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

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...

Examples

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.

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...

Examples

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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