CN101412711A - Carbamate derivatives and use thereof in medicine - Google Patents

Carbamate derivatives and use thereof in medicine Download PDF

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Publication number
CN101412711A
CN101412711A CNA2007101626421A CN200710162642A CN101412711A CN 101412711 A CN101412711 A CN 101412711A CN A2007101626421 A CNA2007101626421 A CN A2007101626421A CN 200710162642 A CN200710162642 A CN 200710162642A CN 101412711 A CN101412711 A CN 101412711A
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aryl
trifluoromethyl
methyl
reaction
pyrroles
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邓炳初
别平彦
钱广桃
杨式波
郝向阳
钟峥嵘
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Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to PCT/CN2008/001593 priority patent/WO2009062371A1/en
Publication of CN101412711A publication Critical patent/CN101412711A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
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    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms

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Abstract

The invention relates to novel five-membered and six-membered ring carbamate derivatives as shown in the general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, application thereof as therapeutic agents in particular as cholesterol ester transfer protein inhibitors, wherein the definition of each substituent in the general formula (I) is identical with that in the instruction.

Description

Carbamate derivates and in pharmaceutically application
Technical field
The present invention relates to a class new five yuan and six-ring carbamate derivates, its preparation method and the pharmaceutical composition that contains this derivative with and as therapeutical agent particularly as the purposes of cholestery ester transfer protein inhibitors.
Background technology
The high serum level of hypercholesterolemia, particularly low density ester gp cholesterol demonstrates the danger of arteriosclerosis disease.At present, atherosclerosis and the coronary heart disease (CHD), apoplexy and the Peripheral blood vessel disease that cause have become the industrialized huge obstruction in the health care system whole world.Only in the U.S., nearly 1,300 ten thousand people suffer from coronary heart disease (CHD), and annual therefore dead number surpasses 500,000, and this numeral is still in continuous growth.Although people attempt treating dyslipidemia by reasonable diet and pharmacotherapy, coronary heart disease (CHD) is total still become the modal cause of death of the U.S. with the ratio that accounts for death toll 44%, and 53% all being caused by atherosclerosis wherein.
Atherosclerotic generation is to be closely related with its blood lipid level.High-caliber low-density lipoprotein (LDL) cholesterol is the dyslipidemia form of generally acknowledging, but it causes unique factor of coronary heart disease (CHD) anything but.Low-level high-density lipoprotein (HDL) (HDL) cholesterol also is to cause the hazard factor (Gordon of coronary heart disease (CHD), D.J., et al., ＂ High-density Lipoprotein Cholesterol andCardiovascular Disease ＂, Circulation, (1989), 79:8-15).Rising low-density lipoprotein (LDL) cholesterol levels will increase atherosclerotic risk level.Recently, prevailing disease association studies show that reducing high-density lipoprotein (HDL) (HDL) cholesterol levels also will increase atherosclerotic risk level.
As everyone knows, increase the HDL cholesterol levels and can prevent or treat arteriosclerotic disease.Yet, do not have high density lipoprotein increasing (HDL) medicine preferably at present.3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitor and chlorine shellfish spy can only partly improve high-density lipoprotein (HDL) (HDL) cholesterol levels, and nicotinic acid derivates can obviously increase HDL, but serious problem of resistance is arranged.Therefore, obviously high density lipoprotein increasing (HDL) cholesterol levels and tolerance excellent drug stop atherosclerosis to need some.
The metabolism of lipoprotein levels control is a complexity that relates to multiple factor and dynamic process.A lot of ester gps in patient's katabolism regulation mechanism are related.In them, cholesteryl ester transfer protein (cholesteryl ester transfer protein, CETP) be an important lipoprotein levels metabolism controlling factor, it is that a kind of appearing at has 70 in human and other animal plasmas, 000 daltonian glycoprotein is responsible for transmitting cholesteryl ester, triglyceride level and some phosphatide between the plasma lipoprotein particulate.Above-mentioned lipoprotein particulate comprises high-density lipoprotein (HDL) (HDL), low-density lipoprotein (LDL), and vldl (VLDL) and breast waste particulate.CETP can transfer to the apoB that contains lipoprotein from high-density lipoprotein (HDL) (HDL) by the catalysis cholesteryl ester, especially transfer to (Hesler in the vldl, C.B., et.al. (1987) Purification andcharacterization of human plasma cholesteryl ester transfer protein.J.Biol.Chem.262 (5), 2275-2282).Under physiological condition, clean reaction is one and transfers to permutoid reaction that high-density lipoprotein (HDL) (HDL) simultaneously from high-density lipoprotein (HDL) (HDL) be transported to cholesteryl ester apoB lipoprotein with triglyceride level from apoB lipoprotein by CETP.Some researchs have pointed out that clearly the plasma concentration of high-density lipoprotein (HDL) (HDL) cholesterol is relative with the CETP activity.(Inazu, A., et.al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr.Opin.Lipidol.11 (4), 389-396), infer thus: pharmaceutically to CETP fat transfer activity suppress to increase high-density lipoprotein (HDL) (HDL) cholesterol levels reduces low-density lipoprotein (LDL) simultaneously thus level is favourable to human body.
The clinical test results of CETP inhibitor shows that human body can utilize this mechanism to improve circulation high-density lipoprotein (HDL) (HDL) cholesterol levels.One studies show that, with every day 900 milligrams dosage use the CETP inhibitor, 4 week back high-density lipoprotein (HDL) (HDL) cholesterol increased by 34% (Circulation, 2002,105:2159).In the research of another CETP inhibitor, adopted each 120 milligrams of every days of 2 these maximum dose level administrations, 4 week back high-density lipoprotein (HDL) (HDL) cholesterol improved 106% (N.Engl.J.Med., 2004,350:1505-15).Improve this mode of blood plasma middle-high density lipoprotein (HDL) cholesterol levels by inhibition CETP activity and may bring this Gospel of atherosclerosis to people.Although show that in the rabbit body CETP inhibitor has antiatherogenic effect, this point is not confirmed in human body as yet, and (Nature 2000,406:203-2071).
The new compound that suppresses CETP is being studied always by some drugmakers, yet does not have the listing of CETP inhibitor at present.Need find safer and more effective newtype drug compound, treat the lipid disease by single drug or with the other drug coupling.Based on this, the invention describes the preparation method of a series of five yuan and six-ring carbamate derivates and in pharmaceutically application, especially as the CETP inhibitor in pharmaceutically application.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide new five yuan and the six-ring amino formate compounds shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt, and meta-bolites and metabolic precursor thereof or prodrug.
Figure A200710162642D00131
Wherein:
R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more alkyl, aryl, trifluoromethyl or Heterocyclylalkyl;
R 3Be selected from hydrogen atom, alkyl, aryl, aralkyl or heteroaryl, wherein alkyl, aryl, aralkyl or heteroaryl are further replaced by one or more halogens or trifluoromethyl;
R 4Be selected from hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl or-C (=O) OR 7
R 5Be selected from hydrogen atom, halogen, alkyl, cycloalkyl, trifluoromethyl or-C (=O) OR 7
R 6Be selected from hydrogen atom, halogen, alkyl, cycloalkyl, trifluoromethyl, Heterocyclylalkyl, aryl, aralkyl or heteroaryl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters;
R 7Be selected from hydrogen atom, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl;
N is 1～2.
Typical compound of the present invention includes but not limited to:
Figure A200710162642D00141
Figure A200710162642D00151
Figure A200710162642D00161
Figure A200710162642D00171
Figure A200710162642D00181
In another aspect of the present invention, be a kind of pharmaceutical composition, contain five yuan and six-ring carbamate derivates or its pharmacy acceptable salt, carrier or vehicle of general formula (I).
In another aspect of the present invention, what relate to is cetp activity inhibitors, comprises the prevention of hyperlipidaemia or the activity of therapeutical agent and atherosclerotic prevention or therapeutical agent.
