CN104829459A - Splitting method for preparing (R)-(+)-1-naphthyl ethylamine - Google Patents
Splitting method for preparing (R)-(+)-1-naphthyl ethylamine Download PDFInfo
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Abstract
The invention discloses a splitting method for preparing (R)-(+)-1-naphthyl ethylamine, and belongs to the field of splitting of mixed levorotatory/dextrorotary compounds. In the provided method, (+)-4-phenyl-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane is taken as the main splitting agent and (+)-4-(2-chlorophenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane is taken as the auxiliary splitting agent so as to split mixed levorotatory/dextrorotary 1-naphthyl ethylamine, and finally (R)-(+)-1-naphthyl ethylamine and (S)-(+)-1-naphthyl ethylamine with a high optical purity can be obtained. The obtained (R)-(+)-1-naphthyl ethylamine has an optical purity as high as 99% e.e. or more. The provided method has the characteristics of high yield, recoverable splitting agent, simple operation, and suitability for industrial production.
Description
Technical field
The present invention relates to a kind of method for splitting of racemoid, be specifically related to a kind of novel method splitting racemization 1-naphthalene ethylamine preparation (R)-(+)-1-naphthalene ethylamine.
Background technology
1-naphthalene ethylamine is important chiral intermediate, has a wide range of applications at organic synthesis, new drug research and Peptides Synthesis, therefore synthesizes that it is significant at field of medicaments.1-naphthalene ethylamine is as chiral auxiliary simultaneously, the chirality N-alkylidene group naphthalene ethylamine that (R) or (S)-1-naphthalene ethylamine and corresponding aldehyde reaction obtain, and N-alkylidene group naphthalene ethylamine is the important intermediate of synthesis s-generation Sensipar cinacalcet.
Yang Wuxing (CN200710094139.7) etc. are resolving agent with L-Aspartic acid, optically pure (R)-1-naphthalene ethylamine and optically pure (S)-1-naphthalene ethylamine is obtained in certain solvent, its e.e. value more than 98%, yield more than 30%.
In addition, Hu Jian (Chinese Journal of Synthetic Chemistry, 2010,18,61) etc. people D-tartrate is that the 1-naphthalene ethylamine of resolving agent to DL splits, and controls certain solid-liquid ratio in certain solvent, finally obtains optically pure (R)-1-naphthalene ethylamine and (S)-1-naphthalene ethylamine, its e.e. value is 98%, yield 31%.
2002, Marco Pallavicini (Tetrahedron:Asymm, 2002,13,2277) propose with (S)-3-carboxyl-2-naphthoic acid isopropylidene glyceryl ester as resolving agent, hybrid reaction in methyl alcohol, obtain (S)-1-naphthalene ethylamine, its e.e. value reaches 91%.
2005, Kazuhiko Saigo (Tetrahedron:Asymm, 2005,16,3807) report a kind of with 6-methoxyl group-2-naphthyl-a-oxyacetic acid for resolving agent prepares the method for optically pure 1-naphthalene ethylamine.Split process is with (S)-6-methoxyl group-2-naphthyl-a-oxyacetic acid for resolving agent, and reflux in alcohol-water, finally obtain optically pure (S)-1-naphthalene ethylamine, e.e. value reaches 99%.
The fractionation of naphthalene ethylamine also can come with some biology resolving agents, but the technique that above-mentioned split process has is comparatively loaded down with trivial details, and some yields are lower, and some costs are higher, and some resolving agents costly, are not very desirable chemical resolution methods.
1985, ten Hoeve and Wyhberg (J. Org. Chem. 1985,50,4508-4514) designed and synthesized out cyclic phosphoric acid class resolving agent.Sun Fengxia etc. utilize cyclic phosphoric acid to carry out a large amount of exploratory development to D-pHPG (CN101792398), Serine (CN103755582), and obtain and split effect preferably.But above-mentioned method for splitting is for fractionation DL, and (1)-naphthalene ethylamine is inapplicable.
