CN101747280B - Method for preparing detomidine and the intermediate thereof - Google Patents

Abstract

The invention provides a method for preparing detomidine and the intermediate thereof. The method for preparing the intermediate of the detomidine comprises the steps that: 4-imidazolecarboxamide is condensed with 2, 3-Dimethylbromobenzene to produce 4-(2, 3- dimethylbenzoyl)-imidazole. The 4-(2, 3- dimethylbenzoyl)-imidazole can be reduced to produce the detomidine. The method of the invention has cheap and easy-to-get raw materials, easy-to-control technological processes, high yield factor and low cost and is suitable for being produced in an industrialized manner.

Description

The method for preparing detomidine and intermediate thereof

Technical field

The present invention relates to prepare the method for detomidine and intermediate thereof.

Background technology

Detomidine (Detomidine) chemistry 4-(2, the 3-dimethyl benzyl) by name-1H-imidazoles, its structural formula is as follows:

Detomidine is a veterinary anaesthetic drugs, and this medicine has calmness and analgesic activity to multiple animal, and is especially better to horse and Niu Xiaoguo.This medicine is the same with xylazine (Xylazine) with clonidine, also belongs to maincenter α _ 2 adrenergic receptor stimulants.

U.S. Pat 4443466 has been reported the synthetic method of detomidine, and synthetic route is as follows:

The technology of above-mentioned patent report is a raw material with the imidazole aldehyde, with 2, and the condensation of 3-dimethyl bromobenzene, and then reduction generates detomidine.Because the raw material otan dipolymer of synthetic imidazole aldehyde is difficult to buy, and obtains the yield also low (26%) of imidazole aldehyde, with the synthetic detomidine raw materials cost height of this method.

Summary of the invention

The purpose of this invention is to provide a kind of method for preparing detomidine and intermediate thereof, to overcome the above-mentioned defective that prior art exists.

The method for preparing the detomidine intermediate of the present invention comprises the steps:

The 4-Imidazole carboxamide is suspended in the organic bases solvent, 60-70 ℃ adds 2 down, the Grignard reagent of 3-dimethyl bromobenzene, reacted then 1.5～2.5 hours, be cooled to 0-10 ℃, add the saturated ammonium chloride solution termination reaction, from reaction product, collect 4-(2 then, the 3-dimethylbenzoyl)-and imidazoles, be the intermediate for preparing detomidine;

Described 4-Imidazole carboxamide can be separated easily by imidazole carboxylate ammonia and obtain, and this method is not seen bibliographical information;

Described organic bases is selected from pyridine, triethylamine or 2,4-dimethylamino pyridine, most preferably pyridine;

4-Imidazole carboxamide and 2, the mol ratio of 3-dimethyl bromobenzene are 1:2-1:8, and that better is 1:4-1:6;

The synthetic method of detomidine of the present invention comprises the steps:

(a) the 4-Imidazole carboxamide is suspended in the organic bases solvent, 60-70 ℃ adds 2 down, the Grignard reagent of 3-dimethyl bromobenzene, reacted then 1.5～2.5 hours, be cooled to 0-10 ℃, add the saturated ammonium chloride solution termination reaction, from reaction product, collect 4-(2 then, the 3-dimethylbenzoyl)-and imidazoles, be the intermediate for preparing detomidine;

Described 4-Imidazole carboxamide can be separated easily by imidazole carboxylate ammonia and obtain;

Described organic bases is selected from pyridine, triethylamine or 2,4-dimethylamino pyridine, most preferably pyridine;

4-Imidazole carboxamide and 2, the mol ratio of 3-dimethyl bromobenzene are 1:2-1:8, and that better is 1:4-1:6;

(b) with 4-(2, the 3-dimethylbenzoyl)-imidazoles in organic solvent, alkaline matter exists down and the reduction reagent react, collects 4-(2, the 3-dimethyl benzyl)-1H-imidazoles (detomidine) then from reaction product;

Described organic solvent is selected from ethylene glycol 1,2-propylene glycol, 1, ammediol or neopentyl glycol;

Described alkaline matter is selected from potassium hydroxide, sodium hydroxide or calcium hydroxide, and the mol ratio of alkaline matter and 4-(2, the 3-dimethylbenzoyl)-imidazoles is 4-6:1;

Temperature of reaction is 120～200 ℃, and the reaction times is 1～2 hour, and 4-(2, the 3-dimethylbenzoyl)-imidazoles is 1:2～1:6 with the mol ratio of going back original reagent;

The described original reagent preferably water of going back is closed hydrazine;

Reaction expression is as follows:

The method of synthetic detomidine of the present invention and intermediate thereof, raw material sources cheaply are easy to get, and technological operation is easy to control, the yield height, cost is low, is fit to suitability for industrialized production.

