CN105884691A - Method for preparing dexmedetomidine and intermediate thereof - Google Patents

Method for preparing dexmedetomidine and intermediate thereof Download PDF

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CN105884691A
CN105884691A CN201610389029.2A CN201610389029A CN105884691A CN 105884691 A CN105884691 A CN 105884691A CN 201610389029 A CN201610389029 A CN 201610389029A CN 105884691 A CN105884691 A CN 105884691A
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CN105884691B (en
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侯宪山
王治安
徐燕
陈永江
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Jiangsu Hengrui Medicine 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
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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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Abstract

The invention provides a method for preparing dexmedetomidine and an intermediate thereof. Specifically speaking, the method comprises the steps that a compound shown as a formula II (please see the formula in the description) reacts with metal magnesium to prepare a metal magnesium Grignard reagent, and then the metal magnesium Grignard reagent reacts with a compound shown as a formula III (please see the formula in the description). The process has the advantages of being few in step, high in yield, easy to operate, high in product purity and the like and is quite suitable for large-scale industrialized production.

Description

A kind of method preparing dexmedetomidine and intermediate thereof
Technical field
The present invention relates to the preparation method of a kind of dexmedetomidine and intermediate thereof.
Background technology
Alpha-2 adrenergic receptor agonists is used to treat giving up of hypertension and medicine and ethanol clinically Symptom.This kind of medicine can produce anxiety, calmness, resist the effects such as sympathetic, can meet perioperative different need Want, thus anesthesia clinically is widely used.As the dexmedetomidine of one of α-2 receptor stimulating agent, Its chemistry entitled (S)-4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles, structure is as follows:
Dexmedetomidine by medetomidine split obtain, its hydrochlorate is dexmedetomidine hydrochloride, be by α-2 adrenoceptor agonists of OrionPharma/Abott company cooperation research and development exploitation, in 2000 3 The moon lists in the U.S., and in January, 2004 lists in Japan.Dexmedetomidine has anti-sympathetic, calm and analgesia Effect, this product is higher to the selectivity that maincenter α-2 adrenoceptor is exciting, is 8 times of clonidine, and Half-life is short, and consumption is little, starts to intubate and use respirator patient during being applicable to intensive care clinically Calmness, this product can also reduce narcotic dosage, improves hemodynamic stability and fall in operation The incidence rate of low myocardial ischaemia.Therefore, these product since listing just receive much concern.
At present, the method preparing medetomidine is broadly divided into two classes: a class is structure imidazole ring in building-up process, Method as shown in WO2012172121, WO2013011156 and WO2013011155；Another kind of, be The method synthesized with the substrate of imidazole ring-containing, the method as shown in WO2009053709 etc..But, due to Need when preparing imidazole ring use poisonous reagent Cyanogran. or use high temperature, high pressure and be passed through the side of ammonia Method, is unfavorable for its industrialized great production, therefore, prepares the method for medetomidine mainly based on the latter's method.
WO2009053709 discloses under lewis acid (e.g., titanium tetrachloride) is catalyzed, 1-(2,3-dimethyl Phenyl) ethanol reacts generation with the N-trimethyl silicon based imidazole needing toxic agent trim,ethylchlorosilane to carry out protecting The method of medetomidine, employs substantial amounts of strong-acid type lewis acid in the method, will necessarily give whole synthesis Technique causes trouble, needs to control moisture in building-up process, notes lewis acidic use, such as, four chlorinations Titanium has strong phenomenon of being fuming, and whole synthesis yield is the highest, is not suitable for technique and produces.
CN101805294 discloses under metallic zinc/lead catalytic condition, imidazoles and 2, and 3-dimethyl acetophenone enters The method that row is synthesized medetomidine.The method use hypertoxicity heavy metal, and its side reaction phenomenon ratio More apparent, the coupled product between two imidazole molecules is more, causes its throwing amount not to be directly proportional to producing material, does not meets Green chemical concept, therefore this type of reaction lacks certain application foundation in commercial production.
