CN105254513A - Resolution method of (S)-3-[1-(dimethylamino) ethyl] phenol (III) - Google Patents
Resolution method of (S)-3-[1-(dimethylamino) ethyl] phenol (III) Download PDFInfo
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- CN105254513A CN105254513A CN201510728607.6A CN201510728607A CN105254513A CN 105254513 A CN105254513 A CN 105254513A CN 201510728607 A CN201510728607 A CN 201510728607A CN 105254513 A CN105254513 A CN 105254513A
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Abstract
The invention provides a resolution method of (S)-3-[1-(dimethylamino) ethyl] phenol (III). The resolution method comprises the steps of enabling a certain ratio of the (S)-3-[1-(dimethylamino) ethyl] phenol (II) and 2-naphthyl phosphate (I) to take a crystallization reaction in an organic solvent for at least 8 hours at the temperature of 0 to 80 DEG C under normal pressure, performing suction filtration on reaction liquid to obtain a filter cake, performing a salt removing reaction on the filter cake in an alkaline solution at the temperature of 0 to 100 DEG C, so as to obtain the (S)-3-[1-(dimethylamino) ethyl] phenol (III). The (S)-3-[1-(dimethylamino) ethyl] phenol (III) prepared through the resolution method of the (S)-3-[1-(dimethylamino) ethyl] phenol (III), disclosed by the invention is good in optical activity, high in yield, simple to operate and easy to produce on industrial scale.
Description
Technical field
The present invention relates to medicinal chemistry art, particularly relate to the method for splitting of intermediate (S)-3-[1-(dimethylamino) ethyl] phenol (III) of hypoglycemic drug rivastigmine.
Background technology
Rivastigmine-hydrogentartrate (IV), chemical formula is as follows:
Rivastigmine-hydrogentartrate (IV) is the anti-senile dementia medicine researched and developed by Novartis, Switzerland, have another name called Exelon, it is a kind of Reversible cholinesterase inhibitor of amino formate, belong to the medicine that the third generation improves choline system function, it, except except acetylcholine esterase inhibition, also can suppressing butyrylcholine esterase, plays double inhibition effect, determined curative effect is stablized, and within 1997, goes on the market in Switzerland.In June, 2000, national drug food Surveillance Authority of China official approval rivastigmine-hydrogentartrate (IV) enters Chinese market.
(S)-3-[1-(dimethylamino) ethyl] phenol (III) is by the key intermediate of antidiabetic drug rivastigmine-hydrogentartrate.In the prior art, usually use (S)-(+)-camphor-10-sulfonic acid as resolving agent.But the product obtaining optical activity qualified exists recrystallization phenomenon, and there is complex operation, cost is high, the rate of recovery is lower problem, be unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to the method for splitting disclosing a kind of (S)-3-[1-(dimethylamino) ethyl] phenol (II), in order to reduce recrystallization phenomenon, realize high-recovery and realize suitability for industrialized production.
For achieving the above object, the invention provides the method for splitting of (S)-3-[1-(dimethylamino) ethyl] phenol (III), comprise: by a certain proportion of (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) under the condition of 0 DEG C-80 DEG C in organic solvent, carry out crystallization reaction at ambient pressure after at least 8 hours, reaction solution suction filtration is obtained filter cake, then filter cake is carried out solution reactant salt under the condition of 0 DEG C-100 DEG C in alkaline solution, to obtain (S)-3-[1-(dimethylamino) ethyl] phenol (III).
Further, organic solvent comprises: the mixture of a kind of or two or more arbitrary proportion in ethanol, methyl alcohol, methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF).
Further, organic solvent is ethanol.
Further, the weight ratio of (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) is 1:10-10:1.
Further, the weight ratio of (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) is 2:1.
Further, crystallization reaction temperature is 30 DEG C-40 DEG C.
Further, the solute in alkaline solution comprises: sodium hydroxide, potassium hydroxide, triethylamine, sodium methylate, sodium ethylate.
Further, the solute in alkaline solution is sodium hydroxide.
Further, the solvent in alkaline solution comprises: water, ethanol, methyl alcohol, tetrahydrofuran (THF), dioxane, chloroform, methylene dichloride.
Further, separating reactant salt temperature is 0 DEG C-5 DEG C.
Compared with prior art, the invention has the beneficial effects as follows: the optical activity of method for splitting preparation-obtained (S)-3-[1-(dimethylamino) ethyl] phenol (III) of disclosed (S)-3-[1-(dimethylamino) ethyl] phenol (III) is good, productive rate is high, simple to operate, be easy to suitability for industrialized production.
