CN101337903A - Method for preparing ethyl levodopa - Google Patents
Method for preparing ethyl levodopa Download PDFInfo
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- CN101337903A CN101337903A CN 200810073735 CN200810073735A CN101337903A CN 101337903 A CN101337903 A CN 101337903A CN 200810073735 CN200810073735 CN 200810073735 CN 200810073735 A CN200810073735 A CN 200810073735A CN 101337903 A CN101337903 A CN 101337903A
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Abstract
The invention relates to a method for preparing levodopa ethyl ester from the raw materials of levodopa and ethanol by adopting the multi-reaction distillation and dehydration method, the improved thionyl chloride method and the hydrogen chloride method. Through the multi-reaction distillation and dehydration method, water in the reactants and water generated by the esterification reaction are removed to promote the esterificaiton reaction to the end point. Then, water or alcohol solutions of different concentrations are adopted to dissolve the reactants, a proper amount of antioxidant is added, and an alkali is added for neutralization to obtain levodopa ethyl ester. The preparation method is simple and easy, and obviates the material drying procedure, improves the yield and shortens the purification operation time. The solvent is selected from water or the alcohol solvents with lower toxicity and has less contamination to the environment and lower cost. The method suits large-scale industrial production, and the prepared levodopa ethyl ester has a purity more than 99% and a yield more than 90%.
Description
Technical field:
The preparation method of medicinal L-Dopa ethyl ester, particularly a kind of purity is higher, and stability, non-hygroscopic, crystallinity be the synthetic and purifying process of L-Dopa ethyl ester preferably.
Background technology:
Effective medicine of Parkinsonism treatment is less, and the compound preparation of levodopa (Levodopa) and carbidopa or benserazide remains one of the most effective medicine.But the levodopa poorly soluble, absorb difficulty, have only 1% to enter maincenter and be converted into the Dopamine HCL onset, and some side effects are arranged.L-Dopa ethyl ester (LDEE) is one of important derivative of levodopa, and it is to be raw material with the levodopa, by the synthetic L-Dopa ethyl ester of single step reaction.L-Dopa ethyl ester has overcome the shortcoming of levodopa, easily enters hemato encephalic barrier, easily makes various oral dosage forms and injection, absorbs soon, and Plasma Concentration reached peak value in 7-8 minute, and curative effect obviously is better than levodopa.
The cat beans are the characteristic resources in Guangxi, the technology of the levodopa that extracts from the cat beans is increasingly mature, make Guangxi become the major production base of international levodopa, and " research of high purity levodopa high efficiency extraction gordian technique " successful implementation achievements conversion that the applicant has, product is found a good sale in European and American areas such as Canada, the U.S., Italy.Carry out research to the levodopa derivative, will be significant to the extension of cat beans industrial chain.
The synthetic method of L-Dopa ethyl ester hydrochloride is mainly by two kinds of methods: hydrogen chloride and sulfur oxychloride method.
The representative document of hydrogen chloride following (US6218566):
100 gram levodopas are dissolved in 500 milliliters of dehydrated alcohols, feed saturated hydrogen chloride gas (37.01g), reflux, react 3 hours must the L-Dopa ethyl ester hydrochloride.
The sulfur oxychloride method is represented literature method following (US5354885):
Add the 250ml dehydrated alcohol under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add the 50g levodopa then, temperature is controlled at 2～5 ℃, and 40 ℃ of following heating reflux reactions 16 hours concentrate, and obtain the L-Dopa ethyl ester hydrochloride.
These two kinds of method synthetic shortcomings are all drying and dehydratings in advance of ethanol, sulfur oxychloride or hydrogen chloride gas, and the moisture that esterification is produced is not removed, and reaction can not be carried through to the end, and productive rate is relatively low.
The L-Dopa ethyl ester hydrochloride is difficult to crystallization, thus only exist with amorphous solid, reach not medicinal requirements (Fix, et al, pharm, Research 6 (6): 501-505 (1989)).In order to reach medicinal requirements, L-Dopa ethyl ester must be higher with a kind of purity, and there be (Cooper, et al, ClinicalNeurophamocology7:88-89 (1984)) in stability, non-hygroscopic form preferably.
