CN1290818C - Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol - Google Patents
Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol Download PDFInfo
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- CN1290818C CN1290818C CN 200510028845 CN200510028845A CN1290818C CN 1290818 C CN1290818 C CN 1290818C CN 200510028845 CN200510028845 CN 200510028845 CN 200510028845 A CN200510028845 A CN 200510028845A CN 1290818 C CN1290818 C CN 1290818C
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Abstract
The present invention discloses a method for synthesizing chiral salbutamol by the asymmetric hydrogen transfer of alpha-imino keton, which relates to a new method for synthesizing salbutamol as an optical pure beta alkamine compound. In the method, firstly, 5-acetyl methyl salicylate is used as a raw material, 5-(1, 1-dihydroxyl)-acetyl-2-hydroxybenzoate is oxygenized by an oxidation agent; secondly, the reaction with tert-butylamine is carried out to obtain alpha-imino keton compounds; thirdly, (S, S)-Ru-TsDPEN or (R, R)-Ru-TsDPEN is used as a catalyst to carry out the asymmetric hydrogen transfer of the alpha-imino keton compounds in formic acid, triethylamine and inert organic solvent systems, and the optically pure product, namely (R) or (S)-5-<2-<(1, 1-dimethylethyl)amino>-1-ethoxyl>-2-hydroxybenzoate, is obtained; finally, the (R) or (S)-5-<2-<(1, 1-dimethylethyl)amino>-1-ethoxyl>-2-hydroxybenzoate is reduced to obtain the optically pure (R) or (S) chiral salbutamol. The present invention has the advantages of good selectivity, mild reaction condition, convenient operation process and reaction post-treatment, favorable repeated and upscating production and low cost.
Description
Technical field
The method of the asymmetric hydrogen transference synthesizing chirality salbutamol of α-imines ketone, relate to synthesizing optical pure-method of β alkamine compound salbutamol, belong to chirality-β alkamine compound synthesis technical field.
Background technology
Optically pure chiral amino alcohol demonstrates more and more important effect in pharmaceutical chemistry and organic chemistry.Aspect pharmaceutical chemistry, many beta-alkamine derivatives can be used as medicine, as-β aminoaryl alcohol compound is the good medicine of treatment respiratory system and cardiovascular system diseases.A large amount of medical practices prove, often have only a kind of optical isomer that curative effect is preferably arranged in the racemic modification medicine, the different enantiomorphs of chiral drug often demonstrate different physiologically actives, therefore, research to optically pure chirality beta-amino aryl alcohol compounds receives related personnel's very big concern at present.Chirality salbutamol (Chiral Salbutamol) wherein, that is: (R) or (S)-2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) alcoholic acid study on the synthesis becomes a focus of current Synthetic Organic Chemistry research, and its structural formula is as follows:
The synthetic method of the chirality salbutamol of present bibliographical information, mainly contain following two kinds of methods: the fractionation of (1) diastereomer, representational document has (' Absolute Configuration of theOptical Isomers of salbulamol ' (absolute configuration of salbutamol optical isomer) Hartley.Detal J.Med.Chem, (1971), 14,895); (' Enantioselective preparation ofoptical pure albuterol ' (the pure salbutamol of enantioselectivity synthesizing optical) Gao.Y etalUS.Pat.No:5,339,765 (1995)); (' Enantioselective preparation of opticalpure albuterol ' (the pure salbutamol of enantioselectivity synthesizing optical) Gao.Y etalUS.Pat.No:5,545,745 (1996)); (' Process for the production of opticallyenriched (R)-or (S)-Albuterol ' (preparation technology of optical purity enrichment (R) or (S)-salbutamol) Tokai.A.S etal, US.Pat.No:6,365,756B1 (2002)).(2) utilize borine and borane of chiral oxazole catalyzer, asymmetric reduction a-imines ketone (' Asymmetric synthesis of (R)-and (S)-arylethanolamines from iminoketones " Gao.Y etal US.Pat.No:5; 442,118 (1995)).The split process of diastereomer is tediously long numerous and diverse, and utilization ratio of raw materials is low, and is that the asymmetry catalysis of catalyzer is synthetic with the borane of chiral oxazole; required catalyst levels big (10%mol); and operation process condition harshness, poor controllability is unfavorable for repetition and large-scale production.The asymmetric hydrogen transfer reactions of development in recent years (Asymmetric transfer hydrogenation reaction), because the reaction conditions of its high enantioselectivity, gentleness, easy operating process and post-reaction treatment, and cheap and easy to get go back original reagent and people's attention extremely, in numerous catalyzer, wherein the most noticeable is the ruthenium catalyst Ru-TsDPEN of Noyori study group exploitation, and its structural formula is as follows:
This catalyzer successfully applies to aromatic ketone, substituted aroma ketone, α, β-acetylenic ketone, α-diketone, and the asymmetric hydrogen transfer reactions of imines, but do not see bibliographical information for the asymmetric hydrogen transfer reactions of α-imines ketone.
