CN107382870A - 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
CN107382870A
CN107382870A CN201710268519.1A CN201710268519A CN107382870A CN 107382870 A CN107382870 A CN 107382870A CN 201710268519 A CN201710268519 A CN 201710268519A CN 107382870 A CN107382870 A CN 107382870A
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Prior art keywords
alkyl
compound
carbocyclic ring
methyl
alkoxy
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CN201710268519.1A
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Inventor
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

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 passes through the Inhibitory receptor GABA with maincenterAAcceptor combines, and makes this receptor It is more sensitive to inhibitory neurotransmitter GABA, so as to produce calm and anesthetic effect.But meanwhile Etomidate mainly passes through suppression Cortin synthesis of the activity of 11- β hydroxylases processed to body is also inhibited, and particularly much time using is to cortex The suppression of hormone is more obvious.Due to cortin itself synthesis be body anti-inflammatory an important factor for, the synthesis of cortin The recovery being suppressed to postoperative patient is unfavorable.There is document to show, the dosage of Etomidate anesthesia is 0.2~0.3mg/kg, together When, the concentration of Etomidate is at least 200ng/ml in blood, and 10ng/ml Etomidates can substantially lower blood plasma in blood Content (the Critical Care 2012,16 of middle cortin: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；
M is selected from C1-6Alkylidene, described alkylidene is optionally further by 0 to 4 RaSubstitution；
RaSelected from F, Cl, Br, CF3、C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocyclic ring or 3 to 8 yuan it is miscellaneous Ring, described alkyl, alkoxy, alkenyl, alkynyl, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, CF by 0 to 43, cyanogen Base, 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；
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；
X is selected from-CRbRc- ,-O- or-S-；
Condition is, when X is selected from-CRbRc- when, M is at least by 1 RaSubstitution；
Rb、RcIt is independently selected from H or C1-4Alkyl；
R3Selected from H, C1-6Alkyl ,-(CH2)m-C3-8Carbocyclic ring ,-(CH2) m-3 is to 8 circle heterocycles ,-(CH2)m-OC3-8Carbocyclic ring or- (CH2) m-O-3 is optionally further selected from F, Cl, Br, CF to 8 circle heterocycles, described alkyl, carbocyclic ring or heterocycle by 0 to 43、 Cyano group, amino, C1-4Alkyl, C1-4Alkoxy, C2-6Alkynyl or-NHC1-4The substituent of alkyl is substituted, and described heterocycle contains There is 1 to 3 hetero atom for being selected from N, O or S；
M is selected from 0,1 or 2.
The preferred scheme of the present invention, compound or its stereoisomer, solvate, pharmacy shown in a kind of logical formula (I) Upper acceptable salt or eutectic, wherein：
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；
M is selected from C1-6Alkylidene, preferably C1-4Alkylidene, more preferably methylene, ethylidene, propylidene or butylidene, it is described Alkylidene, methylene, ethylidene, propylidene or butylidene be optionally further by 0 to 4 RaSubstitution；
RaSelected from F, Cl, Br, CF3、C1-6Alkyl, C1-6Alkoxy, C3-8Carbocyclic ring or 3 to 8 circle heterocycles, described alkyl, alkane Epoxide, carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4Alkyl or C1-4Alkoxy takes Substituted for base, and described heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
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；
X is selected from-CRbRc- ,-O- or-S-；
Condition is, when X is selected from-CRbRc- when, M is at least by 1 RaSubstitution；
Rb、RcIt is independently selected from H or C1-4Alkyl, preferably H, methyl, ethyl, propyl group or isopropyl；
R3Selected from H, C1-6Alkyl ,-(CH2)m-C3-6Carbocyclic ring ,-(CH2) m-3 is to 6 circle heterocycles ,-(CH2)m-OC3-6Carbocyclic ring or- (CH2) m-O-3 is optionally further selected from F, Cl, Br, CF to 6 circle heterocycles, described alkyl, carbocyclic ring or heterocycle by 0 to 43、 Cyano group, amino, C1-4Alkyl, C1-4Alkoxy, C2-6Alkynyl or-NHC1-4The substituent of alkyl is substituted, and described heterocycle contains There is 1 to 3 hetero atom for being selected from N, O or S；
M is selected from 0,1 or 2.
The preferred scheme of the present invention, compound or its stereoisomer, solvate, pharmacy shown in a kind of logical formula (I) Upper acceptable salt or eutectic, wherein：
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；
M is selected from methylene, ethylidene, propylidene or butylidene, described methylene, ethylidene, propylidene or butylidene Optionally further by 0 to 4 RaSubstitution；
RaSelected from F, Cl, Br, CF3, methyl, ethyl, propyl group, isopropyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
Alternatively, two RaCoupled atom forms cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl together；
X is selected from-CRbRc- ,-O- or-S-；
Condition is, when X is selected from-CRbRc- when, M is at least by 1 RaSubstitution；
Rb、RcIt is independently selected from H, methyl or ethyl；
R3Selected from H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, phenyl ,-CH2- phenyl Or-CH2O- phenyl, and described phenyl is optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, methyl, ethyl, third Base, isopropyl, methoxy or ethoxy substituent are substituted.
Compound involved in the present invention, one of compound shown in including but not limited to following structural formula：
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 It is brilliant or comprising the compound described in logical formula (I) or its stereoisomer, solvate, pharmaceutically acceptable salt or eutectic Pharmaceutical composition is 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.
" alkylidene " refers to the divalent saturated hydrocarbon base of straight chain and side chain, including-(CH2)v- (v is 1 to 10 integer), alkylene Base embodiment includes but is not limited to methylene, ethylidene, propylidene and butylidene etc.；Described alkylidene 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, C1-6 Alkoxy, 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-NR19R19a's Substituent is substituted, and when the substituent quantity in alkylidene is more than or equal to 2, substituent can be fused together to form ring-type Structure.Herein presented alkylidene, 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：Isopropyloxycarbonyl group epoxide methyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (compounds 1)
isopropoxycarbonyloxymethyl 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) (0.5g, 2.3mmol) be dissolved in DMF In (5mL), chloromethyl butylperoxyisopropyl carbonate (1.4g, 9.2mmol) and triethylamine (0.94g, 9.2mmol) are added, is warming up to 60 DEG C reaction 2 hours.Reaction solution is cooled to room temperature, ethyl acetate (30mL) is added, successively with water (30mL × 2) and saturated aqueous common salt (20mL × 1) is washed, anhydrous sodium sulfate drying, filtering, and filtrate decompression concentration, residue silica gel column chromatography separating-purifying (is washed De- agent is ethyl acetate/petroleum ether (v/v)=1/1), obtain title compound isopropyloxycarbonyl group epoxide methyl 3- [(1R)- 1- phenylethyls] imidazoles -4- carboxylates (compound 1), colorless oil (0.4g, yield 50%).
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.77(s,1H),7.33(m,3H),7.20(d,2H),6.32 (d,1H),5.92(d,1H),5.85(d,1H),4.99–4.84(m,1H),1.86(d,3H),1.31(d,6H).
LCMS m/z=333.2 [M+1].
Embodiment 2：[1- (acetoxy-methyl) cyclopropyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (chemical combination Thing 2)
[1-(acetoxymethyl)cyclopropyl]3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：1- (methylol) ring propyl alcohol (2B)
1-(hydroxymethyl)cyclopropanol
1- hydroxyls cyclopropane-carboxylic acid (2A) (0.6g, 5.9mmol) is dissolved in anhydrous tetrahydro furan in (10mL), is cooled to 0 DEG C, Lithium Aluminium Hydride (0.33g, 8.8mmol) is added portionwise, then reacts 7 hours at room temperature.Be cooled to 0 DEG C, to reaction solution according to Secondary addition water (0.33mL), 10% sodium hydroxide solution (0.66mL), water (0.99mL), filtering, filter cake tetrahydrofuran (30mL) is washed, and filtrate anhydrous sodium sulfate drying, is concentrated under reduced pressure, is obtained title compound 1- (methylol) ring propyl alcohol (2B), Pale yellow liquid (0.45g, yield 87%).
1H NMR(400MHz,CDCl3)δ3.64(s,2H),0.84(t,2H),0.58(q,2H).
Second step：(1- hydroxycyclopropyls) acetic acid esters (2C)
(1-hydroxycyclopropyl)methyl acetate
1- (methylol) ring propyl alcohol (2B) (0.7g, 7.9mmol) is dissolved in anhydrous methylene chloride (20mL), adds three second Amine (1.6g, 16mmol), acetic anhydride (1.2g, 12mmol) and DMAP (0.097g, 0.79mmol), at room temperature instead Answer 3 hours.Dichloromethane (50mL) and water (50mL), liquid separation, organic phase anhydrous sodium sulfate drying, mistake are added into reaction solution Filter, filtrate decompression concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=0/1~3/1) To title compound (1- hydroxycyclopropyls) acetic acid esters (2C), pale yellow liquid (0.7g, yield 70%).
1H NMR(400MHz,CDCl3)δ4.15(s,2H),2.13(m,3H),0.88(m,2H),0.66(m,2H).
