CN107857731A - A kind of process for preparing dexmedetomidine hydrochloride - Google Patents
A kind of process for preparing dexmedetomidine hydrochloride Download PDFInfo
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- CN107857731A CN107857731A CN201711069890.1A CN201711069890A CN107857731A CN 107857731 A CN107857731 A CN 107857731A CN 201711069890 A CN201711069890 A CN 201711069890A CN 107857731 A CN107857731 A CN 107857731A
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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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- C—CHEMISTRY; METALLURGY
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Abstract
The present invention provides a kind of synthetic method of dexmedetomidine hydrochloride, it is characterised in that this method employ 2,3 dimethylbenzaldehydes with（1‑（Trimethyl silicon substrate）The base of 1H imidazoles 4）Magnesium bromide is that starting material reacts synthetic hydrochloric acid Dexmedetomidine, and the process employs Dess Martin to synthesize compound III, and using Wittig tube- nursery compound IV, this greatly reduces the condition of reaction and shortens synthetic reaction step.Technique of the present invention, simple to operate, control point is gentle, and product purity is high, is adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of dexmedetomidine hydrochloride.
Background technology
Dexmedetomidine hydrochloride parenteral solution is to cooperate to grind by Orion Pharma (Finland) companies and Abott (U.S.) company
The α 2- adrenoceptor agonists of exploitation are made, are listed in March, 2000 in U.S.'s Initial Public Offering, in January, 2004 in Japan.
This product is the dextroisomer of α 2- adrenoceptor agonists Medetomidines, and compared with Medetomidine, this product is to maincenter α 2-
The selectivity of adrenocepter excitement is stronger, and half-life short, dosage very little, clinically suitable for during intensive care
Start to be intubated and the calmness using lung ventilator patient, this product listing formulation is 2mL injections.
Its chemistry of dexmedetomidine hydrochloride is entitled：(+) -4- (S)-[1- (2,3- 3,5-dimethylphenyls) ethyl] -1H- imidazole salts
Hydrochlorate, structural formula are shown below：
Alex A .Cordi et al. reports are known clearly using 4- (1- trityl groups) imidazole aldehydes as the right U.S. support of initiation material synthetic hydrochloric acid
The fixed method of miaow.This method after 3- 3,5-dimethylphenyls magnesium bromide carries out grignard reaction, then passes through oxidation system with starting material and 2
Standby 4- (2,3- dimethylbenzoyl) -1- trityl imidazoles, product is formatted with methyl-magnesium-bromide after then aoxidizing
Reaction prepares 1- (2,3- 3,5-dimethylphenyl) -1- (1H- imidazol-4 yls)-ethanol, finally obtains the right side by deprotection and fractionation
Medetomidine, its synthetic route are as follows：
Using 4- (1- trityl groups) imidazole aldehyde as starting material, raw material is easier to obtain this method.But this method synthetic route compared with
It is long, grignard reaction is repeatedly used in reaction and uses manganese dioxide, therefore the production efficiency is relatively low, is not suitable for work
Industry metaplasia is produced.
CN105254567 is reported with 1-（1- chloroethyls）- 2,3- dimethylbenzene are starting material, by Friedel-Crafts reaction and are torn open
Get target compound, its reaction is as follows
This method step is succinct, but titanium tetrachloride has been used in reacting, and post processing is more difficult, and yield is relatively low, reaction amplification
Controllability is poor afterwards, not easy to operate.
The content of the invention
The invention provides one kind using 2,3- dimethylbenzaldehydes as starting material by with（1-（Trimethyl silicon substrate）-1H-
Imidazoles 4- bases）Magnesium bromide occurs grignard reaction generation compound II, compound II and generates compound III by oxidation reaction again,
Compound III reacts generation compound IV, compound IV by wittig and directly synthesizes Medetomidine by catalytic hydrogenation, finally
Dexmedetomidine hydrochloride is obtained by splitting acidifying, its synthetic route is as follows：
The present invention is for the problem such as the tediously long reaction yield of reactions steps in the prior art is low, it is intended to by find it is a kind of relatively
Simply, easily operation and the higher method of yield prepare dexmedetomidine hydrochloride, it is often more important that this synthetic method
Product quality can not only be ensured, whole production process can more be accomplished controllable, avoid production process unstability.
Present invention synthesis compound II reaction solvent for use is selected from tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertbutyl
Ether, ether, preferably at least one, tetrahydrofuran, 2- methyltetrahydrofurans.
To react fully, synthesize in compound II（1-（Trimethyl silicon substrate）- 1H- imidazoles 4- bases）Magnesium bromide and 2,3- bis-
The equivalent of tolyl aldehyde is 1:1.1-1:3, wherein it is preferred that 1:1.5.
