CN101613349B - Preparation method of S-3-aminoquinuclidine dihydrochloride - Google Patents
Preparation method of S-3-aminoquinuclidine dihydrochloride Download PDFInfo
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- CN101613349B CN101613349B CN2009100633677A CN200910063367A CN101613349B CN 101613349 B CN101613349 B CN 101613349B CN 2009100633677 A CN2009100633677 A CN 2009100633677A CN 200910063367 A CN200910063367 A CN 200910063367A CN 101613349 B CN101613349 B CN 101613349B
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Abstract
The invention relates to a preparation method of S-3-aminoquinuclidine dihydrochloride which is obtained by taking 3-aminoquinuclidine dihydrochloride as a raw material and carrying out resolving, salifying by resolving, recrystallizing, resolving, salifying, decoloring and crystallizing by concentration. The S-3-aminoquinuclidine dihydrochloride serves as an important raw material for preparing palonosetron. In the method, the 3-aminoquinuclidine dihydrochloride is taken as the raw material and is directly subjected to chiral acid resolution in proper solvent without derivation, with resolution ratio over 40% and optical purity over 98%. The method has simple synthetic method and low production cost, has total product yield over 35% and can be used for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of S-3-amino quinine dihydrochloride, it belongs to technical field of organic chemistry, also belongs to the pharmaceutical chemistry technical field.
Background technology
The S-3-amino quinine dihydrochloride is the precursor of chiral ligand, can be used for asymmetry catalysis by the synthesis of chiral part by it; It also is the important source material that the class medicine is told in synthetic town.Having synthesized since the seventies of anti-emetic is the focus of domestic and international pharmaceutical industries concern and the focus of research always.
Document (print during chemical industry, 2005,19 (2), 12-13; And patent CN101161651A) is raw material in the reported method, carries out amination reaction with (R)-phenylethylamine, through NaBH with the quininone hydrochlorate
4Reduction is taken off benzyl through the 10%Pd/C hydrogenolysis again and is obtained product (S)-3-amino quinine dihydrochloride, and this route synthesizing imine productive rate is not high, the separation and purification trouble, and need NaBH in the reaction process in the back
4Reduction and reaction under high pressure are taken off benzyl, complicated operation, and route is long, influences yield and cost.Be that raw material is through the generation acid amides of deriving with the 3-amino quinine dihydrochloride in document (US5290938A1) reported method in addition; split with chiral acid then; with gained salt through hydrolysis; extraction preparation S-3-amino quinine dihydrochloride; adopted acidylate in the route, hydrolytic process, operation inconvenience; and the hydrolysis percentage extraction is not high, influences yield and cost.So people are seeking simply always, fast, production method that cost is low, thereby reduce production costs, promote the well-being of mankind.
Summary of the invention
The preparation method who the purpose of this invention is to provide the S-3-amino quinine dihydrochloride that a kind of method is simple, productive rate is high, cost is low.
To achieve these goals, technical scheme of the present invention is: the preparation method of S-3-amino quinine dihydrochloride is that to be raw material from the 3-amino quinine dihydrochloride get through resolving, split salify, recrystallization, parsing, salify, decolouring, condensing crystal.
Method of the present invention can be used following procedural representation:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) in solvent, with organic bases or mineral alkali and the reaction of the 3-amino quinine dihydrochloride 3-amino quinine that dissociates, in the 3-amino quinine, add the chiral acid resolving agent, the stirring at normal temperature number minute promptly salts out.The mol ratio of solvent and 3-amino quinine dihydrochloride (being substrate) is 5-15: 1, and the mol ratio of alkali and 3-amino quinine dihydrochloride (being substrate) is 1-3: 1; Generated the 3-amino quinine at room temperature reaction 1-2 hour; Add the chiral acid resolving agent afterwards, 0-50 ℃ stirring reaction 1-5 hour, the salify after-filtration, filter cake with a small amount of solvent wash the chirality hydrochlorate solid I of S-3-amino quinine, mother liquor R configuration piece to be recycled.
