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A kind of synthetic method of pharmaceutical intermediate difluoromethoxy compound

A technology of difluoromethoxyl and synthesis method, which is applied in the direction of carbon-based compound preparation, organic compound preparation, chemical instruments and methods, etc., which can solve the problem of limited difluoromethylation due to the limited variety of difluoromethylation reagents Process and other issues, to achieve high yield effect

Active Publication Date: 2016-06-08
南阳市天华制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] As mentioned above, although methods for the halogenation of various compounds such as difluoromethylation have been reported in the prior art, there are not many types of difluoromethylation reagents used in these methods, and many It is suitable for the difluoromethylation reaction of phenolic compounds under alkaline conditions. These factors greatly limit the difluoromethylation process of other substrates, resulting in the fact that it must be converted into a specific precursor in the synthesis of drugs. Subsequent difluoromethylation reaction

Method used

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  • A kind of synthetic method of pharmaceutical intermediate difluoromethoxy compound
  • A kind of synthetic method of pharmaceutical intermediate difluoromethoxy compound
  • A kind of synthetic method of pharmaceutical intermediate difluoromethoxy compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038]

[0039] At room temperature, add 100mmol of formula (II) compound, 150mmol of formula (III) compound, 2mmol of PdCl to an appropriate amount of solvent DMSO in the reaction vessel 2 (cod), 4 mmol of organic ligand L1 and 200 mmol of sodium tert-butoxide, and then heated to 60° C. under stirring, and reacted at this temperature for 6 hours.

[0040] After completion of the reaction, cool down to room temperature naturally, add enough deionized water to the reaction system, mix thoroughly to obtain a mixed solution, then extract 2-3 times with ether, combine the organic phases, dry with anhydrous sodium sulfate, and remove under reduced pressure. Solvent, the residue is separated by 200-300 mesh silica gel column chromatography, wherein a mixed solvent of acetone and n-butanol with a volume ratio of 1:1.5 is used as an eluent, thereby obtaining the compound of formula (I) with a yield of 98.5% .

[0041] 1 H-NMR (400MHz, CDCl 3 )δ: 6.62(t, J=73.5Hz, 1H), 2.65(t, J=...

Embodiment 2

[0044]

[0045] At room temperature, add 100mmol of formula (II) compound, 250mmol of formula (III) compound, 5mmol of PdCl to an appropriate amount of solvent DMSO in the reaction vessel2 (cod), 6mmol of organic ligand L1 and 250mmol of sodium tert-butoxide, then heated to 80°C with stirring, and reacted at this temperature for 5 hours.

[0046] After completion of the reaction, cool down to room temperature naturally, add enough deionized water to the reaction system, mix thoroughly to obtain a mixed solution, then extract 2-3 times with ether, combine the organic phases, dry with anhydrous sodium sulfate, and remove under reduced pressure. Solvent, the residue is separated by 200-300 mesh silica gel column chromatography, wherein the mixed solvent of acetone and n-butanol is used as the eluent with a volume ratio of 1:2.5, so as to obtain the compound of formula (I) with a yield of 98.2% .

[0047] 1 H-NMR (400MHz, CDCl 3 ,)δ: 6.47(t, J=72.0Hz, 1H), 5.44(s, 1H), 2.52-2...

Embodiment 3

[0050]

[0051] At room temperature, add 100mmol of formula (II) compound, 200mmol of formula (III) compound, 4mmol of PdCl to an appropriate amount of solvent DMSO in the reaction vessel 2 (cod), 8 mmol of organic ligand L1 and 300 mmol of sodium tert-butoxide, then heated to 90° C. with stirring, and reacted at this temperature for 3 hours.

[0052] After completion of the reaction, cool down to room temperature naturally, add enough deionized water to the reaction system, mix thoroughly to obtain a mixed solution, then extract 2-3 times with ether, combine the organic phases, dry with anhydrous sodium sulfate, and remove under reduced pressure. Solvent, the residue was separated by 200-300 mesh silica gel column chromatography, wherein a mixed solvent of acetone and n-butanol with a volume ratio of 1:3 was used as the eluent, thereby obtaining the compound of formula (I) with a yield of 98.6% .

[0053] 1 H-NMR (400MHz, CDCl 3 )δ:7.26-7.13(m,5H),6.58(t,J=73.3Hz,1H),3....

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Abstract

The invention provides a synthetic method of a medical intermediate difluoromethoxyl compound which is shown in the formula (I) in the specification. The method comprises the following steps: reacting a compound shown in formula (II) and a compound shown in formula (III) in the presence of a catalyst, an organic ligand and alkali to obtain the compound shown in the formula (I) in the specification, wherein R represents H, C1-C6 alkyl, benzyl, halogen or nitryl. By mutual cooperation and / or combination of suitable catalyst, organic ligand, alkali and solvent, the method can be used for realizing high-efficiency difluoromethoxylation of a reaction substrate is realized, a difluoromethoxyl substituted compound is obtained at a high yield and a totally new synthetic method of the type of midbody for the medical field is provided, so the method is a novel technological method which is quite high in value and is quite wide in application prospect.

Description

technical field [0001] The invention relates to a method for synthesizing a halogenated compound, more particularly to a method for synthesizing a difluoromethoxy compound that can be used as a pharmaceutical intermediate, and belongs to the fields of organic synthesis and pharmaceutical intermediate synthesis. Background technique [0002] Halogenated groups are the basic units that constitute various pharmaceutical compounds with biological activity, for example, enzyme inhibitors, pesticides, etc. usually contain halogenated groups. [0003] Specifically, in the field of medicine, for example, nimodipine containing a halogenated group is a commonly used calcium antagonist, which can be used to treat iron deficiency cerebrovascular disease, migraine, and mild subarachnoid hemorrhage. Cerebral vasospasm, sudden deafness, high blood pressure and other symptoms; Roflumilast is a PDE-4 inhibitor, which can be used to treat symptoms such as bronchitis in severe COPD patients. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C49/753C07C45/64
CPCC07C45/64C07C2601/16C07C49/753
Inventor 王峰李健刘光合朱俊丽王全钦曾庆云崔猛
Owner 南阳市天华制药有限公司