CN107522662A - N substituted imidazole carboxylic acid ester compounds and preparation method thereof and purposes in medicine - Google Patents

N substituted imidazole carboxylic acid ester compounds and preparation method thereof and purposes in medicine Download PDF

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Publication number
CN107522662A
CN107522662A CN201710398132.8A CN201710398132A CN107522662A CN 107522662 A CN107522662 A CN 107522662A CN 201710398132 A CN201710398132 A CN 201710398132A CN 107522662 A CN107522662 A CN 107522662A
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alkyl
compound
alkoxy
och
optionally further
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邱关鹏
魏用刚
卢泳华
黄清平
廖鹏飞
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the compound shown in a kind of logical formula (I) or its stereoisomer, solvate, pharmaceutically acceptable salt or eutectic and combinations thereof, preparation method and purposes in medicine, and it is as follows to lead to formula (I)：It is consistent in the definition of each substituent and specification.

Description

N- substituted imidazole carboxylic acid ester compounds and preparation method thereof and purposes in medicine
Technical field
The present invention relates to a kind of N- substituted imidazoles carboxylic acid ester compound with tranquilizing soporific and/or anesthetic effect and its Preparation method and purposes in medicine.
Background technology
Etomidate is a kind of imidazole derivative with tranquilizing soporific and narcotic activity, and it is as general intravenous anesthesia Rapid-action, the duration is short and revives the characteristics of fast using more than 30 years, having for clinical drug.Etomidate lures for anesthesia Lead, the anesthesia of anesthesia maintenance and day surgery, compared to other products applied to angiocardiopathy, respiratory disease, cranium The operation of situations such as inner high voltage and during gerontal patient with certain superiority.
The mechanism of action of Etomidate mainly by with the Inhibitory receptor GABA with maincenterAAcceptor combine, make this by Body is more sensitive to inhibitory neurotransmitter GABA, so as to produce calm and anesthetic effect.But meanwhile Etomidate mainly passes through Cortin synthesis of the activity of suppression 11- β hydroxylases to body is also inhibited, and particularly much time using is to skin The suppression of matter hormone is more obvious.Due to cortin itself synthesis be body anti-inflammatory an important factor for, the conjunction of cortin It is unfavorable into the recovery being suppressed to postoperative patient.There is document to show, the dosage of Etomidate anesthesia is 0.2~0.3mg/kg, Meanwhile the concentration of Etomidate is at least 200ng/ml in blood, and 10ng/ml Etomidates can substantially lower blood in blood Content (the Critical Care 2012,16 of cortin in slurry:227).
The present invention provide a kind of N- substituted imidazoles carboxylic acid ester compound with tranquilizing soporific and/or anesthetic effect and its Preparation method and purposes in medicine, such compound have the advantages of Etomidate, while can reduce and cortin is closed Into suppression, reduce side effects of pharmaceutical drugs.
The content of the invention
The present invention provides a kind of compound shown in logical formula (I) or its stereoisomer, solvate, pharmaceutically acceptable Salt or eutectic：
Wherein：
R1It is independently selected from F, Cl, Br, CF3、OH、C1-4Alkyl or C1-4Alkoxy；
A is selected from 0,1,2,3,4 or 5；
R2Selected from C1-4Alkyl or-(CH2)n-C3-6Cycloalkyl, described alkyl or cycloalkyl is optionally further by 0 to 3 Selected from F, Cl, Br or CF3Substituent substituted；
N is selected from 0,1 or 2；
R3Selected from C6-10Aryl or 5 to 10 yuan of heteroaryl, described aryl or heteroaryl are optionally further by 1 to 4 Ra Substitution；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl ,-C (=O) OC1-6Alkyl or-OC (=O) OC1-6Alkyl, described alkyl, alkoxy, alkenyl or alkynyl are optionally further by 0 to 4 It is individual to be selected from F, Cl, Br, CF3, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted；
Alternatively, two RaCoupled atom forms C together3-8Carbocyclic ring or 3 to 8 circle heterocycles, described carbocyclic ring Or heterocycle is optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is taken Generation, and described heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
Condition is RaSelected from-C (=O) OC1-6During alkyl ,-C (=O) OC1-6Alkyl withAt least It is spaced 3 atoms.
A preferred embodiment of the present invention, compound or its stereoisomer, solvate shown in a kind of logical formula (I), Pharmaceutically acceptable salt or eutectic：
R1It is independently selected from F, Cl, Br, CF3、OH、C1-4Alkyl or C1-4Alkoxy, preferably F, Cl, Br, CF3、OH、 Methyl, ethyl, isopropyl, methoxy or ethoxy；
A is selected from 0,1,2,3,4 or 5；
R2Selected from C1-4Alkyl or-(CH2)n-C3-6Cycloalkyl, preferably CF3, methyl, ethyl or isopropyl, described alkyl, Cycloalkyl, methyl, ethyl or isopropyl are optionally further selected from F, Cl, Br or CF by 0 to 33Substituent substituted；
N is selected from 0,1 or 2；
R3Selected from phenyl, the phenyl is optionally further by 1 to 4 RaSubstitution；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, C1-6Alkyl, C1-6Alkoxy ,-C (=O) OC1-6Alkyl or- OC (=O) OC1-6Alkyl, described alkyl or alkoxy are optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4 Alkyl or C1-4The substituent of alkoxy is substituted；
Alternatively, two RaCoupled atom forms C together3-6Carbocyclic ring, described carbocyclic ring optionally further by 0 to 4 is selected from F, Cl, Br, CF3, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted；
Condition is RaSelected from-C (=O) OC1-6During alkyl ,-C (=O) OC1-6Alkyl withAt least It is spaced 3 atoms.
