CN104447562A - New method for preparing dexmedetomidine hydrochloride key intermediate - Google Patents

New method for preparing dexmedetomidine hydrochloride key intermediate Download PDF

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Publication number
CN104447562A
CN104447562A CN201410122655.6A CN201410122655A CN104447562A CN 104447562 A CN104447562 A CN 104447562A CN 201410122655 A CN201410122655 A CN 201410122655A CN 104447562 A CN104447562 A CN 104447562A
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Prior art keywords
dimethyl
imidazole
trityl
methyl
protecting group
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CN201410122655.6A
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黄道飞
周瑾
李冬明
徐骥
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NINGBO TEAM PHARM Co Ltd
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NINGBO TEAM PHARM Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides a method for preparing a dexmedetomidine hydrochloride key intermediate 4-(2,3-dimethyl benzoyl)-1-triphenylmethyl imidazole. The method is characterized in that 1-triphenylmethyl-4-(N-methyl-N-methoxy) imidazole formamide is used as a raw material and reacted with a Grignard reagent of 2,3-dimethyl halogenobenzene to obtain the 4-(2,3-dimethyl benzoyl)-1-triphenylmethyl imidazole. The steps of the method are simple, the reaction can well remain on 'ketone', the yield is high, and the raw materials are rich and convenient, so the method can be effectively used for industrial large-scale production.

