CN106588780A - Process for preparing dexmedetomidine hydrochloride intermediate - Google Patents
Process for preparing dexmedetomidine hydrochloride intermediate Download PDFInfo
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- CN106588780A CN106588780A CN201611160202.8A CN201611160202A CN106588780A CN 106588780 A CN106588780 A CN 106588780A CN 201611160202 A CN201611160202 A CN 201611160202A CN 106588780 A CN106588780 A CN 106588780A
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- imidazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—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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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/84—Metals of the iron group
- B01J2531/847—Nickel
Abstract
The invention discloses a process for preparing a dexmedetomidine hydrochloride intermediate. The process comprises the following steps: adding 1-(1-halogenated ethyl)-2,3-dimethyl benzene, iminazole, alkali and NiCl2(dppf) into an organic solvent, and performing heating stirring reaction, thereby obtaining the dexmedetomidine hydrochloride intermediate, namely, 4-[1-(2,3-dimethyl phenyl) ethyl]-1H-imidazole. The dexmedetomidine hydrochloride intermediate, namely 4-[1-(2,3-dimethyl phenyl) ethyl]-1H-imidazole, which is prepared by using the process provided by the invention, is high in yield, and good in selectivity for a target (S)-isomer.
Description
Technical field
The invention belongs to pharmaceutical chemistry preparing technical field, is related to a kind of preparation work of dexmedetomidine hydrochloride intermediate
Skill.
Background technology
Dexmedetomidine hydrochloride is by the α 2- kidneys of Orion Pharma companies of Finland and Abott companies of U.S. R ＆ D Cooperation
Upper parathyrine receptor stimulating agent, in March, 2000 in U.S.'s Initial Public Offering.Dexmedetomidine hydrochloride has anti-sympathetic, calm and town
The effect of pain, compared with U.S. support pyrimidine, with higher selectivity, half-life short, can be clinically used for the intensive care phase
Between start intubation and the calmness using lung ventilator patient, meanwhile, the medicine can also reduce narcotic consumption, improve blood in operation
The stability of Hemodynamics and the incidence of reduction myocardial ischaemia.The chemical name of dexmedetomidine hydrochloride is (S) -4-
[1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazole hydrochlorides, concrete structure is as follows：
The existing method raceme Medetomidine for preparing dexmedetomidine hydrochloride splits, acidifying is obtained, with regard to U.S. support
The fixed preparation method of miaow, mainly divides two categories below：One is that imidazole ring is constructed in building-up process, related report, for example
WO2013011156 etc.；Two is to be reacted using imidazole ring substrate, such as WO2009053709 etc..Due to constructing during imidazole ring
Reaction is complicated, yield is not high, therefore is more with imidazole ring substrate reactions as main method.CN101805294B discloses one
The preparation method of dexmedetomidine hydrochloride intermediate is planted, the method is occurred using 4- iodine imidazoles and 2,3- dimethyl acetophenone
Reformatsky reacts, and has obtained target compound.But the method use hypertoxicity heavy metal Pd, and side reaction compared with
Many, product not easy purification is not suitable for industrialized production.Concrete synthetic route is as follows：
CN103664788B discloses a kind of method for preparing Medetomidine, and the method is with substituted imidazole as raw material and alkyl
Halide reacts, and its product obtains hydroxy compounds in the presence of magnesium or RMgBr with the reaction of 2,3- dimethyl acetophenones, also
Original obtains Medetomidine.The method complex steps, and used active magnesium RMgBr so that severe reaction conditions, no
Beneficial to industrialized production.Concrete course of reaction is as follows：
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.
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
Also there is the defects such as above-mentioned yield is not high, selectivity of product is poor in the preparation process of azoles, there is provided a kind of new 4- [1- (2,3- bis-
Aminomethyl phenyl) ethyl] -1H- imidazoles preparation technology, the method mild condition, high income and for target (S)-isomers
With good selectivity.
To achieve these goals, the present invention provides a kind of preparation technology of dexmedetomidine hydrochloride intermediate, the preparation
Technique includes：By 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and imidazoles and alkali and NiCl2(dppf) it is added to organic solvent
Middle intensification stirring reaction obtains 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, NiCl2(dppf)、
The mole dosage ratio of alkali is 1：1～2：0.005～0.1：2～3.Inventor is in practice, it has been found that for NiCl2(dppf)
I.e. (1,1'- double (diphenylphosphine) ferrocene) Nickel Chloride obtains consumption, and during more than 0.1 equivalent, reaction result does not have too big
Change, such as yield are basicly stable with selective, due to NiCl2(dppf) price is higher, therefore based on cost and reaction result
Consideration, by NiCl2(dppf) consumption is limited to above range.
Present inventor have further discovered that, before stirring reaction is carried out, add metallic zinc to promote instead in reactant liquor
That what is answered is carried out faster, improves NiCl2(dppf) catalytic effect, it is preferable that the addition of the metallic zinc is NiCl2
(dppf) 1～2 equivalent of consumption.
