CN106187901A - A kind of dexmedetomidine and the preparation method of intermediate thereof - Google Patents
A kind of dexmedetomidine and the preparation method of intermediate thereof Download PDFInfo
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- 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
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- 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
- C07D233/62—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 triarylmethyl radicals attached to ring nitrogen atoms
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Abstract
The invention provides the preparation method of a kind of dexmedetomidine and intermediate thereof.Specifically, the method includes the step utilizing Suzuki coupling reaction synthetic compound of formula i；Present invention also offers the method preparing dexmedetomidine and intermediate thereof continuously, this technique has that step is short, yield is high, simple to operate, product purity advantages of higher, is suitable for industrialized great production.
Description
Technical field
The present invention relates to the preparation method of a kind of dexmedetomidine and intermediate thereof.
Background technology
Dexmedetomidine hydrochloride injection is by Orion Pharma company and the α 2-of Abott company cooperation research and development exploitation
Adrenoceptor agonists, listed in Japan in U.S.'s Initial Public Offering, in January, 2004 in March, 2000.This product is α 2-kidney
The dextroisomer of upper parathyrine receptor stimulating agent medetomidine, compared with medetomidine, this product is to α 2 adrenoceptor
Exciting selectivity is higher, and the half-life is short, and consumption is the least, starts to intubate and make during being applicable to intensive care clinically
Calmness with respirator patient.
Medetomidine, chemical entitled 5-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles, dexmedetomidine is that it is right
Rotation isomer, is split by medetomidine and obtains, and structure is the most as follows:
At present, the method preparing medetomidine is broadly divided into two big classes: a class is structure imidazole ring in building-up process, as
Method shown in WO2012172121, WO2013011156 and WO2013011155；Another kind of, it is the substrate with imidazole ring-containing
The method of synthesis, the method as shown in WO2009053709 etc..But, owing to needing to use poisonous reagent when preparing imidazole ring
Cyanogran. or use high temperature, high pressure and the method that is passed through ammonia, is unfavorable for its industrialized great production, therefore, preparation U.S. torr miaow
Fixed method is mainly based on the latter's method.
WO2009053709 discloses under lewis acid (e.g., titanium tetrachloride) is catalyzed, 1-(2,3-3,5-dimethylphenyl) second
Alcohol and the N-trimethyl silicon based imidazole needing toxic agent trim,ethylchlorosilane to carry out protecting react the method generating medetomidine,
The method employs substantial amounts of strong-acid type lewis acid, causes trouble will necessarily to whole synthesis technique, need to control to close
Moisture during one-tenth, the especially use of lewis acid titanium tetrachloride, it has strong phenomenon of being fuming, and whole synthesis is received
Rate is the highest, is not suitable for commercial production.
CN101805294 discloses under metallic zinc/lead catalytic condition, imidazoles and 2, and 3-dimethyl acetophenone reacts
The method of synthesis medetomidine.The method use hypertoxicity heavy metal, and its side reaction phenomenon is obvious, two imidazoles
Intermolecular coupled product 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 exists
Commercial production lacks certain application foundation.
US4544664 discloses with 4-imidazolyl carboxylic acid methyl ester as initiation material, successively with 2, and 3-3,5-dimethylphenyl magnesium bromide
And methyl-magnesium-bromide grignard reagent reaction preparation 1-(2,3-3,5-dimethylphenyl)-1-(1H-imidazol-4 yl) ethanol, then disappear
Removing and conventional hydroprocessed step prepares medetomidine, the most foregoing method, it has certain superiority, and 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 ratios 1:1 to be reached.To this end, its work
Skill yield is on the low side, and needs column chromatography, causes technique production cost higher.
Meanwhile, above-mentioned synthesis technique does not meets the theory of Green Chemistry, produces more industry impurity, especially produces more
Special process impurity, is unfavorable for carrying out of subsequent purification technique, and concrete structure is as follows:
US20100048915 discloses the preparation method of new dexmedetomidine, and its route with 2，3-xylylaldehyde is
Initiation material, 1-trityl imidazole iodo-with 4-reacts, and obtains 4-(2,3-dimethyl phenacyl after manganese dioxide
Base)-1-trityl imidazole, reaction preparation 1-(2,3-3,5-dimethylphenyl)-1-is then formatted with methyl-magnesium-bromide
(1H-imidazol-4 yl)-ethanol.This route steps is many, starting material 4-iodo-1-trityl-1H-imidazoles price, stability
Difference, and manganese dioxide post processing is loaded down with trivial details, production cost is of a relatively high.
