CN102753532A - Process for preparation of medetomidine - Google Patents
Process for preparation of medetomidine Download PDFInfo
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- CN102753532A CN102753532A CN2010800554125A CN201080055412A CN102753532A CN 102753532 A CN102753532 A CN 102753532A CN 2010800554125 A CN2010800554125 A CN 2010800554125A CN 201080055412 A CN201080055412 A CN 201080055412A CN 102753532 A CN102753532 A CN 102753532A
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- CUHVIMMYOGQXCV-UHFFFAOYSA-N CC(c1c[nH]cn1)c1c(C)c(C)ccc1 Chemical compound CC(c1c[nH]cn1)c1c(C)c(C)ccc1 CUHVIMMYOGQXCV-UHFFFAOYSA-N 0.000 description 1
- QEXQEYUFQQOPKP-ATVHPVEESA-N Cc1cccc(C(/C(/N)=C/NCc2ccccc2)=O)c1C Chemical compound Cc1cccc(C(/C(/N)=C/NCc2ccccc2)=O)c1C QEXQEYUFQQOPKP-ATVHPVEESA-N 0.000 description 1
- GXXAAYIDJSDWSZ-UHFFFAOYSA-N Cc1cccc(C(c2c[n](Cc3ccccc3)cn2)=O)c1C Chemical compound Cc1cccc(C(c2c[n](Cc3ccccc3)cn2)=O)c1C GXXAAYIDJSDWSZ-UHFFFAOYSA-N 0.000 description 1
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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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
- C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
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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
Abstract
The present disclosure relates to a process for the preparation of medetomidine, 4-[1-(2,3-Dimethylphenyl)ethyl]- 1H-imidazoIe in an environmentally favourable and commercially feasible manner. Previous methods for the preparation of medetomidine use expensive 4-substituted imidazole derivatives as starting material. A practical way of synthesis is provided in which the imidazole ring is built up during a multi-step process starting from commercially affordable, 2,3-dimethylbenzoic. Mild reaction conditions are used throughout the process.
Description
Background of invention
Background technology
4-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles is commonly referred to as medetomidine (I).
The medetomidine of at first in EP-A-72615, describing is the racemic mixture of the equal proportion of two kinds of optics enantiomers; For being commonly referred to as left-handed and dextral optically active isomer (MacDonald et al., 1991 of left medetomidine (LEV) and dexmedetomidine (DEX) respectively; Savola and Virtanen, 1991).This compound belongs to the high selectivity that has the 2-adrenoceptor, the novel alpha2-receptor stimulant (Savola etal, 1986) that contains the substituted imidazole ring of 4-.
The acceptor that influenced by the catecholamine neurotransmitter, for example, the acceptor of sympathin and suprarenin influence is called as Adrenergic acceptor (or adrenergic receptor), can be divided into alpha and beta subclass.The alpha2-adrenoceptor relates to the automatic inhibition mechanism that neurotransmitter discharges, and in the adjusting of the adjusting of hypertension, bradyrhythmia (heart rate of reduction) even vigilance and pain relieving (to the reduction susceptibility of pain), plays an important role.
Medetomidine is studied in people's clinical trial, and be used as animal have (S)-enantiomer, dexmedetomidine is the narcotic of activeconstituents.
Recently, it is reported that some the pharmacology compound that acts on thrombotonin and Dopamine HCL neurotransmitter has obstruction or promotes the for example ability of adhering to of barnacle of some sea life.USP 7,531,581 have instructed the purposes of medetomidine as anti-alluvial agent first.After a while, USP 7,311,766 disclose the coating composition that comprises medetomidine with USP 7,531,581, are used to suppress or prevent the sea life alluvial on the solid surface.
The possible purposes of medetomidine requires to obtain that can bear, economically feasible equally its preparation method.
Exist several kinds of currently known methodss that are used to prepare medetomidine at present.
Kudzma etc. described the preparation medetomidine multistep rapid method.This method is imperfect, uses highly flammable and corrosive compound because it relates to, and like butyllithium, and further, is reflected at approximately under-78 ℃ the low temperature and carries out.
European patent EP 1918282 has been described the preparation method of medetomidine and its salt.This method has been utilized the metal transferization of halogenated imidazoles with Grignard reagent, and reacts with 2 subsequently.This method relates to protection and the deprotection of trityl chloride to imidazoles nitrogen.