Find stereochemistry today after 150 years at Pasteur, split and remain a process of " repetition test, constantly grope ".Although have a lot of test and attempt, but split process had not both had area of computer aided model now, did not have the detailed inspection of the crystal data of diastereoisomeric salt, did not have the energy difference of diastereoisomeric salt to study, do not have yet experience be correlated with formed hypothesis, say nothing of formed theory remove prediction disassemble technique.Chemical resolution remains needs and makes repeated attempts, the process of constantly groping, do not have rule can reference each other, there is the DL substrate that molecular configurational is very similar, still (Angew. Chem. Int. Ed. 1998,37 (17): 2349-2354) can not be split with the resolving agent of same resolving agent or structural similitude.Explore the method for splitting splitting a certain DL substrate, need to screen chiral resolving agent, explore solvent environment and grope concrete processing condition etc., all need creative thinking and creativity to explore.3-amino piperidine is split: with methyl alcohol for solvent, R configuration double salt is preferentially separated out for α-p-toluenesulfonyl-(S)-phenylalanine; Take ethanol as solvent, S configuration double salt is preferentially separated out.Split and also irregularly between solvent species and resolving agent to say.Fractionation for chipal compounds is the work that a workload is greatly badly in need of exploring.Therefore research and development are applicable to the method for resolution DL 1-naphthalene ethylamine, are the initiative work taken time and effort.
This seminar researchist, on the basis of above-mentioned work, is explored and experiment by creativeness arduous in a large number, explores further solvent environment and concrete technology condition, goes to find a kind of ability of fractionation well and can the method for resolution 1-naphthalene ethylamine.
Summary of the invention
The object of the present invention is to provide a kind of method that yield is high, optical purity is high, fractionation efficiency is high, Split Method that cost is low, simple to operate directly prepares (R)-(+)-1-naphthalene ethylamine.
For achieving the above object, the technical solution used in the present invention is specific as follows:
A kind of method of Split Method preparation (R)-(+)-1-naphthalene ethylamine, it specifically comprises the steps:
(1) reflux in alcoholic solution by DL 1-naphthalene ethylamine and resolving agent, cooling, leaches the diastereomeric salt solid of (R)-(+)-1-naphthalene ethylamine and resolving agent formation;
(2) diastereomeric salt that step (1) obtains is obtained (R)-(+)-1-naphthalene ethylamine after dissociating;
Wherein, described resolving agent comprises main resolving agent and helps resolving agent, described main resolving agent is (+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, the described resolving agent that helps is (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane.
The mole number ratio of described resolving agent and DL 1-naphthalene ethylamine is (1 ~ 2): 1.
Described main resolving agent and the described mole ratio of resolving agent that helps are not less than 1:1.I.e. main resolving agent (+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3, the usage quantity of 2-dioxaphosphorinane is more than or equal to the half of resolving agent total mole number, help resolving agent (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, the usage quantity of 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane is less than or equal to the half of resolving agent total mole number.
Described alcoholic solution is selected from the alcoholic solution of C1-C4.Preferably, be one or more in methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
The dissociating method of described diastereomeric salt is any one in following two kinds of modes:
(1) diastereomeric salt is soluble in water, add alkali, adjust pH >=8, below adopting, in two kinds for the treatment of processs, any one can obtain:
A) adopt organic solvent extraction, remove under reduced pressure by solid drying after organic solvent, (R)-(+)-1-naphthalene ethylamine, acid adding water transfer layer, to strongly-acid, filters, the main resolving agent that drying is recycled and help resolving agent;
B) continue to stir, separate out solid, filter, filtration cakes torrefaction, (R)-(+)-1-naphthalene ethylamine, acid adding adjusts filtrate to strongly-acid, filters, the main resolving agent that drying is recycled and help resolving agent;
(2) diastereomeric salt is soluble in water, acid adding is adjusted to strongly-acid, filters, and reclaim main resolving agent after drying and help resolving agent, filtrate being added alkali and is adjusted to pH >=8, below adopting, in two kinds for the treatment of processs, any one can obtain:
A) adopt organic solvent extraction, remove under reduced pressure by solid drying after organic solvent, (R)-(+)-1-naphthalene ethylamine;
B) continue to stir, separate out solid, filter, filtration cakes torrefaction, obtain (R)-(+)-1-naphthalene ethylamine.
Further, the method for Split Method preparation (R)-(+)-1-naphthalene ethylamine of the present invention is further comprising the steps of:
(3) filtrate step (1) obtained obtains (S)-(-)-1-naphthalene ethylamine after dissociating.
