CN106187901B - A kind of preparation method of Dexmedetomidine and its intermediate - Google Patents
A kind of preparation method of Dexmedetomidine and its intermediate Download PDFInfo
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Abstract
The invention provides a kind of Dexmedetomidine and its preparation method of intermediate.Specifically, the step of the method is using Suzuki coupling reaction synthetic compound of formula i；Method present invention also offers Dexmedetomidine and its intermediate is continuously prepared, the technique has the advantages that short step, high income, simple to operate, product purity are high, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of Dexmedetomidine and its preparation method of intermediate.
Background technology
Dexmedetomidine hydrochloride parenteral solution is the α 2- developed by Orion Pharma companies and Abott companies cooperation research and development
Adrenoceptor agonists, in March, 2000 in U.S.'s Initial Public Offering, in January, 2004 lists in Japan.This product is α 2- kidneys
The dextroisomer of upper parathyrine receptor stimulating agent Medetomidine, compared with Medetomidine, this product is to α 2 adrenoceptor
Exciting selectivity is stronger, and half-life short, consumption very little, clinically suitable for intensive care during start intubation and make
With the calmness of lung ventilator patient.
Medetomidine, chemical entitled 5- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles, Dexmedetomidine is right for it
Rotation isomers, is split by Medetomidine and obtained, and structure difference is as follows：
At present, the method for preparing Medetomidine is broadly divided into two major 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 with the substrate of imidazole ring-containing
The method of synthesis, the method as shown in WO2009053709 etc..But, due to needing to use poisonous reagent when imidazole ring is prepared
Cymag or using high temperature, high pressure and the method for being passed through ammonia, is unfavorable for its industrialized production, therefore, prepare 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 generates Medetomidine with the N- trimethyl silicon based imidazoles reaction for needing toxic agent trim,ethylchlorosilane to be protected,
Substantial amounts of strong-acid type lewis acid is used in the method, trouble will necessarily have been caused to whole synthesis technique, it is necessary to control to close
The moisture during, the especially use of lewis acid titanium tetrachloride, it has strong smoke phenomenon, and whole synthesis is received
Rate is not high, is not suitable for industrial production.
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 material is produced, and does not meet green chemical concept, therefore such reaction exists
Industrial production lacks certain application foundation.
US4544664 is disclosed with 4- imidazolyl carboxylic acid 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 in the reaction of two RMgBrs of control 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 relatively costly.
Meanwhile, above-mentioned synthesis technique does not meet the theory of Green Chemistry, produces more industrial impurity, especially produces more
Special process impurity, is unfavorable for the development of subsequent purification technique, and concrete structure is as follows：
US20100048915 discloses the preparation method of new Dexmedetomidine, and its route is with 2,3- dimethylbenzaldehydes
Initiation material, 1- trityl imidazoles reaction iodo- with 4-, obtains 4- (2,3- dimethyl phenacyls after manganese dioxide
Base) -1- trityl imidazoles, reaction is then formatted with methyl-magnesium-bromide and prepares 1- (2,3- 3,5-dimethylphenyl) -1-
(1H- imidazol-4 yls)-ethanol.This route steps is more, the iodo- 1- trityls -1H- imidazoles prices of starting material 4-, stability
Difference, and manganese dioxide post processing is cumbersome, production cost is of a relatively high.
It is the right U.S. support of initiation material synthesis that Alex A.Cordi et al. are then disclosed with 4- (1- trityl groups) imidazole aldehydes
The fixed method of miaow, after starting material and 2,3- 3,5-dimethylphenyl magnesium bromide are carried out into grignard reaction, then is aoxidized with activity oxidation manganese
4- (2,3- dimethylbenzoyl) -1- trityl imidazoles are prepared, reaction is then formatted with methyl-magnesium-bromide and is prepared
1- (2,3- 3,5-dimethylphenyl) -1- (1H- imidazol-4 yls)-ethanol, then through dehydroxylation-deaminizating protection group and the step of reduction
Rapid generation Medetomidine, specific route is following (referring to Synthetic Communi-cations, 26 (8), 1585~1593
(1996))：
Starting material 4- (1- trityl groups) imidazole aldehyde used is the original by fructose for starting material is prepared in document
Material good stability, purity is high, and market is extremely easy to get, and cheap, has obvious advantage compared with US20100048915,
But its synthesis route is more long, and heavy metal oxidation agent MnO is used in technique2, its handling process is cumbersome, production cost
It is of a relatively high, do not meet the theory of Green Chemistry.
