CN106632051A - Synthetic method of dexmedetomidine hydrochloride intermediate - Google Patents
Synthetic method of dexmedetomidine hydrochloride intermediate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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Abstract
The invention discloses a synthetic method of a dexmedetomidine hydrochloride intermediate. The synthetic method comprises the following step: carrying out contact reaction on 1-(1-haloethyl)-2,3-dimethylbenzene and imidazole in ionic liquid in the presence of alkali and [1,1'-bis(diphenylphosphino) ferrocene] palladium dichloride to obtain the dexmedetomidine hydrochloride intermediate 4-[1-(2,3-dimethyl phenyl) ethyl]-1H-imidazole. The method is short in reaction time and high in yield, and has good selectivity for a target (S)-isomer.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, is related to a kind of synthesis side of dexmedetomidine hydrochloride intermediate
Method.
Background technology
In in March, 2000 in U.S.'s Initial Public Offering, the medicine is public by Finland Orion Pharma to dexmedetomidine hydrochloride
Department and the α 2- adrenoceptor agonists of Abott companies of U.S. R ＆ D Cooperation.Dexmedetomidine hydrochloride has anti-sympathetic, town
The effect of quiet and analgesic, compared with U.S. support pyrimidine, with higher selectivity, half-life short, can be clinically used for Intensive Care Therapy
Start intubation and the calmness using lung ventilator patient during treatment, meanwhile, the medicine can also reduce narcotic consumption, improve hand
The incidence of hemodynamic stability and reduction myocardial ischaemia in art.The chemical name of dexmedetomidine hydrochloride is
(S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazole hydrochlorides, concrete structure is as follows：
What the fractionation of the existing method raceme for preparing dexmedetomidine hydrochloride was obtained, and medical research staff is mainly right
The preparation of raceme is conducted extensive research.These researchs all also there is a problem of more.
CN103694175A discloses a kind of new method for preparing dexmedetomidine hydrochloride, wherein, the method discloses makes
With N- trimethyl silicon based imidazoles and 1- (1- chloroethyls) -2,3- dimethyl benzenes, low temperature generates raceme U.S. under Lewis acid catalysis
Support miaow is determined, and the method adopts the reaction time longer and because the poor yield of substrate chloride activity is also very low, and N-TMS imidazoles
Stable existence is unable in atmosphere, the cost for preserving and reacting is increased, and is unfavorable for industrialized production.
CN105254567A discloses a kind of method for preparing dexmedetomidine hydrochloride key intermediate, the key intermediate
For racemization Medetomidine, the method step is shorter, mild condition, is more adapted to industrialized production, but big used in method
The Louis acid acid of amount, improves production cost, and yield is also compared with additive method without too big raising.
In addition, also existing at present many by active metal reagent synthesis 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H-
The method of imidazoles, metal reagent such as RMgBr, synthesis etc., this kind of method existence condition is harsh, and operation requires pole
Height, is not suitable for industrialized production.
In view of also there are problems that more in the preparation process of dexmedetomidine hydrochloride, this area still needs to develop new hydrochloric acid right
The preparation method of Medetomidine.
The content of the invention
The present invention is directed to existing dexmedetomidine hydrochloride intermediate 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- miaows
The synthesis yield of azoles is undesirable, product does not have selective problem, there is provided a kind of new 4- [1- (2,3- 3,5-dimethylphenyl) second
Base] -1H- imidazoles synthetic method, the method reaction time is short, high income and for target (S)-isomers have it is good
It is selective.
To achieve these goals, the present invention provides a kind of synthetic method of dexmedetomidine hydrochloride intermediate, the synthesis
Method includes：
In ionic liquid, in the presence of alkali and [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, 1- (1- halos
Ethyl) -2,3- dimethyl benzenes and imidazoles haptoreaction obtain dexmedetomidine hydrochloride intermediate 4- [1- (2,3- 3,5-dimethylphenyls)
Ethyl] -1H- imidazoles.
In the present invention, it is preferred in the case of, 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and imidazoles, [1,1'- double (hexichol
Base phosphino-) ferrocene] palladium chloride, alkali mole dosage ratio be 1：1～2：0.005～0.2：2～5.
In the case of further preferably, 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and imidazoles, [1,1'- double (diphenylphosphines
Base) ferrocene] palladium chloride, alkali mole dosage ratio be 1：1.1～1.2：0.01～0.1：2～4.