Further, the method for Split Method preparation (R)-(+)-1-naphthalene ethylamine of the present invention is further comprising the steps of:
(4) (S)-(-)-1-naphthalene ethylamine obtained step (3) carries out racemization Posterior circle and applies mechanically.
Acid described in the present invention is selected from inorganic proton acid or organic acid, and described inorganic proton acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid etc.; Described organic acid is selected from acetic acid etc.Described alkali is selected from mineral alkali or organic bases, and described mineral alkali is selected from sodium hydroxide, potassium hydroxide or ammoniacal liquor etc.; Described organic bases is selected from triethylamine or quadrol etc.The selection of above-mentioned soda acid is that the work that those skilled in the art can be passed through non-creativeness is known, as long as can be applicable to method of the present invention, realizes method of the present invention and all should work as the realm of spirit scope belonging to the present invention's protection.
Resolving agent described in the present invention and the mole number ratio of DL 1-naphthalene ethylamine are (1 ~ 2): 1, for about measuring, its add-on can in generally acknowledged limit of error in the field of business, and to be the scope of application of the molar weight of the DL 1-naphthalene ethylamine of 1 ~ 2 times be resolving agent of the present invention: the amount approximately equal of (R)-(+)-1-naphthalene ethylamine and (S)-(-)-1-naphthalene ethylamine in DL 1-naphthalene ethylamine.According to the difference forming content in DL 1-naphthalene ethylamine, an adaptive adjustment can be done, but the principle split is constant.
Strongly-acid described in the present invention refers to pH≤1.
Compared with prior art, the beneficial effect that the present invention obtains is:
Inventor finds under certain splitting condition, and this resolving agent can selectivity resolution (RS)-1-naphthalene ethylamine, and has good fractionation ability, yield can reach more than 90%, and resolving agent is water-soluble hardly, resolving agent loss is less, can recycle.Having searched out one based on above-mentioned experimental exploration process inventor through a large amount of further investigation utilizes above-mentioned resolving agent resolution DL 1-naphthalene ethylamine to prepare the method for (R)-(+)-1-naphthalene ethylamine, effectively reduce resolving agent consumption, improve the effective rate of utilization of resolving agent; Simple to operate; Recycling after (S)-(-)-1-naphthalene ethylamine racemization of another configuration, effectively improve yield, effectively reduce cost.The present invention is simple to operate, is easy to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is DL 1-naphthalene ethylamine liquid phase spectrogram;
Fig. 2 is the liquid phase spectrogram of (R)-(+)-1-naphthalene ethylamine of embodiment 4 gained;
In FIG, retention time is 20.120min is (S)-(-)-1-naphthalene ethylamine, and retention time is 22.590min is (R)-(+)-1-naphthalene ethylamine; In fig. 2, retention time is 22.361min is (R)-(+)-1-naphthalene ethylamine.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in more detail.
Embodiment 1
Step a: add 171.2 g (1 mol) DL 1-naphthalene ethylamine and 237.4 g (0.98 mol) (+)-4-phenyl-2-hydroxyl-5 in 2.5L methyl alcohol, 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, 5.53 g (0.02 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, reflux is clarified to solution, stirs 1h, cooling crystallization, filter, with 200mL methanol wash filter cake, obtain the double salt of 201.4 g (R)-(+)-1-naphthalene ethylamine.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry, evaporate to dryness organic layer, obtain (R)-(+)-1-naphthalene ethylamine 79.61g, yield 93%, 92%e.e., records solid optically-active
+ 46.4 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 400 mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 77.04 g, yield is 90%, 92%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, and suction filtration reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 235.7g altogether, and the rate of recovery is 97.03%, is combined by the resolving agent of recovery and recycles.
Embodiment 2
Step a: add 171.2g (1mol) DL 1-naphthalene ethylamine and 169.55 g (0.7mol) (+)-4-phenyl-2-hydroxyl-5 in 2L Virahol, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, 110.66 g (0.4 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filter, with 200mL washed with isopropyl alcohol filter cake, obtain 220.4g white solid, obtain (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 10%KOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry organic layer, obtain (R)-(+)-1-naphthalene ethylamine 81.32g, yield 95%, 90%e.e., records solid optically-active
+ 47.4 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%KOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 79.6g, yield is 93%, 95%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 266.3g altogether, and the rate of recovery is 95.03%, is combined by the resolving agent of recovery and recycles.