It is the right U.S. torr of initiation material synthesis that Alex A.Cordi et al. then discloses with 4 (1 trityl group) imidazole aldehyde
The method that miaow is fixed, by starting material and 2, after 3 3,5-dimethylphenyl magnesium bromides carry out grignard reaction, then aoxidizes with activity oxidation manganese
Preparation 4 (2,3 dimethylbenzoyl) 1 trityl imidazole, then formats reaction preparation with methyl-magnesium-bromide
1 (2,3 3,5-dimethylphenyl) 1 (1H imidazoles 4 base) ethanol, then through dehydroxylation deaminizating protection group and the step of reduction
Suddenly generate medetomidine, concrete route following (see Synthetic Communi-cations, 26 (8), 1585～1593
(1996)):
In document, starting material 4-(1-trityl group) imidazole aldehyde used is to be that starting material is prepared by fructose, former
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 longer, and technique employs heavy metal oxidation agent MnO2, it is loaded down with trivial details that it processes technique, production cost
Of a relatively high, do not meet the theory of Green Chemistry.
Successive reaction (flow reaction) has become a novel reaction technology, and it is many to be successfully used to synthesis
Planting organic compound, its reaction unit has syringe pump, micro-reservoir, connects the part groups such as micro-pipe, micro-mixer, microreactor
Become, have an advantage in that the area-volume ratio significantly increasing fluid environment, cause and microfluidic system produces a series of and thing
The peculiar effect that surface is relevant, such as laminar flow effect, surface tension, capillary effect, rapid thermal conduction effect etc..Therefore, utilize
Its technology of successive reaction can strengthen mass transfer and heattransfer effect etc. affects the factor of organic synthesis, and can be by design passage
Changing flow pattern and the combination process of substrate, the direction and degree carried out is reacted in regulation and control, improves selectivity, speed and the manipulation of reaction
Safety, is suitable for commercial production needs.To this end, the present invention provides a kind of new synthesis thinking and route, the letter of whole synthetic route
Short, reduce its synthesis cost；Simultaneously, it is to avoid harsh reaction condition, its reaction condition is simple, and process operability is strong, is beneficial to
Its commercial production needs, and reduces environmental protection pressure, it addition, its synthetic route is brief, it is possible to avoid the generation of certain process contaminants,
Alleviate the pressure of finished product purification.
Summary of the invention
A kind of preparation method of dexmedetomidine intermediate, including: under the conditions of metal palladium catalyst, Formula II compound with
Formula III carries out Suzuki coupling reaction and obtains the step of Formulas I,
Wherein, described R1For selected from hydrogen or amino protecting group, described amino protecting group preferably is selected from alkyl, trityl, uncle
Butoxy carbonyl, p-toluenesulfonyl；R2And R3The most independent for 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 reaction, and Formula II and formula III compound are joined directly together the right U.S. of synthesis
Torr miaow determines intermediate, and concrete reaction is as follows:
Metal palladium catalyst used by described 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。
Described reaction solvent for use be ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, water, acetonitrile,
At least one in dichloromethane, preferably is selected from least one in water, acetonitrile, oxolane, dichloromethane.
Furthermore, above-mentioned Suzuki coupling reaction process also needs to add at least one in alkali or salt, described
Alkali be alkali alcoholate such as sodium tert-butoxide, Sodium ethylate, alkali metal amide such as sodium amide, diisopropyl amination lithium and alkali gold
Belonging to double (trialkylsilkl) aminate such as double (TMS) amination lithiums, tertiary amines is (such as triethylamine, trimethylamine, 4-
Dimethyl aminopyridine, etc.), 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, Sodium ethylate, 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 an embodiment, the amount of described alkali is the mole of 1-5 times of compound of formula I, and preferably 2-4 times amount, it uses measurer
Body can be 2 times amount (equiv), 2.5 times amount, 3 times amount, 3.5 times amount, 4 times amount.