Successive reaction (flow reaction) has turned into a new reaction technology, and it is more to be successfully used to synthesis
Organic compound is planted, its reaction unit there are the part groups such as syringe pump, micro- reservoir, connection micro-pipe, micro-mixer, microreactor
Into, the area-volume ratio for significantly increasing fluid environment is the advantage is that, to cause and produce a series of and thing in microfluidic system
The relevant peculiar effect in body surface face, such as laminar flow effect, surface tension, capillary effect, rapid thermal conduction effect.Therefore, utilize
Successive reaction its technology can strengthen mass transfer and heattransfer effect etc. influences the factor of organic synthesis, and can be by designing passage
Change the flow pattern and combination process of substrate, selectivity, speed and the manipulation of reaction are improved in direction and degree that regulation and control reaction is carried out
Security, is adapted to industrial production needs.Therefore, the present invention provides a kind of new synthesis thinking and route, whole synthetic route letter
It is short, reduce its synthesis cost；Simultaneously, it is to avoid harsh reaction condition, its reaction condition is simple, process operability is strong, is beneficial to
Its industrial production needs, and reduces 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
A kind of preparation method of Dexmedetomidine intermediate, including：Under the conditions of metal palladium catalyst, Formula II compound with
The step of formula III carries out Suzuki coupling reactions acquisition Formulas I,
Wherein, the R1It is that, selected from hydrogen or amino protecting group, the amino protecting group preferably is selected from alkyl, trityl, uncle
Butoxy carbonyl, p-toluenesulfonyl；R2And R3It is independently each alkyl, cycloalkyl, heteroaryl, aryl or R2And R3Formed
Heterocyclylalkyl；X is halogen, selected from chlorine, bromine, iodine, preferably is selected from chlorine, bromine.
Specifically, the present invention uses Suzuki coupling reactions, and Formula II and formula III compound are joined directly together into the right U.S. of synthesis
Support miaow determines intermediate, and specific reaction is as follows：
Metal palladium catalyst used by the reaction is selected from PdCl2、Pd(OAc)2、PdCl2[dtbpf]、PdCl2[dppf]、
PdCl2[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2、Pd/C、(CH3CN)2PdCl2And Polymer-supported
Pd (0), preferably be selected from PdCl2[dtbpf]、PdCl2[dppf]、PdCl2[dcypf]、PdCl2[xantphos]、PdCl2[P(t-
Bu)3)]2。
It is described reaction solvent for use be ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, water, acetonitrile,
At least one in dichloromethane, preferably is selected from least one in water, acetonitrile, tetrahydrofuran, dichloromethane.
Furthermore, also need to add at least one in alkali or salt in above-mentioned Suzuki coupling reaction process, it is described
Alkali be alkali alcoholate such as sodium tert-butoxide, caustic alcohol, alkali metal amide such as sodium amide, diisopropyl amination lithium and alkali are golden
Double (trialkylsilkl) aminates of category such as double (TMS) amination lithiums, tertiary amines (such as triethylamine, trimethylamine, 4-
Dimethyl aminopyridine, etc.), alkali metal or alkaline earth metal carbonate or hydroxide (for example sodium, caesium, magnesium, the carbonate of calcium,
Phosphate, hydroxide and bicarbonate), specifically, it preferably is selected from sodium tert-butoxide, caustic alcohol, potassium carbonate, sodium carbonate, carbonic acid
At least one in caesium, potassium fluoride, cesium fluoride, potassium phosphate；Described salt is alkali metal or alkali earth metal fluoride or the tetrabutyl
Ammonium salt, preferably is selected from least one in potassium fluoride, cesium fluoride, tetrabutyl amine fluoride.
In embodiment, the amount of the alkali is the 1-5 times of mole of compound of formula I, and preferably 2-4 times is measured, and it uses measurer
Body can be 2 times of amounts (equiv), 2.5 times of amounts, 3 times of amounts, 3.5 times of amounts, 4 times of amounts.
The reaction temperature is 0-100 DEG C, preferably 10-80 DEG C, specific embodiment its reaction temperature can for 80 DEG C, 80
DEG C, 70 DEG C, 60 DEG C, 50 DEG C, 40 DEG C, 30 DEG C, 20 DEG C, more preferably 10 DEG C, 20-70 DEG C.