In the present invention, more smoothly carry out to ensure reaction, relative to every g 1- (1- halogenated ethyls) -2,3- bis-
Methylbenzene, the consumption of ionic liquid is 1～10ml；Based on considering for cost and yield etc., relative to every g 1- (1- halos
Ethyl) -2,3- dimethyl benzenes, the consumption of ionic liquid is preferably 2～5ml.
In the present invention, it is preferred in the case of, the ionic liquid is [omim] BF6Or [Bmim] BF6.Using ionic liquid
So that the reactant liquor is more uniform, the reaction time greatly shortens.
Preferably, the catalytic condition includes：Reaction temperature is 80～110 DEG C, and the reaction time is 0.3～1 little
When；In the case of further preferably, reaction temperature is 85～100 DEG C.
In the present invention, halo refers to halogen substiuted in initiation material 1- (1- halogenated ethyls) -2,3- dimethyl benzenes used,
Preferably, 1- (1- halogenated ethyls) -2, the 3- dimethyl benzenes are 1- (1- chloroethyls) -2,3- dimethyl benzenes or 1- (1- bromine second
Base) -2,3- dimethyl benzenes；The alkali is one or more in sodium carbonate, potassium carbonate and cesium carbonate.
Under preferable case, in order to keep the activity of metallic catalyst, more preferably reacted, the haptoreaction is in shielding gas
Carry out in the presence of body.The protective gas can be chemical reaction protective gas commonly used in the art, such as described protective gas
For nitrogen, argon gas or helium.
Dexmedetomidine hydrochloride intermediate prepared by the method that the present invention is provided, can pass through the routine side of this area then
Method is split, is finally obtained dexmedetomidine hydrochloride into steps such as salt.
The synthetic method of the dexmedetomidine hydrochloride intermediate that the present invention is provided, the reaction time is short, substantially increases production
Efficiency, high income, and for (S)-anomeric product have very high selectivity, improve the utilization rate of raw material.
Specific embodiment of the invention, the concrete synthetic route of the present invention is as follows：
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present invention
Protection domain.
The preparation of ionic liquid
[Bmim]BF4(1- butyl -3- methyl imidazolium tetrafluoroborates)
68.60g N- methylimidazoles are added in the 500mL there-necked flasks equipped with agitator, reflux condensing tube and thermometer
With 85.65g chlorobutanes, and 80mL hexamethylenes and toluene are separately added into for reaction intermediary, it is 80 DEG C control the temperature in bottle, is stirred
Upper strata solvent and unreacted raw material are removed with tipping after 36h, lower floor's oily liquids is washed while hot 4 times with ethyl acetate
(each consumption is 20mL), removes layer liquid and is transferred to single port bottle, and vacuum rotary steam (bath temperature is controlled at 70 DEG C) removes part
Unreacted raw material in solvent and raw material.Revolving is finished and is transferred to vacuum drying chamber, and temperature is 70 DEG C, is vacuum dried 36h, is obtained final product
To intermediate product chlorination l- butyl -3- methylimidazoles [Bmim] Cl, yield 70.2%.
By intermediate product [Bmim] Cl 50g and sodium fluoborate, (ratio according to its amount of substance is 1：1.05) add to carry and stir
In mixing the there-necked flask of device, with 100mL acetone as reaction medium, room temperature mechanical stirring 48h, suction filtration (acetone washing) is removed
NaCl, revolving removes acetone, adds CH2C12Washing, revolving removes CH2C12, by obtained ionic liquid in vacuum drying chamber
80 DEG C are dried after 24h to obtain light yellow clear liquid 56.3g：That is l- butyl -3- methylimidazoles tetrafluoro boric acid ionic liquid ([Bmim]
BF4), yield is 86.7%.
1HNMR(400Mhz,D2O, DSS external standard), δ 8.77 (s, 1H)；7.66(d,2H)；4.31(s,2H)；4.04(s,
3H)；1.92(s,2H)；1.37(d,2H)；0.94(t,3H).
[Omim]BF4(l- octyl group -3- methylimidazole tetrafluoro boric acids)
82.1g N- methylimidazoles are added in the 500mL there-necked flasks equipped with agitator, reflux condensing tube and thermometer
With 163.5g 1- chloro-octanes, and 80mL hexamethylenes and toluene are separately added into for reaction intermediary, it is 70 DEG C control the temperature in bottle,
Upper strata solvent and unreacted raw material are removed with tipping after stirring 48h, lower floor's oily liquids washs 4 with ethyl acetate while hot
Secondary (each consumption is 20mL), removes layer liquid and is transferred to single port bottle, and vacuum rotary steam removes unreacted in partial solvent and raw material
Raw material.Revolving is finished and is transferred to vacuum drying chamber, and temperature is 70 DEG C, is vacuum dried 36h, that is, obtain intermediate product chlorination l- pungent
Base -3- methylimidazoles [Omim] Cl, yield 73.7%.
