CN108083997A - A kind of preparation method of chiral aryl cyclopropyl amine derivatives - Google Patents
A kind of preparation method of chiral aryl cyclopropyl amine derivatives Download PDFInfo
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- CN108083997A CN108083997A CN201711123319.3A CN201711123319A CN108083997A CN 108083997 A CN108083997 A CN 108083997A CN 201711123319 A CN201711123319 A CN 201711123319A CN 108083997 A CN108083997 A CN 108083997A
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- C07—ORGANIC CHEMISTRY
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
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- C07C247/22—Compounds containing azido groups with azido groups acylated by carboxylic acids with the acylating carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
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Abstract
The present invention provides a kind of preparation methods of chiral aryl cyclopropyl amine derivatives; using halogeno-benzene or phenyl polyhalide as starting material; it is prepared through Friedel-Crafts reaction, asymmetric reduction reaction, ring-closure reaction, acylation reaction, hydrolysis and Ku Ertisi rearrangement reactions, the halogeno-benzene or phenyl polyhalide are preferably o-difluoro-benzene, 2 chlorofluorobenzenes or fluorobenzene.It is an advantage of the invention that：Using carbonyl asymmetric reduction, acylating reagent carries out structure cyclopropyl ester structure, avoids, using chiral auxiliaries, compared with prior art route, shortening reaction scheme, improving reaction yield；Primary amine is prepared using acyl azide rearrangement simultaneously, easy to operate, yield higher, more suitable for large-scale industrial production.
Description
Technical field
The present invention relates to field of medicine production, and in particular to a kind of preparation method of chiral aryl cyclopropyl amine derivatives.
Background technology
Chiral aryl cyclopropylamine compound is to synthesize important intermediate during Ticagrelor, contains two in molecular structure
A chiral centre.Ticagrelor (Ticagrelor) be by AstraZeneca (AstraZeneca) company research and development it is a kind of it is new,
Selective small molecule anticoagulant, in July, 2011 are ratified to list in U.S. FDA.Ticagrelor can reversibly be made
2 receptor subtype P2Y12 of purine in vascular smooth muscle cells, is not required metabolic activation, to adenosine diphosphate (ADP)（ADP）Cause
Platelet aggregation have apparent inhibitory action, and it is rapid to work after being administered orally, and can effectively improve acute coronary patient's
Symptom.Different from Thienopyridines drug, Ticagrelor is reversible inhibitor to P2Y12 receptors, so need to be for those
It is especially suitable that the patient that row is performed the operation again after anticoagulant therapy is carried out in advance.The preparation of chiral aryl cyclopropyl amine derivatives, the prior art
There are the drawbacks such as operation is relatively complicated, and feed stock conversion is low in route.
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of preparation method of chiral aryl cyclopropyl amine derivatives, behaviour
Make easy, yield higher.
The technical solution adopted by the present invention is：
A kind of preparation method of chiral aryl cyclopropyl amine derivatives, it is anti-through Fu Ke using halogeno-benzene or phenyl polyhalide as starting material
It answers, asymmetric reduction reaction, ring-closure reaction, acylation reaction, hydrolysis and Ku Ertisi rearrangement reactions are prepared.
Further, the halogeno-benzene or phenyl polyhalide are preferably o-difluoro-benzene, 2- chlorofluorobenzenes or fluorobenzene.
Further, specific preparation process is as follows：
A, the preparation of intermediate compound I N-1：Halogeno-benzene or phenyl polyhalide under the action of lewis acid catalyst, with chloracetyl chloride into
Row friedel-crafts acylation, is prepared IN-1；
B, the preparation of intermediate compound I N-2：IN-1 is reduced to IN-2 under the effect of the catalyst, through reducing agent；
C, the preparation of intermediate compound I N-3：IN-3 is prepared under the action of alkali in IN-2；
D, the preparation of intermediate compound I N-4：IN-4 is obtained by the reaction with esterifying agent under highly basic effect in IN-3；
E, the preparation of intermediate compound I N-5：The ester group of IN-4 is prepared into intermediate compound I N-5 through basic hydrolysis；
F, the preparation of intermediate compound I N-6：IN-5 is prepared into intermediate compound I N- in reaction dissolvent after acylation with reaction of sodium azide
6；G, the preparation of purpose product chiral aryl cyclopropyl amine derivatives IN-C：IN-6 occurs Ku Ertisi in the case where acid acts on and resets instead
Should, obtain purpose product IN-C；
Wherein：The molecular structural formula of IN-1 is；
The molecular structural formula of IN-2 is；
The molecular structural formula of IN-3 is；
The molecular structural formula of IN-4 is；
The molecular structural formula of IN-5 is；
The molecular structural formula of IN-6 is；
The molecular structural formula of IN-C is；
R1, R2 in above-mentioned molecular structural formula are selected from F, Cl and H.