In another aspect of the present invention, what relate to is cetp activity inhibitors, comprises prevention or therapeutical agent and the atherosclerotic prevention or the purposes of therapeutical agent in the medicine of treatment painstaking effort tubing diseases associated of hyperlipidaemia.
In another aspect of the present invention, what relate to is cetp activity inhibitors, comprises the prevention of hyperlipidaemia or the preparation method of therapeutical agent and atherosclerotic prevention or therapeutical agent, may further comprise the steps:
(1) under the ice bath, 4,4, the reactant aqueous solution of 4-three fluoro-3-carbonyl-ethyl butyrates and Sodium Nitrite obtains 4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates, again with 3-carbonyl-butyric acid-tert-butyl ester in Glacial acetic acid under the heating condition zinc powder reduction obtain cyclization product trifluoromethyl pyrpole diester;
Under argon shield, the trifluoromethyl pyrpole diester reduces under tetrahydrofuran (THF) and Li-Al hydrogen room temperature and obtains the trifluoromethyl pyrpole alcohol ester;
Figure A200710162642D00183
Under the room temperature, the trifluoromethyl pyrpole alcohol ester obtains the trifluoromethyl pyrpole aldehydo-ester with the pyridinium chloro-chromate oxidation in methylene dichloride.
Figure A200710162642D00191
(2) under the room temperature, the trifluoromethyl pyrpole diester obtains the trifluoromethyl pyrpole acid esters with trifluoroacetic acid selective reduction reaction in methylene dichloride;
The trifluoromethyl pyrpole acid esters obtains the methylpyrrole ester that halogen replaces with the halogen reaction under heating condition;
Figure A200710162642D00193
Under the methylpyrrole ester that halogen replaces heat in tetrahydrofuran (THF)/water/acetic acid with ceric ammonium nitrate generation oxidizing reaction, pyrroles's aldehydo-ester of halogen replacement;
Figure A200710162642D00194
Wherein X is a halogen.
(3) under the room temperature, the trifluoromethyl pyrpole aldehydo-ester obtains trifluoromethyl pyrpole aldehydic acid with trifluoroacetic acid generation reduction reaction in methylene dichloride;
Figure A200710162642D00195
Trifluoromethyl pyrpole aldehydic acid obtains halo trifluoromethyl pyrpole aldehyde with the potassium halide reaction under heating condition;
Figure A200710162642D00196
Wherein X is a halogen.
(4) trifluoromethyl pyrpole aldehydic acid obtains trifluoromethyl pyrpole aldehyde with copper chromite generation reduction reaction under heating condition.
Figure A200710162642D00201
(5) under the nitrogen atmosphere, the SuZuKi linked reaction takes place and obtains the aryl-pyrrolidine aldehydo-ester in the boric acid that pyrroles's aldehydo-ester that halogen replaces and aryl replace;
Figure A200710162642D00202
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
(6) cryosel is bathed down, replaces the nitrated nitro substitution compound that obtains under the aldehyde room temperature;
Figure A200710162642D00203
Under the room temperature, the nitro-compound hydro-reduction obtains amino substitution compound.
Figure A200710162642D00204
(7) under the nitrogen atmosphere ice bath, (S) benzyloxy carbon back alanine obtains the amino substitution compound of methoxyl group of (S) configuration with methoxyl group-methylamine generation reductive amination process in tetrahydrofuran (THF);
Figure A200710162642D00205
Under the nitrogen atmosphere ice bath, (S) amino substitution compound of the methoxyl group of configuration and aryl bromide linked reaction obtain (S) configuration aryl substitution compound;
Figure A200710162642D00206
Under the room temperature, (S) configuration aryl substitution compound and Pd/C reduction reaction obtain (1R, aryl substituted propanol 2S);
Wherein: R 1-R 6As defined above, Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
(8) under the room temperature, aryl formaldehyde and sodium hydride, Trimethylsulfoxonium Iodide generation ring-closure reaction obtains the aryl rings oxidative ethane;
Figure A200710162642D00212
The aryl rings oxidative ethane in tetrahydrofuran (THF) with the cyano group trimethyl silane, the tetrabutylammonium fluoride ring-opening reaction obtains the aryl propionitrile that hydroxyl replaces;
Figure A200710162642D00213
Under the nitrogen atmosphere, aryl propionitrile that hydroxyl replaces and the reaction of the tetrahydrofuran solution of borine obtain the aryl propyl amine that hydroxyl replaces;
Figure A200710162642D00214
Wherein Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
(9) under the room temperature, the invention step 6 in the summary of the invention, 7,8, with each polysubstituted pyrroles's aldehyde, reduction amination obtains polysubstituted pyrroles's methylamine;
Figure A200710162642D00215
Under the argon atmospher, polysubstituted pyrroles's methylamine and triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan and six-ring carbamate;
Figure A200710162642D00222
Under the nitrogen atmosphere, five yuan of general formulas and six-ring carbamate obtain five yuan and the six-ring carbamate compounds that the target compound N shown in the general formula (1) replaces with the haloalkane reaction in tetrahydrofuran (THF) with after the tetrahydrofuran solution effect of sodium hydride;
Figure A200710162642D00223
Wherein, R 1-R 6As defined above, Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
(10) pyrroles's aldehydo-ester of replacing of halogen in methyl alcohol with oxammonium hydrochloride, the sodium-acetate reflux obtains polysubstituted hygron ester;
Figure A200710162642D00231
Under the room temperature, the Arylacetic acids that hydroxyl replaces in benzene with methyl alcohol, the TMSA reaction obtains the aryl ethyl ester that hydroxyl replaces;
Figure A200710162642D00232
Under the room temperature, the aryl ethyl ester that hydroxyl replaces in methylene dichloride with carbon tetrabromide, triphenylphosphine obtains the aryl ethyl ester of bromo;
Figure A200710162642D00233
Polysubstituted hygron ester obtains the hygron diester of aryl replacement with the aryl ethyl ester reaction of bromo in tetrahydrofuran (THF);
Figure A200710162642D00234
The hygron diester that aryl replaces obtains the hygron alcohol ester of aryl replacement with the tetrahydrofuran solution reduction reaction of Li-Al hydrogen in tetrahydrofuran (THF);
Under the nitrogen protection, the hygron alcohol ester that aryl replaces in methylene dichloride with triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan and six-ring carbamate compounds;
Figure A200710162642D00236
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
Further, the present invention relates to a kind of pharmaceutical composition, it comprises compound of the present invention, its prodrug or its pharmacy acceptable salt of medicine effective dose, and pharmaceutically acceptable carrier.
