CN102753532B - Process for preparation of medetomidine - Google Patents
Process for preparation of medetomidine Download PDFInfo
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- CN102753532B CN102753532B CN201080055412.5A CN201080055412A CN102753532B CN 102753532 B CN102753532 B CN 102753532B CN 201080055412 A CN201080055412 A CN 201080055412A CN 102753532 B CN102753532 B CN 102753532B
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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
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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-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles is commonly referred to as medetomidine (I).
First the medetomidine described in EP-A-72615 is the racemic mixture of the equal proportion of two kinds of optical enantiomorphs, for being commonly referred to as optically active isomer (MacDonald et al., 1991 of the left-handed and dextrorotation of left medetomidine (LEV) and dexmedetomidine (DEX) respectively; Savola and Virtanen, 1991).This compound belongs to the high selectivity had 2-adrenoceptor, the novel alpha2-receptor stimulant (Savolaetal, 1986) of imidazole ring replaced containing 4-.
By the acceptor that Neurotransmitter affects, such as, the acceptor of norepinephrine and Effect of Adrenaline is called as Adrenergic acceptor (or adrenergic receptor), can be divided into alpha and beta subclass.Alpha2-adrenoceptor relates to the automatic suppression mechanism of neurotransmitter regulator, plays an important role in the adjustment of adjustment, even vigilance and the pain relieving (the reduction susceptibility to pain) of hypertension, bradyrhythmia (heart rate of reduction).
Medetomidine is studied in people's clinical trial, and be used as animal there is (S)-enantiomer, narcotic that dexmedetomidine is activeconstituents.
Recently, it is reported, some pharmacological compounds acting on thrombotonin and reduction of Dopamine has the ability of the attachment hindering or promote some marine organisms such as barnacle.United States Patent (USP) 7,531,581 teach the purposes of medetomidine as anti-alluvial agent first.After a while, United States Patent (USP) 7,311,766 and United States Patent (USP) 7,531,581 disclose the coating composition comprising medetomidine, for suppressing or preventing the marine organisms on solid surface from depositing.
The possible purposes requirement of medetomidine can obtain that can bear equally, economically feasible its preparation method.
There are several currently known methodss for the preparation of medetomidine at present.
Kudzma etc. describe prepare medetomidine multistage method.This method is imperfect, because it relates to use highly flammable and corrosive compound, as butyllithium, and further, reacts and carries out under the low temperature of about-78 DEG C.
European patent EP 1918282 describes the preparation method of medetomidine and its salt.This process employs the metal transfer of the imidazoles Grignard reagent of halogenation, and react with 2，3-xylylaldehyde subsequently.The method relates to trityl chloride the protection of imidazoles nitrogen and deprotection.
The people such as Cordi disclose the medetomidine preparation method with its tartrate salt.The shortcoming of this method is that synthesis is from quite expensive parent material.
GB2453982 describes the preparation method of medetomidine, comprises and 2,3-dimethyl-methyl benzylalcohol and N-TMS imidazoles are reacted.The shortcoming of the method needs 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.Multi-step process from 2，3-xylic acid is expandable and safe for commercial production.For the preparation of medetomidine, this synthetic route is also economically feasible approach.
Invention field
The present invention relates to the preparation method of imdazole derivatives 4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles and relevant intermediate thereof.Synthesis is that obtainable parent material obtains commercially.Many synthesis previously employ the imdazole derivatives of expensive 4-replacement as parent material.In the present invention, imidazole ring is built between synthesis phase.
Summary of the invention
The invention provides the method preparing medetomidine (formula I),
Formula I
Comprise the following steps:
It is (2-nitrophenyl)-2，3-xylic acid ester by 2，3-xylic acid esterification;
(2-nitrophenyl)-2，3-xylic acid ester is changed into 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone is prepared from 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone body powder is become 2-amino-3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
2-amino-3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone;
(1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles; And
Hydrogenation 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles obtains the compound of formula I.
Replace the imdazole derivatives using expensive 4-to replace as parent material, method of the present invention relies between synthesis phase and builds imidazole ring.In addition, reactions steps does not need the temperature lower than 0 DEG C, because it is quite expensive and time-consuming for large volume being cooled to lower than 0 DEG C, this is a kind of advantage.
