CN106906249A - A kind of preparation method of ticagrelor intermediate and its mandelate - Google Patents
A kind of preparation method of ticagrelor intermediate and its mandelate Download PDFInfo
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Abstract
The invention discloses a kind of ticagrelor midbody compound (I) and its synthetic method of mandelate compound (VI), asymmetric reduction is carried out using enzyme process, the method is simple to operate, reaction condition is gentle, pollution is small and product yield is high, optical purity is good, it is adapted to large-scale production, the discharge of energy consumption and organic wastewater is greatly reduced, the requirement of large-scale industrial production is more suitable for.
Description
Technical field
The present invention relates to biological enzyme and organic synthesis field, and in particular to a kind of ticagrelor intermediate (1R, 2S)-
The synthesis of 2- (3,4- difluorophenyl) cyclopropylamines and its mandelate.
Background technology
Ticagrelor is a kind of new selective small molecule anticoagulation researched and developed by Astrazeneca AB of Britain
Medicine, belongs to cyclopenta triazolo pyrimidine class oral anti-diabetic agent thing, is a kind of selective ADP receptor resistant, effect
In P2Y12ADP acceptors to suppress the platelet activation and aggregation that ADP is mediated, the medicine is approved by the FDA in the United States in July, 2011
City, in November, 2012 is approved in Discussion on Chinese Listed.
(1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine is the key intermediate for preparing ticagrelor, because it is grease
Be inconvenient to store and use, be commonly made to mandelate or hydrochloride is used.(1R, 2S) -2- (3,4- of current document report
Difluorophenyl) synthetic method of cyclopropylamine mainly has following several：
1) WO 2008018822A report with o-difluoro-benzene and chloracetyl chloride as raw material through Friedel-Crafts reaction, it is asymmetric also
Former, cyclisation, Cyclopropanated, ammonolysis and Hofmann degradation obtain (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine, its synthesis road
Line is as follows：
2) CN 201210274432 report with the chloro benzyl carbinol of racemization as raw material through chemical method optical resolution, cyclisation,
Cyclopropanated, hydrolysis and Curtius reset and obtain (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine, and its synthetic route is as follows：
3) CN 201310346985 report with 3,4- difluoro bromobenzenes and chloracetyl chloride be raw material through Friedel-Crafts reaction, it is not right
Reduction, cyclisation, Cyclopropanated, hydrolysis, debrominate, ammonification and Hofmann degradation is claimed to obtain (1R, 2S) -2- (3,4- difluorophenyl) ring
Propylamine, its synthetic route is as follows：
4) CN 201410609709 is reported and is solved monomethyl succinate, monomethyl succinate acyl through alcohol with succinic anhydride
Chlorination reaction obtains compound monomethyl succinate acyl chlorides and obtains compound 4- ketone -4- (3,4- difluoros through Friedel-Crafts reaction with o-difluoro-benzene
Phenyl) sour methyl esters, then degraded to obtain product (1R, 2S) -2- (3,4- difluoros through asymmetric reduction reaction, ring-closure reaction, Hoffman
Phenyl) cyclopropylamine, its synthetic route is as follows：
Asymmetric reduction is carried out using chemical method in said synthesis route, has that yield is low, optical purity is poor, behaviour
Make cumbersome, production cost it is high and seriously polluted the problems such as.
In order to overcome the above-mentioned deficiencies of the prior art, the invention provides a kind of new (1R, 2S) -2- (3,4- difluorobenzenes
Base) cyclopropylamine and its mandelate synthetic method.