On the other hand, the present invention relates to The compounds of this invention, the preparation method of its prodrug or its pharmacy acceptable salt, this method may further comprise the steps:
Under the room temperature, polysubstituted pyrroles's aldehyde, reduction amination obtain polysubstituted pyrroles's methylamine;
Figure A200710162642D00241
Under the argon atmospher, polysubstituted pyrroles's methylamine and triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan or six-ring carbamate respectively;
Figure A200710162642D00242
Under the nitrogen atmosphere, five yuan of general formulas or six-ring carbamate obtain five yuan or the six-ring carbamate compounds that the target compound N shown in the general formula (1) replaces with the haloalkane reaction in tetrahydrofuran (THF) with after the tetrahydrofuran solution effect of sodium hydride;
Figure A200710162642D00251
Wherein: R 1-R 6As defined above, Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
On the other hand, the present invention relates to The compounds of this invention, the preparation method of its prodrug or its pharmacy acceptable salt, this method may further comprise the steps:
Pyrroles's aldehydo-ester that halogen replaces in methyl alcohol with oxammonium hydrochloride, the sodium-acetate reflux obtains polysubstituted hygron ester;
Figure A200710162642D00252
Under the room temperature, the Arylacetic acids that hydroxyl replaces in benzene with methyl alcohol, the TMSA reaction obtains the aryl ethyl ester that hydroxyl replaces;
Figure A200710162642D00253
Under the room temperature, the aryl ethyl ester that hydroxyl replaces in methylene dichloride with carbon tetrabromide, triphenylphosphine obtains the aryl ethyl ester of bromo;
Figure A200710162642D00254
Polysubstituted hygron ester obtains the hygron diester of aryl replacement with the aryl ethyl ester reaction of bromo in tetrahydrofuran (THF);
Figure A200710162642D00255
The hygron diester that aryl replaces obtains the hygron alcohol ester of aryl replacement with the tetrahydrofuran solution reduction reaction of Li-Al hydrogen in tetrahydrofuran (THF);
Figure A200710162642D00261
Under the nitrogen protection, the hygron alcohol ester that aryl replaces in methylene dichloride with triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan and six-ring carbamate compounds;
Figure A200710162642D00262
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
On the other hand, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure
This intermediates preparation may further comprise the steps:
Under the ice bath, 4,4, the reactant aqueous solution of 4-three fluoro-3-carbonyl-ethyl butyrates and Sodium Nitrite obtains 4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates, again with 3-carbonyl-butyric acid-tert-butyl ester in Glacial acetic acid under the heating condition zinc powder reduction obtain cyclization product trifluoromethyl pyrpole diester;
Under argon shield, the trifluoromethyl pyrpole diester reduces under tetrahydrofuran (THF) and Li-Al hydrogen room temperature and obtains the trifluoromethyl pyrpole alcohol ester;
Figure A200710162642D00265
Under the room temperature, the trifluoromethyl pyrpole alcohol ester obtains the trifluoromethyl pyrpole aldehydo-ester with the pyridinium chloro-chromate oxidation in methylene dichloride.
Figure A200710162642D00271
Further, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00272
Wherein X is a halogen.
This intermediates preparation may further comprise the steps:
Under the room temperature, the trifluoromethyl pyrpole diester obtains the trifluoromethyl pyrpole acid esters with trifluoroacetic acid selective reduction reaction in methylene dichloride;
The trifluoromethyl pyrpole acid esters obtains the methylpyrrole ester that halogen replaces with the halogen reaction under heating condition;
Figure A200710162642D00274
Under the methylpyrrole ester that halogen replaces heat in tetrahydrofuran (THF)/water/acetic acid with ceric ammonium nitrate generation oxidizing reaction, pyrroles's aldehydo-ester of halogen replacement;
Figure A200710162642D00275
Wherein X is a halogen.
Further, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00281
Wherein X is a halogen.
This intermediates preparation may further comprise the steps:
Under the room temperature, the trifluoromethyl pyrpole aldehydo-ester obtains trifluoromethyl pyrpole aldehydic acid with trifluoroacetic acid generation reduction reaction in methylene dichloride;
Trifluoromethyl pyrpole aldehydic acid obtains halo trifluoromethyl pyrpole aldehyde with the potassium halide reaction under heating condition;
Figure A200710162642D00283
Wherein X is a halogen.
Again on the one hand, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00284
This intermediates preparation may further comprise the steps:
Trifluoromethyl pyrpole aldehydic acid obtains trifluoromethyl pyrpole aldehyde with copper chromite generation reduction reaction under heating condition
Figure A200710162642D00285
Further, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00291
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
This intermediates preparation may further comprise the steps:
Under the nitrogen atmosphere, the SuZuKi linked reaction takes place and obtains the aryl-pyrrolidine aldehydo-ester in the boric acid that pyrroles's aldehydo-ester that halogen replaces and aryl replace;
Figure A200710162642D00292
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
On the other hand, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00293
Wherein, R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, trifluoromethyl or Heterocyclylalkyl.
This intermediates preparation may further comprise the steps:
Cryosel is bathed down, replaces the nitrated nitro substitution compound that obtains under the aldehyde room temperature;
Figure A200710162642D00294
Under the room temperature, the nitro-compound hydro-reduction obtains amino substitution compound
Wherein, R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, trifluoromethyl or Heterocyclylalkyl.
Further, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00301
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
This intermediates preparation may further comprise the steps:
Under the nitrogen atmosphere ice bath, (S) benzyloxy carbon back alanine obtains the amino substitution compound of methoxyl group of (S) configuration with methoxyl group-methylamine generation reductive amination process in tetrahydrofuran (THF);
Figure A200710162642D00302
Under the nitrogen atmosphere ice bath, (S) amino substitution compound of the methoxyl group of configuration and aryl bromide linked reaction obtain (S) configuration aryl substitution compound;
Figure A200710162642D00303
Under the room temperature, (S) configuration aryl substitution compound and Pd/C reduction reaction obtain (1R, aryl substituted propanol 2S);
Figure A200710162642D00304
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
Further, the present invention relates to the intermediate of synthetic The compounds of this invention, it is represented by following general structure:
Figure A200710162642D00305
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
This intermediates preparation may further comprise the steps:
Under the room temperature, aryl formaldehyde and sodium hydride, Trimethylsulfoxonium Iodide generation ring-closure reaction obtains the aryl rings oxidative ethane;
Figure A200710162642D00311
The aryl rings oxidative ethane in tetrahydrofuran (THF) with the cyano group trimethyl silane, the tetrabutylammonium fluoride ring-opening reaction obtains the aryl propionitrile that hydroxyl replaces;
Figure A200710162642D00312
Under the nitrogen atmosphere, aryl propionitrile that hydroxyl replaces and the reaction of the tetrahydrofuran solution of borine obtain the aryl propyl amine that hydroxyl replaces;
Figure A200710162642D00313
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
Further, the present invention relates to contain general formula 1 compound of the present invention, the pharmaceutical composition of its salt or its pharmacologically acceptable salts.
Further, the present invention relates to the present composition in the purposes of preparation in the cetp activity inhibitors, the present composition in the medicine of preparation prevention or treatment hyperlipidaemia purposes and the present composition in the preparation prevention or treat purposes in the atherosclerotic medicine.
In other words, the present invention relates to The compounds of this invention in the purposes of preparation in the cetp activity inhibitors, The compounds of this invention in the medicine of preparation prevention or treatment hyperlipidaemia purposes and The compounds of this invention in the preparation prevention or treat purposes in the atherosclerotic medicine.
At last, the present invention relates to a kind of method that suppresses cetp activity, comprise to the patient and use the compound shown in the formula 1, its preceding drug compound or its pharmacy acceptable salt.In addition, the invention still further relates to the method for a kind of prevention or treatment hyperlipidaemia, comprise to the patient and use the compound shown in the formula 1, its preceding drug compound or its pharmacy acceptable salt, and the present invention relates to a kind of atherosclerotic method of preventing or treat, comprise to the patient and use the compound shown in the formula 1, its preceding drug compound or its pharmacy acceptable salt.
Detailed description of the invention
Unless the phase counter-statement is arranged, the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl or-C (=O) OR 7
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.Representative example includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from into halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl or-C (=O) OR 7
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan or 6 yuan/6 yuan fused rings of carbon or encircles fused rings (" condensing " ring system mean that each ring in the system share a pair of carbon atom that adjoins with other rings in the system) group more, wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.The example of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenes, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.Cycloalkyl can be to replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, aryl, heteroaryl, Heterocyclylalkyl or-C (=O) OR 7
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, be independently selected from into alkyl, halogen, three alkylhalide groups, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, heteroaryl, Heterocyclylalkyl or-C (=O) OR 7
" aryl " refers to have the group of at least one aromatic ring structure, promptly has the aromatic ring of conjugated πDian Zi system, comprises isocyclic aryl, heteroaryl and dibenzyl.Alkynyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, nitro, cyano group, lower alkoxy, alkyl, heteroaryl, Heterocyclylalkyl or-C (=O) OR 7
" heteroaryl " refers to have 1 to 3 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur and nitrogen.Described ring can be 5 yuan or 6 yuan of rings.The heterocyclic aryl examples of groups comprises furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl etc.Heteroaryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from halogen, three alkylhalide groups, hydroxyl, nitro, cyano group, lower alkoxy, alkyl, aryl, Heterocyclylalkyl or-C (=O) OR 7
" Heterocyclylalkyl " refers to monocycle or condensed ring group, in ring, has 5 to 9 annular atomses, and one of them or two annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is an integer 0 to 2), and all the other annular atomses are carbon.These rings can also have one or more pairs of keys.But, these rings do not have the πDian Zi system of total conjugated.Unsubstituted Heterocyclylalkyl include but not limited to pyrrolidyl, piperidino-(1-position only), Piperazino, morpholinyl, thio-morpholinyl, high piperazine its etc., Heterocyclylalkyl can be that replace or unsubstituted.Alkynyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, aryl, aryloxy, heteroaryl, Heterocyclylalkyl, carboxyl or-C (=O) OR 7
" halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.