Summary of the invention
The objective of the invention is to disclose a kind of novel method of synthesizing chirality salbutamol, the chirality salbutamol for preparing with method of the present invention reaches optical purity, meets the medicine national standard, and cost has big decline.
In order to achieve the above object, the present invention by with (S, S) or (R, R)-Ru-TsPPEN is a catalyzer, the corresponding α of asymmetric hydrogen transference-imines ketone is again through the effective pure chirality salbutamol of synthesizing optical of a step reduction reaction.
The technical solution adopted in the present invention is: at first, be raw material with 5-acetylsalicylic acid methyl esters, be oxidized to corresponding keto-aldehyde compound: 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters with oxidising agent.With 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters and TERTIARY BUTYL AMINE reaction, obtain corresponding α-imines ketone compound: 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters then.Then; with (S; S)-Ru-TsDPEN or (R; R)-Ru-TsDPEN is a catalyzer; the corresponding α of asymmetric hydrogen transference-imines ketone compound: 5-in formic acid, triethylamine, inert organic solvents system ((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters gets optically pure product; that is: (R) or (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-the 2 hydroxybenzoic acid methyl esters.At last, with (R) or (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters reduction, promptly get optically pure (R) or (S) chirality salbutamol, that is: (R) or (S)-2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) ethanol.
Concrete technology is as follows:
The preparation of the first step: 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters.
At first selecting DMSO/HBr (methyl-sulphoxide/Hydrogen bromide) oxidation system for use is oxidising agent, and according to methyl-sulphoxide: Hydrogen bromide: 5-acetylsalicylic acid methyl esters=3: 1: 1.5～2.5 mol ratios are measured wherein preferred 3: 1: 2.0.60～70 ℃ of temperature of reaction, preferred 65 ℃, reaction times 20-24h makes corresponding keto-aldehyde compound: 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters then.
Second step: the preparation of α-imines ketone compound 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters.
The 5-(1 that the first step is made; the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters and TERTIARY BUTYL AMINE feed intake by 1: 1.1～2.0 preferred 1: 1.2 mol ratios; temperature of reaction 25-45 ℃; preferred 40 ℃;-kind or the multiple anhydrous aprotic solvent that is selected from following group in react; anhydrous aprotic solvent is a benzene, toluene, dimethylbenzene; methylene dichloride; trichloromethane, 1.2-ethylene dichloride, ethyl acetate; propyl acetate; wherein preferred toluene obtains corresponding α-imines ketone compound promptly: 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters.
The 3rd step: (R) or (S)-5-[2-[(1,1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-preparation of 2 hydroxybenzoic acid methyl esters.
With (S, S)-Ru-TsDPEN or (R, R)-Ru-TsDPEN is a catalyzer, the corresponding α of asymmetric hydrogen transference-imines ketone compound in formic acid, triethylamine, inert organic solvents system, optically pure product promptly: (R) or (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-the 2 hydroxybenzoic acid methyl esters, but Preparation of catalysts reference [Fujii, A. wherein; Hashiguchi, S.; Noyori.R.etalJ.Am.Chem.Soc, 1996,118,2521] reaction need be at CH
3CN, DMF, DMSO and CH
2Cl
2, CHCl
3Carry out Deng in the inert solvent, wherein preferred DMF, temperature of reaction is generally carried out at 20 ℃-40 ℃, wherein preferred room temperature, reaction times 20-36h, preferred 24h; The mol ratio of 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters and catalyzer, formic acid, triethylamine is: 1: 100～1000: 1.5～2.5: 3～6.
The 4th step: the preparation of optically pure chirality salbutamol.
With the 3rd step (R) that make or (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-reduction of 2 hydroxybenzoic acid methyl esters, promptly get optically pure (R) or (S)-chirality salbutamol i.e.: (R) or (S)-2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) ethanol.Wherein going back original reagent is B
2H
6/ CH
3SCH
3Or LiAlH (BMS),
4, or NaBH
4/ BF
3.C
2H
5OC
2H
5, wherein preferred LiAlH
4, 25 ℃-55 ℃ of temperature of reaction, reaction solvent is selected anhydrous solvent commonly used such as anhydrous THF for use, or anhydrous diethyl ether, or anhydrous diglyme (DME).