A preferred embodiment of the present invention, compound or its stereoisomer, solvate shown in a kind of logical formula (I), Pharmaceutically acceptable salt or eutectic：
R1It is independently selected from F, Cl, Br, CF3, OH, methyl, ethyl, isopropyl, methoxy or ethoxy；
A is selected from 0,1,2,3,4 or 5；
R2Selected from CF3, methyl, ethyl or isopropyl；
R3Selected from phenyl, the phenyl is optionally further by 1 to 4 RaSubstitution；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl ,- C (=O) OCH3,-C (=O) OCH2CH3,-C (=O) OC (CH3)3,-OC (=O) OCH3,-OC (=O) OCH2CH3Or-OC (=O) OCH(CH3)2；
Alternatively, two RaCoupled atom forms 5 yuan of carbocyclic rings together；
Condition is RaSelected from-C (=O) OCH3,-C (=O) OCH2CH3Or-C (=O) OC (CH3)3When ,-C (=O) OCH3、- C (=O) OCH2CH3Or-C (=O) OC (CH3)3WithAt least it is spaced 3 atoms.
Compound shown in logical formula (I) involved in the present invention includes but is not limited to one of following structure：
The present invention provides a kind of pharmaceutical composition, described pharmaceutical composition include compound described in logical formula (I) or its Stereoisomer, solvate, pharmaceutically acceptable salt or eutectic, and one or more pharmaceutically acceptable loads above Body and/or excipient.
Compound or its stereoisomer described in the logical formula (I) of the present invention, solvate, pharmaceutically acceptable salt or common Brilliant or aforementioned pharmaceutical compositions are preparing the application in producing tranquilizing soporific and/or anesthetic effect medicine.
Unless there are opposite statement, the term used in the specification and in the claims has following implications.
Involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include their same position in group of the present invention and compound Involved carbon, hydrogen, oxygen, sulphur, nitrogen or halogen are optionally further by one or more in element, and group of the present invention and compound Their individual corresponding isotopes are substituted, and the isotope of wherein carbon includes12C、13C and14C, the isotope of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), the isotope of oxygen includes16O、17O and18O, the isotope of sulphur include32S 、33S、34S and36S, the isotope of nitrogen include14N and15N, the isotope of fluorine19F, the isotope of chlorine include35Cl and37Cl, bromine it is same Position element includes79Br and81Br。
" alkyl " refers to the univalent saturated hydrocarbon radical of straight chain and side chain, and main chain includes 1 to 10 carbon atom, preferably 1 to 8 Carbon atom, more preferably 1 to 6 carbon atom, the straight chain and branched group of more preferably 1 to 4 carbon atom, most preferably 1 To 2 carbon atoms, the example of alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Zhong Ding It is base, the tert-butyl group, n-pentyl, 2- amyl groups, 3- amyl groups, 2- methyl -2- butyl, 3- methyl -2- butyl, n-hexyl, n-heptyl, just pungent Base, n-nonyl and positive decyl etc.；Described alkyl can optionally further by 0,1,2,3,4 or 5 selected from F, Cl, Br, I ,= O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocyclic ring Base, 3 to 8 circle heterocycles bases ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、- (CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent substituted, wherein R19And R19aIt is each independent Selected from H, hydroxyl, amino, carboxyl, C1-8Alkyl, C1-8Alkoxy, C2-8Alkenyl, C2-8Alkynyl, 3 to 10 yuan of carbocylic radicals, 4 to 10 yuan Heterocyclic radical, 3 to 10 yuan of carbocylic radical epoxides or 4 to 10 circle heterocycles base epoxides, k be selected from 0,1,2,3,4 or 5, j be selected from 0,1 or Person 2.Herein presented alkyl, k, j, R19And R19a, its is as defined above.
" alkoxy " refers to the univalent perssad of O- alkyl, wherein, alkyl as defined herein, alkoxy embodiment include but It is not limited to methoxyl group, ethyoxyl, 1- propoxyl group, 2- propoxyl group, 1- butoxy, 2- methyl isophthalic acids-propoxyl group, 2- butoxy, 2- first Base -2- propoxyl group, 1- amoxys, 2- amoxys, 3- amoxys, 2- methyl -2- butoxy, 3- methyl -2- butoxy, 3- first Base -1- butoxy and 2-methyl-1-butene epoxide etc..
