CN104610215A - Preparation method of nebivolol intermediates and preparation method of nebivolol - Google Patents

Preparation method of nebivolol intermediates and preparation method of nebivolol Download PDF

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Publication number
CN104610215A
CN104610215A CN201510025745.8A CN201510025745A CN104610215A CN 104610215 A CN104610215 A CN 104610215A CN 201510025745 A CN201510025745 A CN 201510025745A CN 104610215 A CN104610215 A CN 104610215A
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China
Prior art keywords
formula
compound
nebivolol
group
chromene
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Inventor
李洪明
褚长虎
吉都明
缪存铅
毕建豪
杨国胜
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Shanghai Hisoar Pharmaceutical Technology Development Co Ltd
Zhejiang Hisoar Pharmaceutical Co Ltd
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Shanghai Hisoar Pharmaceutical Technology Development Co Ltd
Zhejiang Hisoar Pharmaceutical Co Ltd
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Priority to CN201510025745.8A priority Critical patent/CN104610215A/en
Publication of CN104610215A publication Critical patent/CN104610215A/en
Priority to PCT/CN2015/099448 priority patent/WO2016115962A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a preparation method of nebivolol intermediate V compounds. The method steps as follows: (1) a compound shown in Formula RS/RR-IV and a compound shown in Formula S-I have a coupling docking reaction to obtain a material containing a compound shown in Formula RS#S-V and a compound shown in Formula RR#S-V, and the V compounds in two configurations are separated; or (2) a compound shown in Formula SR/SS-IV and a compound shown in Formula R-I have a coupling docking reaction to obtain a material containing a compound shown in Formula SR#R-V and a compound shown in Formula SS#R-V, and the V compounds in two configurations are separated. The invention further provides a method for preparing nebivolol or a pharmaceutically acceptable salt of the nebivolol from the V compounds. The method has the characteristics that the operation is simple and convenient, reaction conditions are mild, the atomic economy is good, the yield is high, the cost is low and the like, and the method is suitable for industrial production.

Description

A kind of preparation method of Nebivolol Intermediates and the preparation method of nebivolol
Technical field
The present invention relates to a kind of preparation method of Nebivolol Intermediates, and apply the preparation method of this Intermediate Preparation nebivolol or its pharmacy acceptable salt.
Background technology
Medicine nebivolol is third generation adrenergic alpha-agonists, and be the mixture of the left-handed of equimolar amount and dextrorotatory isomer, wherein dextrorotatory isomer has powerful β1receptor retardation, and levoisomer has endotheliocyte dependency vasorelaxation action.The chemical structure of nebivolol has four chiral centres, totally ten chiral isomers, and marketed products is the racemic modification of the RSSS configuration of equimolar amount and the nebivolol hydrochloride composition of RRRS configuration.
Patent documentation WO2008/010022A2 discloses a kind of preparation method of nebivolol, the formula RS/SR-IV compound mixture of SR-IV compound (RS-IV compound with) and the formula R/S-I compound mixture of S-I compound (R-I compound with) coupling is docked, obtain the key intermediate formula RS#S/SR#R-V compound (mixture of formula RS#S-V compound and formula SR#R-V compound, wherein # represents the carbonylic carbon atom as chiral centre of diving in compound), through Chemoselective reduction, amino hydrogenation deprotection, obtain RSSS/RRRS type nebivolol.
The method is directly docked with the coupling of formula R/S-I compound with formula RS/SR-IV compound, and combined coefficient is higher.But, being mixed with the by product that cannot apply of larger proportion in formula RS#S/SR#R-V compound generated in the method---formula RS#R/SR#S-V compound, needs to adopt loaded down with trivial details derivatize and/or re-crystallization step to carry out purifying and removes described by product; And simultaneously, formula RS#S/SR#R-V compound of generation cannot split, carry out when sequential reduction reacts comparatively harsh for reaction conditions requirement.
In addition, the method also generates the by product that cannot apply of larger proportion in the process of synthesis type RS/SR-IV compound simultaneously---and formula RR/SS-IV compound, needs to adopt loaded down with trivial details fractional recrystallisation steps to remove described by product equally.
Because above-mentioned by product can not be utilized effectively, cause the yield of target product lower, Atom economy is poor, and the recycling of these by products simultaneously also needs to consume certain cost.
Therefore, need a kind of method of simple to operate, fuel economy good, yield is high, cost is low preparation described Nebivolol Intermediates formula V compound, and apply the method for this Intermediate Preparation nebivolol.
Summary of the invention
The object of the present invention is to provide a kind of simple to operate, Atom economy good, yield is high, cost is low method preparing Nebivolol Intermediates formula V compound.
Another object of the present invention is to provide a kind of method preparing nebivolol or its pharmacy acceptable salt.
The object of the invention is to be achieved through the following technical solutions:
The invention provides a kind of method preparing Nebivolol Intermediates formula RS#S-V compound and formula RR#S-V compound, comprising:
(1) formula RS/RR-IV compound and formula S-I compound are carried out coupling to dock and react, obtain the material containing formula RS#S-V compound and formula RR#S-V compound,
Wherein, X 1and X 2represent hydrogen atom or halogen atom that phenyl ring optional position connects separately; X 1with X 2can be identical group, also can be different;
LG, for being easy to leavings group, is selected from bromine, chlorine, sulfonate group;
PG is the amino protecting group that hydrogen maybe can remove; be selected from methyl, allyl group, the tertiary butyl, benzyl, diphenyl-methyl, trityl, fluorenyl, 9,10-dihydroanthracene-9-bases, when wherein there is aromatic ring in described protecting group; can with substituting group on aromatic ring, described substituting group is selected from halogen, nitro, C 1-C 4alkyl chain ,-CF 3,-CHF 2,-OR 2group, wherein R 2be selected from hydrogen, single replacement or dibasic C 1-C 4alkyl; PG is preferably benzyl;
(2) by step (1) gained feed separation, formula RS#S-V compound and formula RR#S-V compound is obtained respectively.
Wherein, described formula RS/RR-IV compound refers to the mixture of formula RS-IV compound and formula RR-IV compound, and is not specifically limited the mol ratio of the two.
In one embodiment of the present invention, described formula RS/RR-IV compound is formula RS-IV compound of equimolar amount substantially and the mixture of formula RR-IV compound.
It should be noted that, in the present invention, in the structural formula of formula RS/RR-IV compound, hydroxyl is connected with curve with adjacent chiral carbon, and chiral carbon described in this curve representation can be R type or S type." # " in formula RS#S-V compound and formula RR#S-V compound represents the carbonylic carbon atom as chiral centre of diving in compound
Preferably, the chemical reaction of step (1) in the basic conditions, in inert solvent, carries out under catalyst.
Preferably, the alkali in described alkaline condition is selected from carbonate, supercarbonate, organic bases, and described organic bases is as triethylamine, diisopropyl ethyl amine.Preferably, described alkali is sodium bicarbonate or saleratus.
Preferably, described inert solvent to be selected from acetone, tetrahydrofuran (THF), acetonitrile, toluene, methylene dichloride, ethyl acetate, dimethyl formamide any one or multiple, be preferably acetonitrile or tetrahydrofuran (THF).
Preferably, described catalyzer be selected from Potassium Bromide, potassiumiodide, Sodium Bromide, sodium iodide any one or multiple, be preferably Potassium Bromide or Sodium Bromide.
Preferably, the mol ratio of described formula RS/RR-IV compound and described formula S-I compound is (1.0-2.5): 1, is preferably (1.0-1.5): 1.
Preferably, described formula RS/RR-IV compound: formula S-I compound: alkali: the molar ratio of catalyzer is 1.0:(1.0-2.5): (1.0-4.0): (0.05-0.3), is preferably 1.0:(1.0-1.5): 2.0:(0.1-0.15).
Preferably, the temperature of described reaction is 10-80 DEG C, preferred 10-50 DEG C.
Preferably, the time of described reaction is 10-60 hour, preferred 10-24 hour.
Preferably, on the pyranoid ring of described formula RS/RR-IV compound, the purity of chiral centre is greater than 90%, is preferably greater than 95%, more preferably greater than 99%.
Preferably, the enantiomeric excess per-cent of described formula S-I compound is greater than 90%, is preferably greater than 95%, more preferably greater than 99%.
In above-mentioned reaction, described formula S-I compound is by existing method, and such as disclosed in document WO2008/010022A2 or CN102164906A, method is prepared.
In above-mentioned reaction, formula RS/RR-IV compound can be prepared by the following method:
Make formula RS/RR-III compound and NH 2pG reacts production RS/RR-IV compound
Wherein said formula RS/RR-III compound refers to the mixture of formula RS-III compound and formula RR-III compound, is not specifically limited the mol ratio of the two.
In one embodiment of the present invention, described formula RS/RR-III compound is formula RS-III compound of equimolar amount and the mixture of formula RR-III compound.
Described RS/RR-III compound can be prepared by such as method disclosed in patent documentation CN102164906A or WO2008/010022A2, and those skilled in the art suitably can adjust the concrete reaction conditions of preparation method disclosed in the document, with the mixture of formula RS-III compound and formula RR-III compound that obtain different mol ratio.
Obtained formula RS/RR-IV compound also can be separated according to the method for WO2008/010022A2 report, and obtain formula RR-IV and formula RS-IV compound of single configuration respectively, then the two is made into the mixture of arbitrary proportion.
In step (2), by such as filter and/or the mode of further recrystallization by formula RS#S-V compound and formula RR#S-V compound separation.
In one embodiment of the invention, being operating as of step (2) described separating step: the material filtering of step (1) reaction gained is separated, gained filter cake is formula RS#S-V compound is main solid; Gained filtrate concentrates, and obtaining formula RR#S-V compound is main solid or concentrated solution.