According to the method that the present invention is provided, initiation material 1- (1- halogenated ethyls) -2,3- dimethyl benzenes, halo groups are normal
The halogen substiuted of rule, for example, fluorine, chlorine, bromine, iodine etc., it is contemplated that whether easy the acquisition of raw material is and cost, 1- (the 1- halogen
For ethyl) -2,3- dimethyl benzenes are more preferably 1- (1- chloroethyls) -2,3- dimethyl benzenes or 1- (1- bromoethyls) -2,3-
Dimethyl benzene.
In the present invention, stirring reaction is carried out preferably in aprotic solvent, such as described organic solvent be ethyl acetate,
Tetrahydrofuran, 1,4- dioxane, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；The temperature of the stirring reaction is
60～100 DEG C, preferably 65～75 DEG C.
In the present invention, require for alkali is not special, for example, can be commonly used in the art various inorganic
Alkali or organic base, preferably use inorganic base, such as described alkali is one or more in sodium carbonate, potassium carbonate and cesium carbonate.
Under preferable case, in order to keep the catalytic reaction activity of metallic catalyst, more preferably reacted, the haptoreaction
Carry out in the presence of protective gas.The protective gas can be chemical reaction protective gas commonly used in the art, such as described
Protective gas is nitrogen, argon gas or helium.
Dexmedetomidine hydrochloride intermediate prepared by the preparation technology that the present invention is provided, can pass through the normal of this area then
Rule method is split, is finally obtained dexmedetomidine hydrochloride into steps such as salt.
The preparation technology of the dexmedetomidine hydrochloride intermediate that the present invention is provided, using NiCl2(dppf)/Zn catalysis 1-
(1- chloroethyls) -2,3- dimethyl benzenes and imidazoles coupling reaction in high yield, catalytic reagent consumption is few, and reaction condition is easily-controllable, behaviour
Make easy；Simultaneously the method improves the utilization rate of raw material for (S)-anomeric product is with very high selectivity, reduces
The pressure of subsequent resolution, the preparation for dexmedetomidine hydrochloride provides chiral raw material guarantee.
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.
Embodiment 1
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), potassium carbonate 27.6g (200mmol), NiCl2(dppf) 0.7g (1mmol) and metallic zinc 0.07g and 100mlN,
Dinethylformamide is added in reaction flask, 70 DEG C of stirring reactions 5 hours, after monitoring reaction terminates, reacting liquid filtering, and filtrate
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 tied again
Crystalline substance obtains 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 17.9g, yield 89.5%, (S) -4- [1- (2,3- dimethyl
Phenyl) ethyl] -1H- imidazoles ee values 90.61%.
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).
Concrete synthetic route is as follows：
Embodiment 2
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 10.2g
(150mmol), sodium carbonate 31.8g (300mmol), NiCl2(dppf) 0.3g (0.5mmol) and metallic zinc 0.07g and
100mlN, dinethylformamide is added in reaction flask, 75 DEG C of stirring reactions 6 hours, after monitoring reaction terminates, reactant liquor mistake
Filter, filtrate is poured in water, and dichloromethane extraction, organic phase is washed three times, anhydrous sodium sulfate drying organic phase, reduced pressure concentration, stone
Oily ether is recrystallized to give 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 17.6g, yield 87.7%, (S) -4- [1- (2,
3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles ee values 90.25%.
Embodiment 3
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.2g
(120mmol), sodium carbonate 31.8g (300mmol), NiCl2(dppf) 5.5g (8mmol) and metallic zinc 0.8g and 50mlN, N-
Dimethylformamide is added in reaction flask, 65 DEG C of stirring reactions 6 hours, and after monitoring reaction terminates, reacting liquid filtering, filtrate is inclined
In entering water, dichloromethane extraction, organic phase is washed three times, anhydrous sodium sulfate drying organic phase, reduced pressure concentration, petroleum ether recrystallization
Obtain 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 17.7g, yield 88.4%, (S) -4- [1- (2,3- dimethyl benzenes
Base) ethyl] -1H- imidazoles ee values 88.62%.
Embodiment 4
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), sodium carbonate 21.2g (200mmol), NiCl2(dppf) 0.7g (1mmol) and 100mlN, N- dimethyl formyl
Amine is added in reaction flask, 70 DEG C of stirring reactions 6 hours, and after monitoring reaction terminates, reacting liquid filtering, filtrate is poured in water, and two
Chloromethanes is extracted, and 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 14.1g, yield 70.4%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -
1H- imidazoles ee values 88.31%.
Embodiment 5
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), potassium carbonate 27.6g (200mmol), NiCl2(dppf) 0.7g (1mmol) and metallic zinc 0.01g and 100mlN,
Dinethylformamide is added in reaction flask, 70 DEG C of stirring reactions 8 hours, after monitoring reaction terminates, reacting liquid filtering, and filtrate
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 tied again
Crystalline substance obtains 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 15g, yield 75.1%, (S) -4- [1- (2,3- dimethyl benzenes
Base) ethyl] -1H- imidazoles ee values 82.90%.