" alkenyl " refers to the univalent unsaturated hydrocarbon radical of straight chain and side chain, and it has at least one, generally there is 1,2 or 3 carbon carbon Double bond, main chain include 2 to 10 carbon atoms, further preferred 2 to 6 carbon atoms, more preferably there is 2 to 4 carbon originals on main chain Son, alkenyl embodiment include but is not limited to vinyl, pi-allyl, 1- acrylic, 2- acrylic, 1- cyclobutenyls, 2- cyclobutenyls, 3- Cyclobutenyl, 1- pentenyls, 2- pentenyls, 3- pentenyls, 4- pentenyls, 1- methyl isophthalic acids-cyclobutenyl, 2-methyl-1-butene alkenyl, 2- Methyl -3- cyclobutenyls, 1- hexenyls, 2- hexenyls, 3- hexenyls, 4- hexenyls, 5- hexenyls, 1- methyl-1-pentenes alkenyl, 2- Methyl-1-pentene alkenyl, 1- heptenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 1- octenyls, 3- octenyls, 1- nonenyls, 3- nonenyls, 1- decene base, 4- decene base, 1,3- butadiene, 1,3- pentadienes, 1,4- pentadienes and 1,4- hexadienes etc.；Institute The alkenyl stated can be optionally further by 0,1,2,3,4 or 5 selected from F, Cl, Br, I ,=O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocylic radical, 3 to 8 circle heterocycles bases ,-(CH2)a-C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (= O)-O-R19Or-NR19R19aSubstituent substituted.Herein presented alkenyl, its is as defined above.
" alkynyl " refers to the univalent unsaturated hydrocarbon radical of straight chain and side chain, and it has at least one, generally there is 1,2 or 3 carbon carbon Three keys, main chain include 2 to 10 carbon atoms, further preferred 2 to 6 carbon atoms, more preferably there is 2 to 4 carbon originals on main chain Son, alkynyl embodiment include but is not limited to acetenyl, 1- propinyls, 2-propynyl, butynyl, 2- butynyls, 3- butynyls, 1- Methyl -2-propynyl, 4- pentynyls, 3- pentynyls, 1- methyl -2- butynyls, 2- hexin bases, 3- hexin bases, 2- heptynyls, 3- Heptynyl, 4- heptynyls, 3- octynyls, 3- n-heptylacetylenes base and 4- decynyls etc.；Described alkynyl can optionally further by 0,1, 2nd, 3,4 or 5 are selected from F, Cl, Br, I ,=O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alcoxyl Base, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocylic radical, 3 to 8 circle heterocycles bases ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O- R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent Substituted.Herein presented alkynyl, its is as defined above.
" cycloalkyl " refers to the carbocyclic hydrocarbon radicals of monovalence saturation, generally there is 3 to 10 carbon atoms, and non-limiting example includes Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl etc..Described cycloalkyl can optionally further by 0,1,2,3,4 or 5 selected from F, Cl, Br, I ,=O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C2-6Alkene Base, C2-6Alkynyl, C3-8Carbocylic radical, 3 to 8 circle heterocycles bases ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、- (CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent taken Generation.Herein presented cycloalkyl, its is as defined above.
" carbocyclic ring " refers to saturation either undersaturated aromatic rings or non-aromatic ring, and aromatic rings or non-aromatic ring can be 3 to 10 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, carbocylic radical can be connected with bridged ring or loop coil, non- Restricted embodiment includes cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyls, 1- cyclopenta -2- alkenyls, 1- rings penta Base -3- alkenyls, cyclohexyl, 1- cyclohexyl -2- alkenyls, 1- cyclohexyl -3- alkenyls, cyclohexenyl group, cyclohexadienyl, suberyl, Cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, phenyl or naphthyl.Described carbocylic radical can optionally enter One step is by 0,1,2,3,4 or 5 selected from F, Cl, Br, I ,=O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxyl alkane Base, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocylic radical, 3 to 8 circle heterocycles bases ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (=O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or- NR19R19aSubstituent substituted.Herein presented carbocyclic ring, its is as defined above.
" heterocycle " refers to saturation or undersaturated aromatic rings or non-aromatic ring, and aromatic rings or non-aromatic ring can be 3 To 10 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and comprising 1 to 4 be selected from N, O or S hetero atom, It is preferred that 3 to 8 circle heterocycles bases, N, S for selectively substituting in the ring of heterocyclic radical can be oxidized to various oxidation state.Heterocyclic radical can connect It is connected on hetero atom or carbon atom, heterocyclic radical can be connected with bridged ring or loop coil, and non-limiting example includes epoxy second Base, glycidyl, aziridinyl, oxetanylmethoxy, azelidinyl, thietanyl, 1,3- dioxolanyls, 1,4- bis- Butyl oxide link base, 1,3- dioxane base, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine Base, sulphur azatropylidene base, pyridine radicals, piperidyl, homopiperidinyl, furyl, thienyl, pyranose, N- alkyl pyrrole radicals, pyrimidine Base, pyrazinyl, pyridazinyl, piperazinyl, homopiperazine base, imidazole radicals, piperidyl, piperazine sting base, morpholinyl, thio-morpholinyl, Sai Evil Alkyl, the thiophene bases of 1,3- bis-, dihydrofuran base, dihydro pyranyl, the ring group of two thiophene penta, tetrahydrofuran base, tetrahydro-thienyl, tetrahydrochysene pyrrole Mutter base, tetrahydro thiapyran base, nafoxidine base, imidazolidine base, tetrahydro-thiazoles base, THP trtrahydropyranyl, benzimidazolyl, benzo pyrrole Piperidinyl, pyrrolopyridinyl, coumaran base, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxies amyl group, pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, Pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyls, 3- azabicyclos [3.1.0] hexyl, 3- azepines Bicyclic [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 3H- indyl quinolizines base, N- pyridine radicals urea, 1,1- sulphur dioxide generations Morpholinyl, azabicyclic [3.2.1] octyl, azabicyclic [5.2.0] nonyl, oxatricyclo [5.3.1.1] dodecyl, Azaadamantane base and oxa- spiroheptane base.Described heterocyclic radical can be optionally further by 0,1,2,3,4 or 5 choosing From F, Cl, Br, I ,=O, hydroxyl ,-SR19, nitro, cyano group, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6 Alkynyl, C3-8Carbocylic radical, 3 to 8 circle heterocycles bases ,-(CH2)a- C (=O)-R19、-(CH2)k- C (=O)-O-R19、-(CH2)k- C (= O)-NR19R19a、-(CH2)k- S (=O)j-R19,-O-C (=O)-O-R19Or-NR19R19aSubstituent substituted.Go out herein Existing heterocycle, its is as defined above.
