CN103601627A - Method for quantitatively synthesizing prasugrel hydrochloride degradation impurity diketone - Google Patents
Method for quantitatively synthesizing prasugrel hydrochloride degradation impurity diketone Download PDFInfo
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- CN103601627A CN103601627A CN201310609142.3A CN201310609142A CN103601627A CN 103601627 A CN103601627 A CN 103601627A CN 201310609142 A CN201310609142 A CN 201310609142A CN 103601627 A CN103601627 A CN 103601627A
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- diketone
- degradation impurity
- hydrochloric acid
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- prasugrel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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Abstract
The invention relates to a method for quantitatively synthesizing prasugrel hydrochloride degradation impurity diketone. The method comprises the following steps: with 1-cyclopropyl-2-(2-fluorophenyl) ethaneone as a starting material, choosing an appropriate oxidizing agent, oxidizing carbon atoms adjacent to ketonic and carbonyl groups, and then carrying out one-step reaction to obtain the prasugrel hydrochloride degradation impurity diketone, namely 1-cyclopropyl-2-(2-fluorophenyl)-1,2-ethanedione. The synthetic method provided by the invention is capable of synthesizing the degradation impurity diketone of the prasugrel hydrochloride conveniently, quickly and quantitatively, and has the advantages of short steps, few impurities, good quality and high yield.
Description
Technical field
The invention belongs to chemical field, relate in particular to technical field of organic synthesis, be specifically related to a kind of method of quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone.
Background technology
1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone, i.e. hydrochloric acid prasugrel degradation impurity diketone.Hydrochloric acid prasugrel is as platelet aggregation inhibitor; with prevention and treatment thrombosis; it is exposed in air and moisture for a long time can cause certain degraded; according to the degradation pathway of patent documentation (US Patent No. 20080176893) report; hydrochloric acid prasugrel generates N-oxide compound by peroxide-mediated; and N-oxide compound diastereomer is unstable in solution, can be degraded to rapidly TTPO and the diketone of acidylate.Therefore, quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone, has very important meaning for the detection of the quality approach of hydrochloric acid prasugrel and degradation impurity.
Summary of the invention
A kind of method that the object of this invention is to provide quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone, to overcome prior art above shortcomings.
The object of the invention is to be achieved through the following technical solutions:
A kind of method of quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone, the compound being represented by formula II, be 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, for starting material, select suitable oxygenant, in reaction solvent by 1-cyclopropyl-2-(2-fluorophenyl) carbon atom oxidation that the ketone carbonyl of ethyl ketone is adjacent, single step reaction obtains the hydrochloric acid prasugrel degradation impurity diketone that formula I represents, be 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone
Wherein, in synthetic method provided by the invention, oxygenant used is common oxygenant, can be active non-metal simple-substance, as oxygen, fluorine gas, chlorine, bromine, iodine or ozone; The oxygenatedchemicals of high valence state element (inorganic acid salt of high valence state metallic element), as nitrate, permanganate, chromic salt, dichromate, hypochlorite, oxymuriate or perchlorate; The oxygen acid that has oxidisability, as nitric acid, hypochlorous acid, chloric acid, perchloric acid or the vitriol oil; The high oxide that has oxidisability, as plumbic oxide, Manganse Dioxide, tin anhydride, chromium trioxide, sulphur trioxide, nitrogen pentoxide, permanganic anhydride or arsenic powder; There are the high oxide of oxidisability and the coordination compound that organism forms, as the title complex (PCC of the title complex (Sarett reagent and Collins reagent) of chromium trioxide and pyridine formation, chromium trioxide, pyridine and hydrochloric acid formation, be pyridinium chlorochromate drone salt), the title complex (PCDC, i.e. dichromic acid pyridinium salt) that forms of dichromic acid, pyridine and hydrochloric acid; The high valent cationic that has oxidisability, as ferric ion, bivalent cupric ion, silver ions or tetravalent tin ion; Peroxides and Superoxides, as hydrogen peroxide, Potassium peroxide, potassium superoxide, sodium peroxide, sodium superoxide, calcium peroxide, barium peroxide, Potassium Persulfate Peracetic Acid or benzoyl peroxide; Organic oxidizing agent, as N, N-dimethyl sulfoxide (DMSO) and dicyclohexyl diimine and acid (Moffatt oxidation), N, N-dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride, N, N-dimethyl sulfoxide (DMSO) and oxalyl chloride (Swern oxidation).