Embodiment 3
Step a: add 171.2g (1mol) DL 1-naphthalene ethylamine and 217.9 g (0.9mol) (+)-4-phenyl-2-hydroxyl-5 in 2.5L ethanol, 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, 82.99 g (0.3 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filters, with 200mL washing with alcohol filter cake, obtain 229.56g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 20% ammonia soln, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry organic layer, obtain (R)-(+)-1-naphthalene ethylamine 78.75g, yield 92%, 97%e.e., records solid optically-active
+ 46.3 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 20% ammonia soln, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 77.4g, yield is 90%, 98%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 289.2g altogether, and the rate of recovery is 96.08%, is combined by the resolving agent of recovery and recycles.
Embodiment 4
171.2g (1mol) DL 1-naphthalene ethylamine and 237.4 g (0.98 mol) (+)-4-phenyl-2-hydroxyl-5 is added in step a:2.5L methyl alcohol, 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, 5.53 g (0.02 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filters, with 200mL methanol wash filter cake, obtain 199.78g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 400mL water, 36% hydrochloric acid adjusts solution to strongly-acid, and stirring at room temperature 1h, separates out a large amount of solid, filters, and reclaims resolving agent.After filtrate is concentrated, adjust pH=8, stirred at ambient temperature 1h with 10%NaOH solution, filter, use 20mL washing with alcohol, dry, obtain (R)-(+)-1-naphthalene ethylamine 82.18g, yield 96%, 99.88%e.e., records solid specific rotation
+ 46.4 ° (c=1 methyl alcohol), with liquid chromatogram measuring above-mentioned (R)-(+)-1-naphthalene ethylamine.。Fig. 2 is the liquid phase spectrogram of (R)-(+)-1-naphthalene ethylamine after splitting, and chromatographic condition is 8% methyl alcohol+92%10mm SODIUM PHOSPHATE, MONOBASIC, and NaOH regulates pH=6.0, and determined wavelength is 220nm, chirality AGP stationary phase.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 81.32g, yield is 95%, 98%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 232.2g altogether, and the rate of recovery is 95.59%, is combined by the resolving agent of recovery and recycles.
Embodiment 5
171.2g (1mol) DL 1-naphthalene ethylamine and 217.9 g (0.9mol) (+)-4-phenyl-2-hydroxyl-5 is added in step a:2.5L Virahol, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, 82.99 g (0.3 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filter, with 200mL washed with isopropyl alcohol filter cake, obtain 226.56g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 400mL water, 36% hydrochloric acid adjusts solution to strongly-acid, and stirring at room temperature 1h, separates out a large amount of solid, filters, and reclaims resolving agent.After filtrate is concentrated, adjust pH=8, stirred at ambient temperature 1h with 10%KOH solution, filter, use 20mL methanol wash, dry, obtain (R)-(+)-1-naphthalene ethylamine 80.46g, yield 94%, 99.44%e.e., records solid specific rotation
+ 46.8 ° (c=1 methyl alcohol).
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%KOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 79.61g, yield is 93%, 97.6%e.e..Water layer is adjusted to strongly-acid, stirred at ambient temperature, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 290.3g altogether, and the rate of recovery is 96.45%, is combined by the resolving agent of recovery and recycles.
Embodiment 6
Step a: add 171.2g (1mol) DL 1-naphthalene ethylamine and 169.55 g (0.7mol) (+)-4-phenyl-2-hydroxyl-5 in 2L ethanol, 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, 110.66 g (0.4 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filters, with 200mL washing with alcohol filter cake, obtain 219.90g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 400mL water, sulfuric acid adjusts solution to strongly-acid, and stirring at room temperature 1h, separates out a large amount of solid, filters, and reclaims resolving agent.After filtrate is concentrated, adjust pH=8, stirred at ambient temperature 1h with 10%KOH solution, filter, use 20mL methanol wash, dry, obtain (R)-(+)-1-naphthalene ethylamine 79.6g, yield 93%, 97.8%e.e., records solid specific rotation
+ 46.0 ° (c=1 methyl alcohol).
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%KOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 81.32g, yield is 95%, 97.4%e.e..Water layer is adjusted to strongly-acid, stirred at ambient temperature, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 259.6g altogether, and the rate of recovery is 92.64%, is combined by the resolving agent of recovery and recycles.
Embodiment 7
Step a: add 171.2g (1mol) DL 1-naphthalene ethylamine and 193.77 g (0.8mol) (+)-4-phenyl-2-hydroxyl-5 in 2.5L methanol/isopropanol (9/1), 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, 110.66 g (0.4 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane resolving agent, reflux is clarified to solution, stir 1h, cooling crystallization, filter, with 200mL methanol/isopropanol solution washing filter cake, obtain 229.90g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with methylamine solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry organic layer, obtain (R)-(+)-1-naphthalene ethylamine 81.4g, yield 95.1%, 98.3%e.e., records solid optically-active
+ 46.3 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 83.4g, yield is 97.4%, 96.3%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 293.4g altogether, and the rate of recovery is 96.37%, is combined by the resolving agent of recovery and recycles.
Embodiment 8
171.2g (1mol) DL 1-naphthalene ethylamine and 237.4 g (0.98 mol) (+)-4-phenyl-2-hydroxyl-5 is added in step a:2.5L Virahol, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, 5.53 g (0.02 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, reflux is clarified to solution, stir 1h, cooling crystallization, filter, with 200mL washed with isopropyl alcohol filter cake, obtain 202.4g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 10%KOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry organic layer, obtain (R)-(+)-1-naphthalene ethylamine 81.32g, yield 95%, 99.2%e.e., records solid optically-active
+ 47.2 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 82.9g, yield is 96.8%, 96.3%e.e..Water layer is adjusted to strongly-acid, stirred at ambient temperature, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 231.1g altogether, and the rate of recovery is 95.14%, is combined by the resolving agent of recovery and recycles.
Embodiment 9
171.2g (1mol) DL 1-naphthalene ethylamine and 363.32 g (1.5mol) (+)-4-phenyl-2-hydroxyl-5 is added in step a:2.5L ethanol, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane, 110.66 g (0.4 mol) (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5, 5-dimethyl-2-oxo-1, 3, 2-dioxaphosphorinane resolving agent, reflux is clarified to solution, stir 1h, cooling crystallization, filter, with 200mL washing with alcohol filter cake, obtain 227.6g white solid, i.e. (R)-(+)-1-naphthalene ethylamine double salt.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry organic layer, obtain (R)-(+)-1-naphthalene ethylamine 79.32g, yield 92.66%, 98.4%e.e., records solid optically-active
+ 46.8 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 500mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 81.4g, yield is 95.1%, 97.8%e.e..Water layer is adjusted to strongly-acid, stirred at ambient temperature, suction filtration, reclaims remaining resolving agent.
The resolution reagent that above-mentioned steps b and step c reclaims is 461.14g altogether, and the rate of recovery is 97.29%, is combined by the resolving agent of recovery and recycles.
Comparative example 1
Step a: add 171.2 g (1 mol) DL 1-naphthalene ethylamine and 242.1 g (1mol) (+)-4-phenyl-2-hydroxyl-5 in 2.5L methyl alcohol, 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, reflux is clarified to solution, stirs 1h, cooling crystallization, filter, with 200mL methanol wash filter cake, obtain the double salt of 201.4 g (R)-(+)-1-naphthalene ethylamine.
Step b: by molten for above-mentioned filter cake in 500mL water, pH=8 is adjusted with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption is 100mL, dry, evaporate to dryness organic layer, obtain (R)-(+)-1-naphthalene ethylamine 79.61g, yield 85%, 89.54%e.e., records solid optically-active
+ 46.1 ° (c=1 methyl alcohol).Water layer is with salt acid for adjusting pH to strongly-acid, and stirring at room temperature separates out a large amount of solid, filters, and reclaims resolving agent.
Step c: the filtrate in step a and washings are merged, steam except organic solvent, by gained solid 400 mL water dissolution, adjust pH=8 with 10%NaOH solution, stirred at ambient temperature 1h, with dichloromethane extraction three times, each consumption 100mL, dry organic layer, steam except organic solvent, obtain (S)-(-)-1-naphthalene ethylamine 77.04 g, yield is 80%, 83.35%e.e..Water layer is adjusted to strongly-acid, and stirred at ambient temperature separates out a large amount of solid, and suction filtration reclaims remaining resolving agent.
