CN107089920A - L 3 N, N dibenzyl amino 1（3 cyclohexyl methoxies）Phenyl）The preparation method of the third 1 alcohol - Google Patents
L 3 N, N dibenzyl amino 1（3 cyclohexyl methoxies）Phenyl）The preparation method of the third 1 alcohol Download PDFInfo
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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Abstract
The present invention relates to L 3 N, N dibenzyl amino 1 (3 cyclohexyl methoxy) phenyl) preparation methods of the third 1 alcohol.This method is with 3 N, the keto hydrochloride of N dibenzyl aminos 1 (3 (cyclohexyl methoxy) phenyl) the third 1 is raw material, the Ai meter Si Ta alcohol of chiral intermediate L 3 N, N dibenzyl amino 1 (3 (cyclohexyl methoxy) phenyl) the third 1 is obtained under the effect of chiral catalyst, alkali and hydrogen；Wherein described chiral catalyst is the compound with having structure：
Description
Technical field
Ai meter Si Ta (emixustat) intermediate L-3-N, N- dibenzyls are prepared using asymmetric hydrogenation the present invention relates to one kind
Base amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol improved method, belong to technical field of organic chemistry, fall within medicine
Thing technical field of chemistry.
Background technology
Ai meter Si Ta (emixustat) hydrochloride is degenerative disease medicine, is mainly used in ophthalmology disease and disorder, such as year
Age is macular degeneration related and Si Tejiateshi is sick.The structure of Ai meter Si Ta (emixustat) hydrochloride is as follows：
The method of Ai meter Si Ta intermediates (emixustat) document (CN103553945A) report is to use (-)-Dip-Cl
The asymmetric reduction of 3- (9- fluorenylmethoxycarbonyl groups) amino -1- (3- (cyclohexyl methoxy) phenyl) acetone (formula II) is obtained
Arrive.The reducing agent price that its technique is used, the cost of product is high, it is impossible to meet industrialized requirement.
The content of the invention
Reducing agent price in preparation in order to solve above-mentioned Ai meter Si Ta in the prior art (emixustat) intermediate,
The problems such as cost of product is high, 3-N, N- dibenzyl aminos -1- (3- (cyclohexyl first are catalyzed it is an object of the invention to provide one kind
Epoxide) phenyl) propyl- 1- keto hydrochlorides asymmetric hydrogenation preparation Ai meter Si Ta (emixustat) intermediate L-3-N, N- dibenzyl
The novel synthesis of amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- alcohol.This method asymmetry catalysis activity is high, synthesis
The optical purity of product is high, and ee% is up to 98.8%.
To achieve these goals, the technical scheme is that：
Ai meter Si Ta (emixustat) intermediate L-3-N, N- dibenzyl aminos -1- (3- (cyclohexyl methoxy) phenyl)
The preparation method of propyl- 1- alcohol, it is characterised in that：3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- ketone
Hydrochloride asymmetric hydrogenation under the effect of chiral catalyst, alkali and hydrogen produces L-3-N, N- dibenzyl -1- (3- (cyclohexyl first
Epoxide) phenyl) propyl- 1- alcohol；
Wherein described catalyst is the compound with having structure：
Wherein DTB is 3,5- di-tert-butyl-phenyls, and X is H, C1-C8Alkyl, C1-C8Alkoxy, phenyl, substituted-phenyl, 1-
Substituent is C on naphthyl, 2- naphthyls, heteroaryl or benzyl, described phenyl1-C8Alkyl, alkoxy, substituent quantity be 1-
5, described heteroaryl is furyl, thienyl or pyridine radicals.
By such scheme, the X is preferably C1-C4Alkoxy.
By such scheme, described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, caustic alcohol, potassium ethoxide, different
Sodium propoxide, potassium tert-butoxide, tertiary fourth sodium, butyl lithium, tert-butyl lithium, Sodamide, triethylamine, tri-n-butylamine, pyridine or N-methylmorpholine,
Optimal alkali is potassium tert-butoxide.
By such scheme, the reaction solvent for use is methanol, ethanol, propyl alcohol, isopropanol, tetrahydrofuran, toluene, methyl
One kind or wherein several mixed solvents in tertbutyl ether, dioxane, DMF, DMSO, sulfolane.Optimum solvent is ethanol.
By such scheme, the Hydrogen Vapor Pressure is 0.2-10MPa, preferably 1-8MPa.