" trifluoromethyl " refers to-CF 3
" carboxylic acid " refers to (alkyl) C (=O) OH.
" carboxylicesters " refers to (alkyl) C (=O) O R 8, R wherein 8It is alkyl.
" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically acceptable carrier and vehicle for example.The purpose of pharmaceutical composition is to promote the administration of compound to organism.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of general formula of the present invention (I) described five yuan and six-ring carbamate derivates or its salt may further comprise the steps:
(1)
Under the ice bath, 4,4, the reactant aqueous solution of 4-three fluoro-3-carbonyl-ethyl butyrates and Sodium Nitrite obtains 4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates, again with 3-carbonyl-butyric acid-tert-butyl ester in Glacial acetic acid under the heating condition zinc powder reduction obtain cyclization product trifluoromethyl pyrpole diester; Under argon shield, the trifluoromethyl pyrpole diester reduces under tetrahydrofuran (THF) and Li-Al hydrogen room temperature and obtains the trifluoromethyl pyrpole alcohol ester; Under the room temperature, the trifluoromethyl pyrpole alcohol ester obtains the trifluoromethyl pyrpole aldehydo-ester with the pyridinium chloro-chromate oxidation in methylene dichloride.
(2)
Figure A200710162642D00332
Under the room temperature, the trifluoromethyl pyrpole diester obtains the trifluoromethyl pyrpole acid esters with trifluoroacetic acid selective reduction reaction in methylene dichloride; The trifluoromethyl pyrpole acid esters obtains the methylpyrrole ester that halogen replaces with the halogen reaction under heating condition; Under the methylpyrrole ester that halogen replaces heat in tetrahydrofuran (THF)/water/acetic acid with ceric ammonium nitrate generation oxidizing reaction, pyrroles's aldehydo-ester of halogen replacement.
(3)
Figure A200710162642D00341
Under the room temperature, the trifluoromethyl pyrpole aldehydo-ester obtains trifluoromethyl pyrpole aldehydic acid with trifluoroacetic acid generation reduction reaction in methylene dichloride; Trifluoromethyl pyrpole aldehydic acid obtains halo trifluoromethyl pyrpole aldehyde with the potassium halide reaction under heating condition.
(4)
Figure A200710162642D00342
Trifluoromethyl pyrpole aldehydic acid obtains trifluoromethyl pyrpole aldehyde with copper chromite generation reduction reaction under heating condition.
(5)
Figure A200710162642D00343
Under the nitrogen atmosphere, the SuZuKi linked reaction takes place and obtains the aryl-pyrrolidine aldehydo-ester in the pyrroles's aldehydo-ester that halogen replaces and the boric acid of replacement.
(6)
Figure A200710162642D00344
Cryosel is bathed down, replaces the nitrated nitro substitution compound that obtains under the aldehyde room temperature; Under the room temperature, the nitro-compound hydro-reduction obtains amino substitution compound.
Figure A200710162642D00345
Under the nitrogen atmosphere ice bath, (S) benzyloxy carbon back alanine obtains the amino substitution compound of methoxyl group of (S) configuration with methoxyl group-methylamine generation reductive amination process in tetrahydrofuran (THF); Under the nitrogen atmosphere ice bath, (S) amino substitution compound of the methoxyl group of configuration and aryl bromide linked reaction obtain (S) configuration aryl substitution compound; Under the room temperature, (S) configuration aryl substitution compound and Pd/C reduction reaction obtain (1R, aryl substituted propanol 2S).
(8)
Figure A200710162642D00351
Under the room temperature, aryl formaldehyde and sodium hydride, Trimethylsulfoxonium Iodide generation ring-closure reaction obtains the aryl rings oxidative ethane; The aryl rings oxidative ethane in tetrahydrofuran (THF) with the cyano group trimethyl silane, the tetrabutylammonium fluoride ring-opening reaction obtains the aryl propionitrile that hydroxyl replaces; Under the nitrogen atmosphere, aryl propionitrile that hydroxyl replaces and the reaction of the tetrahydrofuran solution of borine obtain the aryl propyl amine that hydroxyl replaces.
(9)
Figure A200710162642D00352
Under the room temperature, (6) of synthesis step, (7), and (8), with each polysubstituted pyrroles's aldehyde, reduction amination obtains polysubstituted pyrroles's methylamine; Under the argon atmospher, polysubstituted pyrroles's methylamine and triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan and six-ring carbamate; Under the nitrogen atmosphere, five yuan of general formulas and six-ring carbamate obtain five yuan and the six-ring carbamate compounds that the target compound N shown in the general formula (1) replaces with the haloalkane reaction in tetrahydrofuran (THF) with after the tetrahydrofuran solution effect of sodium hydride.
The invention still further relates to a kind of pharmaceutical composition, it comprise medicine effective quantity as described compound or its salt of general formula of the present invention (I) and pharmaceutically acceptable carrier.
The invention further relates to the purposes of compound or its salt shown in the general formula of the present invention (I) in the preparation cholestery ester transfer protein inhibitors.
Embodiment
The present invention is described further below in conjunction with embodiment, but these embodiment are not limiting scope of the present invention.
In following embodiment, the structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is to use the BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterochloroform (CDCl 3), deuterated dimethyl sulfoxide (DMSO-D 6), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph.
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
DMSO-D 6: deuterated dimethyl sulfoxide;
CDCl 3: deuterochloroform;
Preparation embodiment:
Embodiment 1
5-[5-(4-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The first step
4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates
Under the ice bath, in the round-bottomed flask of 100ml with 4,4, (3.822g 20.75mmol) is dissolved in the 6ml Glacial acetic acid 4-three fluoro-3-carbonyl-ethyl butyrate 1a, stir the aqueous solution (14.2g that dropwise drips Sodium Nitrite down, 20.75mmol be dissolved in the 4ml water), control reaction temperature is 0～5 ℃, after dropping finishes, add 1ml water again, in ice-water bath, react half an hour, remove ice-water bath, at room temperature continue about 3 hours of reaction, the point plate tracks to raw material and disappears, the point plate is followed the tracks of reaction and is finished, and obtains standard product 4,4, the solution of 4-three fluoro-2-oximido 3-carbonyl-ethyl butyrate 1b is directly cast single step reaction.
Second step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2, the 4 dicarboxylic acid-4-tert-butyl ester-2-ethyl ester
Is furnished with thermometer at one, in the three-necked flask of the 100ml of dropping funnel, with the 3-carbonyl-butyric acid-tert-butyl ester (3.28g, 20.75mmol) be dissolved in the Glacial acetic acid of 9.3ml, be warming up to 65 ℃ under stirring, weighing zinc powder (2.7g, 41.5mmol), drip the product 4,4 that previous step is reacted with dropping funnel, the solution of 4-three fluoro-2-oximido 3-carbonyl-ethyl butyrate 1b, add zinc powder several times, water-bath hierarchy of control temperature remains on about 75 ℃, reacts 2 hours, reduce the temperature to 40～45 ℃ then, reaction is spent the night.Point plate trace point plate is followed the tracks of reaction and is finished, and adds 30ml water and 20ml ethyl acetate in reaction solution, and stirring at room is after 15 minutes, with ethyl acetate (50ml * 3) extractive reaction liquid.Merge organic phase, water (50ml * 2), saturated sodium bicarbonate aqueous solution (50ml * 2), saturated sodium-chloride water solution (50ml * 2) washing successively, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, resistates obtains product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2,4 dicarboxylic acid-4-tert-butyl ester-2-ethyl ester 1c (3.66g), productive rate: 55% with toluene-normal hexane recrystallization.