The content of the invention
The technical scheme that the present invention is provided is as follows：
It is an object of the invention to provide the salt shown in the ticagrelor intermediate shown in compound (I) and compound (VI)
Preparation method, comprises the following steps：
(1) with the chloro- 1- of 2- (3,4- difluorophenyl) ethyl ketone for raw material, reduction obtains Gao Xuan under the catalysis of carbonyl reductase
The compound (II) of selecting property；
(2) compound (II) that will be obtained in step (1) reacts obtain compound (III) in the basic conditions；
(3) compound (III) that will be obtained in step (2) is anti-with phosphine acyl acetic acid three ethyl (TEPA) in the basic conditions
Compound (IV) should be obtained；
(4) compound (IV) that will be obtained in step (3) carries out ammonolysis and obtains compound (V)；
(5) compound (V) that will be obtained in step (4) carries out Hofmann degradation and obtains compound (I)；
(6) compound (I) that will be obtained in step (5) obtains compound (VI) with D- almond acid reactions.
Preparation method on the salt shown in the ticagrelor intermediate shown in compound (I) and compound (VI), this hair
It is bright to further provide some preferred technical schemes.
In some embodiments, solvent for use is the mixture of water and organic solvent in step (1), organic solvent be methyl alcohol,
The ratio of ethanol, isopropanol, tetrahydrofuran and dioxane, water and organic solvent is 1: 0.2~2, preferably isopropanol.
In some embodiments, the concentration of the chloro- 1- of 2- (3,4- difluorophenyl) ethyl ketone is that 5~20%, 2- is chloro- in step (1)
1- (3,4- difluorophenyl) ethyl ketones are 1: 0.2~1 with the weight ratio of the thalline containing carbonyl reductase.
In some embodiments, the range of reaction temperature described in step (1) is 20~40 DEG C, and reaction pH is 7.0~8.0,
2~10h of reaction time.
In some embodiments, Extraction solvent described in step (1) is ethyl acetate, benzene, toluene, dichloromethane or two chloroethenes
Alkane, preferably toluene.
In some embodiments, solvent described in step (2) is benzene, toluene, dichloromethane or dichloroethanes, preferably toluene；
Described alkali is NaOH, potassium hydroxide or lithium hydroxide, preferably NaOH；Described range of reaction temperature is 20~50
℃；Described 1~5h of reaction time.
In some embodiments, solvent described in step (3) is benzene,toluene,xylene or glycol dimethyl ether, preferably first
Benzene；Described alkali is sodium tert-butoxide, potassium tert-butoxide or sodium hydride, preferably sodium tert-butoxide；Described range of reaction temperature be 10~
100℃；The described reaction time is 10~24h.
In some embodiments, the solvent described in step (4) is methyl alcohol, ethanol, acetone or tetrahydrofuran, preferably methyl alcohol；
Described range of reaction temperature is 30~80 DEG C, and the described reaction time is 6~20h.
In some embodiments, solvent described in step (5) is water, methyl alcohol, ethanol, benzene, toluene or dichloromethane, preferably
Water and dichloromethane；Described range of reaction temperature is 0~70 DEG C；Described 1~5h of reaction time；Described alkali is hydroxide
Sodium, potassium hydroxide or lithium hydroxide, preferably NaOH.
In some embodiments, the solvent described in step (6) is methyl alcohol, ethanol, acetone or tetrahydrofuran, preferably methyl alcohol；
Range of reaction temperature described in step (6) is 15~35 DEG C；The described reaction time is 6~15h.
Compared with prior art, the beneficial effects of the invention are as follows：The present invention carries out asymmetric reduction using enzyme process, and carbonyl is also
Protoenzyme wide material sources, are distributed in bacterium, fungi and high animals and plants, are a kind of chemistry of height, region and three-dimensional choosing
The biocatalyst of selecting property, the catalyzing ketone compound asymmetric reduction for being capable of high selectivity obtains the chirality of high-optical-purity
Alcohol, compared with chemical catalysis carbonyl asymmetric reduction, the carbonyl asymmetric reduction of carbonyl reduction enzyme process catalysis has good standing
Body selectivity, reaction condition is gentle, product optical purity is high, accessory substance is few, high income, the outstanding advantage such as environment-friendly, in hand
Property medicine and its intermediate production in act on increasingly important.The inventive method is simple to operate, reaction condition is gentle, pollution is small and produces
Product high income, optical purity are good, are adapted to large-scale production, greatly reduce the discharge of energy consumption and organic wastewater, are more suitable for big
The requirement that technical scale metaplasia is produced.