By such scheme, the reaction temperature is 0-80 DEG C, more preferably preferably 20-80 DEG C, 50-80 DEG C.During reaction
Between be 9-16h.
By such scheme, catalyst and 3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) the propyl- 1-
The mol ratio of keto hydrochloride is 1/100000-1/1000000.Optimum mole ratio is 1：300000-500000；
By such scheme, alkali and 3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) the propyl- 1- ketone salt
The optimum mole ratio of hydrochlorate is 1：1-100, preferably 1：25-50.
By such scheme, L-3-N, the preparation side of N- dibenzyl aminos -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- alcohol
Method, is concretely comprised the following steps：Chiral catalyst and alkali are put in reaction tube, and reaction tube is inserted in autoclave, into reaction tube
Add solvent and raw material 3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides, with nitrogen and
Hydrogen replaces the gas in kettle respectively, pressure needed for making Hydrogen Vapor Pressure, is warming up to design temperature, reaction a period of time, hydrogen
Pressure no longer declines, and stops heating, takes out reaction solution, and post processing obtains target product.
By such scheme, described post processing is：Reaction solution is concentrated, water and ethyl acetate are added into residue, it is quiet
Put layering, aqueous layer with ethyl acetate extraction merges organic layer, by organic layer saturated common salt water washing, anhydrous sodium sulfate drying,
Filtering, filtrate is concentrated to dryness to obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1-
Alcohol.
The L-3-N wherein prepared, N- dibenzyl amino -1- (3- cyclohexyl methoxies phenyl) propyl- 1- alcohol can enter one
Step reaction Synthesis Ai meter Si Ta (emixustat).
The preparation method that the present invention is provided has the advantage that effect is：The inventive method can high enantioselective synthesis L-3-
N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- alcohol, the high truelove meter Si Ta (emixustat) of synthesis
Intermediate L-3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) the propyl- 1- alcohol optics content of hydrochloride is high,
Ee% is up to 98.8%, and catalyst mole dosage be only substrate 1/100000-1/1000000, greatly save
Catalyst cost and raw materials technology cost.Intermediate obtained by reaction need not be separated, and be can be directly used for next step, reduced behaviour
Make and material loss.
Embodiment
Content for a better understanding of the present invention, with reference to the embodiment content that the present invention is furture elucidated, but this
The content of invention is not limited solely to the following examples.
Embodiment 1：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh chiral catalyst (X is 3- methoxyl groups) (1mg, 0.001mmol) and potassium tert-butoxide (1.344g, 12mmol) is put
In reaction tube, reaction inner tube is inserted in autoclave, ethanol 30mL and 3-N, N- dibenzyl are added into reaction inner tube
Amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (143.4g, 0.3mol), are put respectively with nitrogen and hydrogen
The gas changed in kettle, makes Hydrogen Vapor Pressure reach 8MPa, is warming up to 50 DEG C of simultaneously insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines,
Stop heating, take out reaction solution, concentration adds 10 milliliters of water and 10 milliliters of ethyl acetate, stratification, water layer into residue
It is extracted twice with ethyl acetate (10*2), merges organic layer, washed again once with 10 milliliters of saturated aqueous common salts, anhydrous sodium sulfate is done
Dry, filtering, filtrate is concentrated to dryness to obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl-
132.9 grams of 1- alcohol, yield is more than 99%, is converted completely through GC analysis raw materials.The chiral HPLC of product analyzes its ee%
98.8%.
Embodiment 2：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Chiral catalyst (X is 6- ethyoxyls) (1mg, 0.001mmol) and (390mg, 10mmol) Sodamide is weighed to be put in
In reaction tube, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl ammonia are added into reaction inner tube
Base -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (167.3g, 0.35mol), are replaced respectively with nitrogen and hydrogen
Gas in kettle, makes Hydrogen Vapor Pressure reach 8MPa, is warming up to 50 DEG C of simultaneously insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines, and stops
Only heat, reaction solution is post-processed into obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl)
Propyl- 1- alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 97.2%.
Embodiment 3：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh chiral catalyst (X is H) (1mg, 0.001mmol) and caustic alcohol (596mg, 5.3mmol) is put in reaction tube
In, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl amino -1- is added into reaction inner tube
(3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (191.2g, 0.4mol), are replaced in kettle respectively with nitrogen and hydrogen
Gas, Hydrogen Vapor Pressure is reached 8MPa, be warming up to 50 DEG C and insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines, stop plus
Heat, light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl is post-processed to obtain by reaction solution) propyl- 1-
Alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 96.4%.