3rd step：[1- (acetoxy-methyl) cyclopropyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (chemical combination Thing 2)
[1-(acetoxymethyl)cyclopropyl]3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (3.6g, 16.6mmol) are dissolved in dichloromethane (40mL) In, 0 DEG C is cooled to, oxalyl chloride (4.2g, 33.3mmol) is added dropwise, room temperature reaction 3 hours is slowly raised to, is directly concentrated to give centre Body acyl chlorides；By (1- hydroxycyclopropyls) acetic acid esters (2C) (0.7g, 5.4mmol), triethylamine (3.3g, 32mmol) and 4- diformazan ammonia Yl pyridines (0.066g, 0.54mmol) are added in dichloromethane (40mL), are cooled to 0 DEG C, obtained by being slowly added portionwise in Mesosome acyl chlorides, then rise and react 1 hour at room temperature.Water (50mL), liquid separation are added into reaction solution, organic phase uses saturation phosphorus successively Acid dihydride sodium solution (50mL × 1) and saturated nacl aqueous solution (50mL × 1) washing, anhydrous sodium sulfate drying, filtering, filtrate subtract Pressure concentration, residue silica gel column chromatography separating-purifying (petroleum ether：Ethyl acetate (v/v)=0/1~1/4) obtain title compound Thing [1- (acetoxy-methyl) cyclopropyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 2), light yellow oil (0.35g, yield 20%).
1H NMR(400MHz,CDCl3)δ7.74(t,2H),7.32(m,3H),7.20(dd,2H),6.32(m,1H),4.44 (m,1H),4.28(d,1H),2.05(m,3H),1.86(t,3H),0.98(m,4H).
LCMS m/z=329.2 [M+1].
Embodiment 3：1- (2,2- dimethylpropanoyloxies) ethyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (are changed Compound 3)
1-(2,2-dimethylpropanoyloxy)ethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：The chloro- 2,2- dimethyl propylenes acid esters (3B) of 1-
1-chloroethyl 2,2-dimethylpropanoate
Anhydrous zinc dichloride (0.2g) is placed in there-necked flask, under nitrogen protection, adds the tertiary butyric acid acyl chlorides of compound (3A) (7.25g, 60.1mmol), stir 15 minutes at room temperature, be cooled to -5 DEG C, acetaldehyde (5.67g, 129mmol) is slowly added dropwise, Reacting liquid temperature is no more than 0 DEG C, finish, be slowly raised at room temperature.To reaction solution reclaimed water (100mL) and ethyl acetate (100mL), liquid separation, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression are concentrated to give title compound 1- chloro- 2,2- Dimethyl propylene acid esters (3B), pale red liquid (6.8g, yield 68%), it is directly used in and reacts in next step.
Second step：1- (2,2- dimethylpropanoyloxies) ethyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (are changed Compound 3)
1-(2,2-dimethylpropanoyloxy)ethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By the chloro- 2,2- dimethyl propylenes acid esters (3B) (6.8g, 41.62mmol) of 1- and 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylic acids (1A) (3.0g, 13.9mmol) are dissolved in DMF (40mL), addition triethylamine (5.6g, 55.5mmol), 60 DEG C are warming up to react 7 hours.Reaction solution is cooled to room temperature, adds water (50mL), with ethyl acetate (50mL × 1) extract, organic phase is washed with water (50mL × 2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel Pillar layer separation purifies (petroleum ether：Ethyl acetate (v/v)=0/1~1/5) obtain title compound 1- (2,2- dimethyl propionyl Epoxide) ethyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 3) two isomers, wherein compound 3-A, Yellow oily (0.67g, yield 14%)；Compound 3-B, yellow oily (0.56g, yield 12%), the polarity of isomers 1 are less than different Structure body 2, the sample collected earlier during silica gel column chromatography.
Compound 3-A
1H NMR(400MHz,CDCl3)δ7.78(d,2H),7.31(m,3H),7.19(d,2H),7.00(q,1H),6.33 (q,1H),1.86(d,3H),1.52(m,3H),1.22(d,9H).
LCMS m/z=345.2 [M+1].
Compound 3-B
1H NMR(400MHz,CDCl3)δ7.80(d,1H),7.75(s,1H),7.31(m,3H),7.18(dd,2H),6.99 (m,1H),6.31(q,1H),1.85(d,3H),1.53(dd,3H),1.13(d,9H).
LCMS m/z=345.1 [M+1].
Embodiment 4：2- isopropyloxycarbonyl group oxygen ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (compounds 4)
2-isopropoxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：2- ethoxys butylperoxyisopropyl carbonate (4B)
2-hydroxyethyl isopropyl carbonate
Ethylene glycol (4A) (6.078g, 97.92mmol) and pyridine (7.745g, 97.92mmol) are dissolved in dichloromethane In (50mL), 0 DEG C is added dropwise isopropyl chlorocarbonate (4.0g, 32.63mmol), and room temperature reaction is overnight.Reaction solution adds dichloromethane (50mL), washed, organic phase anhydrous sodium sulfate drying, filtered with water (50mL × 2), after filtrate decompression concentration, residue is used Silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20~1/5) separating-purifying, it is different to obtain title compound 2- ethoxys Propyl carbonate (4B), colorless oil (0.8g, yield 20%).
1H NMR(400MHz,CDCl3)δ4.89(dd,1H),4.25(dd,2H),3.85(dd,2H),2.08(s,1H), 1.31(d,6H).
LCMS m/z=171.2 [M+23].
Second step：2- isopropyloxycarbonyl group oxygen ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (compounds 4)
2-isopropoxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 2- ethoxys butylperoxyisopropyl carbonate (4B) (0.617g, 4.16mmol) and 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylic acids (1A) (0.600g, 2.77mmol) are dissolved in dichloromethane (10mL), add 1- (3- dimethylamino-propyls) -3- ethyls Carbodiimide hydrochloride (0.646g, 4.16mmol) and dimethylamino naphthyridine (0.508g, 4.16mmol), are stirred at room temperature 3 hours. Dichloromethane (25mL) and water (50mL), extraction are added to reaction solution, organic phase uses saturation sodium dihydrogen phosphate successively again (50mL × 1) is washed and saturated nacl aqueous solution (50mL × 1) washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0/1~1/3) separating-purifying, it is different to obtain title compound 2- Propyloxycarbonyl group oxygen ethyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 4), yellow oily (0.260g, Yield 27.1%).
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.76(s,1H),7.32(m,3H),7.19(m,2H),6.33 (q,1H),4.88(m,1H),4.41(m,4H),1.86(d,3H),1.28(dd,6H).
LCMS m/z=347.3 [M+1].
Embodiment 5：[1- (isopropyloxycarbonyl group epoxide methyl) cyclopropyl] 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylate (compound 5)
[1-(isopropoxycarbonyloxymethyl)cyclopropyl]3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：(1- hydroxycyclopropyls) isopropyl methyl carbonic ester (5A)
(1-hydroxycyclopropyl)methyl isopropyl carbonate
1- (methylol) ring propyl alcohol (2B) (2.0g, 23mmol) is dissolved in dichloromethane (20mL), adds triethylamine (4.6g, 45mmol), 0 DEG C is added dropwise isopropyl chlorocarbonate (2.5g, 20mmol), drips off room temperature reaction 2 hours.Reaction solution adds water (30mL), extracted with dichloromethane (30mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL × 1), nothing Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20 ~1/5) separating-purifying, title compound (1- hydroxycyclopropyls) isopropyl methyl carbonic ester (5A), colorless oil are obtained (1.5g, yield 38%).
1H NMR(400MHz,CDCl3)δ4.97–4.81(m,1H),4.19(s,2H),1.32(d,6H),0.95–0.85 (m,2H),0.72–0.63(m,2H).
Second step：[1- (isopropyloxycarbonyl group epoxide methyl) cyclopropyl] 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylics Acid esters (compound 5)
[1-(isopropoxycarbonyloxymethyl)cyclopropyl]3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (2.0g, 9.25mmol) are suspended in dichloromethane In (20mL), (1- hydroxycyclopropyls) isopropyl methyl carbonic ester (5A) (1.77g, 10.2mmol), 1- (3- dimethylaminos are added Propyl group) -3- ethyl-carbodiimide hydrochlorides (2.65g, 13.9mmol) and DMAP (1.6 9g, 13.9mmol), It is stirred at room temperature 2 hours.Reaction solution uses saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt (30mL × 1) successively Washing, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/stone Oily ether (v/v)=1/20~1/5) separating-purifying, obtain title compound [1- (isopropyloxycarbonyl group epoxide methyl) ring third Base] 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 5), colorless oil (0.8g, yield 23%).
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.78(s,1H),7.39–7.31(m,3H),7.25–7.18 (m,2H),6.36(d,1H),4.88–4.76(m,1H),4.49(d,1H),4.34(d,1H),1.89(d,3H),1.28(m, 6H),1.12–0.96(m,4H).
LCMS m/z=373.2 [M+1].
Embodiment 6：3- isopropyloxycarbonyl group epoxide propyl group 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (chemical combination Thing 6)
3-isopropoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：3- hydroxypropyls butylperoxyisopropyl carbonate (6B)
3-hydroxypropyl isopropyl carbonate
1,3 propane diols (6A) (5.6g, 73mmol) is dissolved in dichloromethane (50mL), addition triethylamine (7.4g, 73mmol), 0 DEG C is added dropwise isopropyl chlorocarbonate (3.0g, 24mmol), drips off room temperature reaction 2 hours.Reaction solution adds water (30mL), extracted with dichloromethane (30mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL × 1), nothing Aqueous sodium persulfate is dried, filtering, filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20 ~1/5) separating-purifying, title compound 3- hydroxypropyls butylperoxyisopropyl carbonate (6B), colorless oil (1.5g, yield are obtained 38%).