People such as Cordi disclose the medetomidine preparation method with its tartrate form.The shortcoming of this method is to synthesize from quite expensive parent material to begin.
GB2453982 has described the preparation method of medetomidine, comprises making 2 3-dimethyl--xylyl alcohol and the reaction of N-TMS imidazoles.The shortcoming of this method is to need to use strong Lewis acid and excessive reagent.
The invention provides simple and non-obvious process, it can overcome the shortcoming of the known method of prior art.The rapid process of multistep that begins from 2 is expandable and safe for commercial prodn.For the preparation of medetomidine, this synthetic route also is economically feasible approach.
Invention field
The present invention relates to the preparation method of imdazole derivatives 4-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles and relevant intermediate thereof.Synthetic is to obtain from commercial obtainable parent material.Many previous synthetic substituted imdazole derivatives of expensive 4-that used are as parent material.In the present invention, imidazole ring made up between synthesis phase.
Summary of the invention
The invention provides the method for preparing medetomidine (formula I),
Formula I
May further comprise the steps:
With the 2 esterification is (2-nitrophenyl)-2 ester;
(2-nitrophenyl)-2 ester is changed into 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
Prepare 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone from 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone is reduced into 2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone;
(1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles; And
Hydrogenation 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles obtains the compound of formula I.
Replace using the expensive substituted imdazole derivatives of 4-as parent material, method of the present invention relies on and makes up imidazole ring between synthesis phase.In addition, reactions step need not be lower than 0 ℃ temperature, is quite expensive and time-consuming because big volume is cooled to be lower than 0 ℃, and this is a kind of advantage.
Description of drawings
Fig. 1 representes that the present invention is used to prepare the reaction scheme with compound in structural formula I.
Embodiment
The present invention relates to prepare the method for imdazole derivatives 4-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1H-imidazoles and relevant intermediate thereof.
In preferred embodiment, the invention discloses the method for the compound of preparation formula I,
Formula I
Comprise the steps:
With the 2 esterification is (2-nitrophenyl)-2 ester;
(2-nitrophenyl)-2 ester is changed into 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
Prepare 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone from 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone is reduced into 2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone;
(1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles; And
Hydrogenation 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles obtains the compound of formula I.
In yet another embodiment of the present invention, 2 uses oxalyl chloride and 2-nitrophenols to come esterification.
In another embodiment of the present invention, 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone uses Nitromethane 99Min. and alkali to prepare.
In another embodiment of the present invention, said alkali is selected from but is not limited to comprise the group of salt of wormwood, potassium tert.-butoxide, sodium methylate, 4-dimethylaminopyridine, Potassium monofluoride and yellow soda ash; Be preferably salt of wormwood.
In another embodiment of the present invention, said 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone uses phenmethyl amine and triethyl orthoformate preparation.
In another embodiment of the present invention, said reduction uses the reductive agent that is selected from the group that is made up of zinc-ammonium salt, Raney's nickel-hydrogen and palladium carbon-hydrogen to carry out, and is preferably Raney's nickel-hydrogen.
In another embodiment of the present invention, said ammonium salt is selected from the group that is made up of ammonium formiate, ammonium acetate, ammonium oxalate, ammonium chloride and Hydrazine Hydrate 80; Be preferably ammonium formiate.
In another embodiment of the present invention, said (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone uses the triethyl orthoformate preparation.
In another embodiment of the present invention, [1-(2, the 3-3,5-dimethylphenyl) vinyl imidazole uses methylmagnesium-halide and prepares with the acid dehydration subsequently said 1-benzyl-4-.
In another embodiment that the present invention opens, said acid is selected from but is not limited to comprise the group of hydrochloric acid, Hydrogen bromide, acetate and p-toluenesulphonic acids; Be preferably hydrochloric acid.
In another embodiment of the present invention, said methylmagnesium-halide is selected from the group that is made up of methylmagnesium-chloride, methyl magnesium iodide and methyl-magnesium-bromide, preferably methyl-magnesium-bromide.
In another embodiment of the present invention, said 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles uses the hydrogenant agent that is selected from the group that is made up of hydrogen-palladium carbon and palladium hydroxide carbon to come hydrogenation, is preferably hydrogen-palladium carbon.
In another embodiment of the present invention, the method preparation of 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone through may further comprise the steps:
From 2 preparation (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone; With handle (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone with Nitromethane 99Min. and obtain 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone existing under the situation of alkali.
