CN104876856B - A kind of method that Split Method prepares (R) (+) 3 amino piperidine dihydrochloride - Google Patents
A kind of method that Split Method prepares (R) (+) 3 amino piperidine dihydrochloride Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of method that chemical resolution method prepares (R) (+) 3 amino piperidine dihydrochloride, belongs to racemoid and splits field.Specifically use (+) 4 (2 chlorphenyl) 2 hydroxyl 5 of 1 ~ 2 equivalent, the oxo 1 of 5 dimethyl 2,3,2 dioxaphosphorinanes are resolving agent, salt crust is reacted in alcohol solution with the amino piperidine of racemic 3, the amino piperidine dihydrochloride of optical voidness (R) (+) 3 is obtained after cooling precipitation solid is dissociated；Dissociated recovery (S) () the 3 amino piperidine dihydrochloride of mother liquor, (S) () 3 amino piperidine dihydrochloride use through racemization Posterior circle.Simple to operate, resolution reagent recoverable of the invention, is adapted to industrialized production.
Description
Technical field
The invention belongs to racemoid split field, and in particular to a kind of resolution of racemic 3- amino piperidines prepare (R)-
The method of (+) -3- amino piperidine dihydrochlorides.
Background technology
(R)-(+) -3- amino piperidines and its salt are new fine-chemical intermediates, available for synthesizing Egelieting, woods
The anti-diabetes B medicine such as Ge Lieting and BI 1356, due to its less stable, generally with (R)-(+) -3- amino piperidines two
Hydrochloride form preserves.
The synthetic method of (R)-(+) -3- amino piperidine dihydrochlorides mainly has chiral source synthetic method and chemical resolution at present
Method.
Earth tide is bravely using D-Glu as initiation material (East China University of Science, Engineering Master degree are discussed, 2010), through carboxyl ester
Change, amido Cbz protections, 9 steps such as ester group reduction react to obtain (R) -3- amino piperidine dihydrochlorides, total recovery 37.7%, but not
Report its ee value.Mori etc. (WO2008102720) describes ((R))-N- benzyl -3- piperidine formamides and passes through Huffman weight
Row, hydrogenolysis take off the method that benzyl salinization prepares ((R)) -3- amino piperidines dihydrochloride (99.5%e.e.).Due to chiral source synthetic method
Complex steps, non-natural chiral raw material price is higher, limits its application industrially.
Chemical resolution method is industrially to prepare a kind of method that chipal compounds are most widely used.Liu Chun etc.
(CN103319399) using 3- piperidine formamides as raw material, racemic 3- ammonia is obtained under the effect of 1- fluoronaphthalenes, hydrogen peroxide and fluoboric acid
Phenylpiperidines, using D- tartaric acid as resolving agent the resolution of racemic 3- amino piperidines in alcoholic solvent, obtain (R)-(+) -3- amino piperidines
Dihydrochloride, ee values are more than 99.5%.Meek etc. (WO2011160037) prepares racemic using 3- aminopyridines hydrogenating reduction
3- amino piperidines, then using methanol as solvent, dibenzoyl-D-tartaric acid is resolving agent, chemical resolution method be prepared for (R)-
(+) -3- amino piperidine dihydrochlorides, ee values are up to 99.6%.Samuel etc. (WO2007075630) has attempted 20 kinds of resolving agents and used
In resolution of racemic 3- amino piperidines, and dibenzoyl-D-tartaric acid, two o-methyl-benzene formyl-D- winestones are therefrom filtered out
3 kinds of acid and N- acetyl-D- propyl group alanine are suitable for preparing the resolving agent of (R)-(+) -3- amino piperidine dihydrochlorides.
Today after Pasteur has found spatial chemistry 150 years, fractionation is still the one of " repetition test, constantly groping "
Individual process.In spite of many experiments and attempt, but split process had not both had area of computer aided model now, without diastereoisomeric salt
Crystal data detailed inspection, studied without the energy difference of diastereoisomeric salt, also without experience it is related formed it is assumed that less
With say to be formed theory go predict a fractionation technology.Chemical resolution is still that a needs make repeated attempts, the process constantly groped,
Mutual no rule may be referred to, and has the very similar racemic substrate of molecular configurational, still can not use same fractionation
Agent or the similar resolving agent of structure split (Angew. Chem. Int. Ed. 1998,37 (17): 2349-2354).Explore
The method for splitting of a certain racemic substrate is split, it is necessary to screen chiral resolving agent, solvent environment is explored and gropes specific technique
Condition etc., it is required for creative thinking and creation sex exploration.Such as 3- ammonia is split with α-p-toluenesulfonyl-(S)-phenylalanine
Exemplified by phenylpiperidines, when using methanol as solvent, the double salt of R configurations preferentially separates out；And when using ethanol as solvent, S configuration double salt
It is preferential to separate out.Therefore, split and sayed also irregular between solvent species and resolving agent, research and develop and be adapted to resolution to disappear outside
Revolve (3)-amino piperidine method, be one take time and effort start sex work.