Above-mentioned formula RS#S-V compound to be main solid and formula RR#S-V compound be main solid or concentrated solution can for the preparation of nebivolol or its hydrochlorides directly or after being further purified.
Preferably, to be the purification process of main solid can be described formula RS#S-V compound: be that main solid adds in solvent by described formula RS#S-V compound, stir, filter, removing filter residue, filtrate concentrates, and obtains solid.This purification step can carry out once or repeatedly, obtain formula RS#S-V compound of higher degree.Described solvent selected from acetone, tetrahydrofuran (THF), acetonitrile, toluene, methylene dichloride, ethyl acetate or dimethyl formamide or its any mixture, be preferably methylene dichloride.Adopting such purification process can remove described formula RS#S-V compound is the impurity such as the inorganic salt contained in the solid of master, thus obtains purity higher formula RS#S-V compound.
Preferably, described formula RR#S-V compound is the purification process of main solid or concentrated solution: be that main solid or concentrated solution add in poor solvent by described formula RR#S-V compound, stir, filter, gained solid is formula RS#S-V compound, and filtrate is concentrated obtains formula RR#S-V compound.This purification step can carry out once or repeatedly, obtain formula RR#S-V compound of purifying.Wherein, gained formula RS#S-V compound can pass through or without being further purified, merge with formula RS#S-V compound of above-mentioned purifying.Described poor solvent is selected from alkane, ether, alcohol, nitrile, esters solvent, is preferably ether solvent.By adopting the method, formula RR#S-V compound of purifying can be obtained, formula RS#S-V compound of dissolved in filtrate fully can be separated simultaneously, avoid waste.
In another embodiment of the invention, the filtrate of step (1) gained material filtering gained also without concentrating or directly add poor solvent after concentrated, can be stirred, filter, gained solid is formula RS#S-V compound, and filtrate is concentrated obtains formula RR#S-V compound.Described poor solvent is selected from alkane, ether, alcohol, nitrile, esters solvent, is preferably ether solvent.
The present invention also provides a kind of method preparing Nebivolol Intermediates formula SR#R-V compound and formula SS#R-V compound, comprising:
(1) formula SR/SS-IV compound and formula R-I compound are carried out coupling to dock and react, obtain the material containing formula SR#R-V compound and formula SS#R-V compound,
Wherein, X 1and X 2represent hydrogen atom or halogen atom that phenyl ring optional position connects separately; X 1with X 2can be identical group, also can be different;
LG, for being easy to leavings group, is selected from bromine, chlorine, sulfonate group;
PG is the amino protecting group that hydrogen maybe can remove; be selected from methyl, allyl group, the tertiary butyl, benzyl, diphenyl-methyl, trityl, fluorenyl, 9,10-dihydroanthracene-9-bases, when wherein there is aromatic ring in described protecting group; can with substituting group on aromatic ring, described substituting group is selected from halogen, nitro, C 1-C 4alkyl chain ,-CF 3,-CHF 2,-OR 2group, wherein R 2be selected from hydrogen, single replacement or dibasic C 1-C 4alkyl; PG is preferably benzyl;
(2) by step (1) gained feed separation, formula SR#R-V compound and formula SS#R-V compound is obtained respectively.
Wherein, described formula SR/SS-IV compound refers to the mixture of formula SR-IV compound and formula SS-IV compound, and is not specifically limited the mol ratio of the two.
In one embodiment of the present invention, described formula SR/SS-IV compound is formula SR-IV compound of equimolar amount substantially and the mixture of formula SS-IV compound.
It should be noted that, in the present invention, in the structural formula of formula SR/SS-IV compound, hydroxyl is connected with curve with adjacent chiral carbon, and chiral carbon described in this curve representation can be R type or S type." # " in formula RS#S-V compound and formula RR#S-V compound represents the carbonylic carbon atom as chiral centre of diving in compound.
Preferably, the chemical reaction of step (1) in the basic conditions, in inert solvent, carries out under catalyst.
Preferably, described alkali is selected from carbonate, supercarbonate, organic bases as triethylamine, diisopropyl ethyl amine, preferred sodium bicarbonate or saleratus.
Preferably, described inert solvent to be selected from acetone, tetrahydrofuran (THF), acetonitrile, toluene, methylene dichloride, ethyl acetate, dimethyl formamide any one or multiple, be preferably acetonitrile or tetrahydrofuran (THF).
Preferably, described catalyzer be selected from Potassium Bromide, potassiumiodide, Sodium Bromide, sodium iodide any one or multiple, be preferably Potassium Bromide or Sodium Bromide.
Preferably, the mol ratio of described formula SR/SS-IV compound and described formula R-I compound is 1.0-2.5:1, is preferably 1.0-1.5:1.
Preferably, described formula SR/SS-IV compound: formula R-I compound: alkali: the molar ratio of catalyzer is 1.0:1.0-2.5:1.0-4.0:0.05-0.3, is preferably 1.0:1.0-1.5:2.0:0.1-0.15.
Preferably, the temperature of described reaction is 10-80 DEG C, preferred 10-50 DEG C.
Preferably, the time of described reaction is 10-60 hour, preferred 10-24 hour.
Preferably, on the pyranoid ring of described formula SR/SS-IV compound, the purity of chiral centre is greater than 90%, is preferably greater than 95%, more preferably greater than 99%.
Preferably, the enantiomeric excess per-cent of described formula R-I compound is greater than 90%, is preferably greater than 95%, more preferably greater than 99%.
In above-mentioned reaction, described formula R-I compound is by existing method, and such as disclosed in document WO2008/010022A2 or CN102164906A, method is prepared.
In above-mentioned reaction, formula SR/SS-IV compound is prepared by following method:
Make SR/SS-III compound and NH 2pG reacts production SR/SS-IV compound
Wherein said formula SR/SS-III compound refers to the mixture of formula SR-III compound and formula SS-III compound, is not specifically limited the mol ratio of the two.
In one embodiment of the present invention, described formula SR/SS-III compound is formula SR-III compound of equimolar amount and the mixture of formula SS-III compound.
Described formula SR/SS-III compound is prepared by such as method disclosed in patent documentation CN102164906A or WO2008/010022A2, and those skilled in the art suitably can adjust the concrete reaction conditions of preparation method disclosed in above-mentioned document, with the mixture of formula SR-III compound and formula SS-III compound that obtain different mol ratio.
Obtained formula SR/SS-IV compound also can be separated according to the method for WO2008/010022A2 report, and obtain SS-IV and SR-IV compound of single configuration respectively, then the two is made into the mixture of arbitrary proportion.
In step (2), by such as filter and/or the mode of further recrystallization by formula SR#R-V compound and formula SS#R-V compound separation.
In one embodiment of the invention, being operating as of step (2) described separating step: the material filtering of step (1) reaction gained is separated, gained filter cake is formula SR#R-V compound is main solid, and it is main solid or concentrated solution that filtrate concentrating obtains formula SS#R-V compound.
Above-mentioned formula SR#R-V compound to be main solid and formula SS#R-V compound be main solid or concentrated solution can for the preparation of nebivolol or its hydrochlorides directly or after being further purified.
Preferably, to be the purification process of main solid can be described formula SR#R-V compound: be that main solid adds in solvent by described formula SR#R-V compound, stir, filter, removing filter residue, filtrate concentrates, and obtains solid.Described purification step can carry out once or repeatedly, obtain formula SR#R-V compound of higher degree.Described solvent can be selected from acetone, tetrahydrofuran (THF), acetonitrile, toluene, methylene dichloride, ethyl acetate or dimethyl formamide or its any mixture, is preferably methylene dichloride.Adopting such purification process can remove described formula SR#R-V compound is the impurity such as the inorganic salt contained in the solid of master, thus obtains purity higher formula SR#R-V compound.
Preferably, described formula SS#R-V compound is the purification process of main solid or concentrated solution: be that main solid cannon concentrated solution adds poor solvent by described formula SS#R-V compound, stir, filter, gained solid is formula SR#R-V compound, and filtrate is concentrated obtains formula SS#R-V compound.This purification step can carry out once or repeatedly, obtain formula SS#R-V compound of purifying.Wherein, gained formula SR#R-V compound can pass through or without being further purified, merge with formula SR#R-V compound of above-mentioned purifying.Described poor solvent is selected from alkane, ether, alcohol, nitrile, esters solvent, is preferably ether solvent.By adopting the method, formula SS#R-V compound of purifying can be obtained, formula SR#R-V compound of dissolved in filtrate fully can be separated simultaneously, thus avoiding the waste of product.
In another embodiment of the invention, the filtrate of step (1) gained material filtering gained also without concentrating or directly add poor solvent after concentrated, can be stirred, filter, gained solid is formula SR#R-V compound, and filtrate is concentrated obtains formula SS#R-V compound.Described poor solvent is selected from alkane, ether, alcohol, nitrile, esters solvent, is preferably ether solvent.
Further, the invention provides a kind of method preparing nebivolol or its pharmacy acceptable salt, comprising:
(1) aforesaid method preparation formula RS#S-V compound and formula RR#S-V compound is adopted;
(2) gained formula RS#S-V compound and formula RR#S-V compound are carried out selective reduction, obtain formula RSSS-VI compound and formula RRRS-VI compound,
(3) gained formula RSSS-VI compound and formula RRRS-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains RSSS-nebivolol and the RRRS-nebivolol of equimolar amount or prepares its pharmacy acceptable salt further.
One of the present invention preferred embodiment in, step (2) Chinese style RS#S-V compound and formula RR#S-V compound are in the mode of mixture, preferably with the mixture of basic equimolar amount, be such as the mode of the mixture of 1.05:1 ~ 1:1.05 with mol ratio, carry out selective reduction.