US4544664 discloses with 4-imidazolyl carboxylic acid methyl ester as initiation material, successively with 2, and 3-dimethyl benzene bromide Change magnesium and methyl-magnesium-bromide grignard reagent reaction preparation 1 (2,3 3,5-dimethylphenyl) 1 (1H imidazoles 4 base) ethanol, Carrying out eliminating preparing medetomidine with conventional hydroprocessed step, the most foregoing method, it has the most excellent again More property, this route is relatively short, but it is relatively difficult to control the competing conjunction in the reaction of two Grignard reagent, and both Molar ratio 1:1 to be reached.To this end, its process recovery ratio is on the low side, and need column chromatography, cause technique to produce into This is higher.
Its synthesis technique does not meets the theory of Green Chemistry simultaneously, produces more industry impurity, especially produces relatively Many special processes impurity, is unfavorable for carrying out of subsequent purification technique, and concrete structure is as follows.
Therefore, research simple and fast and the preparation method of effective dexmedetomidine, have become as the heat of this area Point problem.To this end, the present invention provides a kind of new synthesis thinking and route, whole synthetic route is brief, reduces It synthesizes cost；Simultaneously, it is to avoid harsh reaction condition, its reaction condition is simple, and process operability is strong, It is beneficial to its commercial production need, and reduces environmental protection pressure, it addition, its synthetic route is brief, it is possible to avoid certain The generation of process contaminants, alleviates the pressure of finished product purification.
Summary of the invention
The invention provides one and prepare type I compound, described method includes: by formula II compound and magnesium metal After magnesium metal Grignard reagent is prepared in reaction, then the step reacted with formula III compound, wherein, R1Selected from hydrogen, ammonia Base protection group, described amino protecting group preferably is selected from alkyl, trityl, tertbutyloxycarbonyl, p-toluenesulfonyl； R2And R3Be independently of one another hydrogen, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, aralkyl, Substituted or unsubstituted aryl or heteroaryl；R4Selected from alkyl, preferably methyl；X is halogen, selected from chlorine, Bromine, iodine, preferably be selected from bromine, iodine.
Specifically, the present invention uses " one pot of two-step method " synthetically prepared type I compound, first prepares formula II Magnesium metal grignard reagent, then carry out nucleophilic addition with stable starting material formula III compound, and obtain Type I compound.Described " one pot of two-step method ", i.e. in a reaction system, feeds and each by controlling each step Response time of step and complete continuous print two-step reaction, period is without the process of intermediate.
It is ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran that the present invention reacts solvent for use, Preferably oxolane.And during preparing grignard reagent, described formula II compound with the mol ratio of magnesium metal is 1:1-1:3, preferably 1:1-1:2.
In order to be beneficial to the process reacted, avoid extra impurity to produce simultaneously, need to control magnesium metal Grignard reagent It is 0-80 DEG C with the reaction temperature of formula III compound, preferably 10-40 DEG C, more preferably 20-35 DEG C.
Furthermore, described formula III compound and magnesium metal Grignard reagent mol ratio are 1:1-1:5, preferably 1:1-1:3。
Furthermore, formula I of the present invention is compound shown in formula IV, and formula II is compound shown in formula V, Formula III is compound shown in formula VI, and wherein, R1 is selected from hydrogen, amino protecting group, and described amino protecting group is preferred From alkyl, trityl, tertbutyloxycarbonyl, p-toluenesulfonyl；X is halogen, selected from chlorine, bromine, iodine.
As a rule, grignard reaction needs to carry out in anhydrous solvent, i.e. used solvent all needs to carry out anhydrous Change processes or the anhydrous solvent of the standard of purchase, even also needs to control the impact of moisture in course of reaction, selects Inert gas shielding, such as, argon or nitrogen.And present inventors have unexpectedly found that use contains the molten of 0.04-1% moisture The reaction yield of agent, reaction rate the most relatively usage amount anhydrous solvent or Conventional solvents good, its end product quality is the most relatively High.Furthermore, the moisture of solvent for use of the present invention is 0.04-1%, is preferable over 0.08-0.8%, Specific embodiment can be 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.7%, 0.8%.
Present invention also offers a kind of method preparing dexmedetomidine, including the above-mentioned step preparing formula IV compound Suddenly, then through dehydroxylation or dehydroxylation-deaminizating protection group, reduction, splitting step.
