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The preparation method of (1r,2s)-2-(3,4-difluorophenyl)cyclopropylamine d-mandelate

A technology of cyclopropanation and triethyl phosphonoacetate, which is applied in the field of medicine and can solve problems such as odor, unfavorable industrial production, and unstable properties

Active Publication Date: 2017-11-17
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the prior art, compound (IV) is obtained by reacting compound (V) with triethyl phosphonoacetate through cyclopropanation, and compound (II) can be obtained by compound (IV) through amide formation and Hofmann degradation. However, in the Compound (Ⅵ) under the catalysis of (S)-OCH3-CBS (which must be prepared in situ from trimethoxyborane and S-diphenylprolinol) with borane-dimethylsulfide complex for CBS asymmetric In the process of reducing compound (Ⅴ), the catalyst for CBS reduction reaction (S)-OCH 3 -CBS is unstable in nature and is not commercialized. It must be prepared in situ from trimethoxyborane and S-diphenylprolinol, which increases the operation process and is not conducive to industrial production; and the reducing agent borane-dimethyl sulfide The complex emits foul-smelling dimethyl sulfide gas during post-processing, which is not conducive to labor protection in production

Method used

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  • The preparation method of (1r,2s)-2-(3,4-difluorophenyl)cyclopropylamine d-mandelate
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  • The preparation method of (1r,2s)-2-(3,4-difluorophenyl)cyclopropylamine d-mandelate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Preparation of 2-chloro-1-(3,4-difluorophenyl)ethanone (compound Ⅵ)

[0067]

[0068] Add anhydrous aluminum chloride (134.4g, 1.01mol) and dichloromethane (300ml) into a 1L four-necked flask. With mechanical stirring, chloroacetyl chloride (113.9 g, 1.01 mol) was added dropwise at 20-25 ° C, and the drop was completed in about 2 hours. The temperature was raised to reflux, and o-difluorobenzene (100.0 g, 0.88 mol) was slowly added dropwise for about 1 hour. Continue to reflux for 2h. After the reaction solution was cooled to room temperature, it was slowly poured into 600 ml of ice water for quenching. The layers were allowed to stand, and the aqueous layer was extracted with dichloromethane (300ml×2). The organic layers were combined and washed successively with saturated sodium bicarbonate solution (1L) and water (1L). After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain compound VI (153.3 g, 91.8%) as a yel...

Embodiment 2-5

[0070] Preparation of 2-chloro-1-S-(3,4-difluorophenyl)-ethanol (compound Ⅴ)

[0071]

[0072] Compound (Ⅵ) reacted at 15°C for 1 hour under the action of borane-dimethyl sulfide complex to generate compound (Ⅴ). The results are shown in Table 1.

[0073] Table 1 The influence of different catalysts on the reaction

[0074] Numbering

[0075] It can be seen from Table 1 that when the substituent is a hydrogen atom, methyl or n-butyl, the (S)-CH 3 -CBS is the catalyst, and the ee value of the product compound (Ⅴ) is higher; choose (S)-CH 3 -CBS as a catalyst for follow-up studies.

Embodiment 6-8

[0077] Preparation of 2-chloro-1-S-(3,4-difluorophenyl)-ethanol (compound Ⅴ)

[0078] Using S-CH 3 -CBS was used as a catalyst, and different borane complexes were used as reducing agents. Compound (Ⅵ) was reacted at 15°C for 1 hour to generate compound (Ⅴ). The results are shown in Table 2.

[0079] The influence of table 2 different reducing agents on the reaction

[0080] Numbering

[0081] It can be seen from Table 2 that when borane-dimethyl sulfide and borane-tetrahydrofuran are used as reducing agents, the ee value of the product is higher, and borane-tetrahydrofuran is selected as the reducing agent for subsequent experiments.

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Abstract

The invention discloses a preparation method of (1R,2S)-2-(3,4-difluorophenyl) rolicyprine.D-mandelate. The preparation method comprises the following steps: carrying out cyclopropanation on a compound shown in a formula V to obtain a compound shown in a formula IV; carrying out amide generation and Hofmann degradation to obtain a compound shown in a formula II; and performing salification with D-mandelic acid to obtain a compound shown in a formula I. The compound shown in the formula V is prepared in a way that a compound shown in a structure formula VI is subjected to CBS asymmetric reduction reaction, wherein a catalyst for the CBS asymmetric reduction reaction is a compound shown in a structural formula VII, and a reduction agent for the CBS asymmetric reduction reaction can be borane-tetrahydrofuran or borane-N,N-diethyl phenylamine.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine·D-mandelate. Background technique [0002] Ticagrelor (ticagrelor), chemical name (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)-cyclopropyl]amino ]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol is an oral antiplatelet drug developed by AstraZeneca AB. The drug can reversibly act on the ADP P2Y12 receptor, has obvious inhibitory effect on platelet aggregation caused by ADP, and has a rapid onset of oral administration. It is clinically used in patients with acute coronary syndrome to reduce the incidence of thrombotic cardiovascular events. [0003] The structural formula of ticagrelor is as follows: [0004] [0005] (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (Ⅱ) is the key intermediate in the synthesis of ticagrelor, because it is oily, which...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C33/46C07C29/143C07C211/40C07C209/58C07C59/50C07C51/41
Inventor 张福利徐建国何晓清吴泰志顾红蕾
Owner SHANGHAI INST OF PHARMA IND
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