1H NMR(400MHz,CDCl3)δ4.93–4.83(m,1H),4.28(t,2H),3.73(t,2H),1.95–1.87 (m,2H),1.30(d,6H).
LCMS m/z=163.1 [M+1].
Second step：3- isopropyloxycarbonyl group epoxide propyl group 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (chemical combination Thing 6)
3-isopropoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.0g, 4.62mmol) are suspended in dichloromethane In (20mL), 3- hydroxypropyls butylperoxyisopropyl carbonate (6B) (0.75g, 4.62mmol), 1- (3- dimethylamino-propyls) -3- second are added Base carbodiimide hydrochloride (1.33g, 6.94mmol) and DMAP (0.847g, 6.94mmol), it is small to be stirred at room temperature 2 When.Reaction solution is washed with saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt (30mL × 1) successively, organic phase With anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue with silica gel column chromatography (ethyl acetate/petroleum ether (v/v)= 1/20~1/5) separating-purifying, title compound 3- isopropyloxycarbonyl group epoxide propyl group 3- [(1R) -1- phenylethyls] is obtained Imidazoles -4- carboxylates (compound 6), colorless oil (1.0g, yield 60%).
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.74(s,1H),7.37–7.28(m,3H),7.21–7.15 (m,2H),6.34(d,1H),4.92–4.82(m,1H),4.32(m,2H),4.22(t,2H),2.12–2.03(m,2H),1.86 (d,3H),1.33–1.26(m,6H).
LCMS m/z=361.1 [M+1].
Embodiment 7：[1- (isopropyloxycarbonyl group epoxide methyl) cyclopropyl] methyl 3- [(1R) -1- phenylethyls] miaow Azoles -4- carboxylates (compound 7)
[1-(isopropoxycarbonyloxymethyl)cyclopropyl]methyl 3-[(1R)-1- phenylethyl]imidazole-4-carboxylate
The first step：[1- (methylol) cyclopropyl] isopropyl methyl carbonic ester (7B)
[1-(hydroxymethyl)cyclopropyl]methyl isopropyl carbonate
[1- (methylol) cyclopropyl] methanol (7A) (7.5g, 73mmol) is dissolved in dichloromethane (50mL), adds three Ethamine (5.0g, 49mmol), 0 DEG C is added dropwise isopropyl chlorocarbonate (3.0g, 24mmol), drips off room temperature reaction 2 hours.Reaction solution adds Enter water (30mL), extracted with dichloromethane (30mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL × 1) Wash, anhydrous sodium sulfate drying, filter, filtrate decompression concentration, residue with silica gel column chromatography (ethyl acetate/petroleum ether (v/v)= 1/20~1/5) separating-purifying, title compound [1- (methylol) cyclopropyl] isopropyl methyl carbonic ester (7B) is obtained, it is colourless Grease (1.5g, yield 33%).
1H NMR(400MHz,CDCl3)δ4.95–4.84(m,1H),4.11(s,2H),3.49(s,2H),2.13(s,1H), 1.31(d,6H),0.65–0.53(m,4H).
LCMS m/z=211.1 [M+23].
Second step：[1- (isopropyloxycarbonyl group epoxide methyl) cyclopropyl] methyl 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylates (compound 7)
[1-(isopropoxycarbonyloxymethyl)cyclopropyl]methyl 3-[(1R)-1- phenylethyl]imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.0g, 4.62mmol) are suspended in dichloromethane In (20mL), [1- (methylol) cyclopropyl] isopropyl methyl carbonic ester (7B) (0.87g, 4.62mmol), 1- (3- diformazans are added Aminopropyl) -3- ethyl-carbodiimide hydrochlorides (1.33g, 6.94mmol) and DMAP (0.847g, 6.94mmol), it is stirred at room temperature 2 hours.Reaction solution uses saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt successively (30mL × 1) is washed, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography (second Acetoacetic ester/petroleum ether (v/v)=1/20~1/5) separating-purifying, obtain title compound [1- (isopropyloxycarbonyl group epoxide first Base) cyclopropyl] methyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 7), colorless oil (1.1g, yield 61.6%).
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.75(s,1H),7.38–7.27(m,3H),7.22–7.15 (m,2H),6.35(d,1H),4.92–4.81(m,1H),4.26–3.96(m,4H),1.86(d,3H),1.28(t,6H),0.73– 0.53(m,4H).
LCMS m/z=387.2 [M+1].
Embodiment 8：(3- isopropyloxycarbonyl group epoxide -2,2- Dimethyl-propyls) 3- [(1R) -1- phenethyls] imidazoles - 4- carboxylates (compound 8)
(3-isopropoxycarbonyloxy-2,2-dimethyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：(3- hydroxyl -2,2- Dimethyl-propyls) butylperoxyisopropyl carbonate (8B)
(3-hydroxy-2,2-dimethyl-propyl)isopropyl carbonate
NPG (8A) (5.1g, 48.96mmol) is dissolved in dichloromethane (50mL), added Triethylamine (3.3g, 32.64mmol), 0 DEG C is added dropwise isopropyl chlorocarbonate (2.0g, 16.32mmol), drips off room temperature reaction 2 hours. Reaction solution adds water (30mL), is extracted with dichloromethane (30mL × 2), merges organic phase, organic phase saturated aqueous common salt (30mL × 1) wash, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20~1/5) separating-purifying, title compound (3- hydroxyls -2,2- Dimethyl-propyl) butylperoxyisopropyl carbonate is obtained (8B), colorless oil (0.8g, yield 30%).
1H NMR(400MHz,CDCl3)δ4.88(m,1H),4.11–3.84(m,2H),3.35(s,2H),1.30(t,6H), 0.99–0.88(m,6H).
Second step：(3- isopropyloxycarbonyl group epoxide -2,2- Dimethyl-propyls) 3- [(1R) -1- phenethyls] imidazoles -4- Carboxylate (compound 8)
(3-isopropoxycarbonyloxy-2,2-dimethyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.0g, 4.62mmol) are suspended in dichloromethane In (20mL), (3- hydroxyls -2,2- Dimethyl-propyl) butylperoxyisopropyl carbonate (8B) (0.88g, 4.62mmol), 1- (3- bis- are added Methylaminopropyl) -3- ethyl-carbodiimide hydrochlorides (1.33g, 6.94mmol) and DMAP (0.847g, 6.94mmol), it is stirred at room temperature 2 hours.Reaction solution uses saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt successively (30mL × 1) is washed, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography (second Acetoacetic ester/petroleum ether (v/v)=1/20~1/5) separating-purifying, obtain title compound (3- isopropyloxycarbonyl groups epoxide -2, 2- Dimethyl-propyls) 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 8), colorless oil (1.3g, yield 72%).
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.74(s,1H),7.40–7.25(m,3H),7.24–7.16 (m,2H),6.35(q,1H),4.85(s,1H),4.05(dd,2H),3.98(s,2H),1.86(d,3H),1.28(dd,6H), 1.01(d,6H).
LCMS m/z=389.2 [M+1].
Embodiment 9：2- carbobenzoxy oxygen ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 9)
2-phenoxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：2- ethoxys 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (9A)
2-hydroxyethyl 3-[(1R)-1-phenylethyl]imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (10g, 46.27mmol) are suspended in dichloromethane In (100mL), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (10.64g, 55.53mmol), 4- are added Dimethylamino naphthyridine (3.39g, 27.76mmol) and ethylene glycol (4A) (2.15g, 34.70mmol), it is small that 3 are reacted at room temperature after adding When.Reaction adds dichloromethane (150mL), and is washed with water (250ml × 2).Organic phase anhydrous sodium sulfate drying, filtering, Residue silica gel chromatographic column separating-purifying (methylene chloride/methanol (v after filtrate decompression concentration:V)=100/1~50/1) obtain Title compound 2- ethoxys 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (9A), colourless liquid (4.7g yields 39.06%).
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.76(s,1H),7.37–7.26(m,3H),7.21–7.13 (m,2H),6.34(m,1H),4.35(m,2H),3.87(t,2H),2.59(s,1H),1.86(d,3H).
LCMS m/z=261.1 [M+1].
Second step：2- carbobenzoxy oxygen ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 9)
2-phenoxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate.
2- ethoxys 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (9A) (1.5g, 5.76mmol) are dissolved in two In chloromethanes (15mL), and add triethylamine (1.16g, 11.54mmol), be added dropwise at 0 DEG C phenyl chloroformate (1.35g, 8.65mmol).Naturally reaction 3 hours is warmed to room temperature after adding.Reaction solution add water (100mL), with dichloromethane (100ml × 2) extract, merge organic phase anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, residue silica gel chromatograph post separation Purify (petrol ether/ethyl acetate (v:V) title compound 2- carbobenzoxy oxygen ethyl 3- [(1R) -1-=10/0~1/1) are obtained Phenylethyl] imidazoles -4- carboxylates (compound 9), white solid (650mg, yield 29.68%).
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.76(s,1H),7.42–7.35(m,2H),7.35–7.29 (m,2H),7.29–7.22(m,2H),7.21–7.13(m,4H),6.33(m,1H),4.62–4.36(m,4H),1.87(d,3H).