The invention still further relates to the compound of formula II:
Formula II
The invention still further relates to the compound of formula III,
Formula III
The invention still further relates to the compound of formula IV,
Formula IV
The invention still further relates to the compound of formula V,
Formula V
In the synthetic final step, removing in an independent step of the reduction of alkene and blocking group carried out.In previous route of synthesis, carry out in these two steps of being everlasting; At first the two keys of reduction are removed blocking group then.During building-up process, temperature can remain on 0 ℃ or more than.Meaning does not need further cooling.It is large-scale synthetic that this makes that with different step disclosed herein this process is suitable for.
At last, medetomidine can be transformed into its salt through using standard method to add organic or mineral acid.If when handling medetomidine, have problems, can produce suitable high density product in 1-methoxyl group-2-propyl alcohol through medetomidine is dissolved into owing to dust forms.
In a word, content of the present invention provides feasible method in the industry for preparing medetomidine.This process relates to use simply, reagent obtains the medetomidine as free alkali cheaply.
The compound that has the structure that this structural formula describes in this any chemical formula that provides intention representative.Especially, possibly have asymmetric center at the compound of this any chemical formula that provides, thereby exist with different enantiomerism forms.All optically active isomers and their mixture comprise racemic mixture, are parts of the present invention.
The present invention is not restricted to the use of the specific implementations of describing among the application, and said embodiment expection is as the illustration of various aspects of the present invention.Can carry out many modifications of the present invention and variation and do not deviate from its spirit and scope, this is conspicuous for those skilled in the art.Function equivalent method in except enumerating at this those, the scope of the disclosure of invention is conspicuous according to above description to those skilled in the art.
It being understood that to the invention is not restricted to specific method, reagent, compound and compsn, it can change natch.Also it will be appreciated that, only is the purpose that is used to describe specific implementations of the present invention in the proper noun of this use, does not mean that restriction the present invention.
Below will describe the present invention in detail.The invention discloses embodiment and experimental detail comes for those skilled in the art better understanding and guide to be provided.
The present invention who gives an example hereinafter should not be understood that to limit this scope of disclosure.Those skilled in the art will appreciate that and how to change the result that the preparation of giving an example obtains to expect.
Step 1a: the preparation of (2-nitrophenyl) 2 ester
(50g, (84.5g, 0.66mol) about 1 hour, prolonged agitation was up to settled solution (～1 hour) occurring 0.42mol) to add dinethylformamide (0.2ml) and oxalyl chloride at the compound 1 in dry methylene chloride (1.8L) under about 15 ℃.Concentrated reaction mixture obtains the acid chloride verivate.2-nitrophenols in methylene dichloride (500ml) (46.5g, 0.33mol), (68g 0.66mol) adds the solution of acid chloride in the methylene dichloride (250ml) to triethylamine, stirs about 2 hours.Reaction mixture quenches with freezing water (500ml), and uses dichloromethane extraction.Organic layer is used saturated NaHCO
3Solution (500ml) washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT, concentrating under reduced pressure obtains beige solid.Roughage uses 20% ETHYLE ACETATE-n-hexane (600ml) crystallization that the 2a of light yellow solid is provided.Output 81g (90).
The compound that after following each step, obtains
1(CDCl 300MHz) uses standard method to measure to H NMR spectrum.Record under 300MHz, and with reference to internal standard thing (TMS).Signal is with ppm (δ) report.
1HNMR(300MHz，CDCl
3)：δ，8.18(d，J＝8.3Hz，1H)，7.83(d，J＝7.5Hz，1H)，7.75-7.69(m，1H)，7.48-7.36(m，3H)，7.25-7.17(m，1H)，2.57(s，3H)，2.40(s，3H)
The preparation of step 2a:1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone
Under about 0 ℃ under nitrogen atmosphere to pulverizing dry K
2CO
3(76.3g, 0.55mol) at N, (47g 0.735mol) about 30 minutes, stirred 20 minutes at 0 ℃ to add Nitromethane 99Min. in the suspension-s of dinethylformamide (300ml).(50g, solution 1.5mol) stirred about 20 minutes at about 0 ℃ to add 2a.Reaction mixture is heated to about 80 ℃ of about 3h then.Reaction mixture is injected in the freezing water (500ml), with dense HCl the pH value is adjusted to 1, with ethyl acetate extraction (2 * 500ml).Organic layer is dry and concentrated on SODIUM SULPHATE ANHYDROUS 99PCT.Thick resistates uses ETHYLE ACETATE-sherwood oil through the rapid column chromatography purifying, obtains 3 of light yellow solid.Output: 21g (60%).