Specific embodiment
The present invention will be expanded on further the preparation of the compound of Formulas I of the present invention with following examples, but to this
Invention is without limitation.
Following examples are merely to illustrate specific embodiment of the invention so that those skilled in the art it will be appreciated that
The present invention, but be not used in and limit the scope of the invention.In specific embodiment of the invention, the technology being not specifically noted
Means or method etc. are ordinary skill in the art means or method etc., are not specifically noted, raw material and examination used by the present invention
Agent is commercially available prod.Unless otherwise indicated, all of part of the present invention and percentage are by weight, and all temperature are equal
Finger degree Celsius.
Following abbreviations have been used in embodiment：
DCM：Dichloromethane；
EA：Ethyl acetate；
ee：Optical purity
g：Gram；
HPLC：High performance liquid chromatography；
min：Minute；
ml：Milliliter；
H or hr：Hour
TEPA：Phosphine acyl acetic acid three ethyl；
TLC：Thin-layer chromatography.
Compound in the present invention can be used in but be not limited to be closed using following one or more general reaction schemes
Into：
Generally, the general synthetic method system that the compound that the present invention is provided can be described according to general routes outlined I
It is standby, but the present invention provide compound be not limited in being prepared using the route.Subsequent embodiment is more specifically explained
General synthetic method in general routes outlined I, so that one of ordinary skill in the art can prepare and use present invention offer
Compound.
General routes outlined I
Embodiment 1：The culture of carbonyl reductase thalline
Seed culture：
Culture medium prescription：Peptone 1.0%, yeast extract 0.5%, sodium chloride 0.5%, pH7.0 before sterilization, precursor of sterilizing
Product 100mL (1000mL shaking flasks), cools down after sterilizing, adds 100uL concentration to be 10mg/mL ammonia benzyl moulds in seed bottle under germ-free condition
Element and 0.1mL glycerol tubes bacterium solution (Escherichia coli, E.Coli BL21), in 37 DEG C of shaking table cultures, rotating speed 200rpm, incubation time
It is 18-20 hours.
Fermented and cultured：
Culture medium prescription：Peptone 2.0%, yeast extract 1.0%, sodium chloride 0.5%, bubble enemy (defoamer) 0.02%,
Glycerine 0.2%.PH7.5 before sterilization, sterilization front volume 5L (10L fermentation tanks)；Accessed by flame inoculation after medium sterilization
Cultured seed culture fluid is fermented, and condition of culture is 30 ± 0.5 DEG C of fermentation temperature, air mass flow 5L/min, rotating speed 500
Rev/min, tank pressure 0.03-0.05MPa；Culture adds the isopropyl-β-D- of 10mg/L under flame condition from tank mouth after 6 hours
Thiogalactopyranoside (IPTG), starts simultaneously at feed supplement, adds glycerine 15-20 by fermentating liquid volume 0.1-0.15% per hour
Hour, control fermentation pH7.0 with 20% phosphoric acid and 17% ammoniacal liquor；Induction 15 hours, bacteria concentration reaches more than 5% stopping fermentation；
After putting tank, thalline about 400g is collected by centrifugation, thalline is stored in standby in -20 DEG C of refrigerators.
Embodiment 2：The preparation of the chloro- 1-S- of 2- (3,4- difluorophenyl) ethanol (II)
The chloro- 1- of 40g 2- (3,4- difluorophenyl) ethyl ketone, 200ml water are sequentially added in the 500ml four-hole bottles of band stirring
In the mixed solvent of 100ml isopropanols, stirring is opened, adds the thalline 20g containing carbonyl reductase obtained in embodiment 1,
It is warming up to 30 DEG C and starts reaction, the residual of 2- chloro- 1- (3,4- difluorophenyl) ethyl ketone is detected every 0.5h samplings after 3h and with HPLC
Stay, reaction is filtered to remove thalline after terminating, filtrate is extracted with toluene, toluene is filtered after being dried with anhydrous magnesium sulfate, is concentrated to give
To 39.5g yellow oilies compound (II), yield 98.8%, HPLC purity 98.5%, ee values 99.9%.
