CN102702019A - Method for synthesizing carbidopa - Google Patents
Method for synthesizing carbidopa Download PDFInfo
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- CN102702019A CN102702019A CN2012101988546A CN201210198854A CN102702019A CN 102702019 A CN102702019 A CN 102702019A CN 2012101988546 A CN2012101988546 A CN 2012101988546A CN 201210198854 A CN201210198854 A CN 201210198854A CN 102702019 A CN102702019 A CN 102702019A
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- carbidopa
- methyldopa
- soluol
- oxygen
- ester
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Abstract
The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing carbidopa. The method is characterized by comprising the following steps of: reacting oxaziridine with methyldopa ester to obtain methyldopa imido ester, and hydrolyzing to obtain the carbidopa. The method has the advantages that the carbidopa is prepared by a brand-new process, the used raw materials are favorable for synthesizing a medicine, and the prepared carbidopa is high in yield and quality.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of compound method of carbidopa.
Background technology
Carbidopa, English name: Carbidopa is (S)-Alpha-Methyl-α-diazanyl-3,4-dihydroxy-benzene propionic acid monohydrate, carbidopa has stronger periphery dopa decarboxylase inhibitor.Be difficult for seeing through hemato encephalic barrier, when share, only suppress the activity of periphery dopadecarboxylase with levodopa; Reduce the generation of Dopamine HCL in peripheral tissues; Alleviate its periphery untoward reaction, and then the levodopa of entering maincenter is increased, improve the concentration of Dopamine HCL in the brain; Strengthen the curative effect of levodopa, so be the important adjuvant drug of levodopa.The carbidopa list is processed compound preparation with carbidopa and levodopa in 1:10 or 1:4 ratio compatibility clinically usually with invalid.
Synthesizing of carbidopa roughly has 3 routes:
Route one:
This route is a raw material with dimethoxy-methyl DOPA hydrochloride, and yield only has 20%, is eliminated.
Route two:
Patent 230865A1 describes, and is raw material with the methyldopa methyl esters, with two hydroxyls of boric acid protection, and then with 3, the reaction of 3-penta methylene radical oxygen acridine, hydrolysis makes then, total recovery about 40%.
Route 3:
Patent WO200704828 is a raw material with the methyldopa methyl esters, directly with 3, and the reaction of 3-penta methylene radical oxygen acridine, hydrolysis makes then, total recovery about 70%.
This route yield is than higher, and is simple to operate, good product quality.But 2 deficiencies are arranged also: 1. 3 in the technology, it is raw material that pimelinketone is used in the preparation of 3-penta methylene radical oxygen acridine, to have carcinogenesis should not be used for medicine synthetic for pimelinketone on the one hand; Pimelinketone boiling point (155.6 ℃) height on the other hand, it is residual defective with also causing easily in product to be not easy to recovery set.2. select for use toluene to make solvent in the technology, 80-85 ℃ of preparation imines ester, the toluene boiling point is high, and the carbidopa of production causes toluene residual defective easily.
Summary of the invention
The compound method that the purpose of this invention is to provide a kind of carbidopa can be prepared the carbidopa of yield height and good product quality through easy technology.
The compound method of a kind of carbidopa of the present invention, oxygen Soluol XC 100 and the reaction of methyldopa ester generate methyldopa imines ester, and hydrolysis generates carbidopa then.
Oxygen Soluol XC 100 (Oxaziridine) is one type of three member ring heterocyclic compound that contains C, O, N, and it is just synthetic by Krimm and Emmons as far back as nineteen fifty-three.Contain a triatomic ring and the more weak N-O key that tension force is stronger in the oxygen Soluol XC 100 molecule, show special activity, oxygen Soluol XC 100 principal feature is when reacting with nucleophilic reagent in reaction, not only can do aminating agent but also can make oxygenant.Nucleophilic reagent depends on substituent size and electronegativity on the N atom to ternary heterocyclic attack position, and when the substituting group on the N atom was less H, the oxygen Soluol XC 100 was an aminating agent, otherwise, then be oxygenant.Primary amine and the reaction of oxygen Soluol XC 100 generate azo cpd; Secondary amine generates hydrazine; Father-in-law's salt in tertiary amine generates.We have adopted this principle just, utilize the imido grpup of methyldopa ester and the reaction of oxygen Soluol XC 100 to generate the imines ester, and then carbidopa are produced in hydrolysis.