Dehydroxylation step condition of the present invention is trifluoroacetic acid/triethyl silicane, and described reduction step condition is Palladium carbon or platinum dioxide catalytic hydrogenation, its concrete reaction condition is well known to skilled person, can be found in " real With organic synthesis technique research and development handbook ".
As R in formula IV compound1Electing amino protecting group as, described amino protecting group preferably is selected from alkyl, triphen first When base, tertbutyloxycarbonyl, tolysulfonyl, the above-mentioned method preparing dexmedetomidine needs add a step and takes off The step of amino protecting group, is referred to as dehydroxylation-deaminizating protection group step in the present invention.
Present invention also offers a kind of method preparing dexmedetomidine officinal salt, prepare formula IV including above-mentioned The step of compound, then through dehydroxylation or dehydroxylation-deaminizating protection group, reduction, splitting step and with accordingly Acid become salt step, described salt be selected from hydrochlorate, hydrobromate, sulfate, preferably hydrochlorate, hydrobromic acid Salt, more preferably hydrochlorate:
" amino protecting group " of the present invention is the suitable group for amido protecting known in the art, ginseng See document (" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene&P.G.M. Wuts) the amido protecting group in, it is preferable that described amino protecting group can be (C1-10 alkyl or virtue Perfume base) acyl group, such as: formoxyl, and acetyl group, benzoyl etc.；Can be (C1-6 alkyl or C6-10 virtue Base) sulfonyl；Can also be (C1-6 alkoxyl or C6-10 aryloxy) carbonyl (such as, tertbutyloxycarbonyl), Boc, Cbz, trityl or p-toluenesulfonyl.
" alkyl " of the present invention refers to saturated aliphatic hydrocarbon group, including 1 to 20 carbon atom straight chain and Branched group.Preferably comprise the alkyl of 1 to 10 carbon atom, such as methyl, ethyl, propyl group, 2-propyl group, Normal-butyl, isobutyl group, the tert-butyl group or amyl group etc..The more preferably low alkyl group containing 1 to 6 carbon atom, Such as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl group or the tert-butyl group, amyl group, heptyl etc..Alkane Base can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following group, Independently selected from alkoxyl, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, Carbonyl.
" aryl " of the present invention refers to 6 to 14 yuan of full carbon monocycles or thick with the pi-electron system of conjugation Close multi-ring (namely sharing the ring of adjacent carbon atoms pair) group, the aryl of preferably 6 to 10 yuan, more excellent Select phenyl and naphthyl, most preferably phenyl.Aryl can be substituted or unsubstituted, when substituted, replaces Base is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, Alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, Cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " of the present invention refers to comprise 1 to 4 hetero atom, the heteroaromatic of 5 to 14 annular atomses System, wherein hetero atom includes oxygen, sulfur and nitrogen.It is preferably 6 to 10 yuan.Heteroaryl be preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N-alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, Imidazole radicals, tetrazole radical etc..Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, wherein The ring linked together with precursor structure is heteroaryl ring.Heteroaryl can be optionally substituted or unsubstituted, When substituted, substituent group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, Alkoxyl, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle alkane Base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl, carboxylic Acid or carboxylate.
Used by the present invention 2,3-dimethyl bromobenzene can be readily available by commercial sources, 1-(1H-imidazol-4 yl) Ethyl ketone or 1 amino protecting group (1H imidazoles 4 base) ethyl ketone can be by commercial sources or pertinent literature or one-tenth Ripe correlation technique synthesis obtains.
Anhydrous solvent of the present invention is that water content is less than 0.02%, and the water content of conventional organic solvent is about 0.02-0.04%.The processing method of solvent of the present invention can be found in " laboratory chemicals Purifica-tion Handbook (original work Five editions) " related content.
Moisture measuring method of the present invention is known to those skilled in the art, is mainly utilized as Ka Shi and divides survey Determining method, device therefor is AKF-1 type full-automatic karl Fischer moisture test apparatus.
The unit of heretofore described moisture is mass percent.