As the demand both at home and abroad on (R)-(+) -3- amino piperidines increasingly increases, new resolving agent is explored, is simplified
Operating procedure, improve reaction yield and optical purity of products has actual anticipate to the industrialized production of (R)-(+) -3- amino piperidines
Justice.The problems such as yet with chemical resolution in the presence of the blindness in limitation and the resolving agent screening for splitting type of compounds,
Need to pay a large amount of creative works in the heuristic process of resolving agent.
The content of the invention
It is an object of the invention to provide a kind of high income, optical purity are high, simple to operate and easy, industrialization is easily realized
The Split Method method that directly prepares (R)-(+) -3- amino piperidine dihydrochlorides.
To achieve the above object, the technical solution used in the present invention is specific as follows：
A kind of method that Split Method prepares (R)-(+) -3- amino piperidine dihydrochlorides, it specifically comprises the following steps：
(1) by racemic 3- amino piperidines and (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,
2- dioxaphosphorinanes are heated to reflux in alcohol solution, cooling, filter out (+) -4- (2- chlorphenyls) -2- hydroxyls -5,5- bis-
Methyl -2- oxo -1,3,2- dioxaphosphorinanes (R)-(+) -3- amino piperidine double salt；
(2) (+) -4- (2- the chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- two obtained step (1)
Oxygen phospha cyclohexane (R)-(+) -3- amino piperidines double salt obtains (R)-(+) -3- ammonia after being dissociated in the alcoholic solution of hydrogen chloride
Phenylpiperidines dihydrochloride；
Wherein (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes
Chemical structural formula is as follows：
(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes.
Described (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes
Mol ratio with racemic 3- amino piperidines is 1 ~ 2 ︰ 1.
The content m of alcoholic solvent meets volumes below percentage in described alcohol solution：50%≤m ＜ 100% (V/V), institute
State monohydric alcohol or dihydric alcohol that alcoholic solvent is less than 6 for carbon number.
Alcohol is the alcohol that carbon number is less than or equal to 4 in the alcoholic solution of described hydrogen chloride, the mass concentration n of hydrogen chloride meets 1%≤
N ＜ 30%.
Described (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The dissociating method of alkane (R)-(+) -3- amino piperidine double salt is：By (+) -4- (2- chlorphenyls) -2- hydroxyls -5,5- two of precipitation
Methyl -2- oxos -1,3,2- dioxaphosphorinanes (R)-(+) -3- amino piperidine double salt are dissolved in ethanolic hydrogen chloride solution,
Stirring, crystal, filtering being separated out, filtration cakes torrefaction obtains (R)-(+) -3- amino piperidine dihydrochlorides, and filtrate is spin-dried for, and washes, filtering,
Filter cake reclaims (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes.
Further, Split Method of the invention prepares the method for (R)-(+) -3- amino piperidine dihydrochlorides also including following
Step：
(3) after the filtrate that obtains step (1) is dissociated (S)-(-) -3- amino piperidine dihydrochlorides, specific method
For：Filtrate is spin-dried for, is dissolved in the alcoholic solution of hydrogen chloride, stir, separate out crystal, filtering, filtration cakes torrefaction obtain (S)-(-)-
3- amino piperidine dihydrochlorides, filtrate are spin-dried for, and wash, and filtering, filter cake reclaims (+) -4- (2- chlorphenyls) -2- hydroxyls -5,5-
Dimethyl -2- oxo -1,3,2- dioxaphosphorinanes.
Further, Split Method of the invention prepares (R)-(+) -3- amino piperidine dihydrochlorides method also including following
Step：
(4) (S)-(-) -3- amino piperidines dihydrochloride that step (3) obtains is used through racemization Posterior circle.
Compared with prior art, what the present invention obtained has the beneficial effect that：
The present invention proposes a kind of utilization (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2-
The method of dioxaphosphorinane resolution of racemic 3- amino piperidines, the hydrochloric acid of (R)-(+) -3- amino piperidines two that this method obtains
Salt optical purity is high, high income, and cost is relatively low.Using hydrogen chloride alcoholic solution dissociate non-corresponding isomers salt, photolytic activity (R)-
(+) -3- amino piperidines dihydrochloride can be separated out directly, simple to operate, good product purity.Resolving agent can be reused, drop
Low production cost, and it is adapted to industrialized production.
