326 min corresponds to compound 4a'; and

[0075] Figure 3 This is the liquid phase spectrum of the crude product obtained in Example 4 of the present invention, wherein the retention time of 8.409 min corresponds to compound 6a;

[0076] Figure 4This is the liquid phase spectrum of compound 7a in Example 6 of the present invention, wherein the retention time of 8.684 min corresponds to compound 7a;

[0077] Figure 5 This is the NMR spectrum of compound 7a in Example 6 of the present invention;

[0078] Figure 6 This is the liquid phase spectrum of compound 3a in Example 10 of the present invention, wherein the retention time of 11.936 min corresponds to compound 3a;

[0079] Figure 7 This is the NMR spectrum of compound 3a in Example 10 of the present invention;

[0080] Figure 8 This is the liquid phase spectrum of compound 3'a in Example 11 of the present invention, wherein the retention time of 12.022 min corresponds to compound 3'a;

[0081] Figure 9 This is the liquid phase spectrum of compound 3b in Example 13 of the present invention, wherein the retention time of 6.516 min corresponds to compound 3b; and

[0082] Figure 10 This is the NMR spectrum of compound 3b in Example 13 of the present invention. Detailed Implementation

[0083] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.

[0084] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.

[0085] In the following embodiments, the Raney copper is RTH-7110 type Raney copper produced by Dalian General Chemical Co., Ltd.

[0086] In the following examples, the Raney nickel is RTH-2110 type Raney nickel produced by Dalian General Chemical Co., Ltd.

[0087] In the following examples, NIS refers to N-iodosuccinimide.

[0088] In the following examples, IClPy refers to pyridine monoiodine chloride.

[0089] <Example 1>

[0090] A method for preparing 3-methyl-5-trifluoromethylaniline

[0091] This embodiment provides a method for preparing 3-methyl-5-trifluoromethylaniline, and the reaction formula is as follows:

[0092]

[0093] Includes the following steps:

[0094] 10 g of compound 4a (48.7 mmol, 1.0 eq), 1.0 g of Raney copper (10 wt%), and 100 mL of ethanol were added to a reaction vessel. The reaction system was heated to 70-75 °C, and under nitrogen protection, 5.0 g of hydrazine hydrate (100 mmol, 2.05 eq) was added dropwise. The reaction was maintained at 70-75 °C for 2 h. The mixture was filtered through a diatomaceous earth filter to remove the solvent. Extraction was performed with 100 mL of ethyl acetate and 150 mL of water. The organic phase was collected, washed with n-heptane to remove the solvent, yielding 8.25 g of compound 5a, with a yield of 96.7% and an HPLC purity of 98.0%. (HPLC chromatogram shown below) Figure 1 (As shown).

[0095] Furthermore, the metal catalyst can be recovered after the reaction is complete, retaining its catalytic activity and thus being recyclable.

[0096] <Comparative Example 1>

[0097] A method for preparing 3-methyl-5-trifluoromethylaniline

[0098] This embodiment provides a method for preparing 3-methyl-5-trifluoromethylaniline, and the reaction formula is as follows:

[0099]

[0100] Includes the following steps:

[0101] 10 g of compound 4a (48.7 mmol, 1.0 eq), 1.0 g of Raney nickel (10 wt%), and 100 mL of ethanol were added to a reaction vessel. The reaction system was heated to 70-75 °C, and under nitrogen protection, 5.0 g of hydrazine hydrate (100 mmol, 2.05 eq) was added dropwise. The temperature was maintained at 70-75 °C for 2 h. Samples were taken and sent for HPLC analysis. Figure 2 This is the HPLC chromatogram for this embodiment. (As shown...) Figure 2 As shown, the reaction system contains 4.6% compound 5a, 59.1% compound 4a, and 35.6% compound 4a'.

[0102] It is evident that the preparation of 3-methyl-5-trifluoromethylaniline using nickel-based catalysts is very ineffective, with very low levels of the target product, mainly consisting of unreacted nitro compounds and nitrosyl byproducts.

[0103] <Example 2>

[0104] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0105] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0106]

[0107] Includes the following steps:

[0108] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0109] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0110] Step 3: Control the temperature at 20℃-25℃, and add raw material solution B dropwise to raw material solution A while stirring. After the addition is complete, stir and react for 2 hours.

