CN105884691B - A kind of method for preparing Dexmedetomidine and its intermediate - Google Patents
A kind of method for preparing Dexmedetomidine and its intermediate Download PDFInfo
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Abstract
The invention provides a kind of method for preparing Dexmedetomidine and its intermediate.Specifically, this method includes preparing the compound of formula II and metal reactive magnesium after magnesium metal RMgBr, the step of being reacted again with the compound of formula III, technique of the present invention has the advantages that short step, high income, simple to operate, product purity are high, is very suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of Dexmedetomidine and its intermediate.
Background technology
What alpha-2 adrenergic receptor agonists were clinically used to treat hypertension and medicine and ethanol gives up disease
Shape.This kind of medicine can produce antianxiety, calmness, resist the effect such as sympathetic, can meet perioperative different needs, thus in clinic
It is widely used in upper anesthesia.As the Dexmedetomidine of one of α -2 receptor stimulating agents, entitled (the S) -4- of its chemistry [1- (2,
3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles, structure is as follows：
Dexmedetomidine by Medetomidine split obtain, its hydrochloride be dexmedetomidine hydrochloride, be by
α -2 adrenoceptor agonists of OrionPharma/Abott companies cooperation research and development exploitation, in March, 2000 in the U.S.
City, in January, 2004 lists in Japan.Dexmedetomidine has anti-sympathetic, calm and analgesic effect, and this product is to maincenter α -2 kidneys
The selectivity of upper parathyrine receptor agonism is stronger, is 8 times of clonidine, and half-life short, and consumption is small, is clinically supervised suitable for severe
Start to be intubated and using the calmness of lung ventilator patient during shield treatment, this product can also reduce the dosage of anesthetic, improve hand
Hemodynamic stability and the incidence of reduction myocardial ischaemia in art.Therefore, the product since listing just receive much concern.
At present, the method for preparing Medetomidine is broadly divided into two classes：One class is that imidazole ring is constructed in building-up process, such as
Method shown in WO2012172121, WO2013011156 and WO2013011155；It is another kind of, it is the substrate with imidazole ring-containing
The method of synthesis, the method as shown in WO2009053709 etc..But, due to needing to use poisonous reagent when preparing imidazole ring
Cymag uses high temperature, high pressure and the method for being passed through ammonia, is unfavorable for its industrialized production, therefore, prepares U.S. support miaow
Fixed method is main based on the latter's method.
WO2009053709 is disclosed under lewis acid (e.g., titanium tetrachloride) catalysis, 1- (2,3- 3,5-dimethylphenyl) second
The method that alcohol and the N- trimethyl silicon based imidazoles reaction for needing toxic agent trim,ethylchlorosilane to be protected generate Medetomidine,
Substantial amounts of strong-acid type lewis acid has been used in this method, trouble will necessarily be caused to whole synthesis technique, it is necessary to control to close
The moisture during, note it is lewis acidic use, for example, titanium tetrachloride has strong smoke phenomenon, and whole synthesis
Yield is not high, is not suitable for technique productions.
CN101805294 is disclosed under metallic zinc/lead catalytic condition, and imidazoles and 2,3- dimethyl acetophenone are reacted
The method for synthesizing Medetomidine.Hypertoxicity heavy metal is the method use, and its side reaction phenomenon is obvious, two imidazoles
Intermolecular coupled product is more, causes its throwing amount not to be directly proportional to production material, does not meet green chemical concept, therefore such reaction exists
Industrial production lacks certain application foundation.
US4544664 is disclosed using 4- imidazolyl carboxylic acids methyl esters as initiation material, successively with 2,3- 3,5-dimethylphenyl magnesium bromides
And the reaction of methyl-magnesium-bromide grignard reagent prepares 1- (2,3- 3,5-dimethylphenyl) -1- (1H- imidazol-4 yls) ethanol, then disappeared
Except preparing Medetomidine with conventional hydroprocessed step, relatively foregoing method, it has certain superiority, and this route is relatively
It is short, but the competing conjunction of two RMgBrs of control in the reaction is relatively difficult, and both molar ratios will reach 1:1.Therefore, its work
Skill yield is relatively low, and needs column chromatography, causes technique productions cost higher.
Its synthesis technique does not meet the theory of Green Chemistry simultaneously, produces more industrial impurity, especially produces more spy
Determine process contaminants, be unfavorable for the development of subsequent purification technique, concrete structure is as follows.