Advantage of the present invention and effect are as follows:
1. the present invention is a raw material with 5-acetylsalicylic acid methyl esters cheap and easy to get; through four-step reaction, effectively synthesizing chirality salbutamol is compared with the resolution process and the asymmetric synthesis technology of existing diastereomer; selectivity is good, reaction conditions is gentle, and operating process and post-reaction treatment are easy.
2. because the route of synthesis step provided by the present invention is short, and easy to operate, aftertreatment is simple, therefore helps repetition and enlarge scale production.
3. because the present invention has adopted asymmetric hydrogen transference technology, it is tediously long numerous and diverse therefore to have overcome the diastereomer split process, the shortcoming that utilization ratio of raw materials is low.
4. because the present invention has adopted asymmetric hydrogen transference technology, therefore overcome and utilized borine and borane of chiral oxazole catalyzer, the required catalyst levels of asymmetry catalysis technology is big, the operation condition harshness, and shortcomings such as poor controllability have advantage with low cost.
Embodiment
The present invention is described by the following specific embodiments, can better understand the present invention by specific embodiment, and are restrictions of embodiment but scope of the present invention is not subjected to these.
Embodiment 1
The preparation of the first step 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters.
Add 75ml methyl-sulphoxide (DMSO) in the 250ml three-necked bottle; 19.5g (0.1mol) 5-acetylsalicylic acid methyl esters; under the room temperature condition, and Hydrogen bromide (HBr) 28ml (40%, 0.2mol; 2.0eq) slowly add; dropwised in 40 minutes, reaction solution is heated to 65 ℃, reacted about 20 hours; TLC detects raw material 5-acetylsalicylic acid methyl esters and disappears; in the slow impouring 200ml of reaction solution frozen water, stirred 30 minutes, filter; solid washs 3 times with the 25ml frozen water; vacuum-drying promptly gets product 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters 20.3g, productive rate 90% under the room temperature; need not be further purified, can directly drop into next step reaction.
The preparation of second step 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters.
Under the nitrogen protection; the 5-(1 that the first step is made; the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters 45.2g (0.2mol) is suspended in the 150ml dry toluene; stir and slowly drip 23ml (0.22mol) TERTIARY BUTYL AMINE down; dropwise reaction solution is heated to 40 ℃; reacted about 3 hours; TLC detects raw material 5-(1; the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters disappearance, with reaction solution 50ml saturated aqueous common salt washed twice, anhydrous sodium sulfate drying; the vacuum rotary steam solvent promptly gets product 5-((1; the 1-dimethyl ethyl) ethanoyl-2 hydroxybenzoic acid methyl esters imido grpup), the sherwood oil recrystallization gets yellow solid product 42.0g, yield 80%.
The 3rd step (R)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-preparation of 2 hydroxybenzoic acid methyl esters.
Under the nitrogen protection, with second compound 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters 0.26g (1mmol) that make of step, (S, S)-Ru-TsDPEN 6.4mg (0.01mmol), Et
3N0.69ml (5.0mmol) is dissolved among the 2.0ml DMF, HCOOH 0.07ml (2.0mmol) slowly adds, stirring at room 24 hours, in reaction solution impouring 5.0ml water, twice of 10ml ethyl acetate extraction, anhydrous sodium sulfate drying, vacuum rotary steam solvent, column chromatography promptly get product (R)-5-[2-[(1,1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters 0.13g, 97%ee, yield 50%.
The 4th step (R)-2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) alcoholic acid preparation.
Under the nitrogen protection condition, LiAlH
457mg (l.5mmol), be suspended among anhydrous tetrahydro furan (THF) 10ml, go on foot (the R)-5-[2-[(1 that makes with the 3rd, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters 0.27g (1mmol) anhydrous tetrahydro furan 2ml solution slowly splashes into, after the stirring at room 30 minutes, reaction solution is heated to 45 ℃ of reactions 2 hours, TLC detects raw material (R)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-the 2 hydroxybenzoic acid methyl esters disappears, and splashes into the reaction of going out of methyl alcohol 2ml collection, filtration, the vacuum rotary steam solvent, column chromatography promptly gets product (R)-Salbutamol 0.21g, 97.5%ee, yield 90%.
Embodiment 2
First and second steps are identical with embodiment 1.
The 3rd step (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-preparation of 2 hydroxybenzoic acid methyl esters.