Wherein, the oxygen Soluol XC 100 preferably uses 3,3-dimethyl oxygen Soluol XC 100, and 3, the concentration of 3-dimethyl oxygen Soluol XC 100 is preferably 0.1 ~ 5mol/L, more preferably 0.5 ~ 3mol/L.3,3-dimethyl oxygen Soluol XC 100 can form according to following prepared in reaction:
Then 3,3-dimethyl oxygen Soluol XC 100 further generates methyldopa imines ester with the reaction of methyldopa ester, and hydrolysis generates carbidopa then, can be expressed from the next:
The methyldopa ester is preferably with alpha-Methyldopa ethyl ester or methyldopa methyl esters.
The mol ratio of oxygen Soluol XC 100 and methyldopa ester is preferably 1.2～1.3:1.
The solvent of oxygen Soluol XC 100 and the reaction of methyldopa ester is preferably with methylene dichloride or ethylene dichloride.Select for use methylene dichloride or ethylene dichloride to make solvent, methyldopa ester, imines ester are had solvability preferably, thereby can temperature of reaction be dropped to below 40 ℃, thereby reduced the generation of side reaction, product yield is also higher.
Oxygen Soluol XC 100 and methyldopa ester temperature of reaction are preferably 10 ~ 45 ℃, more preferably 25 ~ 35 ℃.
Operating process: under the vigorous stirring dilute alkaline soln of chloramines is added drop-wise in methylene dichloride (or ethylene dichloride) solution of acetone (or butanone, methylethylketone) and processes the oxygen Soluol XC 100; Stir under the room temperature oxygen Soluol XC 100 is joined in methylene dichloride (or ethylene dichloride) solution of methyldopa ester; Continue stoichiometric number minute, cooling is filtered and is obtained methyldopa imines ester.Methyldopa imines ester is obtained carbidopa with the Hydrogen chloride hydrolysis.
The invention has the advantages that: adopted brand-new operational path to prepare carbidopa, raw materials used the synthetic of medicine, the carbidopa yield height for preparing, the good product quality of all being suitable for.
Embodiment
Below in conjunction with embodiment the present invention is further specified.
Embodiment 1:
(1) preparation of oxygen Soluol XC 100
With wiring solution-forming among the NaOH solution 100ml of 0.044mol chloramines adding 1N, under the vigorous stirring it is splashed into the 100ml dichloromethane solution that contains 10ml acetone then under stirring, temperature is controlled at 20 ℃, finishes, and stirs 30 seconds, stops to stir branch vibration layer.Contain 3 of theoretical amount 43.5% in the dichloromethane layer, 3-dimethyl oxygen Soluol XC 100.Organic layer is used anhydrous sodium sulfate drying, and control reflux ratio 1:3 uses separation column to be concentrated into oxygen Soluol XC 100 content to be 0.9mol/L.
(2) preparation of imines ester
With the dichloromethane solution of the above-mentioned oxygen Soluol XC 100 of 0.073mol, controlled temperature is 25 ℃, in 15 ~ 20 minutes, is added drop-wise in the 50ml dichloromethane solution of methyldopa methyl esters of 0.068mol; Drip and finish, under this temperature, stir, cool to 0 ℃; Filter, obtain methyldopa imines ester.
(3) carbidopa preparation
Under the nitrogen protection above-mentioned methyldopa imines ester 10.3g and 100ml20% hydrochloric acid soln are heated to 95 ℃ of reactions 4 hours, the pressure reducing and steaming aqueous acid is to doing, and nitrogen protection adds 6 ml waters down; Regulate pH value to 3.5 with 6N ammoniacal liquor, separate out a large amount of solids, filter; Vacuum-drying gets carbidopa 6.0g; Yield is about 87%, 194 ℃ of fusing points, and content is greater than 98.5%.