Further, the lewis acid catalyst in the step a is preferably alchlor, zinc chloride or magnesium chloride, and
The molar ratio of the lewis acid catalyst and halogeno-benzene or phenyl polyhalide is：1.5~1.8:1.0.
Further, the catalyst in the step b includes S-CBS-4 and trimethylborate, and reducing agent is borine diformazan
Thioether, and the molar ratio of the catalyst S-CBS-4 and intermediate compound I N-1 is：0.05:1.0, the catalyst trimethylborate
Molar ratio with intermediate compound I N-1 is：0.1:1.0, the molar ratio of the reducing agent and intermediate compound I N-1 is：2~3:1.0.
Further, the alkali in the step c is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide.
Further, the highly basic in the step d is preferably sodium tert-butoxide or potassium tert-butoxide, and esterifying agent is phosphinylidyne guanidine-acetic acid
Triethyl, and the molar ratio of the highly basic and intermediate compound I N-3 is：1.5~1.8:1.0, the esterifying agent is with intermediate compound I N-3's
Molar ratio is：1.3~1.5:1.0.
Further, the acid in the step e is selected from hydrochloric acid, sulfuric acid and acetic acid, is preferably dilute hydrochloric acid.
Further, the molar ratio of the sodium azide and intermediate compound I N-5 in the step e is：1.2~1.5:1.0.
Further, the reaction dissolvent in the step e is selected from DMF, dimethyl sulfoxide (DMSO) and dichloromethane.
The beneficial effects of the invention are as follows：For the present invention using carbonyl asymmetric reduction, acylating reagent carries out structure cyclopropyl ester
Structure avoids, using chiral auxiliaries, compared with prior art route, shortening reaction scheme, improving reaction yield；Simultaneously should
Primary amine is prepared with acyl azide rearrangement, easy to operate, yield higher, more suitable for large-scale industrial production.
Specific embodiment
In order to deepen the understanding of the present invention, below in conjunction with embodiment, the invention will be further described, the embodiment
It is only used for explaining the present invention, be not intended to limit the scope of the present invention..
Embodiment 1
A, the preparation of intermediate compound I N-1：1000mL dichloromethane, 200g are added in reaction bulb（1.5mol, 1.5eq）Tri-chlorination
Aluminium, stirring, is then added dropwise 136g at 0-5 DEG C（1.2mol, 1.2eq）Chloracetyl chloride；Drop finishes, and stirring is warming up to reflux, drips
Add 114g（1.0mol, 1eq）1,2- difluorobenzenes；Drop finishes, back flow reaction；25 DEG C are cooled to again, is pumped into 500g ice water, and stirring is quiet
Put liquid separation, water layer dichloromethane（500mL×2）Extraction merges organic phase, uses water（800mL×2）, saturated sodium bicarbonate it is molten
Liquid（800mL）And saturated nacl aqueous solution（800mL）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains 175.3g products.It rubs
That yield：92%；
B, the preparation of intermediate compound I N-2：200mL toluene and 12.7g S-CBS-4 are put into reaction bulb（0.05mol,
0.05eq）, stirring；Under nitrogen protection, 9.5g trimethylborates are put into（0.09mol, 0.1eq）, 50 DEG C or so are warming up to, heat preservation
Then 230mL 10mol/L borane dimethylsulf iotades are added dropwise in reaction（2.3mol, 2.5eq）；Drop finishes, and is reacted at 45-50 DEG C, so
The toluene solution of IN-1 is added dropwise afterwards（175.3g, 0.92mol, 1 eq, 550mL toluene）；Drop finishes, insulation reaction, is controlled in TLC anti-
It should；Reaction finishes, and is cooled to 20-25 DEG C, and 200g methanol is added dropwise and is quenched；It is quenched and finishes, remove methanol under reduced pressure；It is molten with HCl
Liquid washs 2 times, combining water layer, is extracted with 800mL toluene, remerges organic phase, and with 5% hydrogen peroxide of 200mL, 200mL saturations
Sodium chloride solution washs, and gained IN-2 toluene solutions directly carry out next step reaction；
C, the preparation of intermediate compound I N-3：IN-2 toluene solutions, stirring cooling, by 73.6g are added in reaction bulb（1.84mol