The invention has the beneficial effects as follows:
1. the present invention i.e. obtains type I compound by " one pot of two-step method ", and synthetic route is brief, and operation is convenient, Simultaneously, it is to avoid route length and the process contaminants that introduces；
The water content of solvent for use the most of the present invention is 0.04-1%, can promote the process of grignard reaction, it is ensured that synthesized The quality of product；Meanwhile, this synthesis technique is especially suitable for the needs produced, it is to avoid troublesome operation in production, Such as, inert gas shielding or the anhydrous operation of solvent for use；
3. the present invention can i.e. obtain type I compound by " one pot of two-step method ", then through conventional dehydroxylation or dehydroxylation Deaminizating protection group, reduce, split, and become the step of salt with acid, i.e. obtain highly purified right U.S. torr Miaow determines salt, such as, only needs simple purification operations, and the purity of dexmedetomidine hydrochloride may be up to 99.5%, The favourable high-quality ensureing dexmedetomidine hydrochloride finished product.
Detailed description of the invention
The present invention being explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate the present invention Technical scheme, the spirit and scope of the invention are not limited thereto.
The preparation of embodiment 1:1-(2,3-3,5-dimethylphenyl)-1-(1H-imidazol-4 yl) ethanol
The method seeing " laboratory chemicals Purifica-tion Handbook (original work the 5th edition) " processes reaction solvent for use tetrahydrochysene Furan, and add suitable quantity of water, utilizing AKF-1 Moisture Meter to survey its moisture is 0.13%.
In 500ml reaction bulb, temperature is less than 50 DEG C, add in the oxolane (140ml) magnesium (5.5g, 224mmol), iodine (10mg) stirring.It is cooled to room temperature, drips 2,3-dimethyl bromobenzene (40.2g, 217mmol) Oxolane (it is 0.13% that 120ml, AKF-1 Moisture Meter surveys its moisture) solution, mixture in 20～25 DEG C of stirring 1.5h.Reheat backflow 1 hour, be then cooled to room temperature.1-(1H-imidazoles is dripped at 20 DEG C -4-base) oxolane (50ml) solution of ethyl ketone (19.8g, 180mmol), to drip and finish, room temperature continues stirring 10h. Drip saturated sodium bicarbonate (80ml) and water (80ml) successively.Filter, separate organic facies, water layer dichloromethane Alkane (100ml) extracts.Merge organic layer, be dried with anhydrous sodium sulfate.Filtering, concentrate, residue adds acetic acid Ethyl ester (60ml) and diisopropyl ether (120ml) stirring 2h, separate out a large amount of solid, filter, 40 DEG C of vacuum drying, To product (35.4g, yield 91%).
1HNMR (400MHz, DMSO-d6): δ 1.78 (s, 3H), 2.0 (s, 3H), 2.16 (s, 3H), 5.26 (br, 1H), 6.68 (s, 1H), 7.02 (d, 1H, J=2.4Hz), 7.46 (s, 1H), 11.77 (br, 1H)；
13C(DMSO-d6): δ 17.2,21.0,30.3,72.1,177.4,124.4,124.8,134.7,134.9, 137.5,146.1；
MS (m/z): 217.1 (MH+)。
The preparation of embodiment 2:1-(trityl group)-1-(1H-imidazol-4 yl) ethyl ketone
In the reaction bulb of 2000ml, put into imidazoles-4-acetophenone hydrochloride (2) 41.3g (282mol), DMF 380ml, triethylamine 114ml, under nitrogen protection, interior temperature is less than 15 DEG C of dropping triphenylchloromethane 91.2g (327mmol) it is dissolved in the solution of DMF (DMF) 570ml gained, within about 1 hour, adds, Continue reaction 1 hour.It is cooled to less than 5 DEG C, filters, drain.Take out, stir in water 1140ml, Filtering, filter cake washes (200ml) with water.Dry to obtain solid 88.4g, yield 89.0%.(TLC detects, exhibition Open agent: chloroform: methanol: ammonia=50:5:1), MS (m/z), 353.3 (MH+)。
The preparation of embodiment 3:4-[(2,3-3,5-dimethylphenyl)-1-ethoxy]-1-(trityl group) imidazoles
The method seeing " laboratory chemicals Purifica-tion Handbook (original work the 5th edition) " processes reaction solvent for use tetrahydrochysene Furan, and add suitable quantity of water, utilizing AKF-1 Moisture Meter to survey its moisture is 0.09%.