When adopting this kind of embodiment, step (2) is obtained by reacting the mixture of formula RSSS-VI compound and formula RRRS-VI compound, this mixture can through purifying or not purified enter next step reaction, obtain the mixture of RSSS-nebivolol and RRRS-nebivolol equimolar ratio.
In addition, step (2) is obtained by reacting described mixture also can through being separated, and obtain formula RSSS-VI compound and formula RRRS-VI compound respectively, the two removes PG group and X respectively 1, X 2substituting group, obtains independently RSSS-nebivolol and RRRS-nebivolol, then RSSS-nebivolol and RRRS-nebivolol is mixed with equimolar amount, obtain product.
Generate a small amount of by product simultaneously---formula RSRS-VI compound and formula RRSS-VI compound, described by product can not remove, and directly enters next step reaction; The separation purification method removing that this area also can be adopted conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
In another embodiment of the invention, step (2) Chinese style RS#S-V compound and formula RR#S-V compound with basic equimolar ratio, such as, take mol ratio as 1.05:1 ~ 1:1.05, carry out selective reduction respectively.
When adopting this kind of embodiment, step (2) obtains independently formula RSSS-VI compound and formula RRRS-VI compound.Get formula RSSS-VI compound and formula RRRS-VI compound of equimolar ratio, enter next step reaction, obtain the mixture of RSSS-nebivolol and RRRS-nebivolol equimolar ratio.
In addition, formula RSSS-VI compound that step (2) obtains and formula RRRS-VI compound, can remove PG group and X respectively 1, X 2substituting group, obtains independently RSSS-nebivolol and RRRS-nebivolol, then RSSS-nebivolol and RRRS-nebivolol is mixed with equimolar amount, obtain product.
Preferably, Chemoselective reduction described in step (2) is being gone back under original reagent existence, is being carried out under Louis acid catalysis.
Preferably, described original reagent of going back is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, one or more in lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, red aluminium and borine, are preferably sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
Preferably, described Lewis acid is selected from boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, Repone K, bariumchloride, Manganous chloride tetrahydrate, titanium tetrachloride, zinc chloride, copper sulfate, palladous sulfate, zinc bromide, lime acetate, Palladous chloride, Manganous chloride tetrahydrate, Aluminum chloride anhydrous, aluminum isopropylate, bismuth chloride, one or more in magnesium perchlorate and alkoxy titanates, are preferably Palladous chloride, zinc chloride or alkoxy titanates.
Described reaction is carried out in a solvent, and preferably, described solvent is selected from tetrahydrofuran (THF), Virahol, acetonitrile, isopropyl ether, t-butyl methyl ether, glycol dimethyl ether, hexanaphthene, dimethylbenzene, toluene, one or more in methylene dichloride.
Preferably, described temperature of reaction is-40 DEG C-50 DEG C, and the reaction times is 0.5-40 hour.
One of the present invention preferred embodiment in, reductive agent adopts sodium borohydride, and Lewis acid adopts zinc chloride or tetra isopropyl titanate, and solvent adopts glycol dimethyl ether, and temperature of reaction is-10 DEG C-10 DEG C, and the reaction times is 15-20 hour.
Step (2) described Chemoselective reduction also can generate a small amount of by product---formula RSRS-VI compound and formula RRSS-VI compound, and described by product can not remove, and directly enters next step reaction; The separation purification method removing that this area also can be adopted conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
Preferably, the solvent selected from methanol that described recrystallization method adopts, ethanol, Virahol, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, toluene, acetone, hexanaphthene or its any mixture, be more preferably methyl alcohol, Virahol, ethyl acetate or its mixture.
Preferably, described recrystallization removal step makes the HPLC chiral purity of material Chinese style RSSS/RRRS-VI compound be greater than 98%, is preferably greater than 99%.
Preferably, step (3) described reaction is carried out under Pd/C catalyzer exists.
For Pd content is 5-10wt% in described Pd/C catalyzer, be preferably 5wt% or 10wt%.
Described reaction is carried out in a solvent, and preferably, described solvent is alcoholic solvent, is more preferably any one in methyl alcohol, ethanol, Virahol, is more preferably methyl alcohol.
Preferably, the temperature of described reaction is 25-85 DEG C, is preferably 30-60 DEG C; Reaction times is 1-30 hour, is preferably 2-10 hour.
When containing by product in step (3) products therefrom, remove by ordinary method.
Further, the present invention also provides the second to prepare the method for nebivolol or its pharmacy acceptable salt, comprising:
(1) aforesaid method preparation formula SR#R-V compound and formula SS#R-V compound is adopted;
(2) gained formula SR#R-V compound and formula SS#R-V compound are carried out selective reduction, obtain formula SRRR-VI compound and formula SSSR-VI compound;
(3) gained formula SRRR-VI compound and formula SSSR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount or prepares its pharmacy acceptable salt further.
One of the present invention preferred embodiment in, step (2) Chinese style SR#R-V compound and formula SS#R-V compound are in the mode of mixture, preferably with the mixture of basic equimolar amount, be such as the mode of the mixture of 1.05:1 ~ 1:1.05 with mol ratio, carry out selective reduction.
When adopting this kind of embodiment, step (2) is obtained by reacting the mixture of formula SRRR-VI compound and formula SSSR-VI compound, this mixture can enter next step reaction through removal of impurities or without removal of impurities, obtains the mixture of SRRR-nebivolol and SSSR-nebivolol equimolar ratio.
In addition, step (2) is obtained by reacting described mixture also can through being separated, and obtain formula SRRR-VI compound and formula SSSR-VI compound respectively, the two removes PG group and X respectively 1, X 2substituting group, obtains independently SRRR-nebivolol and SSSR-nebivolol, then SRRR-nebivolol and SSSR-nebivolol is mixed with equimolar amount, obtain product.
Generate a small amount of by product simultaneously---formula SRSR-VI compound and formula SSRR-VI compound, described by product can not remove, and directly enters next step reaction; The separation purification method removing that this area also can be adopted conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
In another embodiment of the invention, step (2) Chinese style SR#R-V compound and formula SS#R-V compound with basic equimolar ratio, such as, take mol ratio as 1.05:1 ~ 1:1.05, carry out selective reduction respectively.
When adopting this kind of embodiment, step (2) obtains independently formula SRRR-VI compound and formula SSSR-VI compound.Get formula SRRR-VI compound and formula SSSR-VI compound of equimolar ratio, enter next step reaction, obtain the mixture of SRRR-nebivolol and SSSR-nebivolol equimolar ratio.
In addition, formula SRRR-VI compound that step (2) obtains and formula SSSR-VI compound, can remove PG group and X respectively 1, X 2substituting group, obtains independently SRRR-nebivolol and SSSR-nebivolol, then SRRR-nebivolol and SSSR-nebivolol is mixed with equimolar amount, obtain product.
Preferably, step (2) described Chemoselective reduction is being gone back under original reagent existence, is being carried out under Louis acid catalysis.
Preferably, described original reagent of going back is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, one or more in lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, red aluminium and borine, are preferably sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
Preferably, described Lewis acid is selected from boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, Repone K, bariumchloride, Manganous chloride tetrahydrate, titanium tetrachloride, zinc chloride, copper sulfate, palladous sulfate, zinc bromide, lime acetate, Palladous chloride, Manganous chloride tetrahydrate, Aluminum chloride anhydrous, aluminum isopropylate, bismuth chloride, one or more in magnesium perchlorate and alkoxy titanates, are preferably Palladous chloride, zinc chloride or alkoxy titanates.
Described reaction is carried out in a solvent, and preferably, described solvent is selected from tetrahydrofuran (THF), Virahol, acetonitrile, isopropyl ether, t-butyl methyl ether, glycol dimethyl ether, hexanaphthene, dimethylbenzene, toluene, one or more in methylene dichloride.
Preferably, described temperature of reaction is-40 DEG C-50 DEG C, and the reaction times is 0.5-40 hour.
One of the present invention preferred embodiment in, reductive agent adopts sodium borohydride, and Lewis acid adopts calcium chloride or lithium chloride, and solvent adopts tetrahydrofuran (THF), and temperature of reaction is at-5 DEG C-20 DEG C, and the reaction times is 8-12 hour.
Step (2) described Chemoselective reduction can generate a small amount of by product formula SRSR-VI compound and formula SSRR-VI compound, the separation purification method removing that described by product can adopt this area conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
Preferably, the solvent selected from methanol that described recrystallization method adopts, ethanol, Virahol, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, toluene, acetone, hexanaphthene or its any mixture, be more preferably methyl alcohol, Virahol, ethyl acetate or its mixture.
Preferably, described recrystallization removal step makes the HPLC chiral purity of SRRR/SSSR-VI compound in material be greater than 99%.
Preferably, step (3) described reaction is carried out under Pd/C catalyzer exists.
For Pd content is 5-10wt% in described Pd/C catalyzer, be preferably 5wt% or 10wt%.
Described reaction is carried out in a solvent, and preferably, described solvent is alcoholic solvent, is more preferably any one in methyl alcohol, ethanol, Virahol, is more preferably methyl alcohol.
Preferably, the temperature of described reaction is 25-85 DEG C, is preferably 30-60 DEG C; Reaction times is 1-30 hour, is preferably 2-10 hour.
When containing by product in step (3) products therefrom, remove by ordinary method.
Further, the invention provides the method that the third prepares nebivolol or its pharmacy acceptable salt, comprising:
(1) aforesaid method is adopted to prepare formula RS#S-V compound, formula RR#S-V compound, formula SR#R-V compound and formula SS#R-V compound;
(2) get its Chinese style RS#S-V compound and formula SR#R-V compound, carry out selective reduction, obtain formula RSSS-VI compound and formula SRRR-VI compound;
(3) gained formula RSSS-VI compound and formula SRRR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount, or prepares its pharmacy acceptable salt further.