2eq）Sodium hydroxide is dissolved in 100g water, is added to after being cooled to room temperature in above-mentioned reaction solution, is stirred to react at room temperature, in TLC
Control reaction；Reaction finishes, and stands liquid separation, and water layer is extracted once with 800mL toluene, is merged organic phase, is used water（500mL×2）, satisfy
And sodium chloride solution（500mL×1）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, obtains 119.2g products, yield：83%；
D, the preparation of intermediate compound I N-4：109.7g is added in reaction bulb（1.14mol 1.5eq）Sodium tert-butoxide, 800mL first
Benzene, stirring, is then added dropwise 219.4g at room temperature（0.98mol, 1.3eq）Phosphonoacetate；Drop finishes, and stirs 15min
After be warming up to 50 DEG C of reactions；The toluene solution of IN-3 is added dropwise at 50 DEG C（119.2g, 0.76mol, 1eq, 500mL toluene）；Drop
Finish, about 3h is reacted at 50 DEG C, reaction is controlled in TLC；Reaction finishes, and is cooled to room temperature, reaction solution water（800mL×3）Washing,
Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure, is obtained 136.4g oily products.Molar yield：79%；
E, the preparation of intermediate compound I N-5：600mL methanol and 136.4g IN-4, stirring and dissolving are added in reaction bulb, then is slowly taken out
Enter prepared 300mL 2N sodium hydroxide solutions, then react 2h at room temperature, reaction is controlled in TLC；Reaction finishes, at 50 DEG C
Under remove methanol under reduced pressure, add in 200mL water, be cooled to 10 DEG C, use ether（200mL×3）It is counter to carry, then water layer concentrated hydrochloric acid tune
PH=1-3, then use ether（200mL×2）Extraction；Activated carbon is added in ether layer, is warmed to room temperature, is filtered, anhydrous sodium sulfate is done
It is dry, it is concentrated under reduced pressure, obtains 93.2g solid products.Molar yield：78%；
F, the preparation of intermediate compound I N-6：93.2g IN-5 are put into reaction bulb（0.47mol, 1eq）And 200mLDMF, 300mL
Dichloromethane, stirring and dissolving.It opens condensed water and mixes drying tube.20--25 DEG C of dropwise addition 89.6g oxalyl chloride（0.71mol,
1.5eq）, it is added dropwise, heating mantle is warming up to back flow reaction 3h.The reaction was complete, is cooled to 20-25 DEG C, decompression steams solvent, newly
Fresh dichloromethane 300ml bands are dry once, add in the dissolving of 225ml fresh toluenes, and gained toluene mixture liquid is for use；
36.9g sodium azide is put into reaction bulb（0.57mol, 1.2eq）, 2g tetrabutylammonium bromide, 50.4g sodium carbonate
（0.48mol, 1.0eq）And 100mL water.Stirring and dissolving is cooled to 0--5 DEG C.0--5 DEG C is added dropwise above-mentioned toluene mixture liquid, and drop finishes,
0--5 DEG C of insulation reaction controls reaction in TLC；Reaction finishes, and adds in the stirring of 200mL water, stands liquid separation, organic phase uses water respectively
（200ml×2）, saline solution（200ml×1）Washing, 0--5 DEG C of gained IN-6 toluene mixture liquids are placed for use；
G, the preparation of purpose product chiral aryl cyclopropyl amine derivatives IN-C：In reaction bulb, 200 mL toluene, heating mantle are put into
It is warming up to 100-105 DEG C.The toluene mixture liquid of above-mentioned IN-6 is added dropwise in 100-105 DEG C of temperature control.It is added dropwise, 100-105 DEG C of temperature control
It is stirred to react.It is cooled to 20-25 DEG C.Above-mentioned reaction solution is added dropwise in 300mL 1NHCL aqueous solutions, drop finishes, insulation reaction
Overnight.Reaction raw materials remain less, static layering, it is organic be added to 600 mL water stirring it is counter carry, merge water phase, addition 45%
It is 10 that NaOH solution, which adjusts pH value, ethyl acetate（300 ml×3）Extraction, combined ethyl acetate mutually use water respectively（200ml×
2）, brine（200ml×1）Washing, dry, evaporated under reduced pressure obtains 70.1g products, yield 85%.
