CN101343236A - Split method for (S)3-hydroxyl-alpha-N, N-dimethyl phenylethylamine - Google Patents
Split method for (S)3-hydroxyl-alpha-N, N-dimethyl phenylethylamine Download PDFInfo
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- CN101343236A CN101343236A CNA2007100436364A CN200710043636A CN101343236A CN 101343236 A CN101343236 A CN 101343236A CN A2007100436364 A CNA2007100436364 A CN A2007100436364A CN 200710043636 A CN200710043636 A CN 200710043636A CN 101343236 A CN101343236 A CN 101343236A
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- phenpromethamine
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Abstract
The invention relates to a resolution method of an intermediate-(S)3-oxhydryl-Alpha-N, N-phenpromethamine of rivastigmine. The method takes racemic 3-oxhydryl-Alpha-N, N-phenpromethamine as a raw material, D-camphor sulfonic acid as a resolving agent, and acquires the D-camphorsulfonate of (S)3-oxhydryl-Alpha-N, N-phenpromethamine in a solvent system with the volume ratio range of: ethanol: toluene=1: 3-10, then the acquired salt is dissociated and crystallized in an aqueous solution by a dilute alkali solution for obtaining the (S) 3-oxhydryl-Alpha-N, N-phenpromethamine. The method has advantages of simplicity and convenience, economy and high product purity, and is applied to the industrialized production.
Description
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to a kind of profit and cut down the 3-hydroxyl-α-N of this bright intermediate-(S), the method for splitting of N-phenpromethamine.
Background technology
Formula I compound is optically active (S) 3-hydroxyl-α-N, the N-phenpromethamine, it is the bright key intermediate that the anti senile dementia drug profit is cut down this, existing its synthetic method of bibliographical information is to be starting raw material with the meta-methoxy methyl phenyl ketone, obtain 3-hydroxyl-α-N by reduction amination, demethylation, the N-phenpromethamine is a resolving agent with the D-camphorsulfonic acid then, splits to obtain Compound I in the ethanol-ethyl acetate system.It is resolving agent that WO 2004/037771 discloses with S-(+)-camphor-10-sulfonic acid in detail, in the ethanol-ethyl acetate system to racemize 3-hydroxyl-α-N, the method that N-phenpromethamine (Compound I I) splits, its operational path as shown in the formula:
The shortcoming of this method is to use earlier the dissolve with ethanol camphorsulfonic acid, add ethyl acetate then towards separating out crystallization, cause solvent to apply mechanically, cost is very high, and (S) isomer and the D-camphorsulfonic acid purity salt that are obtained are lower, must just make the ratio of R isomer reach below 0.4% through three recrystallizations.Need in the dissociation process of this external (S) isomer and D-camsilate to adopt methylene chloride to extract, separate to concentrate obtaining product Compound I, this method complex operation in scale operation, cost height, poor practicability then.
Summary of the invention
Technical problem to be solved by this invention is on the basis of WO 2004/037771, to adopting D-camphorsulfonic acid resolution of racemic 3-hydroxyl-α-N, the method of N-phenpromethamine is improved, provide a kind of convenient, economical, be applicable to (S) 3-hydroxyl-α-N of suitability for industrialized production, the method for splitting of N-phenpromethamine.
(S) disclosed by the invention 3-hydroxyl-α-N, the method for splitting of N-phenpromethamine is: with racemize 3-hydroxyl-α-N, the N-phenpromethamine is a raw material, the D-camphorsulfonic acid is a resolving agent, obtains (S) 3-hydroxyl-α-N, the D-camsilate of N-phenpromethamine in ethanol-toluene solvant system, then the salt that is obtained is dissociated with dilute alkaline soln in the aqueous solution, crystallization obtains (S) 3-hydroxyl-α-N, the N-phenpromethamine.
The volume ratio scope of used ethanol-toluene solvant system is an ethanol in the method for splitting of the present invention: toluene=1: 3-10, preferable range is 1: 3-8, the best is 1: 5.5.
The used dilute alkaline soln that dissociates in the inventive method is inorganic base aqueous solution commonly used, the aqueous solution as sodium hydroxide, potassium hydroxide, sodium bicarbonate or yellow soda ash etc., concentration is 5-15% (w/w), and the final pH value that dilute alkaline soln is regulated the solution that dissociates is controlled at 9.1-9.3, and the best is 9.2.