It is 0 DEG C -35 DEG C, preferably 20-25 DEG C to synthesize reaction temperature in compound II and be selected from.
Present invention synthesis compound III oxidants are selected from PCC reagents, PDC reagents, manganese dioxide, Dess-Martin, double
Oxygen water, at least one, prioritizing selection Dess-Martin, PCC.
It is 1 to fully react synthesis compound III, compound II and Dess-Martin equivalent proportion:1.5-1:4,
Wherein preferably 1:2.
Furtherly, compound III solvents are synthesized and is selected from ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, second
Ether, ethyl acetate, dichloromethane.
It is 0 DEG C -50 DEG C, preferably 10-25 DEG C that reaction temperature, which is selected from, in present invention synthesis compound III.
Alkali is selected from sodium acid carbonate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, second two in present invention synthesis compound IV
Amine, diethylamine, pyridine, imidazoles, sodium hydrogen, sodium methoxide, methanol first, potassium tert-butoxide, prioritizing selection tert-butyl alcohol first, sodium methoxide.
Temperature is selected from 20-60 DEG C in present invention synthesis compound IV, 20-30 DEG C of prioritizing selection.
Solvent is selected from ethyl acetate, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, second in present invention synthesis compound IV
Ether, toluene, dioxane, methanol, ethanol, preferably tetrahydrofuran, dichloromethane.
To make polymerisable compounds IV fully synthesize, compound III is 1 with wittig reagents equivalent proportion:1-1:1.5, wherein excellent
Select 1:1.1.
Resolving agent of the present invention is selected from D tartaric acid, D dibenzoyl tartaric acids, preferably D camphorsulfonic acids, D tartaric acid.
It is characteristic of the invention that：
1. the present invention synthesizes compound III using Dess-Martin reagents as oxidant, the reagent conditions are gentle, conversion ratio
Height has operated, has post-processed simple and will not introduce heavy metal, is adapted to industrialized production.
This method using wittig reaction synthesis compound IV, compared to first with grignard reaction again dehydrating process step and
Aobvious simple and mild condition is explained, this difficulty for greatly reducing whole technique improves the yield of reaction.
Brief description of the drawings：Fig. 1 is dexmedetomidine hydrochloride mass spectrum；
Fig. 2 composes for dexmedetomidine hydrochloride hydrogen；
Fig. 3 composes for dexmedetomidine hydrochloride carbon.
Form is described in further details to present disclosure again by the following examples, but not this should not be interpreted as with regard to this
Invent in above-mentioned subject area and be only limitted to following examples.It is general according to this area under the premise of the above-mentioned technology of the present invention is not departed from
The modification of corresponding replacement or change that logical technological know-how and customary means are made, is included in the present invention.
Embodiment 1：Compound II preparation
Mg bits (6.57g, 274mmol), the protection of tetrahydrofuran 400ml nitrogen are added in 1L reaction bulb, reaction is warming up to
60-65 DEG C, iodine grain is added, solution is changed into milky, and reaction solution is cooled to 35-45 DEG C, adds the bromo- 1- trimethyls silicon substrate -1-H of 4-
Imidazoles (50g, 228mmol), insulation reaction 2 ~ 4 hours, 20 ~ 25 DEG C are cooled to, add 2,3- dimethylbenzene formaldehyde, react 6h.Instead
It is added dropwise aqueous ammonium chloride solution after should terminating, temperature control is no more than 25 DEG C, drips liquid separation after finishing, and with saturated common salt water washing 2 times, it is organic
Phase anhydrous sodium sulfate drying, filter, concentration, add recrystallisation from isopropanol, filter, drying, obtain interior white solid 41.2g, receive
Rate 89.3%, purity 97.7%.
Embodiment 2：Compound III preparation
Compound II 36.0g (178mmol) are added in 500ml reaction bulbs, dichloromethane 150ml, 20 ~ 30 DEG C stir,
Dess-Martin reagents 113.2g (267mmol) is added into reaction system, adds anhydrous magnesium sulfate 10g, reaction insulation 12h,
Reaction is filtered after terminating, and is concentrated.MTBE 100ml are added into concentrate, stir 1h, are filtered, drying, obtain solid 32.9g, are received
Rate 92.4%.Purity 98.2%.