LCMS m/z=381.1 [M+1].
Embodiment 10：2- benzyloxycarbonyl group oxygen ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 10)
2-benzyloxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
2- ethoxys 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (9A) (1.5g, 5.76mmol) are dissolved in two In chloromethanes (15mL), and add triethylamine (1.16g, 11.54mmol), be added dropwise at 0 DEG C benzyl chloroformate (1.47g, 8.65mmol).Room temperature is slowly increased to after adding, reacts 3h at room temperature.Reaction solution adds water (100mL), and dichloromethane (100ml × 2) extract, and merge organic phase anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, residue silica gel color Compose post separation purification (petrol ether/ethyl acetate (v:V) title compound 2- benzyloxycarbonyl group oxygen ethyls 3-=10/0~1/1) is obtained [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 10), colourless liquid, (550mg, yield 24.22%).
1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.84(s,1H),7.40–7.36(m,5H),7.36–7.30 (m,3H),7.23–7.16(m,2H),6.38(m,1H),5.17(s,2H),4.58–4.31(m,4H),1.88(d,3H).
LCMS m/z=395.1 [M+1].
Embodiment 11：2- isobutyl group Epoxide carbonyl epoxide ethyls 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (are changed Compound 11)
2-isobutoxycarbonyloxyethyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
2- ethoxys 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (9A) (1.5g, 5.76mmol) are dissolved in two In chloromethanes (15mL), and add triethylamine (1.16g, 11.54mmol), be added dropwise at 0 DEG C isobutyl chlorocarbonate (1.18g, 8.65mmol).Room temperature is slowly increased to after adding, is reacted 3 hours at room temperature.Reaction solution adds water (100mL), and dichloromethane (100mL × 2) extract, and merge organic phase anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, residue silica gel color Compose post separation purification (petrol ether/ethyl acetate (v:V) title compound 2- isobutyl group Epoxide carbonyl oxygen=10/0~1/1) is obtained Base ethyl 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 11), colourless liquid (770mg, 24.22%).
1H NMR(400MHz,CDCl3)δ7.83(s,2H),7.38–7.32(m,2H),7.30(m,1H),7.22–7.14 (m,2H),6.33(m,1H),4.52–4.29(m,4H),3.93(d,2H),2.04–1.94(m,1H),1.86(d,3H),0.95 (s,3H).0.93(s,3H).
LCMS m/z=361.2 [M+1].
Embodiment 12：3- methoxycarbonyl epoxide propyl group 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 12)
3-methoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：3- hydroxypropyl methyls carbonic ester (12A)
3-hydroxypropyl methyl carbonate
Triphosgene (1.85g, 6.2mmol) and methanol (0.60g, 18.7mmol) are dissolved in dichloromethane (20mL), it is cold But to 0 DEG C, pyridine (1.85g, 23.4mmol) is added dropwise, 0 DEG C is reacted 3 hours, obtains reaction solution 1.By glycerine (6A) (3.0g, 39.4mmol) it is dissolved in pyridine (1.85g, 23.4mmol) in dichloromethane (50mL), 0 DEG C of dropwise reaction liquid 1, is slowly raised to room Temperature, react 2 hours at room temperature.Reaction solution is washed with water (100mL × 2) and saturation sodium dihydrogen phosphate (100mL × 3) successively Wash, organic phase anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/stone Oily ether (v/v)=0/1~1/5) separating-purifying, obtain title compound 3- hydroxypropyl methyls carbonic ester (12A), colorless oil (0.8g, yield 30%).
1H NMR(400MHz,CDCl3)δ4.30(dd,2H),3.79(s,3H),3.74(t,2H),1.92(m,2H).
Second step：3- methoxycarbonylpropyls 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 12)
3-methoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By 3- hydroxypropyl methyls carbonic ester (12A) (0.62g, 4.6mmol) and 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylic acid (1A) (1.0g, 4.6mmol) is dissolved in dichloromethane (30mL), adds 1- (3- dimethylamino-propyls) -3- ethyls carbon two Inferior amine salt hydrochlorate (1.3g, 6.9mmol) and dimethylamino naphthyridine (0.56g, 4.6mmol), are stirred at room temperature 3 hours.To reaction solution Dichloromethane (25mL) and water (50mL), layering extraction are added, organic phase uses saturation sodium dihydrogen phosphate (50mL × 1) successively Washed with saturated nacl aqueous solution (50mL × 1), anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration, residue silica gel Column chromatography (ethyl acetate/petroleum ether (v/v)=0/1~1/3) separating-purifying, obtains title compound 3- methoxycarbonylpropyls 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 12), colorless oil (1.0g, yield 65%).
1H NMR(400MHz,CDCl3)δ7.76(d,2H),7.32(m,3H),7.19(m,2H),6.34(q,1H),4.32 (m,2H),4.25(t,2H),3.77(s,3H),2.07(m,2H),1.86(d,3H).
LCMS m/z=333.1 [M+1].
Embodiment 13：3- ethoxy carbonyl epoxide propyl group 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 13)
3-ethoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：Ethyl 3- hydroxypropyls carbonic ester (13A)
ethyl 3-hydroxypropyl carbonate
Triphosgene (2.79g, 9.40mmol) and ethanol (1.30g, 28.2mmol) are dissolved in dichloromethane (50mL), it is cold But to 0 DEG C, triethylamine (3.57g, 35.3mmol) is added dropwise, 0 DEG C is reacted 3 hours, obtains reaction solution 1.By glycerine (6A) (6.0g, 78.9mmol) and triethylamine (3.57g, 35.3mmol) are dissolved in dichloromethane (50mL), 0 DEG C of dropwise reaction liquid 1, from So it is warmed to room temperature reaction 2 hours.Reaction solution is washed with water (100mL × 2) and saturation sodium dihydrogen phosphate (100mL × 3) successively Wash, organic phase anhydrous sodium sulfate drying, filter, after filtrate decompression concentration, residue silica gel column chromatography (ethyl acetate/stone Oily ether (v/v)=0/1~1/5) separating-purifying, obtain title compound ethyl 3- hydroxypropyls carbonic ester (13A), colorless oil Thing (0.8g, yield 20%).
1H NMR(400MHz,CDCl3)δ4.30(t,2H),4.21(m,2H),3.74(t,2H),1.92(m,2H),1.31 (t,3H).
Second step：3- ethoxy carbonyl epoxide propyl group 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 13)
3-ethoxycarbonyloxypropyl 3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By ethyl 3- hydroxypropyls carbonic ester (13A) (0.69g, 4.6mmol) and 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylic acids (1A) (1.0g, 4.6mmol) are dissolved in dichloromethane (30mL), add 1- (3- dimethylamino-propyls) -3- ethyl carbon Diimmonium salt hydrochlorate (1.3g, 6.9mmol) and dimethylamino naphthyridine (0.56g, 4.6mmol), are stirred at room temperature 3 hours.To reaction Liquid adds dichloromethane (25mL) and water (50mL), layering extraction, and organic phase uses saturation sodium dihydrogen phosphate successively (50mL × 1) and saturated nacl aqueous solution (50mL × 1) are washed, anhydrous sodium sulfate drying, and after filtrate decompression concentration, residue is used Silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0/1~1/3) separating-purifying, obtains title compound 3- ethoxy carbonyls Epoxide propyl group 3- [(1R) -1- phenethyls] imidazoles -4- carboxylates (compound 13), colorless oil (1.2g, yield 75%).
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.74(s,1H),7.31(m,3H),7.18(d,2H),6.34 (q,1H),4.32(m,2H),4.23(t,2H),4.18(q,2H),2.07(m,2H),1.86(d,3H),1.30(t,3H).
LCMS m/z=347.1 [M+1].
Embodiment 14：(3- isopropoxy carbonyl Oxy-1s, 1- dimethyl propyls) 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylates (compound 14)
(3-isopropoxycarbonyloxy-1,1-dimethyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：(3- hydroxy-3-methyls-butyl) butylperoxyisopropyl carbonate (14B)
(3-hydroxy-3-methyl-butyl)isopropyl carbonate
By 3- methyl isophthalic acids, 3 butanediols (14A) (5.0g, 48mmol) are dissolved in dichloromethane (100mL), add triethylamine (9.7g, 96mmol), 0 DEG C is slowly added dropwise isopropyl chlorocarbonate (8.8g, 72mmol), drips off room temperature reaction 3 hours.Reaction solution adds Enter water (100mL) washing, organic phase is washed with saturated aqueous common salt (100mL × 1) after liquid separation, anhydrous sodium sulfate drying, is filtered, filter After liquid is concentrated under reduced pressure, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/10~1/1) separating-purifying, obtain Title compound (3- hydroxy-3-methyls-butyl) butylperoxyisopropyl carbonate (14B), colorless oil (4.5g, yield 49%).
1H NMR(400MHz,CDCl3)δ4.93–4.82(m,1H),4.30(t,2H),1.88(t,2H),1.78(s, 1H),1.31–1.24(m,12H).