Reaction formula is:
2) with the solid I solvent rising temperature for dissolving of gained, solvent temperature is 50-100 ℃, and dissolving is finished, and is cooled to 0-30 ℃, filter solid II, mother liquor R-3-amino quinine to be recycled.
3) solid II dissolution with solvents adds alkali, and the elimination inorganic salt are crossed in the stirring at room dissolving; The mother liquor concentrating under reduced pressure gets solid III; The mol ratio of alkali and solid II is 1-5: 1.
4) with the solid III of organic solvent dissolution step 3) gained, feed hydrogen chloride gas under the room temperature to pH=1,0-30 ℃ of following stirred crystallization, the adularescent solid is separated out, filter S-3-amino quinine dihydrochloride crude product;
5) with the S-3-amino quinine dihydrochloride crude product that obtains mixed solution, be warming up to 80-100 ℃ of dissolving, add activated carbon with alcohol and water, insulation backflow 0.5-1h, filtered while hot, mother liquor concentrates, and separates out the S-3-amino quinine dihydrochloride.Wherein alcohol is 1-10 with the volume ratio of water: 1, and the consumption of activated carbon is the 5-10% of S-3-amino quinine dihydrochloride crude product quality.
The step 1) solvent for use is carbonatomss such as methyl alcohol, ethanol, n-propyl alcohol, and (volume ratio is: 1-10: mixing solutions 1) at the Fatty Alcohol(C12-C14 and C12-C18) below 5, tetrahydrofuran (THF) or acetonitrile and these solvents and water.
The used alkali of step 1) can be organic bases, mineral alkali.Organic bases is fatty primary secondary amine and tertiary amines such as triethylamine, diethylamine, and mineral alkali is oxyhydroxide, carbonate, supercarbonate, the acetate of basic metal such as sodium hydroxide, potassium hydroxide and alkaline-earth metal.
The used resolving agent of step 1) is a chiral organic acid, as D-tartrate, L-tartrate, D-amygdalic acid, L-amygdalic acid, D-camphorsulfonic acid, L-camphorsulfonic acid, D-dibenzoyl tartaric acid, L-dibenzoyl tartaric acid and D-tartrate or tartaric other derivative of L-.
Step 2) described solvent is Fatty Alcohol(C12-C14 and C12-C18) (as methyl alcohol, ethanol, propyl alcohol etc.), tetrahydrofuran (THF), acetonitrile or N, dinethylformamide, or Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF), acetonitrile, N, the mixed solution of dinethylformamide and water.
Step 2) mol ratio of solvent and solid I is 5-10: 1, and solvent temperature is 50-100 ℃, cooling rate is 3 ℃/hour, temperature 0-30 ℃.
The described alkali of step 3) is yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, volatile salt, diethylamine, triethylamine, sodium alkoxide, potassium alcoholate, sodium hydride, potassium hydride KH or hydrolith.
The step 3) solvent for use is C such as methyl alcohol, ethanol, Virahol, propyl carbinol
1-8Fatty Alcohol(C12-C14 and C12-C18) or tetrahydrofuran (THF), acetonitrile or acetone.
The step 3) dissolution time is 1-5 hour.
The step 4) crystallization time is 1-3 hour.
The used recrystallisation solvent of step 5) is C such as methyl alcohol, ethanol, Virahol, propyl carbinol
1-8Fatty Alcohol(C12-C14 and C12-C18) respectively with the mixed solution of water, alcohol with the volume ratio of water is: 1-10: 1, the consumption of activated carbon is the 5-10% of S-3-amino quinine dihydrochloride crude product weight, reflux temperature is 50-100 ℃.
Adopt method of the present invention to split preparation S-3-amino quinine dihydrochloride (V) from 3-amino quinine dihydrochloride (I) by substep, without deriving, in suitable solvent, directly split with common chiral acid, the fractionation rate is more than 40%, and optical purity is more than 98%, and method is simple, productive rate is high, cost is low, be a kind of effective simple and easy method, have industrial utility value from 3-amino quinine dihydrochloride (I) preparation S-3-amino quinine dihydrochloride.