Embodiment
Below in conjunction with each embodiment, the present invention is described in detail; but should be noted that; these embodiments are not limitation of the present invention; those of ordinary skill in the art are according to these embodiment institute work energy, method or structural equivalent transformations or substitute, and all belong within protection scope of the present invention.
embodiment one:
Dehydrated alcohol 15kg is added in (S) 3-[1-(dimethylamino) ethyl] phenol (II) 6.00kg, 35 DEG C of stirring and dissolving, after reaction solution all dissolves, slowly drip the mixing solutions that bisnapthylphosphoricacid acid (I) 8.86kg and dehydrated alcohol 9.00kg forms again, in whipping appts, carry out mechanical stirring.In whipping process, constantly have solid to separate out, this solid is (S)-3-[1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt.After reaction 8h, by reaction solution suction filtration, obtain wet product 12.00kg.
Getting (the S)-3-after 10kg cryodrying [1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt dissolves in the water of 240kg, be positioned over whipping appts again and carry out mechanical stirring, be cooled to 5 DEG C, drip the sodium hydroxide solution 12L that concentration is 0.1%.Keep temperature not higher than 5 DEG C in the dropping process of sodium hydroxide solution, after dropwising, after it's 12 hours pasts insulated and stirred, a large amount of solid is separated out, and by reaction solution suction filtration, obtains wet product 4.7kg.Wet product is positioned over the dry finished product 2.5kg obtaining (S)-3-[1-(dimethylamino) ethyl] phenol (III) in room temperature in vacuo loft drier, and the optical purity of finished product is 98.76%.
embodiment two:
Dehydrated alcohol 13kg is added in (S) 3-[1-(dimethylamino) ethyl] phenol (II) 5.00kg, 30 DEG C of stirring and dissolving, after reaction solution all dissolves, slowly drip the mixing solutions that bisnapthylphosphoricacid acid (I) 7.47kg and dehydrated alcohol 8.00kg forms again, in whipping appts, carry out mechanical stirring.In whipping process, constantly have solid to separate out, this solid is (S)-3-[1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt.After reaction 8h, by reaction solution suction filtration, obtain wet product 10.87kg.
Getting (the S)-3-after 10kg cryodrying [1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt dissolves in the water of 240kg, be positioned over whipping appts again and carry out mechanical stirring, be cooled to 0 DEG C, drip the sodium hydroxide solution 10L that concentration is 0.2%.Keep temperature not higher than 5 DEG C in the dropping process of sodium hydroxide solution, after dropwising, after it's 12 hours pasts insulated and stirred, a large amount of solid is separated out, and by reaction solution suction filtration, obtains wet product 4.7kg.Wet product is positioned over the dry finished product 2.4kg obtaining (S)-3-[1-(dimethylamino) ethyl] phenol (III) in room temperature in vacuo loft drier, and the optical purity of finished product is 98.24%.
embodiment three:
Dehydrated alcohol 15kg is added in (S) 3-[1-(dimethylamino) ethyl] phenol (II) 7.00kg, 40 DEG C of stirring and dissolving, after reaction solution all dissolves, slowly drip the mixing solutions that bisnapthylphosphoricacid acid (I) 8.41kg and dehydrated alcohol 10.00kg forms again, in whipping appts, carry out mechanical stirring.In whipping process, constantly have solid to separate out, this solid is (S)-3-[1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt.After reaction 8h, by reaction solution suction filtration, obtain wet product 12.00kg.
Getting (the S)-3-after 10kg cryodrying [1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt dissolves in the water of 240kg, be positioned over whipping appts again and carry out mechanical stirring, be cooled to 2 DEG C, drip the sodium hydroxide solution 13L that concentration is 0.15%.Keep temperature not higher than 5 DEG C in the dropping process of sodium hydroxide solution, after dropwising, after it's 12 hours pasts insulated and stirred, a large amount of solid is separated out, and by reaction solution suction filtration, obtains wet product 4.5kg.Wet product is positioned over the dry finished product 2.6kg obtaining (S)-3-[1-(dimethylamino) ethyl] phenol (III) in room temperature in vacuo loft drier, and the optical purity of finished product is 98.81%.
embodiment four:
Dehydrated alcohol 16kg is added in (S) 3-[1-(dimethylamino) ethyl] phenol (II) 6.5kg, 32 DEG C of stirring and dissolving, after reaction solution all dissolves, slowly drip the mixing solutions that bisnapthylphosphoricacid acid (I) 8.45kg and dehydrated alcohol 9.50kg forms again, in whipping appts, carry out mechanical stirring.In whipping process, constantly have solid to separate out, this solid is (S)-3-[1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt.After reaction 8h, by reaction solution suction filtration, obtain wet product 11.50kg.
Getting (the S)-3-after 10kg cryodrying [1-(dimethylamino) ethyl] phenol bisnapthylphosphoricacid acid salt dissolves in the water of 240kg, be positioned over whipping appts again and carry out mechanical stirring, be cooled to 4 DEG C, drip the sodium hydroxide solution 15L that concentration is 0.1%.Keep temperature not higher than 5 DEG C in the dropping process of sodium hydroxide solution, after dropwising, after it's 12 hours pasts insulated and stirred, a large amount of solid is separated out, and by reaction solution suction filtration, obtains wet product 4.61kg.Wet product is positioned over the dry finished product 2.55kg obtaining (S)-3-[1-(dimethylamino) ethyl] phenol (III) in room temperature in vacuo loft drier, and the optical purity of finished product is 98.08%.
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and when not deviating from spirit of the present invention or essential characteristic, the present invention can be realized in other specific forms.Therefore, no matter from which point, all should embodiment be regarded as exemplary, and be nonrestrictive, scope of the present invention is limited by claims instead of above-mentioned explanation, and all changes be therefore intended in the implication of the equivalency by dropping on claim and scope are included in the present invention.
In addition, be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, and the technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
Claims (10)
1. the method for splitting of (S)-3-[1-(dimethylamino) ethyl] phenol (III), it is characterized in that, comprise: by a certain proportion of (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) under the condition of 0 DEG C-80 DEG C in organic solvent, carry out crystallization reaction at ambient pressure after at least 8 hours, reaction solution suction filtration is obtained filter cake, then filter cake is carried out solution reactant salt under the condition of 0 DEG C-100 DEG C in alkaline solution, to obtain (S)-3-[1-(dimethylamino) ethyl] phenol (III).
2. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, described organic solvent comprises: the mixture of a kind of or two or more arbitrary proportion in ethanol, methyl alcohol, methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF).
3. the method for splitting of (S)-3-according to claim 2 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, described organic solvent is ethanol.
4. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, the weight ratio of described (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) is 1:10-10:1.
5. the method for splitting of (S)-3-according to claim 4 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, the weight ratio of described (S) 3-[1-(dimethylamino) ethyl] phenol (II) and bisnapthylphosphoricacid acid (I) is 2:1.
6. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, described crystallization reaction temperature is 30 DEG C-40 DEG C.
7. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, the solute in described alkaline solution comprises: sodium hydroxide, potassium hydroxide, triethylamine, sodium methylate, sodium ethylate.
8. the method for splitting of a kind of new 3-according to claim 7 [1-(dimethylamino) ethyl] phenol, it is characterized in that, the solute in described alkaline solution is sodium hydroxide.
9. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), it is characterized in that, the solvent in described alkaline solution comprises: water, ethanol, methyl alcohol, tetrahydrofuran (THF), dioxane, chloroform, methylene dichloride.
10. the method for splitting of (S)-3-according to claim 1 [1-(dimethylamino) ethyl] phenol (III), is characterized in that, described solution reactant salt temperature is 0 DEG C-5 DEG C.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005061446A2 (en) * | 2003-12-24 | 2005-07-07 | Generics [Uk] Limited | Processes for the preparation of aminoalkyl phenylcarbamates |
| EP1556338A1 (en) * | 2002-10-24 | 2005-07-27 | Zentiva, A.S. | A METHOD OF PRODUCTION OF (-)-(S)-3- 1-(DIMETHYLAMINO)ETHYL& rsqb;PHENYL-N-ETHYL-N-METHYLCARBAMATE |
| CN101016257A (en) * | 2007-02-14 | 2007-08-15 | 杭州盛美医药科技开发有限公司 | Intermediate of rivastigmine, preparation and application thereof |
| CN101270058A (en) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | Process for preparing 3-(1-dimethylamino- ethyl)phynol |
| CN101580482A (en) * | 2009-05-27 | 2009-11-18 | 沈阳药科大学 | Method for preparing rivastigmine hydrogen tartrate and application thereof |
-
2015
- 2015-10-29 CN CN201510728607.6A patent/CN105254513A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1556338A1 (en) * | 2002-10-24 | 2005-07-27 | Zentiva, A.S. | A METHOD OF PRODUCTION OF (-)-(S)-3- 1-(DIMETHYLAMINO)ETHYL& rsqb;PHENYL-N-ETHYL-N-METHYLCARBAMATE |
| WO2005061446A2 (en) * | 2003-12-24 | 2005-07-07 | Generics [Uk] Limited | Processes for the preparation of aminoalkyl phenylcarbamates |
| WO2005061446A3 (en) * | 2003-12-24 | 2006-01-05 | Generics Uk Ltd | Processes for the preparation of aminoalkyl phenylcarbamates |
| CN101016257A (en) * | 2007-02-14 | 2007-08-15 | 杭州盛美医药科技开发有限公司 | Intermediate of rivastigmine, preparation and application thereof |
| CN101270058A (en) * | 2007-03-21 | 2008-09-24 | 北京德众万全药物技术开发有限公司 | Process for preparing 3-(1-dimethylamino- ethyl)phynol |
| CN101580482A (en) * | 2009-05-27 | 2009-11-18 | 沈阳药科大学 | Method for preparing rivastigmine hydrogen tartrate and application thereof |
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Application publication date: 20160120 |