Embodiment 3：The preparation of the chloro- 1-S- of 2- (3,4- difluorophenyl) ethanol (II)
Band stirring 500ml four-hole bottles in sequentially add the chloro- 1- of 40g2- (3,4- difluorophenyl) ethyl ketone, 200ml water and
In the mixed solvent of 40ml tetrahydrofurans, stirring is opened, add the thalline 12g containing carbonyl reductase obtained in embodiment 1, risen
Temperature starts to react to 40 DEG C, and the residual of 2- chloro- 1- (3,4- difluorophenyl) ethyl ketone is detected every 0.5h samplings after 3h and with HPLC,
Reaction is filtered to remove thalline after terminating, filtrate is extracted with EA, and EA phases are filtered after being dried with anhydrous magnesium sulfate, are concentrated to give 39.1g
Yellow oily compound (II), yield 96.7%, HPLC purity 98.6%, ee values 99.8%.
Embodiment 4：The preparation of the chloro- 1-S- of 2- (3,4- difluorophenyl) ethanol (II)
The chloro- 1- of 40g 2- (3,4- difluorophenyl) ethyl ketone, 200ml water are sequentially added in the 500ml four-hole bottles of band stirring
In the mixed solvent of 400ml methyl alcohol, stirring is opened, add the thalline 32g containing carbonyl reductase obtained in embodiment 1, risen
Temperature starts to react to 20 DEG C, and the residual of 2- chloro- 1- (3,4- difluorophenyl) ethyl ketone is detected every 0.5h samplings after 3h and with HPLC,
Reaction is filtered to remove thalline after terminating, filtrate is extracted with DCM, and DCM phases are filtered after being dried with anhydrous magnesium sulfate, are concentrated to give
37.6g yellow oilies compound (II), yield 93.0%, HPLC purity 98.6%, ee values 99.8%.
Embodiment 5：The preparation of (2S) -2- (3,4- difluorophenyl) oxirane (III)
39g compounds (II), 120ml toluene and 120ml 15% are sequentially added in the 500ml four-hole bottles of band stirring
Sodium hydroxide solution, opens stirring, is warming up to 35 DEG C of reaction 2h, and reaction terminates rear split-phase and uses toluene aqueous phase extracted, toluene phase
Filtered after being dried with anhydrous magnesium sulfate, be concentrated to give 30.7g compounds (III), yellow oil, yield 97.2%, HPLC is pure
Degree 98.0%.
Embodiment 6：The preparation of (2S) -2- (3,4- difluorophenyl) oxirane (III)
38g compounds (II), 120ml toluene and 120ml 15% are sequentially added in the 500ml four-hole bottles of band stirring
KOH solution, opens stirring, is warming up to 25 DEG C of reaction 4h, and reaction terminates rear split-phase and with 60ml toluene aqueous phase extracteds, and toluene is mutually used
Anhydrous magnesium sulfate is filtered after drying, and is concentrated to give 28.9g yellow oilies compound (III), yield 93.8%, HPLC purity
98.1%.
Embodiment 7：The preparation of (2S) -2- (3,4- difluorophenyl) oxirane (III)
37g compounds (II), 120ml DCM and 120ml 15% are sequentially added in the 500ml four-hole bottles of band stirring
Sodium hydroxide solution, opens stirring, is warming up to 50 DEG C of reaction 1h, and reaction terminates rear split-phase and with 60ml DCM aqueous phase extracteds, DCM
Filtered after being dried with anhydrous magnesium sulfate, be concentrated to give 29.0g yellow oilies compound (III), yield 96.7%, HPLC purity
98.0%.
