CN114380853A - Preparation method of 4-pyrazole boronic acid pinacol ester - Google Patents

Preparation method of 4-pyrazole boronic acid pinacol ester Download PDF

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CN114380853A
CN114380853A CN202210042801.9A CN202210042801A CN114380853A CN 114380853 A CN114380853 A CN 114380853A CN 202210042801 A CN202210042801 A CN 202210042801A CN 114380853 A CN114380853 A CN 114380853A
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reaction
boronic acid
pinacol ester
stirring
acid pinacol
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王坤鹏
韩月林
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Nanjing Huanran Bio Tech Co ltd
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Nanjing Huanran Bio Tech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Abstract

The invention relates to a preparation method of 4-pyrazole boronic acid pinacol ester, in particular to a preparation method which takes p-phenylenediamine as a raw material and efficiently synthesizes the 4-pyrazole boronic acid pinacol ester through four steps of protection, acylation, cyclization and deprotection.

Description

Preparation method of 4-pyrazole boronic acid pinacol ester
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of 4-pyrazole boronic acid pinacol ester.
Background
4-pyrazole boronic acid pinacol ester is used as an important organic boric reagent in an organic synthesis process and a chemical medicine research and development process, and is mainly used as one of main raw materials in synthesizing oral JAK kinase 1 and JAK kinase 2 inhibitors Baricitinib.
The main synthetic route of the 4-pyrazole boronic acid pinacol ester is as follows:
the method comprises the following steps:
Figure DEST_PATH_IMAGE002A
in the methods disclosed in CN108997309 and CN113336751, 4-bromo-1H-pyrazole is used as a starting material, and boronized to obtain the target product. The raw materials used in the method are expensive, and the industrial significance is not great.
The method 2 comprises the following steps:
Figure DEST_PATH_IMAGE004A
preshlock et al disclose a method in which 1H-pyrazole is used as a starting material and boronated to obtain the target product. The method needs methoxy (cyclooctadiene) iridium (I) dimer and 3,4,7, 8-tetramethyl-1, 10-phenanthroline as catalysts, and has the advantages of high price, large usage amount and no economic significance.
Disclosure of Invention
Aiming at the problems, the invention discloses a preparation method of 4-pyrazole boronic acid pinacol ester, and particularly relates to a preparation method of 4-pyrazole boronic acid pinacol ester, which is prepared from malonaldehyde serving as a raw material through four steps of protective bromination, methyl vulcanization, cyclization and boronation.
The reaction equation is as follows:
Figure DEST_PATH_IMAGE006A
the technical scheme for solving the technical problems is as follows:
(1) adding a solvent I into a reaction bottle, adding 1.3-2.0mol of ethylene glycol, 1.0mol of a catalyst and 1.0mol of malonaldehyde into the reaction bottle under stirring, and heating to 110 ℃ for water separation reaction. After confirming the completion of the reaction, the reaction mixture was cooled to room temperature, water was added thereto, the mixture was stirred, and then liquid was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Adding chloroform, stirring for dissolving, adding 1.1-1.5mol of NBS and 0.2g of benzoyl peroxide, and heating to 40-70 ℃ for reaction. Cooling to room temperature after complete reaction, filtering, adding water for washing, drying an organic phase by using anhydrous sodium sulfate, concentrating to be dry, dissolving by using methyl tert-butyl ether, filtering, and concentrating the filtrate under reduced pressure to be dry to obtain an intermediate I;
(2) adding a solvent II into a reaction bottle, adding 0.8-1.5mol of sodium methyl mercaptide and 0.78-0.84mol of an intermediate I into the reaction bottle under stirring, keeping the reaction at 30-80 ℃ until the reaction is complete, concentrating the reaction product under reduced pressure until the reaction product is dry, adding dichloromethane and water, stirring the reaction product, separating the reaction product, drying an organic phase, and concentrating the organic phase under reduced pressure until the reaction product is dry to obtain an intermediate II;
(3) adding a solvent III and water into a reaction bottle, adding 0.8-1.3mol of cyclization reagent while stirring, and stirring for dissolving. Dissolving 0.73-0.78mol of the intermediate II into a solvent III, and dropwise adding the solution into a reaction bottle at the temperature of 20-70 ℃. After the dropwise addition, the reaction is completed, the solvent III is evaporated, the residue is cooled to room temperature, is neutralized to pH =8 by sodium bicarbonate, is extracted by methyl tert-butyl ether, and is dried and then is concentrated under reduced pressure to be dry, so that an intermediate III is obtained;
(4) introducing nitrogen into a reaction bottle, adding a solvent IV, sequentially adding 0.61-0.64mol of an intermediate III, 0.9-1.3 mol of alkali, 1.2-2.4mol of diamyl diboron and palladium triphenylphosphine chloride under stirring, reacting at 50-90 ℃, concentrating after the reaction is finished, stirring and separating with ethyl acetate and water, drying, decoloring, concentrating and crystallizing, filtering and drying to obtain the 4-pyrazole pinacol borate.
