A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester

Abstract

The present invention relates to a method for synthesizing 1 (3-oxetanes) 1H-pyrazoles 4-boronic acid pinacol esters, comprising the following steps: 1. using 3-iodooxetanes and 4-bromo-1H-pyrazoles as raw materials, N-alkylation reaction occurs in the presence of a weak base to generate an intermediate 4-bromo-1 (oxetanes 3-base) 1H-pyrazoles; 2. after the intermediate reacts with a strong base, triisopropyl borate is added and reacts at low temperature for a period of time, 2,3-dimethylbutane-2,3-diol is added to fully react, the reaction solution is quenched, washed, extracted with ethyl acetate, concentrated, and purified by recrystallization to obtain a qualified purity product. The inventive method provides a synthesis technique with economical raw materials, high reaction yield, and easy pilot scale amplification in post-processing, mainly solving the problems that existing route raw materials are uneconomical, low yield, post-processing requires column separation, etc. are not suitable for pilot scale amplification.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a compound, and in particular to a method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester. Background Art

[0002] 1-(3-Oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester is an important drug building block and can be used to synthesize bioactive molecules such as BTK inhibitors (US2016 / 96834), CSF-1R inhibitors (US2020 / 71302), compounds for treating hepatitis B virus infection (WO2018 / 144605), JAK2 inhibitors (WO2019034973), and TBK1 inhibitors (WO2013075785). Currently, there is no process route that can be used for pilot-scale expansion.

[0003] There are few reported processes for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester. Some existing synthesis methods utilize pyrazole-4-boronic acid pinacol ester and oxetane-3-ol as raw materials, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine as reagents, and react in THF to obtain the final product. The raw material pyrazole-4-boronic acid pinacol ester is relatively expensive, the reaction time is long, and the post-processing steps are not suitable for pilot production.

[0004] Some methods involve reacting pyrazole-4-boronic acid pinacol ester and sodium hydride in DMF for 10 minutes, then cooling to 0°C. A DMF solution of oxetane-3-yl methanesulfonate is then added, followed by reaction at 100°C for more than 20 hours. The final product is purified by column chromatography with a yield of 13%. This route also uses the relatively expensive raw material pyrazole-4-boronic acid pinacol ester and requires column chromatography for post-processing, resulting in a very low yield and, therefore, unsuitable for pilot production. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester. The raw materials and reagents used in the method are economical and easily available, the reaction by-products are small, the yield is high, the post-processing is simple, the production is easy to scale up, and the cost is low.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester comprises the following specific steps:

[0008] 1. Using 3-iodooxetane and 4-bromo-1H-pyrazole as raw materials, an N-alkylation reaction occurs in the presence of a weak base and an acidic agent to produce the intermediate 4-bromo-1-(oxetane-3-yl)-1H-pyrazole. After quenching, extraction, drying, and concentration, the solid is slurried to obtain a compound that can be used in the next reaction.

[0009] 2. After the intermediate 4-bromo-1-(oxetane-3-yl)-1H-pyrazole reacts with a strong base, triisopropyl borate is added and the reaction is carried out at a low temperature for a period of time. Then, 2,3-dimethylbutane-2,3-diol is added. After the temperature is raised to 20°C and the reaction is continued for more than 10 hours, the reaction solution is quenched with NH4Cl solution, washed, extracted with ethyl acetate, concentrated, and recrystallized to obtain a product of qualified purity.

[0010] Preferably, in step 1, the feed ratio of 3-iodooxetane and 4-bromo-1H-pyrazole is 1.0-1.3; the weak base is at least one of potassium carbonate, cesium carbonate, potassium tert-butoxide and sodium hydride; the feed ratio of base to 3-iodooxetane is 1.2-1.4; the solvent is at least one of 1,4-dioxane, toluene, tetrahydrofuran, methanol, N,N-dimethylformamide and dimethyl sulfoxide; the reaction temperature is 20-100° C.; and the reaction time is 2-8 hours.