Recently United States Patent (USP) (patent No. US5354885) has reported that a kind of its key step of method for preparing crystallization, non-hygroscopic, L-Dopa ethyl ester is as follows: (1) levodopa and ethanol react generation L-Dopa ethyl ester hydrochloride under the effect of an acidic catalyst; (2) volatile matter is removed in vacuum distilling; (3) with the salt solution dilution distillation enriched material that contains oxidation inhibitor; (4) add alkali and transfer Ph6～7, get the L-Dopa ethyl ester crude product; (5) with the organic solvent that contains oxidation inhibitor L-Dopa ethyl ester is extracted from aqueous phase; (6) concentrating under reduced pressure organic phase solvent (temperature is lower than 40 ℃) gets the L-Dopa ethyl ester throw out; (7) with the solvent recrystallization throw out that contains oxidation inhibitor, get crystallization, non-hygroscopic L-Dopa ethyl ester.
United States Patent (USP) (patent No. US6218566) has also been reported a kind of method, and its key step is as follows: (1) levodopa and ethanol react under the effect of an acidic catalyst and generate the L-Dopa ethyl ester hydrochloride; (2) the part volatile matter is removed in vacuum distilling; (3) add an amount of water, toluene, oxidation inhibitor; (4) under the condition of special control, add alkali, get the L-Dopa ethyl ester throw out; (5) filter the collecting precipitation thing; (6) add methylbenzene azeotropic distillation dry sediment; (7) with solvent recrystallization (6) products therefrom that contains oxidation inhibitor.
The purifying process of L-Dopa ethyl ester:
US5354885 need extract three times and add salt at aqueous phase, because the adding of salt needs washing, except the extraction and washing of complexity, ethyl acetate layer also contains the water about 7%, need carry out drying to ethyl acetate layer, because L-Dopa ethyl ester-ethyl acetate solution is responsive to temperature, must cryoconcentration, so not only time-consuming but also may cause the degraded of L-Dopa ethyl ester.This complicated technology makes that the product ultimate yield is lower, although report that according to US20030135065 this technology Synthesis conversion is 96%, because complicated purifying process causes whole productive rate to have only 50%.
US6218566 need repeatedly add toluene, and (toluene is two kind solvents; the suggestion restriction is used in bulk drug, auxiliary material and preparation are produced); need control the concentration of different temperature, stirring velocity, alkali, the rate of addition of alkali in different time sections; under the severe condition such as nitrogen protection; just can obtain L-Dopa ethyl ester moist precipitate thing; because L-Dopa ethyl ester moist precipitate thing is responsive to temperature; this technology also need add methylbenzene azeotropic distillation dry sediment, and then the adding ethyl acetate is carried out recrystallization.
Therefore, the suitability for industrialized production of these methods remains in many problems to be solved.
Summary of the invention:
To the present invention seeks in order addressing the above problem, a kind of novel method for preparing L-Dopa ethyl ester to be provided.Make water or low-toxicity organic solvent in present method purge process, a step draws crystallization, more helps industrialized production and environment protection.
The technical solution used in the present invention:
Two kinds of methods that prepare L-Dopa ethyl ester:
Method 1: feed saturated hydrogen chloride gas in levodopa, ethanol, heating reflux reaction 2～4 hours changes reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and moisture is removed in underpressure distillation again, and temperature is lower than 80 ℃; Add ethanol again in the remaining material of distillation, continuation feeds hydrogen chloride gas, reheats to reflux 2～4 hours, and the moisture of ethanol and esterification generation is reclaimed in distillation in kind; As above method is carried out 2～4 times altogether, impels esterification to proceed to terminal point, and after last back flow reaction finished, it was L-Dopa ethyl ester hydrochloride crude product that underpressure distillation recovery ethanol gets oily matter; Add the dissolution with solvents L-Dopa ethyl ester hydrochloride crude product that contains oxidation inhibitor, add alkali neutralized salt acid group again and get L-Dopa ethyl ester, cooling is filtered, washing, and vacuum-drying, promptly.
Method 2: will levodopa, the ethanol ice bath adds sulfur oxychloride down, 60 ℃ of following heating reflux reactions 2 hours change reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and moisture is removed in underpressure distillation again, and temperature is lower than 80 ℃; Add ethanol and sulfur oxychloride as stated above again in the remaining material of distillation, 60 ℃ of following heating reflux reactions 2 hours, the moisture that ethanol and esterification generate is reclaimed in distillation in kind; As above method is carried out 2～4 times altogether, after last back flow reaction finishes, it is L-Dopa ethyl ester hydrochloride crude product that underpressure distillation recovery ethanol gets oily matter, add the dissolution with solvents L-Dopa ethyl ester hydrochloride crude product that contains oxidation inhibitor, add alkali neutralized salt acid group again and get L-Dopa ethyl ester, cooling, filter, washing, vacuum-drying, promptly.