In the step (1), the solvent I is one of toluene and xylene.
The catalyst in the step (1) is one of p-toluenesulfonic acid and sulfuric acid. The mass of the catalyst is 5-15% of that of the malonaldehyde.
In the step (2), the solvent II is one of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
In the step (3), the solvent III is one of methanol, ethanol and isopropanol.
And (3) the cyclization reagent is one of hydrazine sulfate, hydrazine hydrate and hydrazine hydrochloride.
In the step (4), the solvent IV is one of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
In the step (4), the alkali is one of sodium acetate, triethylamine and N, N-diisopropyl isopropylamine. The mass of the triphenylphosphine palladium chloride is 1-3% of that of the intermediate III.
The preparation method of the 4-pyrazole boronic acid pinacol ester has the advantages that:
1) the steps are short;
2) the three wastes are less;
3) the cost is low and the yield is high;
4) the product quality is good.
Detailed Description
The present invention is further illustrated by the following specific examples.
Example 1
A preparation method of 4-pyrazole boronic acid pinacol ester specifically comprises the following steps:
(1) 1000ml of toluene is added into a reaction bottle, 124g of ethylene glycol, 10.8g of p-toluenesulfonic acid and 72.0g of malonaldehyde are added under stirring, and the temperature is raised to 110 ℃ for water-sharing reaction for 6 hours. After completion of the reaction was confirmed, the reaction mixture was cooled to room temperature, 400ml of water was added, followed by stirring, liquid separation, drying over anhydrous sodium sulfate, and concentration under reduced pressure to dryness. Adding 700ml of chloroform, stirring and dissolving, adding 195.8g of NBS and 0.2g of benzoyl peroxide, heating to 40-50 ℃ and reacting for 8 hours. After the reaction is completed, the temperature is reduced to room temperature, the mixture is filtered, water is added for washing by 300ml, an organic phase is dried by anhydrous sodium sulfate and concentrated to be dry, the organic phase is dissolved by 500ml of methyl tert-butyl ether and filtered, filtrate is concentrated to be dry under reduced pressure, and intermediate I, 193.9g of orange viscous liquid and the yield of 81.1 percent are obtained.
(2) Adding 600ml of tetrahydrofuran into a reaction bottle, adding 56.1g of sodium methyl mercaptide and 193.9g of intermediate I under stirring, heating to 30-40 ℃, reacting for 24 hours under heat preservation, and concentrating under reduced pressure until the mixture is dry. 1000ml of methylene chloride and 300ml of water were added, followed by stirring, liquid separation, drying of the organic phase and concentration under reduced pressure to dryness to give intermediate II, an orange-yellow viscous liquid 151.0g, yield 90.3%.
(3) 400ml of methanol and 800ml of water are added into a reaction bottle, 104.1g of hydrazine sulfate is added under stirring, and the mixture is stirred until the mixture is clear. And (3) dissolving 151.0g of the intermediate II in 300ml of methanol, dropwise adding the solution into a reaction bottle at the temperature of 20-30 ℃, and reacting for 24 hours after dropwise adding. Methanol was evaporated under reduced pressure, the residue was cooled to room temperature, neutralized with sodium bicarbonate to pH =8, extracted with 800ml of methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give intermediate iii as a pale yellow solid 82.8g, yield 88.3%.
(4) Introducing nitrogen into a reaction bottle, adding 500ml of tetrahydrofuran, sequentially adding 82.8g of intermediate III, 73.8g of sodium acetate, 307.1g of boron diamyl chloride and 2.5g of palladium chloride triphenylphosphine under stirring, stirring for 30 minutes after adding, and heating to 50-60 ℃ for reaction for 20 hours. Cooling to room temperature, concentrating under reduced pressure to be viscous, stirring and separating by using 600ml of ethyl acetate and 300ml of water, drying, decoloring, concentrating and crystallizing, filtering and drying to obtain the 4-pyrazole pinacol ester borate, wherein the yield is 90.9 percent, and the off-white powder is 113.8g, MP =148 and 149 ℃.1H NMR (300 MHz, CDCl3) δ 7.89 (s, 2H), 1.33 (s, 12H).
Example 2
A preparation method of 4-pyrazole boronic acid pinacol ester specifically comprises the following steps:
(1) 800ml of toluene is added into a reaction bottle, 99.2g of ethylene glycol, 7.2g of p-toluenesulfonic acid and 72.0g of malonaldehyde are added under stirring, and the temperature is raised to 110 ℃ for water-sharing reaction for 6 hours. After completion of the reaction was confirmed, the reaction mixture was cooled to room temperature, 400ml of water was added, followed by stirring, liquid separation, drying over anhydrous sodium sulfate, and concentration under reduced pressure to dryness. Adding 700ml of chloroform, stirring and dissolving, adding 231.4g of NBS and 0.2g of benzoyl peroxide, and heating to 50-60 ℃ for reaction for 8 hours. After the reaction is completed, the temperature is reduced to room temperature, the mixture is filtered, 300ml of water is added for washing, an organic phase is dried by anhydrous sodium sulfate and concentrated to be dry, the organic phase is dissolved by 500ml of methyl tert-butyl ether and then filtered, and filtrate is concentrated to be dry under reduced pressure to obtain 187.6g of orange viscous liquid as intermediate I, wherein the yield is 78.5%.