Brief description of the drawings
Fig. 1：Liquid phase figure after (R)-(+) -3- amino piperidines dihydrochloride processing that embodiment 1 obtains；
Fig. 2：Liquid phase figure after (R)-(+) -3- amino piperidines dihydrochloride processing that embodiment 2 obtains；
Fig. 3：Racemic 3- amino piperidines spread out dihydrochloride processing after liquid phase figure；
In the accompanying drawings：R bodies：(R)-(+) -3- amino piperidines after chlorobenzoyl chloride derivatization, S bodies：Chlorobenzoyl chloride derivatization
(S)-(-) -3- amino piperidines afterwards.
Embodiment
The present invention is described in more detail below in conjunction with specific embodiment.
In following examples, in HPLC detection method, the processing method and liquid-phase condition of sample are as follows：
3- amino piperidine dihydrochlorides obtained by embodiment are neutralized, and testing sample, liquid phase are obtained after chlorobenzoyl chloride derivatization
Detection uses ChromTech CHIRAL-AGP chromatographic columns, and mobile phase is 0.015 mol/L aqueous phosphatics-isopropanol (99:
1), ultraviolet detection wavelength is 254nm, and flow velocity is 0.8 mL/min, and column temperature is 30 DEG C, the μ L of sampling volume 20.
Embodiment 1：
Step a：By 14.7g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in the tert-butyl alcohol water of 40 mL 88%, stirring, is added the g of racemic 3- amino piperidines 5.30, is heated to reflux 2 h,
Cool crystallization, there is white solid precipitation, filters, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,
The g of 2- dioxaphosphorinanes (R)-(+) -3- amino piperidines double salt 9.52, mother liquor are spin-dried for (+) -4- (2- chlorphenyls) -2-
The g of hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 10.43.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The g of alkane (R)-(+) -3- amino piperidines double salt 1.0 is dissolved in the isopropanol solution of hydrogen chloride of 1.94 g 15%, and 2 h are stirred at room temperature,
Solid is separated out, is filtered, drying, obtains (R)-(+) -3- amino piperidines dihydrochloride 0.45 g, yield 93.9%, 99.48%e.e.,
HPLC collection of illustrative plates is shown in Fig. 1；Filtrate is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,
The g of 2- dioxaphosphorinanes 0.72, the rate of recovery 94.6%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 2：
Step a：By 7.06g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in the ethanol waters of 60 mL 95%, stirring, is added racemic 3- amino piperidine 2.12g, is heated to reflux 2 h, is cooled
Crystallization, there is white solid precipitation, filter, obtain (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- bis-
The g of oxygen phospha cyclohexane (R)-(+) -3- amino piperidines double salt 3.85, mother liquor be spin-dried for (+) -4- (2- chlorphenyls) -2- hydroxyls -
The g of 5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 5.3.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The g of alkane (R)-(+) -3- amino piperidines double salt 1.0 is dissolved in the isopropanol solution of hydrogen chloride of 4.12 g 5%, and 2 h are stirred at room temperature, analysis
Go out solid, filter, drying, obtain (R)-(+) -3- amino piperidines dihydrochloride 0.39 g, yield 81.8%, 89.48%e.e.,
HPLC collection of illustrative plates is shown in Fig. 2；Filtrate is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,
2- dioxaphosphorinane 0.72g, the rate of recovery 95.2%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 3：
Step a：By 2.94g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in the normal propyl alcohol water of 15 mL 95%, stirring, is added 1.06g racemic 3- amino piperidines, is heated to reflux 2 h, is dropped
Warm crystallization, there is white solid precipitation, filter, obtain the g of (+)-cycli phosphate (R)-(+) -3- amino piperidines double salt 1.9, mother liquor is spin-dried for
Obtain (+) -4- (2- chlorphenyls) -2- hydroxyls -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3-
The g of amino piperidine double salt 2.05.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The g of alkane (R)-(+) -3- amino piperidines double salt 1.0 is dissolved in the hydrogen chloride methanol solutions of 1.67 g 19%, and 2 h are stirred at room temperature, analysis
Go out solid, filter, drying, obtain the g of (R)-(+) -3- amino piperidines dihydrochloride 0.45, yield 92.8%, 97.26%e.e., filtrate
It is spin-dried for, washes, drying, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxy phosphorus heterocycles
The g of hexane 0.69, the rate of recovery 89.8%, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 4：
Step a：By 3.3 g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in the isopropanol waters of 30 mL 95%, stirring, is added 1.06g racemic 3- amino piperidines, is heated to reflux 2 h, is dropped
Warm crystallization, there is white solid precipitation, filter, obtain (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2-