Therefore, simple and fast is studied and the preparation method of effective Dexmedetomidine, the focus for having become this area is asked
Topic.Therefore, the present invention provides a kind of new synthesis thinking and route, whole synthetic route is brief, reduces it and synthesizes cost；Together
When, it is to avoid harsh reaction condition, its reaction condition is simple, and process operability is strong, is needed beneficial to its industrial production, and reduction
Environmental protection pressure, in addition, its synthetic route is brief, can also avoid the generation of certain process contaminants, mitigate the pressure of finished product purifying.
The content of the invention
Type I compound is prepared the invention provides one kind, methods described includes：By the compound of formula II and metal reactive magnesium system
After standby magnesium metal RMgBr, then the step of reacted with the compound of formula III, wherein, R1Selected from hydrogen, amino protecting group, the amino
Protection 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；R4It is excellent selected from alkyl
Select methyl；X is halogen, selected from chlorine, bromine, iodine, preferably is selected from bromine, iodine.
Specifically, the present invention uses the magnesium metal of " one pot of two-step method " synthetically prepared type I compound, first formula II
Grignard reagent, then nucleophilic addition is carried out with the stable compound of starting material formula III, and obtain type I compound.Described " one
Pot two-step method " completes continuous two i.e. in a reaction system by controlling the reaction time of each step charging and each step
Step reaction, the during which processing without intermediate.
Present invention reaction solvent for use is ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, preferably four
Hydrogen furans.And during grignard reagent is prepared, the mol ratio of the compound of formula II and magnesium metal is 1:1-1:3, preferably 1:
1-1:2。
For the process beneficial to reaction, while avoiding extra impurity from producing, it is necessary to control magnesium metal RMgBr and formula
The reaction temperature of III compound is 0-80 DEG C, more preferably preferably 10-40 DEG C, 20-35 DEG C.
Furthermore, the compound of formula III and magnesium metal RMgBr 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, and formula III is
Compound shown in formula VI, wherein, R1 is selected from hydrogen, amino protecting group, and the amino protecting group preferably is selected from alkyl, trityl, uncle
Butoxy carbonyl, p-toluenesulfonyl；X is halogen, selected from chlorine, bromine, iodine.
As a rule, grignard reaction needs to carry out in anhydrous solvent, i.e. institute all needs to carry out anhydrous processing using solvent
Or the anhydrous solvent of purchase standard, or even also need to control the influence of moisture during the course of the reaction, from inert gas shielding, example
Such as, argon gas or nitrogen.And present inventors have unexpectedly found that using the reaction yield of the solvent of the moisture containing 0.04-1%, reaction rate all compared with
Usage amount anhydrous solvent or Conventional solvents it is good, its final product quality is also higher.Furthermore, the moisture of solvent for use of the present invention
Content is 0.04-1%, is preferable over 0.08-0.8%, specific embodiment can for 0.08%, 0.09%, 0.1%, 0.11%,
0.12%th, 0.13%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%,
0.6%th, 0.7%, 0.8%.
Present invention also offers a kind of method for preparing Dexmedetomidine, including the step of above-mentioned IV compound of formula,
Again through dehydroxylation or dehydroxylation-deaminizating protection group, reduction, splitting step.
Dehydroxylation step condition of the present invention is trifluoroacetic acid/triethyl silicane, and the reduction step condition is palladium carbon
Or platinum dioxide catalytic hydrogenation, its specific reaction condition be skilled person well known to, reference can be made to《Practical organic synthesis work
Skill researches and develops handbook》.
As R in the compound of formula IV1Elect amino protecting group as, the amino protecting group preferably is selected from alkyl, trityl, tertiary fourth
When oxygen carbonyl, tolysulfonyl, the step of one step deaminizating protection group of addition is needed in the above-mentioned method for preparing Dexmedetomidine,
Dehydroxylation-deaminizating protection group step is referred to as in the present invention.
Present invention also offers a kind of method for preparing Dexmedetomidine officinal salt, including the compound of above-mentioned formula IV
The step of, then through dehydroxylation or dehydroxylation-deaminizating protection group, reduction, splitting step and with corresponding acid into salt the step of,
The salt is selected from hydrochloride, hydrobromate, sulfate, preferably hydrochloride, hydrobromate, more preferably hydrochloride：
" amino protecting group " of the present invention is the appropriate group for amido protecting known in the art, referring to document
Ammonia in (" Protective Groups in Organic Synthesis ", 5Th.Ed.T.W.Greene＆P.G.M.Wuts)
Base blocking group, it is preferable that described amino protecting group can be (C1-10 alkyl or aromatic radical) acyl group, for example：Formoxyl,
Acetyl group, benzoyl etc.；It can be (C1-6 alkyl or C6-10 aryl) sulfonyl；Can also be (C1-6 alkoxies or C6-
10 aryloxies) carbonyl (for example, tertbutyloxycarbonyl), Boc, Cbz, trityl or p-toluenesulfonyl.