Accompanying drawing explanation
Fig. 1 represents that the present invention is for the preparation of the reaction scheme of compound with structural formula I.
Embodiment
The present invention relates to the method preparing imdazole derivatives 4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles and relevant intermediate thereof.
In a preferred embodiment, the invention discloses the method for the compound of preparation formula I,
Formula I
Comprise the steps:
It is (2-nitrophenyl)-2，3-xylic acid ester by 2，3-xylic acid esterification;
(2-nitrophenyl)-2，3-xylic acid ester is changed into 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone is prepared from 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone body powder is become 2-amino-3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
2-amino-3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone;
(1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles; And
Hydrogenation 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles obtains the compound of formula I.
In yet another embodiment of the present invention, 2，3-xylic acid uses oxalyl chloride and 2-nitrophenols to carry out esterification.
In another embodiment of the present invention, 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone uses Nitromethane 99Min. and alkali to prepare.
In another embodiment of the present invention, described 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 sodium carbonate; Be preferably salt of wormwood.
In another embodiment of the present invention, described 3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone uses phenmethyl amine and triethyl orthoformate preparation.
In another embodiment of the present invention, described reduction uses the reductive agent being selected from the group be 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, described ammonium salt is selected from the group be made up of ammonium formiate, ammonium acetate, ammonium oxalate, ammonium chloride and hydrazine hydrate; Be preferably ammonium formiate.
In another embodiment of the present invention, described (1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone uses triethyl orthoformate preparation.
In another embodiment of the present invention, [1-(2,3-3,5-dimethylphenyl) vinyl imidazole uses methylmagnesium-halide and prepares with acid dehydration subsequently described 1-benzyl-4-.
In another embodiment that the present invention opens, described acid is selected from but is not limited to comprise the group of hydrochloric acid, Hydrogen bromide, acetic acid and p-toluenesulphonic acids; Be preferably hydrochloric acid.
In another embodiment of the present invention, described methylmagnesium-halide is selected from the group be made up of methylmagnesium-chloride, methylpyridinium iodide magnesium and methyl-magnesium-bromide, preferably methyl-magnesium-bromide.
In another embodiment of the present invention, described 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles uses the hydrogenant agent being selected from the group be made up of hydrogen-palladium carbon and palladium hydroxide carbon to carry out hydrogenation, is preferably hydrogen-palladium carbon.
In another embodiment of the present invention, the method preparation of 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone by comprising the following steps:
From 2，3-xylic acid preparation (2,3-3,5-dimethylphenyl)-imidazoles-1-base-ketone; With obtain 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone with Nitromethane 99Min. process (2,3-3,5-dimethylphenyl)-imidazoles-1-base-ketone in the case of a base depositing.
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 final step of synthesis, reduction and the removing of blocking group of alkene are carried out in one single step.In previous route of synthesis, this often carries out in two steps; First reduce double bond, then remove blocking group.During building-up process, temperature can remain on 0 DEG C or more.Mean and do not need further cooling.This makes this process be suitable for large-scale synthesis together with different step disclosed herein.
Finally, medetomidine can by use standard method to add salt that organic or mineral acid is transformed into it.If had problems because dust is formed when processing medetomidine, applicable high density product can be produced by being dissolved into by medetomidine in 1-methoxy-2-propanol.
In a word, present disclosure provides the industrial feasible method preparing medetomidine.This process relates to the medetomidine using reagent that is simple, low cost to obtain as free alkali.
Any chemical formula intention given herein representative has the compound of the structure that this structural formula is described.Especially, the compound of any chemical formula given herein may have asymmetric center, thus exists with different enantiomeric form.All optically active isomers and their mixture, comprising racemic mixture, is a part of the present invention.
The present invention is not restricted to the use of the particular implementation described in the application, and described embodiment expection is as the illustration of various aspect of the present invention.Can carry out spirit and scope many modifications and variations of the present invention not being deviated to it, this is apparent for those skilled in the art.Except listed herein those, the function equivalent method in the scope of the disclosure of invention is apparent according to above description for those skilled in the art.
It being understood that and the invention is not restricted to specific method, reagent, compound and composition, it can change natch.It is also to be appreciated that proper noun is only the object for describing particular implementation of the present invention as used herein, do not mean that restriction the present invention.