Embodiment 4：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh (1mg, 0.001mmol) chiral catalyst (X is 6- bromines) and sodium hydroxide (267mg, 6.7mmol) is put in instead
Ying Guanzhong, reaction inner tube is inserted in autoclave, added into reaction inner tube ethanol 50mL and 3-N, N- dibenzyl amino-
1- (3- cyclohexyl methoxies phenyl) propyl- 1- keto hydrochlorides (153g, 0.32mol), are replaced in kettle respectively with nitrogen and hydrogen
Gas, Hydrogen Vapor Pressure is reached 8MPa, be warming up to 50 DEG C and insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines, stop plus
Heat, light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl is post-processed to obtain by reaction solution) propyl- 1-
Alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 93.8%.
Embodiment 5：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh (1mg, 0.001mmol) chiral catalyst (X be 6- (4- chlorine) phenyl) and sodium carbonate (1.007g,
9.5mmol) it is put in reaction tube, reaction inner tube is prevented in autoclave, ethanol 80mL and 3- is added into reaction inner tube
N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (182g, 0.38mol), with nitrogen and hydrogen
Qi leel does not replace the gas in kettle, Hydrogen Vapor Pressure is reached 8MPa, is warming up to 50 DEG C of simultaneously insulation reaction 9 hours, Hydrogen Vapor Pressure
No longer decline, stop heating, reaction solution is post-processed into obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl first
Epoxide) phenyl) propyl- 1- alcohol is 99% through HPLC analysis conversion ratios, its ee% is 91.5%.
Embodiment 6：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh (1mg, 0.001mmol) chiral catalyst (X is 6- methoxyl groups) and sodium isopropylate (0.87g, 10.7mmol)
It is put in reaction tube, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl is added into reaction inner tube
Base amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (153g, 0.32mol), are put respectively with nitrogen and hydrogen
The gas changed in kettle, makes Hydrogen Vapor Pressure reach 8MPa, is warming up to 50 DEG C of simultaneously insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines,
Stop heating, reaction solution is post-processed into obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl)
Propyl- 1- alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 97.3%.
Embodiment 7：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh chiral catalyst (X is 3- methoxyl groups) (1mg, 0.001mmol) and potassium tert-butoxide (1.12g, 10mmol) is put
In reaction tube, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl are added into reaction inner tube
Amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (148.2g, 0.31mol), are put respectively with nitrogen and hydrogen
The gas changed in kettle, makes Hydrogen Vapor Pressure reach 1MPa, is warming up to 50 DEG C and insulation reaction no longer declines to Hydrogen Vapor Pressure, stops
Heating, light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl is post-processed to obtain by reaction solution) propyl-
1- alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 98.2%.
Embodiment 8：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh chiral catalyst (X is 3- methoxyl groups) (1mg, 0.001mmol) and potassium tert-butoxide (1.18g, 10.5mmol)
It is put in reaction tube, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl is added into reaction inner tube
Base amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (162.5g, 0.34mol), are distinguished with nitrogen and hydrogen
The gas in kettle is replaced, Hydrogen Vapor Pressure is reached 8MPa, is warming up to 80 DEG C and insulation reaction no longer declines to Hydrogen Vapor Pressure, stop
Only heat, reaction solution is post-processed into obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl)
Propyl- 1- alcohol, is 100% through HPLC analysis conversion ratios, its ee% is 98.1%.
Embodiment 9：L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol preparation
Weigh chiral catalyst (X is 3- methyl) (1mg, 0.001mmol) and triethylamine (1.15g, 11.4mmol) is put in
In reaction tube, reaction inner tube is inserted in autoclave, ethanol 50mL and 3-N, N- dibenzyl ammonia are added into reaction inner tube
Base -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides (176.9g, 0.37mol), are replaced respectively with nitrogen and hydrogen
Gas in kettle, makes Hydrogen Vapor Pressure reach 8MPa, is warming up to 50 DEG C of simultaneously insulation reaction 9 hours, Hydrogen Vapor Pressure no longer declines, and stops
Only heat, reaction solution is post-processed into obtain light yellow liquid L-3-N, N- dibenzyl amino -1- (3- cyclohexyl methoxies) phenyl)
Propyl- 1- alcohol, is 99% through HPLC analysis conversion ratios, its ee% is 96.6%.