" optional " or " optionally " refer to event described later or environment can with but necessarily occur, the explanation includes The occasion that the event or environment occur or do not occurred.Such as：" alkyl optionally substituted by F " refer to alkyl can with but necessarily taken by F In generation, illustrate to include the situation that alkyl is not substituted by the F situations substituted and alkyl by F.
" pharmaceutical composition " represent compound described in one or more texts or its physiology/pharmaceutically acceptable salt with The mixture of other constituents, wherein other components include physiology/pharmaceutically acceptable carrier and excipient.
" carrier " refers to that obvious stimulation will not be produced to organism and will not eliminate the bioactivity of given compound With the carrier or diluent of characteristic.
" excipient " refers to being added in pharmaceutical composition to further rely on the inert substance of compound administration.Assign The example of shape agent include but is not limited to calcium carbonate, calcium phosphate, various sugared and different types of starch, cellulose derivative (including Microcrystalline cellulose), gelatin, vegetable oil, polyethylene glycols, diluent, granulating agent, lubricant, adhesive, disintegrant etc..
" prodrug " refers to that the chemical combination of the present invention with bioactivity can be converted into physiological conditions or by solvolysis The compound of thing.The prodrug of the present invention is prepared by modifying the functional group in the compounds of this invention, and the modification can pass through The operation of routine is removed in vivo, and obtains parent compound.
" stereoisomer " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule, including suitable Trans isomer, enantiomter and rotamer.
" effective dose " has guided the amount of the compound of tissue, system or subject physiologic or medical science translation, and this amount is institute Seek, be included in the one or more of symptoms generation for being enough to prevent treated illness or illness when being applied with subject Or it is set to mitigate to the amount of compound to a certain degree.
" solvate " refers to the compounds of this invention or its salt, and they also include in terms of the chemistry of non-covalent intermolecular forces combination Amount or non-stoichiometric solvent.Then it is hydrate when solvent is water.
Embodiment
The implementation process of the present invention and caused beneficial effect are described in detail below by way of specific embodiment, it is intended to which help is read Reader more fully understand the present invention essence and feature, not as to this case can practical range restriction.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6 (ppm) unit provides.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear-magnetism Instrument, measure solvent are deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as four Methyl-monosilane (TMS).
MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate uses is 0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or can purchase in The companies such as safe smooth science and technology, the resistance to Jilin Chemical of peace, Shanghai moral are silent, Chengdu section dragon chemical industry, splendid remote chemical science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Hydrogenation generally vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Carried out under nitrogen atmosphere without specified otherwise, reaction in embodiment.
Refer to the aqueous solution without specified otherwise, solution in embodiment.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
Embodiment 1：(2- methoxyl group -4- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 1)
(2-methoxy-4-methyl-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A, with reference to Journal of Medicinal Chemistry,46(7),1257-1265；2003 are prepared) (1.0g, 4.62mmol) is suspended in dichloromethane (20mL), It is sub- to add 2- methoxyl group -4- methylphenols (1B) (0.958g, 6.94mmol), 1- (3- dimethylamino-propyls) -3- ethyls carbon two Amine hydrochlorate (1.33g, 6.94mmol) and DMAP (0.847g, 6.94mmol), are stirred at room temperature 2 hours.Reaction Liquid is washed with saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt (30mL × 1) successively, and anhydrous sodium sulfate is done It is dry, filtering, filtrate decompression concentration, residue with silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=1/20~ 1/5) title compound (2- methoxyl group -4- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylate (chemical combination, is obtained Thing 1), colorless oil (1.1g, yield 71%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.80(s,1H),7.36–7.27(m,3H),7.24–7.19 (m,2H),6.93(d,1H),6.78(s,2H),6.34(q,1H),3.71(s,3H),2.34(s,3H),1.88(d,3H)。
LCMS m/z=337.1 [M+1].
Embodiment 2：(2- methoxyphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 2)
(2-methoxyphenyl)3-[(1R)-1-phenylethyl]imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (2g, 9.25mmol) are suspended in dichloromethane (30mL) In, 0 DEG C is cooled to, oxalyl chloride (3.5g, 27.7mmol) is added dropwise, room temperature reaction 3 hours is slowly raised to, is directly concentrated to give centre Body acyl chlorides；2- metoxyphenols (2A) (1.58g, 12.8mmol) and triethylamine (2.59g, 25.5mmol) are added into dichloromethane In (40mL), 0 DEG C is cooled to, resulting acyl chlorides is slowly added portionwise, then rises and reacts 1 hour at room temperature.Into reaction solution Water (50mL), liquid separation are added, organic phase uses saturation biphosphate sodium water solution (50mL × 1) and saturated aqueous common salt (50mL successively × 1) wash, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography separating-purifying (acetic acid second Ester/petroleum ether (v/v)=0/1~1/4), obtain title compound (2- methoxyphenyls) 3- [(1R) -1- phenethyls] imidazoles - 4- carboxylates (compound 2), light yellow oil (0.90g, yield 30%).