Embodiment 2
A, the preparation of intermediate compound I N-1：500mL dichloromethane, 90.1g are added in reaction bulb（0.9mol, 1.8eq）Chlorination
Then 84.8g is added dropwise at 0-5 DEG C in zinc, 2g cuprous iodides, stirring（0.75mol, 1.5eq）Chloracetyl chloride；Drop finishes, stirring,
Reflux is warming up to, 65g is added dropwise（0.5mol, 1eq）Adjacent chlorofluorobenzene；Drop finishes, back flow reaction；25 DEG C are cooled to again, are pumped into 300g ice
Water, stirring stand liquid separation, water layer dichloromethane（300mL×2）Extraction merges organic phase, uses water（300mL×2）, saturation
Sodium bicarbonate solution（200mL）And saturated nacl aqueous solution（200mL）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains
93.2g products.Molar yield：90%；
B, the preparation of intermediate compound I N-2：200mL tetrahydrofurans and 5.1g S-CBS-4 are put into reaction bulb（0.02mol,
0.05eq）, stirring；Under nitrogen protection, 5.2g trimethylborates are put into（0.05mol, 0.1eq）, 50 DEG C or so are warming up to, heat preservation
Then 135mL 10mol/L borane dimethylsulf iotades are added dropwise in reaction（1.35mol 3.0eq）；Drop finishes, and is reacted at 45-50 DEG C, so
The toluene solution of IN-1 is added dropwise afterwards（93.2g, 0.45mol, 1eq, 300mL tetrahydrofuran）；Drop finishes, insulation reaction, is controlled in TLC anti-
It should；Reaction finishes, and is cooled to 20-25 DEG C, and 100g methanol is added dropwise and is quenched；Be quenched and finish, remove under reduced pressure methanol and；Use HCl
Solution washs 2 times, and combining water layer uses toluene（500mL×2）Extraction, remerges organic phase, and with 5% hydrogen peroxide of 100mL,
200mL saturated nacl aqueous solutions wash, and gained IN-2 toluene solutions directly carry out next step reaction；
C, the preparation of intermediate compound I N-3：IN-2 toluene solutions, stirring cooling, by 36g sodium hydroxides are added in reaction bulb
（0.9mol, 2eq）It is dissolved in 100g water, is added to after being cooled to room temperature in above-mentioned reaction solution, is stirred to react at room temperature, in TLC
Control reaction；Reaction finishes, and stands liquid separation, and water layer is extracted once with 500mL toluene, is merged organic phase, is used water（300mL×2）, satisfy
And sodium chloride solution（300mL×1）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, obtains 63.8g products, yield：82%；
D, the preparation of intermediate compound I N-4：75.1g is added in reaction bulb（0.67mol, 1.8eq）Potassium tert-butoxide, 800mL toluene,
Stirring, is then added dropwise 125.4g at room temperature（0.56mol, 1.5eq）Phosphonoacetate；Drop finishes, and is risen after stirring 15min
Temperature to 50 DEG C reaction；The toluene solution of IN-3 is added dropwise at 50 DEG C（63.8g, 0.37mol1eq, 300mL toluene）；Drop finishes, 50
About 3h is reacted at DEG C, reaction is controlled in TLC；Reaction finishes, and is cooled to room temperature, reaction solution water（500mL×3）Washing, anhydrous sulphur
Sour sodium drying, is concentrated under reduced pressure, obtains 69.9g oily products.Molar yield：78%；
E, the preparation of intermediate compound I N-5：400mL ethyl alcohol and 69.9g IN-4, stirring and dissolving are added in reaction bulb, then is slowly taken out
Enter prepared 200mL 2N sodium hydroxide solutions, then react 2h at room temperature, reaction is controlled in TLC；Reaction finishes, at 50 DEG C
Under remove ethyl alcohol under reduced pressure, add in 200mL water, be cooled to 10 DEG C, use methyl tertiary butyl ether(MTBE)（150mL×3）Counter to carry, then water layer is used
Concentrated hydrochloric acid tune pH=1-3, then use methyl tertiary butyl ether(MTBE)（150mL×2）Extraction；Activated carbon is added in methyl tert-butyl ether layers, is risen to
Room temperature filters, and anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains 46.4g solid products.Molar yield：75%；