The bound value and interval value of each raw material of the present invention can realize the present invention, and cited each raw material is all
The present invention can be realized, embodiment is not just enumerated herein.
It should be noted that all documents referred in the present invention are incorporated by reference herein, just as each text
Offer and be individually recited as with reference to the same.It should also be understood that the above-described technology for being the specific embodiment of the present invention and being used
Principle, after the above of the present invention has been read, those skilled in the art can be used for various modifications and change to originally bright
Without departing from the spirit and scope of the present invention, these equivalent form of values are also fallen within the scope of the present invention.
Claims (10)
- The preparation method of 1.L-3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- alcohol, its feature exists In：3-N, N- dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides are in chiral catalyst, alkali and hydrogen The lower asymmetric hydrogenation of gas effect produces L-3-N, N- dibenzyl -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- alcohol；Wherein described catalyst is the compound with having structure：Wherein DTB is 3,5- di-tert-butyl-phenyls, and X is H, C1-C8Alkyl, C1-C8Alkoxy, phenyl, substituted-phenyl, 1- naphthyls, Substituent is C on 2- naphthyls, heteroaryl or benzyl, described phenyl1-C8Alkyl, alkoxy, substituent quantity be 1-5, institute The heteroaryl stated is furyl, thienyl or pyridine radicals.
- 2. preparation method according to claim 1, it is characterised in that：The X is C1-C4Alkoxy.
- 3. preparation method according to claim 1, it is characterised in that：Described alkali is sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, caustic alcohol, potassium ethoxide, sodium isopropylate, potassium tert-butoxide, tertiary fourth sodium, butyl lithium, tert-butyl lithium, Sodamide, three second Amine, tri-n-butylamine, pyridine or N-methylmorpholine.
- 4. preparation method according to claim 1, it is characterised in that：Reaction solvent for use is methanol, ethanol, propyl alcohol, different One kind or wherein several in propyl alcohol, tetrahydrofuran, toluene, methyl tertiary butyl ether(MTBE), dioxane, DMF, DMSO, sulfolane Mixed solvent.
- 5. preparation method according to claim 1, it is characterised in that：The Hydrogen Vapor Pressure is 0.2-10MPa, reaction temperature For 0-80 DEG C.
- 6. preparation method according to claim 1, it is characterised in that：The Hydrogen Vapor Pressure is 1-8MPa, and reaction temperature is 50-80 DEG C, the reaction time is 9-16h.
- 7. preparation method according to claim 1, it is characterised in that：Catalyst and 3-N, N- the dibenzyl amino -1- The mol ratio of (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides is 1/100000-1/1000000.
- 8. preparation method according to claim 1, it is characterised in that：Alkali and 3-N, N- the dibenzyl amino -1- (3- (cyclohexyl methoxy) phenyl) propyl- 1- ketone salt mol ratio be 1：1-100.
- 9. preparation method according to claim 1, it is characterised in that：Concretely comprise the following steps：Chiral catalyst and alkali are put in instead Ying Guanzhong, reaction tube is inserted in autoclave, and solvent and raw material 3-N, N- dibenzyl amino -1- are added into reaction tube (3- (cyclohexyl methoxy) phenyl) propyl- 1- keto hydrochlorides, the gas in kettle is replaced with nitrogen and hydrogen, makes hydrogen pressure respectively Pressure needed for power, is warming up to design temperature, and reaction a period of time, Hydrogen Vapor Pressure no longer declines, and stops heating, takes out reaction solution, Post processing obtains target product.
- 10. preparation method according to claim 9, it is characterised in that：Described post processing is：Reaction solution is concentrated, to Water and ethyl acetate are added in residue, stratification, aqueous layer with ethyl acetate extraction merges organic layer, organic layer is used into full And brine It, anhydrous sodium sulfate drying, filtering, filtrate be concentrated to dryness light yellow liquid L-3-N, N- dibenzyl amino- 1- (3- cyclohexyl methoxies) phenyl) propyl- 1- alcohol.
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| CN107827802A (en) * | 2017-10-17 | 2018-03-23 | 南京红杉生物科技有限公司 | A kind of synthetic method of D proline |
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