Below in detail the present invention will be described.The invention discloses embodiment and experimental detail better to understand for those skilled in the art provide and guide.
Embodiment 1
The present invention illustrated hereinafter should not be understood to the scope limiting the disclosure.Those skilled in the art will appreciate that the preparation how changing and exemplify is to obtain the result of expectation.
Step 1a:(2-nitrophenyl) preparation of 2，3-xylic acid ester
To the compound 1 (50g in dry methylene chloride (1.8L) at about 15 DEG C, 0.42mol) add dinethylformamide (0.2ml) and oxalyl chloride (84.5g, 0.66mol) about 1 hour, until there is settled solution (~ 1 hour) in prolonged agitation.Concentrated reaction mixture obtains acid chloride derivative.In adding methylene dichloride (250ml) to the 2-nitrophenols (46.5g, 0.33mol) in methylene dichloride (500ml), triethylamine (68g, 0.66mol), the solution of acid chloride, stirs about 2 hours.Reaction mixture freezing water (500ml) quenching, and use dichloromethane extraction.The saturated NaHCO of organic layer
3solution (500ml) washs, and dry on anhydrous sodium sulfate, concentrating under reduced pressure obtains beige solid.Roughage uses 20% ethyl acetate-n-hexane (600ml) crystallization to provide the 2a of light yellow solid.Output 81g (90).
The compound obtained after following each step
1h NMR composes (CDCl, 300MHz) and uses standard method to measure.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-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone
Under nitrogen atmosphere to the dry K of pulverizing at about 0 DEG C
2cO
3(76.3g, 0.55mol) adds Nitromethane 99Min. (47g, 0.735mol) about 30 minutes in the suspension of DMF (300ml), stirs 20 minutes at 0 DEG C.Add the solution of 2a (50g, 1.5mol), stir about 20 minutes at about 0 DEG C.Then reaction mixture is heated to about 80 DEG C of about 3h.Reaction mixture is injected in freezing water (500ml), with dense HCl, pH value is adjusted to 1, extracts (2 × 500ml) by ethyl acetate.Organic layer is dry on anhydrous sodium sulfate and concentrated.Thick resistates uses ethyl acetate-light petrol by flash column chromatography, 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)
By using oxalyl chloride and 2-nitrophenols by 2, the esterification of 3-mesitylenic acid is (2-nitrophenyl)-2,3-mesitylenic acid ester, use Nitromethane 99Min. and alkali by (2-nitrophenyl)-2 subsequently, 3-mesitylenic acid ester changes into 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone, compound 3 or 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone as above can illustrate acquisition (step 1a to 2a).Optionally, people can use 2,3-mesitylenic acid (compound 1) prepares (2,3-3,5-dimethylphenyl)-imidazoles-1-base-ketone, it obtains 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone (the step 1b-2b see following) with Nitromethane 99Min. process in the case of a base depositing subsequently.Parent material is identical, but reagent b changes.