MS?m/z(ESI)：320[M-1]
The 3rd step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-methylol-4-carboxylic acid the tert-butyl ester
Under the nitrogen atmosphere ice bath, with Li-Al hydrogen (0.39g, 10mmol) be dissolved in the tetrahydrofuran (THF) of 16ml, slowly be added dropwise to 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2,4-dicarboxyl acid 4-tert-butyl ester 2-ethyl ester 1c (3.214g, tetrahydrofuran (THF) 10mmol) (10ml) solution, after dripping, reaction solution rises to room temperature, and stirring reaction 1 hour, some plate are followed the tracks of reaction and finished.Slowly add less water cancellation reaction, add amount of ethyl acetate, filter, use the ethyl acetate washing leaching cake, with silica gel column chromatography separation and purification gained filter cake, obtain title product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-methylol-4-carboxylic acid tert-butyl ester 1d (0.765g), productive rate 50%.
MS?m/z(ESI)：278[M-1]
The 4th step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid the tert-butyl ester
With 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-methylol-4-carboxylic acid tert-butyl ester 1d (0.636g, 2.28mmol) be dissolved in the methylene dichloride of 10ml, the adding pyridinium chloro-chromate (736mg, 3.418mmol), stirring at room reaction 2 hours, the some plate is followed the tracks of reaction and is finished.Add 10ml acetone diluted reaction solution, filter the filter cake washing with acetone; filtrate decompression concentrates; with silica gel column chromatography separation and purification gained resistates, obtain title product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid tert-butyl ester 1e (0.359g), productive rate 57.1%.
MS?m/z(ESI)：276[M-1]
The 5th step
1-(4-trifluoromethyl-phenyl)-2-nitro-ethanol
Cryosel is bathed down, and (182mg, 1.046mmol), (223.5mg 3.06mmol) is dissolved in the 10ml dehydrated alcohol Nitromethane 99Min., is cooled to 0 ℃ with 4-trifluoromethyl-phenyl aldehyde 1f.Slowly be added dropwise to the sodium hydroxide solution of 44mg10%, stirred 2.5 hours, add the 63mg2% acetum, rise to room temperature, stirring reaction 1 hour, the some plate is followed the tracks of reaction and is finished.With ethyl acetate (30ml * 2), water (15ml * 1) extractive reaction liquid, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 1-(4-trifluoromethyl-phenyl)-2-nitro-ethanol 1g (169mg), productive rate 71.9%.
MS?m/z(ESI)：234[M-1]
The 6th step
1-(4-trifluoromethyl-phenyl)-2-amino-ethanol
In exsiccant hydrogenation bottle, with 1-(4-trifluoromethyl-phenyl)-2-nitro-ethanol 1g (1.584g 6.74mmol) is dissolved in the ethanol of 18ml, slowly adds 10%Pd/C (150mg), room temperature, the 0.3MPa stirring reaction spends the night, the some plate is followed the tracks of reaction and is finished.Use diatomite filtration, concentrating under reduced pressure filtrate.With silica gel column chromatography separation and purification gained resistates, obtain title product 1-(4-trifluoromethyl-phenyl)-2-amino-ethanol 1h (0.4g), productive rate 28.9%.
MS?m/z(ESI)：206[M+1]
The 7th step
5-{[2-(4-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
(0.19g, 0.927mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.234g 0.883mmol) is dissolved in the 5ml methylene dichloride 4-carboxylic acid tert-butyl ester 1e with 1-(4-trifluoromethyl-phenyl)-2-amino-ethanol 1h.Add 0.585g 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction are after 6 hours, and (stirring reaction spends the night for 100.2mg, methyl alcohol 2.65mmol) (1ml) solution, and the some plate is followed the tracks of reaction and finished to add sodium borohydride.Filter, in filtrate, add ethyl acetate (10ml * 1) extractive reaction liquid, with diluted hydrochloric acid aqueous solution (10ml * 1) washing organic layer, use saturated sodium-chloride water solution (20ml * 1) washing organic layer again, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[2-(4-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 1i (0.231g), productive rate 58.6%.
MS?m/z(ESI)：467[M+1]
The 8th step
5-[5-(4-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(4-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 1i (0.132g, 0.283mmol) be dissolved in the methylene dichloride of 5ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (84.1mg successively, 0.283mmol) methylene dichloride (2ml) solution, stir after 5 minutes, add the N of 0.05ml, dinethylformamide slowly adds N again, N-diisopropyl ethyl amine (107.9mg, 0.85mmol), stirring reaction 2 hours, some plate are followed the tracks of reaction and are finished.The dilute hydrochloric acid of 2ml is added in the reaction solution, after stirring half hour, the concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 1), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with silica gel column chromatography separation and purification gained resistates, obtains title product 5-[5-(4-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 1 (0.08g, white solid), productive rate 57.5%.
MS?m/z(ESI)：491[M-1]
1HNMR(400MHz，CDCl 3)δ?9.39(s，1H)，7.66(d，2H)，7.43(d，2H)，5.57(t，1H)，4.52(q，2H)，3.97～3.47(t，2H)，2.46(s，3H)，1.54(s，9H)。
Embodiment 2
5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00391
The first step
1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propyl alcohol
Cryosel is bathed down, and with 3, (5g, 0.021mmol), (5.76g 0.076mmol) is dissolved in the 100ml dehydrated alcohol nitroethane 5-di-trifluoromethyl-phenyl aldehyde 2a, is cooled to-0.2 ℃.The sodium hydroxide solution that slowly adds 8.8ml10% stirred 1 hour, rose to room temperature, and stirring reaction spends the night.The point plate is followed the tracks of reaction and is finished.Add the 66ml2% acetum, the concentrating under reduced pressure reaction solution.With ethyl acetate (50ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(3,5-di-trifluoromethyl-phenyl)-and 2-nitro-propyl alcohol 2b (6.66g), productive rate 100%.
MS?m/z(ESI)：316[M-1]
Second step
1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol
In exsiccant hydrogenation bottle, with 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propyl alcohol 2b (2.0g, 6.3mmol) be dissolved in the methanol of 2.2ml/5ml, slowly add 0.5g Pd/C, room temperature, 40Psi stirring reaction 21 hours, some plate are followed the tracks of reaction and are finished.Use diatomite filtration, concentrating under reduced pressure filtrate.In resistates, add 50ml water, it is 9～10 that strong aqua is regulated PH, with ethyl acetate (50ml * 3) extraction gained residual solution, merges organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol 2c (0.68g), productive rate 39.1%.
MS?m/z(ESI)：288[M+1]
The 3rd step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, (0.35g, 1.22mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.225g 0.813mmol) is dissolved in the 10ml methyl alcohol 4-carboxylic acid tert-butyl ester 1e with 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol 2c.Add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, after stirring reaction spent the night, (129mg, methyl alcohol 3.23mmol) (2ml) solution, stirring reaction were after 4 hours, and the some plate is followed the tracks of reaction and finished to add sodium borohydride.Filter, in filtrate, add 20ml water, concentrating under reduced pressure filtrate, remove methyl alcohol, with ethyl acetate (50ml * 3) extraction gained residual solution, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 2d (0.2g), productive rate 45%.
MS?m/z(ESI)：547[M-1]
The 4th step
5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 2d (0.16g, 0.292mmol) be dissolved in the methylene dichloride of 40ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (173.4mg successively, 0.584mmol) methylene dichloride (4ml) solution, N, N-diisopropyl ethyl amine (222.5mg, 1.752mmol), be warming up to 0 ℃, stirring reaction 1 hour is warming up to 15 ℃, stirring reaction 1 hour, some plate are followed the tracks of reaction and are finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 1), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 2 (Soviet Union's formula) (0.01g, white solid), productive rate 11.9%.