Embodiment
In order to understand the present invention better, further illustrate content of the present invention below in conjunction with embodiment, but content of the present invention not only is confined to the following examples.
Embodiment 1:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine-D-tartrate
Add 3-amino quinine dihydrochloride 10g in 250ml single port bottle, 150ml methyl alcohol, ice-water bath are cooled to 0-5 ℃, add salt of wormwood 6.9g, finish back stirring at room 1h, remove by filter inorganic salt Repone K, under 50 ℃ of stirrings, in mother liquor, add D-tartrate 7.3g, stir salify 1h, have a large amount of solids to separate out, cross filter solid, solid washs with a small amount of solvent, the dry 7.2g that gets.
Mp：213-215℃，[α]
D 20＝-35.0
0(C＝1，H
2O)。
2) recrystallization of S-3-amino quinine-D-tartrate,
Measure 50ml methyl alcohol and place 250ml single port bottle, add step 1) gained salt, be warming up to 50 ℃, treat to stop after salt dissolves fully heating, slowly cooling, rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 0 ℃, filter solid 5.6g, mother liquor another kind of configuration body to be recycled.
Mp：215-217℃，[α]
D 20＝-40.6
0(C＝1，H
2O)。
3) parsing of S-3-amino quinine-D-tartrate
S-3-amino quinine-D-the tartrate of gained is dissolved in the ethanol, adds salt of wormwood to pH=9, stirred 1 hour, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, and mother liquor is evaporated to dried.There is solid to separate out, gets S-3-amino quinine 2.3g.
4) salify of S-3-amino quinine
With the solids dissolve with methanol in the step 3), filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1,0 ℃ of stirred crystallization 1 hour has a large amount of solids to separate out, filter crude product 3.2g.
Mp：313-315℃，[α]
D 20＝-21.6
0(C＝1，H
2O)。
5) with the crude product volume ratio of gained in the step 4) be 8: 1 methyl alcohol: the mixed solution of water is warming up to the dissolving that refluxes, and adds 5% gac, refluxes and stirs 0.5 hour, and filtered while hot, filtrate decompression are steamed to 1/2nd crystallisation by cooling and separated out white solid 3.0g.
Mp：313-315℃，[α]
D 20＝-24.1
0(C＝1，H
2O)
Embodiment 2:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine-D-camsilate
Add 3-amino quinine dihydrochloride 10g in 250ml single port bottle, 150ml dehydrated alcohol, ice-water bath are cooled to 0-5 ℃, slowly add sodium bicarbonate 8.5g, whole adition process continues 1h, finishes back stirring at room 1.5h, remove by filter inorganic salt sodium-chlor, under 30 ℃ of stirrings, in mother liquor, add D-camphorsulfonic acid 12.8g, stir salify 2h, there is solid to separate out, cross filter solid, solid washs with a small amount of solvent, the dry 9.9g that gets
Mp：＞300℃，[α]
D 20＝-49.5
0(C＝1，H
2O)。
2) recrystallization of S-3-amino quinine-D-camsilate,
Measure the 60ml dehydrated alcohol and place 250ml single port bottle, add step 1) gained salt, be warming up to 80 ℃, treat to stop after salt dissolves fully heating, slowly cooling, rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 5 ℃, filter solid 7.8g, mother liquor another kind of configuration body to be recycled.
Mp：＞300℃，[α]
D 20＝-57.3
0(C＝1，H
2O)。
3) parsing of S-3-amino quinine-D-camsilate
S-3-amino quinine-D-the camsilate of gained is dissolved in the ethanol, adds sodium bicarbonate to pH=9, stirred 1.5 hours, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, and mother liquor is evaporated to dried.Get S-3-amino quinine 2.4g.
4) salify of S-3-amino quinine
With the solids dissolve with methanol in the step 3), filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1,10 ℃ are stirred half an hour down, have a large amount of solids to separate out, filter crude product 3.5g.