Under the nitrogen protection, with the second compound 0.26g (1mmol) that make of step, (R, R)-Ru-TsDPEN6.4mg (0.01mmol), Et
3N 0.69ml (5.0mmol) is dissolved among the 2.0ml DMF, HCOOH 0.07ml (2.0mmol) slowly adds, stirring at room 24 hours, in reaction solution impouring 5.0ml water, twice of 10ml ethyl acetate extraction, anhydrous sodium sulfate drying, vacuum rotary steam solvent, column chromatography promptly get product (S)-5-[2-[(1,1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters 0.13g, 96%ee, yield 48%.
The 4th goes on foot (S)-Salbutamol promptly: (S)-and 2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) alcoholic acid preparation
Under the nitrogen protection condition; product (S)-5-[2-[(1 with the 3rd step; the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters 0.27g (1.0mmol); adding 25ml fills in the three-necked bottle of exsiccant anhydrous two sweet dme (DME) 10ml; with BMS 0.16ml (10M; 1.6mmol) slowly join in the above-mentioned solution, stirring at room was heated to 55 ℃ of reactions 3 hours with reaction solution after 30 minutes; reduce to room temperature; splash into methyl alcohol 4ml, then reaction solution is heated to 65 ℃ and refluxed 1.5 hours, reduce to room temperature and add N; N; N, N-Tetramethyl Ethylene Diamine (TMEDA) 0.23ml (1.5mmol), 6 hours after-filtration of stirring at room; the vacuum rotary steam solvent; column chromatography promptly gets product (S)-Salbutamol 0.20g, 96.5%ee, yield 85%.
Embodiment 3
First, second and third step is identical with embodiment 1.
The 4th goes on foot (R)-Salbutamol promptly: (R)-and 2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) alcoholic acid preparation.
Under the nitrogen protection condition, take by weighing the product 0.27g (1mmol) that the 3rd step made, NaBH
495mg (2.5mmol) is suspended among anhydrous tetrahydro furan (THF) 10ml, and room temperature slowly drips BF
3.Et
2O solution 0.4ml (content 47%, d, 1.13,1.5mmol), dropwise reaction solution is heated to 55 ℃ of reactions 3 hours, reduce to room temperature, splash into methyl alcohol 4ml, then reaction solution is heated to 55 ℃ of reactions 1.5 hours, reduce to room temperature, add N, N, N, N-Tetramethyl Ethylene Diamine (TMEDA) 0.23ml (1.5mmol), 6 hours after-filtration of stirring at room, vacuum rotary steam solvent, it is 0.18g that column chromatography promptly gets product (R)-Salbutamol, 98%ee, yield 75%.
Claims (6)
1. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α-imines ketone is characterized in that:
The first step, the preparation of 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters
At first selecting the DMSO/HBr oxidation system for use is oxidising agent, and according to DMSO: Hydrogen bromide: 5-acetylsalicylic acid methyl esters=3: 1: 1.5～2.5 mol ratios are measured, then 60～70 ℃ of temperature of reaction, make 5-(1, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters under the reaction times 20-24h;
Second step, the preparation of α-imines ketone compound
The 5-(1 that the first step is made, the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters and TERTIARY BUTYL AMINE feed intake by 1: 1.1～2.0 mol ratios, temperature of reaction 25-45 ℃, in one or more anhydrous aprotic solvent, react, obtain corresponding α-imines ketone compound promptly: 5-((1, the 1-dimethyl ethyl) imido grpup) ethanoyl-2 hydroxybenzoic acid methyl esters; Anhydrous aprotic solvent is a benzene, toluene, dimethylbenzene, methylene dichloride, trichloromethane, 1.2-ethylene dichloride, ethyl acetate, propyl acetate;
The 3rd step, (R) or (S)-5-[2-[(1,1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-preparation of 2 hydroxybenzoic acid methyl esters
With (S; S)-Ru-TsDPEN or (R, R)-Ru-TsDPEN is a catalyzer, presses 5-((1; the 1-dimethyl ethyl) ethanoyl-2 hydroxybenzoic acid methyl esters imido grpup): catalyzer: formic acid: the mol ratio of triethylamine is 1: 100～1000: 1.5～2.5: 3～6 to measure, at CH
3CN, DMF, DMSO and CH
2Cl
2, CHCl
3Carry out in the inert organic solvents, temperature of reaction is carried out at 20 ℃-40 ℃, reaction times 20-36h, optically pure product promptly: amino (R) or (S)-5-[2-[(1,1-dimethyl ethyl)]-the 1-hydroxyethyl]-the 2 hydroxybenzoic acid methyl esters;
The 4th step, the preparation of optically pure chirality salbutamol
With the 3rd step (R) that make or (S)-5-[2-[(1, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-reduction of 2 hydroxybenzoic acid methyl esters, promptly get optically pure (R) or (S) chirality salbutamol, that is: (R) or (S)-2-(nitrogen-tertiary butyl amino)-1-(4-hydroxyl-3-hydroxymethyl phenyl) ethanol, wherein going back original reagent is B
2H
6/ CH
3SCH
3, or LiAlH
4, or NaBH
4/ BF
3.C
2H
5OC
2H
5, 25 ℃-55 ℃ of temperature of reaction, reaction solvent is selected anhydrous THF for use, or anhydrous diethyl ether, or anhydrous diglyme.
2. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α according to claim 1-imines ketone; it is characterized in that: the 5-(1 of the described the first step; the 1-dihydroxyl)-during the preparation of ethanoyl-2 hydroxybenzoic acid methyl esters according to DMSO: Hydrogen bromide: 5-acetylsalicylic acid methyl esters=mol ratio was measured in 3: 1: 2.0, was reflected at then under 65 ℃ and carried out.
3. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α according to claim 1-imines ketone; it is characterized in that: the α-imines ketone compound 5-((1 in described second step; the 1-dimethyl ethyl) imido grpup) preparation of ethanoyl-2 hydroxybenzoic acid methyl esters is the 5-(1 that the first step is made; the 1-dihydroxyl)-ethanoyl-2 hydroxybenzoic acid methyl esters and TERTIARY BUTYL AMINE feed intake by 1: 1.2 mol ratio; 40 ℃ of temperature of reaction prepare in toluene.
4. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α according to claim 1-imines ketone is characterized in that: the preparation of the chirality salbutamol in described the 4th step is under the nitrogen protection condition, with the LiAlH of 1.5mmol
457mg is suspended among the anhydrous tetrahydro furan THF10ml, (R)-5-[2-[(1 with the 3rd 1mmol that make of step, the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-2 hydroxybenzoic acid methyl esters 1.0mmol is dissolved in the 2ml anhydrous tetrahydro furan, slowly splash into then, stirring at room will be heated to 45 ℃ of reactions 2 hours after 30 minutes, splash into the reaction of going out of methyl alcohol 2ml collection, filter, vacuum rotary steam solvent, column chromatography promptly get optically pure (the R)-chirality salbutamol of product.
5. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α according to claim 1-imines ketone; it is characterized in that: the preparation of the chirality salbutamol in described the 4th step is under the nitrogen protection condition; (S)-5-[2-[(1 with the 3rd product 1.0mmol that goes on foot; the 1-dimethyl ethyl) amino]-the 1-hydroxyethyl]-the 2 hydroxybenzoic acid methyl esters; add among the anhydrous two sweet dme DME10ml; then with 10M; 0.16ml BMS slowly join in the above-mentioned solution; after the stirring at room 30 minutes; reaction solution is heated to 55 ℃ of reactions 3 hours, reduces to room temperature, splash into methyl alcohol 4ml; then reaction solution is heated to 55 ℃ of reactions 1.5 hours; reduce to room temperature and add N, N, N; N-Tetramethyl Ethylene Diamine TMEDA 1.5mmol 0.23ml; 6 hours after-filtration of stirring at room, vacuum rotary steam solvent, column chromatography promptly get product (S)-chirality salbutamol 0.20g; 96.5%ee, yield 85%.
6. the method for the asymmetric hydrogen transference synthesizing chirality salbutamol of α according to claim 1-imines ketone; it is characterized in that: the preparation of the chirality salbutamol in described the 4th step is under the nitrogen protection condition; take by weighing the 1mmol product 0.27g that the 3rd step made, 2.5mmol NaBH
495mg is suspended among the anhydrous THF10ml, and room temperature slowly drips content 47%, d=1.13, the BF of 1.5mmol
3.Et
2O solution 0.4ml is heated to 55 ℃ of reactions 3 hours, reduces to room temperature, splash into methyl alcohol 4ml, then reaction solution is heated to 55 ℃ of reactions 1.5 hours, reduce to room temperature, add 1.5mmol N, N, N, N-Tetramethyl Ethylene Diamine 0.23ml, 6 hours after-filtration of stirring at room, vacuum rotary steam solvent, column chromatography promptly get product (R)-chirality salbutamol 0.18g, 98%ee, yield 75%.
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