CN104557563B - Method for synthesizing (R)-1-phenylbutylamine - Google Patents
Method for synthesizing (R)-1-phenylbutylamine Download PDFInfo
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Abstract
The invention discloses a method for synthesizing (R)-1- phenylbutylamine, and belongs to the technical field of synthesis of chiral amine. The method is characterized in that after 1-phenyl butyl-1-imine serving as a reactant is synthesized into salt, asymmetric catalytic hydrogenization is carried out on 1-phenyl butyl-1-imine salt in an acetic acid solvent under the action of a chiral catalyst, wherein the reaction pressure is 1-10 Mpa, the reaction temperature is 30-100 DEG C, the mass ratio of the raw material to the catalyst is 100-1,000,000, the reaction time is 1-20 h, the used chiral catalyst is an in-situ catalyst formed by stirring chiral diphosphine ligand, a dimerization iridium cyclooctadiene complex, tetrabutylammonium iodide and acetic acid under room temperature according to the mole ratio of 1.0:(1.2-3.0):(1.0-4.5):(1.0-25.0); after alkaline washing, purification is carried out, so that (R)-1-phenylbutylamine with optical activity is obtained.
Description
Technical field
A kind of synthesis（R）The method of -1- phenyibutylamines, belongs to the synthesis technical field of Chiral Amine, and in particular to Yi Zhongya
Amine Jing prepares the synthetic method of Chiral Amine into salt, asymmetric catalytic hydrogenation, alkali cleaning.
Background technology
（R）- 1- phenyibutylamine main usess are used as medicine intermediate,（R）- 1- phenyibutylamines are due to living with optics
Property, it is the high value intermediate of synthesis of chiral medicine.
Chiral pharmacy is the Disciplinary Frontiers of pharmaceuticals industry.In recent years, due to the high speed development and chirality of pharmaceutical industry
Outstanding representation of the medicine in clinicing aspect, chiral drug are increasingly subject to people's attention, and future drugs research and development it is important
Direction.With the development and the appearance of advanced analysis technology of synthetic method, increasing chiral drug can pass through chemosynthesis
Method is obtained, and asymmetric synthesis become the important means for obtaining chiral material.The global chiral drug market sales revenue in 2010 is
200,000,000,000 dollars are broken through,（R）- 1- phenyibutylamines are the important intermediate for synthesizing many chiral drugs, wide market.
（R）- 1- phenyibutylamines belong to the category of chipal compounds, are a kind of chiral primary amines.Its synthetic method is existing at present
Report.Merck Frosst Canada Ltd. provides a kind of with (R)-[(Me-BPE) in WO2009158308 patents
Rh(cod)BF4]、(R,S)-PFP-P(tBu)2[the Ir (cod) of combination2Cl]2、 [(R)-(tol-BINAP)RuCl2]2·Et3N
(R, S)-PFP-P (tBu)2The Ir (cod) of combination2BF4Four class catalyst system and catalyzings are catalyst, are catalyzed inferior amine salt hydrochlorate and prepare handss
Property primary amine, reaction yield and enantiomeric excess value it is higher, but expensive catalyst, complicated process of preparation are unfavorable for industrialized production.
The content of the invention
The technical problem to be solved in the present invention is：Overcome the deficiencies in the prior art, there is provided a kind of to high financial profit, prepare
A kind of synthesis of process is simple（R）The method of -1- phenyibutylamines.