Realizing the mode of its temperature can be realized by conventional mode of heating or by microwave condition, in specific embodiment
In, microwave condition has preferably influence on reaction yield, conversion ratio or its product quality, beneficial to acquisition better quality and yield
Intermediate.The microwave condition is：Reaction time is 5-20min, microwave power 50-250W (watt), furthermore, institute
State reaction time preferably 5-15min, more preferably 5-10min；The microwave power is preferably 50-200W, more preferably 80-
150W。
Furthermore, the reaction compound of formula H and the mol ratio of formula III compound are 1:1-1:5 (feed intake
Amount), preferably 1:1-1:3, specifically its mole ratio (1 can be adjusted according to real reaction process:0-1:3、1:1-1:2.5、1:1-1:
2、1:1-1:1.7、1:1-1:1.5)；The transition metal palladium catalyst amount is 0.01-2mol (mole) % (relative to starting
For the mole of material compound of formula I), preferably 0.05-1mol%, more preferably 0.1-0.8mol%, specific embodiment
Consumption can be：0.1st, 0.2,0.3,0.4,0.5,0.6,0.7,0.8mol%.
The solution concentration of the Formula II compound and formula III compound is 0.01-2.0M (mole/milliliter), preferably
0.05-1.0M, in embodiment, numerical value can for 0.05,0.08,0.1,0.15,0.2,0.3,0.4,0.5,0.6,0.7,0.8,
0.9、1.0M。
Formula III compound of the present invention passes through the R2And R3Different structures can be obtained, in specific embodiment, formula III can
For but be not limited to following structure：
The present invention also provides a kind of continuous method for preparing Dexmedetomidine intermediate Formulas I, including：Formula II and formula will be contained
The solution of III compounds is injected in micro-mixer by connecting tube with 5-50ul/min flow velocitys, while metallic catalyst will be contained
After solution in same flow velocity injection micro-mixer to mix, into micro-pipe reactor reaction, micro-pipe reactor reaction temperature is
0-100 DEG C, the solution containing compound of formula I is collected in reactor outlet.Specific embodiment, its reaction temperature can for 90 DEG C, 80 DEG C,
70℃、60℃、50℃、40℃、30℃、20℃、10℃。
The metal palladium catalyst is selected from PdCl2、Pd(OAc)2、PdCl2[dtbpf]、PdCl2[dppf]、PdCl2
[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2、Pd/C、(CH3CN)2PdCl2And the Pd of Polymer-supported
(0), it preferably is selected from PdCl2[dtbpf]、PdCl2[dppf]、PdCl2[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu
)3)]2。
The flow velocity is preferably 8-40ul/min, and more preferably from 10-30ul/min, in a particular embodiment, its flow velocity can
For 10,15,20,25,30ul/min.
The solution concentration of the Formula II compound and formula III compound is 0.01-2.0M (mole/milliliter), preferably
0.05-1.0M, in specific embodiment, numerical value can for 0.05,0.08,0.1,0.15,0.2,0.3,0.4,0.5,0.6,0.7,
0.8、0.9、1.0M。
It is described reaction solvent for use be ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, water, acetonitrile,
At least one in dichloromethane, preferably is selected from least one in water, acetonitrile, tetrahydrofuran, dichloromethane.
Furthermore, also need to add at least one of alkali or salt in course of reaction, described alkali is alkali metal alcoholization
Double (the trialkyl first silicon of thing such as sodium tert-butoxide, caustic alcohol, alkali metal amide such as sodium amide, diisopropyl amination lithium and alkali metal
Alkyl) aminate such as double (TMS) amination lithiums, tertiary amines (such as triethylamine, trimethylamine, 4-dimethylaminopyridine,
Deng), alkali metal or alkaline earth metal carbonate or hydroxide (such as sodium, caesium, magnesium, the carbonate of calcium, phosphate, hydroxide
And bicarbonate), specifically, it preferably is selected from sodium tert-butoxide, caustic alcohol, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, fluorination
At least one in caesium, potassium phosphate；Described salt is alkali metal or alkali earth metal fluoride or 4-butyl ammonium, preferably is selected from fluorination
At least one in potassium, cesium fluoride, tetrabutyl amine fluoride.
The amount of the alkali is the 1-5 times of mole of compound of formula I, and preferably 2-4 times is measured, and in instantiation, its consumption can
It is 2 times of amounts, 2.5 times of amounts, 3 times of amounts, 3.5 times of amounts, 4 times of amounts.