(2) Adding 800ml of dioxane into a reaction bottle, adding 84.1g of sodium methyl mercaptide and 187.6g of intermediate I under stirring, heating to 40-50 ℃, reacting for 16 hours under heat preservation, and concentrating under reduced pressure until the mixture is dry. 1000ml of methylene chloride and 300ml of water were added, followed by stirring, liquid separation, drying of the organic phase and concentration to dryness under reduced pressure to give 157.8g of an orange-yellow viscous liquid as intermediate II in a yield of 94.3%.
(3) 500ml of ethanol and 800ml of water were put into a reaction flask, and 64.7g of hydrazine hydrate of 85% concentration was added with stirring and stirred until it became clear. 157.8g of the intermediate II is dissolved in 400ml of ethanol, and the mixture is dripped into a reaction bottle at the temperature of 40-50 ℃ and reacts for 24 hours after the dripping is finished. Ethanol was evaporated under reduced pressure, the residue was cooled to room temperature, neutralized with sodium bicarbonate to pH =8, extracted with 800ml of methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to give intermediate iii as a pale yellow solid 77.6g, yield 79.1%.
(4) Introducing nitrogen into a reaction bottle, adding 700ml of dioxane, sequentially adding 77.6g of intermediate III, 111.1g of triethylamine, 435.2g of bis (valeryl) diboron and 1.6g of palladium chloride triphenylphosphine under stirring, stirring for 30 minutes after the addition is finished, and heating to 80-90 ℃ for reaction for 12 hours. Cooling to room temperature, concentrating under reduced pressure to be viscous, stirring and separating by using 600ml of ethyl acetate and 300ml of water, drying, decoloring, concentrating and crystallizing, filtering and drying to obtain the 4-pyrazole boronic acid pinacol ester, namely 106.9g of off-white powder with the yield of 91.2%.
Example 3
A preparation method of 4-pyrazole boronic acid pinacol ester specifically comprises the following steps:
(1) 600ml of xylene is added into a reaction bottle, 80.6g of ethylene glycol, 3.6g of sulfuric acid and 72.0g of malonaldehyde are added under stirring, and the temperature is raised to 110 ℃ for water-sharing reaction for 6 hours. After completion of the reaction was confirmed, the reaction mixture was cooled to room temperature, 400ml of water was added, followed by stirring, liquid separation, drying over anhydrous sodium sulfate, and concentration under reduced pressure to dryness. Adding 700ml of chloroform, stirring and dissolving, adding 267.1g of NBS and 0.2g of benzoyl peroxide, heating to 60-70 ℃ and reacting for 8 hours. After the reaction is completed, the temperature is reduced to room temperature, the mixture is filtered, water is added for washing by 300ml, an organic phase is dried by anhydrous sodium sulfate and concentrated to be dry, the organic phase is dissolved by 500ml of methyl tert-butyl ether and filtered, filtrate is concentrated to be dry under reduced pressure, and intermediate I, 198.8g of orange viscous liquid and 83.2% of yield are obtained.
(2) Adding 1000ml of 2-methyltetrahydrofuran into a reaction bottle, adding 105.0g of sodium methyl mercaptide and 198.8g of intermediate I under stirring, heating to 70-80 ℃, reacting for 6 hours under heat preservation, and concentrating under reduced pressure to dryness. 1000ml of dichloromethane and 300ml of water were added, the mixture was stirred, separated, the organic phase was dried and concentrated to dryness under reduced pressure to give intermediate II, an orange-yellow viscous liquid 158.3g, a yield of 92.2%.
(3) 700ml of isopropanol and 800ml of water are added into a reaction bottle, 136.3g of hydrazine hydrochloride is added under stirring, and the mixture is stirred until the solution is clear. 158.3g of the intermediate II is dissolved in 400ml of isopropanol, and the mixture is dripped into a reaction bottle at the temperature of 60-70 ℃ and reacts for 12 hours after the dripping is finished. The isopropanol was evaporated under reduced pressure and the residue was cooled to room temperature, neutralized to pH =8 with sodium bicarbonate, extracted with 800ml of methyl tert-butyl ether, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give intermediate iii as a pale yellow solid 78.4g with a yield of 79.7%.
(4) Introducing nitrogen into a reaction bottle, adding 800ml of 2-methyltetrahydrofuran, sequentially adding 78.4g of intermediate III, 167.7g of N, N-diisopropylethylamine, 614.2g of diamyl diboron and 0.8g of palladium chloride triphenylphosphine under stirring, stirring for 30 minutes after adding, and heating to 70-80 ℃ for reacting for 24 hours. Cooling to room temperature, concentrating under reduced pressure to be viscous, stirring and separating by using 600ml of ethyl acetate and 300ml of water, drying, decoloring, concentrating and crystallizing, filtering and drying to obtain the 4-pyrazole boronic acid pinacol ester with 106.7g of off-white powder and 89.8% of yield.