The technical solution adopted for the present invention to solve the technical problems is：The synthesis（R）The method of -1- phenyibutylamines, its
It is characterised by, concrete synthesis step is：
（1）1- phenyl butyl- 1- imines and acid are synthesized into 1- phenyl butyl- 1- inferior amine salts in normal-pressure reaction kettle；
（2）1- phenyl butyl- 1- inferior amine salts, chiral catalyst and acetate solvate are added to into autoclave, hydrogen is passed through,
Asymmetric catalytic hydrogenation is carried out to 1- phenyl butyl- 1- inferior amine salts under chiral catalyst effect；Reaction pressure is 1 ~ 10Mpa, instead
Temperature is answered to be 30 ~ 100 DEG C, the ratio of raw material and catalyst quality is 100 ~ 1000000:1, the response time is 1 ~ 20h；Described
Chiral catalyst is massaged at room temperature for dimerization iridium cyclo-octadiene coordination compound, chiral diphosphine ligand, tetrabutylammonium iodide and acetic acid
That proportioning 1.0:（1.2~3.0）:（1.0~4.5）:（1.0~25.0）The situ catalytic agent that stirring is formed；
（3）Reactant is carried out into alkali cleaning, then is purified and is obtained with optically active（R）- 1- phenyibutylamines.
The method provided using the present invention, building-up process are included into salt, are carried out not using the chiral catalyst of economical and efficient
Asymmetric hydrogenation, alkali cleaning and separation.Can directly be prepared by 1- phenyl butyl- 1- imines（R）- 1- phenyibutylamines.Reaction is not right
Claim selectivity good, technological process is simple, can directly obtain（R）- 1- phenyibutylamines, it is to avoid chiral separation.Chiral catalyst used
Low cost, catalysis activity are high.
Step（1）Described acid is hydrochloric acid, sulphuric acid, phosphoric acid, formic acid or acetic acid；Aqueous acid mass concentration be 5% ~
38%.Wherein preferred hydrochloric acid and acetic acid, more preferably hydrochloric acid.Step（1）Described acid is Bronsted acid.Aqueous acid concentration, preferably
20~30%。
Step（2）Described dimerization iridium cyclo-octadiene coordination compound is [Ir (cod) Cl]2。
Step（2）The solvent is acetic acid.
Step（3）Described in alkali cleaning be using concentration for 20 ~ 40% sodium hydrate aqueous solution wash, alkali cleaning temperature 25 ~ 35
℃。
Step（1）The reaction condition of the synthesis 1- phenyl butyl- 1- inferior amine salts is：10 ~ 50 DEG C of reaction temperature；Response time
1~8h.Preferably 25 ~ 35 DEG C of reaction temperature；Response time preferably 3 ~ 5h.
Step（2）The chiral diphosphine ligand is (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] two (3,5- of ethyl
3,5-dimethylphenyl) phosphine, (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diethyl phenyls) phosphine, (R) -
Two (3,5- dipropyl phenyl) phosphine of 1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl or (R) -1- [(S) -2- (diphenyl
Phosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine.The chiral diphosphine ligand and [Ir (cod) Cl]2In the tetrabutyl
Situ catalytic agent made by stirring in the environment of ammonium iodide and acetic acid, it is very good to 1- phenyl butyl- 1- inferior amine salts to show
Affinity, the carrying capability of tetrabutylammonium iodide is by above-mentioned chiral diphosphine ligand and [Ir (cod) Cl]2Catalytic action have
The unification of effect simultaneously accelerates catalysis.Under acetic acid environment obtained situ catalytic agent with above-mentioned chiral diphosphine ligand and [Ir (cod)
Cl]2Not only increase affinity with reference to after, can more prevent the loss of catalyst.
To the with strong points of reactant 1- phenyl butyl- 1- inferior amine salts, adaptability is good for the situ catalytic agent that the present invention is prepared, parent
It is high with power.During the asymmetric catalytic hydrogenation of inferior amine salt, asymmetry catalysis rate is high.
Preferably, step（2）The chiral diphosphine ligand is (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl
Two (3,5- dipropyl phenyl) phosphines or (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] two (3,5- diisopropyl benzenes of ethyl
Base) phosphine.It is furthermore preferred that step（2）The chiral diphosphine ligand is (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl
Two (3,5- diisopropyl phenyls) phosphine.