The reaction temperature is preferably 10-80 DEG C, more preferably 20-70 DEG C.And realize that the mode of its temperature can be by normal
The mode of heating of rule can be realized by microwave condition, in a particular embodiment, microwave condition to reaction yield, conversion ratio or its
Product quality has preferably influence, beneficial to the intermediate for obtaining better quality and yield.
The microwave condition is：Reaction time is 5-20min, microwave power 50-250W, furthermore, the reaction
Time is preferably 5-15min, more preferably 5-10min；The microwave power is preferably 50-200W, more preferably 80-150W.
Furthermore, the reaction compound of formula H and the mol ratio of formula III compound are 1:1-1:5, preferably
1:1-1:3；Its described transition metal palladium catalyst amount be 0.01-2mol% (relative to starting material compound of formula I mole
For amount), preferably 0.05-1mol%, more preferably 0.1-0.8mol%, specific embodiment consumption can be：0.1、0.2、
0.3rd, 0.4,0.5,0.6,0.7,0.8mol%.
The present invention also provides a kind of preparation method of Dexmedetomidine, including the step of above-mentioned preparation compound of formula I, then passes through
Deaminizating protection group-fractionation or splitting step.
The present invention also provides a kind of preparation method of Dexmedetomidine officinal salt, including the above-mentioned Dexmedetomidine for preparing
Step, and with corresponding acid into salt the step of, the salt is selected from hydrochloride, hydrobromate, sulfate, preferably hydrochloride, hydrogen
Bromate, more preferably hydrochloride.
As R in compound of formula I1Elect amino protecting group as, the amino protecting group preferably is selected from alkyl, trityl, tertiary fourth
When oxygen carbonyl, tolysulfonyl, the step of adding a step deaminizating protection group is needed in the above-mentioned method for preparing Dexmedetomidine,
Deaminizating protection group-splitting step is referred to as in the present invention.
" 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.
4- (1- trityl groups) imidazole aldehydes used of the invention and imidazoles -4- formaldehyde can be readily available by commercial sources,
1- (1- bromoethyls) -2,3- dimethyl ethylbenzene is reference《ACAD J GCP》, 28 (2), 135-137；2012 self-controls.
Micro-pipe reactor of the present invention can be Labtrix start；The unit of heretofore described moisture is
Mass percent.
The HPLC methods of present invention detection Dexmedetomidine：Relevant material：Chromatographic column：C18；Mobile phase：0.05% phosphorus
Acid (adjusting PH to 7.0 with triethylamine)-acetonitrile (60:40) it is mobile phase；Detection wavelength：220nm；Isomery body detecting method：With
0.03mol/L phosphate buffer (take 2.04 grams of potassium dihydrogen phosphate, plus 0.1mol/L sodium hydroxide solution 80ml, use water
It is diluted to 500ml)-acetonitrile (82.5:17.5) it is mobile phase, Detection wavelength is 220nm.
Term is explained：
| 1 | [double (di-t-butyl phosphine) ferrocene of 1,1'-] palladium chloride (II) | |
| 2 | The double Diphenyl phosphino ferrocene palladium chlorides of 1,1'- | |
| 3 | 1,1 '-bis- (two-cyclohexylphosphino) ferrocene palladium chlorides | |
| 4 | Double diphenylphosphine -9,9- dimethyl the xanthenes of 4,5- | |
| 5 | Double tri-butyl phosphine palladium chlorides | |
| 6 | ul/min | It is microlitre per minute |
| 7 | 9-BBN | Bicyclic (the 3,3,1)-nonane of 9- boron |
| 8 | B(Pin) | Boric acid pinacol ester |
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate skill of the invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1：
The preparation of 1- (1- bromoethyls) 2,3- dimethyl benzenes
In 5L there-necked flasks, tetrahydrofuran 1L, magnesium rod 60g (2.5mol) are added, be heated to reflux, 2,3- dimethyl is added dropwise
The tetrahydrofuran solution 750mL of bromobenzene 463g (2.5mol).After backflow 1h, room temperature is cooled to, acetaldehyde 180ml is added dropwise
(3.2mol)/tetrahydrofuran 500mL solution, continues the 1h that flows back, and tetrahydrofuran is removed under reduced pressure, and ammonium chloride water is slowly added into after cooling
Solution (125g ammonium chlorides add 400ml water) and ethyl acetate 1.5L.Stratification, uses anhydrous sodium sulfate drying organic phase, mistake
Filter, steams solvent, then vacuum distillation, collects 115~118 DEG C/300Pa cuts.Distillation products obtained therefrom 330g is dissolved in
In 1.5L dichloromethane, 0 DEG C is cooled to, the 1L dichloromethane solutions of phosphorus tribromide (1188g, 4.4mol) are added dropwise, drop finishes, room temperature
Stirring 12h.It is neutral that the slow saturated sodium bicarbonate solution of reaction solution is adjusted to pH, separates organic layer, water layer 1.5L dichloros
Methane is extracted.Merge organic layer, dry, be concentrated under reduced pressure, obtain product 426g, yield 91%.