(S) 3-hydroxyl-α-N, the D-camsilate of N-phenpromethamine preferably continued to carry out recrystallization with the identical ethanol-toluene solvant of split system before dissociating, usually carry out twice recrystallization, can obtain highly purified (S) 3-hydroxyl-α-N after dissociating like this, the N-phenpromethamine.Detect through HPLC, with (S) 3-hydroxyl-α-N that method for splitting of the present invention obtains, N-phenpromethamine purity can reach more than 99%.
Another significant advantage of method for splitting of the present invention is that the solvent of split system can repeat recovery set and use, (S) 3-hydroxyl-α-N simultaneously, mother liquor behind the D-camsilate recrystallization of N-phenpromethamine can be directly used in and split or once more as the solvent of recrystallization, thereby the consumption of solvent is reduced greatly, also reduced manufacturing cost.
Preferred (S) 3-hydroxyl-α of the present invention-N, N-phenpromethamine method for splitting concrete steps comprise:
1, salify
With mol ratio is 1: 0.5-1 racemize 3-hydroxyl-α-N, N-phenpromethamine and D-camphorsulfonic acid add volume be racemize weight 6-10 doubly, volume ratio is 1: in 3-8 ethanol-toluene solvant system, heating for dissolving, be cooled to 5-6 ℃, filter, obtain (S) 3-hydroxyl-α-N, the D-camsilate crude product of N-phenpromethamine;
2, refining
The crude product volume ratio that step 1 is obtained is 1: twice of the ethanol of 3-8-toluene solution recrystallization;
3, dissociate
The elaboration that step 2 is obtained is dissolved in the 1.5-3 times of weight water, regulates pH to 9.1-9.3 with dilute alkaline soln, separates out crystallization, is cooled to 5-6 ℃, filters, and drying promptly gets (S) 3-hydroxyl-α-N, the N-phenpromethamine.
The present invention (S) 3-hydroxyl-α-N, N-phenpromethamine method for splitting has adopted new solvent systems, and salify and recrystallization all can fully dissolve crystallisation by cooling then by heating, make the efficient of purification higher, and solvent is convenient to reclaim use or directly apply mechanically; Got rid of loaded down with trivial details steps such as solvent extraction in the prior art dissociation process simultaneously, the salt that directly dissociates in the aqueous solution obtains highly purified (S) 3-hydroxyl-α-N, the N-phenpromethamine easily.Compare with WO 2004/037771 disclosed prior art, the inventive method is easier, economy, product purity height, and is suitable for suitability for industrialized production.
Below in conjunction with embodiment the present invention is further described.
Description of drawings
Fig. 1 raw material racemize 3-hydroxyl-α-N, the HPLC analytical results of N-phenpromethamine
(S) 3-hydroxyl-α-N that Fig. 2 embodiment 1 method obtains, the HPLC analytical results of N-phenpromethamine
Embodiment
16.5g (0.1mol) (R, S) 3-hydroxyl-α-N, N-phenpromethamine (mass analysis HPLC sees Fig. 1) and 16.2g (0.07mol) D-camphorsulfonic acid drop in the 250ml reaction flask, add 100ml toluene, 18ml ethanol, stir heating for dissolving, crystallisation by cooling, filter next day, drying, camsilate crude product 19g, mp:170～173 ℃.
The 19g crude product drops in the reaction flask, adds 105ml toluene, and 19ml ethanol stirs, and heating for dissolving is cooled to 5 ℃, filters win time highly finished product 16.5g mp176～178 ℃ of drying.
16.5g for the first time highly finished product are dissolved in 95ml toluene and the 17ml ethanol, the stirring heating dissolving is cooled to 5 ℃, filters, dry second time highly finished product 14.5g, mp:178～180 ℃.
14.5g highly finished product are dissolved in the 30ml water for the second time, drop to PH=9.2 with 10%NaOH, separate out crystallization, are cooled to 5～6 ℃ of insulation 1h, filter, and are drying to obtain (S) 3-hydroxyl-α-N, N-phenpromethamine 5.0g.Yield 30%, HPLC detection level 99.92% (see figure 2).
16.5g (0.1mol) (R, S) 3-hydroxyl-α-N, N-phenpromethamine and 16.2g (0.07mol) D-camphorsulfonic acid drops in the 250ml reaction flask, adds 110ml embodiment 1 refinement mother liquor (it is about 93% wherein to contain toluene, ethanol about 7%) and 10ml ethanol for the first time, stir, heating for dissolving, crystallisation by cooling, filter next day, camsilate crude product 20g, mp:170～173 ℃.