[0111] Step 4: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 27.5g of crude product. HPLC showed that in addition to compound 6a, the crude product contained an unknown impurity. The content of compound 6a (HPLC purity) was 85.2%, and the impurity content was 5.7%.

[0112] <Example 3>

[0113] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0114] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0115]

[0116] Includes the following steps:

[0117] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0118] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0119] Step 3: Control the temperature at 20℃-25℃, and add raw material solution A dropwise to raw material solution B while stirring. After the addition is complete, stir and react for 2 hours.

[0120] Step 4: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 26.1g of crude product. HPLC showed that in addition to compound 6a, the crude product contained two unknown impurities. The content of compound 6a was 80.0%, and the sum of the contents of the two impurities was 11.9%.

[0121] <Example 4>

[0122] A method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline

[0123] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylaniline, the reaction formula of which is as follows:

[0124]

[0125] Includes the following steps:

[0126] Step 1: Dissolve 17.6g ICl (108.5mmol, 0.95eq) in 100mL acetic acid to obtain raw material solution A;

[0127] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of acetic acid to obtain raw material solution B;

[0128] Step 3: Control the temperature at 20℃-25℃. While stirring, add raw material solution A dropwise to raw material solution B. After the addition is complete, stir and react for 1 hour. Then add 8.9g sodium acetate (108.5mmol, 0.95eq) and continue stirring and reacting for another hour.

[0129] Step 4: Quench the reaction with 50g of saturated sodium thiosulfate aqueous solution, add 250g of water and 250g of ethyl acetate, extract, collect the organic phase, concentrate under reduced pressure, wash with n-heptane, and dry to obtain 29.6g of crude product. The HPLC chromatogram of the crude product is shown below. Figure 3 As shown, the HPLC purity of compound 6a is 97.3%.

[0130] <Example 5>

[0131] Screening of iodination reaction conditions

[0132] This embodiment, based on Examples 2-3, screened the solvents and iodizing reagents used in the preparation method of 2-iodo-3-methyl-5-trifluoromethylaniline. The screening method is as follows:

[0133] Step 1: Dissolve the iodine reagent in 100 mL of solvent to obtain raw material solution A;

[0134] Step 2: Dissolve 20g of compound 5a (114.2mmol, 1.0eq) in 200mL of solvent to obtain raw material solution B;

[0135] Step 3: Control the temperature at 20℃-25℃, and add raw material solution B dropwise to raw material solution A while stirring. After the addition is complete, stir the reaction for 2 hours, take a sample and send it to HPLC for detection to determine the liquid phase yield (HPLC purity) of the product (compound 6a).

[0136] The method for calculating liquid phase yield is as follows:

[0137] Liquid phase yield = (peak area of ​​the product peak) / (sum of the areas of all peaks except the solvent peak) × 100%

[0138] The screening results are shown in Table 1.

[0139] Table 1

[0140] 1 NIS(1.1eq) Acetic acid 62.1％ 2 NIS(1.1eq) ethanol 23.1％ 3 NIS(1.1eq) Acetonitrile 22.2％ 4 NIS(1.1eq) dichloromethane 12.3％ 5 NIS(1.1eq) Acetic acid / toluene (1:1, v / v) 67.1％ 6 ICl(1.1eq) ethanol 23.4％ 7 IClPy(1.0eq) methanol 45.4％ 8 IClPy(1.0eq) Acetic acid 48.6％ 9 IClPy(1.0eq) Trifluoroacetic acid 20.4％

[0141] As can be seen from the table above, in addition to the conditions in Examples 2-4, this application has also explored a large number of iodination conditions. However, since the iodination reactions in the table generate a variety of iodinated isomers and polyiodinated products, good selectivity has not been demonstrated. Therefore, the liquid phase yield of the target compound, 2-iodo-3-methyl-5-trifluoromethylaniline, is below 70%.

