CN102702019B - Method for synthesizing carbidopa - Google Patents
Method for synthesizing carbidopa Download PDFInfo
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- CN102702019B CN102702019B CN201210198854.6A CN201210198854A CN102702019B CN 102702019 B CN102702019 B CN 102702019B CN 201210198854 A CN201210198854 A CN 201210198854A CN 102702019 B CN102702019 B CN 102702019B
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- carbidopa
- methyldopa
- oxaziridine
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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 synthetic 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, while share with levodopa, only suppress the activity of periphery dopa decarboxylase, reduce the generation of Dopamine HCL in peripheral tissues, alleviate its periphery untoward reaction, and then the levodopa of the maincenter that enters is increased, improve the concentration of Dopamine HCL in brain, strengthen the curative effect of levodopa, so be the important adjuvant drug of levodopa.Carbidopa is alone invalid, conventionally carbidopa and levodopa is made to compound preparation in 1:10 or 1:4 ratio compatibility clinically.
Synthesizing of carbidopa roughly has 3 routes:
Route one:
This route is take dimethoxy-methyl DOPA hydrochloride as raw material, and yield only has 20%, is eliminated.
Route two:
Patent 230865A1 describes, and take methyldopa methyl esters as raw material, with two hydroxyls of boric acid protection, then, with 3,3-, penta methylene radical oxygen acridine reaction, then hydrolysis makes, total recovery approximately 40%.
Route 3:
Patent WO200704828, take methyldopa methyl esters as raw material, directly with 3,3-penta methylene radical oxygen acridine reaction, then hydrolysis makes, total recovery approximately 70%.
This route yield is higher, simple to operate, good product quality.But also there are 2 deficiencies: 1. 3 in technique, it is raw material that pimelinketone is used in the preparation of 3-penta methylene radical oxygen acridine, it is synthetic that one side pimelinketone has carcinogenesis should not be used for medicine; Pimelinketone boiling point (155.6 ℃) height, is not easy to recovery and also easily causes in product residual defective on the other hand.2. in technique, select toluene to make solvent, prepare imines ester for 80-85 ℃, toluene boiling point is high, and the carbidopa of production easily causes Residual Toluene defective.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of carbidopa, can be by easy technique, prepare the carbidopa of the high and good product quality of yield.
The synthetic method of a kind of carbidopa of the present invention, oxaziridine reacts with methyldopa ester and generates methyldopa imines ester, and then hydrolysis generates carbidopa.
Oxaziridine (Oxaziridine) is the three member ring heterocyclic compound that a class contains C, O, N, and it is just synthetic by Krimm and Emmons as far back as nineteen fifty-three.In oxaziridine molecule, contain triatomic ring and weak N-O key that tension force is stronger, show special activity, in reaction, oxaziridine principal feature is while reacting with nucleophilic reagent, not only can do aminating agent but also can make oxygenant.Nucleophilic reagent depends on substituent size and electronegativity on N atom to the attack position of ternary heterocycle, and in the time that the substituting group on N atom is less H, oxaziridine is aminating agent, otherwise, be oxygenant.Primary amine reacts with oxaziridine and generates azo-compound; 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 to react generation imines ester with oxaziridine, and then carbidopa are produced in hydrolysis.
Wherein, oxaziridine is preferably used 3,3-dimethyl oxygen aziridine, and the concentration of 3,3-dimethyl oxygen aziridine is preferably 0.1 ~ 5mol/L, more preferably 0.5 ~ 3mol/L.3,3-dimethyl oxygen aziridine can be prepared from according to following reaction:
Then 3,3-dimethyl oxygen aziridine further reacts with methyldopa ester and generates methyldopa imines ester, and then hydrolysis generates carbidopa, can be expressed from the next:
Methyldopa ester is preferably with alpha-Methyldopa ethyl ester or methyldopa methyl esters.
The mol ratio of oxaziridine and methyldopa ester is preferably 1.2～1.3:1.
The solvent that oxaziridine reacts with methyldopa ester is preferably with methylene dichloride or ethylene dichloride.Select methylene dichloride or ethylene dichloride to make solvent, methyldopa ester, imines ester are had to good solvability, thereby temperature of reaction can be dropped to below 40 ℃, thereby reduced the generation of side reaction, product yield is also higher.