One of the present invention preferred embodiment in, step (2) Chinese style RS#S-V compound and formula SR#R-V compound are in the mode of mixture, preferably with the mixture of basic equimolar amount, be such as the mode of the mixture of 1.05:1 ~ 1:1.05 with mol ratio, carry out selective reduction.
When adopting this kind of embodiment, step (2) is obtained by reacting the mixture of formula RSSS-VI compound and formula SRRR-VI compound, this mixture can enter next step reaction through removal of impurities or without removal of impurities, obtains the mixture of RSSS-nebivolol and SRRR-nebivolol equimolar ratio.
In addition, step (2) is obtained by reacting described mixture also can through being separated, and obtain formula RSSS-VI compound and formula SRRR-VI compound respectively, the two removes PG group and X respectively 1, X 2substituting group, obtains independently RSSS-nebivolol and SRRR-nebivolol, then RSSS-nebivolol and SRRR-nebivolol is mixed with equimolar amount, obtain product.
Step (2) generates a small amount of by product simultaneously---formula RSRS-VI compound and formula SRSR-VI compound, and described by product can not remove, and directly enters next step reaction; The separation purification method removing that this area also can be adopted conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
In another embodiment of the invention, step (2) Chinese style RS#S-V compound and formula SR#R-V compound with basic equimolar ratio, such as, take mol ratio as 1.05:1 ~ 1:1.05, carry out selective reduction respectively.
When adopting this kind of embodiment, step (2) obtains independently formula RSSS-VI compound and formula SRRR-VI compound.Get formula RSSS-VI compound and formula SRRR-VI compound of equimolar ratio, enter next step reaction, obtain the mixture of RSSS-nebivolol and SRRR-nebivolol equimolar ratio.
In addition, formula RSSS-VI compound that step (2) obtains and formula SRRR-VI compound, can remove PG group and X respectively 1, X 2substituting group, obtains independently RSSS-nebivolol and SRRR-nebivolol, then RSSS-nebivolol and SRRR-nebivolol is mixed with equimolar amount, obtain product.
Preferably, step (2) described Chemoselective reduction is being gone back under original reagent existence, is being carried out under Louis acid catalysis.
Preferably, described original reagent of going back is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, one or more in lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, red aluminium and borine, are preferably sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
Preferably, described Lewis acid is selected from boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, Repone K, bariumchloride, Manganous chloride tetrahydrate, titanium tetrachloride, zinc chloride, copper sulfate, palladous sulfate, zinc bromide, lime acetate, Palladous chloride, Manganous chloride tetrahydrate, Aluminum chloride anhydrous, aluminum isopropylate, bismuth chloride, one or more in magnesium perchlorate and alkoxy titanates, are preferably Palladous chloride, zinc chloride or alkoxy titanates.
Described reaction is carried out in a solvent, and preferably, described solvent is selected from tetrahydrofuran (THF), Virahol, acetonitrile, isopropyl ether, t-butyl methyl ether, glycol dimethyl ether, hexanaphthene, dimethylbenzene, toluene, one or more in methylene dichloride.
Preferably, described temperature of reaction is-40 DEG C-50 DEG C, and the reaction times is 0.5-40 hour.
One of the present invention preferred embodiment in, reductive agent adopts sodium borohydride, and Lewis acid adopts zinc chloride or tetra isopropyl titanate, and solvent adopts glycol dimethyl ether, and temperature of reaction is-10 DEG C-10 DEG C, and the reaction times is 15-20 hour.
Step (2) described Chemoselective reduction also can generate a small amount of by product formula RSRS-VI compound and formula SRSR-VI compound, the separation purification method removing that described by product can adopt this area conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
Preferably, the solvent selected from methanol that described recrystallization method adopts, ethanol, Virahol, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, toluene, acetone, hexanaphthene or its any mixture, be more preferably methyl alcohol, Virahol, ethyl acetate or its mixture.
Preferably, described recrystallization removal step makes the HPLC chiral purity of RSSS/SRRR-VI compound in material be greater than 99%.
Preferably, step (3) described reaction is carried out under Pd/C catalyzer exists.
For Pd content is 5-10wt% in described Pd/C catalyzer, be preferably 5wt% or 10wt%.
Described reaction is carried out in a solvent, and preferably, described solvent is alcoholic solvent, is more preferably any one in methyl alcohol, ethanol, Virahol, is more preferably methyl alcohol.
Preferably, the temperature of described reaction is 25-85 DEG C, is preferably 30-60 DEG C; Reaction times is 1-30 hour, is preferably 2-10 hour.
When containing by product in step (3) products therefrom, remove by ordinary method.
Further, the present invention also provides the 4th kind of method preparing nebivolol or its pharmacy acceptable salt, comprising:
(1) aforesaid method is adopted to prepare formula RS#S-V compound, formula RR#S-V compound, formula SR#R-V compound and formula SS#R-V compound;
(2) gained formula RR#S-V compound and formula SS#R-V compound are carried out selective reduction, obtain formula RRRS-VI compound and formula SSSR-VI compound;
(3) gained formula RRRS-VI compound and formula SSSR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount, or prepares its pharmacy acceptable salt further.
One of the present invention preferred embodiment in, step (2) Chinese style RR#S-V compound and formula SS#R-V compound are in the mode of mixture, preferably with the mixture of basic equimolar amount, be such as the mode of the mixture of 1.05:1 ~ 1:1.05 with mol ratio, carry out selective reduction.
When adopting this kind of embodiment, step (2) is obtained by reacting the mixture of formula RRRS-VI compound and formula SSSR-VI compound, this mixture can enter next step reaction through removal of impurities or without removal of impurities, obtains the mixture of RRRS-nebivolol and SSSR-nebivolol equimolar ratio.
In addition, step (2) is obtained by reacting described mixture also can through being separated, and obtain formula RRRS-VI compound and formula SSSR-VI compound respectively, the two removes PG group and X respectively 1, X 2substituting group, obtains independently RRRS-nebivolol and SSSR-nebivolol, then RRRS-nebivolol and SSSR-nebivolol is mixed with equimolar amount, obtain product.
Step (2) generates a small amount of by product simultaneously---formula RRSS-VI compound and formula SSRR-VI compound, and described by product can not remove, and directly enters next step reaction; The separation purification method removing that this area also can be adopted conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
In another embodiment of the invention, step (2) Chinese style RR#S-V compound and formula SS#R-V compound with basic equimolar ratio, such as, take mol ratio as 1.05:1 ~ 1:1.05, carry out selective reduction respectively.
When adopting this kind of embodiment, step (2) obtains independently formula RRRS-VI compound and formula SSSR-VI compound.Get formula RRRS-VI compound and formula SSSR-VI compound of equimolar ratio, enter next step reaction, obtain the mixture of RRRS-nebivolol and SSSR-nebivolol equimolar ratio.
In addition, formula RRRS-VI compound that step (2) obtains and formula SSSR-VI compound, can remove PG group and X respectively 1, X 2substituting group, obtains independently RRRS-nebivolol and SSSR-nebivolol, then RRRS-nebivolol and SSSR-nebivolol is mixed with equimolar amount, obtain product.
Preferably, step (2) described Chemoselective reduction is being gone back under original reagent existence, is being carried out under Louis acid catalysis.
Preferably, described original reagent of going back is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, one or more in lithium borohydride, calcium borohydride, zinc borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, red aluminium and borine, are preferably sodium borohydride, POTASSIUM BOROHYDRIDE or lithium borohydride.
Preferably, described Lewis acid is selected from boron trifluoride, calcium chloride, magnesium chloride, lithium chloride, Repone K, bariumchloride, Manganous chloride tetrahydrate, titanium tetrachloride, zinc chloride, copper sulfate, palladous sulfate, zinc bromide, lime acetate, Palladous chloride, Manganous chloride tetrahydrate, Aluminum chloride anhydrous, aluminum isopropylate, bismuth chloride, one or more in magnesium perchlorate and alkoxy titanates, are preferably Palladous chloride, zinc chloride or alkoxy titanates.
Described reaction is carried out in a solvent, and preferably, described solvent is selected from tetrahydrofuran (THF), Virahol, acetonitrile, isopropyl ether, t-butyl methyl ether, glycol dimethyl ether, hexanaphthene, dimethylbenzene, toluene, one or more in methylene dichloride.
Preferably, described temperature of reaction is-40 DEG C-50 DEG C, and the reaction times is 0.5-40 hour.
One of the present invention preferred embodiment in, reductive agent adopts sodium borohydride, and Lewis acid adopts calcium chloride or lithium chloride, and solvent adopts tetrahydrofuran (THF), and temperature of reaction is at-5 DEG C-20 DEG C, and the reaction times is 8-12 hour.
Step (2) described Chemoselective reduction can generate a small amount of by product---formula RRSS-VI compound and formula SSRR-VI compound, the separation purification method removing that described by product can adopt this area conventional, such as column chromatography, recrystallization method etc., be preferably recrystallization method.
Preferably, the solvent selected from methanol that described recrystallization method adopts, ethanol, Virahol, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, toluene, acetone, hexanaphthene or its any mixture, be more preferably methyl alcohol, Virahol, ethyl acetate or its mixture.
Preferably, described recrystallization removal step makes the HPLC chiral purity of material Chinese style RRRS/SSSR-VI compound be greater than 99%.
Preferably, step (3) described reaction is carried out under existing at Pd/C catalyzer.
For Pd content is 5-10wt% in described Pd/C catalyzer, be preferably 5wt% or 10wt%.