[0142] <Example 6>

[0143] A method for preparing 2-iodo-3-methyl-5-trifluoromethylphenol

[0144] This embodiment provides a method for preparing 2-iodo-3-methyl-5-trifluoromethylphenol, and the reaction formula is as follows:

[0145]

[0146] Includes the following steps:

[0147] S1, 10g of compound 6a (33.2mmol, 1.0eq) was added to 100mL of 1mol / L sulfuric acid aqueous solution, cooled to -5℃, 8.8g of 30% sodium nitrite aqueous solution was added dropwise, the mixture was stirred for 1h, and 0.4g of urea was added to form a reaction solution;

[0148] S2, the reaction solution was added dropwise to 500 mL of 20% sulfuric acid aqueous solution preheated to 100 °C. After the addition was complete, the system temperature was lowered to 20 °C, 250 mL of dichloromethane was added, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to remove the solvent, yielding 9.0 g of compound 7a with a yield of 90.0% and an HPLC purity of 95.4%.

[0149] The HPLC and NMR spectra of compound 7a are shown below. Figure 4-5 .

[0150] <Example 7>

[0151] Screening of methods for preparing 2-iodo-3-methyl-5-trifluoromethylphenol

[0152] Based on Example 6, this embodiment screened the preparation method of 2-iodo-3-methyl-5-trifluoromethylphenol, and the steps are as follows:

[0153] S1, 10g of compound 6a (33.2mmol, 1.0eq) was added to 100mL of acid solution, cooled to -5℃, 8.8g of 30% sodium nitrite aqueous solution was added dropwise, the mixture was stirred for 1h, and 0.4g of urea was added to form a reaction solution;

[0154] S2, the reaction solution was added dropwise to 500 mL of quenching solution preheated to 100 °C. After the addition was complete, the system temperature was lowered to 20 °C, 250 mL of dichloromethane was added, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to remove the solvent, yielding 9.0 g of compound 7a, with a yield of 90.0%.

[0155] The screening results are shown in Table 2.

[0156] Table 2

[0157] 1 1 mol / L sulfuric acid + acetic acid (V / V = 1:1) water 85.2％ 2 1 mol / L sulfuric acid Toluene + Water (V / V = 3:5) 73.3％

[0158] As shown in the table above, the conversion from amino to phenolic hydroxyl groups can be achieved under various reaction conditions, with yields all exceeding 70%.

[0159] <Example 8>

[0160] Preparation of compound 1a

[0161] This embodiment provides a method for preparing compound 1a, and the reaction formula is as follows:

[0162]

[0163] Includes the following steps:

[0164] 10 g of compound 7a (33.1 mmol, 1.0 eq) and 10.8 g of cesium carbonate (33.1 mmol, 1.0 eq) were added to 100 mL of LDM. The temperature was maintained between 10 and 15 °C. 4.1 g of chloromethyl ethyl ether (43.0 mmol, 1.3 eq) was added dropwise. The mixture was stirred for 1 h while maintaining the temperature between 10 and 15 °C. 70 mL of n-heptane and 300 mL of water were added, and the mixture was extracted. The organic phase was collected, concentrated under reduced pressure, and subjected to column chromatography to give 11.2 g of compound 1a, with a yield of 93.9%.

[0165] <Example 9>

[0166] Preparation of compound 1b

[0167] This embodiment provides a method for preparing compound 1b, and the reaction formula is as follows:

[0168]

[0169] Includes the following steps:

[0170] 10 g of compound 7a (33.1 mmol, 1.0 eq) and 10.8 g of cesium carbonate (33.1 mmol, 1.0 eq) were added to 100 mL of LDM. The temperature was maintained between 10 and 15 °C. 3.5 g of chloromethyl methyl ether (43.0 mmol, 1.3 eq) was added dropwise. The mixture was stirred for 1 h while maintaining the temperature between 10 and 15 °C. 70 mL of n-heptane and 300 mL of water were added, and the mixture was extracted. The organic phase was collected, concentrated under reduced pressure, and subjected to column chromatography to give 9.6 g of compound 1b, with a yield of 84.0%.

[0171] <Example 10>

[0172] Preparation of compound 3a

[0173] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0174]

[0175] Includes the following steps:

[0176] S1, under nitrogen protection, 10.4 mL of tetrahydrofuran solution of isopropyl magnesium chloride (2 mol / L, 1.5 eq) was added to 10 mL of anhydrous tetrahydrofuran. The reaction system was cooled to -10℃ to -5℃, and tetrahydrofuran solution of compound 1a (5 g of compound 1a dissolved in 25 mL of anhydrous tetrahydrofuran, 13.9 mmol, 1.0 eq) was added dropwise. After the addition was complete, the temperature was controlled at -10℃ to -5℃ and stirred for 30 min. Then, 5.2 g of isopropanol pinacol boronic acid ester (27.8 mmol, 2.0 eq) was added dropwise, and the temperature was controlled at -30℃ to -25℃ and stirred for 30 min to obtain the reaction solution.

