CN102452984A - Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole - Google Patents
Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole Download PDFInfo
- Publication number
- CN102452984A CN102452984A CN2010105145102A CN201010514510A CN102452984A CN 102452984 A CN102452984 A CN 102452984A CN 2010105145102 A CN2010105145102 A CN 2010105145102A CN 201010514510 A CN201010514510 A CN 201010514510A CN 102452984 A CN102452984 A CN 102452984A
- Authority
- CN
- China
- Prior art keywords
- dimethylphenyl
- vinyl
- imidazole
- reaction
- imidazoles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole, and mainly solves the technical problems of expensive reagents, complex operations, and no benefit to industrial production for existing synthetic methods. The technical scheme of the invention is that: the synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole allows phosphorus ylide and 2,3-dimethylphenyl-1-R1-2-R2 imidazole-4-ketone to react so as to synthesize 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole. The reaction needs stirring overnight (12-16 hours), and the reaction product is filtered, concentrated, washed and purified by a silica gel column. The product is an important intermediate in pharmaceutical synthesis.
Description
Technical field
The present invention relates to the method for the synthetic medetomidine midbody 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] of a kind of employing Ylide reaction-1-R1-2-R2 imidazoles, be mainly used in the application of medetomidine medicine important intermediate in synthetic.
Background technology
(±)-4-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles, the Chinese name medetomidine, English name Medetomidine is considered to selective and effective α
2-acceptor gaonist thing.[1-(2 for (+)-(S)-4-; The 3-3,5-dimethylphenyl) ethyl]-the 1H-imidazoles; The dextrorotation enantiomorph that is medetomidine has following structure:
; Dexmedetomidine is the active dextrorotatory isomer of medetomidine, has anti-sympathetic, calmness and analgesic effect, compares with medetomidine; These article are stronger to the exciting selectivity of maincenter α 2-adrenoceptor, are 8 times of clonidine to α 2-adrenoceptor.In the main pharmacology and treatment effect of these article of mediation, α 2A receptor subtype plays an important role, and α 2A acceptor is present in presynaptic and postsynaptic, relates generally to the release and the neuronic excitement that suppress sympathin.These article have suppressed the release of sympathin, and have stopped the conduction of pain signal through exciting presynaptic membrane alpha-2 receptor; Through exciting postsynaptic membrane acceptor, thereby dexmedetomidine has suppressed the decline that sympathetic activity causes blood pressure and heart rate; When combining to produce analgesic activity, can cause calmness and anxiety to be alleviated with alpha-2 receptor in the spinal cord.These article can also reduce narcotic dosage, improve hemodynamic stability and the incidence that reduces myocardial ischaemia in the operation.United states drug and food control office (FDA) have ratified its calmness and analgesic as adult's CICU (ICU) short period of time (< 24 hours) in 1999; And because its unique pharmacological activity; In the research of the many Europe and the U.S., dexmedetomidine also is applied in FDA regulation and the various indications beyond the description of product.
The active methylene group midbody
1Be the important intermediate during medetomidine synthesizes, this midbody reduction can be obtained the medetomidine of medetomidine or band protection.The concrete reaction as follows:
And this active methylene group midbody
1Basically all be by the ketone midbody
2Obtain, document Synthetic communication 26 (8) reports among the 1585-1593, with the ketone midbody that obtains
2With the reaction of methyl grignard reagent, handle with triethyl silicon hydrogen then and obtain medetomidine earlier; Document Synthesis 1991,11 reports among the 1021-1022, with the ketone midbody
2Obtain medetomidine earlier with the lithium methide reaction, and then with the reduction of liquefied ammonia metallic lithium; Document US 4910214 then adopts methyl grignard reagent elder generation and ketone midbody among the GB2101114
2Reaction obtains the target midbody with the sal enixum high temperature dehydration then.
These synthetic routes of above-reported have adopted relatively more expensive reagent, and the operation of suitability for industrialized production is also more loaded down with trivial details, is unfavorable for suitability for industrialized production.
Summary of the invention
The objective of the invention is to disclose the method for a kind of synthetic 4-[1-(2, the 3-3,5-dimethylphenyl) ethene]-1-R1-2-R2 imidazoles, mainly solve the technical problem that reagent is expensive, complex operation is unfavorable for suitability for industrialized production that existing compound method exists.