In the reaction bulb of 2000ml, by 2, the oxolane of 3-dimethyl bromobenzene (46g, 248mmol) (it is 0.09% that 800ml, AKF-1 Moisture Meter surveys its moisture) solution, is added drop-wise to magnesium (6g, 0.25mmol), In the solution of the oxolane (200ml) of appropriate iodine, after adding, it is heated to reflux 1 hour, is then cooled to room temperature. The above-mentioned solution prepared is added drop-wise to 1-(trityl group) imidazoles ethyl ketone 4 (70g, 199mmol) in lower 20 DEG C Oxolane (800ml) solution in.After adding, mixture is heated to room temperature and is stirred for 2 hours.Then add Entering saturated ammonium chloride solution (1000ml), aqueous phase dichloromethane (300ml × 3) extracts, and merges organic facies nothing Aqueous sodium persulfate is dried, and decompression boils off solvent.It is concentrated to dryness, adds acetone 100ml, stir, filter, Dry to obtain white solid 81.7g, yield 89.7%, mp 217～220 DEG C (document: fusing point 225 DEG C).
1HNMR (400MHz, DMSO-d6): δ 1.72 (s, 3H), δ 1.88 (s, 3H), δ 2.11 (s, 3H), δ 5.21 (s, 1H), δ 6.45 (s, 1H), δ 6.98 (m, 2H), δ 7.09 (d, 6H, J=6.4Hz), δ 7.24 (s, 1H), δ 7.38 (m, 10H)；
13C(DMSO-d6): δ 17.2, δ 21.0, δ 20.9, δ 25.6, δ 30.2, δ 67.5, δ 72.8, δ 74.9, δ 117.8, δ 124.4, δ 124.7, δ 128.4, δ 128.6, δ 129.6, δ 134.9, δ 137.2, δ 137.4, δ 142.8, δ 146.1, δ149.4；
MS (m/z): 480.9 (MNa+)。
Embodiment 4:4-(1-2,3-3,5-dimethylphenyl) 1-hydroxyethyl) preparation of-1-(1H-imidazoles)-1-carboxylic acid tert-butyl ester
The method seeing " laboratory chemicals Purifica-tion Handbook (original work the 5th edition) " processes reaction solvent for use tetrahydrochysene Furan, and add suitable quantity of water, utilizing AKF-1 Moisture Meter to survey its moisture is 0.11%.
In the reaction bulb of 500ml, by 2, the oxolane of 3-dimethyl bromobenzene (23g, 124mmol) (400ml, It is 0.11% that AKF-1 Moisture Meter surveys its moisture) solution, it is added drop-wise to magnesium (3g, 125mmol), appropriate iodine Oxolane (100ml) solution in, after adding, be heated to reflux 1 hour, be then cooled to room temperature.By upper State the solution for preparing in lower 20 DEG C be added drop-wise to 4-acetyl group-1-(1H-imidazoles)-1-carboxylic acid tert-butyl ester (21g, In oxolane (400ml) solution 100mmol).After adding, mixture is heated to room temperature and is stirred for 2 hours. Being subsequently adding saturated ammonium chloride solution (500ml), aqueous phase dichloromethane (150ml × 3) extracts, and merges organic Being dried with anhydrous sodium sulfate, decompression boils off solvent.It is concentrated to dryness, adds acetone 21ml, stir, Filter, dry to obtain 4-(1-2,3-3,5-dimethylphenyl) 1-hydroxyethyl)-1-(1H-imidazoles)-1-carboxylic acid tert-butyl ester 28.6g, Yield 90.4%.