Described reaction temperature is 0-100 DEG C, preferably 10-80 DEG C, and its reaction temperature of specific embodiment can be 80 DEG C, 80
DEG C, 70 DEG C, 60 DEG C, 50 DEG C, 40 DEG C, 30 DEG C, 20 DEG C, 10 DEG C, more preferably 20-70 DEG C.
The mode realizing its temperature maybe can be realized by microwave condition, at specific embodiment by conventional mode of heating
In, microwave condition has preferably impact to reaction yield, conversion ratio or its product quality, is beneficial to obtain better quality and yield
Intermediate.Described microwave condition is: the response time is 5-20min, microwave power 50-250W (watt), furthermore, and institute
Stating the response time is preferably 5-15min, more preferably 5-10min；Described microwave power is preferably 50-200W, more preferably 80-
150W。
Furthermore, described reaction compound of formula H is that 1:1-1:5 (feeds intake with the mol ratio of formula III compound
Amount), preferably 1:1-1:3, specifically can according to real reaction process regulate its mole ratio (1:0-1:3,1:1-1:2.5,1:1-1:
2、1:1-1:1.7、1:1-1:1.5)；Described transition metal palladium catalyst amount is that 0.01-2mol (mole) % is (relative to initial
For the mole of material compound of formula I), preferably 0.05-1mol%, more preferably 0.1-0.8mol%, specific embodiment
Consumption can be: 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8mol%.
The solution concentration of described Formula II compound and formula III compound is 0.01-2.0M (mole/milliliter), is preferably
0.05-1.0M, in embodiment, numerical value can be 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 is by this R2And R3Can obtain different structures, in specific embodiment, formula III can
For but be not limited to following structure:
The present invention also provides for a kind of method preparing dexmedetomidine intermediate Formulas I continuously, including: will be containing Formula II and formula
The solution of III compound injects in micro-mixer by connecting tube with 5-50ul/min flow velocity, simultaneously by containing metallic catalyst
Solution injects with same flow velocity after mixing in micro-mixer, enters the reaction of micro-pipe reactor, and micro-pipe reactor reaction temperature is
0-100 DEG C, collect the solution containing compound of formula I at reactor outlet.Specific embodiment, its reaction temperature can be 90 DEG C, 80 DEG C,
70℃、60℃、50℃、40℃、30℃、20℃、10℃。
Described 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。
Described flow velocity is preferably 8-40ul/min, and more preferably from 10-30ul/min, in a particular embodiment, its flow velocity can
Be 10,15,20,25,30ul/min.
The solution concentration of described Formula II compound and formula III compound is 0.01-2.0M (mole/milliliter), is preferably
0.05-1.0M, in specific embodiment, numerical value can be 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。
Described reaction solvent for use be ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, water, acetonitrile,
At least one in dichloromethane, preferably is selected from least one in water, acetonitrile, oxolane, dichloromethane.
Furthermore, also needing to add at least one in 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, Sodium ethylate, 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, Sodium ethylate, 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 described alkali is the mole of 1-5 times of compound of formula I, preferably 2-4 times amount, and in instantiation, its consumption can
It is 2 times amount, 2.5 times amount, 3 times amount, 3.5 times amount, 4 times amount.
Described reaction temperature is preferably 10-80 DEG C, more preferably 20-70 DEG C.And the mode realizing its temperature can be by often
Rule mode of heating maybe can be realized by microwave condition, in a particular embodiment, microwave condition to reaction yield, conversion ratio or its
Product quality has preferably impact, is beneficial to obtain better quality and the intermediate of yield.
Described microwave condition is: the response time is 5-20min, microwave power 50-250W, furthermore, and described reaction
Time is preferably 5-15min, more preferably 5-10min；Described microwave power is preferably 50-200W, more preferably 80-150W.
Furthermore, described reaction compound of formula H is 1:1-1:5 with the mol ratio of formula III compound, is 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
0.1,0.2 for amount), preferably 0.05-1mol%, more preferably 0.1-0.8mol%, specific embodiment consumption can be:,
0.3,0.4,0.5,0.6,0.7,0.8mol%.