Embodiment 8：The preparation of (1R, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid ethyl ester (IV)
74g sodium tert-butoxides and 350ml toluene are sequentially added in the 1000ml four-hole bottles of band stirring, is controlled below 30 DEG C
The 100ml toluene solutions of 87g TEPA are added dropwise, control 1h is dripped off, and 30 DEG C of insulation 1h, then heat to 50 DEG C after dripping off, and are added dropwise
The 100ml toluene solutions of 30g compounds (III), control 1h is dripped off, and 70 DEG C is warming up to after dripping off and continues to react 16h, and TLC is monitored,
Reaction is cooled to less than 10 DEG C and adds 600ml water to stir 5min after terminating, point liquid, 300ml washing organic phases, organic phase nothing
Water magnesium sulfate is filtered after drying, and is concentrated to give 40.5g yellow oilies compound (IV), yield 93.8%, HPLC purity 92.5%.
Embodiment 9：The preparation of (1R, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid ethyl ester (IV)
72g sodium tert-butoxides and 350ml glycol dimethyl ethers are sequentially added in the 1000ml four-hole bottles of band stirring, control exists
Less than the 30 DEG C 100ml ethylene glycol dimethyl ether solutions that 84g TEPA are added dropwise, control 1h is dripped off, 30 DEG C of insulation 1h after dripping off, then
50 DEG C are warming up to, the 100ml ethylene glycol dimethyl ether solutions of 28g compounds (III) are added dropwise, control 1h is dripped off, is warming up to after dripping off
70 DEG C are continued to react 16h, TLC monitorings, and reaction is cooled to less than 10 DEG C and adds 600ml water to stir 5min after terminating, point liquid,
300ml washes organic phase, and organic phase is filtered after being dried with anhydrous magnesium sulfate, is concentrated to give 37.6g yellow oilies compound (IV),
Yield 92.7%, HPLC purity 92.0%.
Embodiment 10：The preparation of (1R, 2R) -2- (3,4- difluorophenyl) ethylene-acetic acid ethyl ester (IV)
72g sodium hydrides and 350ml toluene are sequentially added in the 1000ml four-hole bottles of band stirring, control is dripped below 30 DEG C
Plus the 100ml toluene solutions of 84g TEPA, control 1h to drip off, 30 DEG C of insulation 1h, then heat to 50 DEG C after dripping off, and 30g is added dropwise
The 100ml toluene solutions of compound (III), control 1h is dripped off, and 70 DEG C is warming up to after dripping off and continues to react 16h, and TLC is monitored, instead
Less than 10 DEG C are cooled to after should terminating and 600ml water is added, stirred 5 minutes, point liquid, 300ml washing organic phases, organic phase nothing
Water magnesium sulfate is filtered after drying, and is concentrated to give 3g.0g yellow oilies compound (IV), yield 93.7%, HPLC purity 92.2%.
Embodiment 11：The preparation of (1R, 2R) -2- (3,4- difluorophenyl) cyclopropyl carboxamide (V)
To sequentially adding 40g compounds (IV), 20% ammonia methanol solution 160ml, 30% sodium methoxide in 350ml pressure bottles
Methanol solution 72ml, 70 DEG C of reaction 12h are warming up to after tightening bottle cap, and reaction adds water under room temperature, stirring are cooled to after terminating
200ml, is cooled to 20 DEG C of crystallization below after adding, filtering, washing, dry 31.5g compound as white solid (V), yield
90.3%, HPLC purity 98.5%.
Embodiment 12：The preparation of (1R, 2R) -2- (3,4- difluorophenyl) cyclopropyl carboxamide (V)
To sequentially adding 37g compounds (IV), 20% ammonia methanol solution 160ml, 30% sodium methoxide in 350ml pressure bottles
Methanol solution 70ml, 50 DEG C of reaction 20h are warming up to after tightening bottle cap, and reaction adds water under room temperature, stirring are cooled to after terminating
200ml, is cooled to 20 DEG C of crystallization below after adding, filtering, washing, dry 28.9g compound as white solid (V), yield
89.6%, HPLC purity 98.2%.