1HNMR (400MHz, DMSO-d6): δ 1.56 (s, 3H), δ 1.77 (s, 3H), δ 2.05 (s, 3H), δ 2.16 (s, 3H), δ 5.43 (s, 1H), δ 7.28 (m, 2H), δ 7.16 (s, 1H), δ 7.37 (t, 1H, J=1.2Hz), δ 8.06 (s, 1H)；
13C(DMSO-d6): δ 17.3, δ 20.97, δ 27.88, δ 30.20, δ 72.83, δ 85.72, δ 112.83, δ 124.57, δ 124.83, δ 128.92, δ 135.06, δ 136.57, δ 137.58, δ 145.22, δ 147.37, δ 151.61；
MS (m/z): 339.2 (MNa+)。
Embodiment 5: the preparation of medetomidine
In the reaction bulb of 3000ml, put into 1-(2,3-3,5-dimethylphenyl)-1-(1H-imidazol-4 yl) ethanol 10.8g (50mmol), triethyl silicane 29g, dichloromethane 600ml, it is cooled to-10 DEG C, the lower dropping trifluoro second of stirring Acid 32ml, drips off for about 1 hour, continues reaction 4 hours, is slowly raised to room temperature, and reaction is overnight.With saturated Cold sodium bicarbonate solution 150ml washs three times, and water 150ml washed once, and anhydrous sodium sulfate is dried, and is concentrated to dryness, Filter to obtain solid 8.8g, mp 168.5～170 DEG C, yield 87.9% (document: fusing point 172 DEG C).
1HNMR (400MHz, DMSO-d6): δ 1.46 (d, 3H, J=7.2Hz), δ 2.36 (m, 6H), δ 4.32 (q, 1H, J=6.8Hz), δ 6.69 (s, 1H), δ 6.95 (m, 3H), δ 7.49 (d, 1H, J=0.8Hz), δ 11.87 (br, 1H)；
MS (m/z): 201.2 (MH+)。
Embodiment 6: the preparation of medetomidine
In the reaction bulb of 3000ml, put into 4-(1-2,3-3,5-dimethylphenyl) 1-hydroxyethyl)-1-(1H-imidazoles)-1- Carboxylic acid tert-butyl ester 21.4g (67.6mmol), triethyl silicane 40g, dichloromethane 1000ml, be cooled to-10 DEG C, The lower dropping trifluoroacetic acid 54ml of stirring, drips off, continues reaction 4 hours, be slowly raised to room temperature for about 1 hour, Reaction is overnight.With unsaturated carbonate hydrogen receive solution 300ml wash three times, water 200ml washed once, anhydrous slufuric acid Sodium is dried, and is concentrated to dryness, and adds ethyl acetate 400ml, with 2N hydrochloric acid extraction (100ml × 2), united extraction Liquid, adds 10%Pd/C 1.0 grams, and normal pressure leads to H2Overnight, kieselguhr filters, and uses 20% sodium hydroxide in reduction Solution neutralizes, and extracts (200ml × 2) by ethyl acetate, merges organic layer, washs (100ml) with saline, anhydrous Sodium sulfate is dried, and is concentrated to dryness, add acetone 20ml stir 30 minutes, filter to obtain solid 10.8g, mp 169～ 171 DEG C, yield 79.8% (document: fusing point 172 DEG C).
Embodiment 7: the preparation of medetomidine
In the reaction bulb of 3000ml, put into 4-[(2,3-3,5-dimethylphenyl)-1-ethoxy]-1-(trityl group) Imidazoles 62.0g (135mmol), triethyl silicane 80.2g, dichloromethane 2000ml, be cooled to-10 DEG C, stirring Lower dropping trifluoroacetic acid 108ml, drips off for about 1 hour, continues reaction 4 hours, is slowly raised to room temperature, reaction Overnight.With unsaturated carbonate hydrogen receive solution 400ml wash three times, water 400ml washed once, anhydrous sodium sulfate do Dry, it is concentrated to dryness, adds ethyl acetate 900ml, with 2N hydrochloric acid extraction (100ml × 4), united extraction liquid, Adding 10%Pd/C 1.0 grams, normal pressure leads to H2Overnight, kieselguhr filters, and uses 20% sodium hydroxide solution in reduction Neutralize, extract (400ml × 2) by ethyl acetate, merge organic layer, wash (200ml) with saline, anhydrous slufuric acid Sodium is dried, and is concentrated to dryness, add acetone 40ml stir 30 minutes, filter to obtain solid 22.2g, mp 168～ 170 DEG C, yield 82.1% (document: fusing point 172 DEG C).