Preferably, oxygenant is oxygenatedchemicals (inorganic acid salt of high valence state metallic element), the organic oxidizing agent of high valence state element, the coordination compound that has the high oxide of oxidisability or itself and organism to form.More preferably, oxygenant is the coordination compound that organic oxidizing agent, the high oxide that has oxidisability or itself and organism form.Particularly preferably, oxygenant is the high oxide that has oxidisability; Most preferably, oxygenant is tin anhydride.
Reaction solvent used in synthetic method provided by the invention can adopt any organic solvent, unless it suppresses this reaction, reaction solvent can be lower alcohol, as methyl alcohol, ethanol, propyl alcohol, Virahol, the trimethyl carbinol etc.; Aprotic polar solvent, as DMF, N, N-dimethyl sulfoxide (DMSO), acetonitrile etc.; Carboxylic acid, as formic acid, acetic acid, phenylformic acid, oxalic acid etc.; And the solvent mixture that is selected from above-mentioned solvent.
Preferably, solvent is carboxylic acid.More preferably, solvent is acetic acid.Most preferably, solvent is 70%(volume fraction) aqueous acetic acid.
In synthetic method provided by the invention, temperature of reaction is according to variations such as reagent, solvents.Yet usually, temperature of reaction is-20 ℃ ~ 200 ℃.Preferably, temperature of reaction is 50 ℃ ~ 150 ℃.More preferably, temperature of reaction is 80 ℃ ~ 120 ℃.Most preferably, temperature of reaction is 100 ℃ ~ 110 ℃.
In synthetic method provided by the invention, the reaction times is according to variations such as reagent, solvent, temperature of reaction.Yet usually, the reaction times is 5 minutes ~ 12 hours.Preferably, the reaction times is 15 minutes ~ 8 hours.Most preferably, the reaction times is 30 minutes ~ 2 hours.
After reaction process finishes, remove by filter solid matter insoluble in reaction solution, concentration of reaction solution obtains required compound, i.e. 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone.This required compound obtaining can further carry out purifying by ordinary method if desired, as washing, recrystallization, chromatographic separation etc.
Beneficial effect of the present invention is: by synthetic method provided by the invention, can convenient, fast, quantitatively synthesize the degradation impurity diketone that obtains hydrochloric acid prasugrel, have advantages of that step is short, impurity is few, quality is good, yield is high.
Embodiment
The present invention further more explains detailedly by the following example, yet following embodiment is not for the scope of the invention is limited.
Embodiment 1
By 1-cyclopropyl-2-(2-fluorophenyl) the synthetic 1-cyclopropyl-2-(2-fluorophenyl of ethyl ketone)-1,2-second diketone
70%(volume fraction) in aqueous acetic acid 10ml, add 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 1.78g(10mmol) and tin anhydride 1.22g(11mmol), stirring is warming up to 100 ℃ ~ 110 ℃ reactions, and within 2 hours, (TLC monitoring condition is sherwood oil: ethyl acetate=20:1); After completion of the reaction, remove by filter solid matter insoluble in reaction solution, concentration of reaction solution obtains 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone,
1h-NMR (DMSO-d6): 7.41 (m, 2H, Ar-H), 7.81 (m, 2H, Ar-H), 2.53 (m, H ,-CH-), 1.24 (m, 2H ,-CH
2-), 1.16 (m, 2H ,-CH
2-).
1-cyclopropyl-2-(2-fluorophenyl)-1, the purifying of 2-second diketone:
1-cyclopropyl-2-(2-the fluorophenyl obtaining)-1, in 2-second diketone, add methylene dichloride 20ml and water 20ml, slowly add the hydrochloric acid soln 4ml of 3mol/L, stir 15 minutes; Standing separatory, dichloromethane layer is washed with water to neutrality, then uses saturated common salt water washing, and dewaters with desiccant dryness; Dichloromethane solution after concentrate drying dewaters, obtains the 1-cyclopropyl-2-(2-fluorophenyl after purifying)-1,2-second diketone.
Embodiment 2
By 1-cyclopropyl-2-(2-fluorophenyl) the synthetic 1-cyclopropyl-2-(2-fluorophenyl of ethyl ketone)-1,2-second diketone
In 10ml water, add 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 1g(4mmol), stir and to be warming up to 100 ℃ of reactions and to spend the night that (TLC monitoring condition is sherwood oil: ethyl acetate=15:1); After completion of the reaction, add 5ml cyclohexane extract, in the oil obtaining after concentrating, add 3ml methylene dichloride, under room temperature, add 0.4gPCC(2mmol in batches), stirring at room reaction 3 hours; Concentration of reaction solution obtains 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone.