Step 1b:(2,3-3,5-dimethylphenyl) preparation of-imidazoles-1-base-ketone
To the compound 1 (250g in dry methylene chloride (1.8L) at 15 DEG C, 1.66mol) add dinethylformamide (15ml) and oxalyl chloride (222g, 1.75mol) about 1 hour, continue to stir about 1 hour at about 25 DEG C.Drip the solution of imidazoles (225.7g, 3.32mol) in methylene dichloride (1.8L) at 0 DEG C, and stir about 1 hour.Reaction mixture freezing water (1.5L) quenching, and use dichloromethane extraction.The saturated NaHCO of organic layer
3solution (1.25L) washs, and dry on anhydrous sodium sulfate, 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)
Step 2b:1-(2,3-3,5-dimethylphenyl)-2-nitro ketone
The dry K pulverized in DMF (900ml) at about 0 DEG C under nitrogen atmosphere
2cO
3add Nitromethane 99Min. (325ml, 6mol) in the suspension of (622g, 4.5mol) about 30 minutes, stir about 1h at about 0 DEG C.Drip the solution of 2b (300g, 1.5mol) in DMF (300ml) at 0-5 DEG C, stir about 30 minutes.Reaction mixture is slowly heated to 45 DEG C, stirs 12h.Reaction mixture injects freezing water (6L), and the dense HCl of pH value is adjusted to 7.5.Filter the solid produced, be suspended in 2.5N HCl (1.5L), and extract by ethyl acetate (3L).Organic layer is dry on anhydrous sodium sulfate, 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-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone (compound of formula II)
Compound 3 (120g, 0.62mol) in Glacial acetic acid (600ml) adds triethyl orthoformate (321.7g, 2.17mol) and stirs about 1 hour at about 100 DEG C.In this reflux solution, slowly add phenmethyl amine (99.5g, 0.93mol), stir about 2 hours.Reaction mixture is injected in freezing water (750ml), basified with 20%NaOH, and extracts (2 × 600ml) by ethyl acetate.Organic layer 1N HCl solution (300ml) washing, dry on anhydrous sodium sulfate, concentrating under reduced pressure.Thick resistates 20% Virahol and normal hexane (1.5L) crystallization, obtain 4 (compounds of formula II) of light yellow solid.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-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone (mixture of formula III)
Compound 4 (150g, 0.48mol) in methyl alcohol (1.5L) is hydrogenation about 6 hours under about 50 DEG C and about 3kg pressure on 50% Raney's nickel (RaneyNi) (75g).Reaction mixture is by diatomite filtration, and diatomite methyl alcohol (100ml) washs.The organic filtrate of concentrated combination obtains semisolid 5 (compounds of formula III) of viscous brownish.Output 115g (85%).LCMS(m/z)：281.3(M+1)
The preparation of step 5:1-benzyl imidazole-4-base-(2,3-3,5-dimethylphenyl) ketone (compound of formula IV)
In ethanol (1L) 5 (115g, 0.41mol) solution in add triethyl orthoformate (304.8g, 2.05mol) and acetic acid (2ml) and reflux 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 DEG C, in the time of about 30 minutes, add the methyl-magnesium-bromide (3M solution, 270ml, 0.812mol) in ether to the suspension of 6 (78.6g, 0.27mol) in tetrahydrofuran (THF) (780ml).The browning reaction mixture produced stirs about 2 hours at about 25 DEG C.6N HCl (780ml) adds in reaction mixture, and refluxes about 3 hours.Reaction mixture, extracts (2 × 400ml) by ethyl acetate.The saturated NaHCO of organic layer
3solution (400ml), salt brine solution (400ml) wash, and dry on anhydrous sodium sulfate, concentrating under reduced pressure obtains brown color roughage.Roughage 20% Virahol-N-hexane (930ml) crystallization, obtains 7 (compounds of formula V) of beige solid.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-(2,3-3,5-dimethylphenyl) ethyl 1H-imidazoles (compound of formula I)
Compound 7 (47g, 0.162mol) in methyl alcohol (470ml) is in 10% palladium carbon (20g, 50% humidity) hydrogenation about 5 hours under about 70 DEG C and 5Kg pressure.Reaction mixture, by diatomite filtration, washed with additional methanol (100ml).The organic filtrate of concentrated combination, obtains dense light yellow viscous paste material.Roughage 10% first benzol-cyclohexane (470ml) crystallization is provided as 8 (compounds of formula I) of white solid, 4-[1-(2,3-3,5-dimethylphenyl) ethyl]-1H-imidazoles or medetomidine.Output 28.5g (87%).
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).
Although 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 are not 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 (16)
1. a method for the compound of preparation formula I, said method comprising the steps of:
A) using oxalyl chloride and 2-nitrophenols, is (2-nitrophenyl)-2，3-xylic acid ester by 2，3-xylic acid esterification;
B) use Nitromethane 99Min. and alkali, (2-nitrophenyl)-2，3-xylic acid ester is changed into 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
C) use phenmethyl amine and triethyl orthoformate, 3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone prepared by 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone;
D) reductive agent being selected from the group be made up of zinc-ammonium salt, Raney's nickel-hydrogen and palladium carbon-hydrogen is used, by 3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl)-2-nitro-propyl-2-alkene-1-ketone body powder becomes 2-amino-3-(benzyl amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone;
E) use triethyl orthoformate, 2-amino-3-(benzyl is amino)-1-(2,3-3,5-dimethylphenyl) third-2-alkene-1-ketone is cyclized into (1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone;
F) use methylmagnesium-halide and subsequently with acid dehydration, (1-benzyl imidazole-4-base)-(2,3-3,5-dimethylphenyl) ketone is changed into 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles; And
G) use the hydrogenant agent being selected from the group be made up of hydrogen-palladium carbon and palladium hydroxide carbon, carry out the compound that hydrogenation 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl] imidazoles obtains formula I.