" alkyl " of the present invention refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.
Preferably comprise the alkyl of 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2- propyl group, normal-butyl, isobutyl group, the tert-butyl group or
Amyl group etc..Low alkyl group more preferably 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..Alkyl can be substituted or unsubstituted, and when substituted, substituent is preferably
One or more following groups, independently selected from alkoxy, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, miscellaneous
Aryl, carbonyl.
" aryl " of the present invention refer to the pi-electron system with conjugation 6 to 14 yuan of full carbon are monocyclic or fused polycycle (also
It is the ring of shared adjacent carbon atoms pair) group, preferably 6 to 10 yuan of aryl, more preferably phenyl and naphthyl, most preferably phenyl.
Aryl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, is independently selected
From alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle
Alkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
" heteroaryl " of the present invention refers to comprising 1 to 4 hetero atom, the heteroaromatic system of 5 to 14 annular atoms, wherein miscellaneous
Atom includes oxygen, sulphur and nitrogen.Preferably 6 to 10 yuan.It is 5 yuan or 6 yuan, such as furyl, thienyl, pyridine that heteroaryl, which is preferably,
Base, pyrrole radicals, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed in virtue
On base, heterocyclic radical or cycloalkyl ring, wherein being heteroaryl ring with the ring that precursor structure links together.Heteroaryl can be optional
Substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carbonyl, carboxylic acid or carboxylate.
2,3- dimethyl bromobenzenes of the invention used can be readily available by commercial sources, 1- (1H- imidazol-4 yls) ethyl ketones or
1- amino protecting groups-(1H- imidazol-4 yls)-ethyl ketone can pass through commercial sources or pertinent literature or the correlation technique of maturation
Synthesis is obtained.
Anhydrous solvent of the present invention is that water content is less than 0.02%, the water content about 0.02- of conventional organic solvent
0.04%.The processing method of solvent of the present invention can be found in《Laboratory chemicals Purifica-tion Handbook (original work the 5th edition)》Mutually inside the Pass
Hold.
Moisture measuring method of the present invention is known to those skilled in the art, is mainly utilized as Cattell point measure
Method, device therefor is the full-automatic karl Fischer moisture teller of AKF-1 types.
The unit of heretofore described moisture is mass percent.
The beneficial effects of the invention are as follows：
1. the present invention is to obtain type I compound by " one pot of two-step method ", synthetic route is brief, operation facility, meanwhile, keep away
The process contaminants exempted from route length and introduced；
2. the water content of solvent for use of the present invention is 0.04-1%, the process of grignard reaction can be promoted, it is ensured that synthesized production
The quality of product；Meanwhile, the need for the synthesis technique is especially suitable for production, it is to avoid troublesome operation in production, for example, inert gas is protected
The anhydrous operation of shield or solvent for use；
3. the present invention can be to obtain type I compound by " one pot of two-step method ", then through conventional dehydroxylation or dehydroxylation-deamination
Base protection group, reduction, split, and with acid into salt the step of, that is, obtain high-purity Dexmedetomidine salt, for example, only need letter
Single purification operations, the purity of dexmedetomidine hydrochloride may be up to 99.5%, the favourable height for ensureing dexmedetomidine hydrochloride finished product
Quality.
Embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate the skill of the present invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1：The preparation of 1- (2,3- 3,5-dimethylphenyls) -1- (1H- imidazol-4 yls) ethanol
Referring to《Laboratory chemicals Purifica-tion Handbook (original work the 5th edition)》Method processing reaction solvent for use tetrahydrofuran,
And suitable quantity of water is added, it is 0.13% to survey its moisture using AKF-1 Moisture Meters.