Embodiment 8:(S)-MPV-1440-L-(+) preparation of-tartrate
By L-(+)-tartaric acid (36g, 240mmol) joins the ethanol of medetomidine (48g, 240mmol) (1000ml) in solution.Suspension is heated to reflux to being completely dissolved, and then at stirred overnight at room temperature, filters white Solid (36.7g).Gained solid is heated to reflux being dissolved in isopropanol (800ml), then at stirred overnight at room temperature, mistake Filter (27g).Gained solid is refined once by this same method again, obtains solid 30.2g, purity 99.8%, receives Rate 72%, mp183.5～185.5 DEG C (document: fusing point 184 DEG C).
1HNMR (400MHz, DMSO-d6): δ 1.47 (d, 3H, J=7.2Hz), δ 2.22 (s, 3H), δ 2.24 (s, 3H), δ 4.237 (s, 2H), δ 4.39 (d, 1H, J=7.2Hz), δ 6.90 (d, 2H, J=6.8Hz), δ 6.99 (d, 2H, J=4.0Hz).
Embodiment 9: the preparation of dexmedetomidine hydrochloride
Dexmedetomidine L-(+)-tartaric acid tartrate (17.4g, 49.7mmol), add water 100ml, dropping 5N sodium hydroxide is neutralized to PH=8.5, adds chloroform extraction (200ml, 100ml), merges washing secondary, is dried, Concentrate, add 4N Hydrochlorine-Ethanol 17.4ml and dissolve, be concentrated to dryness, add acetone 60ml and dissolve, place crystallize, Next day filters, and obtains dexmedetomidine hydrochloride 10.2g, mp:155～157 DEG C, purity 99.9%, yield 86.8%.
1HNMR (400MHz, DMSO-d6): δ 1.53 (d, 3H, J=6.8Hz), δ 2.58 (d, 6H, J=2.8Hz), δ 4.54 (q, 1H, J=6.8Hz), δ 6.91 (m, 1H), δ 7.03 (m, 2H), δ 7.45 (s, 1H), δ 9.09 (d, 1H, J=1.2Hz), δ 14.81 (s, 1H)；
13C(DMSO-d6): δ 14.94, δ 20.84, δ 20.98, δ 32.23, δ 116.00, δ 124.46, δ 126.04, δ 128.66, δ 134.16, δ 137.02, δ 137.84, δ 141.42；
MS (m/z): 201.2 (MH+)。
The preparation of embodiment 10:4-[(2,3-3,5-dimethylphenyl)-1-ethoxy]-1-(trityl group) imidazoles
The method seeing " laboratory chemicals Purifica-tion Handbook (original work the 5th edition) " processes reaction solvent for use tetrahydrochysene Furan, utilizing AKF-1 Moisture Meter to survey its moisture is 0.01%.
Under argon atmosphere, by 2, the oxolane (400ml) of 3-dimethyl bromobenzene (23g, 124mmol) Solution, is added drop-wise to magnesium (3g, 0.125mmol), in the solution of the oxolane (100ml) of appropriate iodine, after adding, It is heated to reflux 1 hour, is then cooled to room temperature.The above-mentioned solution prepared is added drop-wise to 1-(triphen in lower 20 DEG C Ylmethyl) imidazoles ethyl ketone 4 (35g, 100mmol) oxolane (400ml) solution in.After adding, mixture It is heated to room temperature and is stirred for 4 hours.It is subsequently adding saturated ammonium chloride solution (500ml), aqueous phase dichloromethane Alkane (150ml × 3) extracts, and merges organic facies anhydrous sodium sulfate and is dried, and decompression boils off solvent.It is concentrated to dryness, Add acetone 100ml, stir, filter, dry to obtain white solid 32.7g, yield 71.7%, mp 217～ 220 DEG C (document: fusing point 225 DEG C).