Technical scheme of the present invention is: [1-(2 for 4-; The 3-3,5-dimethylphenyl) ethene]-compound method of 1-R1-2-R2 imidazoles; Adopt phosphonium ylide and 2; Medetomidine midbody 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl]-1-R1-2-R2 imidazoles is synthesized in the reaction of 3-3,5-dimethylphenyl-1-R1-2-R2 imidazol-4-one.Reaction formula is following:
R1 is selected from a kind of in hydrogen, trityl or the dimethyl methyl carboxamido-group, and R2 is selected from hydrogen or tertiary butyl dimethyl-is silica-based.
Reaction needs stirred overnight (12-16 hour), reaction product is through filtration, concentrated, silicagel column washing purifying.
The invention has the beneficial effects as follows: reaction conditions is gentle, and room temperature can be carried out, and yield is good, does not need polystep reaction, helps the industrial scale production of medetomidine key intermediate 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl]-1-R1-2-R2 imidazoles.
Embodiment
Embodiment 1
In the there-necked flask of 500mL, add 0.1mol n-butyllithium solution, anhydrous tetrahydro furan 200 mL, under agitation 35.7g trityl group bromo-phosphonium is added, stirring at room is 4 hours then.Then under agitation add 20g 2,3-3,5-dimethylphenyl imidazol-4-one finishes, with the reactant stirred overnight.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column, and (elutriant: the methanol dichloromethane of concentration expressed in percentage by weight 5% to 15%) purifying obtains 17.6g 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles.
Embodiment 2
In the there-necked flask of 500mL, add 0.1mol n-butyllithium solution, anhydrous tetrahydro furan 300 mL, under agitation 35.7g trityl group bromo-phosphonium is added, stirring at room is 4 hours then.Then under agitation add 44.2g 2,3-dimethyl--1-(trityl) imidazol-4-one finishes, with the reactant stirred overnight.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column (elutriant is the sherwood oil ETHYLE ACETATE of concentration expressed in percentage by weight 10% to 20%) purifying obtain 41g 4-[1-(2,3 3,5-dimethylphenyl) vinyl]-1-(trityl) imidazoles.
Embodiment 3
In the there-necked flask of 500mL, add 0.1mol n-butyllithium solution, anhydrous tetrahydro furan 300mL, under agitation 35.7g trityl group bromo-phosphonium is added, stirring at room is 4 hours then.Then under agitation add 42.1g 2, the 3-3,5-dimethylphenyl-1-dimethyl methyl carboxamido-group-silica-based imidazol-4-one of 2-tertiary butyl dimethyl-finishes, with the reactant stirred overnight.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column (elutriant is the sherwood oil ETHYLE ACETATE of concentration expressed in percentage by weight 5% to 10%) purifying obtain 35.2g 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl]-1-dimethyl methyl carboxamido-group-silica-based imidazoles of 2-tertiary butyl dimethyl-.
Claims (2)
1. [1-(2 for a 4-; The 3-3,5-dimethylphenyl) vinyl]-compound method of 1-R1-2-R2 imidazoles; It is characterized in that adopting phosphonium ylide and 2; 3-3,5-dimethylphenyl-synthetic medetomidine midbody the 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] of 1-R1-2-R2 imidazol-4-one reaction-1-R1-2-R2 imidazoles, reaction formula is following:
R1 is selected from a kind of in hydrogen, trityl or the dimethyl methyl carboxamido-group, and R2 is selected from hydrogen or tertiary butyl dimethyl-is silica-based.