The present invention also provides for the preparation method of a kind of dexmedetomidine, including the step of above-mentioned formula I, then warp
Deaminizating protection group-fractionation or splitting step.
The present invention also provides for the preparation method of a kind of dexmedetomidine officinal salt, including above-mentioned dexmedetomidine of preparing
Step, and become the step of salt with corresponding acid, described salt is selected from hydrochlorate, hydrobromate, sulfate, preferably hydrochlorate, hydrogen
Bromate, more preferably hydrochlorate.
As R in compound of formula I1Electing amino protecting group as, described amino protecting group preferably is selected from alkyl, trityl, tertiary fourth
When oxygen carbonyl, tolysulfonyl, the above-mentioned method preparing dexmedetomidine needs to add the step of a step deaminizating protection group,
The present invention is referred to as deaminizating protection group-splitting step.
" amino protecting group " of the present invention is the suitable group for amido protecting known in the art, sees 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, such as: formoxyl,
Acetyl group, benzoyl etc.；It can be (C1-6 alkyl or C6-10 aryl) sulfonyl；Can also be (C1-6 alkoxyl or C6-
10 aryloxies) carbonyl (such as, tertbutyloxycarbonyl), Boc, Cbz, trityl or p-toluenesulfonyl.
(1-trityl group) imidazole aldehyde of 4-used by the present invention and imidazoles-4-formaldehyde can be readily available by commercial sources,
1-(1-bromoethyl)-2,3-dimethyl ethylbenzene is with reference to " 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 present invention detects the HPLC method of dexmedetomidine: have related substance: chromatographic column: C18；Flowing phase: the phosphorus of 0.05%
Acid (regulating PH to 7.0 with triethylamine)-acetonitrile (60:40) is flowing phase；Detection wavelength: 220nm；Isomer detection method: with
The phosphate buffer of 0.03mol/L (takes potassium dihydrogen phosphate 2.04 grams, adds the sodium hydroxide solution 80ml of 0.1mol/L, use water
Be diluted to 500ml)-acetonitrile (82.5:17.5) for flowing phase, detection wavelength is 220nm.
Term is explained:
| 1 | PdCl2[dtbpf] | [double (di-t-butyl phosphine) ferrocene of 1,1'-] palladium chloride (II) |
| 2 | PdCl2[dppf] | The double Diphenyl phosphino ferrocene palladium chloride of 1,1'- |
| 3 | PdCl2[dcypf] | 1,1 '-bis-(two-cyclohexylphosphino) ferrocene palladium chlorides |
| 4 | PdCl2[xantphos] | Double diphenylphosphine-9,9-dimethyl the xanthene of 4,5- |
| 5 | PdCl2[P(t-Bu)3)]2 | Double tri-butyl phosphine palladium chlorides |
| 6 | ul/min | Microliter per minute |
| 7 | 9-BBN | 9-boron dicyclo (3,3,1)-nonane |
| 8 | B(Pin) | Boric acid pinacol ester |
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 skill of the present invention
Art scheme, the spirit and scope of the invention are not limited thereto.
Embodiment 1:
The preparation of 1-(1-bromoethyl) 2,3-dimethyl benzene
In 5L there-necked flask, add oxolane 1L, magnesium rod 60g (2.5mol), be heated to reflux, drip 2,3-dimethyl
The tetrahydrofuran solution 750mL of bromobenzene 463g (2.5mol).After backflow 1h, it is cooled to room temperature, drips acetaldehyde 180ml
(3.2mol)/oxolane 500mL solution, continues backflow 1h, and decompression removes oxolane, is slowly added into ammonium chloride water after cooling
Solution (125g ammonium chloride adds 400ml water) and ethyl acetate 1.5L.Stratification, is dried organic facies, mistake with anhydrous sodium sulfate
Filter, steams solvent, distillation of then reducing pressure, and collects 115～118 DEG C/300Pa fraction.Distillation products obtained therefrom 330g is dissolved in
In 1.5L dichloromethane, it is cooled to 0 DEG C, the 1L dichloromethane solution of dropping phosphorus tribromide (1188g, 4.4mol), drip and finish, room temperature
Stirring 12h.It is neutral that reactant liquor slowly regulates to pH with saturated sodium bicarbonate solution, separates organic layer, water layer 1.5L dichloro
Methane extracts.Merge organic layer, be dried, concentrating under reduced pressure, obtain product 426g, yield 91%.