Contrast experiment's example 1: utilize method described in US4544664 to prepare dexmedetomidine
In reporting according to document US4544664 strictly according to the facts, the concrete grammar of embodiment 7 prepares compound 4-[(2,3-bis- Aminomethyl phenyl)-1-ethoxy]-1-(trityl group) imidazoles, its yield about 35%, and embodiment hereof 3 work Skill yield is 89.7%, obtains sample by embodiment 3 and is better than document report at yield, simultaneously, it is to avoid some The generation of peculiar impurity, it is simple to subsequent purification technique, finally can obtain the dexmedetomidine of better quality.

Claims (9)

1. the method preparing type I compound,
Including: after magnesium metal Grignard reagent is prepared in formula II compound and magnesium metal reaction, then with formula III compound The step of reaction；
Wherein, R1Selected from hydrogen, amino protecting group, described amino protecting group preferably be selected from alkyl, trityl, Tertbutyloxycarbonyl, p-toluenesulfonyl；R2And R3It is hydrogen, cycloalkyl, cycloalkenyl, alkane independently of one another Base, alkenyl, alkynyl, aralkyl, substituted or unsubstituted aryl or heteroaryl；R4Selected from alkyl, Preferably methyl；X is halogen, selected from chlorine, bromine, iodine, preferably is selected from bromine, iodine.
Method the most according to claim 1, it is characterised in that reaction solvent for use is ether, methyl-tert Butyl ether, oxolane, 2-methyltetrahydrofuran, preferably oxolane；Described formula II compound and magnesium metal Mol ratio be 1:1-1:3, preferably 1:1-1:2.
Method the most according to claim 1 and 2, it is characterised in that magnesium metal Grignard reagent and formula III The temperature of compound reaction is 0-80 DEG C, preferably 10-40 DEG C, more preferably 20-35 DEG C.
Method the most according to claim 1 and 2, it is characterised in that described formula III compound and magnesium metal Grignard reagent mol ratio is 1:1-1:5, preferably 1:1-1:3.
Method the most according to claim 1 and 2, it is characterised in that the moisture of described solvent is 0.05-1%, is preferable over 0.08-0.8%.
6. according to the method described in any one of claim 1-5, it is characterised in that described formula I is formula IV shownization Compound, formula II is compound shown in formula V, and formula III is compound shown in formula VI, wherein, R1Selected from hydrogen, ammonia Base protection group, described amino protecting group preferably is selected from alkyl, trityl, tertbutyloxycarbonyl, p-toluenesulfonyl； R4Selected from alkyl；X is halogen, selected from chlorine, bromine, iodine,
7. the method preparing dexmedetomidine, including preparing formula I described in any one of claim 1-6 The step of compound, also include formula IV compound through dehydroxylation or dehydroxylation-deaminizating protection group, reduce, split,
Method the most according to claim 7, it is characterised in that described dehydroxylation step condition is trifluoro second Acid/triethyl silicane, described reduction step condition is palladium carbon or platinum dioxide catalytic hydrogenation.
9. a preparation method for the officinal salt of dexmedetomidine, including the preparation side described in claim 7 Method and the step with corresponding acid one-tenth salt, described salt is selected from hydrochlorate, hydrobromate, sulfate, preferably salt Hydrochlorate, hydrobromate, more preferably hydrochlorate.
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CN106749028A (en) * 2016-11-28 2017-05-31 无锡福祈制药有限公司 A kind of method for splitting dexmedetomidine
CN108314654A (en) * 2018-03-22 2018-07-24 山东百诺医药股份有限公司 A kind of intermediate and its preparation method and application being used to prepare Medetomidine
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KR102253950B1 (en) * 2019-07-24 2021-05-20 (주)에니켐텍 Novel method for the preparation of Medetomidine
WO2022206512A1 (en) * 2021-04-02 2022-10-06 四川大学华西医院 5-benzylimidazole compound and preparation method therefor and use thereof
CN115197149A (en) * 2021-04-02 2022-10-18 四川大学华西医院 5-benzyl imidazole compound and preparation method and application thereof
CN115197149B (en) * 2021-04-02 2023-09-22 四川大学华西医院 5-benzyl imidazole compound and preparation method and application thereof
WO2023182903A1 (en) 2022-03-22 2023-09-28 Общество с ограниченной ответственностью "ВИК-здоровье животных" Method for producing medetomidine and its derivatives

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