Dimerization iridium cyclo-octadiene coordination compound, chiral diphosphine ligand, tetrabutylammonium iodide and vinegar in described chiral catalyst
Sour mol ratio is 1.0:（2.0~2.5）:（7.8~8）:（10.0~20.0）.Each material collocation under the proportioning most rationally, can
Ensure catalytic effect, and maximum can reduce preparation cost.
Preferably, step（2）The condition of described asymmetric catalytic hydrogenation is：Reaction pressure is 3 ~ 5Mpa；Reaction temperature
For 50 ~ 80 DEG C；The ratio s of raw material and catalyst:C is 2000 ~ 100000；Response time is 6 ~ 12h.
The product that separating-purifying is obtained Jing after alkali cleaning is mainly（R）- 1- phenyibutylamines.Can be by adjusting salt-forming reaction temperature
With asymmetric catalytic hydrogenation condition, the conversion ratio for reaching 1- phenyl butyl- 1- imines is 70 ~ 90%, enantiomeric excess value（E.e values）
Reach 70 ~ 80%.
The present invention is a kind of（R）The synthetic method of -1- phenyibutylamines, prepares 1- phenyl butyl- 1- with 1- phenyl butyl- 1- imines
Inferior amine salt is catalytic substrate, is formed with chiral diphosphine ligand and dimerization iridium cyclo-octadiene coordination compound, tetrabutylammonium iodide, glacial acetic acid
Situ catalytic agent, carry out asymmetric catalytic hydrogenation, then carry out alkali cleaning synthesis（R）The synthetic method of -1- phenyibutylamines.
Compared with prior art, a kind of synthesis of the invention（R）The method of -1- phenyibutylamines is had the advantage that
It is：A kind of synthetic method of Chiral Amine of the present invention, it is particularly a kind of（R）The synthetic method of -1- phenyibutylamines.The present invention
With a kind of catalysis activity height, low production cost, be not lost in, and the high chiral catalyst of reactant affinity carry out not chiral catalysis
Hydrogenation, can make catalysis activity improve 50%, and catalyst cost reduces by 52%, and target product total recovery reaches 70 ~ 90%, e.e values and reaches
70~80%.The synthesis of 1- phenyl butyl- 1- inferior amine salts is realized using normal-pressure reaction kettle；Using chiral catalyst and autoclave
The asymmetric catalytic hydrogenation of inferior amine salt is realized, is a kind of both economical synthetic method.What the present invention was obtained（R）- 1- phenyl
Butylamine purity is more than 99%.1- phenyl butyl- 1- imines effective rates of utilization can reach more than 90%.
Specific embodiment
Below by a kind of synthesis of the specific embodiment to the present invention（R）The method of -1- phenyibutylamines is described further,
Wherein embodiment 1 is most preferred embodiment.
Raw material of the present invention is 1- phenyl butyl- 1- imines, hydrochloric acid or acetic acid and hydrogen.Catalyst is chiral diphosphine
The situ catalytic agent that part, dimerization iridium cyclo-octadiene coordination compound, tetrabutylammonium iodide and acetic acid are formed.
1- phenyl butyl- 1- imines purity ﹥ 99%；Aqueous hydrochloric acid solution is SILVER REAGENT, and purity is 5 ~ 30%；Hydrogen is High Purity Hydrogen；
Chiral diphosphine ligand is SILVER REAGENT, purity ﹥ 97%, e.e values ﹥ 95%；Tetrabutyl iodate amine is SILVER REAGENT；Acetic acid is SILVER REAGENT.
In the examples below, 1- phenyl butyl- 1- imines abbreviation imines, 1- phenyl butyl- 1- inferior amine salt abbreviation inferior amine salts.
The content is mass percent.
Embodiment 1
Imines 147g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube（1mol）,
The hydrochloric acid 135g of concentration 30%, is stirred at room temperature reaction 3.5h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum drying oven
Drying, obtains inferior amine salt hydrochlorate 180.1g.