Embodiment:2：The preparation of 4- [(2,3- 3,5-dimethylphenyls)-ethyl] -1- (trityl group) imidazoles
Under argon atmosphere, in the reaction bulb of 5L, add compound 1 (52.3g, 0.12mol), compound 2 (21.2g,
0.1mol) and 300mL tetrahydrofurans/water (2:1), then add 52.9g potassium phosphates, 0.5g PdCl2[dtbpf], through 2-3 argon gas
After displacement, 65 DEG C of stirring reactions are heated to, HPLC detects that after completion of the reaction filtering is concentrated under reduced pressure to boil off solvent, then through column chromatography
Purifying obtains 39.9g, yield 90.3%.
Embodiment 3：The preparation of 4- [(2,3- 3,5-dimethylphenyls)-ethyl] -1- (trityl group) imidazoles
Prepare starting material 1：Weigh Compound 1 (52.3g, 0.12mol), adds 300ml tetrahydrofurans/water (2:1), identify
Solution A is with standby；
Prepare starting material 2：Weigh Compound 2 (21.2g, 0.1mol), adds 300ml tetrahydrofurans/water (2:1), then add
Enter 52.9g potassium phosphates, mark B solution is with standby；
Prepare catalyst 0.5g PdCl2The tetrahydrofuran solution of [dtbpf], adds 10ml tetrahydrofurans mark C solution mark
Know C solution；
Solution A, B solution are injected in micro-mixer with 25ul/min flow velocitys with pump, while C solution is added with same speed
Enter wherein, a diameter of 0.5mm, pipe range are entered after mixing to be reacted in the micro-pipe reactor of 1.5m, micro-pipe reactor oil temperature is 65
DEG C, and detected with HPLC detectors, the solution containing compound of formula I is collected in reactor outlet, filter, being concentrated under reduced pressure, it is molten to boil off
Agent, then obtain 41.6g, yield 94.8% through column chromatography purifying.
Embodiment 4：The preparation of 4- [(2,3- 3,5-dimethylphenyls)-ethyl] -1- (trityl group) imidazoles
Under argon atmosphere, in the reaction bulb of 5L, compound 1 (26.15g, 0.06mol), compound 2 are added
(10.6g, 0.05mol) and 150mL tetrahydrofurans/water (2:1) 26.45g potassium phosphates, 0.25g PdCl, are added2[dtbpf],
After being replaced through 2-3 argon gas, to 65 DEG C, HPLC detections reaction is finished after 10min, is filtered, and being concentrated under reduced pressure, it is molten to boil off for heating using microwave
Agent, then obtain 19.74g, yield 95.1% through column chromatography purifying.
Embodiment 5：The preparation of 4- [(2,3- 3,5-dimethylphenyls)-ethyl] -1- (trityl group) imidazoles
Prepare starting material 1：Weigh Compound 1 (52.3g, 0.12mol), adds 300ml tetrahydrofurans/water (2:1), identify
Solution A is with standby；
Prepare starting material 2：Weigh Compound 2 (21.2g, 0.1mol), adds 300ml tetrahydrofurans/water (2:1), then add
Enter 52.9g potassium phosphates, mark B solution is with standby；
Prepare catalyst 0.5g PdCl2The tetrahydrofuran solution of [dtbpf], adds 10ml tetrahydrofurans mark C solution mark
Know C solution；
Solution A, B solution are injected in micro-mixer with 25ul/min flow velocitys with pump, while C solution is added with same speed
Enter wherein, a diameter of 0.5mm, pipe range are entered after mixing to be reacted in the micro-pipe reactor of 1.5m, the logical microwave control of micro-pipe reactor
Its reaction temperature is made for 65 DEG C, and is detected with HPLC detectors, the solution containing compound of formula I is collected in reactor outlet, filtered,
It is concentrated under reduced pressure to boil off solvent, then obtain 43.1g, yield 97.5% through column chromatography purifying.
