CN102276436A - Preparation method of aromatic cyclopropyl ketone compound and purpose - Google Patents
Preparation method of aromatic cyclopropyl ketone compound and purpose Download PDFInfo
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- CN102276436A CN102276436A CN201010199108XA CN201010199108A CN102276436A CN 102276436 A CN102276436 A CN 102276436A CN 201010199108X A CN201010199108X A CN 201010199108XA CN 201010199108 A CN201010199108 A CN 201010199108A CN 102276436 A CN102276436 A CN 102276436A
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- ethyl ketone
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Abstract
The invention relates to the technical field of carbocyclic ring chemical technology, concretely relates to a preparation method of an aromatic cyclopropyl ketone compound and its purpose. The preparation method comprises the following steps: mixing a compound in a formula (a) with alkali and stirring, reacting with a compound in a formula (b) to obtain the aromatic cyclopropyl ketone compound which is a compound in a formula (c), the compound in a formula (c) is used for preparing a tetrahydrothienopyridine derivative, when R1 is 2 position fluorine atom, the compound in the formula (c) is an important intermediate for preparing prasugrel. The structural formula of the compound is shown as the following: wherein, R1 is halogen or C1-C4 alkyl; R2 is C1-C4 alkyl.
Description
Technical field
The present invention relates to organic chemistry filed, particularly the carbocyclic ring technical field of chemistry.
Background technology
Aromatic nucleus propyl group ethyl ketone compounds is the important intermediate of tetrahydrobiopterin synthesis thienopyridine derivative, wherein important tetramethylene sulfide and pyridine derivate is prasugrel at present, chemistry 2-acetoxyl group-5-(a-cyclopropyl carbonyl-2-luorobenzyl)-4 by name, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine, structural formula is to be developed jointly by Japan three common (sankyo) and Lilly shown in following formula (1) compound, is used for the treatment of the medicine of thrombus.Method by aromatic nucleus propyl group ethyl ketone compounds tetrahydrobiopterin synthesis thienopyridine derivative is on the books in patent CN101177430 or patent CN101250193, announces that specifically route is as follows:
At present the synthetic of aromatic nucleus propyl group ethyl ketone compounds can be with reference to following document:
Reference one, patent WO2009122440 (date of publication on October 8th, 2009, contriver: RAO, people such as A.V.V.Srinivas) announces route:
The reaction process of this route is that 1-(brooethyl)-2-fluorobenzene and the reaction of magnesium simple substance make (2-luorobenzyl) magnesium chloride, and then carry out grignard reaction with the cyclopropyl nitrile, obtain 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone crude product, yield only is 72.18%, and cost is also higher.And the cyclopropyl nitrile is easy to generate by product prussiate and ethylene-acetic acid in reaction process, and this has also increased the cost and the difficulty of aftertreatment undoubtedly, and solvent for use is an ether in addition, and during technology, especially the high temperature area very easily produces dangerous.
Reference two, patent JP09031010 (date of publication on February 4th, 1997, the contriver: people such as horizontal field Shang Zhi, now getting wherein, best results one example is illustrated):
This reaction process is benzene, the tetrahydrofuran solution (1: 2) and 2-(2-fluorophenyl) acetate of isopropylmagnesium chloride under the anhydrous and oxygen-free condition, after triethylamine mixes stirring, drip the methyl cyclopropane carboxylic acid, need after reaction finishes to use the dilute hydrochloric acid cancellation, obtain 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone crude product.The isopropylmagnesium chloride consumption is 3.5 times of reaction substrate in this reaction, after reaction finishes, cause a large amount of isopropylmagnesium chlorides that residue is arranged, can produce a large amount of magnesium chloride solids after the cancellation during aftertreatment, can increase difficulty of post-processing during technology, need a large amount of solvents that reaction liquid is washed, otherwise can reduce the yield of product 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, isopropylmagnesium chloride market value costliness, a large amount of application (consumption is 3.5 times of reaction substrate herein) makes the cost of reaction very high, and is unfavorable for environmental protection.Isopropylmagnesium chloride is all very strict to preservation and operational requirement in addition, preserves misoperation, oxidation easily, hydrolysis.Simultaneously, this method requires harsh to temperature of reaction, need remain in the constant temp scope, and the benzene of using in the reaction solvent has very big toxicity; To use dilute hydrochloric acid in the aftertreatment, increase cost.
