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Preparation method of crisaborole

A technology of cleaborol and tolyl boronic acid, which is applied in the field of medicines for the treatment of skin diseases, can solve problems such as unsatisfactory yield and purity, and achieve the effects of novel synthesis route, mild reaction, and avoiding ultra-low temperature reaction.

Pending Publication Date: 2021-09-03
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The yield of the 4-(4-halogen-3-methylphenoxy group) benzonitrile of V obtained after halogenation first in this synthetic method, the purity is not ideal enough

Method used

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  • Preparation method of crisaborole
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  • Preparation method of crisaborole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Embodiment 1: the preparation of 4-(3-methylphenoxy)benzonitrile of structural formula VI

[0110]

[0111] Put 35g of m-cresol (0.32mol), 46g of 4-fluorobenzonitrile (0.38mol), 350mL of DMF and 90g of potassium carbonate into a 1L reaction flask in sequence; raise the temperature to 120°C, react for 12 hours, then cool down to 25°C; 800mL of water, stirred for 1 hour, filtered; the filter cake was dissolved in 300mL of dichloromethane, concentrated under reduced pressure, the residue was recrystallized with n-heptane and ethyl acetate, filtered; dried to obtain 4-(3-methyl phenoxy)benzonitrile 57g, yield 85%, purity 99%.

[0112] Mass: m / z 210.1[M-H] + ;

[0113] 1H NMR (400MHz, CDCl 3 )δ7.63-7.53(m,2H),7.30-7.24(m,1H),7.03(d,J=7.6Hz,1H),7.01-6.96(m,2H),6.89-6.82(m,2H) ,2.36(s,3H).

Embodiment 2

[0114] Embodiment 2: the preparation of 4-(3-methylphenoxy)benzonitrile of structural formula VI

[0115]

[0116] Put 35g of m-cresol (0.32mol), 52g of 4-chlorobenzonitrile (0.38mol), 350mL of DMF, and 90g of potassium carbonate into a 1L reaction flask in sequence; heat up to 160°C, react for 18 hours, and cool down to 25°C; Add 800mL of water, stir for 1 hour, and filter; the filter cake is dissolved in 300mL of dichloromethane, concentrated under reduced pressure, and the residue is recrystallized with n-heptane and ethyl acetate, and filtered; dried to obtain 4-(3-methanol as a white solid) phenoxy) benzonitrile 54g, yield 80%, purity 99%.

[0117] Mass: m / z 210.1[M-H] + ;

[0118] 1H NMR (400MHz, CDCl 3 )δ7.63-7.53(m,2H),7.30-7.24(m,1H),7.03(d,J=7.6Hz,1H),7.01-6.96(m,2H),6.89-6.82(m,2H) ,2.36(s,3H).

Embodiment 3

[0119] Embodiment 3: Preparation of 4-(4-bromo-3-methylphenoxy)benzonitrile of structural formula V

[0120]

[0121] 63g of 4-(3-methylphenoxy)benzonitrile (0.3mol), 58g of N-bromosuccinimide (0.33mol), and 300mL of methanol were successively put into a 1L reaction flask; the temperature was raised to 50°C, and the reaction After 6 hours, cool down to 25°C; add the reaction solution to 300mL water, stir for 1 hour, and filter; dissolve the filter cake in 300mL of dichloromethane, concentrate under reduced pressure, recrystallize the residue with n-heptane and ethyl acetate, filter; dry 69 g of 4-(4-bromo-3-methylphenoxy)benzonitrile was obtained as a white solid, with a yield of 80% and a purity of 99%.

[0122] Mass: m / z 288.0[M-H]+ ;

[0123] 1H NMR (400MHz, CDCl 3 )δ7.61(d, J=7.2Hz, 2H), 7.54 (d, J=7.2Hz, 1H), 7.00(d, J=6.8Hz, 2H), 6.95(s, 1H), 6.64 (dd, J1=2.0Hz, J2=6.8Hz, 1H), 2.39(s, 3H).

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Abstract

The invention discloses a preparation method of crisaborole. The preparation method comprises the following steps: by taking m-methylphenol as a raw material, firstly coupling the m-methylphenol with 4-halogenated-cyanophenyl, and then under the action of a halogenating reagent, increasing the yield of an intermediate product 4-(4-halogen-3-methylphenoxy) cyanophenyl; and carrying out halogen-metal exchange, halogenation, ring closing and other reactions to prepare the crisaborole. Compared with the prior art, the method has advantages that the raw materials are cheap and easy to obtain, and expensive reagents and raw materials in the prior art are not used; the reaction is mild, and ultralow-temperature reaction in the prior art can be avoided; the method is short in reaction time, free of column chromatography purification, simple in process, convenient to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drugs for treating skin diseases, and in particular relates to a preparation method of crisborole. Background technique [0002] Crisaborole, CAS: 906673-24-3, is a phosphodiesterase 4 (PDE-4) inhibitor, chemical name: 4-[(1,3-dihydro-1-hydroxy- 2,1-benzoxaborolan-5-yl)oxy]benzonitrile, its structural formula is as shown in formula I below: [0003] [0004] Criborole is the first new molecular entity drug for the treatment of atopic dermatitis approved by the U.S. FDA in the past 15 years. It is used for the treatment of moderate to severe eczema in infants and adults aged 3 months and above, with excellent efficacy and safety. And it has good long-term safety and tolerance. The market prospect is very optimistic. [0005] The preparation method of criborol was first disclosed in the patent CN101914109A of Anacor Company, that is, sodium borohydride reduces 2-bromo-5-(4-cyanophenoxy)benzaldehyde of structura...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 叶四明刘翊康禄朱高翔杨峰吴望腾
Owner JIANGXI SYNERGY PHARMA
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