The g of dioxaphosphorinane (R)-(+) -3- amino piperidines double salt 1.92, mother liquor are spin-dried for (+) -4- (2- chlorphenyls) -2- hydroxyls
The g of base -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 2.45.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (R)-(+) -3- amino piperidine double salt 1.0g is dissolved in the hydrogen chloride isobutanol solutions of 1.62 g 23%, and 2 h are stirred at room temperature, analysis
Go out solid, filter, drying, obtain the g of (R)-(+) -3- amino piperidines dihydrochloride 0.46, yield 95.8%, 98.19%e.e.；
Filtrate is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxy phospha hexamethylenes
The g of alkane 0.68, the rate of recovery 87.1%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 5：
Step a：By 2.94g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphas
Hexamethylene is dissolved in the tert-butyl alcohol water of 56 mL 95%, stirring, is added 1.06g racemic 3- amino piperidines, is heated to reflux 2 h, is cooled
Crystallization, there is white solid precipitation, filter, obtain (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- bis-
The g of oxygen phospha cyclohexane (R)-(+) -3- amino piperidines double salt 1.85, mother liquor be spin-dried for (+) -4- (2- chlorphenyls) -2- hydroxyls -
The g of 5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 2.1.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The g of alkane (R)-(+) -3- amino piperidines double salt 1.0 is dissolved in the ethanol solution of hydrogen chloride of 1.55 g 16%, and 2 h are stirred at room temperature, analysis
Go out solid, filter, drying, obtain the g of (R)-(+) -3- amino piperidines dihydrochloride 0.45, yield 91.7%, 96.28%e.e.；Filter
Liquid is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxaphosphorinanes
0.66 g, the rate of recovery 83.0%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 6：
Step a：By 5.29 g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in the tert-butyl alcohol water of 28 mL 90%, stirring, is added 1.06g racemic 3- amino piperidines, is heated to reflux 2 h, is dropped
Warm crystallization, there is white solid precipitation, filter, obtain (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2-
The g of dioxaphosphorinane (R)-(+) -3- amino piperidines double salt 1.89, mother liquor are spin-dried for (+) -4- (2- chlorphenyls) -2- hydroxyls
The g of base -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 4.45.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (R)-(+) -3- amino piperidine double salt 1.0g is dissolved in the hydrogen chloride t-butanol solutions of 1.33 g 26%, and 2 h are stirred at room temperature, analysis
Go out solid, filter, drying, obtain the g of (R)-(+) -3- amino piperidines dihydrochloride 0.46, yield 93.9%, 95.69%e.e.；Filter
Liquid is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxaphosphorinanes
0.66 g, the rate of recovery 85.1%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment 7：
Step a：By 2.94g (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus
Azacyclohexane is dissolved in 15 mL85% tert-butyl alcohol water, stirring, is added 1.06g racemic 3- amino piperidines, is heated to reflux 2 h, is dropped
Warm crystallization, there is white solid precipitation, filter, obtain (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2-
The g of dioxaphosphorinane (R)-(+) -3- amino piperidines double salt 1.6, mother liquor are spin-dried for (+) -4- (2- chlorphenyls) -2- hydroxyls
The g of base -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes (S)-(-) -3- amino piperidines double salt 2.5.
Step b：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
The g of alkane (R)-(+) -3- amino piperidines double salt 1.0 is dissolved in the hydrogen chloride normal propyl alcohol solution of 1.85 g 18%, and 2 h are stirred at room temperature,
Solid is separated out, is filtered, drying, obtains the g of (R)-(+) -3- amino piperidines dihydrochloride 0.45, yield 79.7%, 95.42%e.e.；
Filtrate is spin-dried for, and washing, obtains (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxy phospha hexamethylenes
The g of alkane 0.69, the rate of recovery 74.8%, dry, recycle.
Step c：(+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phospha hexamethylenes
Alkane (S)-(-) -3- amino piperidines double salt is dissociated using step b method and is reclaimed resolving agent, gained (S)-(-) -3- amino
Piperidines dihydrochloride uses through hot racemization processing Posterior circle.
Embodiment described above is only the preferred embodiments of the present invention, and the simultaneously exhaustion of the feasible implementation of non-invention.It is right
For persons skilled in the art, on the premise of without departing substantially from the principle of the invention and spirit to any aobvious made by it and
The change being clear to, it should all be contemplated as falling with the claims of the present invention.