1HNMR(300MHz，CDCl
3)：δ7.4-7.2(m，3H)，5.76(s，2H)，2.44(s，3H)，2.32(s，3H)LCMS(m/z)：192.6(M-1)
Through using oxalyl chloride and 2-nitrophenols with 2; The esterification of 3-mesitylenic acid is (2-nitrophenyl)-2 ester, uses Nitromethane 99Min. and alkali with (2-nitrophenyl)-2 subsequently; 3-mesitylenic acid ester changes into 1-(2; The 3-3,5-dimethylphenyl)-and 2-nitro ethyl ketone, compound 3 or 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone can as above be explained acquisition (step 1a is to 2a).Optionally; People can use 2 (compound 1) to prepare (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone; It obtains 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone (referring to following step 1b-2b) existing under the situation of alkali to handle with Nitromethane 99Min. subsequently.Parent material is identical, but reagent b has changed.
Step 1b: the preparation of (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone
(250g, (222g 1.75mol) about 1 hour, continues to stir about 1 hour down at about 25 ℃ 1.66mol) to add dinethylformamide (15ml) and oxalyl chloride at the compound 1 in dry methylene chloride (1.8L) under 15 ℃.Imidazoles in 0 ℃ of drip dichloromethane (1.8L) (225.7g, solution 3.32mol), and stirred about 1 hour.Reaction mixture quenches with freezing water (1.5L), and uses dichloromethane extraction.Organic layer is used saturated NaHCO
3Solution (1.25L) washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT, concentrating under reduced pressure obtains faint yellow viscous paste material 2b.Output 291g (87%).
1H?NMR(300MHz，CDCl
3)：δ7.84(s，1H)，7.46-7.35(m，2H)，7.23(d，J＝4.8Hz，2H)，7.11(m，1H)，2.36(s，3H)，2.22(s，3H)LCMS(m/z)：200.6(M+1)
Under nitrogen atmosphere about 0 ℃ to N, the dry K that pulverizes in the dinethylformamide (900ml)
2CO
3(622g, (325ml 6mol) about 30 minutes, stirs about 1h at about 0 ℃ to add Nitromethane 99Min. in suspension-s 4.5mol).Drip N at 0-5 ℃, (300g, solution 1.5mol) stirred about 30 minutes 2b in the dinethylformamide (300ml).Reaction mixture slowly is heated to 45 ℃, stirs 12h.Reaction mixture injects freezing water (6L), and the pH value is adjusted to 7.5 with dense HCl.Filter the solid that produces, be suspended among the 2.5N HCl (1.5L), and extract with ETHYLE ACETATE (3L).Organic layer is dry on SODIUM SULPHATE ANHYDROUS 99PCT, and concentrating under reduced pressure obtains 3 of beige solid.Output: 173g (60%).
1H?NMR(300MHz，CDCl
3)：δ7.4-7.2(m，3H)，5.76(s，2H)，2.44(s，3H)，2.32(s，3H)，LCMS(m/z)：192.6(M-1)
The preparation of step 3:3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone (compound of formula II)
(120g, (321.7g 2.17mol) and at about 100 ℃ stirred about 1 hour compound 3 in the Glacial acetic acid min. 99.5 (600ml) 0.62mol) to add triethyl orthoformate.(99.5g 0.93mol), stirred about 2 hours in this reflux solution, slowly to add phenmethyl amine.Reaction mixture is injected in the freezing water (750ml), with the alkalization of 20%NaOH solution, and with ethyl acetate extraction (2 * 600ml).Organic layer is with 1N HCl solution (300ml) washing, and is dry on SODIUM SULPHATE ANHYDROUS 99PCT, concentrating under reduced pressure.Thick resistates obtains 4 (compounds of formula II) of light yellow solid with 20% Virahol and normal hexane (1.5L) crystallization.Output: 153g (80%).
1HNMR(300MHz，CDCI
3)：δ10.97(bs，1H)，8.72(d，J＝14.4Hz，1H)，7.48-7.3(m，5H)，7.20-6.94(m，3H)，4.68(d，J＝6Hz，2H)，2.36(s，3H)，2.24(s，3H)LCMS(m/z)：311.2(M).
