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Synthesis method of difluorodeuteromethoxy(thio) function group-containing aromatic compound

A synthesis method and technology of functional groups, applied in the field of deuterium-containing compound synthesis, can solve the problems of inappropriate synthesis of aromatic compounds, inability to meet the purity of deuterated drugs, low deuteration rate, etc.

Inactive Publication Date: 2017-10-03
TETRANOV PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

With reference to this document, the solvent water is replaced by heavy water, and the synthesis experiment is carried out. As a result, the difluorodeuteromethoxy aromatic compound with a lower deuteration rate (less than 80%) can only be obtained, which cannot meet the requirements for the purity of deuterated drugs
The main reason for the analysis is that the potassium hydroxide and acetonitrile used in the reaction system will seriously affect the abundance of deuterium isotopes in the product, so it is not suitable for the synthesis of aromatic compounds with difluorodeuteromethoxy (sulfur) group functional groups

Method used

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  • Synthesis method of difluorodeuteromethoxy(thio) function group-containing aromatic compound
  • Synthesis method of difluorodeuteromethoxy(thio) function group-containing aromatic compound
  • Synthesis method of difluorodeuteromethoxy(thio) function group-containing aromatic compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] The compound 2-naphthol (144mg, 1mmol) was dissolved in 4.0ml of dry (metal sodium dehydrated) 1,4-dioxane, under the protection of argon, the temperature was cooled to 15°C in an ice-water bath, and added in batches NaH (60%, 400mg, 10mmol), ensure that the temperature of the reaction system is lower than 25°C during the addition process, then react for 0.5h, and then slowly add heavy water 1ml (50mmol), and ensure that the temperature of the reaction system is lower than 40°C during the dropwise addition. After the dropwise addition, react for 0.5h, add diethyl bromodifluoromethylphosphate (534mg, 2mmol) dropwise, keep the temperature of the reaction system lower than 30°C during the dropwise addition, and raise it to room temperature for 0.5h. After the reaction, 20ml of ether was added, the organic phase was separated from the water phase, the organic phase was washed with saturated ammonium chloride solution (20ml×3), the organic phase was dried with anh...

Embodiment 2- Embodiment 9

[0057] The following are examples 2-9, the other conditions of the reaction are the same as in Example 1, the only difference is that the amount of alkali NaH is adjusted, and the influence on the yield of the target compound and the deuteration rate under the conditions of different alkali amounts is investigated.

[0058]

[0059] As can be seen from the data in the table above, the amount of alkali has a greater impact on the yield, and at 8-15 equivalents, the yield is higher; but the amount of alkali has little effect on the deuterium substitution rate, and with the adjustment of the amount of alkali, deuterium The generation rate fluctuates very little, and the deuterium rate is ≥98.5%.

Embodiment 10- Embodiment 16

[0061] The following are examples 10-16, the other conditions of the reaction are the same as in Example 1, the difference is only that the amount of heavy water is adjusted, and the influence on the yield of the target compound and the deuterium rate under the conditions of different amounts of heavy water is investigated.

[0062]

[0063] As can be seen from the data in the above table, the amount of heavy water has a greater impact on the yield. When it is 40 equivalents, the yield reaches 65%, and when it is more than 100 equivalents, it reaches more than 80%. Considering the cost problem, you can choose about 50 equivalents; similarly, The amount of heavy water has little effect on the deuterium rate. With the increase of the heavy water amount, the deuterium rate increases from 95% to 98.7%. Above 30 equivalents, the deuterium rate is greater than or equal to 98.5%.

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Abstract

The invention belongs to the technical field of deuterium-containing compound synthesis and discloses a synthesis method of an aromatic compound containing a difluorodeuteromethoxy functional group or a difluorodeuterothio functional group. In the presence of an alkali, a difluorocarbene donor, a group shown in the description and heavy water undergo a reaction to produce a deuterated product shown in the description, wherein the difluorocarbene donor is BrCF2PO(OR)2 or (chlorodifluoromethyl)trimethylsilane or (bromodifluoromethyl)trimethylsilane and the alkali is selected from Na, K, Li, Mg, Zn, Al, NaH, KH, LiH, LiAlH4, KOD, NaOD, NaOMe, NaOEt, NaOBu, sodium carbonate, potassium carbonate and cesium carbonate. The method has the advantages of use of cheap and easily available raw materials, simple and mild reaction, high yield, high deuteration rate, and production amplification easiness.

Description

technical field [0001] The invention relates to the technical field of synthesis of deuterium-containing compounds, in particular to a method for synthesizing aromatic compounds containing difluorodeuteromethoxy functional groups or difluorodeuteromethylthio functional groups. Background technique [0002] In April 2017, the US FDA approved the first deuterated drug, Teva's deuterated tetrabenazine (trade name Austedo), which is mainly used for the treatment of Huntington's disease, which marks the arrival of the era of deuterated drugs. Compounds containing difluoromethoxy, especially aromatic compounds, are widely used in the field of medicine. There have been many reports on the synthesis method of introducing difluoromethoxy, but there are few reports on the synthesis of deuterated difluoromethoxy aromatic compounds so far. [0003] Our company disclosed in the patent CN 106083736 that sodium phenate, ethyl bromodifluoroacetate and heavy water are used to synthesize nit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B59/00C07C41/16C07C43/225C07C253/30C07C255/54C07C201/12C07C205/37C07C213/06C07C217/84C07D333/54C07D209/08C07J1/00C07C319/14C07C323/09C07D213/65
CPCC07B59/001C07B59/002C07B59/007C07B2200/05C07C41/16C07C201/12C07C213/06C07C253/30C07C319/14C07D209/08C07D213/65C07D333/54C07J1/00C07C43/225C07C255/54C07C205/37C07C217/84C07C323/09
Inventor 吴豫生耿阳邹大鹏李敬亚牛成山郑茂林梁阿朋
Owner TETRANOV PHARMA CO LTD
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