LCMS m/z=213.1 [M+23]
Second step：(3- isopropoxy carbonyl Oxy-1s, 1- dimethyl propyls) 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylate (compound 14)
(3-isopropoxycarbonyloxy-1,1-dimethyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.5g, 6.9mmol) are suspended in dichloromethane In (20ml), (3- hydroxy-3-methyls-butyl) butylperoxyisopropyl carbonate (14B) (1.3g, 6.9mmol), 1- (3- diformazan ammonia are added Base propyl group) -3- ethyl-carbodiimide hydrochlorides (2.0g, 10mmol), DMAP (1.3g, 10mmol), room temperature is stirred Mix 2 hours.Reaction solution is washed with saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt (30mL × 1) successively, point Organic phase anhydrous sodium sulfate drying after liquid, filtering, residue silica gel column chromatography (ethyl acetate/stone after filtrate decompression concentration Oily ether (v/v)=1/20~1/5) separating-purifying, obtain title compound (3- isopropoxy carbonyl Oxy-1s, 1- dimethyl propylenes Base) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 14), colorless oil (0.6g, yield 20%).
1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.66(s,1H),7.31(m,,3H),7.21–7.13(m, 2H),6.33(d,1H),4.91–4.79(m,1H),4.21(m,2H),2.21(m,2H),1.85(d,3H),1.54(t,6H), 1.28(dd,6H).
LCMS m/z=389.2 [M+1].
Embodiment 15:[(1R, 2R)-2- isopropoxy carbonyls Oxy-1-methyI-oropvD] 3- [(1R)-1- phenylethyls] Imidazoles -4- carboxylates (compound 15)
[(1R,2R)-2-isopropoxycarbonyloxy-1-methyl-propyl]3-[(1R)-1- phenylethyl]imidazole-4-carbox ylate
The first step：[(1R, 2R) -2- hydroxyl -1- methyI-oropvDs] butylperoxyisopropyl carbonate (15B)
[(1R,2R)-2-hydroxy-1-methyl-propyl]isopropyl carbonate
(2R, 3R)-(-) -2,3-butanediol (15A) (3.6g, 39.9mmol) is dissolved in dichloromethane (20mL), added Triethylamine (8.08g, 79.9mmol), 0 DEG C is added dropwise isopropyl chlorocarbonate (4.41g, 36.0mmol), drips off room temperature reaction 2 hours. Water (30mL) is added to reaction solution, is extracted with 30ml dichloromethane (30mL × 2), organic phase is with saturated aqueous common salt (30mL × 1) Washing, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography separating-purifying (petroleum ether/acetic acid Ethyl ester (v/v)=1/10~1/1), obtain title compound [(1R, 2R) -2- hydroxyl -1- methyI-oropvDs] butylperoxyisopropyl carbonate (15B), colorless oil (0.5g, yield 7%).
1H NMR(400MHz,CDCl3)δ4.88(m,1H),4.58(dd,1H),4.37–4.28(m,1H),3.82–3.69 (m,1H),1.29(m,9H),1.20(d,3H)。
LCMS m/z=199.1 [M+23].
Second step:[(1R, 2R)-2- isopropoxy carbonyls Oxy-1-methyI-oropvD] 3- [(1R)-1- phenylethyls] miaow Azoles -4- carboxylates (compound 15)
[(1R,2R)-2-isopropoxycarbonyloxy-1-methyl-propyl]3-[(1R)-1- phenylethyl]imidazole-4-carbox ylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (1.0g, 4.6mmol) are suspended in dichloromethane In (20mL), [(1R, 2R) -2- hydroxyl -1- methyI-oropvDs] butylperoxyisopropyl carbonate (15B) (0.9g, 5.1mmol), 1- are added (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (1.3g, 6.9mmol), DMAP (0.85g, 6.9mmol), it is stirred at room temperature 2 hours.Reaction solution uses saturation biphosphate sodium water solution (30mL × 2) and saturated aqueous common salt successively (30mL × 1) is washed, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue silica gel column chromatography (second Acetoacetic ester/petroleum ether (v/v)=1/20~1/5) separating-purifying, obtain title compound [(1R, 2R) -2- isopropoxy carbonyls Oxy-1-methyI-oropvD] 3- [(1R)-1- phenylethyls] imidazoles-4- carboxylates (compound 15), colorless oil (0.4g, Yield 20%).
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.72(s,1H),7.32(m,3H),7.23–7.15(m, 2H),6.36(d,1H),5.15–5.03(m,1H),4.97–4.79(m,2H),1.86(d,3H),1.31–1.24(m,9H), 1.22(d,3H).
LCMS m/z=375.1 [M+1].
Embodiment 16：(3- isopropoxy carbonyls Oxy-1-methyI-oropvD) 3- [(1R)-1- phenethyls] imidazoles-4- carboxylic acids Methyl esters (compound 16)
(3-isopropoxycarbonyloxy-1-methyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：Butane -1,3- glycol (16B)
butane-1,3-diol
4- hydroxy-2-butanones (16A) (3.6g, 20.9mmol) is dissolved in methanol (20mL), 0 DEG C of addition sodium borohydride (0.79g, 20.4mmol), stir 30 minutes.Reaction solution is concentrated under reduced pressure, residue silica gel column chromatography (ethyl acetate/oil Ether (v/v)=1/20~1/1) separating-purifying, obtain title compound butane -1,3- glycol (16B), colorless oil (2.5g, Yield 68%)
1H NMR(400MHz,CDCl3)δ3.86(m,1H),3.72(m,2H),1.80(m,3H),1.70(m,1H),1.25 (m,3H).
Second step：3- hydroxybutyls butylperoxyisopropyl carbonate (16C)
3-hydroxybutyl isopropyl carbonate
By butane -1,3- glycol (16B) (2.5g, 28mmol), triethylamine (3.3g, 33.3mmol) is dissolved in dichloromethane In (50mL), 0 DEG C is added dropwise isopropyl chlorocarbonate (2.0g, 16mmol), drips off room temperature reaction 2 hours.Two are added into reaction solution Chloromethanes (50mL), organic phase are washed with water (50mL × 2), anhydrous sodium sulfate drying, filtering, residue after filtrate decompression concentration With silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20~1/5) separating-purifying, title compound 3- hydroxyl fourths are obtained Base butylperoxyisopropyl carbonate (16C), colorless oil (1.3g, yield 45%)
1H NMR(400MHz,CDCl3)δ4.88(m,1H),4.36(m,1H),4.20(m,1H),3.94(m,1H),1.84 (m,2H),1.30(d,6H),1.23(d,3H).
3rd step：(3- isopropoxy carbonyls Oxy-1-methyI-oropvD) 3- [(1R)-1- phenethyls] imidazoles-4- carboxylates (compound 16)
(3-isopropoxycarbonyloxy-1-methyl-propyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
By 3- hydroxybutyls butylperoxyisopropyl carbonate (16C) (1.30g, 7.40mmol) and 3- [(1R) -1- phenylethyls] miaow Azoles -4- carboxylic acids (1A) (1.60g, 7.40mmol) are dissolved in dichloromethane (30mL), add 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride (2.13g, 11.1mmol), dimethylamino naphthyridine (0.90g, 7.40mmol), react at room temperature 3 hours. Dichloromethane (50mL) and water (50mL), layering extraction are added into reaction solution, organic phase uses saturation sodium dihydrogen phosphate molten respectively Liquid (50mL) and saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying, filtering, residue silica gel after filtrate decompression concentration Column chromatography (ethyl acetate/petroleum ether (v/v)=0/1~1/3) separating-purifying, obtains title compound (3- isopropoxy carbonyls Oxy-1-methyI-oropvD) 3- [(1R)-1- phenethyls] imidazoles-4- carboxylates (compound 16), pale yellowish oil (1.20g, production Rate 43%).
1H NMR(400MHz,CDCl3)δ7.74(d,2H),7.32(m,3H),7.19(d,2H),6.35(q,1H),5.16 (m,1H),4.84(m,1H),4.15(m,2H),1.98(m,2H),1.88(t,3H),1.29(m,9H).
LCMS m/z=375.1 [M+1]
Take (3- isopropoxy carbonyls Oxy-1-methyI-oropvD) 3- [(1R)-1- phenethyls] imidazoles-4- carboxylate (chemical combination Thing 16) (1.2g) be used for split.
Preparation condition：Instrument：Thar 350preparative SFC(SFC-6)；Post：ChiralPak AD,300× 50mm I.D.,10μm.；Mobile phase：A for CO2and B for methanol；Gradient：B 25%；Flow：200mL/ min；Back pressure：100bar；Column temperature：38℃；Wavelength：220nm；Cycle：3.5min；Sample preparation：Compound 16 is dissolved in 60mL In methanol；Injection：5mL/ pins.
After separation, by cut at 40 DEG C, concentrate, dry via Rotary Evaporators, obtain two optical isomer chemical combination Thing 16-A (605.50mg, e.e.=100%), compound 16-B (498.50mg, e.e.=99.8%).
Compound 16-A
1H NMR(400MHz,CDCl3)δ7.75(d,2H),7.32(m,3H),7.20(m,2H),6.35(q,1H),5.18 (m,1H),4.85(m,1H),4.17(t,2H),2.00(s,2H),1.85(t,3H),1.29(m,9H).
LCMS m/z=375.2 [M+1]
Compound 16-B
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.71(s,1H),7.32(m,3H),7.19(d,2H),6.35 (q,1H),5.16(m,1H),4.82(m,1H),4.15(t,2H),2.00(m,2H),1.86(d,3H),1.32(d,3H),1.27 (d,6H).