The preparation of embodiment: 2:4-[(2,3-3,5-dimethylphenyl)-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 oxolane/water (2:1), then add 52.9g potassium phosphate, 0.5g PdCl2[dtbpf], through 2-3 argon
After displacement, being heated to 65 DEG C of stirring reactions, HPLC detects after completion of the reaction, filters, and concentrating under reduced pressure boils off solvent, then through column chromatography
Purification obtains 39.9g, yield 90.3%.
The preparation of embodiment 3:4-[(2,3-3,5-dimethylphenyl)-ethyl]-1-(trityl group) imidazoles
Preparation starting material 1: Weigh Compound 1 (52.3g, 0.12mol), adds 300ml oxolane/water (2:1), mark
Solution A is with standby；
Preparation starting material 2: Weigh Compound 2 (21.2g, 0.1mol), adds 300ml oxolane/water (2:1), then adds
Entering 52.9g potassium phosphate, mark B solution is with standby；
Preparation catalyst 0.5g PdCl2The tetrahydrofuran solution of [dtbpf], adds 10ml oxolane mark C solution mark
Know C solution；
With pump, solution A, B solution are injected in micro-mixer with 25ul/min flow velocity, C solution is added with same speed simultaneously
Enter wherein, enter a diameter of 0.5mm after mixing, pipe range be 1.5m micro-pipe reactor in react, micro-pipe reactor oil temperature is 65
DEG C, and detect with HPLC detector, to collect the solution containing compound of formula I at reactor outlet, filter, concentrating under reduced pressure boils off molten
Agent, then obtain 41.6g, yield 94.8% through column chromatography purification.
The preparation of embodiment 4:4-[(2,3-3,5-dimethylphenyl)-ethyl]-1-(trityl group) imidazoles
Under argon atmosphere, in the reaction bulb of 5L, add compound 1 (26.15g, 0.06mol), compound 2
(10.6g, 0.05mol) and 150mL oxolane/water (2:1), adds 26.45g potassium phosphate, 0.25g PdCl2[dtbpf],
After 2-3 argon displacement, microwave heating to 65 DEG C, after 10min, HPLC detection reaction is complete, filters, and concentrating under reduced pressure boils off molten
Agent, then obtain 19.74g, yield 95.1% through column chromatography purification.
The preparation of embodiment 5:4-[(2,3-3,5-dimethylphenyl)-ethyl]-1-(trityl group) imidazoles
Preparation starting material 1: Weigh Compound 1 (52.3g, 0.12mol), adds 300ml oxolane/water (2:1), mark
Solution A is with standby；
Preparation starting material 2: Weigh Compound 2 (21.2g, 0.1mol), adds 300ml oxolane/water (2:1), then adds
Entering 52.9g potassium phosphate, mark B solution is with standby；
Preparation catalyst 0.5g PdCl2The tetrahydrofuran solution of [dtbpf], adds 10ml oxolane mark C solution mark
Know C solution；
With pump, solution A, B solution are injected in micro-mixer with 25ul/min flow velocity, C solution is added with same speed simultaneously
Enter wherein, enter a diameter of 0.5mm after mixing, pipe range be 1.5m micro-pipe reactor in react, micro-pipe reactor leads to microwave control
Making its reaction temperature is 65 DEG C, and detects with HPLC detector, collects the solution containing compound of formula I at reactor outlet, filters,
Concentrating under reduced pressure boils off solvent, then obtains 43.1g, yield 97.5% through column chromatography purification.
Process conditions grope to screen reaction condition
With reference to condition described in embodiment 2, select different catalyst, solvent, alkali respectively, that reaction temperature investigates Suzuki is even
Connection reaction condition, specific as follows:
Table 1
Embodiment 5-10 data show that the method for the invention can be effectively synthesized compound 3, especially embodiment 8 and 9, with
And previous embodiment 2, simultaneously, it is considered to production cost and reagent TBFA (tetrabutyl amine fluoride) are to technological operation rigors, more
Add the reaction condition tended to selected from described in embodiment 2.