Embodiment 3
By 1-cyclopropyl-2-(2-fluorophenyl) the synthetic 1-cyclopropyl-2-(2-fluorophenyl of ethyl ketone)-1,2-second diketone
Cyclopropyl-2-(2-fluorophenyl) ethyl ketone 1g(4mmol) be dissolved in 6ml N, in N-dimethyl sulfoxide (DMSO), add sodium bicarbonate 0.4g(4.8mmol), stirring is warming up to 45 ℃ of reactions, and within 4 hours, (TLC monitoring condition is sherwood oil: ethyl acetate=15:1); After completion of the reaction, add 20ml water, by 5ml ethyl acetate, extract twice, concentration of reaction solution obtains 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone.
Embodiment 4
By 1-cyclopropyl-2-(2-fluorophenyl) the synthetic 1-cyclopropyl-2-(2-fluorophenyl of ethyl ketone)-1,2-second diketone
20%(quality volume fraction) sodium methylate-methanol solution 5.4ml(20mmol), add 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 1g(4mmol), stirring is warming up to back flow reaction 1 hour, and (TLC monitoring condition is sherwood oil: ethyl acetate=20:1); After completion of the reaction, with 2mol/L hydrochloric acid soln, regulate pH=7, concentration of reaction solution obtains 1-cyclopropyl-2-(2-fluorophenyl)-1,2-second diketone.
The present invention is not limited to above-mentioned preferred forms; anyone can draw other various forms of products under enlightenment of the present invention; no matter but do any variation in its shape or structure; every have identical with a application or akin technical scheme, within all dropping on protection scope of the present invention.
Claims (10)
1. the method for a quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone, it is characterized in that: by 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and suitable oxygenant, in reaction solvent by 1-cyclopropyl-2-(2-fluorophenyl) carbon atom oxidation that the ketone carbonyl of ethyl ketone is adjacent, single step reaction obtains hydrochloric acid prasugrel degradation impurity diketone.
2. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 1, is characterized in that: described oxygenant is wherein a kind of of the oxygenatedchemicals of active non-metal simple-substance, high valence state element, the oxygen acid that has oxidisability, the high oxide that has oxidisability, the high oxide that has oxidisability and the organism coordination compound, the high valent cationic that has oxidisability, superoxide or the super-oxide that form.
3. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 1, is characterized in that: described oxygenant is the high oxide that has oxidisability.
4. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 1, is characterized in that: described oxygenant is tin anhydride.
5. according to the method for the quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone described in claim 1-4 any one, it is characterized in that: described reaction solvent is lower alcohol, aprotic polar solvent, carboxylic acid and the mixture that is selected from above-mentioned solvent.
6. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 5, is characterized in that: described lower alcohol is methyl alcohol, ethanol, propyl alcohol, Virahol or the trimethyl carbinol; Described aprotic polar solvent is DMF, N, N-dimethyl sulfoxide (DMSO) or acetonitrile; Described carboxylic acid is formic acid, acetic acid, phenylformic acid or oxalic acid.
7. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 5, is characterized in that: described reaction solvent is that volume fraction is 70% aqueous acetic acid.
8. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 5, is characterized in that: temperature of reaction is-20 ℃ ~ 200 ℃, and the reaction times is 5 minutes ~ 12 hours.
9. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 8, is characterized in that: temperature of reaction is 50 ℃ ~ 150 ℃, and the reaction times is 15 minutes ~ 8 hours.
10. the method for quantitative synthetic hydrochloric acid prasugrel degradation impurity diketone according to claim 9, is characterized in that: temperature of reaction is 100 ℃ ~ 110 ℃, and the reaction times is 30 minutes ~ 2 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056803A (en) * | 2017-05-19 | 2017-08-18 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
-
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Non-Patent Citations (3)
| Title |
|---|
| ALDER,KURT ET AL: "Diene synthesis. XLIII. Diene syntheses with dienes unsymmetrically substituted in the 2,3-position", 《JUSTUS LIEBIGS ANNALEN DER CHEMIE》 * |
| QI,CHAORONG ET AL: "DABCO-catalyzed oxidation of deoxybenzoins to benzils with air and one-pot synthesis of quinoxalines", 《SYNTHESIS》 * |
| WEGMANN,JACQUES ET AL: "Carbonyl groups and aromatic hydrocarbons. V. The effect of neighboring substituents upon the addition capacity of carbonyl groups", 《HELVETICA CHIMICA ACTA》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056803A (en) * | 2017-05-19 | 2017-08-18 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
| CN107056803B (en) * | 2017-05-19 | 2019-06-11 | 兰州大学 | The method for synthesizing intermediate of prasugrel and preparation method thereof and synthesis prasugrel |
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Application publication date: 20140226 |