The present invention has the following advantages:
1. the advantage of synthesis technique: adopt repeatedly the reaction distillation evaporation than the single reaction method, can remove the moisture that moisture in the reactant and esterification generate, that can omit raw material and solvent dehydrates operation in advance, overcome the reversibility esterification, the levodopa reaction can be carried out thoroughly, and transformation efficiency is near 100%.
2. the advantage of purifying process: selected solvent is to contain the water of oxidation inhibitor or the alcoholic solution of different concns during dissolving L-Dopa ethyl ester hydrochloride crude product; one step was separated out the L-Dopa ethyl ester crystallized product from water or alcoholic solution; avoid using poisonous and the big organic solvent of toxicity; help the protection of environment; technology is simple; production cost is low, is fit to industrialized production.
3. quality product height: the L-Dopa ethyl ester purity that makes is more than 99%, and productive rate is greater than 90%, and product is stable, and water absorbability is less.
Embodiment
The invention will be further described below in conjunction with specific embodiment, but content of the present invention not only is confined to cited example.
Embodiment 1:
23 gram levodopas are dissolved in 150 milliliters of ethanol, feed saturated hydrogen chloride gas, reflux 2 hours changes reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to below 60 ℃, the ethanol that adds 150ml continues to feed saturated hydrogen chloride gas in the remaining material of distillation, reheats and refluxes 2 hours, and ethanol is removed in first underpressure distillation, slightly elevated temperature again underpressure distillation remove moisture, as above method is carried out 4 times altogether.Reaction finishes back pressure reducing and steaming ethanol, obtain oily matter and be L-Dopa ethyl ester hydrochloride crude product 29.8g, add entry 150ml, Sodium Metabisulfite 8g, dissolving, adding concentration is 50% sodium hydroxide 20ml, cooling is filtered, and uses the Sodium Metabisulfite solution washing, 40 ℃ of following vacuum-dryings, obtain 24.5g off-white color product, productive rate 93.3%, the HPLC method is measured L-Dopa ethyl ester content greater than 99%.
Embodiment 2:
Under the ice bath cooling, add 100ml ethanol, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add entry 100ml, sodium bisulfite 10g, dissolving adds 10% sodium hydroxide solution 56ml, cooling, filter, with the aqueous solution of sodium bisulfite washing,, obtain the 23.7g white products 40 ℃ of following vacuum-dryings, productive rate 90.1%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 3: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add entry 150ml, Sulfothiorine 7g, dissolving adds 40% potassium hydroxide solution 25ml, cooling, filter, with the sodium thiosulfate solution washing,, obtain 25.0g off-white color product 40 ℃ of following vacuum-dryings, productive rate 95.0%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 4: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add entry 80ml, vitamins C 10g, dissolving adds 40% hydroxylamine solution 25ml, cooling, filter, use the vitamins C solution washing,, obtain 24.3g off-white color product 40 ℃ of following vacuum-dryings, productive rate 92.5%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 5: 23 gram levodopas are dissolved in 150 milliliters of ethanol, feed saturated hydrogen chloride gas, reflux 2 hours changes reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to below 60 ℃, the ethanol that adds 150ml continues to feed saturated hydrogen chloride gas in the remaining material of distillation, reheats and refluxes 2 hours, and recovery ethanol is removed in first underpressure distillation, slightly elevated temperature again underpressure distillation remove moisture, as above method is carried out 4 times altogether.Reaction finishes back pressure reducing and steaming ethanol, obtain oily matter and be L-Dopa ethyl ester hydrochloride crude product 29.8g, add entry 80ml, sodium bisulfite 11g, dissolving, add 40% sodium hydrogen carbonate solution 30ml, cooling is filtered, and washs with aqueous solution of sodium bisulfite, 40 ℃ of following vacuum-dryings, obtain 24.5g off-white color product, productive rate 93.3%, the HPLC method is measured L-Dopa ethyl ester content greater than 99%.