Generally, Suzuki coupling reaction is provided that and realizes C-C coupling effective means or mode, but it there is also defect,
As a example by the present invention, reaction is highly susceptible to generate impurity 1 and impurity 2, affects yield and product quality.The present invention is by screening
Suitably reaction system avoids the generation of problems；Meanwhile, microwave heating, successive reaction system more solution by dominance are utilized
Certainly the problems referred to above, improve product quality and yield, reduce production cost, and concrete data are shown in Table 2.
Table 2
Embodiment 12: the preparation of medetomidine
In the reaction bulb of 3L, put into 4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1-(trityl group) imidazoles 44.2g
(100mmol), methanol 2000ml, 10% palladium carbon 2g, room temperature reaction is overnight.TLC detection raw material reaction is complete, filters, reduces pressure dense
Contracting, adds acetone 20ml and stirs 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)-MPV-1440-L-(+) preparation of-tartrate
By L-(+) to join the ethanol (500ml) of medetomidine (24g, 120mmol) molten for-tartaric acid (18g, 120mmol)
In liquid.Suspension is heated to reflux to being completely dissolved, and then at 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 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, and dropping 5N sodium hydroxide is neutralized to
PH=8.5, adds chloroform extraction (240ml, 120ml), merges washing secondary, is dried, concentrates, add 4N Hydrochlorine-Ethanol 21ml molten
Solving, be concentrated to dryness, add acetone 75ml and dissolve, place crystallize, next day filters, and obtains hydrochloric acid medetomidine 12.8g, purity 99.9%,
Yield 90.8%.
Comparative example 1: utilize 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, in 30min, join titanium tetrachloride
In dichloromethane solution, stir 2h, add the dichloromethane solution of 1-(2,3-3,5-dimethylphenyl) ethanol, 6h is stirred at room temperature, adds
Entering water, separate organic layer, water layer dichloromethane extracts, and merges organic layer, regulates pH to 3.5-with 2N sodium hydroxide solution
4.0, filter, add 2N sodium hydroxide solution regulation pH=12, obtain medetomidine, yield 72%, HPLC:90.9%.
It is found through experiments, it will be seen that this course of reaction needs to use the N-trimethyl silicon based imidazole of 6 equivalents, can complete
Reaction, causes the waste of raw material, increases production cost simultaneously.Concrete data see table:
| Sequence number | N-trimethyl silicon based imidazole consumption | Conversion ratio |
| 1 | 1equiv | 31% |
| 2 | 2equiv | 56% |
| 3 | 4equiv | 78% |
| 4 | 5equiv | 89% |
| 5 | 6equiv | 98% |
The preparation of embodiment 15:4-[(2,3-3,5-dimethylphenyl)-ethyl]-1-(trityl group) imidazoles
Under argon atmosphere, in the reaction bulb of 5L, add compound 4 (61.48g, 0.318mol), compound 2
(56.18g, 2.65mol) and 795mL oxolane/water (2:1), adds 140.45g potassium phosphate, 1.0g PdCl2
[dtbpf], after 2-3 argon displacement, is heated to 65 DEG C, and after 10min, HPLC detection reaction is complete, filters, and concentrating under reduced pressure steams
Remove solvent, then obtain 48.76g, yield 92% through column chromatography purification.
Claims (14)
1. a preparation method for dexmedetomidine intermediate Formulas I, including: under the conditions of metal palladium catalyst, Formula II compound
Carry out Suzuki coupling reaction with formula III compound and obtain the step of Formulas I,
Wherein, described R1For hydrogen or amino protecting group, described amino protecting group preferably be selected from alkyl, trityl, tertbutyloxycarbonyl,
P-toluenesulfonyl；R2And R3The most independent for hydrogen, alkyl, cycloalkyl, heteroaryl, aryl or R2And R3Form heterocycle alkane
Base；X is halogen, selected from chlorine, bromine, iodine, preferably is selected from chlorine, bromine.