MS?m/z(ESI)：573[M-1]
1HNMR(400MHz，CDCl 3)δ?9.28(brs，1H)，7.90(s，1H)，7.75(s，2H)，5.10(d，1H)，4.61(d，1H)，4.48(d，1H)，3.66(m，1H)，2.46(s，3H)，1.53(s，9H)，1.48(d，3H).
Embodiment 3
(4S, 5R)-5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00411
The first step
5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Repeat the four-step reaction of the embodiment of the invention 2, use resulting compound 5-{[2-(3 among the embodiment 2,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 2d and triphosgene, N, the reaction of N-diisopropyl ethyl amine, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 3 (erythro form) (0.018g, white solid), productive rate 21.4%.
MS?m/z(ESI)：573[M-1]
1HNMR(400MHz，CDCl 3)δ?9.28(brs，1H)，7.91(s，1H)，7.73(s，2H)，5.71(d，1H)，4.63(d，1H)，4.44(d，1H)，4.22(m，1H)，2.48(s，3H)，1.55(s，9H)，0.82(d，3H).
Embodiment 4
5-[5-(2-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The first step
1-(2-trifluoromethyl-phenyl)-2-nitro-ethanol
Cryosel is bathed down, and (1.067g, 6.13mmol), (1.496g 2.45mmol) is dissolved in the 10ml dehydrated alcohol Nitromethane 99Min., is cooled to 0 ℃ with 2-trifluoromethyl-phenyl aldehyde 4a.Slowly be added dropwise to the sodium hydroxide solution of 258mg10%, stirred 1 hour, be added dropwise to 387mg 2% acetum, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.With ethyl acetate (30ml * 2), water (15ml * 1) extractive reaction liquid, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 1-(2-trifluoromethyl-phenyl)-2-nitro-ethanol 4b (1.371g), productive rate 93.5%.
MS?m/z(ESI)：234[M-1]
Second step
1-(2-trifluoromethyl-phenyl)-2-amino-ethanol
In exsiccant hydrogenation bottle, with 1-(2-trifluoromethyl-phenyl)-2-nitro-ethanol 4b (1.285g 5.47mmol) is dissolved in the ethanol of 15ml, slowly adds 480mg Pd/C, room temperature, the 40PSi stirring reaction spends the night, the some plate is followed the tracks of reaction and is finished.Use diatomite filtration, concentrating under reduced pressure filtrate obtains title product 1-(2-trifluoromethyl-phenyl)-2-amino-ethanol 4c (0.171g), productive rate 15.3%.
MS?m/z(ESI)：206[M+1]
The 3rd step
5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
(0.178g, 0.868mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.230g 0.868mmol) is dissolved in the 4ml methylene dichloride 4-carboxylic acid tert-butyl ester 1e with 1-(2-trifluoromethyl-phenyl)-2-amino-ethanol 4c.Add 0.550g 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction spends the night, and (stirring reaction 2 hours, some plate are followed the tracks of to react and are finished for 99mg, methyl alcohol 2.61mmol) (1ml) solution to add sodium borohydride.Add a small amount of dilute hydrochloric acid, stir after 15 minutes, filter, filtrate decompression concentrates.Add ethyl acetate (10ml * 1), water (3ml * 1) extraction gained resistates, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 4d, be directly used in next step reaction.
MS?m/z(ESI)：492[M+23]
The 4th step
5-[5-(2-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(2-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 4d (0.332g, 0.712mmol) be dissolved in the methylene dichloride of 8ml, temperature adds N less than 0 ℃ in keeping, N-diisopropyl ethyl amine (190mg, 1.5mmol) and a little sodium-chlor, slowly be added dropwise to triphosgene (148mg, methylene dichloride 0.5mmol) (2ml) solution again, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (20ml * 1), dilute hydrochloric acid (5ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (10ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with silica gel column chromatography separation and purification gained resistates, obtains title product 5-[5-(2-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 4 (0.118g, white solid), productive rate 33.7%.
MS?m/z(ESI)：491[M-1]
1HNMR(400MHz，CDCl 3)δ?9.73(s，1H)，7.69(d，1H)，7.63(m，2H)，7.62(m，1H)，5.91(t，1H)，4.53(q，2H)，3.97(t，1H)，3.33(t，1H)，2.47(s，3H)，1.54(s，9H).
Embodiment 5
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
The first step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2,4 dicarboxylic acid-2-ethyl ester
(0.95g 2.96mmol) is dissolved in the 15ml methylene dichloride, and (2.4ml, 32.3mmol), stirring at normal temperature 3 hours is put plate and followed the tracks of the reaction end to add trifluoroacetic acid with 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2,4 dicarboxylic acid-4-tert-butyl ester-2-ethyl ester 1c.Pressure reducing and steaming methylene dichloride and trifluoroacetic acid, the yellow solid of gained filters with ethyl acetate (50ml * 3) washing, collect solid, obtain standard product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2,4 dicarboxylic acid-2-ethyl ester 5a (0.586g, white solid), productive rate: 74.7%.
MS?m/z(ESI)：264[M-1]
Second step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester-4-iodine
With iodine (2.2g, 8.68mmol), potassiumiodide (5.76g, 34.72mmol), be dissolved in the water of 5ml, stir adding 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2 down, 4 dicarboxylic acid-2-ethyl ester 5a (2.3g, 8.68mmol), sodium bicarbonate (5.83g, 69.44mmol), the mixed solution of water (20ml), be heated to 90 ℃, emit a large amount of gases after for some time, and have a large amount of white solids to generate.Solution colour also becomes light yellowly from dark red, and the some plate is followed the tracks of reaction and finished, solid collected by filtration, and oven dry obtains standard product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester-4-iodine 5b (2.89g, white solid), productive rate: 96%.
MS?m/z(ESI)：346[M-1]
The 3rd step
5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
With compound 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester-4-iodine 5b (2.25g, 6.48mmol) be dissolved in tetrahydrofuran (THF)/water/acetic acid of 30ml/30ml/30ml, add ceric ammonium nitrate (14.57g, 26.57mmol), add and be warming up to 80 ℃, behind the stirring reaction 2 hours, the some plate is followed the tracks of reaction and is finished.With ethyl acetate (50ml * 3); water (30ml * 3) extractive reaction liquid; merge organic phase; use saturated sodium bicarbonate aqueous solution (50ml * 1), saturated sodium-chloride water solution (50ml * 1) washing organic layer respectively, the ethyl acetate layer anhydrous sodium sulfate drying filters; filtrate decompression concentrates; with silica gel column chromatography separation and purification gained resistates, obtain title product 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (1.38g), productive rate 59%.
MS?m/z(ESI)：362[M+1]
The 4th step
1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-propyl alcohol
Cryosel is bathed down, and with 3, (10g, 0.0413mmol), (9.2g 0.151mol) is dissolved in the 200ml dehydrated alcohol Nitromethane 99Min. 5-di-trifluoromethyl-phenyl aldehyde 2a, is cooled to-0.2 ℃.The sodium hydroxide solution that slowly adds 17.3ml10% keeps temperature less than 3 ℃, and stirring reaction 4 hours is added dropwise to the 130ml2% acetum, keeps temperature less than 5 ℃, rises to room temperature.Stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution.There are a large amount of yellow solids to occur, filter,, merge organic phase with ethyl acetate (50ml * 3) extraction gained filtrate, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, merge filter cake and obtain title product 1-(3,5-di-trifluoromethyl-phenyl)-and 2-nitro-ethanol 5d (10.65g, yellow solid), productive rate 85.2%.