The preparation of step 4:2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone (mixture of formula III)
The preparation of step 5:1-benzyl imidazole-4-base-(2, the 3-3,5-dimethylphenyl) ketones (compound of formula IV)
In ethanol (1L) 5 (115g, add in solution 0.41mol) triethyl orthoformate (304.8g, 2.05mol) and acetate (2ml) and refluxing 4 hours.Concentrated reaction mixture uses methyl-n-butyl ether (360ml) crystallization, produces 6 (compounds of formula IV) of beige solid.Output 80g (67%).
1HNMR(300MHz，CDCl
3)：δ7.59(s，1H)，7.55(s，1H)，7.43-7.31(m，3H)，7.29-7.13(m，5H)，5.16(s，2H)，2.33(s，3H)，2.26(s，3H)LCMS(m/z)：291.3(M+1)
The preparation of step 6:1-benzyl-4-[1-(2,3-dimethyl styrene base] imidazoles (compound of formula V)
At about 25 ℃, in about 30 minutes time in THF (780ml) 6 (78.6g, suspension-s 0.27mol) add methyl-magnesium-bromide in the ether (3M solution, 270ml, 0.812mol).The browning reaction mixture that produces stirred about 2 hours at about 25 ℃.6N HCl (780ml) adds in the reaction mixture, and refluxes about 3 hours.Reaction mixture is with ethyl acetate extraction (2 * 400ml).Organic layer is used saturated NaHCO
3Solution (400ml), salt brine solution (400ml) washing, dry on SODIUM SULPHATE ANHYDROUS 99PCT, concentrating under reduced pressure obtains pale brown look roughage.Roughage obtains 7 (compounds of formula V) of beige solid with 20% Virahol-N-hexane (930ml) crystallization.Output 48g (62%).
1HNMR(300MHz，CDCl
3)：δ7.61(s，1H)，7.36-7.31(m，3H)，7.12-7.06(m，5H)，6.33(s，1H)，6.15(d，J＝2.1Hz，1H)，5.05(s，2H)，5.01(d，J＝2.1Hz，1H)，2.3(s，3H)，2.12(s，3H)LCMS(m/z)：289.1(M+1)
Step 7:4-[the preparation of 1-(2, the 3-3,5-dimethylphenyl) ethyl 1H-imidazoles (compound of formula I)
1HNMR(300MHz，CDCl
3)：δ7.38(s，1H)，7.07-6.94(m，3H)，6.70(s，1H)，4.38(q，J＝7.2Hz，1H)，2.29(s，3H)，2.22(s，3H)，1.58(d，J＝7.2Hz，3H)LCMS(m/z)：200.7(M+1).
Though disclose all respects and embodiment at this, other aspects and embodiment it will be apparent to those skilled in the art.All respects disclosed herein and embodiment are for illustrative purposes, and not to be intended to be restrictive.
Reference
1、Kudzma，Linas?V.；Turnbull，Stanhope?P.，Jr.Synthesis，pp1021-22，1991
2、Cordi，Alex?A.；Persigand，Thierry；Lecouve，Jean-Pierre.Synthetic?Communications，26(8)，1585-93，1996
Claims (17)
1. method for preparing the compound of formula I said method comprising the steps of:
A) with the 2 esterification be (2-nitrophenyl)-2 ester;
B) (2-nitrophenyl)-2 ester is changed into 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
C) prepare 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone from 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
D) 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone is reduced into 2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
E) 2-amino-3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone;
F) (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles; And
G) hydrogenation 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl] imidazoles obtains the compound of formula I.
2. the method for claim 1, wherein 2 uses oxalyl chloride and 2-nitrophenols to come esterification.
3. the method for claim 1, wherein 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ethyl ketone uses Nitromethane 99Min. and alkali to prepare.
4. method as claimed in claim 3, wherein, said alkali is selected from but is not limited to comprise the group that salt of wormwood, potassium tert.-butoxide, sodium methylate, 4-dimethylaminopyridine, Potassium monofluoride and yellow soda ash constitute; Salt of wormwood preferably.
5. the method for claim 1, wherein 3-(benzyl is amino)-1-(2, the 3-3,5-dimethylphenyl)-2-nitro-third-2-alkene-1-ketone uses phenmethyl amine and triethyl orthoformate preparation.