Oxaziridine and methyldopa ester temperature of reaction are preferably 10 ~ 45 ℃, more preferably 25 ~ 35 ℃.
Operating process: under vigorous stirring, the dilute alkaline soln of chloramines is added drop-wise in methylene dichloride (or ethylene dichloride) solution of acetone (or butanone, methylethylketone) and makes oxaziridine, stir under room temperature oxaziridine 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 to carbidopa with dilute hydrochloric acid hydrolysis.
The invention has the advantages that: adopted brand-new operational path to prepare carbidopa, raw materials used being all suitable for synthesizing of medicine, the carbidopa yield preparing is high, good product quality.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1:
(1) preparation of oxaziridine
Under stirring, 0.044mol chloramines is added to wiring solution-forming in the NaOH solution 100ml of 1N, then under vigorous stirring, splashed into the 100ml dichloromethane solution that contains 10ml acetone, temperature is controlled at 20 ℃, finishes, and stirs 30 seconds, stops stirring branch vibration layer.In dichloromethane layer, contain 3 of theoretical amount 43.5%, 3-dimethyl oxygen aziridine.By organic layer anhydrous sodium sulfate drying, it is 0.9mol/L that control reflux ratio 1:3 is concentrated into oxaziridine content with fractional column.
(2) preparation of imines ester
By the dichloromethane solution of the above-mentioned oxaziridine of 0.073mol, controlling temperature is 25 ℃, is added drop-wise in the 50ml dichloromethane solution of methyldopa methyl esters of 0.068mol in 15 ~ 20 minutes, drip and finish, at this temperature, stir, cool to 0 ℃, filter, obtain methyldopa imines ester.
(3) carbidopa preparation
Under nitrogen protection, above-mentioned methyldopa imines ester 10.3g and 100ml20% hydrochloric acid soln are heated to 95 ℃ of reactions 4 hours; pressure reducing and steaming aqueous acid is to dry; under nitrogen protection, add 6 ml waters; with 6N ammoniacal liquor adjusting pH value to 3.5, separate out a large amount of solids, filter; vacuum-drying obtains carbidopa 6.0g; yield approximately 87%, 194 ℃ of fusing points, content is greater than 98.5%.
Claims (1)
1. a synthetic method for carbidopa, is characterized in that:
(1) preparation of oxaziridine
Under stirring, 0.044mol chloramines is added to wiring solution-forming in the NaOH solution 100ml of 1N, then under stirring, splashed into the 100ml dichloromethane solution that contains 10ml acetone, temperature is controlled at 20 ℃, finishes, and stirs 30 seconds, stop stirring, branch vibration layer, contains 3 of theoretical amount 43.5% in dichloromethane layer, 3-dimethyl oxygen aziridine, by organic layer anhydrous sodium sulfate drying, it is 0.9mol/L that control reflux ratio 1:3 is concentrated into oxaziridine content with fractional column;
(2) preparation of imines ester
By the dichloromethane solution of the above-mentioned oxaziridine of 0.073mol, controlling temperature is 25 ℃, is added drop-wise in the 50ml dichloromethane solution of methyldopa methyl esters of 0.068mol in 15 ~ 20 minutes, drip and finish, at this temperature, stir, cool to 0 ℃, filter, obtain methyldopa imines ester;
(3) carbidopa preparation
Under nitrogen protection, above-mentioned methyldopa imines ester 10.3g and 100ml20% hydrochloric acid soln are heated to 95 ℃ of reactions 4 hours; pressure reducing and steaming aqueous acid is to dry; under nitrogen protection, add 6 ml waters; with 6N ammoniacal liquor adjusting pH value to 3.5, separate out a large amount of solids, filter; vacuum-drying obtains carbidopa 6.0g; yield 87%, 194 ℃ of fusing points, content is greater than 98.5%.
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| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
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| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
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| 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 |
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| HU227283B1 (en) * | 2005-10-12 | 2011-01-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Process for the preparation of carbidopa |
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