LCMS m/z=375.2 [M+1]
Embodiment 17：(2- acetoxyl group -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (are changed Compound 17)
(2-acetoxy-1-methyl-ethyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
The first step：1- [tert-butyl group (dimethyl) silicyl] Ethylene Oxide -2- alcohol (17B)
1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol
1,2-PD (17A) (5g, 65.74mmol) is dissolved in dichloromethane (100mL), addition imidazoles (8.9g, 131.49mmol), tert-butyl chloro-silicane (9.9g, 65.74mmol) dichloromethane solution is slowly added at 0 DEG C (50mL), room temperature reaction 4 hours is slowly increased to after adding.Reaction solution is washed with water (150mL × 2), organic phase nothing after liquid separation Aqueous sodium persulfate is dried, filtering, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/50 after filtrate decompression concentration ~1/10) separating-purifying, title compound 1- [tert-butyl group (dimethyl) silicyl] Ethylene Oxide -2- alcohol (17B) is obtained, it is colourless Liquid (6.5g, yield 52.04%)
1H NMR(400MHz,CDCl3)δ3.88–3.72(m,1H),3.59(dd,1H),3.35(dd,1H),2.33(s, 1H),1.11(d,3H),0.90(s,9H),0.08(s,6H).
LCMS m/z=213.1 [M+23].
Second step：(2- hydroxyl -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (17C)
(2-hydroxy-1-methyl-ethyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (4.92g, 22.80mmol) are suspended in dichloromethane (40mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (5.24g, 27.36mmol), 4- diformazans Aminopyridine (1.67g, 13.68mmol) and 1- [tert-butyl group (dimethyl) silicyl] Ethylene Oxide -2- alcohol (17B) (6.5g, 34.21mmol), when 4 are reacted at room temperature after adding.Dichloromethane (40mL) is added in reaction solution, and is washed with water (80mL × 2), Layering extraction, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue are dissolved in tetrahydrofuran (50mL) In, tetrabutyl ammonium fluoride (5.96g, 22.80mmol) is added, room temperature reaction is overnight.Reaction solution is washed with water (100mL), is used in combination Ethyl acetate (150mL × 2) extracts, and merges organic phase, organic phase anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/10~1/1) separating-purifying, obtains title compound (2- Hydroxyl -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (17C), colourless liquid (2.5g, gross production rate 40.06%)
1H NMR(400MHz,CDCl3)δ7.79(d,1H),7.75(d,1H),7.39–7.26(m,3H),7.21–7.10 (m,2H),6.33(q,1H),4.21–4.02(m,2H),3.72–3.63(m,1H),2.43(s,1),1.85(dd,3H),1.29– 1.18(dd,3H).
LCMS m/z=275.1 [M+1].
3rd step：(2- acetoxyl group -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (chemical combination Thing 17)
(2-acetoxy-1-methyl-ethyl)3-[(1R)-1-phenylethyl]imidazole-4- carboxylate
By (2- hydroxyl -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carbonic esters (17C) (2.5g, 9.12mmol) it is dissolved in dichloromethane (20mL), adds triethylamine (1.84g, 18.24mmol), 0 DEG C is slowly added dropwise acetic anhydride (1.86g, 18.24mmol), reaction 1 hour is warmed to room temperature after adding.Dichloromethane (40mL) is added in reaction solution, and uses water (80mL × 2) are washed, layering extraction, organic phase anhydrous sodium sulfate drying, filtering, residue silica gel after filtrate decompression concentration Column chromatography (ethyl acetate/petroleum ether (v/v)=0/10~1/1) separating-purifying, obtains title compound (2- acetoxyl groups -1- Methyl-ethyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 17), colourless liquid (1.8g, yield 62.50%)
LCMS m/z=317.1 [M+1]
Take (2- acetoxyl group -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 17) (1.8g) is used to split.
Preparation condition：Instrument：MGⅡpreparative SFC(SFC-11)；Post：ChiralPak AY,250×30mm I.D.,10μm.；Mobile phase：A for CO2and B for iso-propanol；Gradient：B 40%；Flow：60mL/min； Back pressure：100bar；Column temperature：38℃；Wavelength：220nm；Cycle：6min；Sample preparation：Compound 17 is dissolved in 60mL methanol； Injection：3mL/ pins.
After separation, by cut, at 40 DEG C, concentrate, dry via Rotary Evaporators, obtain two optical isomer chemical combination Thing 17-A (585.46mg, e.e.=100%), compound 17-B (990.54mg, e.e.=100%).
Compound 17-A
1H NMR(400MHz,CDCl3)δ7.74(d,2H),7.36–7.28(m,3H),7.21–7.14(m,2H),6.33 (q,1H),5.30–5.22(m,1H),4.24–4.09(m,2H),2.05(s,3H),1.86(d,3H),1.28(d,3H).
LCMS m/z=317.1 [M+1]
Compound 17-B
1H NMR(400MHz,CDCl3)δ7.77(d,2H),7.38–7.27(m,3H),7.20–7.17(m,2H),6.33 (q,1H),5.22–5.14(m,1H),4.32–4.17(m,2H),2.00(s,3H),1.86(d,3H),1.27(d,3H).
LCMS m/z=317.1 [M+1]
Embodiment 18：(1- cyclopropyl -2- isopropyloxycarbonyls oxygen-ethyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylics Acid esters (compound 18)
(1-cyclopropyl-2-isopropoxycarbonyloxy-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step:2- [tert-butyl group (dimethyl) silicon substrate] ethoxy-ethanol (18A)
2-[tert-butyl(dimethyl)silyl]oxyethanol
Ethylene glycol (4A) (80g, 1.29mol) is dissolved in dichloromethane (1L), addition imidazoles (175.58g, 2.58mol), the dichloromethane (200mL) that tert-butyl chloro-silicane (194.35g, 1.29mol) is slowly added at 0 DEG C is molten Liquid, slowly recover to room temperature reaction overnight after adding.Reaction solution is washed with water (1L × 2), and organic phase is again with saturated sodium-chloride The aqueous solution (500mL) washs, organic phase anhydrous sodium sulfate drying, filtering, residue silica gel column layer after filtrate decompression concentration (ethyl acetate/petroleum ether (v/v)=1/50~1/20) separating-purifying is analysed, obtains the title compound 2- [tert-butyl groups (dimethyl) Silicon substrate] ethoxy-ethanol (18A), colourless liquid (76.3g, yield 33.61%)
1H NMR(400MHz,CDCl3)δ3.73–3.69(m,2H),3.66–3.62(m,2H),1.94(s,1H),0.91 (s,9H),0.08(s,6H).
Second step：2- [tert-butyl group (dimethyl) silicon substrate] oxy-aldehyde (18B)
2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde
2- [tert-butyl group (dimethyl) silicon substrate] ethoxy-ethanol (18A) (76.3g, 433.23mmol) is dissolved in tetrahydrofuran In (400mL), Dai Si-Martin (202.12g, 476.55mmol) is added portionwise, reacts 4 hours at room temperature.Add in equal volume Saturated sodium bicarbonate aqueous solution and saturated aqueous sodium thiosulfate altogether (500mL), are stirred 1 hour at room temperature, and filtering, filter cake is used Ethyl acetate (100mL × 2) is washed, and filtrate is extracted with ethyl acetate (400mL × 2), merges organic phase, and organic phase is eaten with saturation Salt solution (400mL) washs, anhydrous sodium sulfate drying, filtering, residue silica gel column chromatography (acetic acid second after filtrate decompression concentration Ester/petroleum ether (v/v)=1/40~1/10) separating-purifying, obtain title compound 2- [tert-butyl group (dimethyl) silicon substrate] epoxide Acetaldehyde (18B), colourless liquid (39.7g, yield 52.63%)
1H NMR(400MHz,CDCl3)δ9.69(s,1H),4.20(d,2H),0.92(s,9H),0.10(s,6H).
3rd step：2- [tert-butyl group (dimethyl) silicon substrate] Oxy-1-cyclopropyl-ethanol (18C)
2-[tert-butyl(dimethyl)silyl]oxy-1-cyclopropyl-ethanol
2- [tert-butyl group (dimethyl) silicon substrate] oxy-aldehyde (18B) (39.7g, 228mmol) is dissolved in tetrahydrofuran In (300mL), under nitrogen protection, cyclopropyl magnesium bromide (49.69g, 342mmol) tetrahydrofuran solution is slowly added dropwise at 0 DEG C, Reacted at room temperature 4 hours after adding.Reaction is quenched with saturated aqueous ammonium chloride (400mL), and with ethyl acetate (400mL × 2) Extraction, merge organic phase, organic phase is washed with saturated aqueous common salt (400mL), anhydrous sodium sulfate drying, filtering, and filtrate decompression is dense Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/30~1/8) separating-purifying, obtains title compound after contracting Thing 2- [tert-butyl group (dimethyl) silicon substrate] Oxy-1-cyclopropyl-ethanol (18C), brown liquid (36.5g, yield 74.06%).
1H NMR(400MHz,CDCl3)δ3.74–3.71(m,1H),3.56–3.52(m,1H),2.96–2.91(m,1H), 2.47(s,1H),0.90(s,9H),0.86–0.76(m,1H),0.56–0.33(m,3H),0.22–0.16(m,1H),0.06(d, 6H).