In 500ml reaction bulbs, temperature is less than 50 DEG C, and magnesium (5.5g, 224mmol) is added in tetrahydrofuran (140ml),
Iodine (10mg) is stirred.Be cooled to room temperature, be added dropwise 2,3- dimethyl bromobenzenes (40.2g, 217mmol) tetrahydrofuran (120ml,
It is 0.13%) solution that AKF-1 Moisture Meters, which survey its moisture, and mixture stirs 1.5h in 20~25 DEG C.Reheat backflow 1 small
When, then it is cooled to room temperature.The tetrahydrofuran (50ml) of 1- (1H- imidazol-4 yls) ethyl ketones (19.8g, 180mmol) is added dropwise at 20 DEG C
Solution, drop finishes, and room temperature continues to stir 10h.Saturated sodium bicarbonate (80ml) and water (80ml) are added dropwise successively.Filtering, is separated organic
Phase, water layer is extracted with dichloromethane (100ml).Merge organic layer, use anhydrous sodium sulfate drying.Filtering, concentration, residue is added
Ethyl acetate (60ml) and isopropyl ether (120ml) stirring 2h, separate out a large amount of solids, and filtering, 40 DEG C of vacuum drying obtain 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+)。
Embodiment 2：The preparation of 1- (trityl group) -1- (1H- imidazol-4 yls) ethyl ketone
In 2000ml reaction bulb, input imidazoles -4- acetophenone hydrochlorides (2) 41.3g (282mol), DMF380ml, three
Ethamine 114ml, under nitrogen protection, triphenylchloromethane 91.2g (327mmol) is added dropwise less than 15 DEG C and is dissolved in N, N- dimethyl for interior temperature
Solution obtained by formamide (DMF) 570ml, is added for about 1 hour, continues to react 1 hour.It is cooled to less than 5 DEG C, filtering is drained.Take
Go out, stirred in water 1140ml, filtered, filter cake is washed with water (200ml).Dry to obtain solid 88.4g, yield 89.0%.
(TLC detections, solvent:Chloroform:Methanol:Ammoniacal liquor=50:5:1), MS (m/z), 353.3 (MH+)。
Embodiment 3：The preparation of 4- [(2,3- 3,5-dimethylphenyls) -1- ethoxys] -1- (trityl group) imidazoles
Referring to《Laboratory chemicals Purifica-tion Handbook (original work the 5th edition)》Method processing reaction solvent for use tetrahydrofuran,
And suitable quantity of water is added, it is 0.09% to survey its moisture using AKF-1 Moisture Meters.
In 2000ml reaction bulb, by tetrahydrofuran (800ml, the AKF- of 2,3- dimethyl bromobenzenes (46g, 248mmol)
It is 0.09%) solution that 1 Moisture Meter, which surveys its moisture, is added drop-wise to magnesium (6g, 0.25mmol), the tetrahydrofuran of appropriate iodine
In the solution of (200ml), after adding, it is heated to reflux 1 hour, is then cooled to room temperature.By the above-mentioned solution prepared in lower 20 DEG C
It is added drop-wise in tetrahydrofuran (800ml) solution of 1- (trityl group) imidazoles ethyl ketone 4 (70g, 199mmol).After adding, mixing
Thing is heated to room temperature and is stirred for 2 hours.Then the ammonium chloride solution (1000ml) of saturation, aqueous phase dichloromethane (300ml are added
× 3) extract, merge organic phase anhydrous sodium sulfate drying, decompression boils off solvent.It is concentrated to dryness, adds acetone 100ml, stirring
Uniformly, filter, dry to obtain white solid 81.7g, yield 89.7%, 217~220 DEG C of (documents of mp：225 DEG C of fusing point).
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, δ 149.4；
MS(m/z)：480.9(MNa+)。
Embodiment 4：4- (1-2,3- 3,5-dimethylphenyls) 1- hydroxyethyls) -1- (1H- imidazoles) -1- carboxylic acid tert-butyl esters system
It is standby
Referring to《Laboratory chemicals Purifica-tion Handbook (original work the 5th edition)》Method processing reaction solvent for use tetrahydrofuran,
And suitable quantity of water is added, it is 0.11% to survey its moisture using AKF-1 Moisture Meters.