Described reaction is carried out in a solvent, and preferably, described solvent is alcoholic solvent, is more preferably any one in methyl alcohol, ethanol, Virahol, is more preferably methyl alcohol.
Preferably, the temperature of described reaction is 25-85 DEG C, is preferably 30-60 DEG C; Reaction times is 1-30 hour, is preferably 2-10 hour.
When containing by product in step (3) products therefrom, remove by ordinary method.
It should be noted that, because nebivolol has symmetrical chemical structure, therefore formula SRRR-nebivolol and formula RRRS-nebivolol are same compound, and formula SSSR-nebivolol and formula RSSS-nebivolol are same compound.
Compared with prior art, nebivolol preparation method of the present invention have employed new synthesis thinking, namely first generate the intermediate formula V compound that the three-dimensional arrangement of the chiral carbon on the pyranoid ring of two ends is fixing, then utilize chiral induction to control the stereochemistry of hydroxy position.Specifically, first adopt R-I compound as Material synthesis RS/RR-IV compound, then using RS/RR-IV compound and formula S-I compound as Material synthesis intermediate formula V compound, the three-dimensional arrangement of the chiral carbon thus on the pyranoid ring of formula V compound two ends is fixed as R and S type respectively; Or, first adopt S-I compound as Material synthesis SR/SS-IV compound, then using SR/SS-IV compound and formula R-I compound as Material synthesis intermediate formula V compound, on the pyranoid ring of formula V compound two ends, the three-dimensional arrangement of chiral carbon is fixed as S and R type respectively thus; Then utilize chiral induction to control the stereochemistry of hydroxy position, it is main product that above-mentioned formula V compound selective reduction is obtained RSSS/SRRR-VI compound, by subsequent operations, finally obtains RSSS/SRRR-nebivolol.
Visible, RSSS/SRRR-nebivolol preparation method of the present invention avoids the generation of a large amount of isomer waste material formula RR/SS-IV compound, formula RS#R/SR#S-V compound in prior art, thus substantially increase the utilization ratio of raw material and the combined coefficient of RSSS/SRRR-nebivolol, reduce cost.Meanwhile, inventive process avoids in prior art the problem that lock out operation such as being separated loaded down with trivial details recrystallization needed for above-mentioned isomer waste material and waste recovery utilize, operation steps simplifies greatly, and cost reduces, and is more suitable for suitability for industrialized production.
Embodiment
With specific embodiment, technical scheme of the present invention is described in detail below, but protection scope of the present invention is not limited thereto.
The preparation of the chloro-1-of embodiment 1 2-[6-fluoro-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (formula RS/RR-II compound)
Under room temperature, the chloro-1-of 2-(the fluoro-1-chromene of (R)-6--2-base)-ethyl ketone (50g is added in the there-necked flask of 1L, 0.21mol) (i.e. formula R-I compound, this compound can refer to method preparation disclosed in CN102164906A embodiment 6), dehydrated alcohol (300mL), adds NaBH in batches 4(9.9g, 0.26mol), reaction 30min, add saturated ammonium chloride solution cancellation reaction, filter, filtrate is steamed except ethanol, residue adds water (300mL) and ethyl acetate (600mL) separatory, ethyl acetate layer is with anhydrous sodium sulfate drying, filter, filtrate concentrated the mixture (49.4g, yield 98.0%) of the chloro-1-of 2-[6-fluoro-(2R)-1-chromene-2-base]-(1S)-1-ethanol and the chloro-1-of 2-[6-fluoro-(2R)-1-chromene-2-base]-(1R)-1-ethanol.
The preparation of embodiment 2 R-6-fluoro-(2R/S)-2-epoxy ethyl-1-chromene (formula RS/RR-III compound)
Under room temperature, the chloro-1-of the 2-prepared according to the method for embodiment 1 [6-fluoro-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (51.5g is added in 500mL there-necked flask, 0.22mol), sodium hydroxide solution (2M, 0.44mol), reaction 18h, reaction solution is extracted with ethyl acetate, ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate concentrated the mixture (43.1g of oily liquids R-6-fluoro-(2S)-2-epoxy ethyl-1-chromene and R-6-fluoro-(2R)-2-epoxy ethyl-1-chromene, yield 98%).
The preparation of embodiment 3 2-[(phenmethyl) is amino]-1-[6-fluoro-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (formula RS/RR-IV compound)
The R-6-prepared according to the method for embodiment 2 fluoro-(2R/S)-2-epoxy ethyl-1-chromene (50.36g is added in 500mL single port flask, 0.26mol), benzylamine (97g, 0.90mol) with Virahol (150mL), back flow reaction 3h, remove Virahol under reduced pressure, residue adds hexanaphthene (500mL), stirring at room temperature 2h, filtration obtains white solid, dry, obtain the mixture (51.6g (0.17mol) of 2-[(phenmethyl) is amino]-1-[6-fluoro-(2R)-1-chromene-2-base]-(1S)-1-ethanol and 2-[(phenmethyl) is amino]-1-[6-fluoro-(2R)-1-chromene-2-base]-(1R)-1-ethanol, yield is 66%).
The preparation of embodiment 4 2-[(phenmethyl) is amino]-1-[6-fluoro-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol (formula SR/SS-IV)
With formula S-I compound (wherein X 2for H, LG is Cl, method preparation disclosed in reference CN102164906A embodiment 7) be raw material, with reference to operation steps synthesis 2-[(phenmethyl) is amino]-1-[6-fluoro-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol of embodiment 1-3.
Embodiment 5 2-{ benzyl-[2-(6-fluoro-(2R)-1-chromene-2-base)-(2R/S)-hydroxy-ethyl]-amino } synthesis of-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (formula RS#S-V compound and formula RR#S-V compound)
2-[(phenmethyl) is amino]-1-[6-fluoro-(2R)-1-chromene-2-base]-(the 1R/S)-1-ethanol (29.98g prepared according to the method for embodiment 3 is added in the there-necked flask of 500mL, 0.99mol, RR/RS=48/52), the chloro-1-of 2-(the fluoro-1-chromene of (S)-6--2-base)-ethyl ketone (27.2g, 0.119mol) (S-I, can refer to method preparation disclosed in CN102164906A embodiment 7), KBr (1.17g, 9.9mmol), NaHCO 3(12.4g, 0.148mol, 1.5eq.), acetonitrile (250mL), after stirring at room temperature 18h, is warming up to 40 DEG C to reacting completely, and filters to obtain white solid and filtrate A.
White solid methylene dichloride dissolves, suction filtration, filtrate concentrates to obtain 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (RS#S-V) 23.5g, yield 91%, purity 99.3%.
Filtrate A concentrating under reduced pressure, obtain 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (RR#S-V), head product 40.5g, purity 84%, directly next step is for selective reduction.
Embodiment 6 2-{ benzyl-[2-(6-fluoro-(2S)-1-chromene-2-base)-(2R/S)-hydroxy-ethyl]-amino } synthesis of-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone (formula SR#R-V compound and formula SS#R-V compound)
2-[(phenmethyl) is amino]-1-[6-fluoro-(2S)-1-chromene-2-base]-(the 1R/S)-1-ethanol prepared using embodiment 4 method and the chloro-1-of 2-(the fluoro-1-chromene of (R)-6--2-base)-ethyl ketone (method preparation disclosed in reference CN102164906A embodiment 6) are as raw material, with reference to the operation steps of embodiment 5, prepare 2-{ benzyl-[2-(6-fluoro-(2S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone (SR#R-V) and 2-{ benzyl-[2-(6-fluoro-(2S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone (SS#R-V).
Embodiment 7 2-R [S [S (S)]]-[[benzyl imines] two-(methylene radical)] is two]-6-fluoro-1-chromene-2-methyl alcohol and 2-S [R [R (R)]]-[[benzyl imines] two-(methylene radical)] be two] synthesis of the fluoro-1-chromene of-6--2-methyl alcohol (formula RSSS-VI compound and formula SRRR-VI compound) raceme
In 3L there-necked flask, add the formula RS#S-V compound (49.2g that embodiment 5 method prepares, 0.1mol), the formula SR#R-V compound (49.2g, 0.1mol) that embodiment 6 method prepares and glycol dimethyl ether (1460ml), stirred at ambient temperature is clearly molten, be cooled to-5 DEG C, fast drop tetra isopropyl oxygen base titanic acid ester (113.6g, 0.4mol), adds NaBH after stirring 1h in batches 4(15.2g, 0.4mol), continue reaction 15h, raw material reaction is complete, is cooled to-15 DEG C, drips 4N hydrochloric acid (800ml), drips Bi Jixu and stirs 2h, filter to obtain white solid A;
At 0 DEG C, by white solid A acetic acid ethyl dissolution, add NaOH solution and be neutralized to ethyl acetate layer pH about 12, separatory obtains ethyl acetate layer, wash twice with saturated aqueous common salt, anhydrous sodium sulfate drying, concentrates and obtains white solid 91g, the HPLC purity 97.6% of its Chinese style RSSS/SRRR-VI compound.
Recrystallizing and refining: upper step gained white solid is added Virahol (600ml), backflow is lower clearly molten, and the abundant crystallization 15h of mechanical stirring under room temperature, filters to obtain white solid 75.6g, the HPLC purity 99.3% of formula RSSS/SRRR-VI compound.
Chiral analysis: positive HPLC condition: Chiracel AD-H Column (250mm); Moving phase: normal hexane: Virahol: diethylamine=80:20:0.1; Determined wavelength: UV280nm; Flow velocity: 0.8mL/min; Appearance time is respectively 16min (SRSR-VI), 25min (SRRR-VI), 31min (RSSS-VI), 39min (SSRR-VI).
