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Preparation method of boracic micromolecule

A technology of small molecules and borate esters, which is applied in the field of preparation of boron-containing small molecule crisborole, can solve the problems of high cost and low yield, and achieve the effects of low cost, simple operation, and cheap and easy-to-obtain raw materials

Inactive Publication Date: 2018-11-23
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The reaction route in this document also has the problems of low yield and high cost, and the single-step yield of the ring-closing step is only about 30%, which has obvious defects

Method used

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  • Preparation method of boracic micromolecule
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  • Preparation method of boracic micromolecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1 Synthetic 2-bromo-5-hydroxybenzyl alcohol (III)

[0059]

[0060] Add 40g (0.20mol) 2-bromo-5-hydroxybenzaldehyde (II) and 400mL MeOH to the reaction flask, and stir evenly; add 5.6g (0.15mol) sodium borohydride in batches under an ice bath, and keep the reaction for 0.5h~ 1.5h. TLC detected that the reaction of the raw material was basically complete, quenched by adding 100mL of water, extracted with 400mL of ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an off-white solid, added 100mL of dichloromethane to beat at room temperature for 0.5h, filtered, and the filter cake was air-dried Obtained 37.2g white solid namely 2-bromo-5-hydroxybenzyl alcohol (III), molar yield 91.6%, MS (m / z): 200.9 [M-H] - .

Embodiment 2

[0061] Example 2 Synthesis of 4-benzyloxy-2-benzyloxymethyl-1-bromobenzene (IV-1)

[0062]

[0063] Add 34g (0.17mol) 2-bromo-5-hydroxybenzyl alcohol (III), 50mL N,N-dimethylformamide solution to the reaction flask, add 12.3g (60%, 0.51mol) in batches under ice-cooling Sodium hydrogen, keep warm at 0~5℃ for 0.5h~1.5h after adding, slowly add 73.5g benzyl bromide (0.43mol) dropwise, keep warm for 0.5h~1.5h after dropping, add 100mL water to quench, 200mL acetic acid Extract with ethyl ester, dry over anhydrous sodium sulfate, concentrate under reduced pressure, remove benzyl bromide through column chromatography (PE:EA=80:1~40:1), and obtain 59.4 g of colorless oily liquid which is 4-benzyloxy -2-Benzyloxymethyl-1-bromobenzene (IV-1), the molar yield is 91.2%. 1 H-NMR (400Hz, CDCl 3 ) δ (ppm) 4.59 (s, 2H), 4.63 (s, 2H), 5.06 (s, 2H), 6.79 (dd, J = 4Hz, 1H), 7.20 (d, J = 4Hz, 1H), 7.38 ( m, 11H).

Embodiment 3

[0064] Example 3 Synthesis of 4-benzyloxy-2-benzyloxymethylphenylboronic acid (V-1)

[0065]

[0066] Add 59g (0.15mol) 4-benzyloxy-2-benzyloxymethyl-1-bromobenzene (IV-1) and 580ml tetrahydrofuran solution into the reaction flask, stir evenly, protect with nitrogen, cool to -78°C, Add dropwise 72mL of 2.5mol / L n-butyllithium n-hexane solution, keep warm for 0.5h, add dropwise 37.6g (0.2mol) triisopropyl borate, keep warm at -65~-78℃ during the dropping process, keep warm for 0.5h , TLC detected that the reaction of the raw material was complete, raised to room temperature, quenched with saturated ammonium chloride solution, extracted with 500ml ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a yellow oily liquid, added 450mL of n-heptane, and stirred at room temperature for 0.5h , precipitated off-white solid, filtered, and dried to obtain 43.4 g of white solid, namely 4-benzyloxy-2-benzyloxymethylphenylboronic acid (V-1), ...

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Abstract

The invention discloses a preparation method of a boracic micromolecule 5-(4-cyanophenoxyl)-1,3-dihydro-1-hydroxy-2,1-benzodioxole. The preparation method includes the steps of (1) subjecting 2-bromine-5-hydroxybenzaldehyde to reduction reaction in solvent with the presence of reducing agents to obtain 2-bromine-5-hydroxybenzyl alcohol; (2) subjecting 2-bromine-5-hydroxybenzyl alcohol and a hydroxyl protection reagent to reaction in solvent with the presence of alkali; (3) subjecting the previous reactant to borate reaction in solvent under an alkaline condition; (4) removing hydroxyl protecting groups from the previous reactant to obtain a benzo[c][1,2]heterocyclopentadiene-1,5(3H)-glycol body; (5) subjecting the previous reactant to reaction in solvent under an alkaline condition to obtain a target object. The preparation method has the advantages of low cost of technological raw materials, easiness in obtaining of the technological raw materials, remarkably improved reaction yield,simplicity in operation, low cost and applicability to industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of boron-containing small molecule crisborole. Background technique [0002] Crisaborole is a phosphodiesterase 4 (PDE4) inhibitor that results in increased intracellular levels of cyclic adenosine monophosphate (cAMP) and is used in the treatment of fungal infections, more specifically in Treatment of onychomycosis and / or fungal skin infections. The drug was approved by the U.S. Food and Drug Administration (FDA) in December 2016. It was developed by Anacor Pharmaceuticals and is responsible for marketing in the U.S. under the trade name The chemical name of criborole is 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborine, and its English name is 4 -((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile, the chemical structural formula is as shown in formula (I): [0003] [0004] At present, there are few relevant repor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07F7/18
CPCC07F5/02C07F5/025C07F7/1892Y02P20/55
Inventor 田广辉吴建忠俞蒋辉田辉肖建虎庞珍强
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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