[0011] Preferably, in step 2, the feed ratio of 4-bromo-1-(oxetane-3-yl)-1H-pyrazole and the strong base is 1:2 to 1.6; the strong base is at least one of n-butyl lithium, isobutyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (HMDSLi); the feed ratio of 4-bromo-1-(oxetane-3-yl)-1H-pyrazole and triisopropyl borate is 1:2 to 1.6. .0~1.3; the feed ratio of 4-bromo-1-(oxetane-3-yl)-1H-pyrazole to 2,3-dimethylbutane-2,3-diol is 1.0~1.3; the solvent is at least one of 1,4-dioxane, toluene, tetrahydrofuran, methanol, N,N-dimethylformamide and dimethyl sulfoxide; the recrystallization solvent is at least one of n-hexane, petroleum ether, dichloromethane and ethyl acetate; the temperature is 0-20℃.

[0012] Compared with the prior art, the present invention has the following advantages: the process raw materials and reagents used in the present invention are economical and readily available, the reaction by-products are few, the yield is high, the two-step reaction post-processing is simple, and the process is suitable for pilot scale-up. The present invention is an economical and feasible process for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The following is a reaction flow chart for the synthesis of 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester;

[0014] Figure 2 The following is a flow chart showing a comparative case of the synthesis reaction of 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester;

[0015] 1 is: 2 is: 3 is: 4 is: 5 is: 6 is: 7 is: DETAILED DESCRIPTION

[0016] The above scheme is further described below with reference to specific examples. It should be understood that these examples are used to illustrate the present invention and are not intended to limit the scope of the present invention. The following examples are helpful in understanding the content of the present invention, and the present invention includes but is not limited to the following related contents:

[0017] Example 1:

[0018] like Figure 1 As shown, the first step is to a mixed solution of 3-iodooxetane (1) (1.00 kg, 5.44 mol) and 4-bromo-1H-pyrazole (2) (0.79 kg, 5.44 mol) in DMF (10.0 L), maintaining the reaction temperature at 30°C, and adding Cs2CO3 (2.13 kg, 6.53 mol) in batches over 2 hours. The reaction solution is heated to 80°C and reacted for 4 hours. Thin layer chromatography shows that compound (1) is completely consumed and a new product spot is formed. The reaction mixture is cooled to room temperature and filtered. The filter cake is washed twice with ethyl acetate. The filtrate is then divided into three batches and quenched with water. The filtrate is extracted with ethyl acetate (10.00 L*2). The organic layer is washed with saturated salt water and dried over anhydrous Na2SO4. The concentrated solid is slurried with petroleum ether (5.00 L) at room temperature for 4 hours to obtain compound (3) as a yellow solid (0.80 kg, 3.98 mol, yield 73.2%). 1 H NMR (400MHz, CDCl3): δ4.92-5.10(m,4H),5.37-5.48(m,1H),7.56(s,1H)and 7.62(s,1H).

[0019] Step 2: Under N2 atmosphere, the THF solvent of compound (3) (1.50 kg, 7.39 mol) was cooled to -60℃~-70℃ and then n-BuLi solution in n-hexane (2.5 M, 4.43 L) was added dropwise. The reaction mixture was kept at low temperature for 2 hours, and then triisopropyl borate (1.53 kg, 8.13 mol) was slowly added. The reaction was kept at -60~-70℃ for another 2 hours. 2,3-Dimethylbutane-2,3-diol (0.96 kg, 8.13 mol) was added to the reaction system at low temperature, and then the temperature was slowly raised to 30℃ and the reaction was continued for 10 hours. Thin layer chromatography showed that the intermediate (3) had been consumed and a new product was generated. The reaction solution was quenched with NH4Cl aqueous solution and the pH was adjusted to 6~7. It was stirred at 25℃ for 2 hours, and then the water layer was added. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated. The combined crude products were recrystallized from petroleum ether to obtain compound (4) as a yellow solid (1.13 g, 4.51 mol, yield 61.0%). 1 H NMR, (400Hz, CDCl3) δ7.89(s,1H),7.86(s,1H),5.44-5.51(m,1H),5.03-5.01(m,4H),1.32(s,12H).