In 500ml reaction bulb, by tetrahydrofuran (400ml, the AKF-1 of 2,3- dimethyl bromobenzenes (23g, 124mmol)
It is 0.11%) solution that Moisture Meter, which surveys its moisture, is added drop-wise to magnesium (3g, 125mmol), the tetrahydrofuran (100ml) of appropriate iodine
Solution in, after adding, be heated to reflux 1 hour, be then cooled to room temperature.The above-mentioned solution prepared is added drop-wise to 4- in lower 20 DEG C
In tetrahydrofuran (400ml) solution of acetyl group -1- (1H- imidazoles) -1- carboxylic acid tert-butyl esters (21g, 100mmol).After adding, mix
Compound is heated to room temperature and is stirred for 2 hours.Then the ammonium chloride solution (500ml) of saturation, aqueous phase dichloromethane are added
(150ml × 3) are extracted, and merge organic phase anhydrous sodium sulfate drying, and 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- hydroxyethyls) -1- (1H- imidazoles) -1- carboxylic acid tert-butyl esters
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 3000ml reaction bulb, 1- (2,3- 3,5-dimethylphenyl) -1- (1H- imidazol-4 yls) ethanol 10.8g is put into
(50mmol), triethyl silicane 29g, dichloromethane 600ml are cooled to -10 DEG C, and stirring is lower to be added dropwise trifluoroacetic acid 32ml, about 1 hour
Drip off, continue to react 4 hours, be slowly raised to room temperature, reaction is stayed overnight.The solution 150ml that received with unsaturated carbonate hydrogen washs three times, water
150ml washed once, anhydrous sodium sulfate drying, be concentrated to dryness, and filter to obtain 168.5~170 DEG C of solid 8.8g, mp, yield
87.9% (document：172 DEG C of fusing point).
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 3000ml reaction bulb, 4- (1-2,3- 3,5-dimethylphenyl) 1- hydroxyethyls are put into) -1- (1H- imidazoles) -1-
Carboxylic acid tert-butyl ester 21.4g (67.6mmol), triethyl silicane 40g, dichloromethane 1000ml, are cooled to -10 DEG C, and stirring is lower to be added dropwise three
Fluoroacetic acid 54ml, is dripped off for about 1 hour, is continued to react 4 hours, is slowly raised to room temperature, reaction is stayed overnight.Receive solution with unsaturated carbonate hydrogen
300ml is washed three times, and water 200ml be washed once, and anhydrous sodium sulfate drying is concentrated to dryness, and is added ethyl acetate 400ml, is used 2N
Hydrochloric acid extraction (100ml × 2), merges extract solution, adds 1.0 grams of 10%Pd/C, normal pressure leads to H2Reduction is stayed overnight, diatomite filtering,
Neutralized, extracted with ethyl acetate (200ml × 2) with 20% sodium hydroxide solution, merge organic layer, with salt water washing (100ml),
Anhydrous sodium sulfate drying, is concentrated to dryness, and adds acetone 20ml and stirs 30 minutes, filters to obtain 169~171 DEG C of solid 10.8g, mp,
(the document of yield 79.8%：172 DEG C of fusing point).
Embodiment 7：The preparation of Medetomidine
In 3000ml reaction bulb, 4- [(2,3- 3,5-dimethylphenyl) -1- ethoxys] -1- (trityl group) miaow is put into
Azoles 62.0g (135mmol), triethyl silicane 80.2g, dichloromethane 2000ml, are cooled to -10 DEG C, and stirring is lower to be added dropwise trifluoroacetic acid
108ml, is dripped off for about 1 hour, is continued to react 4 hours, is slowly raised to room temperature, reaction is stayed overnight.Receive solution 400ml with unsaturated carbonate hydrogen
Washing three times, water 400ml be washed once, and anhydrous sodium sulfate drying is concentrated to dryness, and is added ethyl acetate 900ml, is carried with 2N hydrochloric acid
Take (100ml × 4), merge extract solution, add 1.0 grams of 10%Pd/C, normal pressure leads to H2Reduction is stayed overnight, diatomite filtering, with 20%
Sodium hydroxide solution is neutralized, and is extracted with ethyl acetate (400ml × 2), merges organic layer, with salt water washing (200ml), anhydrous sulphur
Sour sodium is dried, and is concentrated to dryness, and is added acetone 40ml and is stirred 30 minutes, filters to obtain 168~170 DEG C of solid 22.2g, mp, yield
82.1% (document：172 DEG C of fusing point).