Preparation method the most according to claim 1, it is characterised in that described 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, it preferably is selected from PdCl2[dtbpf]、PdCl2[dppf]、PdCl2
[dcypf]、PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2。
Preparation method the most according to claim 1 and 2, it is characterised in that reaction solvent for use is ether, methyl tertbutyl
At least one in ether, oxolane, 2-methyltetrahydrofuran, water, acetonitrile, preferably is selected from water, acetonitrile, oxolane at least
A kind of.
Preparation method the most according to claim 1 and 2, it is characterised in that also need to add in alkali or salt extremely in described reaction
Few one, described alkali is alkali alcoholate, alkali metal or alkaline earth metal carbonate or hydroxide, preferably is selected from the tert-butyl alcohol
In sodium, Sodium ethylate, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, potassium phosphate at least one；Described salt is alkali gold
Belong to or alkali earth metal fluoride or 4-butyl ammonium, preferably be selected from least one in potassium fluoride, cesium fluoride, tetrabutyl amine fluoride.
Preparation method the most according to claim 1 and 2, it is characterised in that reaction temperature is 0-100 DEG C, preferably 10-80
DEG C, more preferably 20-70 DEG C.
6. the method preparing dexmedetomidine intermediate Formulas I continuously, including: molten by containing Formula II and formula III compound
Liquid injects in micro-mixer by connecting tube with 5-50ul/min flow velocity, simultaneously by the solution containing metallic catalyst with same stream
Speed is injected after mixing in micro-mixer, enters the reaction of micro-pipe reactor, and micro-pipe reactor reaction temperature is 0-100 DEG C, in reaction
The solution containing compound of formula I is collected in device outlet.
Method the most according to claim 6, it is characterised in that described 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, it preferably is selected from PdCl2[dtbpf]、PdCl2[dppf]、PdCl2[dcypf]、
PdCl2[xantphos]、PdCl2[P(t-Bu)3)]2。
8. according to the method described in claim 6 or 7, it is characterised in that described flow velocity is 8-40ul/min, preferably is selected from 10-
30ul/min。
9. according to the method described in claim 6 or 7, it is characterised in that reaction solvent for use be ether, methyl tertiary butyl ether(MTBE), four
At least one in hydrogen furan, 2-methyltetrahydrofuran, water, acetonitrile, dichloromethane, preferably be selected from water, acetonitrile, oxolane, two
At least one in chloromethanes.
10. according to the method described in claim 6 or 7, it is characterised in that described reaction also needs add in alkali or salt at least
One, described alkali is alkali alcoholate, alkali metal or alkaline earth metal carbonate or hydroxide, preferably be selected from sodium tert-butoxide,
At least one in Sodium ethylate, potassium carbonate, sodium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, potassium phosphate；Described salt is alkali metal
Or alkali earth metal fluoride or 4-butyl ammonium, it preferably is selected from least one in potassium fluoride, cesium fluoride, tetrabutyl amine fluoride.
11. according to the method described in claim 6 or 7, it is characterised in that Formula II compound and the solution concentration of formula III compound
For 0.1-2.0M, preferably 0.5-1.0M.
12. according to the method described in claim 6 or 7, it is characterised in that described reaction temperature is 10-80 DEG C, preferably 20-70
℃。
The preparation method of 13. 1 kinds of dexmedetomidines, including the system described in claim 1-5 or claim 6-12 any one
The step of standby compound of formula I, also includes deaminizating protection group-fractionation or splitting step.
The preparation method of the officinal salt of 14. 1 kinds of dexmedetomidines, including the preparation method described in claim 13 and with
Corresponding acid becomes the step of salt, and described salt is selected from hydrochlorate, hydrobromate, sulfate, and preferably hydrochlorate, hydrobromate, more excellent
Select hydrochlorate.
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| CN109608400A (en) * | 2018-12-31 | 2019-04-12 | 辰欣药业股份有限公司 | A kind of synthetic method of dexmedetomidine hydrochloride |
| CN113896684A (en) * | 2020-07-06 | 2022-01-07 | 复旦大学 | Preparation method of medetomidine |
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| CN108147999A (en) * | 2017-12-29 | 2018-06-12 | 上海博志研新药物技术有限公司 | The preparation method of dexmedetomidine hydrochloride and its intermediate |
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| 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 |
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