1H NMR(400MHz,CDCl3)δ8.04(d,1H),7.85(s,1H),7.32(m,3H),7.22(m,3H),7.07 (dd,1H),6.97(m,2H),6.36(q,1H),3.74(s,3H),1.89(d,3H)。
LCMS m/z=323.2 [M+1].
Embodiment 3：(2- methoxyl group -6- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 3)
(2-methoxy-6-methyl-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 2- methoxyl group -6- methylphenols (3A) (0.94g, 6.94mmol) and 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylic acid (1A) (1.0g, 4.62mmol) is suspended in dichloromethane (30mL), adds 1- (3- dimethylamino-propyls) -3- ethyl carbon Diimmonium salt hydrochlorate (1.33g, 6.94mmol) and dimethylamino naphthyridine (0.85g, 6.94mmol), are stirred at room temperature 3 hours.To anti- Answer and water (30mL) and water (50mL) added in liquid, layering extraction, organic phase use successively saturation biphosphate sodium water solution (50mL × 1) concentrated with saturated aqueous common salt (50mL × 1) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression, residue silica gel column layer Separating-purifying (ethyl acetate/petroleum ether (v/v)=0/1~1/3) is analysed, obtains title compound (2- methoxyl groups -6- methyl-benzene Base) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 3), yellow oily (0.760g, yield 48.9%).
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.83(s,1H),7.32(m,3H),7.20(m,2H),7.10 (t,1H),6.81(dd,2H),6.33(q,1H),3.71(s,3H),2.06(d,3H),1.89(d,3H)。
LCMS m/z=337.3 [M+1].
Embodiment 4:Indenes -5- bases 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 4)
indan-5-yl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate
By indenes -5- alcohol (4A) (0.93g, 6.94mmol) and 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.0g, 4.62mmol) is dissolved in dichloromethane (30mL), adds 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides Salt (1.33g, 6.94mmol), dimethylamino naphthyridine (0.85g, 6.94mmol), it is stirred at room temperature 3 hours.Added into reaction solution Dichloromethane (30mL) and water (50mL), layering extraction, organic phase successively with saturation biphosphate sodium water solution (50mL × 1) and Saturated aqueous common salt (10mL × 1) washs, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography point From purification (ethyl acetate/petroleum ether (v/v)=0/1~1/3), title compound indenes -5- bases 3- [(1R) -1- phenyl second is obtained Base] imidazoles -4- carboxylates (compound 4), white solid (0.80g, yield 52%).
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.83(s,1H),7.32(m,3H),7.22(dd,3H),6.96 (s,1H),6.85(dd,1H),6.35(q,1H),2.90(dd,4H),2.10(m,2H),1.89(d,3H)。
LCMS m/z=333.3 [M+1].
Embodiment 5：(4- methoxycarbonyl group -2- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylate (compounds 5)
(4-methoxycarbonyl-2-methyl-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：4- hydroxy-3-methyls-methyl benzoate (5B)
methyl 4-hydroxy-3-methyl-benzoate
By 4- hydroxy-3-methyls benzoic acid (4A) (1.3g, 8.5mmol) and it is dissolved in absolute methanol (10mL), adds two Chlorine sulfoxide (1.5g, 13mmol), heat up 60 DEG C and stir 2 hours.Reaction solution is cooled to room temperature, is directly concentrated under reduced pressure, and adds acetic acid Ethyl ester (20ml), washed successively with water (30mL × 2) and saturated aqueous common salt (10mL × 1), organic phase anhydrous sodium sulfate drying, Filtering, filtrate decompression concentration, obtain title compound 4- hydroxy-3-methyls-methyl benzoate (5B), yellow solid (1.2g, production Rate 85%).
1H NMR(400MHz,CDCl3)δ7.84(d,1H),7.79(dd,1H),6.80(d,1H),3.91(m,3H),2.29 (d,3H)。
Second step：(4- methoxycarbonyl group -2- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylate (compounds 5)
(4-methoxycarbonyl-2-methyl-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 4- hydroxy-3-methyls-methyl benzoate (5B) (0.77g, 4.62mmol) and 3- [(1R) -1- phenylethyls] miaow Azoles -4- carboxylic acids (1A) (1.0g, 4.62mmol) are dissolved in dichloromethane (30mL), add 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride (1.33g, 6.94mmol), dimethylamino naphthyridine (0.85g, 6.94mmol), it is stirred at room temperature 3 hours. Dichloromethane (30mL) and water (50mL), layering extraction are added into reaction solution, organic phase uses saturation sodium dihydrogen phosphate water successively Solution (50mL × 1) and saturated aqueous common salt (10mL × 1) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residual Thing obtains title compound (4- methoxies with silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=0/1~1/3) Carbonyl -2- methylphenyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 5), white solid (1.0g, yield 59%).
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.92(m,3H),7.32(m,3H),7.19(m,2H),7.12 (d,1H),6.30(q,1H),3.91(s,3H),2.13(s,3H),1.93(t,3H).