Mp：312-315℃。[α]
D 20＝-23.1
0(C＝1，H
2O)。
5) with the crude product volume ratio of gained in the step 4) be 6: 1 propyl alcohol: the mixed solution of water is warming up to the dissolving that refluxes, and adds 10% gac, refluxes and stirs 1 hour, and filtered while hot, filtrate decompression are steamed to 1/2nd crystallisation by cooling and separated out white solid 3.2g.
Mp：314-316℃，[α]
D 20＝-24.10(C＝1，H
2O)
Embodiment 3:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine-L-dibenzoyl tartaric acid salt
Add 3-amino quinine dihydrochloride 10g in 250ml single port bottle, 150ml Virahol, ice-water bath are cooled to 0-5 ℃, slowly add sodium-acetate 8.3g, whole adition process continues 1h, finishes back stirring at room 2h, remove by filter inorganic salt sodium-chlor, under 20 ℃ of stirrings, in mother liquor, add L-dibenzoyl tartaric acid 18.9g, stir salify 3h, there are a large amount of solids to separate out, cross filter solid, solid washs with a small amount of solvent, the dry 14.0g that gets
Mp：179-181℃，[α]
D 25＝+135
0(C＝1，H
2O)。
2) recrystallization of S-3-amino quinine-D-dibenzoyl tartaric acid salt,
Measure the 70ml Virahol and place 250ml single port bottle, add step 1) gained salt, be warming up to 90 ℃, treat to stop after salt dissolves fully heating, slowly cooling, rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 10 ℃, filter, dry that solid 10.7g restrains mother liquor another kind of configuration body to be recycled.
Mp：181-183℃，[α]
D 25＝+145
0(C＝1，H
2O)。
3) parsing of S-3-amino quinine-D-dibenzoyl tartaric acid salt
S-3-amino quinine-D-dibenzoyl tartaric acid the salt of gained is dissolved in the ethanol, adds salt of wormwood, stirred 2.5 hours to pH=9, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, mother liquor is evaporated to dried, gets solid S-3-amino quinine 2.6g.
4) salify of S-3-amino quinine
With 3) in the solids dissolve with methanol, filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1,20 ℃ were stirred 2 hours, had a large amount of solids to separate out, filter crude product 3.7g.
Mp：312-315℃，[α]
D 25＝-22.3
0(C＝1，H
2O)。
5) with 4) in the crude product volume ratio of gained be 4: 1 ethanol: the mixed solution temperature rising reflux dissolving of water, add 8% gac, reflux and stir half an hour, filtered while hot, filtrate decompression steaming to 1/2nd crystallisation by cooling are separated out white solid 3.4g.
Mp：313-315℃，[α]
D 25＝-23.80(C＝1，H2O)
Embodiment 4:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine-D-camsilate
Add the 3-amino quinine dihydrochloride in 250ml single port bottle, 150ml acetonitrile, ice-water bath are cooled to 0-5 ℃, slowly add salt of wormwood 13.8g, whole adition process continues 1h, finishes back stirring at room 2h, remove by filter inorganic salt Repone K, under 40 ℃ of stirrings, in mother liquor, add D-camphorsulfonic acid 12.8g, stir salify 4h, there are a large amount of solids to separate out, cross filter solid, solid washs with a small amount of solvent, the dry 10.8g that gets.
Mp：＞300℃，[α]
D 20＝-49.0
0(C＝1，H
2O)。
2) recrystallization of S-3-amino quinine-D-camsilate,
Measure the 80ml acetonitrile and place 250ml single port bottle, add step 1) gained salt, be warming up to backflow, treat to stop after salt dissolves fully heating, slowly cooling, rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 15 ℃, filtering solid 8.1g, mother liquor another kind of configuration body to be recycled.
Mp：＞300℃，[α]
D 20＝-55.7
0(C＝1，H
2O)。
3) parsing of S-3-amino quinine-D-camsilate
S-3-amino quinine-D-the camsilate of gained is dissolved in the acetonitrile, adds sodium hydroxide to pH=9, stirred 3 hours, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, and mother liquor is evaporated to dried.There is solid to separate out, gets S-3-amino quinine 2.6g.
4) salify of S-3-amino quinine
With 3) in the solids dissolve with methanol, filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1,25 ℃ were stirred 2.5 hours, and had a large amount of solids to separate out, filtering thick 3.7g.
Mp：312-315℃。[α]
D 20＝-22.4
0(C＝1，H
2O)。
5) with 4) in the crude product volume ratio of gained be 2: 1 butanols: water mixed liquid is warming up to the dissolving that refluxes, and adds 6% gac, and the stirring half an hour of refluxing, filtered while hot, filtrate decompression steam 1/2nd solvent crystallisation by cooling and separate out white solid 3.5g.
Mp：314-316℃，[α]
D 20＝-24.1
0(C＝1，H
2O)。
Embodiment 5:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine-D-tartrate
Add 3-amino quinine dihydrochloride 10g in 250ml single port bottle, the 150ml tetrahydrofuran (THF) slowly adds salt of wormwood 20.8g under the ice-water bath, and whole adition process continues 1h, room temperature reaction 2h.After finishing, remove by filter inorganic salt Repone K, under 0 ℃ of stirring, in mother liquor, add D-tartrate 7.9g, stir salify 5h, have a large amount of solids to separate out, filtering solid, solid washs with a small amount of solvent, the dry 7.9g that gets
Mp：213-215℃，[α]
D 20＝-35.8
0(C＝1，H
2O)。
2) recrystallization of S-3-amino quinine-D-tartrate,
Measure the 90ml tetrahydrofuran (THF) and place 250ml single port bottle, add step 1) gained salt, be warming up to backflow, treat to stop after salt dissolves fully heating, slowly cooling, rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 25 ℃, filter solid 6.0g, mother liquor another kind of configuration body to be recycled.
Mp：215-217℃，[α]
D 20＝-43.6
0(C＝1，H
2O)。
3) parsing of S-3-amino quinine-D-tartrate
S-3-amino quinine-D-the tartrate of gained is dissolved in the ethanol, adds sodium-acetate to pH=9, stirred 4 hours, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, and mother liquor is evaporated to dried.There is solid to separate out, gets S-3-amino quinine 2.5g.
4) salify of S-3-amino quinine
With 3) in the solids dissolve with methanol, filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1,25 ℃ of stirred crystallization 3 hours have a large amount of solids to separate out, filtering crude product 3.6g.
Mp：313-315℃，[α]
D 20＝-23.7
0(C＝1，H
2O)。
5) with 4) in the crude product volume ratio of gained be 1: 1 methyl alcohol: water is warming up to the dissolving that refluxes, and adds 10% gac, and the stirring half an hour of refluxing, filtered while hot, filtrate decompression steam 1/2nd solvent crystallisation by cooling and separate out white solid 3.3g.
Mp：313.1-315.2℃，[α]
D 20＝-24.1
0(C＝1，H
2O)。
Embodiment 6:
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine amine chirality hydrochlorate
In 250ml single port bottle, add 3-amino quinine dihydrochloride and organic solvent, mol ratio is 1: 5, and ice-water bath slowly adds alkali down, and salt and alkali mol ratio are 1: 1, stir 1h under the room temperature, remove by filter salt, add resolving agent under stirring in mother liquor, salt and resolving agent mol ratio are 1: 1,0 ℃ is stirred 1h, a large amount of solids are arranged, cross filter solid, solid washs with a small amount of solvent.
Used organic solvent is that volume ratio is 1: 1 the propyl carbinol and the mixing solutions of water, and alkali is yellow soda ash, and resolving agent is the D-amygdalic acid
2) recrystallization of S-3-amino quinine amine chirality hydrochlorate,
Measure solvent and place 250ml single port bottle, add step 1) gained salt, mol ratio is 5: 1, heats up to treat to stop after salt dissolves fully heating, temperature is 80 ℃, slowly cooling, and rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 0 ℃, filtering solid, mother liquor another kind of configuration body to be recycled.
Used organic solvent is that volume ratio is 1: 1 the propyl carbinol and the mixing solutions of water
3) parsing of S-3-amino quinine-D-mandelate
With step 2) in the salt that obtains be dissolved in the organic solvent, add alkali and stirred 1 hour, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, mother liquor is evaporated to dried.There is solid to separate out, gets the S-3-amino quinine
Used organic solvent is an ethanol, and alkali is sodium ethylate
4) salify of S-3-amino quinine
With 3) in the solids dissolve with methanol, filter, at room temperature in filtrate, feed hydrogen chloride gas to pH=1, have a large amount of solids to separate out 25 ℃ of stirred crystallization half an hour, filter crude product.
5) with 4) in an amount of methyl alcohol of crude product of gained: water mixed liquid, volume ratio is 10: 1, being warming up to the dissolving that refluxes, and adds 5% gac, the stirring 0.5h that refluxes, filtered while hot, filtrate decompression steam 1/2nd solvent crystallisation by cooling and separate out white solid.
Embodiment 7
The preparation method of S-3-amino quinine dihydrochloride, realize by following step:
1) preparation of S-3-amino quinine amine chirality hydrochlorate
In 250ml single port bottle, add 3-amino quinine dihydrochloride and organic solvent, mol ratio is 1: 15, slowly add alkali, salt and alkali mol ratio are 1: 3, stirring at normal temperature 1h, remove by filter salt, add resolving agent under stirring in mother liquor, mol ratio is 1: 1, and 50 ℃ are stirred salify 5h, cross filter solid, solid washs with a small amount of solvent.
Used organic solvent is that volume ratio is 10: 1 the tetrahydrofuran (THF) and the mixed solution of water, and alkali is yellow soda ash, and resolving agent is the D-camphorsulfonic acid
2) recrystallization of S-3-amino quinine amine chirality hydrochlorate,
Measure solvent and place 250ml single port bottle, add step 1) gained salt, mol ratio heated up and treats to stop after salt dissolves fully heating than 5: 1, temperature is 100 ℃, slowly cooling, and rate of temperature fall is controlled at 3 ℃/minute, when temperature is reduced to 30 ℃, filtering solid, mother liquor another kind of configuration body to be recycled.
Solvent for use is that volume ratio is 10: 1 the tetrahydrofuran (THF) and the mixed solution of water
3) parsing of S-3-amino quinine-D-tartrate
With step 2) in the salt that obtains be dissolved in the organic solvent, add alkali and stirred 5 hours, solid dissolves gradually, separates out inorganic salt, removes by filter inorganic salt, mother liquor is evaporated to dried.There is solid to separate out, gets the S-3-amino quinine.
Used organic solvent is a methyl alcohol, and alkali is yellow soda ash
4) salify of S-3-amino quinine
With 3) in the solids dissolve with ethanol, filter, to pH=1, stirred crystallization 3 hours has a large amount of solids to separate out at the ice-cooled hydrogen chloride gas that feeds in filtrate down, filter crude product.
5) with 4) in an amount of ethanol of crude product of gained: water mixed liquid, volume ratio are 1: 1, and the intensification 100 ℃ dissolving that refluxes adds 10% gac, backflow stirring 1h, filtered while hot, filtrate decompression steam the partial solvent crystallisation by cooling and separate out white solid.
The bound value and the interval value of each raw material of the present invention can both be realized the present invention, and each cited raw material can both realize the present invention, just do not enumerate embodiment one by one at this.