By 36.7g（0.2mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 23mg（0.032mmol）,
[Ir(cod)Cl]210mg（0.015mmol）, tetrabutyl iodate amine 45mg（0.12mmol）10mL acetic acid is dissolved in, chirality is made into and is urged
Agent is added in autoclave, is passed through hydrogen, and is kept pressure 5.0Mpa, temperature 70 C, reacts 10h.After reaction terminates,
Decompression precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and adjust pH value=
10, precipitation, vacuum distillation obtain product 33.5g, and by chiral HPLC, e.e values are 80%.
Embodiment 2
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 55.05g（0.3mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 26.3mg（0.035mmol）,
[Ir(cod)Cl]212.5mg（0.0188mmol）, tetrabutyl iodate amine 56mg（0.15mmol）10mL acetic acid is dissolved in, handss are made into
Property catalyst be added in autoclave, be passed through hydrogen, and keep 75 DEG C of pressure 6.0Mpa, temperature, react 12h.Reaction knot
Shu Hou, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and adjust pH
Value=10, precipitation, vacuum distillation obtain product 48.6g, and by chiral HPLC, e.e values are 76.3%.
Embodiment 3
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 36.7g（0.2mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- 3,5-dimethylphenyls) phosphine 20mg（0.028mmol）, [Ir
(cod)Cl]210mg（0.015mmol）, tetrabutyl iodate amine 45mg（0.12mmol）10mL acetic acid is dissolved in, chiral catalysis are made into
Agent is added in autoclave, is passed through hydrogen, and is kept pressure 5.0Mpa, temperature 70 C, reacts 10h.After reaction terminates, subtract
Pressure-off is molten, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and pH value=10 are adjusted,
Precipitation, vacuum distillation obtain product 32.5g, and by chiral HPLC, e.e values are 75%.
Embodiment 4
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 91.75g（0.5mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diethyl phenyls) phosphine 30mg（0.043mmol）, [Ir
(cod)Cl]210.2mg（0.0153mmol）, tetrabutyl iodate amine 43mg（0.115mmol）10mL acetic acid is dissolved in, chirality is made into
Catalyst is added in autoclave, is passed through hydrogen, and is kept 65 DEG C of pressure 4.5Mpa, temperature, reacts 11h.Reaction terminates
Afterwards, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and adjust pH value
=10, precipitation, vacuum distillation obtain product 81.6g, and by chiral HPLC, e.e values are 75.5%.
Embodiment 5
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 73.4g（0.4mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- dipropyl phenyl) phosphine 22.5mg（0.03mmol）, [Ir
(cod)Cl]210.2mg（0.0153mmol）, tetrabutyl iodate amine 56.3mg（0.15mmol）12mL acetic acid is dissolved in, chirality is made into
Catalyst is added in autoclave, is passed through hydrogen, and is kept 72 DEG C of pressure 5.2Mpa, temperature, reacts 11h.Reaction terminates
Afterwards, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and adjust pH value
=10, precipitation, vacuum distillation obtain product 64.5g, and by chiral HPLC, e.e values are 75.7%.
Embodiment 6
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 55.05g（0.3mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 19.5mg（0.26mmol）,
[Ir(cod)Cl]212.5mg（0.0188mmol）, tetrabutyl iodate amine 56mg（0.15mmol）50mL acetic acid is dissolved in, handss are made into
Property catalyst be added in autoclave, be passed through hydrogen, and keep 75 DEG C of pressure 6.0Mpa, temperature, react 12h.Reaction knot
Shu Hou, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and adjust pH
Value=10, precipitation, vacuum distillation obtain product 48.6g, and by chiral HPLC, e.e values are 76.3%.
Embodiment 7
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 110g（0.6mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 37.7mg（0.054mmol）,
[Ir(cod)Cl]210.24mg（0.018mmol）, tetrabutyl iodate amine 51.6mg（0.138mmol）100mL acetic acid is dissolved in, is matched somebody with somebody
It is added in autoclave into chiral catalyst, is passed through hydrogen, and keeps 80 DEG C of pressure 7.0Mpa, temperature, reacts 12h.Instead
After should terminating, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and
PH value=10, precipitation, vacuum distillation are adjusted to obtain product 97.7g, by chiral HPLC, e.e values are 76.9%.