2. the method for claim 1, wherein described alkali is selected from the group be made up of salt of wormwood, potassium tert.-butoxide, sodium methylate, 4-dimethylaminopyridine, Potassium monofluoride and sodium carbonate.
3. method as claimed in claim 2, wherein, described alkali is salt of wormwood.
4. the method for claim 1, wherein described reduction uses Raney's nickel-hydrogen reduction agent to carry out.
5. the method for claim 1, wherein described ammonium salt is selected from the group be made up of ammonium formiate, ammonium acetate, ammonium oxalate, ammonium chloride and hydrazine hydrate.
6. method as claimed in claim 5, wherein, described ammonium salt is ammonium formiate.
7. the method for claim 1, wherein described acid is selected from the group be made up of hydrochloric acid, Hydrogen bromide, acetic acid and p-toluenesulphonic acids.
8. method as claimed in claim 7, wherein, described acid is hydrochloric acid.
9. the method for claim 1, wherein described methylmagnesium-halide is selected from the group be made up of methylmagnesium-chloride, methylpyridinium iodide magnesium and methyl-magnesium-bromide.
10. method as claimed in claim 9, wherein, described methylmagnesium-halide is methyl-magnesium-bromide.
11. the method for claim 1, wherein 1-benzyl-4-[1-(2,3-3,5-dimethylphenyl) vinyl imidazole uses hydrogen-palladium hydrocarbon agent to carry out hydrogenation.
12. methods as described in claim 1,3 or 4, wherein, 1-(2,3 3,5-dimethylphenyl)-2-nitro ethyl ketone is prepared by comprising the following steps:
A) from 2，3-xylic acid preparation (2,3-3,5-dimethylphenyl)-imidazoles-1-base-ketone; With
B) 1-(2,3-3,5-dimethylphenyl)-2-nitro ethyl ketone is obtained with Nitromethane 99Min. process (2,3-3,5-dimethylphenyl)-imidazoles-1-base-ketone in the case of a base depositing.
13. 1 kinds of compounds with formula II structure, wherein,
14. 1 kinds of compounds with formula III structure, wherein,
15. 1 kinds of compounds with formula IV structure, wherein,
16. 1 kinds of compounds with formula V structure, wherein,
Applications Claiming Priority (3)
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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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| CN102753532A CN102753532A (en) | 2012-10-24 |
| CN102753532B true CN102753532B (en) | 2015-05-13 |
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| CN201080055412.5A Expired - Fee Related CN102753532B (en) | 2009-12-09 | 2010-12-08 | Process for preparation of medetomidine |
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| ES2557638T3 (en) | 2012-05-08 | 2016-01-27 | Lonza Ltd | Method for the preparation of 2- (2,3-dimethylphenyl) -1-propanal |
| WO2012172120A2 (en) | 2012-05-08 | 2012-12-20 | Lonza Ltd | 2-(2,3-dimethylphenyl)-1-propanal and its use as perfume |
| CN104245679B (en) | 2012-05-08 | 2016-03-02 | 隆萨有限公司 | The preparation method of medetomidine |
| WO2013011157A1 (en) * | 2012-06-28 | 2013-01-24 | Lonza Ltd | Method for preparation of medetomidine with chloroacetone |
| WO2012172121A1 (en) * | 2012-06-28 | 2012-12-20 | Lonza Ltd | Method for the preparation of medetomidine with chloroacetone |
| ES2565065T3 (en) | 2012-06-28 | 2016-03-31 | Lonza Ltd | Method for the preparation of 2- (2,3-dimethylphenyl) -1-propanal with chloroacetone |
| WO2015011177A1 (en) * | 2013-07-24 | 2015-01-29 | I-Tech Ab | Use of the enantiomer levomedetomidine as inhibitor for marine biofouling of surfaces |