In view of aromatic nucleus propyl group ethyl ketone compounds excellent drug prospect, therefore need exploitation a kind of more economical, easy being used to prepares the preparation method of aromatic nucleus propyl group ethyl ketone compounds.
Summary of the invention
The objective of the invention is to adopt highly basic, substitute isopropylmagnesium chloride, it is serious to overcome the environmental pollution of prior art cyclopropyl nitrile, easily produces prussiate; The isopropylmagnesium chloride instability, the aftertreatment difficulty, environmental pollution is serious, and is strict to anhydrous oxygen condition, and reaction solvent toxicity is big, and the shortcoming that cost is high provides a kind of more economical, and easy being used to prepares the synthetic method of aromatic nucleus propyl group ethyl ketone compounds.
To achieve these goals, the present invention adopts following technical scheme:
R wherein
1Be halogen or C
1-C
4Alkyl; R
2Be C
1-C
4Alkyl; Described halogen is specially: F, Cl; C
1-C
4Alkyl be specially methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl.
Concrete reaction process is: formula (a) compound mixes stirring with highly basic after, the solution adding reaction system with formula (b) compound obtains formula (c) compound, just aromatic nucleus propyl group ethyl ketone compounds.
Described highly basic is sodium hydride, hydrolith, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
The reaction solvent of this reaction is selected from ethers, substituted benzene, and the benzene class, alkanes, or its any two or more mixed solvent are preferably ether, tetrahydrofuran (THF), benzene, toluene, normal hexane or its be two or more mixed solvent arbitrarily; When described highly basic was pure quasi-alkali, solvent also can be alcoholic solvent.
Described solvent load is 10～50 times of described formula (a) compound, is preferably 15～30 times.
Described formula (a) compound is 1 with described alkaline mole dosage ratio: (1～5); The mole dosage ratio of described formula (a) compound and formula (b) compound is 1: (1～1.1); Temperature of reaction is 10～40 ℃, 6～24 hours reaction times, preferred 10～15 hours.
When wherein R1 was 2 fluorine atoms, formula (c) compound was the intermediate of synthetic prasugrel.
The present invention utilizes the highly basic compounds as reaction reagent aspect preparation aromatic nucleus propyl group ethyl ketone compounds, and reaction type is oversimplified, and is simple substitution reaction; This type of reagent is more stable than isopropylmagnesium chloride, reaction solution can not purifiedly promptly obtain the purity high product during aftertreatment after the ammonium chloride cancellation, and by product is a sodium chloride salt soluble in water, the reaction preferred solvent is an alcohols, has effectively reduced the pollution to environment; Because highly basic class reagent its cheap market price has also effectively reduced the cost for preparing aromatic nucleus propyl group ethyl ketone compounds simultaneously.Therefore the present invention has very high industrial application and economic worth.
Embodiment
Content for a better understanding of the present invention is described further below in conjunction with specific embodiment.
The preparation of embodiment 1:1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone
With 2-(2-fluorophenyl) acetate (10.0g, 64.9mmol) add in the 30ml anhydrous tetrahydro furan, under 10 ℃, drip and contain sodium hydride (3.9g, 97.4mmol) and the muddy liquid of 140mL tetrahydrofuran (THF) in, drip to finish reaction mixture is heated to 30 ℃ of stirrings 1 hour, drip then the methyl cyclopropyl-carboxylic acid (7.0ml, 69.8mmol, 1.07eq) and the mixed solution of 30ml anhydrous tetrahydro furan, dropwising the back continues to stir 10 hours, after finishing, reaction drips the unnecessary sodium hydride of ammonium chloride solution cancellation, separatory, extraction, organic phase concentrates, the liquid underpressure distillation of gained obtains 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 10.8g, and yield is 93.5%.