Embodiment 13：The preparation of (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (I)
30g compounds (V) and the sodium hydroxide solutions of 200g 30% are added in the 1000ml four-hole bottles of band stirring, is opened
Stir and lower the temperature, control 0~5 DEG C 12% liquor natrii hypochloritis 260g is added dropwise, about 1h is dripped off, continue to stir clear to solution after dripping off
It is warming up to 65 DEG C after clear to continue to react 1h, reaction is cooled to less than 5 DEG C after terminating, and pH8~8.5 is adjusted with concentrated hydrochloric acid, then with two
Chloromethanes is extracted, and organic phase is filtered after being dried with anhydrous magnesium sulfate, is concentrated to give 20.8g yellow oilies compound (I), yield
80.8%, HPLC purity 98.9%.
Embodiment 14：The preparation of (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine (I)
28g compounds (V) and the ammoxidation potassium solutions of 200g 30% are added in the 1000ml four-hole bottles of band stirring, is opened
Stir and lower the temperature, control 0~5 DEG C 12% liquor natrii hypochloritis 251g is added dropwise, about 1h is dripped off, continue to stir clear to solution after dripping off
It is warming up to 65 DEG C after clear to continue to react 1h, reaction is cooled to less than 5 DEG C after terminating, and pH8~8.5 is adjusted with concentrated hydrochloric acid, then with two
Chloromethanes is extracted, and organic phase is filtered after being dried with anhydrous magnesium sulfate, is concentrated to give 17.9g yellow oilies compound (I), yield
74.5%, HPLC purity 98.6%.
Embodiment 15：The preparation of (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine D- mandelates (VI)
Addition 20g compounds (I) and 100ml methyl alcohol in the 500ml four-hole bottles of band stirring, unlatching stirring and temperature control 25~
28 DEG C, the 180ml methanol solutions of 22g D- mandelic acids are added dropwise, continue to react 12h after dripping off, filter and wash filter with a small amount of methyl alcohol
Cake, dries, and obtains 24.3g compound as white solid (VI), yield 50.6%, HPLC purity 99.8%, ee values 99.9%.
Embodiment 16：The preparation of (1R, 2S) -2- (3,4- difluorophenyl) cyclopropylamine D- mandelates (VI)
Addition 17g compounds (I) and 100ml ethanol in the 500ml four-hole bottles of band stirring, unlatching stirring and temperature control 30~
35 DEG C, the 180ml ethanol solutions of 20g D- mandelic acids are added dropwise, continue to react 15h after dripping off, filter and wash filter with a small amount of ethanol
Cake, dries, and obtains 16.5g compound as white solid (VI), yield 50.1%, HPLC purity 99.8%, ee values 99.9%.
Claims (10)
1. the preparation method of the salt shown in ticagrelor intermediate shown in compound (I) and compound (VI), it is characterised in that
Comprise the following steps：
(1) with the chloro- 1- of 2- (3,4- difluorophenyl) ethyl ketone for raw material, reduction obtains high selectivity under the catalysis of carbonyl reductase
Compound (II)；
(2) compound (II) that will be obtained in step (1) reacts obtain compound (III) in the basic conditions；
(3) compound (III) that will be obtained in step (2) reacts with phosphine acyl acetic acid three ethyl (TEPA) in the basic conditions
To compound (IV)；
(4) compound (IV) that will be obtained in step (3) carries out ammonolysis and obtains compound (V)；
(5) compound (V) that will be obtained in step (4) carries out Hofmann degradation and obtains compound (I)；
(6) compound (I) that will be obtained in step (5) obtains compound (VI) with D- almond acid reactions.
2. preparation method according to claim 1, it is characterised in that carbonyl reductase used is large intestine in step (1)
Bacillus E.Coli BL21；Solvent for use is the mixture of water and organic solvent, and organic solvent is methyl alcohol, ethanol, isopropanol, four
The ratio of hydrogen furans and dioxane, water and organic solvent is 1: 0.2~2, preferably isopropanol.
3. preparation method according to claim 1, it is characterised in that the chloro- 1- of 2- (3,4- difluorophenyl) second in step (1)
The concentration of ketone is 1 with the weight ratio of the thalline containing carbonyl reductase for the chloro- 1- of 5~20%, 2- (3,4- difluorophenyl) ethyl ketones:
0.2~1.