LCMS m/z=365.2 [M+1].
Embodiment 6：(2- methoxyl group -5- methylphenyls) -3- [(1R) -1- phenethyls] imidazoles -4- carboxylate (compounds 6)
(2-methoxy-5-methyl-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 2- methoxyl group -5- methylphenols (6A) (0.64g, 4.62mmol) and 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylic acid (1A) (1.0g, 4.62mmol) is dissolved in dichloromethane (30mL), adds 1- (3- dimethylamino-propyls) -3- ethyls carbon two Inferior amine salt hydrochlorate (1.33g, 6.94mmol), dimethylamino naphthyridine (0.85g, 6.94mmol), it is stirred at room temperature 3 hours.Reaction solution Middle addition dichloromethane (30mL) and water (50mL), layering extraction, organic phase use saturation biphosphate sodium water solution (50mL successively × 1) concentrated with saturated aqueous common salt (10mL × 1) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression, residue silicagel column Chromatography purify (ethyl acetate/petroleum ether (v/v)=0/1~1/3), obtain title compound (2- methoxyl group -5- methyl - Phenyl) -3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 6), light yellow oil (1.5g, yield 96%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.80(s,1H),7.32(m,3H),7.22(m,2H),7.01 (m,1H),6.87(dd,2H),6.35(q,1H),3.71(s,3H),2.28(m,3H),1.88(d,3H)。
LCMS m/z=337.1 [M+1].
Embodiment 7：(the fluoro- 2- methoxyl groups-phenyl of 4-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 7)
(4-fluoro-2-methoxy-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and the fluoro- 2- metoxyphenols (2A) (1.48g, 10.41mmol) of 4-, react at room temperature after adding 3 hours.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, Filtering, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:V)= 10:1~1:1) title compound (the fluoro- 2- methoxyl groups-phenyl of 4-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters is obtained (compound 7), white liquid solid (0.77g, yield 32.62%).
1H NMR(400MHz,CDCl3)δ8.02(s,1H),7.82(s,1H),7.37–7.26(m,3H),7.20(m,2H), 7.00(m,1H),6.74–6.59(m,2H),6.31(m,1H),3.71(s,3H),1.88(d,3H)。
LCMS m/z=341.1 [M+1].
Embodiment 8：[2- (trifluoromethyl) phenyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 8)
[2-(trifluoromethyl)phenyl]3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and 2- (trifluoromethyl) phenol (8A) (1.69g, 10.41mmol), 3 are reacted at room temperature after adding Hour.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, mistake Filter, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:V)=10: 1~1:1) title compound [2- (trifluoromethyl) phenyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic ester (chemical combination is obtained Thing 8), white liquid solid (0.95g, yield 38.00%).
1H NMR(400MHz,CDCl3)δ8.06(s,1H),7.83(s,1H),7.69(d,1H),7.57(t,1H),7.33 (m,5H),7.21(m,2H),6.28(m,1H),1.89(d,3H).
LCMS m/z=361.1 [M+1].
Embodiment 9：O-tolyl 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 9)
o-tolyl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and orthoresol (9A) (1.13g, 10.41mmol), are reacted at room temperature 3 hours after adding.Reaction Dichloromethane (30mL) dilution is added, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, filtering, filtrate subtract With silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after pressure concentration：Ethyl acetate (v:V)=10:1~1:1) To title compound o-tolyl 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 9), white liquid solid (1.12g, yield 52.58%).
1H NMR(400MHz,CDCl3)δ8.04(s,1H),7.86(s,1H),7.39–7.27(m,3H),7.25–7.12 (m,5H),7.07–7.00(m,1H),6.33(m,1H),2.09(s,3H),1.90(d,3H).
LCMS m/z=307.1 [M+1].
Embodiment 10：(3- chlorphenyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 10)
(3-chlorophenyl)3-[(1R)-1-phenylethyl]imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and m-Chlorophenol (10A) (1.33g, 10.41mmol), are reacted at room temperature 3 hours after adding.Instead Dichloromethane (30mL) dilution should be added, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, filtering, filtrate With silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after being concentrated under reduced pressure：Ethyl acetate (v:V)=10:1~1:1) Title compound (3- chlorphenyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 10) are obtained, white liquid is consolidated Body (1.03g, yield 45.57%).
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.84(s,1H),7.38–7.27(m,4H),7.25–7.18 (m,3H),7.17(m,1H),7.03(m,1H),6.31(m,1H),1.89(d,3H)。
LCMS m/z=327.1 [M+1].
Embodiment 11：(the fluoro- 2- anisyls of 5-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 11)
(5-fluoro-2-methoxy-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and fluoro- 2- metoxyphenols (11A) 1.48g, 10.41mmol of 5-), reacted at room temperature after adding 3 hours.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, Filtering, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:V)= 10:1~1:1) title compound (the fluoro- 2- anisyls of 5-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters are obtained (to change Compound 11), white liquid solid (0.88g, yield 37.28%).
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.84(s,1H),7.38–7.27(m,3H),7.23–7.15 (m,2H),6.97–6.79(m,3H),6.31(m,1H),3.71(s,3H),1.89(d,3H)。
LCMS m/z=341.1 [M+1].