F, the preparation of intermediate compound I N-6：46.4g IN-5 are put into reaction bulb（0.23mol, 1eq）And 150mL dimethyl sulfoxide (DMSO)s
, 200mL dichloromethane, stirring and dissolving.It opens condensed water and mixes drying tube.20--25 DEG C of dropwise addition 54.8g oxalyl chloride
（0.43mol, 2.0eq）, it is added dropwise, heating mantle is warming up to back flow reaction 3h.The reaction was complete, is cooled to 20-25 DEG C, decompression is steamed
Go out solvent, fresh methylene chloride 200ml bands are dry once, add in the dissolving of 150ml fresh toluenes, and gained toluene mixture liquid is for use；
21.5g sodium azide is put into reaction bulb（0.33mol, 1.5eq）, 2g tetrabutylammonium bromide, 23.3g sodium carbonate
（0.22mol, 1.0eq）And 100mL water.Stirring and dissolving is cooled to 0--5 DEG C.0--5 DEG C is added dropwise above-mentioned toluene mixture liquid, and drop finishes,
0--5 DEG C of insulation reaction controls reaction in TLC；Reaction finishes, and adds in the stirring of 150mL water, stands liquid separation, organic phase uses water respectively
（100ml×2）, saline solution（100ml×1）Washing, 0--5 DEG C of gained IN-6 toluene mixture liquids are placed for use；
G, the preparation of purpose product chiral aryl cyclopropyl amine derivatives IN-C：In reaction bulb, 150 mL toluene, heating mantle are put into
It is warming up to 100-105 DEG C.The toluene mixture liquid of above-mentioned IN-6 is added dropwise in 100-105 DEG C of temperature control.It is added dropwise, 100-105 DEG C of temperature control
It is stirred to react.It is cooled to 20-25 DEG C.Above-mentioned reaction solution is added dropwise in 200mL 1N HCL aqueous solutions, drop finishes, insulation reaction
Overnight.Reaction raw materials remain less, static layering, it is organic be added to 400 mL water stirring it is counter carry, merge water phase, addition 45%
It is 10 that NaOH solution, which adjusts pH value, ethyl acetate（200 ml×3）Extraction, combined ethyl acetate mutually use water respectively（150ml×
2）, brine（150ml×1）Washing, dry, evaporated under reduced pressure obtains 27.8g products, yield 86%.
Embodiment 3
A, the preparation of intermediate compound I N-1：1000mL dichloromethane, 240g are added in reaction bulb（1.8mol, 1.8eq）Tri-chlorination
Aluminium, stirring, is then added dropwise 170g at 0-5 DEG C（1.5mol, 1.5eq）Chloracetyl chloride；Drop finishes, and stirring is warming up to reflux, drips
Add 96g（1.0mol, 1eq）Fluorobenzene；Drop finishes, back flow reaction；25 DEG C are cooled to again, are pumped into 800g ice water, stirring stands liquid separation,
Water layer dichloromethane（500mL×2）Extraction merges organic phase, uses water（800mL×2）, saturated sodium bicarbonate solution
（800mL）And saturated nacl aqueous solution（800mL）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, obtains 160.5g products.Mole
Yield：93%；
B, the preparation of intermediate compound I N-2：300mL toluene and 12.7gS-CBS-4 are put into reaction bulb（0.05mol, 0.05eq）,
Stirring；Under nitrogen protection, 9.6g trimethylborates are put into（0.09mol, 0.1eq）, it is warming up to 50 DEG C or so, insulation reaction, so
186mL 10mol/L borane dimethylsulf iotades are added dropwise afterwards（1.86mol 2.0eq）；Drop finishes, and reacts at 45-50 DEG C, is then added dropwise
The toluene solution of IN-1（160.5g, 0.93mol, 1eq, 600mL toluene）；Drop finishes, insulation reaction, and reaction is controlled in TLC；It has reacted
Finish, be cooled to 20-25 DEG C, 250g methanol is added dropwise and is quenched；It is quenched and finishes, remove methanol under reduced pressure；It is washed 2 times with HCl solution,
Combining water layer is extracted with 800mL toluene, remerges organic phase, and with 5% hydrogen peroxide of 200mL, 200mL saturated nacl aqueous solutions
Washing, gained IN-2 toluene solutions directly carry out next step reaction；
C, the preparation of intermediate compound I N-3：IN-2 toluene solutions are added in reaction bulb, stirring cooling is molten by 74.8g sodium hydroxides