Claims (9)
1. the compound method of a carbidopa is characterized in that the reaction of oxygen Soluol XC 100 and methyldopa ester generates methyldopa imines ester, and hydrolysis generates carbidopa then.
2. the compound method of carbidopa according to claim 1 is characterized in that the oxygen Soluol XC 100 selects 3 for use, 3-dimethyl oxygen Soluol XC 100.
3. the compound method of carbidopa according to claim 2 is characterized in that 3, and the concentration of 3-dimethyl oxygen Soluol XC 100 is 0.1 ~ 5mol/L.
4. the compound method of carbidopa according to claim 3 is characterized in that 3, and the concentration of 3-dimethyl oxygen Soluol XC 100 is 0.5 ~ 3mol/L.
5. the compound method of carbidopa according to claim 1 is characterized in that the methyldopa ester selects alpha-Methyldopa ethyl ester or methyldopa methyl esters for use.
6. the compound method of carbidopa according to claim 1, the mol ratio that it is characterized in that oxygen Soluol XC 100 and methyldopa ester is 1.2～1.3:1.
7. the compound method of carbidopa according to claim 1 is characterized in that the solvent of oxygen Soluol XC 100 and methyldopa ester reaction is selected methylene dichloride or ethylene dichloride for use.
8. the compound method of carbidopa according to claim 1 is characterized in that oxygen Soluol XC 100 and methyldopa ester temperature of reaction are 10 ~ 45 ℃.
9. the compound method of carbidopa according to claim 8 is characterized in that oxygen Soluol XC 100 and methyldopa ester temperature of reaction are 25 ~ 35 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
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| CN102702019A true CN102702019A (en) | 2012-10-03 |
| CN102702019B CN102702019B (en) | 2014-05-14 |
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| CN201210198854.6A Active CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986772A (en) * | 2017-04-06 | 2017-07-28 | 宁波四明化工有限公司 | The synthetic method of 2 nitropropanes |
| CN108276333A (en) * | 2018-04-26 | 2018-07-13 | 山东新华制药股份有限公司 | A kind of preparation process and its device of carbidopa midbody acridine |
| CN114478303A (en) * | 2022-02-23 | 2022-05-13 | 浙江野风药业股份有限公司 | Method for synthesizing carbidopa |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD230865A1 (en) * | 1982-08-09 | 1985-12-11 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF HYDRAZINOCARBONSAEUREDERIVATES BY N-AMINATION OF AMINOCARBONSAEUREDERIVATES |
| WO2007042848A2 (en) * | 2005-10-12 | 2007-04-19 | Egis Gyógyszergyár | Process for the preparation of carbidopa |
-
2012
- 2012-06-16 CN CN201210198854.6A patent/CN102702019B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD230865A1 (en) * | 1982-08-09 | 1985-12-11 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF HYDRAZINOCARBONSAEUREDERIVATES BY N-AMINATION OF AMINOCARBONSAEUREDERIVATES |
| WO2007042848A2 (en) * | 2005-10-12 | 2007-04-19 | Egis Gyógyszergyár | Process for the preparation of carbidopa |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986772A (en) * | 2017-04-06 | 2017-07-28 | 宁波四明化工有限公司 | The synthetic method of 2 nitropropanes |
| CN106986772B (en) * | 2017-04-06 | 2019-01-18 | 宁波四明化工有限公司 | The synthetic method of 2- nitropropane |
| CN108276333A (en) * | 2018-04-26 | 2018-07-13 | 山东新华制药股份有限公司 | A kind of preparation process and its device of carbidopa midbody acridine |
| CN114478303A (en) * | 2022-02-23 | 2022-05-13 | 浙江野风药业股份有限公司 | Method for synthesizing carbidopa |
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| CN102702019B (en) | 2014-05-14 |
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