6. the method for claim 1, wherein said reduction use is selected from but is not limited to comprise that the reductive agent of the group that zinc-ammonium salt, Raney's nickel-hydrogen and palladium carbon-hydrogen constitutes carries out, preferably Raney's nickel-hydrogen.
7. method as claimed in claim 6, wherein, said ammonium salt is selected from the group that comprises that ammonium formiate, ammonium acetate, ammonium oxalate, ammonium chloride and Hydrazine Hydrate 80 constitute; Ammonium formiate preferably.
8. the method for claim 1, wherein (1-benzyl imidazole-4-yl)-(2, the 3-3,5-dimethylphenyl) ketone uses the triethyl orthoformate preparation.
The method of claim 1, wherein 1-benzyl-4-[1-(2, the 3-3,5-dimethylphenyl) vinyl imidazole uses methylmagnesium-halide and dewaters with acid subsequently and prepares.
10. method as claimed in claim 9, wherein, said acid is selected from but is not limited to comprise the group that hydrochloric acid, Hydrogen bromide, acetate and p-toluenesulphonic acids constitute; Be preferably hydrochloric acid.
11. the method for claim 1, wherein said methylmagnesium-halide be selected from by but be not limited to the group that comprises that methylmagnesium-chloride, methyl magnesium iodide and methyl-magnesium-bromide constitute, methyl-magnesium-bromide preferably.
12. the method for claim 1, wherein [use of 1-(2, the 3-3,5-dimethylphenyl) vinyl imidazole is selected from but is not limited to comprise that the hydrogenant agent of the group that hydrogen-palladium carbon and palladium hydroxide carbon constitute comes hydrogenation 1-benzyl-4-, is preferably hydrogen-palladium carbon.
13. like claim 1,3 or 4 described methods, wherein, 1-(2,3 3,5-dimethylphenyl)-2-nitro ethyl ketone prepares through may further comprise the steps:
A) from 2 preparation (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone; With
B) handle (2, the 3-3,5-dimethylphenyl)-imidazoles-1-base-ketone with Nitromethane 99Min. and obtain 1-(2, the 3-3,5-dimethylphenyl)-2-nitro ketone existing under the situation of alkali.
14. the compound with formula II structure, wherein,
15. the compound with formula III structure, wherein,
16. the compound with formula IV structure, wherein,
formula IV.
17. the compound with formula V structure, wherein,
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| US28382709P | 2009-12-09 | 2009-12-09 | |
| US61/283,827 | 2009-12-09 | ||
| PCT/EP2010/069175 WO2011070069A1 (en) | 2009-12-09 | 2010-12-08 | Process for preparation of medetomidine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1918282A1 (en) * | 2006-11-06 | 2008-05-07 | "Joint Stock Company Grindeks" | Method for preparing medetomidine and its salts |
| GB2453982A (en) * | 2007-10-24 | 2009-04-29 | Norbrook Lab Ltd | Chemical process for the preparation of Medetomidine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2101114B (en) | 1981-07-10 | 1985-05-22 | Farmos Group Ltd | Substituted imidazole derivatives and their preparation and use |
| US7311766B2 (en) | 2005-03-11 | 2007-12-25 | I-Tech Ab | Method and use of nanoparticles to bind biocides in paints |
| US7531581B2 (en) | 2005-03-11 | 2009-05-12 | I-Tech Ab | Method and use of acidified modified polymers to bind biocides in paints |
-
2010
- 2010-12-08 WO PCT/EP2010/069175 patent/WO2011070069A1/en active Application Filing
- 2010-12-08 CN CN201080055412.5A patent/CN102753532B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1918282A1 (en) * | 2006-11-06 | 2008-05-07 | "Joint Stock Company Grindeks" | Method for preparing medetomidine and its salts |
| GB2453982A (en) * | 2007-10-24 | 2009-04-29 | Norbrook Lab Ltd | Chemical process for the preparation of Medetomidine |
Non-Patent Citations (1)
| Title |
|---|
| KAVANAGH P. V. ETAL: "Synthesis of possible metabolites of medetomidine {1-(2,3-dimethylphenyl)-1-[imidazol-4(5)-yl]ethane}", 《JOURNAL OF CHEMICAL RESEARCH》 * |
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| CN102753532B (en) | 2015-05-13 |
| WO2011070069A1 (en) | 2011-06-16 |
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