（1.86mol 2eq）In 120g water, it is added to after being cooled to room temperature in above-mentioned reaction solution, is stirred to react at room temperature, in TLC
Control reaction；Reaction finishes, and stands liquid separation, and water layer is extracted once with 800mL toluene, is merged organic phase, is used water（600mL×2）, satisfy
And sodium chloride solution（600mL×1）Washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure into dry, obtains 102.8g products, yield：80%；
D, the preparation of intermediate compound I N-4：128.9g is added in reaction bulb（1.34mol 1.8eq）Sodium tert-butoxide, 1000mL first
Benzene, stirring, is then added dropwise 248.9g at room temperature（1.11mol 1.5eq）Phosphonoacetate；Drop finishes, and stirs 15min
After be warming up to 50 DEG C of reactions；The toluene solution of IN-3 is added dropwise at 50 DEG C（102.8g, 0.74mol, 1eq, 500mL toluene）；Drop
Finish, about 3h is reacted at 50 DEG C, reaction is controlled in TLC；Reaction finishes, and is cooled to room temperature, reaction solution water（800mL×3）Washing,
Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure, is obtained 117.8g oily products.Molar yield：76%；
E, the preparation of intermediate compound I N-5：500mL methanol and 117.8g IN-4, stirring and dissolving are added in reaction bulb, then is slowly taken out
Enter prepared 250mL 2N sodium hydroxide solutions, then react 2h at room temperature, reaction is controlled in TLC；Reaction finishes, at 50 DEG C
Under remove methanol under reduced pressure, add in 250mL water, be cooled to 10 DEG C, use ether（200mL×3）It is counter to carry, then water layer concentrated hydrochloric acid tune
PH=1-3, then use ether（200mL×2）Extraction；Activated carbon is added in ether layer, is warmed to room temperature, is filtered, anhydrous sodium sulfate is done
It is dry, it is concentrated under reduced pressure, obtains 77.4g solid products.Molar yield：76%；
F, the preparation of intermediate compound I N-6：77.4g IN-5 (0.43mol, 1eq) and 150mLDMF, 250mL are put into reaction bulb
Dichloromethane, stirring and dissolving.It opens condensed water and mixes drying tube.20--25 DEG C of dropwise addition 97.2g oxalyl chloride（0.77mol,
1.8eq）, it is added dropwise, heating mantle is warming up to back flow reaction 3h.The reaction was complete, is cooled to 20-25 DEG C, decompression steams solvent, newly
Fresh dichloromethane 300ml bands are dry once, add in the dissolving of 300ml fresh toluenes, and gained toluene mixture liquid is for use；
41.7g sodium azide is put into reaction bulb（0.65mol, 1.5eq）, 2g tetrabutylammonium bromide, 54.2g sodium carbonate
（0.52mol, 1.2eq）And 150mL water.Stirring and dissolving is cooled to 0--5 DEG C.0--5 DEG C is added dropwise above-mentioned toluene mixture liquid, and drop finishes,
0--5 DEG C of insulation reaction controls reaction in TLC；Reaction finishes, and adds in the stirring of 300mL water, stands liquid separation, organic phase uses water respectively
（200ml×2）, saline solution（200ml×1）Washing, 0--5 DEG C of gained IN-6 toluene mixture liquids are placed for use；
G, the preparation of purpose product chiral aryl cyclopropyl amine derivatives IN-C：In reaction bulb, 300 mL toluene, heating mantle are put into
It is warming up to 100-105 DEG C.The toluene mixture liquid of above-mentioned IN-6 is added dropwise in 100-105 DEG C of temperature control.It is added dropwise, 100-105 DEG C of temperature control
It is stirred to react.It is cooled to 20-25 DEG C.Above-mentioned reaction solution is added dropwise in 300mL 1N HCL aqueous solutions, drop finishes, insulation reaction
Overnight.Reaction raw materials remain less, static layering, it is organic be added to 600 mL water stirring it is counter carry, merge water phase, addition 45%
It is 10 that NaOH solution, which adjusts pH value, ethyl acetate（300 ml×3）Extraction, combined ethyl acetate mutually use water respectively（200ml×
2）, brine（200ml×1）Washing, dry, evaporated under reduced pressure obtains 53.9g products, yield 83%.