By intermediate product [Omim] Cl 100g and sodium fluoborate, (ratio according to its amount of substance is 1：1.05) add to carry and stir
In mixing the there-necked flask of device, with 120mL acetone as reaction medium, room temperature mechanical stirring 48h, suction filtration (acetone washing) is removed
NaCl, revolving removes acetone, adds CH2C12Washing, revolving removes CH2C12, by obtained ionic liquid in vacuum drying chamber
80 DEG C are dried after 24h to obtain light yellow clear liquid 103.8g：That is l- octyl groups -3- methylimidazoles tetrafluoro boric acid ionic liquid
([Omim]BF4), yield is 84.7%.
1HNMR(400Mhz,D2O, DSS external standard), δ 8.71 (s, 1H)；7.58(s,1H)；7.52(s,1H)；4.22(s,
2H)；3.92(s,3H)；1.89(s,2H)；1.32-1.25(m,10H)；0.86(m,3H).
Embodiment 1
The synthesis of dexmedetomidine hydrochloride intermediate (4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles)
In the presence of nitrogen, by sodium carbonate 21.2g (200mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride 1.4g (2mmol), imidazoles 7.5g (110mmol) with
And 50ml ionic liquids ([Bmim] BF4) flask is added, 90 DEG C of stirring reactions 30 minutes after monitoring reaction terminates, are poured into water
In, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized to give
4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 16.9g, yield 81.1%, (S) -4- [1- (2,3- 3,5-dimethylphenyl)
Ethyl] -1H- imidazoles ee values 89.72%.
1HNMR(400MHz,CDCl3)：δ 7.35 (s, 1H), 7.08-6.95 (m, 3H), 6.71 (s, 1H), 4.40 (q, J=
), 21.2,7.2,1H 2.29 (s, 3H), 2.31 (s, 3H), 1.57 (d, J=7.6,3H).
Embodiment 2
The synthesis of dexmedetomidine hydrochloride intermediate (4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles)
In the presence of nitrogen, by sodium carbonate 31.8g (300mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride 0.7g (1mmol), imidazoles 7.5g (110mmol) with
And 65ml ionic liquids ([Bmim] BF4) flask is added, 100 DEG C of stirring reactions 20 minutes after monitoring reaction terminates, are poured into water
In, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized to give
4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 15.9g, yield 79.4%, (S) -4- [1- (2,3- 3,5-dimethylphenyl)
Ethyl] -1H- imidazoles ee values 89.91%.
Embodiment 3
The synthesis of dexmedetomidine hydrochloride intermediate (4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles)
In the presence of nitrogen, by potassium carbonate 55.3g (400mmol), 1- (1- bromoethyls) -2,3- dimethyl benzene 21.3g
(100mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride 3.6g (5mmol), imidazoles 8.2g (120mmol) with
And 45ml ionic liquids ([Omim] BF6) flask is added, 85 DEG C of stirring reactions 30 minutes after monitoring reaction terminates, are poured into water
In, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized to give
4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 16.1g, yield 80.6%, (S) -4- [1- (2,3- 3,5-dimethylphenyl)
Ethyl] -1H- imidazoles ee values 86.76%.
Embodiment 4
The synthesis of dexmedetomidine hydrochloride intermediate (4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles)
In the presence of nitrogen, by sodium carbonate 53g (500mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride 0.4g (0.5mmol), imidazoles 6.8g (100mmol)
And 50ml ionic liquids ([Bmim] BF4) flask is added, 110 DEG C of stirring reactions 50 minutes after monitoring reaction terminates, are poured into
In water, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized
To 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 14.3g, yield 71.6%, (S) -4- [1- (2,3- dimethyl benzenes
Base) ethyl] -1H- imidazoles ee values 79.27%.
Embodiment 5
The synthesis of dexmedetomidine hydrochloride intermediate (4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles)
In the presence of nitrogen, by potassium carbonate 55.3g (400mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride 14.6g (20mmol), imidazoles 12.3g (180mmol)
And 17ml ionic liquids ([Omim] BF6) flask is added, 80 DEG C of stirring reactions 1 hour after monitoring reaction terminates, are poured into water
In, dichloromethane extraction, organic phase is washed three times, anhydrous sodium sulfate drying organic phase, reduced pressure concentration, column chromatography (DCM：MeOH
=15:1, volume ratio) obtain 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 15.9g, yield 79.7%, (S) -4-
[1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles ee values 86.55%.
Embodiment 6
In the presence of nitrogen, by sodium carbonate 21.2g (200mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride 1.4g (2mmol), imidazoles 7.5g (110mmol) with
And 50ml ionic liquids ([BuPy] BF4) flask is added, 90 DEG C of stirring reactions 30 minutes after monitoring reaction terminates, are poured into water
In, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized to give
4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 12.2g, yield 61.1%, (S) -4- [1- (2,3- 3,5-dimethylphenyl)
Ethyl] -1H- imidazoles ee values 67.80%.
Comparative example 1
In the presence of nitrogen, by sodium carbonate 21.2g (200mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), palladium chloride 0.4g (2mmol), imidazoles 7.5g (110mmol) and 50ml ionic liquids ([Bmim] BF4) plus
In entering flask, 90 DEG C of stirring reactions 30 minutes, after monitoring reaction terminates, in being poured into water, dichloromethane extraction, organic phase washing three
It is secondary, anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether be recrystallized to give 4- [1- (2,3- 3,5-dimethylphenyl) ethyl]-
1H- imidazoles 13.2g, yield 65.7%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles ee values 10.63%.
Comparative example 2
In the presence of nitrogen, by sodium carbonate 21.2g (200mmol), 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g
(100mmol), [1,1'- double (diphenylphosphino) ferrocene] palladium chloride 1.4g (2mmol), imidazoles 7.5g (110mmol) with
And 50ml DMF are added in flask, 90 DEG C of stirring reactions 30 minutes (monitoring and extend to 5 hours), in being poured into water, dichloromethane
Extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether is recrystallized to give 4- [1- (2,3-
3,5-dimethylphenyl) ethyl] -1H- imidazoles 10.7g, yield 53.4%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- miaows
Azoles ee values 59.41%.
Claims (9)
1. a kind of synthetic method of dexmedetomidine hydrochloride intermediate, it is characterised in that the synthetic method includes：
In ionic liquid, in the presence of alkali and [1,1'- double (diphenylphosphino) ferrocene] palladium chloride, 1- (1- halo second
Base) -2,3- dimethyl benzenes and imidazoles haptoreaction obtain dexmedetomidine hydrochloride intermediate 4- [1- (2,3- 3,5-dimethylphenyls) second
Base] -1H- imidazoles.
2. synthetic method according to claim 1, it is characterised in that 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and miaow
Azoles, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, the mole dosage ratio of alkali are 1：1～2：0.005～0.2：2
～5.
3. synthetic method according to claim 2, it is characterised in that 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and miaow
Azoles, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride, the mole dosage ratio of alkali are 1：1.1～1.2：0.01～0.1：2
～4.
4. the synthetic method according to claim 1-3, it is characterised in that relative to every g 1- (1- halogenated ethyls) -2,3-
Dimethyl benzene, the consumption of ionic liquid is 1～10ml, preferably 2～5ml.
5. synthetic method according to claim 1, it is characterised in that the ionic liquid is [omim] BF6Or [Bmim]
BF6。
6. synthetic method according to claim 1, it is characterised in that the catalytic condition includes：Reaction temperature
For 80～110 DEG C, the reaction time is 0.3～1 hour.
7. the synthetic method according to claim 1-4, it is characterised in that 1- (1- halogenated ethyls) -2, the 3- dimethyl
Benzene is 1- (1- chloroethyls) -2,3- dimethyl benzenes or 1- (1- bromoethyls) -2,3- dimethyl benzenes, and the alkali is sodium carbonate, carbonic acid
One or more in potassium and cesium carbonate.
8. the synthetic method according to claim 1-7, it is characterised in that the haptoreaction is entered in the presence of protective gas
OK.
9. synthetic method according to claim 8, it is characterised in that the protective gas is nitrogen, argon gas or helium.
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| CN103664788A (en) * | 2013-12-04 | 2014-03-26 | 人福医药集团股份公司 | Method for preparing medetomidine |
| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
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| WO1997049704A1 (en) * | 1996-06-27 | 1997-12-31 | Janssen Pharmaceutica N.V. | N-[4-(heteroarylmethyl)phenyl]-heteroarylamines |
| CN102753532A (en) * | 2009-12-09 | 2012-10-24 | I-技术有限公司 | Process for preparation of medetomidine |
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| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
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Application publication date: 20170510 |