4th step：1- cyclopropyl ethane -1,2- glycol (18D)
1-cyclopropylethane-1,2-diol
By 2- [tert-butyl group (dimethyl) silicon substrate] Oxy-1-cyclopropyl-ethanol (18C) (36.5g, 168.86mmol) dissolving In tetrahydrofuran (300mL), tetrabutyl ammonium fluoride (66.22g, 253.30mmol) is added, reaction at room temperature is stayed overnight.Depressurize dense After contracting, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/30~1/4) separating-purifying, title compound is obtained Thing 1- cyclopropyl ethane -1,2- glycol (18D), colourless liquid (12.3g, yield 71.38%).
1H NMR(400MHz,CDCl3)δ3.74–3.71(m,1H),3.59–3.54(m,1H),3.10–2.86(m,3H), 0.90–0.81(m,1H),0.56–0.46(m,2H),0.36–0.30(m,1H),0.24–0.18(m,1H).
5th step：(2- cyclopropyl -2- hydroxy-ethyls) butylperoxyisopropyl carbonate (18E)
(2-cyclopropyl-2-hydroxy-ethyl)isopropyl carbonate
1- cyclopropyl ethane -1,2- glycol (18D) (12.3g, 120.5mmol) is dissolved in dichloromethane (100mL), Triethylamine (24.39g, 241mmol) is added, isopropyl chlorocarbonate (22.15g, 180.76mmol), room temperature is slowly added dropwise at 0 DEG C Reaction is overnight.Reaction solution is washed with water (100mL × 2), liquid separation, organic phase anhydrous sodium sulfate drying, filtering, and filtrate decompression is dense Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/15~1/1) separating-purifying, obtains title compound after contracting Thing (2- cyclopropyl -2- hydroxy-ethyls) butylperoxyisopropyl carbonate (18E), colourless liquid (5.1g, yield 22.50%).
1H NMR(400MHz,CDCl3)δ4.92–4.82(m,1H),4.30–4.26(m,1H),4.14–4.09(m,1H), 3.22–3.17(m,1H),2.14(s,1H),1.28(d,6H),0.96–0.87(m,1H),0.60–0.46(m,2H),0.42– 0.34(m,1H),0.31–0.20(m,1H).
6th step：(1- cyclopropyl -2- isopropyloxycarbonyl groups oxygen-ethyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylics Acid esters (compound 18)
(1-cyclopropyl-2-isopropoxycarbonyloxy-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxyl ate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (3g, 13.89mmol) are suspended in dichloromethane In (25mL), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (3.99g, 20.83mmol), 4- dimethylaminos Pyridine (1.01g, 8.34mmol), addition (2- cyclopropyl -2- hydroxy-ethyls) butylperoxyisopropyl carbonate (18E) (2.5g, 13.3mmol), react at room temperature 4 hours.Water (150mL) is added into reaction solution, is extracted (150mL × 2) with dichloromethane, is merged Organic phase, organic phase are washed with saturation biphosphate sodium water solution (200mL), anhydrous sodium sulfate drying, concentration, residue silicon Plastic column chromatography (ethyl acetate/petroleum ether (v/v)=1/10~1/1) separating-purifying, obtains title compound (1- cyclopropyl -2- Isopropyloxycarbonyl group oxygen-ethyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 18), brown liquid (1.35g, yield 25.18%).
LCMS m/z=387.1 [M+1]
Take (1- cyclopropyl -2- isopropyloxycarbonyl groups oxygen-ethyl) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 18) (1.35g) is used to split.
Preparation condition：Instrument：Thar 350preparative SFC(SFC-6)；Post：ChiralPak AD,300× 50mm I.D.,10μm.；Mobile phase：A for CO2and B for Ethanol；Gradient：B 25%；Flow：200mL/min； Back pressure：100bar；Column temperature：38℃；Wavelength：220nm；Cycle：1.7min；Sample preparation：Compound 18 is dissolved in 80mL methanol In；Injection：3mL/ pins.
After separation, by cut, at 40 DEG C, concentrate, dry via Rotary Evaporators, obtain two optical isomer chemical combination Thing 18-A (638.51mg, e.e.=100%), compound 18-B (613.52mg, e.e.=99.1%).
Compound 18-A
1H NMR(400MHz,CDCl3)δ7.77(d,2H),7.36–7.28(m,3H),7.22–7.16(m,2H),6.37– 6.31(q,1H),4.87–4.82(m,1H),4.70–4.54(m,1H),4.40–4.28(m,2H),1.87(d,3H),1.25 (dd,6H),1.14–0.98(m,1H),0.65–0.32(m,4H).
LCMS m/z=387.1 [M+1]
Compound 18-B
1H NMR(400MHz,CDCl3)δ7.76(d,2H),7.36–7.27(m,3H),7.21–7.17(m,2H),6.35– 6.29(q,1H),4.91–4.82(m,1H),4.67–4.56(m,1H),4.43–4.39(m,1H),4.29–4.24(m,1H), 1.85(d,3H),1.27(dd,6H),1.12–0.99(m,1H),0.62–0.28(m,4H).
LCMS m/z=387.1 [M+1]
Embodiment 19：(2- butyloxycarbonyl oxygen -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 19)
(2-isopropoxycarbonyloxy-1-methyl-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：2- hydroxypropyls butylperoxyisopropyl carbonate (19A)
2-hydroxypropyl isopropyl carbonate
1,2-PD (17A) (10g, 131.49mmol) is dissolved in dichloromethane (150mL), adds triethylamine (8.87g, 87.66mmol), isopropyl chlorocarbonate (5.37g, 43.83mmol) is slowly added dropwise at 0 DEG C, 4 are reacted at room temperature after adding Hour.Reaction is quenched with water (150mL), liquid separation, organic phase anhydrous sodium sulfate drying, filtering, is remained after filtrate decompression concentration Thing silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/10~1/1) separating-purifying, it is different to obtain title 2- hydroxypropyls Propyl carbonate (19A), colourless liquid (4.2g, yield 19.17%).
1H NMR(400MHz,CDCl3)δ4.86(m,1H),4.18–4.01(m,2H),3.97–3.93(m,1H),2.19 (s,1H),1.28(d,6H),1.20(d,3H).
Second step：(2- butyloxycarbonyl oxygen -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 19)
(2-isopropoxycarbonyloxy-1-methyl-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
3- [(1R) -1- phenylethyls] imidazoles -4- carboxylic acids (1A) (4.92g, 22.80mmol) are suspended in dichloromethane (40mL), add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (5.24g, 27.36mmol), 4- diformazans Aminopyridine (4.2g, 13.68mmol) and 2- hydroxypropyls butylperoxyisopropyl carbonate (19A) (4.2g, 34.21mmol), after adding Room temperature reaction 4 hours.Dichloromethane (40mL) is added in reaction solution, and is washed with water (80mL × 2), liquid separation, organic phase nothing Aqueous sodium persulfate is dried, filtering, residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0/10 after filtrate decompression concentration ~1/1) separating-purifying, title compound (2- butyloxycarbonyl oxygen -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] is obtained Imidazoles -4- carboxylates (compound 19), colourless liquid (3.5g, yield 42.52%).
LCMS m/z=361.2 [M+1].
Take (2- butyloxycarbonyl oxygen -1- methyl-ethyls) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylate (compounds 19) (3.5g) is used to split.
Preparation condition：Instrument：Thar 350preparative SFC(SFC-9)；Post：ChiralPak AD,300× 50mm I.D.,10μm.；Mobile phase：Afor CO2and B for Ethanol；Gradient：B 15%；Flow：200mL/min； Back pressure：100bar；Column temperature：38℃；Wavelength：220nm；Cycle：3.2min；Sample preparation：Compound 18 is dissolved in 2000mL first In alcohol/DCM；Injection：6mL/ pins.
After separation, by cut, at 40 DEG C, concentrate, dry via Rotary Evaporators, obtain two optical isomer chemical combination Thing 19-A (1.67g, e.e.=100%), compound 19-B (1.27g, e.e.=98.8%).
Compound 19-A
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.70(s,1H),7.36–7.30(m,2H),7.29–7.27 (m,1H),7.22–7.10(m,2H),6.33(q,1H),5.43–5.09(m,1H),5.02–4.64(m,1H),4.21(m,2H), 1.85(d,3H),1.33–1.25(m,9H).
LCMS m/z=361.2 [M+1].
Compound 19-B
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.71(s,1H),7.36–7.30(m,2H),7.28–7.27 (m,1H),7.22–7.12(m,2H),6.32(q,1H),5.08–5.02(m,1H),4.95–4.75(m,1H),4.32–4.20 (m,2H),1.84(d,3H),1.32–1.21(m,9H).
LCMS m/z=361.2 [M+1].
Embodiment 20：(2- isopropoxy carbonyl Oxy-1s, 1- dimethyl-ethyIs) 3- [(1R) -1- phenylethyls] imidazoles - 4- carboxylates (compound 20)
(2-isopropoxycarbonyloxy-1,1-dimethyl-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
The first step：(2- hydroxy-2-methyls-propyl group) butylperoxyisopropyl carbonate (20B)
(2-hydroxy-2-methyl-propyl)isopropyl carbonate
By 2- methylpropanes -1,2- glycol (20A) (4.0g, 44.4mmol), triethylamine (4.49g, 44.4mmol) is dissolved in In dichloromethane (50mL), 0 DEG C is added dropwise isopropyl chlorocarbonate (2.72g, 22.2mmol), reacts at room temperature 2 hours.Into reaction solution Dichloromethane (50mL) is added, is washed with water (50mL × 2), liquid separation, organic phase anhydrous sodium sulfate drying, is filtered, filtrate subtracts Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/20~1/5) separating-purifying after pressure concentration, obtains title Compound (2- hydroxy-2-methyls-propyl group) butylperoxyisopropyl carbonate (20B), colorless oil (1.0g, yield 26%).
1H NMR(400MHz,CDCl3)δ4.89(m,1H),4.00(s,2H),1.94(s,1H),1.31(dd,6H), 1.27(m,6H).
Second step：(2- isopropoxy carbonyl Oxy-1s, 1- dimethyl-ethyIs) 3- [(1R) -1- phenylethyls] imidazoles -4- Carboxylate (compound 20)
(2-isopropoxycarbonyloxy-1,1-dimethyl-ethyl)3-[(1R)-1-phenylethyl] imidazole-4-carboxylate
By (2- hydroxy-2-methyls-propyl group) butylperoxyisopropyl carbonate (20B) (0.0.81g, 4.6mmol) and 2- [(1R) -1- Phenethyl] pyrazoles -3- carboxylic acids (1.0g, 4.6mmol) are dissolved in dichloromethane (30mL), add 1- (3- dimethylamino-propyls) - 3- ethyl-carbodiimide hydrochlorides (1.3g, 6.9mmol), dimethylamino naphthyridine (0.56g, 4.6mmol), react at room temperature 3 hours. Dichloromethane (50mL) and water (50mL), extracting and demixing are sequentially added into reaction solution, organic phase uses saturation biphosphate successively Sodium solution (50mL) washs, saturated nacl aqueous solution (50mL) washing, anhydrous sodium sulfate drying, filtering, after filtrate decompression concentration Residue silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=0/3~1/3) separating-purifying, obtains title compound (2- Isopropoxy carbonyl Oxy-1,1- dimethyl-ethyIs) 3- [(1R) -1- phenylethyls] imidazoles -4- carboxylates (compound 20), Pale yellowish oil (0.250g, yield 14%).
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.73(s,1H),7.33(m,3H),7.21(m,2H),6.34 (q,1H),4.87(m,1H),4.31(q,2H),1.86(d,3H),1.56(d,6H),1.29(d,6H).
LCMS m/z=375.2 [M+1].
Biological test example
1st, rat Righing reflex
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).Each test-compound is as shown in table 1 using one or two dosage test anesthesia drug effect, experimental result.
And with effective dose 50 (ED50), median lethal dose (LD50), therapeutic index (TI, i.e. LD50/ED50), safety index (SI, i.e. LD5/ED95) metrics evaluation part of compounds validity and security (table 2).
Table 1：Rat Righing reflex data
LORR：Righting reflex loss (Loss of Righting Reflex).
Conclusion：The compounds of this invention is rapid-action, has different degrees of anesthesia drug effect.
Table 2：Rat turns over evaluating drug effect result
Compound number ED50(mg/kg) LD50(mg/kg) TI SI
Compound 7 2.36 38.37 16.26 10.33
Conclusion：The security of the compounds of this invention 7 is preferable.
2nd, Rat Adrenal Cortex Function detection
Tested compound is formulated in the physiological saline containing 10%DMSO and 5%HS-15 to required concentration.SPF levels SD is big Mouse, 250-300g, overnight fasting are weighed.Next day, all animals ivs inject dexamethasone 0.2mg/kgBW, and the 2h after injection 200 μ l of jugular sinus blood sampling.After blood sampling, intravenously administrable again, tested group：It is injected intravenously dexamethasone sodium phosphate injection 0.2mg/kgBW+ test-compounds+ACTH (1-24) 25 μ g/kg；Control group：It is injected intravenously dexamethasone sodium phosphate injection 0.2mg/kgBW+ solvents (5%DMSO, 5%HS-15,90% physiological saline)+ACTH (1-24) 25 μ g/kg, after injection 200 μ l of jugular sinus blood sampling after 15min, 30min.After the whole blood room temperature solidification 30min collected twice, supernatant is collected respectively, And in -80 DEG C of preservations, treat that ELISA detects serum corticosterone concentration, analysis result is as shown in table 3.
ACTH(1-24)：The peptide of N-terminal 24 of corticotropin (adrenocorticotrphin, ACTH).
Table 3：Rat Adrenal Cortex Function detection experimental result
Conclusion：Cortex renis function inhibitio is acted under the compounds of this invention ED50 2 multiple doses weak.

Claims (6)

1. compound or its stereoisomer, solvate, pharmaceutically acceptable salt or common shown in a kind of logical formula (I) It is brilliant：
(I)
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；
M is selected from C1-6Alkylidene, described alkylidene is optionally further by 0 to 4 RaSubstitution；
RaSelected from F, Cl, Br, CF3、C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Carbocyclic ring or 3 to 8 circle heterocycles, institute Alkyl, alkoxy, alkenyl, alkynyl, carbocyclic ring or the heterocycle stated optionally further are 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；
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；
X is selected from-CRbRc- ,-O- or-S-；
Condition is, when X is selected from-CRbRc- when, M is at least by 1 RaSubstitution；
Rb、RcIt is independently selected from H or C1-4Alkyl；
R3Selected from H, C1-6Alkyl ,-(CH2)m-C3-8Carbocyclic ring ,-(CH2) m-3 is to 8 circle heterocycles ,-(CH2)m-OC3-8Carbocyclic ring or-(CH2) M-O-3 is optionally further selected from F, Cl, Br, CF to 8 circle heterocycles, described alkyl, carbocyclic ring or heterocycle by 0 to 43, cyano group, Amino, C1-4Alkyl, C1-4Alkoxy, C2-6Alkynyl or-NHC1-4The substituent of alkyl is substituted, and described heterocycle contains 1 to 3 The individual hetero atom selected from N, O or S；
M is selected from 0,1 or 2.
2. compound according to claim 1 or its stereoisomer, solvate, pharmaceutically acceptable salt or common Crystalline substance, wherein：
RaSelected from F, Cl, Br, CF3、C1-6Alkyl, C1-6Alkoxy, C3-8Carbocyclic ring or 3 to 8 circle heterocycles, described alkyl, alkoxy, Carbocyclic ring or heterocycle are optionally further selected from F, Cl, Br, CF by 0 to 43, cyano group, C1-4Alkyl or C1-4The substituent institute of alkoxy Substitution, and described heterocycle contains 1 to 3 hetero atom for being selected from N, O or S；
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；
R3Selected from H, C1-6Alkyl ,-(CH2)m-C3-6Carbocyclic ring ,-(CH2) m-3 is to 6 circle heterocycles ,-(CH2)m-OC3-6Carbocyclic ring or-(CH2) M-O-3 is optionally further selected from F, Cl, Br, CF to 6 circle heterocycles, described alkyl, carbocyclic ring or heterocycle by 0 to 43, cyano group, Amino, C1-4Alkyl, C1-4Alkoxy, C2-6Alkynyl or-NHC1-4Alkyl substituent is substituted, and described heterocycle contains 1 to 3 Hetero atom selected from N, O or S.
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；
M is selected from methylene, ethylidene, propylidene or butylidene, and described methylene, ethylidene, propylidene or butylidene are optional Further by 0 to 4 RaSubstitution；
RaSelected from F, Cl, Br, CF3, methyl, ethyl, propyl group, isopropyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
Alternatively, two RaCoupled atom forms cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl together；
X is selected from-CRbRc- ,-O- or-S-；
Condition is, when X is selected from-CRbRc- when, M is at least by 1 RaSubstitution；
Rb、RcIt is independently selected from H, methyl or ethyl；
R3Selected from H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, phenyl ,-CH2- phenyl or- CH2O- phenyl, and described phenyl is optionally further selected from F, Cl, Br, CF by 0 to 43, it is cyano group, methyl, ethyl, propyl group, different Propyl group, methoxy or ethoxy substituent are substituted.
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 (6)

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CN107652239A (en) * 2017-02-24 2018-02-02 四川大学华西医院 N substituted imidazoles carboxylic acid ester compound, Preparation method and use
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CN107652239B (en) * 2017-02-24 2020-08-04 四川大学华西医院 N-substituted imidazole carboxylic ester compound, preparation method and application
WO2018153228A1 (en) * 2017-02-24 2018-08-30 四川大学华西医院 N-substituted imidazole carboxylate compound, preparation method and use
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CN107652239A (en) * 2017-02-24 2018-02-02 四川大学华西医院 N substituted imidazoles carboxylic acid ester compound, Preparation method and use
CN109748876A (en) * 2017-11-02 2019-05-14 北京蓝丹医药科技有限公司 Etomidate derivative and preparation method thereof
CN109776509A (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
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JP2021512132A (en) * 2018-01-30 2021-05-13 チェンドゥ・エムエフエス・ファーマ・カンパニー・リミテッド Substituted imidazole carboxylic acid ester derivative and its use
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CN109776511A (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
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CN110003188A (en) * 2019-03-27 2019-07-12 成都安诺晨创医药科技有限公司 Substituted azole formate ester derivative and application thereof
CN112079783A (en) * 2019-06-14 2020-12-15 四川大学华西医院 Nitrogen-containing heterocyclic compound and preparation method and application thereof
CN112079783B (en) * 2019-06-14 2022-06-10 四川大学华西医院 Nitrogen-containing heterocyclic compound and preparation method 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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