Embodiment 6
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), potassium carbonate 27.6g (200mmol), NiCl2(dppf) 0.7g (1mmol) and metallic zinc 0.07g and 100mlN,
Dinethylformamide is added in reaction flask, 95 DEG C of stirring reactions 7 hours, after monitoring reaction terminates, reacting liquid filtering, and filtrate
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 tied again
Crystalline substance obtains 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 16.5g, yield 82.3%, (S) -4- [1- (2,3- dimethyl
Phenyl) ethyl] -1H- imidazoles ee values 75.49%.
Comparative example 1
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), potassium carbonate 27.6g (200mmol), PdCl2(dppf) (0.5～0.8 works as 0.7g (1mmol) and metallic zinc 0.07g
Amount 100mmol) and 50mlN, dinethylformamide added in reaction flask, 70 DEG C of stirring reactions 8 hours, monitoring reaction knot
Shu Hou, reacting liquid filtering, filtrate is poured in water, and dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying is organic
Phase, reduced pressure concentration, petroleum ether is recrystallized to give 4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 11.2g, yield
55.8%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles ee values 59.67%.
Comparative example 2
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 8.8g
(130mmol), sodium carbonate 21.2g (200mmol), NiCl20.3g (2mmol) and metallic zinc 0.08g and 100mlN, N- bis-
NMF is added in reaction flask, 70 DEG C of stirring reactions 8 hours, and after monitoring reaction terminates, reacting liquid filtering, filtrate is poured into
In water, dichloromethane extraction, organic phase is washed three times, and anhydrous sodium sulfate drying organic phase, reduced pressure concentration, column chromatography obtains 4-
[1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles 9.6g, yield 48.0%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) second
Base] -1H- imidazoles ee values 12.70%.
Comparative example 3
The preparation of 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles
In the presence of nitrogen, by 1- (1- chloroethyls) -2,3- dimethyl benzene 16.8g (100mmol), imidazoles 7.5g
(110mmol), alkali 21.2g (200mmol) and NiCl20.3g and 100mlN, dinethylformamide adds reaction flask
In, 70 DEG C of stirring reactions 7 hours, after monitoring reaction terminates, reacting liquid filtering, filtrate is poured in water, dichloromethane extraction, organic
Mutually washing three times, anhydrous sodium sulfate drying organic phase, reduced pressure concentration, column chromatography obtains 4- [1- (2,3- 3,5-dimethylphenyl) second
Base] -1H- imidazoles 8.5g, yield 42.7%, (S) -4- [1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazoles ee values 11.75%.
Claims (8)
1. a kind of preparation technology of dexmedetomidine hydrochloride intermediate, it is characterised in that the preparation technology includes：By 1- (1- halogen
For ethyl) -2,3- dimethyl benzenes and imidazoles and alkali and NiCl2(dppf) it is added to intensification stirring reaction in organic solvent to obtain
Dexmedetomidine hydrochloride intermediate 4- [1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazoles.
2. preparation technology according to claim 1, it is characterised in that 1- (1- halogenated ethyls) -2,3- dimethyl benzenes and miaow
Azoles, NiCl2(dppf), the mole dosage ratio of alkali is 1：1～2：0.005～0.1：2～3.
3. preparation technology according to claim 1 and 2, it is characterised in that the preparation technology is additionally included in stirring reaction
Metallic zinc is added, the consumption of metallic zinc is NiCl2(dppf) 1～2 equivalent of consumption.
4. preparation technology according to claim 1 and 2, 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.
5. preparation technology according to claim 1, it is characterised in that the organic solvent be ethyl acetate, tetrahydrofuran,
1,4- dioxane, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；The temperature of the stirring reaction is 65～75 DEG C.
6. preparation technology according to claim 1 and 2, it is characterised in that the alkali is sodium carbonate, potassium carbonate and cesium carbonate
In one or more.
7. the preparation technology according to claim 1-6, it is characterised in that the stirring reaction is entered in the presence of protective gas
OK.
8. preparation technology according to claim 7, it is characterised in that the protective gas is nitrogen, argon gas or helium.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979552A (en) * | 2019-12-16 | 2021-06-18 | 广安凯特制药有限公司 | Preparation method of high-purity 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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2016
- 2016-12-15 CN CN201611160202.8A patent/CN106588780A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Title |
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| 乐长高: "《离子液体及其在有机合成反应中的应用》", 30 April 2007, 华东理工大学出版社 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979552A (en) * | 2019-12-16 | 2021-06-18 | 广安凯特制药有限公司 | Preparation method of high-purity dexmedetomidine hydrochloride |
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Application publication date: 20170426 |