Embodiment 12：(4- methoxycarbonyl groups phenyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 12)
(4-methoxycarbonylphenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and 4-HBA methyl esters (12A) (1.58g, 10.41mmol), are reacted at room temperature after adding 3 hours.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, Filtering, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:V)= 10:1~1:1) title compound (4- methoxycarbonyl groups phenyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters are obtained (to change Compound 12), white liquid solid (0.85g, yield 34.97%).
1H NMR(400MHz,CDCl3)δ8.13–8.05(m,2H),8.03(s,1H),7.85(s,1H),7.33(m,3H), 7.23–7.17(m,4H),6.31(m,1H),3.91(s,3H),1.89(d,3H)。
LCMS m/z=351.1 [M+1].
Embodiment 13：(3- methoxycarbonyl groups phenyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 13)
(3-methoxycarbonylphenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and 3- methyl hydroxybenzoates (13A) (1.58g, 10.41mmol), are reacted at room temperature after adding 3 hours.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase anhydrous sodium sulfate drying, Filtering, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:V)= 10:1~1:1) title compound (3- methoxycarbonyl groups phenyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters are obtained (to change Compound 13), white liquid solid (0.84g, yield 34.56%).
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.94(m,1H),7.84(s,1H),7.82–7.78(m,1H), 7.47(t,1H),7.39–7.27(m,4H),7.22(m,2H),6.32(m,1H),3.92(s,3H),1.89(d,3H)。
LCMS m/z=351.1 [M+1].
Embodiment 14：(the fluoro- 2- anisyls of 3-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (compound 14)
(3-fluoro-2-methoxy-phenyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.95mmol) are suspended in dichloromethane (20mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (1.6g, 8.33mmol), 4- diformazan ammonia Yl pyridines (510mg, 4.17mmol) and the fluoro- 2- metoxyphenols (14A) (1.48g, 10.41mmol) of 3-, it is anti-to add rear room temperature Answer 3 hours.Reaction adds dichloromethane (30mL) dilution, and is washed with water (50mL × 2).Organic phase is done with anhydrous sodium sulfate Dry, filtering, with silica gel chromatographic column separating-purifying, (eluant, eluent is petroleum ether to residue after filtrate decompression concentration：Ethyl acetate (v:v) =10:1~1:1) title compound (the fluoro- 2- anisyls of 3-) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters are obtained (compound 14), white solid (0.91g, yield 38.55%).
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.87(s,1H),7.39–7.26(m,3H),7.19(m,2H), 7.08–6.94(m,2H),6.92–6.79(m,1H),6.31(m,1H),3.75(m,3H),1.90(d,3H).
LCMS m/z=341.1 [M+1].
Biological test example
Tested compound is formulated in the physiological saline containing 10%DMSO and 5%HS-15 to required concentration.SPF levels SD is big Mouse, 200-220g, male and female half and half, every group 8, laboratory environment adapts to 3 days, overnight fasting.Next day is quiet according to 5ml/kg volumes Arteries and veins drug administration by injection, experiment start before start timer, according to point：Second form record respectively administration time (drug administration by injection start to The end time is administered), (injection terminates to righting reflex loss anesthesia onset time, is allowed in dorsal position and can continue 5s Time), the anesthesia maintenance time, (righting reflex loss to righting reflex ability was recovered, and is allowed to right the time in dorsal position small In 2s time) and travel time (righting reflex ability recover to occur it is autonomous travel forward, four limbs Muscle tensility recover when Between).As a result as shown in table 1, each item data in table is the average of each group rat.
Part of compounds continues the test of rat dose-effect relationship, with effective dose 50 (ED50), median lethal dose (LD50), therapeutic index (TI, i.e. LD50/ED50), safety index (SI, i.e. LD5/ED95) etc. metrics evaluation validity and security. Experimental result is as shown in table 2.
LORR：The disappearance (Loss of Righting Reflex) of righting reflex.
Table 1：Rat Righing reflex data
Conclusion：The compounds of this invention has the advantages of rapid-action, has anesthetic effect.
Table 2：Rat evaluating drug effect result
Compound number ED50(mg/kg) LD50(mg/kg) TI SI
Compound 7 3.8 37.1 9.7 6.3
Conclusion：Compound 7 has preferable security window.

Claims (6)

1. compound or its stereoisomer, solvate, pharmaceutically acceptable salt or common shown in a kind of logical formula (I) It is brilliant：
Wherein：
R1It is independently selected from F, Cl, Br, CF3、OH、C1-4Alkyl or C1-4Alkoxy；
A is selected from 0,1,2,3,4 or 5；
R2Selected from C1-4Alkyl or-(CH2)n-C3-6Cycloalkyl, described alkyl or cycloalkyl are optionally further selected from by 0 to 3 F, Cl, Br or CF3Substituent substituted；
N is selected from 0,1 or 2；
R3Selected from C6-10Aryl or 5 to 10 yuan of heteroaryl, described aryl or heteroaryl are optionally further by 1 to 4 RaTake Generation；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl ,-C (=O) OC1-6Alkyl or-OC (=O) OC1-6Alkyl, described alkyl, alkoxy, alkenyl or alkynyl are optionally further selected from by 0 to 4 F、Cl、Br、CF3, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted；
Alternatively, two RaCoupled atom forms C together3-8Carbocyclic ring or 3 to 8 circle heterocycles, described carbocyclic ring or Heterocycle is optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted, And described heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
Condition is RaSelected from-C (=O) OC1-6During alkyl ,-C (=O) OC1-6Alkyl withAt least it is spaced 3 Atom.