2. the compound method of 4-according to claim 1 [1-(2, the 3-3,5-dimethylphenyl) vinyl]-1-R1-2-R2 imidazoles is characterized in that the reaction needs stirred overnight, and reaction product is through filtration, concentrated, silicagel column washing purifying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010514510 CN102452984B (en) | 2010-10-21 | 2010-10-21 | Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010514510 CN102452984B (en) | 2010-10-21 | 2010-10-21 | Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102452984A true CN102452984A (en) | 2012-05-16 |
| CN102452984B CN102452984B (en) | 2013-10-23 |
Family
ID=46036713
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010514510 Active CN102452984B (en) | 2010-10-21 | 2010-10-21 | Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102452984B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588711A (en) * | 2013-11-27 | 2014-02-19 | 天津炜捷制药有限公司 | Preparation method for medetomidine intermediate |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535272A (en) * | 2006-11-06 | 2009-09-16 | 格林代克斯联合股份公司 | Method for preparing medetomidine and its salts |
-
2010
- 2010-10-21 CN CN 201010514510 patent/CN102452984B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535272A (en) * | 2006-11-06 | 2009-09-16 | 格林代克斯联合股份公司 | Method for preparing medetomidine and its salts |
Non-Patent Citations (4)
| Title |
|---|
| 《Synthesis》 19911130 Linas V.Kudzma, et al. Expedient Synthesis of 4(5)-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole,the alpha2-Adrenergic Agonist Medetomidine 第1021-1022页 1-2 , * |
| 《Synthetic Communications》 19961231 Alex A.Cordi,et al. Efficient synthesis of (s)-4(5)-[1-(2,3-dimethylphenyl)rthyl]imidazole tarttrate,the potent alpha2 adrenoceptor agonist dexmedetomidine 第1585-1593页 1-2 第26卷, 第8期 * |
| ALEX A.CORDI,ET AL.: "Efficient synthesis of (s)-4(5)-[1-(2,3-dimethylphenyl)rthyl]imidazole tarttrate,the potent α2 adrenoceptor agonist dexmedetomidine", 《SYNTHETIC COMMUNICATIONS》 * |
| LINAS V.KUDZMA, ET AL.: "Expedient Synthesis of 4(5)-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole,the α2-Adrenergic Agonist Medetomidine", 《SYNTHESIS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588711A (en) * | 2013-11-27 | 2014-02-19 | 天津炜捷制药有限公司 | Preparation method for medetomidine intermediate |
| CN103588711B (en) * | 2013-11-27 | 2015-04-08 | 天津炜捷制药有限公司 | Preparation method for medetomidine intermediate |
| US9540331B2 (en) | 2013-11-27 | 2017-01-10 | Tianjin Weijie Pharmaceutical Co., Ltd | Preparation method of dexmedetomidine intermediate |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102452984B (en) | 2013-10-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2719590C2 (en) | Method of producing androgen receptor antagonists and their intermediate compounds | |
| JP2011513282A (en) | Process for producing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxobutyrate | |
| CN106749027B (en) | A kind of synthesis technology of dexmedetomidine hydrochloride intermediate | |
| CN105254567A (en) | Method for preparing dexmedetomidine hydrochloride key intermediate | |
| CN109705102A (en) | The preparation method of voriconazole and its intermediate | |
| CN102452984B (en) | Synthetic method of 4-[1-(2,3-dimethylphenyl)vinyl-1-R1-2-R2 imidazole | |
| CN106083724B (en) | A kind of preparation method of Dexmedetomidine | |
| US8912345B2 (en) | Method for preparing optically pure (−)-clausenamide compound | |
| KR20080046611A (en) | An improved process for the preparation of losartan | |
| CN104529872B (en) | A kind of synthetic method of benidipine hydrochloride intermediate | |
| CN103788023A (en) | Method for preparing styrene oxide through epoxidation of styrene | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN101891693B (en) | New method for preparing fluconazole | |
| CN1473825A (en) | Process for preparing voriconazole | |
| CN102127006B (en) | Production method of donepezil hydrochloride | |
| CN105461516A (en) | A synthetic process of L-menthol | |
| CN102417482B (en) | Method for synthesizing ozagrel ethyl ester or ozagrel methyl ester | |
| CN102344419A (en) | Preparation method of broad-spectrum antifungal drug fluconazole | |
| CN102850288A (en) | Method for preparing linezolid | |
| CN112194626A (en) | Synthesis method of medetomidine | |
| CN102351650B (en) | Method for preparing magnesium tert-butoxide | |
| CN107857731A (en) | A kind of process for preparing dexmedetomidine hydrochloride | |
| CN101676263A (en) | Method for synthesizing N-tert-butoxycarbonyl group-3-hydroxy azetidine | |
| CN103641772A (en) | Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound | |
| CN106588780A (en) | Process for preparing dexmedetomidine hydrochloride intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |