CN102452984B - 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
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- CN102452984B CN102452984B CN 201010514510 CN201010514510A CN102452984B CN 102452984 B CN102452984 B CN 102452984B CN 201010514510 CN201010514510 CN 201010514510 CN 201010514510 A CN201010514510 A CN 201010514510A CN 102452984 B CN102452984 B CN 102452984B
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000741 silica gel Substances 0.000 claims abstract description 6
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 claims description 15
- 229960002140 medetomidine Drugs 0.000 claims description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- 229920002554 vinyl polymer Polymers 0.000 claims description 10
- 150000002460 imidazoles Chemical class 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229960001866 silicon dioxide Drugs 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- JLXZMLLNPNOODV-UHFFFAOYSA-N imidazol-4-one Chemical compound O=C1C=NC=N1 JLXZMLLNPNOODV-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical group CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229910052698 phosphorus Inorganic materials 0.000 abstract 1
- 239000011574 phosphorus Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- IJJURYQDEVNZCW-UHFFFAOYSA-N bromophosphane Chemical compound BrP IJJURYQDEVNZCW-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 3
- 229960004253 dexmedetomidine Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 2
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- -1 methyl grignard reagent Chemical class 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000001242 postsynaptic effect Effects 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- NPZDCTUDQYGYQD-UHFFFAOYSA-N 1-tritylimidazole Chemical class C1=NC=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NPZDCTUDQYGYQD-UHFFFAOYSA-N 0.000 description 1
- LCNIHGANDPAESH-UHFFFAOYSA-N 2,3-dimethyl-1-tritylimidazolidin-4-one Chemical compound CC1N(CC(N1C)=O)C(C1=CC=CC=C1)(C1=CC=CC=C1)C1=CC=CC=C1 LCNIHGANDPAESH-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002181 anti-sympathetic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
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 synthetic medetomidine intermediate 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl of a kind of employing Ylide reaction]-method of 1-R1-2-R2 imidazoles, be mainly used in the application of medetomidine medicine important intermediate in synthetic.
Background technology
(±)-4-[1-(2,3-3,5-dimethylphenyl) ethyl]-the 1H-imidazoles, the Chinese name medetomidine, English name Medetomidine is considered to selective and effective α
2-acceptor gaonist thing.(+)-(S)-4-[1-(2,3-3,5-dimethylphenyl) ethyl]-the 1H-imidazoles, namely the dextrorotation enantiomorph of medetomidine has following structure:
, dexmedetomidine is the active dextrorotatory isomer of medetomidine, has anti-sympathetic, calmness and analgesic effect, compares with medetomidine, this product is stronger to the selectivity of α 2 adrenoceptor excitement, is 8 times of clonidine to α 2-adrenoceptor.In the main pharmacology and treatment effect of mediation this product, 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 norepinephrine.This product has suppressed the release of norepinephrine, and has stopped the conduction of pain signal by exciting presynaptic membrane alpha-2 receptor; By exciting postsynaptic membrane acceptor, thereby dexmedetomidine has suppressed the decline that sympathetic activity causes blood pressure and heart rate; Be combined when producing analgesic activity with the alpha-2 receptor in the spinal cord, can cause calmness and anxiety to be alleviated.This product can also reduce narcotic dosage, improves 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 intensive care unit(ICU) (ICU) short period of time (＜24 hours) in 1999, and because its unique pharmacological activity, in the research of many Europe and the U.S., dexmedetomidine also is applied in FDA regulation and the description of product various indications in addition.
The active methylene group intermediate
1Be the important intermediate during medetomidine synthesizes, this intermediate reduction can be obtained the medetomidine of medetomidine or band protection.Concrete reaction is as follows:
And this active methylene group intermediate
1Basically all be by the ketone intermediate
2Obtain, document Synthetic communication 26 (8) reports among the 1585-1593, with the ketone intermediate that obtains
2With the reaction of methyl grignard reagent, then process with triethyl silicon hydrogen and obtain medetomidine first; Document Synthesis 1991,11 reports among the 1021-1022, with the ketone intermediate
2Obtain medetomidine first with the lithium methide reaction, and then with the reduction of liquefied ammonia metallic lithium; Document US 4910214 then adopts the methyl grignard reagent first and the ketone intermediate among the GB2101114
2Then reaction obtains the target intermediate with the sal enixum high temperature dehydration.
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 object of the invention is to disclose a kind of synthetic 4-[1-(2,3-3,5-dimethylphenyl) ethene]-method of 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 synthetic method exists.
Technical scheme of the present invention is: 4-[1-(2, the 3-3,5-dimethylphenyl) ethene]-synthetic method of 1-R1-2-R2 imidazoles, adopt phosphonium ylide and 2, medetomidine intermediate 4-[1-(2,3-3,5-dimethylphenyl) vinyl is synthesized in the reaction of 3-3,5-dimethylphenyl-1-R1-2-R2 imidazol-4-one]-the 1-R1-2-R2 imidazoles.Reaction formula is as follows:
R1 is selected from a kind of in hydrogen, trityl or the dimethyl methyl amide group, and R2 is selected from hydrogen or t-Butyldimethylsilyl.
Reaction need to be stirred and to be spent the night (12-16 hour), reaction product after 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, is conducive to medetomidine key intermediate 4-[1-(2,3-3,5-dimethylphenyl) vinyl]-the industrial scale production of 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, then stirring at room is 4 hours.Then under agitation add 20g 2,3-3,5-dimethylphenyl imidazol-4-one finishes, and reactant is stirred spend the night.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column (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, then stirring at room is 4 hours.Then under agitation add 44.2g 2,3-dimethyl-1-(trityl) imidazol-4-one, finish, reactant is stirred spend the night.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column (elutriant is the sherwood oil ethyl acetate of concentration expressed in percentage by weight 10% to 20%) purifying obtains 41g 4-[1-(2,3 3,5-dimethylphenyls) vinyl]-the 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, then stirring at room is 4 hours.Then under agitation add 42.1g 2,3-3,5-dimethylphenyl-1-dimethyl methyl amide group-2-t-Butyldimethylsilyl imidazol-4-one finishes, and reactant is stirred spend the night.After reaction finishes, filter, filtrate decompression is concentrated into dried.Enriched material is crossed silicagel column (elutriant is the sherwood oil ethyl acetate of concentration expressed in percentage by weight 5% to 10%) purifying obtains 35.2g 4-[1-(2,3-3,5-dimethylphenyl) vinyl]-1-dimethyl methyl amide group-2-t-Butyldimethylsilyl imidazoles.
Claims (2)
1. a 4-[1-(2,3-3,5-dimethylphenyl) vinyl]-1-R
1-2-R
2The synthetic method of imidazoles is characterized in that adopting phosphonium ylide and 2,3-3,5-dimethylphenyl-1-R
1-2-R
2Synthetic medetomidine intermediate 4-[1-(2, the 3-3,5-dimethylphenyl) vinyl of imidazol-4-one reaction]-1-R
1-2-R
2Imidazoles, reaction formula is as follows:
R
1Be selected from a kind of in hydrogen, trityl or the dimethyl methyl amide group, R
2Be selected from hydrogen or t-Butyldimethylsilyl.
2. 4-[1-according to claim 1 (2,3-3,5-dimethylphenyl) vinyl]-1-R
1-2-R
2The synthetic method of imidazoles, it is characterized in that reaction need to be stirred spends the night, reaction product after filtration, concentrated, silicagel column washing purifying.
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| CN103588711B (en) * | 2013-11-27 | 2015-04-08 | 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
|---|
| AlexA.Cordi et al..Efficient synthesis of (s)-4(5)-[1-(2 |
| Efficient synthesis of (s)-4(5)-[1-(2,3-dimethylphenyl)rthyl]imidazole tarttrate,the potent α2 adrenoceptor agonist dexmedetomidine;Alex A.Cordi,et al.;《Synthetic Communications》;19961231;第26卷(第8期);第1585-1593页 * |
| Expedient Synthesis of 4(5)-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole,the α2-Adrenergic Agonist Medetomidine;Linas V.Kudzma, et al.;《Synthesis》;19911130;第1021-1022页 * |
| LinasV.Kudzma et al..Expedient Synthesis of 4(5)-[1-(2 |
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