Claims (10)
1.S-3-the preparation method of amino quinine dihydrochloride is characterized in that: realize by following step:
1) in suitable solvent, with organic bases or mineral alkali and the reaction of the 3-amino quinine dihydrochloride 3-amino quinine that dissociates; In the 3-amino quinine, add the chiral acid resolving agent, stirred 1-5 hour down at 0-50 ℃, salify filter 3-amino quinine amine chirality hydrochlorate solid I;
2) with the solid I solvent rising temperature for dissolving of gained, solvent temperature is 50-100 ℃, and dissolving is finished, and is cooled to 0-30 ℃, filter the solid II;
3) solid II dissolution with solvents adds alkali, and the elimination inorganic salt are crossed in the stirring at room dissolving; The mother liquor concentrating under reduced pressure gets the solid III; The mol ratio of alkali and solid II is 1-5: 1;
4) with the solid III of organic solvent dissolution previous step gained, feed hydrogen chloride gas under the room temperature to pH=1,0-30 ℃ of following stirred crystallization, the adularescent solid is separated out, filter S-3-amino quinine dihydrochloride crude product;
5) the S-3-amino quinine dihydrochloride crude product that obtains is used mixed solution pure and water, be warming up to 80-100 ℃ of dissolving, add activated carbon, backflow 0.5-1h, filtered while hot, mother liquor concentrates, and separates out the S-3-amino quinine dihydrochloride; Wherein alcohol is 1-10 with the volume ratio of water: 1, and the consumption of activated carbon is the 5-10% of S-3-amino quinine dihydrochloride crude product quality;
The step 1) solvent for use is Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF) or acetonitrile, or the mixed solution of Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF) or acetonitrile and water, and the volume ratio of Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF) or acetonitrile and water is: 1-10: 1;
Step 2) described solvent is Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF), acetonitrile or N, dinethylformamide, or Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF), acetonitrile or N, the mixed solution of dinethylformamide and water;
The step 3) solvent for use is C
1-8Fatty Alcohol(C12-C14 and C12-C18), tetrahydrofuran (THF), acetonitrile or acetone.
2. preparation method according to claim 1 is characterized in that: the mol ratio of 3-amino quinine dihydrochloride and organic bases or mineral alkali is 1 in the step 1): 1-3; Used chiral acid resolving agent is D-tartrate, L-tartrate, D-amygdalic acid, L-amygdalic acid, D-camphorsulfonic acid, L-camphorsulfonic acid, D-dibenzoyl tartaric acid or L-dibenzoyl tartaric acid.
3. preparation method according to claim 1 and 2 is characterized in that: the described Fatty Alcohol(C12-C14 and C12-C18) of step 1) is methyl alcohol, ethanol or propyl alcohol.
4. preparation method according to claim 1 and 2 is characterized in that: the used organic bases of step 1) is fatty primary secondary amine or tertiary amine; Mineral alkali is the oxyhydroxide of carbonate, supercarbonate, acetate or basic metal or alkaline-earth metal.
5. preparation method according to claim 4 is characterized in that: organic bases is triethylamine or diethylamine; Mineral alkali is sodium hydroxide or potassium hydroxide.
6. preparation method according to claim 1 and 2 is characterized in that: step 2) described Fatty Alcohol(C12-C14 and C12-C18) is methyl alcohol, ethanol or propyl alcohol.
7. preparation method according to claim 1 and 2 is characterized in that: step 2) mol ratio of solvent and solid I is 5-10: 1; Cooling rate is 3 ℃/hour.
8. preparation method according to claim 1 and 2 is characterized in that: the described alkali of step 3) is yellow soda ash, salt of wormwood, saleratus, sodium bicarbonate, volatile salt, diethylamine, triethylamine, sodium alkoxide, potassium alcoholate, sodium hydride, potassium hydride KH or hydrolith.
9. preparation method according to claim 1 and 2 is characterized in that: the described C of step 3)
1-8Fatty Alcohol(C12-C14 and C12-C18) be methyl alcohol, ethanol, Virahol or propyl carbinol.
10. the preparation method of S-3-amino quinine dihydrochloride according to claim 1 and 2 is characterized in that: the step 3) dissolution time is 1-5 hour; The stirred crystallization time is 1-3 hour behind the step 4) feeding hydrogen chloride gas.
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