Embodiment 3：Compound IV preparation
Compound III 75g (375mmol) are added in 1L reaction bulbs, tetrahydrofuran 150ml, 20 ~ 25 DEG C stir, to anti-
Answer and wittig reagents 147.4g is added in system（413mmol）Reaction is stirring evenly and then adding into potassium tert-butoxide 21.0g
（0.187mmol）, reaction stirring 18h, anhydrous magnesium sulfate drying is added after reaction terminates, washing, liquid separation, concentration, is obtained not solid
Change grease 64.6g, yield 94.0%, purity 95.9%.
Embodiment 4：The preparation of Medetomidine
Compound IV 20g (109mmol), methanol 160ml are added in 500mL reaction bulbs, adds Pd/C 2g, reaction is warming up to
Hydrogen is bubbled into after 40 DEG C, after reaction is complete, concentration of reaction solution, grease is beaten with MTBE, is filtered, and is dried, is obtained solid
17.1g yield 84.6%.
Embodiment 5：The preparation of dexmedetomidine hydrochloride
Medetomidine 5g is added in 100ml reaction bulbs（25.0mmol）, D dibenzoyl tartaric acids 8.96g（25.0mmol）,
Isopropanol 25ml, continue to stir after temperature rising reflux dissolved clarification, there are a large amount of solids to wash out, cool crystallization, filters, dry right U.S. support miaow
Surely salt is split, salt will be split and be added to isopropanol temperature rising reflux, concentrated hydrochloric acid 0.5ml, solid dissolved clarification is added dropwise, cooling crystallization solid is washed
Go out, filter, dry to obtain dexmedetomidine hydrochloride 2.16g, yield 36.5%.
1HNMR (300MHz, DCl3)：δ1.64 (d, 3H),δ2.18(s, 3H),δ2.25(s, 3H),δ4.54(m,
1H), δ 6.72 (s, 1H), δ 6.96 (m, 1H), δ 7.02 (m, 2H), δ 8.90 (s, 1H); 13 CNMR(300MHz, DCl3):
δ11.94, δ20.55, δ20.93, δ32.25, δ115.04, δ123.94, δ125.94, δ129.03, δ133.17,
δ134.20, δ137.39, δ138.63, δ139.48。
Claims (6)
1. a kind of synthetic process of dexmedetomidine hydrochloride, it is led to one kind with 2,3- dimethylbenzaldehydes for starting material
Cross with（1-（Trimethyl silicon substrate）- 1H- imidazoles 4- bases）Magnesium bromide occurs grignard reaction and generates compound II, and compound II passes through again
Oxidation reaction generates compound III, and compound III reacts generation compound IV by Wittig, and compound IV is by being catalyzed hydrogen
Change and directly synthesize Medetomidine, obtain dexmedetomidine hydrochloride finally by acidifying is split, its synthetic route is as follows：
。
2. wanting the preparation method in 1 according to right, it uses Dess-Martin reagents as gentle oxidising agent, in order to fill
The equivalent proportion for dividing reaction synthesis compound III, compound II and Dess-Martin is 1:1.5-1:4, wherein it is preferred that 1:2.
3. according to the preparation method described in claim 1,2, the solvent that synthesis compound III is used is selected from ethyl acetate, tetrahydrochysene
Furans, dichloromethane, chloroform, acetonitrile, ether, ethyl acetate, dichloromethane.
4. preparation method according to claim 1, the alkali synthesized in compound IV is selected from sodium acid carbonate, sodium carbonate, carbonic acid
Potassium, cesium carbonate, triethylamine, ethylenediamine, diethylamine, pyridine, imidazoles, sodium hydrogen, sodium methoxide, methanol first, potassium tert-butoxide, prioritizing selection
Tert-butyl alcohol first, sodium methoxide.
5. according to the preparation method described in claim 1,4, in synthesis compound IV solvent be selected from ethyl acetate, tetrahydrofuran,
Dichloromethane, chloroform, acetonitrile, ether, toluene, dioxane, methanol, ethanol, preferably tetrahydrofuran, dichloromethane.
6. according to the preparation method described in claim 1,4,5, to make compound IV fully synthesize, compound III and Wittig
Reagent equivalent proportion is 1:1-1:1.5, wherein it is preferred that 1:1.1.
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| CN201711069890.1A CN107857731A (en) | 2017-11-03 | 2017-11-03 | A kind of process for preparing dexmedetomidine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023182903A1 (en) | 2022-03-22 | 2023-09-28 | Общество с ограниченной ответственностью "ВИК-здоровье животных" | Method for producing medetomidine and its derivatives |
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2017
- 2017-11-03 CN CN201711069890.1A patent/CN107857731A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023182903A1 (en) | 2022-03-22 | 2023-09-28 | Общество с ограниченной ответственностью "ВИК-здоровье животных" | Method for producing medetomidine and its derivatives |
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Application publication date: 20180330 |