4. preparation method according to claim 1, it is characterised in that the range of reaction temperature described in step (1) is 20
~40 DEG C, reaction pH is 7.0~8.0,2~10h of reaction time.
5. preparation method according to claim 1, it is characterised in that Extraction solvent described in step (1) be ethyl acetate,
Benzene, toluene, dichloromethane or dichloroethanes, preferably toluene.
6. preparation method according to claim 1, it is characterised in that solvent described in step (2) is benzene, toluene, dichloro
Methane or dichloroethanes, preferably toluene；Described alkali is NaOH, potassium hydroxide or lithium hydroxide, preferably NaOH；Institute
The range of reaction temperature stated is 20~50 DEG C；Described 1~5h of reaction time.
7. preparation method according to claim 1, it is characterised in that solvent described in step (3) is benzene, toluene, diformazan
Benzene or glycol dimethyl ether, preferably toluene；Described alkali is sodium tert-butoxide, potassium tert-butoxide or sodium hydride, preferably sodium tert-butoxide；Institute
The range of reaction temperature stated is 10~100 DEG C；The described reaction time is 10~24h.
8. preparation method according to claim 1, it is characterised in that the solvent described in step (4) is methyl alcohol, ethanol,
Acetone or tetrahydrofuran, preferably methyl alcohol；Described range of reaction temperature is 30~80 DEG C, and the described reaction time is 6~20h.
9. preparation method according to claim 1, it is characterised in that the solvent described in step (5) is water, methyl alcohol, second
Alcohol, benzene, toluene or dichloromethane, preferably water and dichloromethane；Described range of reaction temperature is 0~70 DEG C；Described reaction
1~5h of time；Described alkali is NaOH, potassium hydroxide or lithium hydroxide, preferably NaOH.
10. preparation method according to claim 1, it is characterised in that the solvent described in step (6) is methyl alcohol, ethanol,
Acetone or tetrahydrofuran, preferably methyl alcohol；Range of reaction temperature described in step (6) is 15~35 DEG C；The described reaction time
It is 6~15h.
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| CN107686447A (en) * | 2017-08-25 | 2018-02-13 | 许昌恒生制药有限公司 | A kind of preparation method of ticagrelor intermediate |
| CN111575334A (en) * | 2020-06-03 | 2020-08-25 | 湖州颐盛生物科技有限公司 | Method for preparing (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol |
| CN111747916A (en) * | 2019-03-27 | 2020-10-09 | 尚科生物医药（上海）有限公司 | Preparation method of (R) -2- (2-methoxyphenyl) -2- (tetrahydropyran-4-oxy) ethan-1-ol |
| CN115368245A (en) * | 2021-05-20 | 2022-11-22 | 上海医药工业研究院 | Preparation method of (1R, 2S) - (3, 4-difluorophenyl) cyclopropylamine hydrochloride crystal form |
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| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
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| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
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| CN107686447A (en) * | 2017-08-25 | 2018-02-13 | 许昌恒生制药有限公司 | A kind of preparation method of ticagrelor intermediate |
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| CN111575334A (en) * | 2020-06-03 | 2020-08-25 | 湖州颐盛生物科技有限公司 | Method for preparing (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol |
| CN111575334B (en) * | 2020-06-03 | 2021-09-07 | 湖州颐盛生物科技有限公司 | Method for preparing (S) -2-chloro-1- (3, 4-difluorophenyl) ethanol |
| CN115368245A (en) * | 2021-05-20 | 2022-11-22 | 上海医药工业研究院 | Preparation method of (1R, 2S) - (3, 4-difluorophenyl) cyclopropylamine hydrochloride crystal form |
| CN115368245B (en) * | 2021-05-20 | 2024-03-22 | 上海医药工业研究院 | Preparation method of hydrochloride crystal form of (1R, 2S) - (3, 4-difluorophenyl) cyclopropylamine |
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