Comparative example 1
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 110g（0.6mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 37.7mg（0.054mmol）,
[Ir(cod)Cl]210.24mg（0.018mmol）, 100mL acetic acid is dissolved in, chiral catalyst is made into and is added to autoclave
In, hydrogen is passed through, and keeps 80 DEG C of pressure 7.0Mpa, temperature, react 12h.After reaction terminates, reduce pressure precipitation, removes most of
Solvent, is concentrated into original volume 30%.With 30% NaOH aqueous solution room temperature washings, and pH value=10 are adjusted, precipitation, vacuum distillation are obtained
Product 92.7g, by chiral HPLC, e.e values are 56.9%.
Comparative example 2
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 110g（0.6mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 37.7mg（0.054mmol）,
[Ir(cod)Cl]210.24mg（0.018mmol）, tetrabutyl iodate amine 51.6mg（0.138mmol）, height is added directly into respectively
In pressure reactor, hydrogen is passed through, and keeps 80 DEG C of pressure 7.0Mpa, temperature, react 12h.After reaction terminates, reduce pressure precipitation, removes
Most of solvent is removed, original volume 30% is concentrated into.With 30% NaOH aqueous solution room temperature washings, and pH value=10 are adjusted, precipitation, decompression
Distillation obtains product 93.4g, and by chiral HPLC, e.e values are 60.1%.
Comparative example 3
Imines 220.5g will be added in being furnished with the 500mL four-hole boiling flasks of stirring rod, thermometer, reflux condensing tube
（1.5mol）, the hydrochloric acid 200g of concentration 30%, 40 DEG C of stirring reactions 4h.The precipitation that reduces pressure after terminating is reacted, solid is obtained, in vacuum
Dry in drying baker, obtain inferior amine salt hydrochlorate 273.6g.
By 110g（0.6mol）Inferior amine salt hydrochlorate is added in 500mL autoclaves, adds 190mL acetic acid.Will
(R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diisopropyl phenyls) phosphine 37.7mg（0.054mmol）,
[Ir(cod)Cl]210.24mg（0.018mmol）, it is added directly in autoclave respectively, is passed through hydrogen, and keeps pressure
80 DEG C of 7.0Mpa, temperature, reacts 12h.After reaction terminates, reduce pressure precipitation, removes most of solvent, is concentrated into original volume 30%.With
30% NaOH aqueous solution room temperature washings, and pH value=10, precipitation are adjusted, vacuum distillation obtains product 89.2g, by chiral HPLC point
Analysis, e.e values are 49.2%.
Can be seen that chiral catalyst prewired in the embodiment of the present invention can be more effectively by embodiment and comparative example
Promote catalytic asymmetric hydrogenation, or even yield is improve in the case of same process, same catalyst raw material.From enforcement
The data of example and comparative example can be seen that the present invention under prewired chiral catalyst, and the lifting of e.e values is larger, reaches 70
~80%.And chiral catalyst provisioning process is simply easily realized, the synergism of prewired rear chiral catalyst substantially, works well.
The above, is only presently preferred embodiments of the present invention, can fully understand the present invention by these embodiments
Essence and invention scope, further appreciate that synthesis of the present invention and the characteristics of separating technology.It is not to the present invention
Make the restriction of other forms, any those skilled in the art changed possibly also with the technology contents of the disclosure above or
It is modified as the Equivalent embodiments of equivalent variations.But it is every without departing from technical solution of the present invention content, according to the technology of the present invention
Any simple modification, equivalent variations and remodeling that essence is made to above example, still fall within the protection of technical solution of the present invention
Scope.