The 20g crude product drops in the reaction flask, adds 110ml embodiment 1 refinement mother liquor (it is about 93% wherein to contain toluene, ethanol about 7%) and 10ml ethanol for the second time, stirs, and heating for dissolving is cooled to 5 ℃, filters the drying inferior highly finished product of winning: 16.5g mp176～178 ℃.
16.5g for the first time highly finished product are dissolved in 83ml toluene and the 17ml ethanol, the stirring heating dissolving is cooled to 5 ℃, filters, dry second time highly finished product 15.5g, mp:178～180 ℃.
15.5g highly finished product are dissolved in the 30ml water for the second time, drop to PH=9.2 with 15%NaOH, separate out crystallization, are cooled to 5～6 ℃ of insulation 1h, filter, and are drying to obtain (S) 3-hydroxyl-α-N, N-phenpromethamine 5.5g.Yield 33%, HPLC detection level 99.96%.
16.5g (0.1mol) (R, S) 3-hydroxyl-α-N, N-phenpromethamine and 18.5g (0.08mol) D-camphorsulfonic acid drops in the 250ml reaction flask, adds 130ml toluene, 19ml ethanol, stir heating for dissolving, crystallisation by cooling, filter next day, drying, camsilate crude product 18.5g, mp:170～173 ℃.
18.5g crude product drops in the reaction flask, adds 112ml toluene, 16ml ethanol stirs, and heating for dissolving is cooled to 5 ℃, filters win time highly finished product 16.1gmp176～178 ℃ of drying.
16.1g for the first time highly finished product are dissolved in 98ml toluene and the 14ml ethanol, the stirring heating dissolving is cooled to 5 ℃, filters, dry second time highly finished product 14g, mp:178～180 ℃.
14g highly finished product for the second time is dissolved in the 30ml water, uses 10%Na
2CO
3Drop to PH=9.2, separate out crystallization, be cooled to 5～6 ℃ of insulation 1h, filter, be drying to obtain (S) 3-hydroxyl-α-N, N-phenpromethamine 4.6g.Yield 27.9%, HPLC detection level 99.9%.
Claims (5)
1, (S) 3-hydroxyl-α-N, the method for splitting of N-phenpromethamine, it is characterized in that this method is with racemize 3-hydroxyl-α-N, the N-phenpromethamine is a raw material, and the D-camphorsulfonic acid is a resolving agent, in the volume ratio scope is ethanol: toluene=1: obtain (S) 3-hydroxyl-α-N in the 3-10 solvent systems, the D-camsilate of N-phenpromethamine dissociates the salt that is obtained crystallization then with dilute alkaline soln in the aqueous solution, obtain (S) 3-hydroxyl-α-N, the N-phenpromethamine.
2, method for splitting according to claim 1 is characterized in that this method comprises the following steps:
1) salify
With mol ratio is 1: 0.5-1 racemize 3-hydroxyl-α-N, N-phenpromethamine and D-camphorsulfonic acid add volume be racemize weight 6-10 doubly, volume ratio is 1: in 3-10 ethanol-toluene solvant system, heating for dissolving, be cooled to 5-6 ℃, filter, obtain (S) 3-hydroxyl-α-N, the D-camsilate crude product of N-phenpromethamine;
2) refining
The crude product volume ratio that step 1 is obtained is 1: twice of the ethanol of 3-10-toluene solution recrystallization;
3) dissociate
The elaboration that step 2 is obtained is dissolved in the 1.5-3 times of weight water, regulates pH to 9.1-9.3 with dilute alkaline soln, separates out crystallization, is cooled to 5-6 ℃, filters, and drying promptly gets (S) 3-hydroxyl-α-N, the N-phenpromethamine.
3, method for splitting according to claim 1 and 2, the volume ratio that it is characterized in that ethanol-toluene in wherein said ethanol-toluene solution is 1: 3-8.
4, method for splitting according to claim 2 is characterized in that wherein said dilute alkaline soln is that concentration is the aqueous solution of sodium hydroxide, potassium hydroxide, sodium bicarbonate or the yellow soda ash of 5-15%w/w.
5, method for splitting according to claim 2 is characterized in that wherein said dilute alkaline soln adjusting pH to 9.2.
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| CNA2007100436364A CN101343236A (en) | 2007-07-10 | 2007-07-10 | Split method for (S)3-hydroxyl-alpha-N, N-dimethyl phenylethylamine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070469A (en) * | 2010-12-31 | 2011-05-25 | 河北科技大学 | Resolution method for preparing optically pure metoprolol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102070469A (en) * | 2010-12-31 | 2011-05-25 | 河北科技大学 | Resolution method for preparing optically pure metoprolol |
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