Process conditions are groped --- screening reaction condition
The condition with reference to described in embodiment 2, selects different catalyst, solvent, alkali, reaction temperature to investigate Suzuki idols respectively
Connection reaction condition, it is specific as follows：
Table 1
Embodiment 5-10 as shown by data the method for the invention can be effectively synthesized compound 3, especially embodiment 8 and 9, with
And previous embodiment 2, while, it is considered to production cost and reagent TBFA (tetrabutyl amine fluoride) to technological operation rigors, more
Plus tend to selected from the reaction condition described in embodiment 2.
Generally, Suzuki coupling reactions can be provided and realize that C-C is coupled effective means or mode, but it there is also defect,
It is highly susceptible to generating impurity 1 and impurity 2 by taking the present invention as an example, in reaction, influences yield and product quality.The present invention is by screening
Suitable reaction system avoids the generation of problems；Meanwhile, using microwave heating, successive reaction system more solution by dominance
Certainly above mentioned problem, improve product quality and yield, reduce production cost, and specific data are shown in Table 2.
Table 2
Embodiment 12：The preparation of Medetomidine
In the reaction bulb of 3L, 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1- (trityl group) imidazoles 44.2g is put into
(100mmol), methyl alcohol 2000ml, 10% palladium carbon 2g, room temperature reaction is overnight.TLC detections raw material reaction completely, depressurize dense by filtering
Contracting, adds acetone 20ml to stir 30 minutes, filters to obtain solid 18.6g, mp168~170 DEG C, yield：93%, m/z:201,
HPLC：95.6%.
1HNMR (400MHz, DMSO-d6)：δ 1.45 (d, 3H, J=7.2Hz), δ 2.22 (d, 6H, J=9.6Hz), δ 4.31
(q, 1H, J=6.8Hz), δ 6.71 (s, 1H), δ 6.93 (m, 3H), δ 7.54 (s, 1H)；MS(m/z)：201.2(MH+)。
Embodiment 13：(S) preparation of-MPV-1440-L- (+)-tartrate
The ethanol (500ml) that L- (+)-tartaric acid (18g, 120mmol) is added into Medetomidine (24g, 120mmol) is molten
In liquid.Suspension is heated to reflux to being completely dissolved, and then at being stirred overnight at room temperature, filters to obtain white solid (18.2g).Gained solid
It is heated to reflux being dissolved in isopropanol (400ml), then at being stirred overnight at room temperature, filters (13.5g).Gained solid is same by this again
Method is refined once, obtains solid 15.8g, purity 99.8%, yield 75.2%.
Embodiment 14：The preparation of dexmedetomidine hydrochloride
Medetomidine L- (+)-tartrate (20.9g, 59.7mmol), add water 120ml, 5N NaOH is added dropwise and is neutralized to
PH=8.5, plus chloroform recovery (240ml, 120ml), merge and wash secondary, dry, and concentration, plus 4N Hydrochlorine-Ethanols 21ml is molten
Solution, is concentrated to dryness, plus acetone 75ml dissolvings, places crystallization, and next day filtering obtains hydrochloric acid Medetomidine 12.8g, purity 99.9%,
Yield 90.8%.
Comparative example 1：Using Organic Preparations and Procedures International, 47 (2),
141-148；Technique described in 2015 or WO2009053709 prepares Medetomidine
By the solution of N- trimethyl silicon based imidazole dichloromethane, under condition of ice bath, titanium tetrachloride is added in 30min
In dichloromethane solution, 2h is stirred, add the dichloromethane solution of 1- (2,3- 3,5-dimethylphenyl) ethanol, 6h is stirred at room temperature, plus
Enter water, separate organic layer, water layer is extracted with dichloromethane, merges organic layer, and pH to 3.5- is adjusted with 2N sodium hydroxide solutions
4.0, filtering adds 2N sodium hydroxide solutions regulation pH=12, obtains Medetomidine, yield 72%, HPLC：90.9%.