MS?m/z(ESI)：302[M-1]
The 5th step
1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol
In exsiccant hydrogenation bottle, (10.4g 34.3mmol) is dissolved in the methyl alcohol of 100ml, slowly adds 2.5g Pd/C, room temperature, 30Psi stirring reaction 17 hours, some plate tracking reaction end with 1-(3,5-di-trifluoromethyl-phenyl)-2-nitro-ethanol 5d.Use diatomite filtration, concentrating under reduced pressure filtrate.With ethyl acetate/normal hexane recrystallization gained resistates, obtain title product 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (3.82g), productive rate 39.5%.
MS?m/z(ESI)：274[M+1]
The 6th step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid
Ethyl ester
With compound 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (1.38g; 3.82mmol); 1-(3; 5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (114mg; 0.416mmol) be dissolved in 1 of 3ml; in the 2-ethylene dichloride, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.Stir and slowly add sodium borohydride (63mg down, 1.662mmol), the stirring at room reaction is after 1 hour, with reacting liquid filtering, in filtrate, add the proper amount of sodium hydroxide dilute solution, with 50ml ethyl acetate extraction filtrate, the organic layer that obtains washs with sodium chloride aqueous solution (30ml * 1), and the ethyl acetate layer anhydrous sodium sulfate drying filters, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5f (0.091g, yellow solid), productive rate 81%.
MS?m/z(ESI)：491[M-1]
The 7th step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5f (0.091g, 0.185mmol), sodium-chlor (17mg) is dissolved in the methylene dichloride of 30ml, temperature slowly is added dropwise to triphosgene (53mg, methylene dichloride 0.178mmol) (10ml) solution successively less than 0 ℃ in keeping, N, (141mg 1.11mmol), is warming up to 0 ℃ to the N-diisopropyl ethyl amine, stirring reaction 2 hours, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 1), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5 (0.056g, white solid), productive rate 58.4%.
MS?m/z(ESI)：517[M-1]
1HNMR(400MHz，CDCl 3)δ?10.84(s，1H)，7.88(s，1H)，7.84(s，2H)，6.43(s，1H)，5.67(t，1H)，4.37～4.64(m，2H)，4.34(q，2H)，4.00(t，1H)，3.43(t，1H)，1.35(t，3H).
Embodiment 6
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00461
Figure A200710162642D00471
The first step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Under the nitrogen atmosphere; with 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (0.333g, 1.22mmol); 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.225g 0.812mmol) is dissolved in the 10ml ethylene dichloride 4-carboxylic acid tert-butyl ester 1e.After the stirring at room reaction was spent the night, (390mg, methyl alcohol 9.74mmol) (3ml) solution, stirring reaction were after 4 hours, and the some plate is followed the tracks of reaction and finished to add sodium borohydride.Filter, in filtrate, add 20ml water, have solid to separate out, leave standstill 1 hour after, filter, remove filter cake.Concentrating under reduced pressure filtrate, remove methyl alcohol, with ethyl acetate (50ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6a (0.23g), productive rate 53.1%.
MS?m/z(ESI)：533[M-1]
Second step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6a (0.23g, 0.43mmol) be dissolved in the methylene dichloride of 30ml, add sodium-chlor (17mg), temperature slowly is added dropwise to triphosgene (76.8mg successively less than 0 ℃ in keeping, 0.258mmol) methylene dichloride (10ml) solution, after stirring half hour, add N again, N-diisopropyl ethyl amine (327.7mg, 2.58mmol), keep temperature less than 0 ℃, stirring reaction rose to room temperature after 2 hours, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 3), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with ethyl acetate/normal hexane recrystallization gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 6 (0.13g, white solid), productive rate 54%.
MS?m/z(ESI)：559[M-1]
1HNMR(400MHz，CDCl 3)δ?9.50(brs，1H)，7.90(s，1H)，7.79(s，2H)，5.65(m，1H)，4.60(m，2H)，4.06(m，1H)，3.47(m，1H)，2.46(s，3H)，1.54(s，9H).
Embodiment 7
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl }-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Figure A200710162642D00481
The first step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, with compound 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (0.433g, 1.20mmol); (410mg 1.5mmol) is dissolved in 1 of 12ml to 2-amino-1-(3,5-di-trifluoromethyl-phenyl)-ethanol 5e; in the 2-ethylene dichloride, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction spends the night, slow adding sodium cyanoborohydride under stirring (190mg, 3mmol), the stirring at room reaction is spent the night, and end is reacted in the tracking of some plate.With reacting liquid filtering, in filtrate, add the proper amount of sodium hydroxide dilute solution, with 50ml ethyl acetate extraction filtrate, the organic layer that obtains washs with sodium chloride aqueous solution (30ml * 1), the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with n-hexane/ethyl acetate recrystallization gained resistates, concentrating under reduced pressure order liquid, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[2-(3 altogether, 5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 7a (0.085g, white solid), productive rate 81.4%.
MS?m/z(ESI)：617[M-1]
Second step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4 iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 7a (0.670g, 1.08mmol), sodium-chlor (100mg) is dissolved in the methylene dichloride of 100ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (321mg successively, 1.08mmol) methylene dichloride (50ml) solution, stirring reaction added N after 2 hours, N-diisopropyl ethyl amine (823mg, 6.48mmol) methylene dichloride (10ml) solution, stirring reaction rose to room temperature after 2 hours, and stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (150ml * 1), water (50ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 7 (0.3g, white solid), productive rate 43%.
MS?m/z(ESI)：643[M-1]
1HNMR(400MHz，CDCl 3)δ?10.85(s，1H)，7.90(s，1H)，7.83(s，2H)，5.67(t，1H)，4.69～4.49(m，2H)，4.37(q，2H)，4.09(t，1H)，3.51(t，1H)，1.37(t，3H).
Embodiment 8
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles
Figure A200710162642D00491
The first step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid
With 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid tert-butyl ester 1e (0.9g; 3.25mmol) be dissolved in the methylene dichloride of 15ml, add trifluoroacetic acid (4.12g, methylene dichloride 36.1mmol) (5ml) solution; the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution adds normal hexane in the resistates of gained, separate out solid, filters to obtain title product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid 8a (0.675g, white solid), productive rate 94%.
MS?m/z(ESI)：220[M-1]
Second step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-iodine
With potassiumiodide (775mg; 3.05mmol) be dissolved in the water of 2ml; add saleratus (2.05g; 23.4mmol) water (2ml) solution; add 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid 8a (0.675g again; 3.05mmol), temperature rising reflux stirring reaction 3 hours, some plate are followed the tracks of reaction and are finished.With ethyl acetate (50ml * 3); water (20ml * 1) extractive reaction liquid; merge organic phase; with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters; filtrate decompression concentrates; obtain title product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-iodine 8b (0.838g, yellow solid), productive rate 92.6%.
MS?m/z(ESI)：302[M-1]
The 3rd step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine
Under the nitrogen atmosphere, (1.13g, 4.15mmol), (0.838g 2.77mmol) is dissolved in the 80ml ethylene dichloride 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-iodine 8b with 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e.After the stirring at room reaction is spent the night, be warming up to 40 ℃, stirring reaction is chilled to room temperature after half an hour, and (1.33g 33.23mmol), adds 6ml methyl alcohol, and stirring reaction is after 2 hours, and the some plate is followed the tracks of reaction and finished slowly to add sodium borohydride.Concentrating under reduced pressure filtrate, with ethyl acetate (50ml * 3), water (30ml * 1) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 8c (1.25g), productive rate 80.6%.
MS?m/z(ESI)：559[M-1]
The 4th step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 8c (1.25g, 2.23mmol) be dissolved in the methylene dichloride of 200ml, add 100mg sodium-chlor, temperature slowly is added dropwise to triphosgene (662.3mg, methylene dichloride 0.892mmol) (50ml) solution successively less than 0 ℃ in keeping, N, (1.7g 13.38mmol), keeps temperature less than 0 ℃ to the N-diisopropyl ethyl amine, behind the stirring reaction 1 hour, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 3), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles 8 (0.32g, faint yellow solid), productive rate 46.5%.