Claims (10)

1. A preparation method of 4-pyrazole boronic acid pinacol ester is characterized by comprising the following steps: the method specifically comprises the following steps:
adding a solvent I into a reaction bottle, adding 1.3-2.0mol of ethylene glycol, 1.0mol of a catalyst and 1.0mol of malonaldehyde under stirring, and heating to 110 ℃ for water-splitting reaction; after the reaction is confirmed to be complete, cooling to room temperature, adding water, stirring, separating liquid, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to dryness; adding chloroform, stirring for dissolving, adding 1.1-1.5mol of NBS and 0.2g of benzoyl peroxide, and heating to 40-70 ℃ for reaction; cooling to room temperature after complete reaction, filtering, adding water for washing, drying an organic phase by using anhydrous sodium sulfate, concentrating to be dry, dissolving by using methyl tert-butyl ether, filtering, and concentrating the filtrate under reduced pressure to be dry to obtain an intermediate I;
adding a solvent II into a reaction bottle, adding 0.8-1.5mol of sodium methyl mercaptide and 0.78-0.84mol of an intermediate I into the reaction bottle under stirring, keeping the reaction at 30-80 ℃ until the reaction is complete, concentrating the reaction product under reduced pressure until the reaction product is dry, adding dichloromethane and water, stirring the reaction product, separating the reaction product, drying an organic phase, and concentrating the organic phase under reduced pressure until the reaction product is dry to obtain an intermediate II;
adding a solvent III and water into a reaction bottle, adding 0.8-1.3mol of cyclization reagent while stirring, and stirring for dissolving; dissolving 0.73-0.78mol of the intermediate II into a solvent III, and dropwise adding the solution into a reaction bottle at the temperature of 20-70 ℃; after the dropwise addition, the reaction is completed, the solvent III is evaporated, the residue is cooled to room temperature, is neutralized to pH =8 by sodium bicarbonate, is extracted by methyl tert-butyl ether, and is dried and then is concentrated under reduced pressure to be dry, so that an intermediate III is obtained;
introducing nitrogen into a reaction bottle, adding a solvent IV, sequentially adding 0.61-0.64mol of an intermediate III, 0.9-1.3 mol of alkali, 1.2-2.4mol of diamyl diboron and palladium triphenylphosphine chloride under stirring, reacting at 50-90 ℃, concentrating after the reaction is finished, stirring and separating with ethyl acetate and water, drying, decoloring, concentrating and crystallizing, filtering and drying to obtain the 4-pyrazole pinacol borate.
2. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (1), the solvent I is one of toluene and xylene.
3. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: the catalyst in the step (1) is one of p-toluenesulfonic acid and sulfuric acid.
4. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: the mass of the catalyst in the step (1) is 5-15% of that of the malonaldehyde.
5. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (2), the solvent II is one of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
6. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (3), the solvent III is one of methanol, ethanol and isopropanol.
7. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: and (3) the cyclization reagent is one of hydrazine sulfate, hydrazine hydrate and hydrazine hydrochloride.
8. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (4), the solvent IV is one of tetrahydrofuran, dioxane and 2-methyltetrahydrofuran.
9. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (4), the alkali is one of sodium acetate, triethylamine and N, N-diisopropyl isopropylamine.
10. The method for producing 4-pyrazole boronic acid pinacol ester according to claim 1, characterized in that: in the step (4), the mass of the palladium chloride triphenylphosphine is 1-3% of that of the intermediate III.
CN202210042801.9A 2022-01-14 2022-01-14 Preparation method of 4-pyrazole boronic acid pinacol ester Pending CN114380853A (en)

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Application publication date: 20220422