The above embodiment is only the preferred embodiments of the present invention, and and the feasible enforcement of non-invention exhaustive.For persons skilled in the art, to any apparent change done by it under the prerequisite not deviating from the principle of the invention and spirit, all should be contemplated as falling with within claims of the present invention.
Claims (7)
1. a method for Split Method preparation (R)-(+)-1-naphthalene ethylamine, it is characterized in that, it specifically comprises the steps:
(1) reflux in alcoholic solution by DL 1-naphthalene ethylamine and resolving agent, cooling, leaches the diastereomeric salt solid of (R)-(+)-1-naphthalene ethylamine and resolving agent formation;
(2) diastereomeric salt that step (1) obtains is obtained (R)-(+)-1-naphthalene ethylamine after dissociating;
Wherein, described resolving agent comprises main resolving agent and helps resolving agent, described main resolving agent is (+)-4-phenyl-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, the described resolving agent that helps is (+)-4-(2-chloro-phenyl-)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane.
2. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 1, it is characterized in that, the mole number ratio of described resolving agent and DL 1-naphthalene ethylamine is (1 ~ 2): 1.
3. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 1, it is characterized in that, described main resolving agent and the described mole ratio of resolving agent that helps are not less than 1:1.
4. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 1, it is characterized in that, described alcoholic solution is selected from C
1-C
4alcoholic solution.
5. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 1, is characterized in that, the dissociating method of described diastereomeric salt is any one in following two kinds of modes:
(1) diastereomeric salt is soluble in water, add alkali, adjust pH >=8, below adopting, in two kinds for the treatment of processs, any one can obtain:
A) adopt organic solvent extraction, remove under reduced pressure by solid drying after organic solvent, (R)-(+)-1-naphthalene ethylamine, acid adding water transfer layer, to strongly-acid, filters, the main resolving agent that drying is recycled and help resolving agent;
B) continue to stir, separate out solid, filter, filtration cakes torrefaction, (R)-(+)-1-naphthalene ethylamine, acid adding adjusts filtrate to strongly-acid, filters, the main resolving agent that drying is recycled and help resolving agent;
(2) diastereomeric salt is soluble in water, acid adding is adjusted to strongly-acid, filters, and reclaim main resolving agent after drying and help resolving agent, filtrate being added alkali and is adjusted to pH >=8, below adopting, in two kinds for the treatment of processs, any one can obtain:
A) adopt organic solvent extraction, remove under reduced pressure by solid drying after organic solvent, (R)-(+)-1-naphthalene ethylamine;
B) continue to stir, separate out solid, filter, filtration cakes torrefaction, obtain (R)-(+)-1-naphthalene ethylamine.
6. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 1, it is characterized in that, the method for Split Method preparation (R)-(+)-1-naphthalene ethylamine of the present invention is further comprising the steps of:
(3) filtrate step (1) obtained obtains (S)-(-)-1-naphthalene ethylamine after dissociating.
7. the method for a kind of Split Method preparation (R)-(+)-1-naphthalene ethylamine according to claim 6, it is characterized in that, the method for Split Method preparation (R)-(+)-1-naphthalene ethylamine of the present invention is further comprising the steps of:
(4) (S)-(-)-1-naphthalene ethylamine obtained step (3) carries out racemization Posterior circle and applies mechanically.
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| JPS61260044A (en) * | 1985-05-13 | 1986-11-18 | Nippon Chemiphar Co Ltd | Optical resolution of (+-)-1-(2-naphthyl)ethylamine |
| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
| CN101407465A (en) * | 2007-10-12 | 2009-04-15 | 天津药明康德新药开发有限公司 | Method for preparing optical pure 1-(1-naphthyl)ethylamine by separation |
| CN101735070A (en) * | 2009-12-17 | 2010-06-16 | 华东理工大学 | Resolution method of R-(+)-1-(1-naphthyl) ethylamine |
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| JPS61260044A (en) * | 1985-05-13 | 1986-11-18 | Nippon Chemiphar Co Ltd | Optical resolution of (+-)-1-(2-naphthyl)ethylamine |
| CN1182068A (en) * | 1996-10-23 | 1998-05-20 | Dsm有限公司 | Process for separation of mixture of enantiomers |
| CN101407465A (en) * | 2007-10-12 | 2009-04-15 | 天津药明康德新药开发有限公司 | Method for preparing optical pure 1-(1-naphthyl)ethylamine by separation |
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