Embodiment 8 2-R [S [S (S)]]-[[benzyl imines] two-(methylene radical)] is two] (the synthesis of (formula RSSS-VI compound) of the fluoro-1-chromene of-6--2-methyl alcohol
With reference to the operation steps of embodiment 7, formula RS#S-V compound prepared with embodiment 5 method, for raw material, prepares RSSS-VI compound.
Embodiment 9 2-S [R [R (R)]]-[[benzyl imines] two-(methylene radical)] is two] synthesis of the fluoro-1-chromene of-6--2-methyl alcohol (formula SRRR-VI compound)
With reference to the operation steps of embodiment 7, formula SR#R-V compound prepared with embodiment 6 method prepares SRRR-VI compound.
Embodiment 10 2-S [R [R (R)]]-[[benzyl imines] two-(methylene radical)] is two] the fluoro-1-chromene of-6-
-2-methyl alcohol and 2-R [S [S (S)]]-[[benzyl imines] two-(methylene radical)] is two] preparation of the fluoro-1-chromene of-6--2-methanol-fueled CLC and hydrochloride thereof
With CaCl 2(6.5g, 58.4mmol) and NaBH 4(4.43g, 116.8mmol) refluxes 2h under tetrahydrofuran (THF) (150ml); Be cooled to greenhouse, the formula RR#S-V compound (12g that embodiment 5 method is prepared, 24.34mmol), the formula SS#R-V compound (12g that embodiment 6 method prepares, THF (50ml) solution 24.34mmol) slowly instills, it is complete that reaction 2h, TLC detect raw material reaction, RRSS/ (RRRS+SSSR)-VI=40/60.
Reaction solution is poured in frozen water, add extraction into ethyl acetate, respectively with 1N HCl and saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, stirring at room temperature 4h, separate out RSSS/RRRS-VI hydrochloride 13g, chiral purity is RRSS/ (RRRS+SSSR)-VI hydrochloride=5/95, and formula RRRS-VI hydrochloride compound and formula SSSR-VI hydrochloride compound mol ratio are 1:1.
Embodiment 11 2-S [R [R (R)]]-[[benzyl imines] two-(methylene radical)] is two] preparation of its hydrochloride of the fluoro-1-chromene of-6--2-methyl alcohol
With reference to the operation steps of embodiment 10, formula RR#S-V compound prepared with embodiment 5 method, for raw material, prepares titled reference compound.
Embodiment 12 2-R [S [S (S)]]-[[benzyl imines] two-(methylene radical)] is two] preparation of its hydrochloride of the fluoro-1-chromene of-6--2-methyl alcohol
With reference to the operation steps of embodiment 10, formula SS#R-V compound prepared with embodiment 6 method prepares titled reference compound.
Embodiment 13 [imines] is two-preparation of (methylene radical) two [the fluoro-1-chromene of 6-]-2-methyl alcohol (SRRR/RSSS-nebivolol) and hydrochloride thereof
To in 250mL autoclave, drop into 2-S [R [R (R)]] that the method for embodiment 11 prepares-[[benzyl imines] two-(methylene radical)] two] 2-R [S [S (S)]]-[[the benzyl imines] two-(methylene radical)] that prepare of the method for 6-fluoro-1-chromene-2-methyl alcohol and embodiment 12 be two] the 6-fluoro-1-chromene each 18g of-2-methyl alcohol (36.4mmol), Pd/C 1.8g, methyl alcohol 320mL, hydrogenation, pressure 0.8MPa, be heated to 50 DEG C, reaction 2h, after TLC detection reaction is complete, cross and filter Pd/C, concentrated, obtain SRRR/RSSS-nebivolol 14.7g.
Gained SRRR/RSSS-nebivolol is added methyl alcohol 300ml dissolve, under low temperature, logical hydrogen chloride gas, makes nebivolol hydrochloride, add activated carbon decolorizing, while hot filtering gac, filtrate stirs cooling crystallization, filter to obtain white solid nebivolol hydrochloric acid 13.8g, HPLC purity 99.5%.
Embodiment 14 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone and 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone, and
2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone and 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino } preparation of-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone
Prepared by the chloro-1-of embodiment 14.1 2-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (formula RS/RR-II compound)
The chloro-1-of 2-[6-fluoro-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (1.4g is added in 50mL there-necked flask, 6mmol), trifluoroacetic acid (8mL), NBS (1.62g, 9mmol), room temperature reaction 1h, GC follow the tracks of reaction, steam except trifluoroacetic acid after reacting completely, residue methylene dichloride (20mL) extraction, saturated NaHCO 3(10mL) wash, saturated sodium-chloride washs, anhydrous sodium sulfate drying, filters, filtrate is concentrated obtains the chloro-1-of 2-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol 1.8g, directly next step reaction.
Product structure confirms: 1H NMR (CDCl 3, 400MHz) and δ=7.09-7.12 (m, 1H), 6.74-6.77 (m, 1H), 3.73-4.29 (m, 4H), 2.77-2.98 (m, 2H), 1.99-2.05 (m, 1H), 1.77-1.87 (m, 1H).
Prepared by the fluoro-8-of embodiment 14.2 R-6-bromo-(2R/S)-2-epoxy ethyl-1-chromene (formula RS/RR-III compound)
Under room temperature, the chloro-1-of 2-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (1.8g that the method adding embodiment 14.1 in 50mL there-necked flask prepares, 6mol), pre-configured sodium hydroxide solution (sodium hydroxide 0.48g, 12mmol, water 6mL), reaction 18h, it is complete that TLC monitors feedstock conversion, extraction into ethyl acetate, dry, concentrate to obtain the fluoro-8-of R-6-bromo-(2R/S)-2-epoxy ethyl-1-chromene 1.45g, bromo-one-tenth epoxy two step yield is 88%.
Product structure confirms: 1H NMR (CDCl 3, 400MHz) and δ=7.08-7.12 (m, 1H), 6.71-6.75 (m, 1H), 3.90-4.14 (m, 1H), 3.16-3.23 (m, 1H), 2.78-2.98 (m, 4H), 2.06-2.18 (m, 1H), 1.85-1.99 (m, 1H).
The preparation of embodiment 14.3 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol (formula RS/RR-IV compound)
The fluoro-8-of R-6-bromo-(the 2R/S)-2-epoxy ethyl-1-chromene (1.45g prepared according to embodiment 14.2 method is added in 100ml single port flask, 5.3mmol), benzylamine (1.99g, 18.6mmol) with Virahol (10mL), back flow reaction 3h, reacts complete.Steaming desolventizes, residue adds hexanaphthene (15mL), stirring at room temperature 2h, filtration obtains white solid, dry, obtain white solid 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(1R/S)-1-ethanol 1.3g, yield 63%.
Product structure confirms data: 1H NMR (CDCl 3, 400MHz) and δ=7.26-7.34 (m, 5H), 7.06-7.08 (m, 1H), 6.72-6.74 (m, 1H), 3.08-4.04 (m, 4H), 2.75-3.09 (m, 4H), 1.94-2.04 (m, 2H).
The preparation of embodiment 14.4 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol (formula SR/SS-IV compound)
With the chloro-1-of 2-[6-fluoro-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol (1.4g, 6mmol) as raw material, the method with reference to embodiment 14.1-14.3 prepares 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol.
Embodiment 14.5 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone, and 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino the preparation of-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (formula RS#S-V compound and formula RR#S-V compound)
Under room temperature, 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2R)-1-chromene-2-base]-(the 1R/S)-1-ethanol (8.2g prepared according to the method for embodiment 14.3 is dropped in 50mL there-necked flask, 21mmol), the chloro-1-of S-2-(the fluoro-1-chromene of (R)-6--2-base)-ethyl ketone (5.44g, 23mmol), NaHCO 3(5.29g, 63mmol), KBr (0.25g, 2.1mol), acetonitrile (80mL), magnetic agitation, TLC follows the tracks of reaction.After reacting completely, filter to obtain white solid and liquor B.
White solid methylene dichloride dissolves, suction filtration, filtrate concentrates to obtain 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone 2.25g.
Liquor B concentrating under reduced pressure, obtains 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone 4.2g.
Embodiment 14.6 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone, and 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino the preparation of-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone (formula SR#R-V compound and formula SS#R-V compound)
Under room temperature, 2-[(phenmethyl) is amino]-1-[the fluoro-8-of 6-bromo-(2S)-1-chromene-2-base]-(the 1R/S)-1-ethanol (11.18g prepared according to embodiment 14.4 method is dropped in 50mL there-necked flask, 29.4mmol), the chloro-1-of R-2-(the fluoro-1-chromene of (R)-6--2-base)-ethyl ketone (7.41g, 32.4mmol), NaHCO 3(7.4g, 88.2mol), KBr (0.35g, 2.94mmol), acetonitrile (120mL), magnetic agitation, TLC follows the tracks of reaction.After reacting completely, filter to obtain white solid and liquor C.
White solid methylene dichloride dissolves, suction filtration, filtrate concentrates to obtain 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone 5g.
Liquor C concentrating under reduced pressure, obtains 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone 8.61g.
Product 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone: 1H NMR (CDCl3, 400MHz) δ=7.29-7.37 (m, 5H), 7.06-7.08 (m, 1H), 6.71-6.75 (m, 4H), 4.02-4.08 (m, 1H), 3.92-3.97 (m, 1H), 3.83-3.86 (m, 1H), 3.62-3.69 (m, 2H), 3.31-3.34 (m, 1H), 3.17-3.20 (m, 1H), 2.75-2.82 (m, 4H), 2.09-2.26 (m, 4H), 1.91-2.02 (m, 1H), 1.70-1.80 (m, 1H).