Claims (7)
1. a kind of synthesis（R）The method of -1- phenyibutylamines, it is characterised in that specifically synthesis step is：
（1）1- phenyl butyl- 1- imines and acid are synthesized into 1- phenyl butyl- 1- inferior amine salts in normal-pressure reaction kettle；
（2）1- phenyl butyl- 1- inferior amine salts, chiral catalyst and acetate solvate are added to into autoclave, hydrogen is passed through, in handss
Asymmetric catalytic hydrogenation is carried out to 1- phenyl butyl- 1- inferior amine salts under property catalyst action；Reaction pressure is 1 ~ 10Mpa, reacts temperature
Spend for 30 ~ 100 DEG C, the ratio of raw material and catalyst quality is 100 ~ 1000000:1, the response time is 1 ~ 20h；Described chirality
Catalyst is matched somebody with somebody by mole at room temperature for dimerization iridium cyclo-octadiene coordination compound, chiral diphosphine ligand, tetrabutylammonium iodide and acetic acid
Than 1.0:2.13:8:（10.0~20.0）The situ catalytic agent that stirring is formed；
（3）Reactant is carried out into alkali cleaning, then is purified and is obtained with optically active（R）- 1- phenyibutylamines.
2. step（1）The reaction condition of the synthesis 1- phenyl butyl- 1- inferior amine salts is：10 ~ 50 DEG C of reaction temperature；Response time 1 ~
8h。
3. a kind of synthesis according to claim 1（R）The method of -1- phenyibutylamines, it is characterised in that：Step（1）It is described
Acid be hydrochloric acid, sulphuric acid, phosphoric acid, formic acid or acetic acid；Aqueous acid mass concentration is 5% ~ 38%.
4. a kind of synthesis according to claim 1（R）The method of -1- phenyibutylamines, it is characterised in that：Described dimerization iridium
Cyclo-octadiene coordination compound is [Ir (cod) Cl]2。
5. a kind of synthesis according to claim 1（R）The method of -1- phenyibutylamines, it is characterised in that：Step（3）Middle institute
It is to be washed for 20 ~ 40% sodium hydrate aqueous solution using concentration to state alkali cleaning, 25 ~ 35 DEG C of alkali cleaning temperature.
6. a kind of synthesis according to claim 1（R）The method of -1- phenyibutylamines, it is characterised in that：Step（2）It is described
Chiral diphosphine ligand be (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- 3,5-dimethylphenyls) phosphine, (R) -
1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two (3,5- diethyl phenyls) phosphine, (R) -1- [(S) -2- (diphenyl
Phosphine) ferrocenyl] two (3,5- dipropyl phenyl) phosphine of ethyl or (R) -1- [(S) -2- (diphenylphosphine) ferrocenyl] ethyl two
(3,5- diisopropyl phenyls) phosphine.
7. a kind of synthesis according to claim 1（R）The method of -1- phenyibutylamines, it is characterised in that：Step（2）It is described
The condition of asymmetric catalytic hydrogenation be：Reaction pressure is 3 ~ 5MPa；Reaction temperature is 50 ~ 80 DEG C；The ratio of raw material and catalyst
2000~100000；Response time is 6 ~ 12h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1139930A (en) * | 1994-02-02 | 1997-01-08 | 希巴-盖吉股份公司 | Hydrogenation catalyst, process for the preparation thereof and hydrogenation process |
| CN1117727C (en) * | 1994-02-02 | 2003-08-13 | 辛根塔参与股份公司 | Process for the hydrogenation of imines |
| CN102076634A (en) * | 2008-06-27 | 2011-05-25 | 默克弗罗斯特加拿大有限公司 | Synthesis of chiral amines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1139930A (en) * | 1994-02-02 | 1997-01-08 | 希巴-盖吉股份公司 | Hydrogenation catalyst, process for the preparation thereof and hydrogenation process |
| CN1117727C (en) * | 1994-02-02 | 2003-08-13 | 辛根塔参与股份公司 | Process for the hydrogenation of imines |
| CN102076634A (en) * | 2008-06-27 | 2011-05-25 | 默克弗罗斯特加拿大有限公司 | Synthesis of chiral amines |
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