CN101735070A - Resolution method of R-(+)-1-(1-naphthyl) ethylamine - Google Patents
Resolution method of R-(+)-1-(1-naphthyl) ethylamine Download PDFInfo
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- CN101735070A CN101735070A CN200910201301A CN200910201301A CN101735070A CN 101735070 A CN101735070 A CN 101735070A CN 200910201301 A CN200910201301 A CN 200910201301A CN 200910201301 A CN200910201301 A CN 200910201301A CN 101735070 A CN101735070 A CN 101735070A
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- racemization
- naphthalene
- ethamine
- tartrate
- alkali
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Abstract
The invention discloses a resolution method of R-(+)-1-(1-naphthyl) ethylamine, comprising the following steps of: reacting racemate 1-(1-naphthyl) ethylamine with the D-(-)-tartaric acid at room temperature or under a heating condition by using D-(-)-tartaric acid as a chiral resolving agent and a solution of alcohol and water as a solvent so as to generate enantiomer salt; then separating R-(+)-1-(1-naphthyl) ethylamine.D-(-)-tartrate out according to the different solubility of the enantiomer salt in the R-(+)-1-(1-naphthyl) ethylamine; then obtaining the R-(+)-1-(1-naphthyl) ethylamine through alkalization and dissociation, wherein an e.e. value can be achieved more than 95 percent, yield coefficient can be achieved by 30 percent, and a resolved mother solution can be converted into the racemate 1-(1-naphthyl) ethylamine through racemization and be resolved again. The resolution method has low cost and easy obtaining of raw materials, easy and convenient process operation and low cost; and in addition, the resolved mother solution can be resolved again through the racemization.
Description
Technical field
The present invention relates to a kind of method for preparing optical purity R-(+)-1-(1-naphthalene) ethamine.
Background technology
Optical purity R-(+)-1-(1-naphthalene) ethamine is a kind of pharmaceutical intermediate, can be used for preparing the responsive agonist cinacalcet of II type calcium.Its preparation method generally has following several: (1) enzyme splits (Synthesis.2008,14,2283-2287; IndianJ.Chem.Sect.B 2005,44,1312-1316; J.Org.Chem.1997,62,3488-3495); (2) chemistry splits, and the resolving agent of bibliographical information has: chirality aspartic acid (CN101407465A), chirality Alpha-hydroxy naphthylacetic acid (US6342636; Tetrahedron:asymmetry, 1998,9,2219-2212), the protection chirality glyceryl alcohol derivative (Tetrahedron:asymmetry, 1996,7,1117-1122; Tetrahedron:asymmetry, 2002,13,2277-2282), chirality tartrate (WO2004110976); (3) asymmetric synthesis: obtain (WO2004110976 through asymmetric synthesis by 1-(1-naphthalene) ethyl ketone; J.Org.Chem.1992,57,1237-1241).
In existing report, enzyme splits, asymmetric synthesis method cost is higher, and resolving agent prices such as aspartic acid, chirality Alpha-hydroxy naphthylacetic acid are more expensive.Mentioned among the WO2004110976 with L-(+)-tartrate fractionation and obtained S-(-)-1-(1-naphthalene) ethamine, but do not relate to concrete technological process.The present invention splits raceme 1-(1-naphthalene) ethamine with D-(-)-tartrate on this basis.
Summary of the invention
The present invention has overcome above-mentioned weak point, and a kind of lower-cost R-(+)-1-(1-naphthalene) is provided the method for splitting of ethamine.
Technical scheme of the present invention: do the chiral separation agent with D-(-)-tartrate, make solvent with the alcohol and the solution of water, (1-naphthalene) the ethamine raceme of 1-under room temperature or heating state and D-(-)-tartrate effect form enantiomer salt.Then, the difference separation according to its enantiomer salt solubility obtains R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate, free R-(+)-1-(1-naphthalene) ethamine that obtains of process alkalization.Mother liquor after the fractionation can be converted into raceme 1-(1-naphthalene) ethamine through racemization, is used for splitting again.Technical process is as follows:
In resolution process process of the present invention, with racemize 1-(1-naphthalene) ethamine as raw material, do the chiral separation agent with D-(-)-tartrate, make solvent, raceme 1-(1-naphthalene) ethamine is split according to the difference of its enantiomer salt solubility with the alcohol and the solution of water.During fractionation, earlier D-(-)-tartrate and racemize 1-(1-naphthalene) ethamine are dissolved in mixed solution pure and water under heating state, through overcooling, crystallization filters, and obtains R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate.Then, through alkalization, extract, drying concentrates and makes R-(+)-1-(1-naphthalene) ethamine.The fractionation mother liquor of front filtration gained obtains being rich in 1-(1-naphthalene) ethamine of S type after alkalizing, extract, concentrating, then this unhindered amina is dissolved in certain solvent, adds acid or alkali and heats racemization, gets racemic 1-(1-naphthalene) ethamine, is used for splitting again.