Product 2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone: 1H NMR (CDCl3, 400MHz) δ=7.29-7.35 (m, 5H), 7.04-7.07 (m, 1H), 6.68-6.75 (m, 4H), 4.26-4.30 (m, 1H), 3.92-3.97 (m, 1H), 3.83-3.86 (m, 1H), 3.63 (S, 2H), 3.31-3.34 (m, 1H), 3.17-3.20 (m, 1H), 2.75-2.82 (m, 4H), 2.09-2.26 (m, 4H), 1.91-2.02 (m, 1H), 1.70-1.80 (m, 1H).
Embodiment 152-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino } preparation of-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (S)-ethanol (formula RSSS-VI compound)
2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino is dropped in 100mL single port flask }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (4.0g, 7mmol), glycol dimethyl ether 25mL, be cooled to-10 DEG C, add Ti (Oi-Pr) 4(3.97g.14mmol, NaBH 4(0.53g, 14mmol), reacts 18h at-10 DEG C, and TLC follows the tracks of reaction, reacts completely.Add the aqueous ammonium chloride solution cancellation reaction of ice, methylene dichloride (30mL) extracts, 0.5M sodium hydroxide solution (5mL) washs, saturated sodium-chloride washs, column chromatography purification (P:E=10:1), obtain 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (S)-ethanol 3.6g, yield 89%, RSSS/RSRS=92.7/7.3.
Product structure confirms: 1H NMR (CDCl3,400MHz) δ=7.25-7.35 (m, 5H), 7.06-7.09 (m, 1H), 6.67-6.78 (m, 4H), 3.68-3.94 (m, 6H), 2.70-3.14 (m, 10H), 2.20-2.25 (m, 1H), 1.76-1.86 (m, 3H).
Embodiment 16 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino } preparation of-1-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-1 (R)-ethanol (formula SRRR-VI compound)
2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino is dropped in 100mL single port flask }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (1.85g, 3.2mmol), glycol dimethyl ether 25mL, be cooled to-10 DEG C, add Ti (Oi-Pr) 4(3.97g, 14mmol), NaBH 4(0.53g, 14mmol), reacts 18h at-10 DEG C, and TLC follows the tracks of reaction, reacts completely.Add the aqueous ammonium chloride solution cancellation reaction of ice, methylene dichloride (30mL) extracts, 0.5M sodium hydroxide solution (5mL) washs, saturated sodium-chloride washs, column chromatography purification (P:E=10:1), obtain 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (S)-ethanol 1g, yield 54%, SRRR/SRSR=92.1/7.9.
Product structure confirms: 1H NMR (CDCl3,400MHz) δ=7.25-7.35 (m, 5H), 7.06-7.09 (m, 1H), 6.66-6.78 (m, 4H), 3.68-3.94 (m, 6H), 2.64-3.13 (m, 10H), 2.20-2.23 (m, 1H), 1.76-1.86 (m, 3H).
Embodiment 17 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino } preparation of-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (R)-ethanol (formula RRRS-VI compound)
2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino is dropped in 100mL single port flask }-1-(6-fluoro-2 (S)-1-chromene-2-base)-ethyl ketone (4.1g, 7.16mmol), tetrahydrofuran (THF) (50mL), be cooled to-10 DEG C, add anhydrous LiCl (1.2g, 28.6mmol), KBH 4(0.58,10.7mmol), TLC follows the tracks of reaction.After reacting completely, aqueous ammonium chloride solution cancellation is reacted, methylene dichloride (30mL) extracts, sodium hydroxide solution (0.5M, 5mL) with saturated sodium-chloride washing, anhydrous sodium sulfate drying, filter, filtrate concentrates, column chromatography purification, obtain 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (R)-ethanol 2g, yield is 60%, RRRS/RRSS=54/45.
Product structure confirms: 1H NMR (CDCl 3, 400MHz) and δ=7.24-7.35 (m, 5H), 7.04-7.08 (m, 1H), 6.65-6.78 (m, 4H), 3.80-3.96 (m, 6H), 2.69-3.07 (m, 10H), 2.11-2.14 (m, 1H), 1.83-1.93 (m, 3H).
Embodiment 18 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino } preparation of-1-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-1 (S)-ethanol (formula SSSR-VI compound)
2-{ benzyl-[2-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino is dropped in 100mL single port flask }-1-(6-fluoro-2 (R)-1-chromene-2-base)-ethyl ketone (8.2g, 14.3mmol) with tetrahydrofuran (THF) (50mL), be cooled to-10 DEG C, add anhydrous LiCl (2.41g, 57.3mmol), KBH 4(1.15g, 21.4mmol), TLC follows the tracks of reaction.After reacting completely, add aqueous ammonium chloride solution cancellation reaction, methylene dichloride (40mL) extracts, sodium hydroxide solution (0.5M, 5mL) with saturated sodium-chloride washing, anhydrous sodium sulfate drying, filter, filtrate concentrates, column chromatography purification, obtain 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-1 (S)-ethanol head product 4.2g, yield is 51%, SSSR/SSRR=56/44.
Product structure confirms: 1H NMR (CDCl 3, 400MHz) and δ=7.24-7.34 (m, 5H), 7.04-7.08 (m, 1H), 6.65-6.76 (m, 4H), 3.80-3.97 (m, 6H), 2.69-3.07 (m, 10H), 2.11-2.15 (m, 1H), 1.86-1.96 (m, 3H).
Embodiment 19 (2S [R [R (R)]]]-[[imines] two-(methylene radical)] two [the fluoro-1-chromene of 6--2-methyl alcohol) synthesis of hydrochloride (SRRR-nebivolol hydrochloride)
The 2-{ benzyl that the method dropping into embodiment 17 in high-pressure hydrogenation still prepares-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (R)-ethanol (1.1g, 1.9mmol), Pd/C 0.11g, methyl alcohol 20mL, salt of wormwood (0.53g, 3.8mmol, 2eq.), oil bath 50 DEG C, H 2pressure 0.7Mpa, magnetic stirrer over night, TLC follows the tracks of reaction, after reacting completely, cross and filter Pd/C and salt, filtrate is concentrated to be desolventized, and residue filters after adding Virahol dissolving again, passes into HCl gas in Virahol mother liquor, stir 2h, filter, dry RRRS-nebivolol hydrochloride 0.55g.
The preparation of embodiment 20 RRRS-nebivolol hydrochloride, SSSR-nebivolol hydrochloride
Adopt 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino prepared by the method for embodiment 15 respectively }-1-(the fluoro-8-of 6-bromo-2 (R)-1-chromene-2-base)-1 (S)-ethanol, 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino prepared by the method for embodiment 16 }-1-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-1 (R)-ethanol, 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino prepared by the method for embodiment 18 }-1-(the fluoro-8-of 6-bromo-2 (S)-1-chromene-2-base)-1 (S)-ethanol is as reactant, adopt the method for embodiment 19, prepare RSSS-nebivolol hydrochloride respectively, RRRS-nebivolol hydrochloride, SSSR-nebivolol hydrochloride (wherein RSSS-nebivolol hydrochloride and SSSR-nebivolol hydrochloride are same compound).
Embodiment 21 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-chloro-2 (S)-1-chromene-2-base)-ethyl ketone, and 2-{ benzyl-[2-(6-fluoro-2 (R)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino the preparation of-1-(the fluoro-8-of 6-chloro-2 (S)-1-chromene-2-base)-ethyl ketone
The preparation of the chloro-1-chromene of the fluoro-8-of embodiment 21.1 R-6--2-methyl-formiate
R-6-fluoro-1-chromene-2-methyl-formiate (5g, 23.8mmol) is dropped into, NCS (4.76g, 35.3mmol), FeCl in 100mL there-necked flask 3(0.384g, 2.38mmol), chloroform (50mL), is heated to backflow.After reacting completely, be cooled to room temperature, reaction solution washs with saturated sodium-chloride, anhydrous sodium sulfate drying, filters, and filtrate concentrates, obtain the chloro-1-chromene of the fluoro-8-of white solid R-6--2-methyl-formiate 4.91g with silica gel column chromatography separating purification, yield 84%, HPLC purity is 98.73%.
Product structure confirms data: 1H NMR (400MHz, CDCl3) δ=6.98 (dd, J=8.1,3.0Hz, 1H), 6.68 (dd, J=8.4,3.0Hz, 1H), 4.89 (t, J=5.1Hz, 1H), 3.79 (s, 3H), 2.87 – 2.67 (m, 2H), 2.32 – 2.21 (m, 2H).
The preparation of the chloro-1-of embodiment 21.2 R-2-(the chloro-1-chromene of the fluoro-8-of 6--2-base)-ethyl ketone (formula R-I compound)
In 100mL there-necked flask, drop into R-6-fluoro-8-chloro-1-chromene-2-methyl-formiate (3.0g, 12.2mmol), add anhydrous tetrahydro furan (35mL) under nitrogen protection, bromochloromethane (2.35g, 18.4mmol).Be cooled to less than-70 DEG C, drip n-Butyl Lithium hexane solution (2.5M, 7.4mL, 18.4mmol), dropwise, stir 0.5h.Drip glacial acetic acid (3mL), add water (15mL) after continuing to stir 0.5h, and control temperature is below-30 DEG C.After water dropwises, rise to room temperature, add ethyl acetate (50mL) extraction, saturated sodium-chloride washs, anhydrous sodium sulfate drying, filter, filtrate concentrates, and obtains micro-yellow solid, then uses n-hexane-ethyl acetate mixed solvent recrystallization, obtain the chloro-1-of white solid R-2-(the chloro-1-chromene of the fluoro-8-of 6--2-base)-ethyl ketone 2.3g, yield 71%.