[0177] S2, with the temperature controlled at 20-25℃, add 5 mL of saturated ammonium chloride aqueous solution (prepared at 20℃) to the reaction solution, then add 30 mL of water and 30 mL of ethyl acetate, extract, take the organic phase, concentrate under reduced pressure, remove the solvent, add 15 mL of n-heptane, and beat at -40℃ for 30 min to obtain 4.34 g of compound 3a, with a yield of 86.3% and an HPLC purity of 98.5%.

[0178] The liquid phase spectrum and NMR spectrum of compound 3a are shown below. Figure 6-7 As shown.

[0179] <Example 11>

[0180] Preparation of compound 3'a

[0181] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0182]

[0183] Includes the following steps:

[0184] S1, under nitrogen protection, 10.4 mL of tetrahydrofuran solution of isopropyl magnesium chloride (2 mol / L, 1.5 eq) was added to 10 mL of anhydrous tetrahydrofuran. The reaction system was cooled to -10℃ to -5℃, and tetrahydrofuran solution of compound 1a (5 g of compound 1a dissolved in 25 mL of anhydrous tetrahydrofuran, 13.9 mmol, 1.0 eq) was added dropwise. After the addition was complete, the temperature was controlled at -10℃ to -5℃ and stirred for 30 min. Then, 5.2 g of isopropanol pinacol boronic acid ester (27.8 mmol, 2.0 eq) was added dropwise, and the temperature was controlled at -30℃ to -25℃ and stirred for 30 min to obtain the reaction solution.

[0185] S2, under controlled temperature of 45℃-50℃, add 5mL of saturated ammonium chloride aqueous solution (prepared at 20℃) to the reaction solution, stir for 30min, then add 30mL of water and 30mL of ethyl acetate, extract, take the organic phase, concentrate under reduced pressure, remove the solvent, add 15mL of n-heptane, and beat at -40℃ for 30min to obtain 4.0g of compound 3'a, yield 95.2%, HPLC purity 98.8%.

[0186] The liquid phase spectrum of compound 3'a is as follows: Figure 8 As shown.

[0187] <Example 12>

[0188] Preparation methods of compounds 3a and 3'a

[0189] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0190]

[0191] Includes the following steps:

[0192] S1, under nitrogen protection, 10.4 mL of tetrahydrofuran solution of isopropyl magnesium chloride (2 mol / L, 1.5 eq) was added to 10 mL of anhydrous tetrahydrofuran. The reaction system was cooled to -10℃ to -5℃, and tetrahydrofuran solution of compound 1a (5 g of compound 1a dissolved in 25 mL of anhydrous tetrahydrofuran, 13.9 mmol, 1.0 eq) was added dropwise. After the addition was complete, the temperature was controlled at -10℃ to -5℃ and stirred for 30 min. Then, 5.2 g of isopropanol pinacol boronic acid ester (27.8 mmol, 2.0 eq) was added dropwise, and the temperature was controlled at -30℃ to -25℃ and stirred for 30 min to obtain the reaction solution.

[0193] S2, temperature controlled at 35℃-40℃, add 5mL of saturated ammonium chloride aqueous solution (prepared at 20℃) to the reaction solution, stir for 30min, then add 30mL of water and 30mL of ethyl acetate, extract, take the organic phase, concentrate under reduced pressure to obtain 4.88g of crude product, HPLC analysis shows that the crude product is mainly a mixture of compound 3a and compound 3'a;

[0194] S3, 2.44 g of crude product and 2.26 g of cesium carbonate were added to 25 mL of DMF, and the temperature was controlled between 10-15 °C. 0.85 g of chloromethyl ethyl ether was added dropwise, and the mixture was stirred at 10-15 °C for 1 h. 18 mL of n-heptane and 75 mL of water were added, and the mixture was extracted. The organic phase was collected, concentrated under reduced pressure, and subjected to column chromatography to obtain 2.23 g of compound 3a.