1H?NMR(CDCl
3，Me
4Si)δ0.86-0.90(m，2H)，1.05-1.08(m，2H)，1.97-2.02(m，1H)，3.87(s，2H)，7.04-7.18(m，2H)，7.18-7.27(m，2H)；MS(EI)：179.1[M+1]。
The preparation of embodiment 2:1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone
With 2-(2-fluorophenyl) acetate (10.0g, 64.9mmol) add in the 30ml anhydrous methanol, under 10 ℃, drip and contain sodium methylate (4.6g, 85mmol) and in the muddy liquid of 100ml methyl alcohol, drip to finish reaction mixture is heated to 30 ℃ of stirrings 1 hour, drip methyl cyclopropyl-carboxylic acid (7.0ml then, 69.8mmol, 1.07eq) and the mixed solution of 30ml methyl alcohol, dropwise the back and continue to stir reaction in the 10 hours back that finishes and drip the unnecessary sodium methylate of ammonium chloride solution cancellation, separatory, extraction, organic phase concentrates, the liquid underpressure distillation of gained, obtain 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 9.4g, yield is 81.3%.
The preparation of embodiment 3:1-cyclopropyl-2-(3-toluene) ethyl ketone
Take by weighing 2-(3-toluene) acetate 10.0g, sodium hydride 4.0g operates with method according to the method for embodiment 1, obtains 1-cyclopropyl-2-(3-toluene) ethyl ketone 9.18g, and yield is 79.2%.
The preparation of embodiment 4:2-(2-chloro-phenyl-)-1-cyclopropyl ethyl ketone
Take by weighing 2-(2-chloro-phenyl-) acetate 10.0g, sodium tert-butoxide 6.8g operates with method according to the method for embodiment 1, obtains 2-(2-chloro-phenyl-)-1-cyclopropyl ethyl ketone 9.9g, and yield is 86.4%.
The preparation of embodiment 5:1-cyclopropyl-2-(2-sec.-propyl) ethyl ketone
Take by weighing 2-(2-isopropyl phenyl) acetate 10.0g, sodium tert-butoxide 8.0g operates with method according to the method for embodiment 1, obtains 1-cyclopropyl-2-(2-sec.-propyl) ethyl ketone 8.37g, and yield is 73.8%.
In sum, the present invention relates to the preparation method of aromatic nucleus propyl group ethyl ketone compounds.Above-mentioned preparation method is formula (a) compound is mixed stirring with highly basic after, react with formula (b) compound, obtain aromatic nucleus propyl group ethyl ketone compounds, when 2 of formula (c) compounds are fluorine atom, be 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, it is the important intermediate of preparation prasugrel.
Need to prove that all documents of mentioning in the present invention quote as a reference in this application, just quoted as a reference separately as each piece document.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (5)
1. the preparation method of an aromatic nucleus propyl group ethyl ketone compounds, by mix with highly basic as shown in the formula (a) compound stir after, with the reaction of formula (b) compound, obtain aromatic nucleus propyl group ethyl ketone compounds, i.e. formula (c) compound,
R wherein
1Be halogen or C
1-C
4Alkyl; R
2Be C
1-C
4Alkyl.
2. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, wherein R
1Be 2 fluorine atoms; R
2Be methyl.
3. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, wherein said halogen is F, Cl.
4. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, wherein said highly basic is sodium hydride, hydrolith, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium tert-butoxide.
5. the purposes of formula according to claim 1 (c) compound is used to prepare tetramethylene sulfide and pyridine derivatives.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617593A (en) * | 2012-03-13 | 2012-08-01 | 山东新华制药股份有限公司 | Method for preparing prasugrel intermediate |
| CN115124440A (en) * | 2022-06-27 | 2022-09-30 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101070278A (en) * | 2007-06-08 | 2007-11-14 | 上海万凯化学有限公司 | Phenyl-3-(3-trifluoro-methyl-phenyl)-2-propanone |
-
2010
- 2010-06-10 CN CN201010199108.XA patent/CN102276436B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101070278A (en) * | 2007-06-08 | 2007-11-14 | 上海万凯化学有限公司 | Phenyl-3-(3-trifluoro-methyl-phenyl)-2-propanone |
Non-Patent Citations (1)
| Title |
|---|
| 程兴栋: "普拉格雷的合成工艺研究", 《CHINESE JOURNAL OF NEW DRUGS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617593A (en) * | 2012-03-13 | 2012-08-01 | 山东新华制药股份有限公司 | Method for preparing prasugrel intermediate |
| CN115124440A (en) * | 2022-06-27 | 2022-09-30 | 江苏七洲绿色科技研究院有限公司 | Preparation method of prothioconazole intermediate |
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