Claims (6)
1. a kind of method that Split Method prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is characterised in that its specifically include as
Lower step：
(1) by racemic 3- amino piperidines and (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- two
Oxygen phospha cyclohexane is heated to reflux in alcohol solution, cooling, filter out (+) -4- (2- chlorphenyls) -2- hydroxyls -5,5- dimethyl -
2- oxo -1,3,2- dioxaphosphorinanes (R)-(+) -3- amino piperidine double salt；
(2) (+) -4- (2- the chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxy phosphorus obtained step (1)
Azacyclohexane (R)-(+) -3- amino piperidines double salt obtains (R)-(+) -3- amino piperazines after being dissociated in the alcoholic solution of hydrogen chloride
Pyridine dihydrochloride；
The chemistry of wherein (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes
Structural formula is as follows：
Explanation:Explanation:Explanation: http://pic.cnipr.com/XmlData/fm/20150902/201510222982.3/DEST_PATH_IMAGE002.GIF；
Described (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes with it is outer
The mol ratio of racemization 3- amino piperidines is 1 ~ 2 ︰ 1.
2. the method that a kind of Split Method according to claim 1 prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is special
Sign is that the content m of alcoholic solvent meets volumes below percentage in described alcohol solution：50%≤m ＜ 100% (V/V), it is described
Alcoholic solvent is the monohydric alcohol or dihydric alcohol that carbon number is less than 6.
3. the method that a kind of Split Method according to claim 1 prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is special
Sign is that the alcohol in the alcoholic solution of described hydrogen chloride is the alcohol that carbon number is less than or equal to 4, and the mass concentration n of hydrogen chloride meets 1%
≤ n ＜ 30%.
4. the method that a kind of Split Method according to claim 1 prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is special
Sign is, described (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxos -1,3,2- dioxaphosphorinanes
(R)-(+) dissociating method of -3- amino piperidines double salt is：By (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- diformazans of precipitation
Base -2- oxos -1,3,2- dioxaphosphorinanes (R)-(+) -3- amino piperidine double salt are dissolved in ethanolic hydrogen chloride solution, stirred
Mix, separate out crystal, filtering, filtration cakes torrefaction obtains (R)-(+) -3- amino piperidine dihydrochlorides, and filtrate is spin-dried for, and washes, and filters, filter
Cake reclaims (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes.
5. the method that a kind of Split Method according to claim 1 prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is special
Sign is, further comprising the steps of：
(3) after the filtrate that obtains step (1) is dissociated (S)-(-) -3- amino piperidine dihydrochlorides, specific method are：Will
Filtrate is spin-dried for, and is dissolved in ethanolic hydrogen chloride solution, stirring, separates out crystal, filtering, and filtration cakes torrefaction obtains (S)-(-) -3- amino piperazines
Pyridine dihydrochloride, filtrate are spin-dried for, and wash, and filtering, filter cake reclaims (+) -4- (2- chlorphenyls) -2- hydroxyl -5,5- dimethyl -2-
Oxo -1,3,2- dioxaphosphorinanes.
6. the method that a kind of Split Method according to claim 5 prepares (R)-(+) -3- amino piperidine dihydrochlorides, it is special
Sign is, further comprising the steps of：
(4) (S)-(-) -3- amino piperidines dihydrochloride that step (3) obtains is used through racemization Posterior circle.
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| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
| CN102741220A (en) * | 2009-12-22 | 2012-10-17 | 彼得·格迈纳 | New aminotetraline derivatives |
| CN103319399A (en) * | 2013-05-29 | 2013-09-25 | 威海迪素制药有限公司 | Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride |
| CN104387315B (en) * | 2013-11-12 | 2017-10-10 | 药源药物化学（上海）有限公司 | Compound I and（R）3 amido piperidine hydrochlorate II, its preparation method and its application in Li Gelieting synthesis |
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| JP2013533866A (en) * | 2010-06-17 | 2013-08-29 | ドクター レディズ ラボラトリーズ リミテッド | Process for preparing a single enantiomer of 3-aminopiperidine dihydrochloride |
| CN102070469B (en) * | 2010-12-31 | 2013-11-20 | 河北科技大学 | Resolution method for preparing optically pure metoprolol |
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| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
| CN102741220A (en) * | 2009-12-22 | 2012-10-17 | 彼得·格迈纳 | New aminotetraline derivatives |
| CN103319399A (en) * | 2013-05-29 | 2013-09-25 | 威海迪素制药有限公司 | Preparation method for alogliptin intermediate R-3-aminopiperidine dihydrochloride |
| CN104387315B (en) * | 2013-11-12 | 2017-10-10 | 药源药物化学（上海）有限公司 | Compound I and（R）3 amido piperidine hydrochlorate II, its preparation method and its application in Li Gelieting synthesis |
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