| WO2015011178A1 (en) * | 2013-07-24 | 2015-01-29 | I-Tech Ab | Use of the enantiomer dexmedetomidine as inhibitor for marine biofouling of surfaces |
| RU2018105761A (en) | 2013-10-07 | 2019-02-26 | ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. | DEVICES FOR TRANSDERMAL DELIVERY OF DEXMEDETOMIDIDINE AND WAYS OF THEIR APPLICATION |
| RU2648449C2 (en) | 2013-10-07 | 2018-03-26 | ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. | Methods and compositions for transdermal delivery of a non-sedative amount of dexmedetomidine |
| TWI629066B (en) | 2013-10-07 | 2018-07-11 | 帝國製藥美國股份有限公司 | Methods and compositions for treating attention deficit hyperactivity disorder, anxiety and insomnia using dexmedetomidine transdermal compositions |
| CN103588711B (en) | 2013-11-27 | 2015-04-08 | 天津炜捷制药有限公司 | Preparation method for medetomidine intermediate |
| CN103664788B (en) * | 2013-12-04 | 2015-11-25 | 湖北生物医药产业技术研究院有限公司 | Prepare the method for dexmedetomidine |
| CN105481705A (en) * | 2014-08-23 | 2016-04-13 | 南京海纳医药科技有限公司 | Preparation and application of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethyl alcohol |
| DK179655B1 (en) | 2015-05-06 | 2019-03-13 | I-Tech Ab | Medetomidine for use in controlling parasitic crustaceans on fish |
| CN107556245B (en) * | 2016-06-30 | 2021-02-02 | 江苏云阳集团药业有限公司 | Preparation method of nyconazole hydrochloride |
| CN106588780A (en) * | 2016-12-15 | 2017-04-26 | 青岛辰达生物科技有限公司 | Process for preparing dexmedetomidine hydrochloride intermediate |
| CN106632051A (en) * | 2016-12-15 | 2017-05-10 | 青岛辰达生物科技有限公司 | Synthetic method of dexmedetomidine hydrochloride intermediate |
| CN106588779A (en) * | 2016-12-15 | 2017-04-26 | 青岛辰达生物科技有限公司 | Method for synthesizing dexmedetomidine hydrochloride intermediate |
| CN106632052A (en) * | 2016-12-15 | 2017-05-10 | 青岛辰达生物科技有限公司 | Method for preparing dexmedetomidine hydrochloride for anesthesia and sedation during operation |
| CN106588778A (en) * | 2016-12-15 | 2017-04-26 | 青岛辰达生物科技有限公司 | Preparation process of dexmedetomidine hydrochloride for ICU (intensive care unit) sedation and analgesia |
| ES2882193T3 (en) | 2017-03-29 | 2021-12-01 | I Tech Ab | Antifouling item |
| CN108840800A (en) * | 2018-05-28 | 2018-11-20 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of phenyl nitro ethyl ketone |
| CN108872431B (en) * | 2018-07-09 | 2021-03-23 | 成都倍特药业股份有限公司 | Method for detecting 4- (1- (2, 5-dimethylphenyl) ethyl) -1H-imidazole or/and hydrochloride thereof |
| US12050293B2 (en) | 2018-12-19 | 2024-07-30 | Pgs Geophysical As | Medetomidine compositions having improved anti-fouling characteristics |
| CN116348557B (en) | 2020-10-21 | 2024-07-05 | I-技术有限公司 | Antifouling compounds |
| CN115073354A (en) * | 2021-03-11 | 2022-09-20 | 江苏润安制药有限公司 | Preparation method of apremilast intermediate |
| WO2023182903A1 (en) | 2022-03-22 | 2023-09-28 | Общество с ограниченной ответственностью "ВИК-здоровье животных" | Method for producing medetomidine and its derivatives |
| CN114671811A (en) * | 2022-04-14 | 2022-06-28 | 南京正科医药股份有限公司 | Racemization recovery method of dexmedetomidine resolution byproduct |
| WO2024047144A1 (en) | 2022-09-01 | 2024-03-07 | I-Tech Ab | Composition protecting wood against marine woodborers |
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| CN102753532A (en) | 2012-10-24 |
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