2. compound according to claim 1 or its stereoisomer, solvate, pharmaceutically acceptable salt or common Crystalline substance, wherein：
R3Selected from phenyl, the phenyl is optionally further by 1 to 4 RaSubstitution；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, C1-6Alkyl, C1-6Alkoxy ,-C (=O) OC1-6Alkyl or-OC (=O) OC1-6Alkyl, described alkyl or alkoxy are optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted；
Alternatively, two RaCoupled atom forms C together3-6Carbocyclic ring, described carbocyclic ring is optionally further by 0 to 4 It is individual to be selected from F, Cl, Br, CF3, cyano group, C1-4Alkyl or C1-4The substituent of alkoxy is substituted.
3. compound according to claim 2 or its stereoisomer, solvate, pharmaceutically acceptable salt or common Crystalline substance, wherein：
R1It is independently selected from F, Cl, Br, CF3, OH, methyl, ethyl, isopropyl, methoxy or ethoxy；
R2Selected from CF3, methyl, ethyl or isopropyl；
Each RaIndependently selected from F, Cl, Br, CF3, cyano group, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl ,-C (= O)OCH3、-C(=O)OCH2CH3、-C(=O)OC(CH3)3、-OC(=O)OCH3、-OC(=O)OCH2CH3Or-OC (=O) OCH (CH3)2；
Alternatively, two RaCoupled atom forms 5 yuan of carbocyclic rings together;
Condition is RaSelected from-C (=O) OCH3、-C(=O)OCH2CH3Or-C (=O) OC (CH3)3When ,-C (=O) OCH3、-C(=O) OCH2CH3Or-C (=O) OC (CH3)3WithAt least it is spaced 3 atoms.
4. compound according to claim 3 or its stereoisomer, solvate, pharmaceutically acceptable salt or common Crystalline substance, described compound are selected from one of compound shown in following structural formula：
。
5. a kind of pharmaceutical composition, described pharmaceutical composition includes compound described in any one of claim 1 ~ 4 or it is vertical Body isomers, solvate, pharmaceutically acceptable salt or eutectic, and one or more pharmaceutically acceptable carriers above And/or excipient.
It is 6. compound or its stereoisomer, solvate according to any one of claim 1 ~ 4, pharmaceutically acceptable Salt or eutectic, or pharmaceutical composition described in claim 5 is in preparing and producing tranquilizing soporific and/or anesthetic effect medicine Using.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109761906A (en) * 2019-03-02 2019-05-17 成都安诺晨创医药科技有限公司 A kind of substituted imidazole formate ester derivative and application thereof
CN109776512A (en) * 2018-01-30 2019-05-21 成都安诺晨创医药科技有限公司 A kind of N- substituted imidazole formate ester derivative and application thereof
WO2021068943A1 (en) * 2019-10-11 2021-04-15 成都麻沸散医药科技有限公司 Substituted nitrogen heterocyclic compound and anesthetic effect thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102046607A (en) * 2008-03-31 2011-05-04 通用医疗公司 Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties
CN102548964A (en) * 2009-07-10 2012-07-04 通用医疗公司 Etomidate analogues that do not inhibit adrenocortical steroid synthesis
CN103588757A (en) * 2013-01-04 2014-02-19 四川大学华西医院 N-substituted imidazole carboxylic ester compound with ultrashort-effect anesthesia effect, preparation method and application
CN103739553A (en) * 2013-12-23 2014-04-23 四川大学华西医院 N-substituted imidazole carboxylate chiral compound containing ether side chain, preparation method and application
CN104168899A (en) * 2012-01-13 2014-11-26 通用医疗公司 Anesthetic compounds and related methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102046607A (en) * 2008-03-31 2011-05-04 通用医疗公司 Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties
CN102548964A (en) * 2009-07-10 2012-07-04 通用医疗公司 Etomidate analogues that do not inhibit adrenocortical steroid synthesis
CN104168899A (en) * 2012-01-13 2014-11-26 通用医疗公司 Anesthetic compounds and related methods of use
CN103588757A (en) * 2013-01-04 2014-02-19 四川大学华西医院 N-substituted imidazole carboxylic ester compound with ultrashort-effect anesthesia effect, preparation method and application
CN103739553A (en) * 2013-12-23 2014-04-23 四川大学华西医院 N-substituted imidazole carboxylate chiral compound containing ether side chain, preparation method and application

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109776512A (en) * 2018-01-30 2019-05-21 成都安诺晨创医药科技有限公司 A kind of N- substituted imidazole formate ester derivative and application thereof
CN109776509B (en) * 2018-01-30 2023-07-07 成都麻沸散医药科技有限公司 N-substituted imidazole formate derivative and application thereof
CN109761906A (en) * 2019-03-02 2019-05-17 成都安诺晨创医药科技有限公司 A kind of substituted imidazole formate ester derivative and application thereof
CN109761906B (en) * 2019-03-02 2023-08-11 成都麻沸散医药科技有限公司 Substituted imidazole formate derivative and application thereof
WO2021068943A1 (en) * 2019-10-11 2021-04-15 成都麻沸散医药科技有限公司 Substituted nitrogen heterocyclic compound and anesthetic effect thereof

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