Embodiment

The present invention is further detailed explanation below in conjunction with embodiment.

Embodiment 1

The preparation of 4-Imidazole carboxamide:

4-imidazole carboxylate (8.5g) is joined in the water (68ml), blasts ammonia, reflux 6 hours, concentrate white solid, acetone (10ml) making beating refining white solid 6.7g, be the 4-Imidazole carboxamide, mother liquor reclaims to merge and can continue ammonia and separate.

Embodiment 2

The preparation of 4-(2, the 3-dimethylbenzoyl)-imidazoles

(45.0g 1.88mol) covers with the 150ml tetrahydrofuran (THF) with magnesium chips.With 2, (220.0ml 1.62mol) is dissolved in the 600ml tetrahydrofuran (THF) 3-dimethyl bromobenzene.This drips of solution is added in the magnesium chips, continues after the initiation reaction slowly to drip, keep refluxing.After adding, reflux is intact to reactive magnesium, reacts to obtain Grignard reagent in 30 minutes again.

(50.0g 0.45mol) is suspended in the 1500ml pyridine, is heated to 70 ℃, drips above-mentioned Grignard reagent, drips the back insulation reaction 2 hours with the 4-Imidazole carboxamide.Ice bath is cooled to 0 ℃, drips 1500ml saturated ammonium chloride solution termination reaction, and interior temperature control is at 5 ℃.With the gained solid filtering, filtrate layering, water layer ethyl acetate extraction three times (500ml * 3).The organic layer drying, evaporate to dryness is used the ether crystallization.The gained crystal is filtered, and washing gets yellow solid 48.2g.

Embodiment 3

The preparation of 4-(2, the 3-dimethylbenzoyl)-imidazoles:

(72.0g 3.00mol) covers with the 240ml tetrahydrofuran (THF) with magnesium chips.With 2, (350.0ml 2.58mol) is dissolved in the 800ml tetrahydrofuran (THF) 3-dimethyl bromobenzene.This drips of solution is added in the magnesium chips, continues after the initiation reaction slowly to drip, keep refluxing.After adding, reflux is intact to reactive magnesium, reacts to obtain Grignard reagent in 30 minutes again.

(50.0g 0.45mol) is suspended in the 1500ml pyridine, is heated to 60 ℃, drips above-mentioned Grignard reagent, drips the back insulation reaction 2 hours with the 4-Imidazole carboxamide.The ice bath cooling drips 1500ml saturated ammonium chloride solution termination reaction down, and interior temperature control is at 5 ℃.With the gained solid filtering, filtrate layering, water layer ethyl acetate extraction three times (500ml * 3).The organic layer drying, evaporate to dryness is used the ether crystallization.The gained crystal is filtered, and washing gets yellow solid 50.1g.

Embodiment 4

The preparation of 4-(2, the 3-dimethylbenzoyl)-imidazoles

(2.4g 0.10mol) covers with the 10ml tetrahydrofuran (THF) with magnesium chips.With 2, (12.5ml 0.092mol) is dissolved in the 40ml tetrahydrofuran (THF) 3-dimethyl bromobenzene.This drips of solution is added in the magnesium chips, continues after the initiation reaction slowly to drip, keep refluxing.After adding, reflux is intact to reactive magnesium, reacts to obtain Grignard reagent in 30 minutes again.

(5.0g 0.045mol) is suspended in the 150ml pyridine, is heated to 60 ℃, drips above-mentioned Grignard reagent, drips the back insulation reaction 2 hours with the 4-Imidazole carboxamide.The ice bath cooling drips 150ml saturated ammonium chloride solution termination reaction down, and interior temperature control is at 0 ℃.With the gained solid filtering, filtrate layering, water layer ethyl acetate extraction three times (50ml * 3).The organic layer drying, evaporate to dryness is used the ether crystallization.The gained crystal is filtered, and washing gets yellow solid 2.5g.

Embodiment 5

The preparation of 4-(2, the 3-dimethylbenzoyl)-imidazoles

(8.8g 0.37mol) covers with the 35ml tetrahydrofuran (THF) with magnesium chips.With 2, (45.0ml 0.33mol) is dissolved in the 120ml tetrahydrofuran (THF) 3-dimethyl bromobenzene.This drips of solution is added in the magnesium chips, continues after the initiation reaction slowly to drip, keep refluxing.After adding, reflux is intact to reactive magnesium, reacts to obtain Grignard reagent in 30 minutes again.

(5.0g 0.045mol) is suspended in the 150ml pyridine, is heated to 70 ℃, drips above-mentioned Grignard reagent, drips the back insulation reaction 2 hours with the 4-Imidazole carboxamide.The ice bath cooling adds 150ml saturated ammonium chloride solution termination reaction down, and interior temperature control is at 0 ℃.With the gained solid filtering, filtrate layering, water layer ethyl acetate extraction three times (50ml * 3).The organic layer drying, evaporate to dryness is used the ether crystallization.The gained crystal is filtered, and washing gets yellow solid 4.5g.