Embodiment 6: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add entry 150ml, Sulfothiorine 7g, dissolving adds 40% potassium bicarbonate solution 40ml, cooling, filter, with the washing of sulfo-sulphur sodium water solution,, obtain 23.7g off-white color product 40 ℃ of following vacuum-dryings, productive rate 90.4%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 7: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add entry 150ml, Sulfothiorine 10g, dissolving adds 30% hydroxylamine solution 20ml, cooling, filter, with the washing of sulfo-sulphur sodium water solution,, obtain 23.9g off-white color product 40 ℃ of following vacuum-dryings, productive rate 91.2%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 8: 23 gram levodopas are dissolved in 150 milliliters of ethanol, feed saturated hydrogen chloride gas, reflux 2 hours changes reflux into water distilling apparatus, and recovery ethanol is removed in first underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to below 60 ℃, the ethanol that adds 150ml continues to feed saturated hydrogen chloride gas in the remaining material of distillation, reheats and refluxes 2 hours, and ethanol is removed in first underpressure distillation, slightly elevated temperature again underpressure distillation remove moisture, as above method is carried out 4 times altogether.Reaction finishes back pressure reducing and steaming ethanol, obtain oily matter and be L-Dopa ethyl ester hydrochloride crude product 29.8g, add 20% ethanolic soln 100ml, Sulfothiorine 10g, dissolving, add 30% hydroxylamine solution 30ml, cooling is filtered, with the washing of sulfo-sulphur sodium ethoxide solution, 40 ℃ of following vacuum-dryings, obtain 24.7g off-white color product, productive rate 94%, the HPLC method is measured L-Dopa ethyl ester content greater than 99%.
Embodiment 9: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, recovery ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add 70% ethanolic soln 135ml, Sulfothiorine 5g, dissolving adds 50% sodium hydroxide solution 30ml, cooling, filter, with the washing of sulfo-sulphur sodium ethoxide solution,, obtain 24.4g off-white color product 40 ℃ of following vacuum-dryings, productive rate 93.0%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Embodiment 10: add 100ml ethanol under the ice bath cooling, stir and drip the 30ml sulfur oxychloride down, add 23g levodopa (temperature is controlled at 2～8 ℃) then, be heated to 60 ℃ of reactions 2 hours, change reflux into water distilling apparatus, ethanol is removed in elder generation's underpressure distillation, and elevated temperature (about 80 ℃) underpressure distillation is again removed moisture.Be cooled to normal temperature, add 80ml under ice bath cooling, stir and drip the 30ml sulfur oxychloride down, be heated to 60 ℃ of reactions 2 hours, ethanol is removed in first underpressure distillation, slightly elevated temperature (about 80 ℃) again underpressure distillation remove moisture, as above method is carried out 2 times altogether.Pressure reducing and steaming ethanol obtained oily matter and is L-Dopa ethyl ester hydrochloride crude product 30.1g after reaction finished, add 25% methanol solution 110ml, Sulfothiorine 10g, dissolving adds 40% potassium hydroxide solution 30ml, cooling, filter, with the washing of sulfo-sulphur sodium methanol solution,, obtain 24.1g off-white color product 40 ℃ of following vacuum-dryings, productive rate 91.8%, HPLC method are measured L-Dopa ethyl ester content greater than 99%.
Claims (8)
1. the preparation method of a L-Dopa ethyl ester, it is characterized in that levodopa and ethanol are carried out esterification as raw material, adopt repeatedly reaction distillation dewatering, remove the moisture that original moisture and esterification are produced in the reaction raw materials, impel esterification to proceed to terminal point, its method is as follows:
Method 1: feed saturated hydrogen chloride gas in levodopa, ethanol, heating reflux reaction 2～4 hours changes reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and moisture is removed in underpressure distillation again, and temperature is lower than 80 ℃; Add ethanol again in the remaining material of distillation, continuation feeds hydrogen chloride gas, reheats to reflux 2～4 hours, and the moisture of ethanol and esterification generation is reclaimed in distillation in kind; As above method is carried out 2～4 times altogether, impels esterification to proceed to terminal point, and after last back flow reaction finished, it was L-Dopa ethyl ester hydrochloride crude product that underpressure distillation recovery ethanol gets oily matter; Add the dissolution with solvents L-Dopa ethyl ester hydrochloride crude product that contains oxidation inhibitor, add alkali neutralized salt acid group again and get L-Dopa ethyl ester, cooling is filtered, washing, and vacuum-drying, promptly.
