Preparation method of 2-formyl-4-(4-cyanophenoxy) phenylboronic acid pinacol ester

A pinacol ester and formyl technology is applied in the field of intermediates for preparing criborole, can solve the problems of many side reactions, high cost, serious environmental pollution and the like, achieves improved yield and purity, reduced side reactions, Environmentally friendly effect

Active Publication Date: 2021-09-03
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011]1. In the first method, the structure of the starting material is complex and needs to be prepared by itself, the preparation process is relatively complicated, and the yield of the target product is not high
[0012]2. The second method has many side reactions and the yield is not ideal. For example, the yields of the two-step reactions in the patent WO2018115362 are 71% and 54%, respectively. The yields of the two-step reactions in WO2018224923 are 59.6% and 72.7%, respectively
The disadvantages of this process are as follows: ① DMF is heated under alkaline conditions, and it is easy to degrade to produce gases such as dimethylamine and CO, and there is a potential risk of explosion; ② The mother liquor after obtaining the intermediate is mainly DMF and water, and the nitrogen-containing wastewater will pollute the environment Serious, the cost of environmental treatment is high; ③There is a risk of producing nitrosamine genotoxic impurities
[0014] 4. Both methods need to use [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride as catalyst, the catalyst The price is expensive and the cost is high, and the prepared raw materials need to be strictly controlled for elemental impurities

Method used

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  • Preparation method of 2-formyl-4-(4-cyanophenoxy) phenylboronic acid pinacol ester
  • Preparation method of 2-formyl-4-(4-cyanophenoxy) phenylboronic acid pinacol ester
  • Preparation method of 2-formyl-4-(4-cyanophenoxy) phenylboronic acid pinacol ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Compound Ⅵ-a

[0036]

[0037] 1L three-neck flask was added 300mL of methylene chloride and N- hydroxy-phthalimide (17.9g, 0.11mol), stirred clear solution, was added 2-formyl-4-chlorobenzoic acid (22.2g, 0.12mol) and 4-dimethylaminopyridine (0.61g, 5mmol), was added dropwise at room temperature, dicyclohexyl carbodiimide (24.8g, 0.12mol) in dichloromethane (100mL) and stirring was continued for 3h after the addition was complete. Filtered, the white precipitate was filtered off, the filtrate was concentrated under reduced pressure to dryness compound Ⅵ-a, was used without further purification in the next reaction.

Embodiment 2

[0039] Preparation of Compound Ⅱ

[0040]

[0041] Acetone compound obtained in Example 1 Ⅵ-a was dissolved in acetone (200mL) was added anhydrous potassium carbonate (19.4g, 0.14mol), a solution of 4-hydroxybenzonitrile at room temperature (14.3g, 0.12mol) in (60 mL) was, after the dropwise addition was stirred for 6h. 650mL of cold water was added dropwise, the temperature controlled at 20 ~ 30 ℃, After completion of the dropwise addition stirring was continued for 2h, filtered and the filter cake was rinsed with 150mL of water three times. The resulting solid was refluxed in ethyl acetate (90 mL) IH beating, cooling, stirring was continued at 0 ~ 5 ℃ 2h, filtered and the filter cake was dried under reduced pressure to give 36.7g compound Ⅱ. Yield 80.9% (Ⅴ compound basis).

[0042] MS (ESI, m / z): 413.1 (M + 1) +

[0043] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.87-7.91 (m, 2H), 7.84-7.88 (m, 3H), 7.59-7.61 (m, 2H), 7.08 (m, 1H), 7.00-7.03 (m, 2H), 6.97 (m, 1H).

Embodiment 3

[0045] Preparation of compound Ⅰ

[0046]

[0047] 500mL three-neck flask was added compound Ⅱ (20.6g, 50mmol) and the compound Ⅲ (25.4g, 100mmol), was added after the nitrogen thrice with ethyl acetate (250 mL) and isonicotinic acid tert-butyl ester (1.79g, 10mmol), nitrogen heated to 70 ℃ ~ 75 ℃ reaction was 17h. Cooling, concentrated under reduced pressure, the residue was added 100mL of n-heptane and 0.8g of activated carbon, heated to reflux for 10min, filtered while hot and the filtrate cooled crystallization, stirred for 3h, filtered off with suction, the filter cake was dried to give 14.8g compound Ⅰ 0 ℃ ~ 5 ℃ a yield of 84.8%.

[0048] MS (ESI, m / z): 350.1 (M + 1) +

[0049] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.85 (m, 1H), 7.61 (m, 2H), 7.08 (m, 1H), 7.00 ~ 7.03 (m, 2H), 6.97 (m, 1H), 1.34 (s, 12H).

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Abstract

The present invention relates to a novel process for the preparation of 4-[3-formyl-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborol-2-yl) phenoxy] benzonitrile; and the compound is used as an intermediate for the synthesis of crisaborole. The method adopted by the invention is a non-palladium-catalyzed decarboxylation boronation method which takes carboxylic ester as a substrate and isonicotinate as a catalyst; and compared with a palladium-catalyzed coupling boronation method which takes halide as a substrate in the prior art, the method has the advantages of safety in operation, low cost, environmental friendliness and the like.

Description

Technical field [0001] The present invention relates to the preparation of 2-formyl-4- (4-cyanophenoxy) phenylboronic acid pinacol ester method, the preparation of the compound useful as an intermediate Peclet boron Lo. Background technique [0002] This art has disclosed the preparation of 2-formyl-4 pinacol ester (also known as (4-cyanophenoxy) benzene boronic acid: 4- [3-formyl-4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] benzonitrile, compound ⅰ) in two ways, both catalyzed by a palladium catalyst containing boric acid with pinacolato coupling reaction occurs esters and halogenated aromatic hydrocarbons, i.e., boride prepared by reacting Miyaura obtained. [0003] [0004] The first method is disclosed in patent US2017305936, synthetic route as shown below: [0005] [0006] In the method, an acetal structure containing bromide as a starting material, with boronic acid pinacol ester Miyaura boration reaction occurs, followed by deprotection under acidic con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 任文杰张利剑张琳李帅史潇瑀刘葵葵赵国敏李欣刘文涛汤漩郑德强段崇刚
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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