It is found through experiments that, it will be seen that the N- trimethyl silicon based imidazoles of 6 equivalents are needed to use in the course of reaction, can be completed
Reaction, causes the waste of raw material, while increasing production cost.Specific data see the table below：
| Sequence number | N- trimethyl silicon based imidazole consumptions | Conversion ratio |
| 1 | 1equiv | 31% |
| 2 | 2equiv | 56% |
| 3 | 4equiv | 78% |
| 4 | 5equiv | 89% |
| 5 | 6equiv | 98% |
Embodiment 15：The preparation of 4- [(2,3- 3,5-dimethylphenyls)-ethyl] -1- (trityl group) imidazoles
Under argon atmosphere, in the reaction bulb of 5L, compound 4 (61.48g, 0.318mol), compound 2 are added
(56.18g, 2.65mol) and 795mL tetrahydrofurans/water (2:1) 140.45g potassium phosphates, 1.0g PdCl, are added2
[dtbpf], after being replaced through 2-3 argon gas, is heated to 65 DEG C, and HPLC detections reaction is finished after 10min, is filtered, and is concentrated under reduced pressure and is steamed
Solvent is removed, then 48.76g, yield 92% are obtained through column chromatography purifying.
Claims (17)
1. a kind of preparation method of Dexmedetomidine intermediate Formulas I, including：Under the conditions of metal palladium catalyst, Formula II compound
The step of Suzuki coupling reactions acquisition Formulas I being carried out with formula III compound,
Wherein, the R1It is hydrogen or amino protecting group；R2And R3Each be independently hydrogen, alkyl, cycloalkyl, heteroaryl, aryl or
Person R2And R3Form Heterocyclylalkyl；X is halogen, selected from chlorine, bromine, iodine.
2. preparation method according to claim 1, it is characterised in that the amino protecting group be selected from alkyl, trityl,
Tertbutyloxycarbonyl, p-toluenesulfonyl.
3. preparation method according to claim 1, it is characterised in that the X is selected from chlorine, bromine.
4. preparation method according to claim 1, it is characterised in that the metal palladium catalyst is selected from PdCl2、Pd
(OAc)2、PdCl2[dtbpf]、PdCl2[dppf]、PdCl2[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2、
Pd/C、(CH3CN)2PdCl2And the Pd (0) of Polymer-supported.
5. preparation method according to claim 1, it is characterised in that the metal palladium catalyst is selected from PdCl2[dtbpf]、
PdCl2[dppf]、PdCl2[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2。
6. the preparation method according to claim any one of 1-5, it is characterised in that reaction solvent for use is ether, methyl- tert
At least one in butyl ether, tetrahydrofuran, 2- methyltetrahydrofurans, water, acetonitrile.
7. preparation method according to claim 6, it is characterised in that the reaction solvent for use is selected from water, acetonitrile, tetrahydrochysene
At least one in furans.
8. the preparation method according to claim any one of 1-5, it is characterised in that also need to add alkali or salt in the reaction
In at least one, described alkali is alkali alcoholate, alkali metal or alkaline earth metal carbonate or hydroxide；Described salt
It is alkali metal or alkali earth metal fluoride or 4-butyl ammonium.
9. preparation method according to claim 8, it is characterised in that described alkali is selected from sodium tert-butoxide, caustic alcohol, carbonic acid
At least one of potassium, sodium carbonate, cesium carbonate.
10. preparation method according to claim 8, it is characterised in that described salt is selected from potassium fluoride, cesium fluoride, the tetrabutyl
At least one in ammonium fluoride.
11. preparation method according to claim any one of 1-5, it is characterised in that reaction temperature is 0-100 DEG C.
12. preparation methods according to claim 11, it is characterised in that reaction temperature is 10-80 DEG C.
13. preparation methods according to claim 11, it is characterised in that reaction temperature is 20-70 DEG C.
A kind of 14. preparation methods of Dexmedetomidine, including preparation compound of formula I described in claim 1-13 any one
Step, also including deaminizating protection group-fractionation or splitting step.
A kind of 15. preparation methods of the officinal salt of Dexmedetomidine, including preparation method described in claim 14 and with
The step of corresponding acid is into salt, the salt is selected from hydrochloride, hydrobromate, sulfate.
16. preparation methods according to claim 15, it is characterised in that the salt is selected from hydrochloride, hydrobromate.
17. preparation methods according to claim 15, it is characterised in that the salt is selected from hydrochloride.
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| CN105254567A (en) * | 2015-11-18 | 2016-01-20 | 扬子江药业集团有限公司 | Method for preparing dexmedetomidine hydrochloride key intermediate |
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| CN105254567A (en) * | 2015-11-18 | 2016-01-20 | 扬子江药业集团有限公司 | Method for preparing dexmedetomidine hydrochloride key intermediate |
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