Method 2: will levodopa, the ethanol ice bath adds sulfur oxychloride down, 60 ℃ of following heating reflux reactions 2 hours change reflux into water distilling apparatus, and ethanol is removed in first underpressure distillation, and moisture is removed in underpressure distillation again, and temperature is lower than 80 ℃; Add ethanol and sulfur oxychloride as stated above again in the remaining material of distillation, 60 ℃ of following heating reflux reactions 2 hours, the moisture that ethanol and esterification generate is reclaimed in distillation in kind; As above method is carried out 2～4 times altogether, after last back flow reaction finishes, it is L-Dopa ethyl ester hydrochloride crude product that underpressure distillation recovery ethanol gets oily matter, add the dissolution with solvents L-Dopa ethyl ester hydrochloride crude product that contains oxidation inhibitor, add alkali neutralized salt acid group again and get L-Dopa ethyl ester, cooling, filter, washing, vacuum-drying, promptly.
2. the preparation method of L-Dopa ethyl ester as claimed in claim 1, it is characterized in that: the levodopa of described esterification and ethanol raw material do not need processed in advance; The reflux temperature is 40～90 ℃; Selected solvent is to contain the water of oxidation inhibitor or the alcoholic solution of different concns during dissolving L-Dopa ethyl ester hydrochloride crude product.
3. a L-Dopa ethyl ester hydrochloride is converted into the method for L-Dopa ethyl ester, it is characterized in that the solvent of selecting for use is alcoholic solutions such as the methyl alcohol that contains the water of oxidation inhibitor or different concns, ethanol, propyl alcohol, Virahol, propyl carbinol, and its step is as follows:
(1) adds the dissolution with solvents L-Dopa ethyl ester hydrochloride crude product that contains oxidation inhibitor; (2) add alkali neutralized salt acid group and get L-Dopa ethyl ester; (3) cooling; (4) filter; (5) washing; (6) vacuum-drying.
4. L-Dopa ethyl ester hydrochloride as claimed in claim 3 is converted into the method for L-Dopa ethyl ester, it is characterized in that: the weight (g) of crude product in this step (1): the volume of solvent (ml) is than being 1: 40～1: 0.3.
5. L-Dopa ethyl ester hydrochloride as claimed in claim 3 is converted into the method for L-Dopa ethyl ester, it is characterized in that: this step (1) oxidation inhibitor is: S-WAT, sodium bisulfite, Sodium Metabisulfite, Sulfothiorine, vitamins C etc.
6. L-Dopa ethyl ester hydrochloride as claimed in claim 3 is converted into the method for L-Dopa ethyl ester, it is characterized in that: this step (1) antioxygen dosage (g): liquor capacity (ml) is 0.01%～30%.
7. L-Dopa ethyl ester hydrochloride as claimed in claim 3 is converted into the method for L-Dopa ethyl ester, it is characterized in that: this step (2) alkali is: its concentration such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus, azanol are: 1%～50%.
8. be converted into the method for L-Dopa ethyl ester as claim 3 or 4 described L-Dopa ethyl ester hydrochlorides, it is characterized in that: the solvent phase that adds in used cleaning solvent and the step (1) in this step (5) with.
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| CN 200810073735 CN101337903A (en) | 2008-08-12 | 2008-08-12 | Method for preparing ethyl levodopa |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911072A (en) * | 2012-06-21 | 2013-02-06 | 浙江手心医药化学品有限公司 | Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid |
| CN104271547A (en) * | 2012-04-26 | 2015-01-07 | 日油株式会社 | Ester for refrigerator oils and method for producing same |
| CN104945270A (en) * | 2015-05-01 | 2015-09-30 | 李玉山 | Synthesis method of L-dopa methyl ester hydrochloride |
-
2008
- 2008-08-12 CN CN 200810073735 patent/CN101337903A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104271547A (en) * | 2012-04-26 | 2015-01-07 | 日油株式会社 | Ester for refrigerator oils and method for producing same |
| EP2842934A4 (en) * | 2012-04-26 | 2015-10-07 | Nof Corp | Ester for refrigerator oils and method for producing same |
| CN102911072A (en) * | 2012-06-21 | 2013-02-06 | 浙江手心医药化学品有限公司 | Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid |
| CN102911072B (en) * | 2012-06-21 | 2014-12-24 | 浙江手心医药化学品有限公司 | Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid |
| CN104945270A (en) * | 2015-05-01 | 2015-09-30 | 李玉山 | Synthesis method of L-dopa methyl ester hydrochloride |
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