Claims (10)
1. a kind of preparation method of chiral aryl cyclopropyl amine derivatives, which is characterized in that using halogeno-benzene or phenyl polyhalide as starting
Raw material, through Friedel-Crafts reaction, asymmetric reduction reaction, ring-closure reaction, acylation reaction, hydrolysis and Ku Ertisi rearrangement reaction systems
It is standby to obtain.
A kind of 2. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 1, which is characterized in that the halogen
It is preferably o-difluoro-benzene, 2- chlorofluorobenzenes or fluorobenzene for benzene or phenyl polyhalide.
A kind of 3. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 1, which is characterized in that specific system
Standby process is as follows：
A, the preparation of intermediate compound I N-1：Halogeno-benzene or phenyl polyhalide under the action of lewis acid catalyst, with chloracetyl chloride into
Row friedel-crafts acylation, is prepared IN-1；
B, the preparation of intermediate compound I N-2：IN-1 is reduced to IN-2 under the effect of the catalyst, through reducing agent；
C, the preparation of intermediate compound I N-3：IN-3 is prepared under the action of alkali in IN-2；
D, the preparation of intermediate compound I N-4：IN-4 is obtained by the reaction with esterifying agent under highly basic effect in IN-3；
E, the preparation of intermediate compound I N-5：The ester group of IN-4 is prepared into intermediate compound I N-5 through basic hydrolysis；
F, the preparation of intermediate compound I N-6：IN-5 is prepared into intermediate compound I N- in reaction dissolvent after acylation with reaction of sodium azide
6；G, the preparation of purpose product chiral aryl cyclopropyl amine derivatives IN-C：IN-6 occurs Ku Ertisi in the case where acid acts on and resets instead
Should, obtain purpose product IN-C；
Wherein：The molecular structural formula of IN-1 is；
The molecular structural formula of IN-2 is；
The molecular structural formula of IN-3 is；
The molecular structural formula of IN-4 is；
The molecular structural formula of IN-5 is；
The molecular structural formula of IN-6 is；
The molecular structural formula of IN-C is；
R1, R2 in above-mentioned molecular structural formula are selected from F, Cl and H.
A kind of 4. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Lewis acid catalyst in rapid a is preferably alchlor, zinc chloride or magnesium chloride, and the lewis acid catalyst with it is halogenated
The molar ratio of benzene or phenyl polyhalide is：1.5~1.8:1.0.
A kind of 5. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Catalyst in rapid b includes S-CBS-4 and trimethylborate, and reducing agent is borane dimethylsulf iotade, and the catalyst S-CBS-4
Molar ratio with intermediate compound I N-1 is：0.05:1.0, the molar ratio of the catalyst trimethylborate and intermediate compound I N-1 is：
0.1:1.0, the molar ratio of the reducing agent and intermediate compound I N-1 is：2~3:1.0.
A kind of 6. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Alkali in rapid c is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide.
A kind of 7. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Highly basic in rapid d is preferably sodium tert-butoxide or potassium tert-butoxide, and esterifying agent is phosphonoacetate, and the highly basic with it is intermediate
The molar ratio of body IN-3 is：1.5~1.8:1.0, the molar ratio of the esterifying agent and intermediate compound I N-3 is：1.3~1.5:1.0.
A kind of 8. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Acid in rapid e is selected from hydrochloric acid, sulfuric acid and acetic acid, is preferably dilute hydrochloric acid.
A kind of 9. preparation method of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that the step
Suddenly the molar ratio of the sodium azide and intermediate compound I N-5 in e is：1.2~1.5:1.0.
10. the preparation method of a kind of chiral aryl cyclopropyl amine derivatives according to claim 3, which is characterized in that described
Reaction dissolvent in step e is selected from DMF, dimethyl sulfoxide (DMSO) and dichloromethane.
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