Description

A kind of novel method preparing dexmedetomidine hydrochloride key intermediate
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate; especially a kind of be applicable to intensive care during start intubate and use the preparation method of medicine dexmedetomidine hydrochloride intermediate 4-(2,3-dimethylbenzoyl)-1-trityl imidazole of respirator patient calmness.
Background technology
Dexmedetomidine hydrochloride (English name: dexmedetomidine hydrochloride; Chemical name: (R)-4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles mono-hydrochloric salts) be α 2-adrenoceptor agonists that is efficient, highly selective, there is the effects such as the calmness of dose-dependently, analgesia, anxiety, sympathetic nerve suppression, few side effects and light, be used for calmness that intensive care unit(ICU) (ICU) is grown up, analgesia in 1999 in U.S.'s approval, and the application that succeeds in many clinical practices such as premedicate in neurosurgery, general anesthesia adjuvant, Postoperative Analgesia After, treatment withdrawal reaction.Its chemical structural formula is as follows:
Its preparation method is obtained through grignard reaction, elimination and asymmetric hydrogenation by " ketone " described in the invention; Also can be obtained, reference Synth.Commun, 1996,26 (8): 1585-1593 by conventional hydroprocessed rear fractionation.
4-(2 in having been reported, 3-dimethylbenzoyl) preparation method of-1-trityl imidazole mainly contains two lines: US20100048915 is with 2,3-dimethylbenzaldehyde is starting raw material, after 4-iodo-1-trityl imidazole generation grignard reaction, target product is obtained again through manganese dioxide, this route expensive raw material price, not easily obtains, and manganese dioxide aftertreatment is loaded down with trivial details; US4826864, reacts with the Grignard reagent of 2,3-dimethyl bromobenzene for starting raw material with imidazoles-4-carboxylate methyl ester; go up protection again and obtain target product, though this route is relatively short, yield is extremely low, by product is a lot of and want column chromatography; cause reaction uneconomical, cost is very high.
Summary of the invention
The object of this invention is to provide the method that one prepares 4-(2,3-dimethylbenzoyl)-1-trityl imidazole.This method is for raw material with 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide; with 2; the organometallic reagent of 3-dimethyl halogeno-benzene reacts; obtain 4-(2,3-dimethylbenzoyl)-1-trityl imidazole, its synthesis step short (1 step); abundant raw material source is convenient; can hundred feather weight produce, low price, can be effective to large-scale production.
Another object of the present invention is to provide a kind of 1-trityl-4-novel key intermediates of (N-methyl-N-methoxy) Imidazole carboxamide and large-scale preparation method thereof.
Method of the present invention comprises the following steps:
1) 2,3-dimethyl halogeno-benzenes and MAGNESIUM METAL reaction, obtain the organomagnesium reagent of 2,3-dimethyl halogeno-benzene.
Or 2,3-dimethyl halogeno-benzene and butyllithium reaction, obtain the organolithium reagent of 2,3-dimethyl halogeno-benzene.
2) organomagnesium reagent of 2,3-dimethyl halogeno-benzenes and the reaction of 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide, obtain 4-(2,3-dimethylbenzoyl)-1-trityl imidazole.
Or the organolithium reagent of 2,3-dimethyl halogeno-benzene and 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide reaction, obtain 4-(2,3-dimethylbenzoyl)-1-trityl imidazole.
In step 1) and 2) in, 2,3-dimethyl halogeno-benzene is 2,3-dimethylated chlorobenzene, 2,3-dimethyl bromobenzenes and 2,3-dimethyl iodobenzene, preferably 2,3-dimethyl bromobenzenes.
In step 1) in, the mol ratio of 2,3-dimethyl halogeno-benzene and MAGNESIUM METAL is 1: 1 ~ 3, preferably 1: 1.5; Solvent for use is ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrochysene furan are fed, 2-methyltetrahydrofuran, and preferred tetrahydrochysene furan is fed.
In step 1) in, the mol ratio of 2,3-dimethyl halogeno-benzene and butyllithium is 1: 1 ~ 4, preferably 1: 2; Solvent for use is ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, preferred tetrahydrofuran (THF).
In step 2) in, the organomagnesium reagent of 2,3-dimethyl halogeno-benzene and the mol ratio of 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide are 1 ~ 10: 1, preferably 1 ~ 3: 1; Solvent for use is ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), 2-methyl tetrahydrochysene furan are fed, preferred tetrahydrofuran (THF).
In step 2) in, the organolithium reagent of 2,3-dimethyl halogeno-benzene and the mol ratio of 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide are 1 ~ 10: 1, preferably 1 ~ 3: 1; Solvent for use is ether, methyl tertiary butyl ether, isopropyl ether, tetrahydrochysene furan are fed, 2-methyltetrahydrofuran, preferred tetrahydrofuran (THF).
The present invention is for raw material with 1-protecting group-4-(N-methyl-N-methoxy) Imidazole carboxamide; with 2; organomagnesium reagent or the organolithium reagent of 3-dimethyl halogeno-benzene react, and obtain 4-(2,3-dimethylbenzoyl)-1-protecting group imidazoles.
Method synthetic route proposed by the invention is as follows:
In above reaction formula, protecting group R can be N, N-dimethyl methyl acyl group, trityl etc., and the protecting group that we select is trityl; Halogen can be chlorine, bromine, iodine, and what we selected is bromine.
Raw material 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide can be obtained by following approach:
In above reaction formula, CDMT is 2-chlorine-4,6-dimethoxy-1,3,5-triazine, and DMHH is N, O-dimethyl hydroxylamine hydrochloride, and DCC is N, N-dicyclohexylcarbodiimide.As can be seen from above synthetic route, 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide can be protected obtained again by imidazoles-4-formyl chloride and N, O-dimethyl hydroxylamine hydrochloride under the condition of acid binding agent made by triethylamine through Triphenyl methane chloride 99; Also obtained under the condition can making dewatering agent by 1-trityl imidazole-4-carboxylic acid and N, O-dimethyl hydroxylamine hydrochloride in N, N-dicyclohexylcarbodiimide; Also can by 1-trityl imidazole-4-carboxylic acid and chloro-4, the 6-dimethoxys of 2--1,3,5-triazines condensation, then and the reaction of N, O-dimethyl hydroxylamine hydrochloride obtained; Also can there is ester amine exchange reaction by 1-trityl imidazole-4-carboxylate methyl ester and N, O-dimethyl hydroxylamine hydrochloride under the effect of sodium carbonate to obtain.
Therefore the present invention takes up from raw material; first tetrahydrofuran (THF) and 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide stirring at room temperature are dissolved; nitrogen protection; drip 2 of 1mol/L; 3-3,5-dimethylphenyl magnesium bromide tetrahydrofuran solution; reaction is in-5 ~ 100 DEG C of temperature ranges; complete in 1-48h; drip saturated ammonium chloride solution; organic phase anhydrous sodium sulfate drying; obtain crude product except after desolventizing, crude product dehydrated alcohol is refining obtains 4-(2,3-dimethylbenzoyl)-1-trityl imidazole.
Synthetic route step of the present invention is short, simple to operate, yield is high and aftertreatment easy, is conducive to repetition and the preparation of expansion scale.
Embodiment
The present invention by the following specific embodiments son is described.By embodiment, the present invention may be better understood, but scope of the present invention is not by the restriction of these embodiments.
The preparation of embodiment 11-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide
By tetrahydrofuran (THF) 100mL, 1-trityl imidazole-4-carboxylic acid 25g stirring at room temperature is dissolved, add CDMT19g in batches, finish temperature in controlling and be no more than 30 DEG C of dropping triethylamine 29g, reaction 1 ~ 2h, it is complete that TLC shows raw material reaction, add DMHH21g, room temperature reaction spends the night, and TLC display reaction is complete, filter, filtrate reduced in volume is to dry; Add methylene dichloride 300mL stirring and dissolving, use water, saturated sodium bicarbonate aqueous solution, 1N dilute hydrochloric acid, water washing successively, anhydrous sodium sulfate drying, filter, be concentrated into dry, add 50mL sherwood oil (60 ~ 90) and stir 30min, filter, filter cake 50 DEG C of constant pressure and dry 6h, obtain 1-trityl-4-(N-methyl-N-methoxy) Imidazole carboxamide 23g, molar yield: 83.2%.
The preparation of embodiment 22,3-3,5-dimethylphenyl magnesium bromide tetrahydrofuran solution
Tetrahydrochysene furan is fed 100mL, and magnesium sheet 2.7g is placed in 1L there-necked flask, nitrogen protection, stirring at room temperature, drips 2,3-dimethyl bromobenzene 18.5g, drips off continuation stirred overnight at room temperature, so obtain 2, the 3-3,5-dimethylphenyl magnesium bromide tetrahydrofuran solutions of 1mol/L.
The preparation of embodiment 34-(2,3-dimethylbenzoyl)-1-(trityl) imidazoles
Tetrahydrochysene furan is fed 120mL, intermediate formula II20g is placed in 1L there-necked flask, nitrogen protection, stirring at room temperature is dissolved, drip 2 of 1mol/L, 3-3,5-dimethylphenyl magnesium bromide tetrahydrochysene furan feeds solution 200mL, drip Bi Fanying 1-2h, TLC monitors, react complete, slowly drip saturated ammonium chloride solution 200mL, stirring at room temperature 1h, stratification, organic phase saturated brine washs once, organic phase is through anhydrous sodium sulfate drying, suction filtration, appropriate tetrahydrofuran (THF) washing leaching cake, filtrate 40 DEG C is evaporated to and dryly obtains crude product 22g, add 100mL dehydrated alcohol backflow 30min, be cooled to 0 DEG C, stirring and crystallizing 1h, suction filtration, filter cake 60 DEG C of normal pressures dry to obtain 17.5g product formula I, HPLC purity: 99.42%, molar yield 78.6%. 1H NMR(CDCl 3)δ7.57(d，1H)，7.48(d，1H)，7.34(m，9H)，7.29(m，1H)，7.21(d，1H)，7.13(m，7H)，2.28(s，3H)，2.25(s，3H)。
C 31H 26N 20 cal. C84.13 H5.92 N6.33
(442.55) found 84.15 5.98 6.30 。