Embodiment 6

The preparation of 4-(2,3-dimethyl benzene ylmethyl)-imidazole hydrochloride (detomidine)

(15.0g 0.27mol) joins in the 60ml ethylene glycol, is heated to solid and all dissolves with potassium hydroxide.Add 4-(2, the 3-dimethylbenzoyl)-imidazoles (10.0g, 0.050mol), weight concentration is that (10ml 0.20mol), is heated to 50 ℃ to 100% hydrazine hydrate, continues to be heated to 150 ℃ and insulation reaction after the initiation reaction 1 hour.To react and produce moisture and steam, and follow the tracks of to react to raw material and disappear.Pressure reducing and steaming ethylene glycol carries out elutriation with 1000ml water.The dry crude product that gets.Activated carbon decolorizing, acetone recrystallization obtain white solid (4-(2,3-dimethyl benzene ylmethyl)-imidazoles) 5.0g, are the target product detomidine.

4-(2,3-dimethyl benzene ylmethyl)-imidazoles (5.0g) is added 100ml acetone, and heating for dissolving is cooled to room temperature.With 4ml 30%HCl-ethanolic soln 10ml acetone diluted, be added drop-wise in the aforementioned solution under the room temperature, there is solid to separate out.0 ℃ of crystallization 1 hour, crystal is filtered again, use washing with acetone, dry must Dormosedan 5.4g.HPLC detects purity 99.97%.

Claims (9)

1. prepare 4-(2; the 3-dimethylbenzoyl)-method of imidazoles; it is characterized in that; comprise the steps: the 4-Imidazole carboxamide is suspended under the organic bases solvent action; with 2; 4-(2, the 3-dimethylbenzoyl)-imidazoles is collected in the Grignard reagent reaction of 3-dimethyl bromobenzene then from reaction product.

2. method according to claim 1 is characterized in that, the 4-Imidazole carboxamide is suspended under the organic bases solvent action, 60-70 ℃ adds 2 down, and the Grignard reagent reaction of 3-dimethyl bromobenzene was reacted 1.5～2.5 hours then, be cooled to 0-10 ℃, add the saturated ammonium chloride solution termination reaction.

3. method according to claim 1 is characterized in that, described organic bases is selected from pyridine, triethylamine or 2,4-dimethylamino pyridine.

4. method according to claim 1 is characterized in that, 4-Imidazole carboxamide and 2, and the mol ratio of 3-dimethyl bromobenzene is 1: 2-1: 8.

5. method according to claim 1 is characterized in that, described 4-Imidazole carboxamide is separated by imidazole carboxylate ammonia and obtained.

6. the synthetic method of a detomidine is characterized in that, comprises the steps:

(a) the 4-Imidazole carboxamide is suspended under the organic bases solvent action, with 2,4-(2, the 3-dimethylbenzoyl)-imidazoles is collected in the reaction of the Grignard reagent of 3-dimethyl bromobenzene then from reaction product,

(b) with 4-(2, the 3-dimethylbenzoyl)-imidazoles in organic solvent, alkaline matter exists down and the reduction reagent react, collects 4-(2, the 3-dimethyl benzyl)-1H-imidazoles (detomidine) then from reaction product; The described original reagent of going back is a hydrazine hydrate.

7. method according to claim 6; it is characterized in that; the 4-Imidazole carboxamide is suspended in the organic bases solvent; 60-70 ℃ adds 2 down, and the Grignard reagent of 3-dimethyl bromobenzene reacted 1.5～2.5 hours then; be cooled to 0-10 ℃; add the saturated ammonium chloride solution termination reaction, from reaction product, collect 4-(2, the 3-dimethylbenzoyl)-imidazoles then.

8. method according to claim 7 is characterized in that, described organic bases is selected from pyridine, triethylamine or 2,4-dimethylamino pyridine.

9. method according to claim 7 is characterized in that, 4-Imidazole carboxamide and 2, and the mol ratio of 3-dimethyl bromobenzene is 1: 2-1: 8, described organic solvent is selected from ethylene glycol, 1,2-propylene glycol, 1, ammediol or neopentyl glycol;

Described alkaline matter is selected from potassium hydroxide, sodium hydroxide or calcium hydroxide, and the mol ratio of alkaline matter and 4-(2, the 3-dimethylbenzoyl)-imidazoles is 4-6: 1;

Temperature of reaction is 120～200 ℃, and the reaction times is 1～2 hour, and 4-(2, the 3-dimethylbenzoyl)-imidazoles is 1: 2～1: 6 with the mol ratio of going back original reagent.