[0020] Comparative Example 1:

[0021] like Figure 2 As shown, the first step is to a mixed solution of 4-bromo-1h-pyrazole (1.0 g, 6.80 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) in DMF (10.0 L), maintained at 25°C and under a N2 atmosphere, KOAc (2.0 g, 20.41 mmol) and Pd(dppf)Cl2·CH2Cl2 (278 mg, 0.34 mmol) were added in sequence. The reaction solution was heated to 100°C and reacted for 16 hours. Thin layer chromatography showed that compound (2) was completely consumed and a new product spot was formed. The reaction solution was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate / hexane as eluent to obtain compound (6) as a yellow solid (330 mg, 1.55 mmol, yield 25%). 1 H NMR (400MHz, CDCl3): δ7.90 (s, 2H), 1.33 (s, 12H).

[0022] Step 2: Compound (6) (3.88 g, 20.0 mmol), oxadiazol-3-ol (1.78 g, 48.0 mmol), and triphenylphosphine (6.29 g, 24.0 mmol) were dissolved in THF (40 ml). Diisopropyl azodicarboxylate (4.76 ml, 24.0 mmol) was added dropwise at 0°C under a N2 atmosphere, and the reaction solution was reacted at 25°C for 16 hours. 1.78 g (48.0 mmol) of oxadiazol-3-ol, triphenylphosphine (6.29 g, 24.0 mmol), and diisopropyl azodicarboxylate (3.00 ml, 15.1 mmol) were then added in sequence, and the reaction was continued at 25°C for 3 days. Thin layer chromatography showed that compound (2) was completely consumed and a new product spot was formed. The reaction mixture was concentrated and filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography using cyclohexane / ethyl acetate as the eluent to obtain compound (4) as a yellow solid (1.75 g, 6.99 mmol, yield 35.0%). 1H NMR, (400 Hz, CDCl3) δ 7.89 (s, 1H), 7.86 (s, 1H), 5.44-5.51 (m, 1H), 5.03-5.01 (m, 4H), 1.32 (s, 12H).

Claims

1. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester, characterized in that: The following steps are involved: 1) using 3-iodooxetane and 4-bromo-1H-pyrazole as raw materials, an N-alkylation reaction occurs in the presence of Cs2CO3 at a temperature of 80°C for 4 hours to produce the intermediate 4-bromo-1-(oxetane-3-yl)-1H-pyrazole. The solid is quenched, extracted, dried, and concentrated, and slurried to obtain a compound that can be used in the next reaction; 2) After the intermediate 4-bromo-1-(oxetane-3-yl)-1H-pyrazole is reacted with a strong base at -60°C to -70°C, triisopropyl borate is added and the reaction is carried out at low temperature for a period of time, and then 2,3-dimethylbutane-2,3-diol is added. After the temperature is raised to 20°C and the reaction is carried out for more than 10 hours, the reaction solution is quenched with NH4Cl solution, washed, extracted with ethyl acetate, concentrated, and recrystallized to obtain a product of qualified purity. The strong base is at least one of n-butyllithium, isobutyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, and lithium hexamethyldisilazide.

2. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1, characterized in that: In step 1), the feed ratio of the 3-iodooxetane to the 4-bromo-1H-pyrazole is 1.0 to 1.

3.

3. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that, In step 1), the feed ratio of Cs2CO3 to 3-iodooxetane is 1.2 to 1.

4.

4. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that, In step 1), the solvent is at least one of 1,4-dioxane, toluene, tetrahydrofuran, methanol, N,N-dimethylformamide and dimethyl sulfoxide; the reaction temperature is 20-100° C.; and the reaction time is 2-8 hours.

5. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that, In step 2), the feed ratio of the 4-bromo-1-(oxetane-3-yl)-1H-pyrazole to the strong base is 1:2 to 1.

6.

6. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that, In step 2), the feed ratio of the 4-bromo-1-(oxetane-3-yl)-1H-pyrazole to the triisopropyl borate is 1.0 to 1.

3.

7. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that: In step 2), the feed ratio of the 4-bromo-1-(oxetane-3-yl)-1H-pyrazole to the 2,3-dimethylbutane-2,3-diol is 1.0 to 1.

3.

8. A method for synthesizing 1-(3-oxetanyl)-1H-pyrazole-4-boronic acid pinacol ester according to claim 1 or 2, characterized in that: In step 2), the solvent is at least one of 1,4-dioxane, toluene, tetrahydrofuran, methanol, N,N-dimethylformamide and dimethyl sulfoxide; and the recrystallization solvent is at least one of n-hexane, petroleum ether, dichloromethane and ethyl acetate.

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