Claims (5)

1. prepare dexmedetomidine hydrochloride key intermediate 4-(2 for one kind; 3-dimethylbenzoyl) method of-1-protecting group imidazoles; it is characterized in that with 1-protecting group-4-(N-methyl-N-methoxy) Imidazole carboxamide for raw material; with 2; the organometallic reagent of 3-dimethyl halogeno-benzene reacts; obtain 4-(2,3-dimethylbenzoyl)-1-protecting group imidazoles.
2., according to claim 1, described protecting group is trityl.
3., according to claim 1, the organometallic reagent of 2,3-described dimethyl halogeno-benzenes is 2,3-3,5-dimethylphenyl magnesium bromide.
4. according to claim 1, the solvent that reaction uses is selected from ether solvent or ethers and alkanes mixed solvent, and preferred tetrahydrochysene furan is fed.
5., according to claim 1, the organometallic reagent of 2,3-dimethyl halogeno-benzene and the mol ratio of substrate 1-protecting group-4-(N-methyl-N-methoxy) Imidazole carboxamide are greater than 1: 1, and preferably 1 ~ 3: 1.
CN201410122655.6A 2014-03-27 2014-03-27 New method for preparing dexmedetomidine hydrochloride key intermediate Pending CN104447562A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632053A (en) * 2016-12-20 2017-05-10 青岛辰达生物科技有限公司 Dexmedetomidine hydrochloride intermediate resolution method
CN112194626A (en) * 2020-11-16 2021-01-08 康普药业股份有限公司 Synthesis method of medetomidine

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826864A (en) * 1981-07-10 1989-05-02 Farmos Group Ltd. Substituted imidazole derivatives useful as antihypertensive or antithromtic agent or divretic
EP1918282A1 (en) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Method for preparing medetomidine and its salts
CN101921234A (en) * 2009-06-12 2010-12-22 中国中化股份有限公司 Method for preparing dexmedetomidine
CN103588711A (en) * 2013-11-27 2014-02-19 天津炜捷制药有限公司 Preparation method for medetomidine intermediate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826864A (en) * 1981-07-10 1989-05-02 Farmos Group Ltd. Substituted imidazole derivatives useful as antihypertensive or antithromtic agent or divretic
EP1918282A1 (en) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Method for preparing medetomidine and its salts
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
CN101921234A (en) * 2009-06-12 2010-12-22 中国中化股份有限公司 Method for preparing dexmedetomidine
CN103588711A (en) * 2013-11-27 2014-02-19 天津炜捷制药有限公司 Preparation method for medetomidine intermediate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
王玉平，等: "盐酸右美托咪定的合成", 《广东药学院学报》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106632053A (en) * 2016-12-20 2017-05-10 青岛辰达生物科技有限公司 Dexmedetomidine hydrochloride intermediate resolution method
CN106632053B (en) * 2016-12-20 2019-01-08 徐州医科大学 A kind of method for splitting of dexmedetomidine hydrochloride intermediate
CN112194626A (en) * 2020-11-16 2021-01-08 康普药业股份有限公司 Synthesis method of medetomidine

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Address after: 315201, No. three, No. 6, Zhuang Road, Zhenhai District, Zhejiang, Ningbo

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