Wherein, the mol ratio of D-(-)-tartrate and raceme 1-(1-naphthalene) ethamine is 1: 1.0～1.2; Used resolution solvent is C
1～C
3The mixed solvent of lower alcohol (as methyl alcohol, ethanol, propyl alcohol, Virahol) and water, the alcohol in the mixed solvent and the volume ratio of water are 1: 3～10: 1; In split process, temperature is the boiling temperature of room temperature to reaction solvent, is preferably 40～90 ℃; Reaction times is 0.5～12 hour, is preferably 3～5 hours.
In the free process of alkalization, the free used alkali of alkalization is alkali-metal oxyhydroxide (as sodium hydroxide, potassium hydroxide), alkali-metal carbonate (as yellow soda ash, salt of wormwood), alkali-metal supercarbonate (as sodium bicarbonate, saleratus), its consumption are the 1.0-5 molar equivalent of R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate;
Splitting the back mother liquor can reclaim by racemization under acid or alkali effect.Wherein, used acid can be hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoracetic acid etc.Treat that the amine of racemization and the mol ratio of acid are 1: 1～20.Used alkali can be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood etc.Treat that the amine of racemization and the mol ratio of alkali are 1: 1～5.The racemization temperature is 30～150 ℃; Reaction times is 1～30 hour.The used solvent of racemization can be methyl alcohol, ethanol, Virahol, DMF, DMSO etc.
The invention has the beneficial effects as follows: the invention provides a kind of easy, effective circulate method of resolving racemic 1-(1-naphthalene) ethamine, method for splitting is simple to operation, and cost is low, and the e.e. value can reach more than 95%, and resolution yield reaches 30%.Mother liquor after the fractionation can be converted into racemize 1-(1-naphthalene) ethamine through racemization, is used for splitting again.
Embodiment:
The present invention will further explain in following examples.Yet, should not think that the present invention is limited by it.Those of ordinary skills should understand how to change cited synthetic method to obtain required result.
Specific embodiment 1:
(3.75g 25mmol) with 10ml water, is heated to 55 ℃ while stirring, and D-(-)-tartrate dissolves fully to add D-(-)-tartrate in the 100ml there-necked flask.In 1 hour, drip 1-(1-naphthalene) ethamine (4.28g, 25mmol) and the mixing solutions of 40ml methyl alcohol.After dripping end, continue insulation 3 hours.Being cooled to 30 ℃ stirred 1 hour.Suction filtration reclaims filtrate.Filter cake 5ml methanol wash gets white solid R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate 2.57g, yield: 32% after the drying.m.p.：185.5-185.7℃。
Specific embodiment 2:
(3.75g 25mmol) with 10ml water, is heated to 60 ℃ while stirring, and D-(-)-tartrate dissolves fully to add D-(-)-tartrate in the 100ml there-necked flask.(4.28g is 25mmol) with 50ml alcoholic acid mixing solutions to drip 1-(1-naphthalene) ethamine in 1 hour.After dripping end, continue insulation 3 hours.Being cooled to 40 ℃ stirred 1 hour.Suction filtration reclaims filtrate.Filter cake 5ml washing with alcohol gets white solid R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate 2.81g, yield: 35% after the drying.m.p.：185.3-185.5℃。
Specific embodiment 3:
In the 100ml there-necked flask, add R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate 2.57g that makes by embodiment 1 under the room temperature, add 10ml water, 20ml CH
2Cl
2Under agitation, drip the NaOH aqueous solution and regulate pH value to 11.Extracting and separating goes out organic layer, uses CH again
2Cl
2(20ml * 2) aqueous layer extracted merges organic layer.Anhydrous magnesium sulfate drying, CH is removed in decompression
2Cl
2Get light yellow oily product R-(+)-1-(1-naphthalene) ethamine, yield 97.0%, optically-active [α]
D+ 62 ° (C=0.4, methyl alcohol), e.e. value 96%.
Specific embodiment 4:
Be dissolved in 30ml water after the mother liquor removal of solvent under reduced pressure with embodiment 1.Add 30ml CH
2Cl
2, under agitation, regulate pH value to 12 with NaOH solution.Extracting and separating goes out organic layer, and CH is removed in decompression
2Cl
2Get oily matter 2.9g.The DMSO of adding 30ml and potassium hydroxide (2.3g, 40mmol).Reaction solution is heated to 100 ℃ of reactions 5 hours, is cooled to room temperature, adds water 30ml, with methyl tertiary butyl ether (30ml * 3) extraction, isolate organic layer, the organic phase anhydrous magnesium sulfate drying, decompression is removed methyl tertiary butyl ether and is got oily matter 2.59g, the racemization rate of recovery: 89%, and optically-active [α]
D=0 ° (C=0.4, methyl alcohol).