Embodiment 8：(S) preparation of-MPV-1440-L- (+)-tartrate
L- (+)-tartaric acid (36g, 240mmol) is added to Medetomidine (48g, 240mmol) ethanol (1000ml)
In solution.Suspension is heated to reflux to being completely dissolved, then at being stirred overnight at room temperature, and filters to obtain white solid (36.7g).Gained is consolidated
Body is heated to reflux being dissolved in isopropanol (800ml), then at being stirred overnight at room temperature, filters (27g).Gained solid is same by this again
Method is refined once, obtains solid 30.2g, purity 99.8%, yield 72%, mp183.5~185.5 DEG C (document:Fusing point 184
℃)。
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, and 5N hydroxides are added dropwise
Sodium is neutralized to PH=8.5, plus chloroform recovery (200ml, 100ml), merges and washes secondary, dries, concentration, plus 4N hydrogen chloride-second
Alcohol 17.4ml dissolves, and is concentrated to dryness, plus acetone 60ml dissolvings, places crystallization, and next day filtering 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+)。
Embodiment 10:The preparation of 4- [(2,3- 3,5-dimethylphenyls) -1- ethoxys] -1- (trityl group) imidazoles
Referring to《Laboratory chemicals Purifica-tion Handbook (original work the 5th edition)》Method processing reaction solvent for use tetrahydrofuran,
It is 0.01% to survey its moisture using AKF-1 Moisture Meters.
Under argon atmosphere, 2,3- dimethyl bromobenzenes (23g, 124mmol) tetrahydrofuran (400ml) solution is added dropwise
To magnesium (3g, 0.125mmol), in the solution of the tetrahydrofuran (100ml) of appropriate iodine, after adding, 1 hour is heated to reflux, then
It is cooled to room temperature.The above-mentioned solution prepared is added drop-wise to 1- (trityl group) imidazoles ethyl ketone 4 (35g, 100mmol) in lower 20 DEG C
Tetrahydrofuran (400ml) solution in.After adding, mixture is heated to room temperature and is stirred for 4 hours.Then the chlorination of saturation is added
Ammonium salt solution (500ml), aqueous phase is extracted with dichloromethane (150ml × 3), merges organic phase anhydrous sodium sulfate drying, and decompression is steamed
Remove solvent.It is concentrated to dryness, adds acetone 100ml, stir, filters, dry to obtain white solid 32.7g, yield 71.7%, mp
217~220 DEG C of (documents：225 DEG C of fusing point).
Contrast experiment's example 1：Dexmedetomidine is prepared using US4544664 methods describeds
Specific method prepare compound 4- [(the 2,3- dimethyl of embodiment 7 in being reported strictly according to the facts according to document US4544664
Phenyl) -1- ethoxys] -1- (trityl group) imidazoles, its yield about 35%, and the process recovery ratio of embodiment hereof 3 is
89.7%, obtain sample by embodiment 3 and be better than document report in yield, simultaneously, it is to avoid the generation of some peculiar impurity, be easy to
Subsequent purification technique, can finally obtain the Dexmedetomidine of better quality.
Claims (6)
1. a kind of method of formula IV compounds,
Including：In tetrahydrofuran solvent, by Formula V compound and magnesium metal using mole ratio as 1:1-1:2 reactions prepare metal
After magnesium RMgBr, then at 20-35 DEG C with magnesium metal RMgBr mol ratio be 1:1-1:The step of 3 Formula IV compound reaction
Suddenly, wherein R1Selected from hydrogen, amino protecting group, the amino protecting group be selected from alkyl, trityl, tertbutyloxycarbonyl, to toluene
Sulfonyl；R4Selected from alkyl；X is halogen, selected from chlorine, bromine, iodine, it is characterised in that tetrahydrofuran solvent moisture used in the reaction
Content is 0.08-0.15%.
2. a kind of method for preparing Dexmedetomidine, including the step of formula IV compounds described in claim 1, in addition to
The compound of formula IV through dehydroxylation or dehydroxylation-deaminizating protection group, reduction, split,
3. method according to claim 2, it is characterised in that the dehydroxylation step condition is trifluoroacetic acid/triethyl group silicon
Alkane, the reduction step condition is palladium carbon or platinum dioxide catalytic hydrogenation.
4. a kind of preparation method of the officinal salt of Dexmedetomidine, including the preparation method described in claim any one of 1-3
And with it is corresponding acid into salt the step of, the salt be selected from hydrochloride, hydrobromate, sulfate.
5. preparation method according to claim 4, it is characterised in that the salt is hydrochloride, hydrobromate.
6. preparation method according to claim 5, it is characterised in that the salt is hydrochloride.
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| KR102253950B1 (en) * | 2019-07-24 | 2021-05-20 | (주)에니켐텍 | Novel method for the preparation of Medetomidine |
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