Product structure confirms: 1H NMR (400MHz, CDCl3) δ 7.03 (dd, J=8.0,3.0Hz, 1H), 6.75 (dd, J=8.3,3.0Hz, 1H), 4.73 (dd, J=8.0,4.0Hz, 1H), 4.72 (d, J=17.4Hz, 1H), 4.57 (d, J=17.4Hz, 1H), 2.99-2.71 (m, 2H), 2.43-2.36 (m, 1H), 2.12-2.03 (m, 1H).
Embodiment 21.3 2-{ benzyl-[2-, (6-fluoro-2, (S)-1-chromene-2-base)-, (2R)-hydroxy-ethyl]-amino-1-, (the fluoro-8-of 6-chloro-2, (R)-1-chromene-2-base)-ethyl ketone and 2-{ benzyl-[2-, (6-fluoro-2, (S)-1-chromene-2-base)-, (2S)-hydroxy-ethyl]-amino-1-, (the fluoro-8-of 6-chloro-2, (R)-1-chromene-2-base)-ethyl ketone, the preparation of (formula SR#R-V compound and formula SS#R-V compound)
The chloro-1-of R-2-(the chloro-1-chromene of the fluoro-8-of the 6--2-base)-ethyl ketone (2.3g that embodiment 21.2 method prepares is dropped in 100mL single port flask, 8.74mmol), 2-[(phenmethyl) is amino]-1-[6-fluoro-(2S)-1-chromene-2-base]-(1R/S)-1-ethanol (2.39g, 7.94mmol), NaHCO 3(1.33g, 15.89mmol), KBr (0.104g, 0.874mmol), acetonitrile (15mL).Stirring at room temperature is to having reacted, direct column chromatography, separation obtains white solid 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-ethyl ketone 1.24g, yield is 24%, with yellow viscous liquid 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2S)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-ethyl ketone 2.1g, yield is 46%.
Embodiment 22 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino } preparation of-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-1 (R)-ethanol (formula SRRR-VI compound)
2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino is dropped in 100mL single port flask }-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-ethyl ketone (1.04g, 1.97mmol), glycol dimethyl ether (15mL), Ti (Oi-Pr) 4(1.12g, 3.94mmol), is cooled to-10 DEG C, continues to add NaBH 4(0.149g, 3.94mmol), 18h is reacted at-10 DEG C, TLC follows the tracks of reaction, after reacting completely, saturated aqueous ammonium chloride cancellation is reacted, methylene dichloride (30mL) extracts, respectively with 0.5M aqueous sodium hydroxide solution (5mL) and saturated sodium-chloride washing, anhydrous sodium sulfate drying, filter, filtrate concentrates, purification by silica gel column chromatography obtains 2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino }-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-1 (R)-ethanol head product 0.76g, yield is 72%, SRRR/SRSR=86/14.
The synthesis of embodiment 23 (2S [R [R (R)]]-[[imines] two-(methylene radical)] is two] the fluoro-1-chromene of 6--2-methyl alcohol) hydrochloride (SRRR-nebivolol hydrochloride)
2-{ benzyl-[2-(6-fluoro-2 (S)-1-chromene-2-base)-(2R)-hydroxy-ethyl]-amino is dropped in high-pressure hydrogenation still }-1-(the fluoro-8-of 6-chloro-2 (R)-1-chromene-2-base)-1 (R)-ethanol (1.0g, 1.9mmol), Pd/C 0.11g, methyl alcohol 20mL, salt of wormwood (0.53g, 3.8mmol, 2eq.), oil bath 50 DEG C, H 2pressure 0.7Mpa, magnetic stirrer over night, TLC follows the tracks of reaction, after reacting completely, cross filtering Pd/C and salt, filtrate is concentrated except desolventizing, adds after Virahol dissolves and again filters, pass into HCl gas in Virahol mother liquor, stir 2h, filter, dry SRRR-nebivolol hydrochloride 0.54g.
The preparation of embodiment 24 equimolar ratio SRRR/RSSS-nebivolol hydrochloride
The SRRR-nebivolol hydrochloride obtain embodiment 19,20 method respectively and RSSS-nebivolol hydrochloride mix with equimolar amount, obtain SRRR/RSSS-nebivolol hydrochloride racemic modification.
It should be noted that, above embodiment is only exemplary, and non-exclusive, being construed as limiting not to scope.Those skilled in the art can, according to the method for above-described embodiment, can select to adopt multiple variation pattern, preparation SRRR-nebivolol hydrochloride and RSSS-nebivolol hydrochloride racemic modification.

Claims (10)

1. a preparation method for Nebivolol Intermediates formula RS#S/RR#S-V compound, comprising:
(1) formula RS/RR-IV compound and formula S-I compound are carried out coupling to dock and react, obtain the material containing formula RS#S/RR#S-V compound,
Wherein, X 1and X 2represent hydrogen atom or the halogen atom of the connection of phenyl ring optional position separately; X 1with X 2the group that may be the same or different;
LG, for being easy to leavings group, is selected from bromine, chlorine, sulfonate group;
PG is the amino protecting group that hydrogen maybe can remove; be selected from methyl, allyl group, the tertiary butyl, benzyl, diphenyl-methyl, trityl, fluorenyl, 9,10-dihydroanthracene-9-bases, when wherein there is aromatic ring in described protecting group; can with substituting group on aromatic ring, described substituting group is selected from halogen, nitro, C 1-C 4alkyl chain ,-CF 3,-CHF 2,-OR 2group, wherein R 2be selected from hydrogen, single replacement or dibasic C 1-C 4alkyl; PG is preferably benzyl;
(2) from the material of step (1) gained, separation obtains formula RS#S-V compound and formula RR#S-V compound.
2. preparation method according to claim 1, is characterized in that, step (1) described reaction in the basic conditions, in inert solvent, is carried out under catalyst.
3. preparation method according to claim 1 and 2, is characterized in that, step (2) passes through the mode of filtration and/or fractional recrystallisation by formula RS#S-V compound and formula RR#S-V compound separation.
4. a preparation method for formula SR#R/SS#R-V compound of Nebivolol Intermediates, comprising:
(1) formula SR/SS-IV compound and formula R-I compound are carried out coupling to dock and react, obtain the material containing formula SR#R/SS#R-V compound,
Wherein, X 1and X 2represent hydrogen atom or the halogen atom of the connection of phenyl ring optional position separately; X 1with X 2for identical or different group;
LG, for being easy to leavings group, is selected from bromine, chlorine, sulfonate group;
PG is the amino protecting group that hydrogen maybe can remove; be selected from methyl, allyl group, the tertiary butyl, benzyl, diphenyl-methyl, trityl, fluorenyl, 9,10-dihydroanthracene-9-bases, when wherein there is aromatic ring in described protecting group; can with substituting group on aromatic ring, described substituting group is selected from halogen, nitro, C 1-C 4alkyl chain ,-CF 3,-CHF 2,-OR 2group, wherein R 2be selected from hydrogen, single replacement or dibasic C 1-C 4alkyl; PG is preferably benzyl;
(2) from the material of step (1) gained, separation obtains formula SR#R-V compound and formula SS#R-V compound.
5. preparation method according to claim 4, is characterized in that, step (1) described reaction in the basic conditions, in inert solvent, is carried out under catalyst.
6. preparation method according to claim 1 and 2, is characterized in that, step (2) passes through the mode of filtration and/or fractional recrystallisation by formula SR#R-V compound and formula SS#R-V compound separation.
7. prepare a method for nebivolol or its pharmacy acceptable salt, comprising:
(1) method preparation formula RS#S/RR#S-V compound described in any one of claim 1-3 is adopted;
(2) gained formula RS#S-V compound and formula RR#S-V compound are carried out selective reduction, obtain formula RSSS-VI compound and formula RRRS-VI compound,
(3) gained formula RSSS-VI compound and formula RRRS-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula RSSS-nebivolol and the formula RRRS-nebivolol of equimolar amount or prepares its pharmacy acceptable salt further.
8. prepare a method for nebivolol or its pharmacy acceptable salt, comprising:
(1) method preparation formula SR#R/SS#R-V compound described in any one of claim 4-6 is adopted;
(2) gained formula SR#R-V compound and formula SS#R-V compound are carried out selective reduction, obtain formula SRRR-VI compound and formula SSSR-VI compound;
(3) gained formula SRRR-VI compound and formula SSSR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount or prepares its pharmacy acceptable salt further.
9. prepare a method for nebivolol or its pharmacy acceptable salt, comprising:
(1) adopt method preparation formula RS#S/RR#S-V compound described in any one of claim 1-3, adopt method preparation formula SR#R/SS#R-V compound described in any one of claim 4-6;
(2) modus ponens RS#S-V compound and formula SR#R-V compound, carry out selective reduction, obtains formula RSSS-VI compound and formula SRRR-VI compound;
(3) gained formula RSSS-VI compound and formula SRRR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount, or prepares its pharmacy acceptable salt further.
10. prepare a method for nebivolol or its pharmacy acceptable salt, comprising:
(1) adopt method preparation formula RS#S/RR#S-V compound described in any one of claim 1-3, adopt method preparation formula SR#R/SS#R-V compound described in any one of claim 4-6;
(2) gained formula RR#S-V compound and formula SS#R-V compound are carried out selective reduction, obtain formula RRRS-VI compound and formula SSSR-VI compound;
(3) gained formula RRRS-VI compound and formula SSSR-VI compound are removed PG group, and work as X 1, X 2when not being H, remove X 1, X 2group, obtains formula SRRR-nebivolol and the formula SSSR-nebivolol of equimolar amount, or prepares its pharmacy acceptable salt further.
CN201510025745.8A 2015-01-19 2015-01-19 Preparation method of nebivolol intermediates and preparation method of nebivolol Pending CN104610215A (en)

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