[0195] S4, 2.44 g of crude product was dissolved in 80 mL of dichloromethane, the temperature was controlled at 0 °C, 15 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred for 30 min. The solvent was removed by concentration under reduced pressure to obtain 1.97 g of compound 3'a.

[0196] <Example 13>

[0197] Preparation of compound 3b

[0198] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0199]

[0200] Includes the following steps:

[0201] S1, under nitrogen protection, 10.4 mL of tetrahydrofuran solution of isopropyl magnesium chloride (2 mol / L, 1.5 eq) was added to 10 mL of anhydrous tetrahydrofuran. The reaction system was cooled to -10℃ to -5℃, and tetrahydrofuran solution of compound 1a (5 g of compound 1a dissolved in 25 mL of anhydrous tetrahydrofuran, 13.9 mmol, 1.0 eq) was added dropwise. After the addition was complete, the temperature was controlled at -10℃ to -5℃ and stirred for 30 min. Then, 2.89 g of trimethyl borate (27.8 mmol, 2.0 eq) was added dropwise, and the temperature was controlled at -30℃ to -25℃ and stirred for 30 min to obtain the reaction solution.

[0202] S2, at a controlled temperature of 25℃, 5 mL of saturated ammonium chloride aqueous solution (prepared at 20℃) was added to the reaction solution, followed by 30 mL of water and 30 mL of ethyl acetate. Extraction was performed, the organic phase was collected, concentrated under reduced pressure, the solvent was removed, 15 mL of n-heptane was added, and the mixture was stirred at -40℃ for 30 min to obtain 3.33 g of compound 3b, with a yield of 86.2% and an HPLC purity of 98.3%.

[0203] The liquid phase spectrum and NMR spectrum of compound 3b are shown below. Figure 9-10 As shown.

[0204] The role and effect of the embodiments

[0205] According to the preparation method of boric acid derivatives involved in the above embodiments, since an alkyl Grignard reagent is used as a base, the present invention not only does not require the use of expensive palladium catalysts, but also reduces the reaction time to 1 hour and improves the yield.

[0206] Furthermore, because the temperature is controlled at 45-100℃ during the quenching reaction, the ethoxymethyl group can be directly removed during the post-processing, thereby obtaining the hydroxyl-unprotected boric acid derivative in high yield and saving production steps.

[0207] The embodiments provided above are not intended to limit the scope of the invention, nor are the described steps intended to limit the order of execution. Any obvious modifications made to the invention by those skilled in the art based on existing common knowledge also fall within the scope of protection defined by the claims.

Claims

1. A method for preparing a boric acid derivative, characterized in that, The reaction formula is as follows: In the formula, PG is ethoxymethyl; R is a C1-C5 alkoxy group; R1 and R2 are bonded to their adjacent atoms to form a ring, which is a borate ester ring; Includes the following steps: In the presence of alkyl magnesium chloride and a solvent, compound 1 reacts with compound 2 to form a reaction solution. A quencher is added to the reaction solution, and the temperature of the reaction solution is controlled at 45℃-100℃ during the quenching process. After purification, compound 3' is obtained. The quenching agent is a saturated aqueous solution of ammonium chloride.

2. The method for preparing boric acid derivatives according to claim 1, characterized in that: in, The compound 2 is .

3. The method for preparing boric acid derivatives according to claim 1, characterized in that: in, The alkyl magnesium chloride is isopropyl magnesium chloride.

4. The method for preparing the boric acid derivative according to claim 1, Its features are, The reaction formula for the preparation method of compound 1 is as follows: Includes the following steps: a. At least in the presence of a reducing agent, compound 4 is converted into compound 5; b. In the presence of an iodine reagent, compound 5 is converted into compound 6; c. Compound 6 is converted into the corresponding diazonium salt and then hydrolyzed to obtain compound 7; d. Compound 7 reacts with a hydroxyl protecting agent to give compound 1; In step a, compound 4 is converted into compound 5 in the presence of a reducing agent and a catalyst. The reducing agent is hydrazine or hydrated hydrazine, and the catalyst is Raney copper.

5. The method for preparing the boric acid derivative according to claim 4, characterized in that, in, The iodizing reagent mentioned in step b is ICl.

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