Specific embodiment 5:
Be dissolved in 30ml water after the mother liquor removal of solvent under reduced pressure with embodiment 2.Add 30ml CH
2Cl
2, under agitation, regulate pH value to 12 with NaOH solution.Extracting and separating goes out organic layer, and CH is removed in decompression
2Cl
2Get oily matter 2.78g.Add 3mL ethanol, 20ml concentrated hydrochloric acid, heating reflux reaction 5 hours, be cooled to room temperature, regulate pH value to 8～9 with NaOH solution,, isolate organic layer with methyl tertiary butyl ether (30ml * 3) extraction, the organic phase anhydrous magnesium sulfate drying, decompression is removed methyl tertiary butyl ether and is got oily matter 2.42g, the racemization rate of recovery: 87%, and optically-active [α]
D=0 ° (C=0.4, methyl alcohol).
Claims (10)
1. a circulation splits the method for preparing R-(+)-1-(1-naphthalene) ethamine, it is characterized in that: with D-(-)-tartrate is resolving agent, make solvent with the alcohol and the solution of water, (1-naphthalene) ethamine of raceme 1-under room temperature or heating state and D-(-)-tartrate effect form enantiomer salt.Then,, separate obtaining R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate, through free R-(+)-1-(1-naphthalene) ethamine (structural formula I) that obtains of alkalization according to the difference of its enantiomer salt solubility.Split the back mother liquor through the racemization recycling.
Structural formula I
2. according to claim 1, it is characterized in that the mol ratio of D-(-)-tartrate and raceme 1-(1-naphthalene) ethamine is 1: 1.0～1.2.
3. according to claim 1, it is characterized in that in the split process that resolution solvent is C
1～C
3The mixed solvent of lower alcohol (as methyl alcohol, ethanol, propyl alcohol, Virahol) and water, the alcohol in the mixed solvent and the volume ratio of water are 1: 3～10: 1.
4. according to claim 1, it is characterized in that in the split process that temperature is the boiling temperature of room temperature to reaction solvent, be preferably 40～90 ℃; Reaction times is 0.5～12 hour, is preferably 3～5 hours.
5. according to claim 1, it is characterized in that alkalizing in the free process, the free used alkali of alkalization is alkali-metal oxyhydroxide (as sodium hydroxide, potassium hydroxide), alkali-metal carbonate (as yellow soda ash, salt of wormwood), alkali-metal supercarbonate (as sodium bicarbonate, saleratus).Its consumption is 1.0～5 molar equivalents of R-(+)-1-(1-naphthalene) ethamine D-(-)-tartrate;
6. according to claim 1, it is characterized in that splitting the back mother liquor can reclaim by racemization.
7. according to claim 6, it is characterized in that racemization carries out under acid or alkali effect.
8. according to claim 7, it is characterized in that in the racemization that used acid can be hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, trifluoracetic acid etc.Wherein, treat that the amine of racemization and the mol ratio of acid are 1: 1～20.Used alkali can be sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood etc.Wherein, treat that the amine of racemization and the mol ratio of alkali are 1: 1～5.
9. according to claim 7, it is characterized in that in the racemization that used solvent can be methyl alcohol, ethanol, Virahol, DMF, DMSO etc.
10. according to claim 7, it is characterized in that in the racemization that temperature of reaction is 30～150 ℃; Reaction times is 1～30 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420845A (en) * | 2013-08-21 | 2013-12-04 | 中国药科大学 | Method for preparing cinacalcet intermediate R-(+)-1-(1-naphthyl)ethamine |
| CN104829459A (en) * | 2015-05-06 | 2015-08-12 | 河北凯力昂生物科技有限公司 | Splitting method for preparing (R)-(+)-1-naphthyl ethylamine |
| CN105294449A (en) * | 2014-06-16 | 2016-02-03 | 连云港手性化学有限公司 | Preparation method for (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(-)-1-(1-naphthyl)ethylamine |
-
2009
- 2009-12-17 CN CN200910201301A patent/CN101735070A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420845A (en) * | 2013-08-21 | 2013-12-04 | 中国药科大学 | Method for preparing cinacalcet intermediate R-(+)-1-(1-naphthyl)ethamine |
| CN103420845B (en) * | 2013-08-21 | 2015-09-02 | 中国药科大学 | One prepares the method for cinacalcet intermediate R-(+)-1-(1-naphthyl) ethamine |
| CN105294449A (en) * | 2014-06-16 | 2016-02-03 | 连云港手性化学有限公司 | Preparation method for (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(-)-1-(1-naphthyl)ethylamine |
| CN105294449B (en) * | 2014-06-16 | 2017-02-08 | 连云港手性化学有限公司 | Preparation method for (R)-(+)-1-(1-naphthyl)ethylamine and (S)-(-)-1-(1-naphthyl)ethylamine |
| CN104829459A (en) * | 2015-05-06 | 2015-08-12 | 河北凯力昂生物科技有限公司 | Splitting method for preparing (R)-(+)-1-naphthyl ethylamine |
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Application publication date: 20100616 |