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Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method

A technology of hypochlorite and compound, which is applied to the preparation method of chiral aromatic cyclopropylamine and its salt and the field of intermediates used, can solve the problem of unfriendly environment, low catalytic efficiency of chiral oxazolidinone, and limited production. application and other issues, to achieve the effect of reducing cost, simplifying operation, and high chiral purity

Active Publication Date: 2020-06-05
苏州元兴生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This route uses expensive chiral oxazolidine catalyst, and highly toxic and flammable borane dimethyl sulfide, and explosive sodium hydrogen as raw materials; properties, very unfriendly to the environment; at the same time, the catalytic efficiency of chiral oxazolidinone is not high, the ee value is only 76%, and the final product (1R,2S)-2-(3,4-difluorophenyl) is prepared The ee value of cyclopropylamine is only 81%, and a second resolution is required
Many disadvantages limit the production application of this route

Method used

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  • Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method
  • Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method
  • Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Preparation of 3,4-difluorobenzyl diethyl phosphite (VI-1)

[0068]

[0069] Add triethyl phosphite (25.7g, 0.15mol) and 3,4-difluorobenzyl bromide (27.5g, 0.13mol) into the reaction flask, and heat to 110°C for 20 hours. After the reaction was completed, the reaction was cooled to room temperature, and the excess triethyl phosphite was removed by vacuum concentration to obtain a light yellow oil (VI-1) (31 g, 88.6%), which was directly used in the next reaction.

Embodiment 2

[0070] Example 2: Preparation of 3,4-difluorobenzyl diisopropyl phosphite (VI-2)

[0071]

[0072] Add triisopropyl phosphite (31.2g, 0.15mol) and 3,4-difluorobenzyl bromide (27.5g, 0.13mol) into the reaction flask, and heat to 110°C for 27 hours. After the reaction was completed, it was cooled to room temperature, concentrated under high vacuum and reduced pressure to remove excess triethyl phosphite, and a light yellow oil (VI-2) (27.6 g, 72.6%) was obtained, which was directly used in the next reaction.

Embodiment 3

[0073] Example 3: Preparation of ethyl (1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (III-1)

[0074]

[0075] Add 3,4-difluorobenzyl diethyl phosphite (VI-1) (30 g, 0.11 mol) prepared in the previous step into the reaction flask, then add 250 mL of toluene, stir to dissolve, protect with nitrogen, and cool down to 10-15 ℃, add sodium tert-butoxide (11.5g, 0.12mol) in batches, heat up to 50℃ and keep it warm for 2 hours after adding, then cool down to 10-15℃, add R-ethyl glycidate (VII-1) dropwise (12.8g, 0.11mol, chiral purity greater than 99%), the rate of addition was controlled so that the temperature did not exceed 15°C. After the dropwise addition, the temperature was slowly raised to reflux, and the reaction was maintained at reflux for 16 hours. After the reaction, cool down to about 30°C in an ice bath, add 100 mL of water to quench the reaction, separate the toluene layer, extract the water phase with 50 mL of toluene once, combine the organic phases, was...

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Abstract

The embodiment of the invention provides a preparation method of a compound as shown in a formula I or salt thereof, which comprises the following steps: (1) reacting a compound as shown in a formulaVI with a compound as shown in a formula VII in a first reaction solvent in the presence of first strong alkali to generate a compound as shown in a formula III; and (2) converting the compound shownin the formula III into a compound shown in a formula I or a salt thereof. According to the preparation method of the chiral aromatic cyclopropylamine and the salt thereof provided by the embodiment of the invention, an expensive chiral catalyst does not need to be used in the preparation process; the obtained product is high in chiral purity, and secondary resolution is not needed; the operationis simplified, and the cost is reduced.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of chiral aromatic cyclopropylamine and a salt thereof and an intermediate used therefor. Background technique [0002] Ticagrelor, also known as ticagrelor, the chemical name is (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorobenzene Base) cyclopropyl] amino] -5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol , is a new drug for the treatment of acute coronary syndrome developed by AstraZeneca in the United Kingdom. It was approved by the US FDA in July 2011. After listing, it was recommended by many international treatment guidelines for ACS (acute coronary syndrome) syndrome) in the treatment of patients. In November 2012, ticagrelor obtained the import drug license issued by the State Food and Drug Administration (SFDA), and was approved to be officially listed in China. The chemical structural formula of ticagre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/00C07C211/40C07F9/40C07C67/343C07C69/753C07C231/02C07C233/58
CPCC07C209/00C07F9/4056C07F9/4075C07C67/343C07C231/02C07B2200/07C07C2601/02C07C211/40C07C69/753C07C233/58
Inventor 王伸勇毛彦利徐军李国候
Owner 苏州元兴生物医药有限公司
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