MS?m/z(ESI)：459[M-1]
1HNMR(400MHz，CDCl 3)δ?9.14(brs，1H)，7.89(s，1H)，7.79(s，2H)，6.00(d，1H)，5.64(m，1H)，4.55(m，2H)，4.05(m，1H)，3.46(m，1H)，2.23(s，3H).
Embodiment 9
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine
Figure A200710162642D00511
The first step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 8c (0.095g, 0.17mmol) be dissolved in the methylene dichloride of 50ml, add sodium-chlor (10mg), temperature is less than 0 ℃ in keeping, add triphosgene (20.2mg rapidly, 0.068mmol) methylene dichloride (10ml) solution, add N again, and the N-diisopropyl ethyl amine (1300mg, 10.2mmol), the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (20ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 9 (0.077g, faint yellow solid), productive rate 75%.
MS?m/z(ESI)：585[M-1]
1HNMR(400MHz，CDCl 3)δ?9.48(brs，1H)，7.90(s，1H)，7.79(s，2H)，5.65(m，1H)，4.59(m，2H)，4.06(m，1H)，3.47(m，1H)，2.27(s，3H).
Embodiment 10
5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00521
The first step
1-(4-trifluoromethyl-phenyl)-2-nitro-propyl alcohol
Cryosel is bathed down, and (3.411g, 19.6mmol), (5.88g 78.4mmol) is dissolved in the 40ml dehydrated alcohol nitroethane, is cooled to 0 ℃ with 4-trifluoromethyl-phenyl aldehyde 1f.Slowly be added dropwise to the sodium hydroxide solution of 784mg 10%, stirred 1.5 hours, add 7.176g 2% acetum, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 2), water (15ml * 1) extraction gained resistates merges organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 1-(4-trifluoromethyl-phenyl)-2-nitro-propyl alcohol 10a (3.86g), productive rate 79%.
MS?m/z(ESI)：238[M-1]
Second step
1-(4-trifluoromethyl-phenyl)-2-amino-propanol
In exsiccant hydrogenation bottle, with 1-(4-trifluoromethyl-phenyl)-2-nitro-propyl alcohol 10a (1.558g 6.34mmol) is dissolved in the ethanol of 20ml, slowly adds 157mg Pd/C, room temperature, the 0.3MPa stirring reaction is after 3 hours, the some plate is followed the tracks of reaction and is finished.Use diatomite filtration, concentrating under reduced pressure filtrate.With silica gel column chromatography separation and purification gained resistates, obtain title product 1-(4-trifluoromethyl-phenyl)-2-amino-propanol 10b (0.612g), productive rate 44.6%.
MS?m/z(ESI)：220[M+1]
The 3rd step
5-{[2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
(0.262g, 1.2mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.315g 1.14mmol) is dissolved in the 5ml methylene dichloride 4-carboxylic acid tert-butyl ester 1e with 1-(4-trifluoromethyl-phenyl)-2-amino-propanol 10b.Add 0.805g 4
Figure A200710162642D0077151852QIETU
Molecular sieve, after stirring reaction spent the night, (stirring reaction 2 hours, some plate were followed the tracks of to react and are finished for 136mg, methyl alcohol 3.6mmol) (1ml) solution to add sodium borohydride.Filter concentrating under reduced pressure filtrate.With ethyl acetate (10ml * 1), dilute hydrochloric acid (10ml * 1) extraction gained resistates, use saturated sodium bicarbonate solution (20ml * 1) successively, saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 5-{[2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 10c (0.55g), be directly used in next step reaction.
MS?m/z(ESI)：481[M+1]
The 4th step
5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 10c (0.550g, 1.146mmol) be dissolved in the methylene dichloride of 5ml and the N of 0.05ml, in N-dimethyl-methane amide, add N, N-diisopropyl ethyl amine (437mg, 3.44mmol), temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (340mg successively, 1.14mmol) methylene dichloride (2ml) solution, stirring reaction 2 hours, some plate are followed the tracks of reaction and are finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 1), dilute hydrochloric acid (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, use saturated sodium bicarbonate solution (20ml * 1) successively, saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 10 (Soviet Union's formula) (0.2g, white solid), productive rate 44.6%.
MS?m/z(ESI)：505[M-1]
1HNMR(400MHz，CDCl 3)δ?9.32(s，1H)，7.66(d，2H)，7.42(d，2H)，5.03(d，1H)，4.49(q，2H)，3.62(m，1H)，2.46(s，3H)，1.54(s，9H)，1.42(d，3H).
Embodiment 11
5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The first step
5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Repeat the four-step reaction of the embodiment of the invention 10, use resulting compound 5-{[2-(4-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine among the embodiment 10]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 10c and triphosgene, N, the reaction of N-diisopropyl ethyl amine, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-[5-(4-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 11 (erythro form) (0.2g, white solid), productive rate 44.6%.
MS?m/z(ESI)：505[M-1]
1HNMR(400MHz，CDCl 3)δ?9.32(s，1H)，7.67(d，2H)，7.38(d，2H)，5.64(d，1H)，4.48(q，2H)，4.14(m，1H)，2.47(s，3H)，1.55(s，9H)，0.80(d，3H).
Embodiment 12
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl]-1,2-dimethyl-4-Trifluoromethyl-1 H-pyrroles
The first step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl]-1,2-dimethyl-4-Trifluoromethyl-1 H-pyrroles
The nitrogen atmosphere cryosel is bathed down, with sodium hydride (80mg, 3.33mmol) be dissolved in the tetrahydrofuran solution of 5ml, be cooled to 0 ℃, Dropwise 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles 8 (0.06g, 0.13mmol) tetrahydrofuran (THF) (20ml) solution, keep temperature less than 0 ℃, stirring reaction is warming up to 50 ℃ after half hour, be cooled to 5 ℃ at once, (37.5mg, 0.264mmol), stirring reaction spends the night to add methyl iodide immediately.The point plate is followed the tracks of reaction and is finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 3), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl]-1,2-dimethyl-4-Trifluoromethyl-1 H-pyrroles 12 (0.028g, faint yellow solid), productive rate 44%.
MS?m/z(ESI)：475[M+1]
1HNMR(400MHz，CDCl 3)δ?7.88(brs，1H)，7.75(s，2H)，6.06(s，1H)，5.59(m，1H)，4.69(d，1H)，4.56(d，1H)，3.93(m，1H)，3.53(s，3H)，3.30(m，1H)，2.20(s，3H).
Embodiment 13
5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
Figure A200710162642D00561
The first step
5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical
Copper chromite (2.0g) is dissolved in the quinoline of 2ml; being warming up to oil bath temperature is 200～205 ℃, and the system that is heated to adds 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid 8a (2g not after having gas to emit; 9.05mmol), there are a large amount of white cigarettes to emerge immediately.Keep this temperature, stirring reaction 30 minutes, some plate are followed the tracks of reaction and are finished.System is cooled to about 160 ℃; the ethyl acetate washing flask that adds 30ml; filter, the concentrating under reduced pressure elutriant is to 30ml, with dilute hydrochloric acid (10ml * 3) the washing organic phase of 2mol/L; use saturated sodium bicarbonate (10ml * 2) more successively; saturated sodium-chloride water solution (10ml * 2) washing, the ethyl acetate layer anhydrous sodium sulfate drying filters; filtrate decompression concentrates and obtains title product 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical 13a (0.823g), productive rate 57.4%.
MS?m/z(ESI)：176[M-1]
Second step
1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl
(0.33g, 1.15mmol), (0.136g 0.77mmol) is dissolved in the methylene dichloride of 10ml 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical 13a, adds a small amount of 4 with 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol 2c
Figure A200710162642D0077151852QIETU
Molecular sieve, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and is finished.Add sodium borohydride (176mg), add the methyl alcohol of 2ml again.Stirring at room reaction 5 hours, the some plate is followed the tracks of reaction and is finished.Filter, filtrate decompression concentrates, and removes methylene dichloride, methyl alcohol.Water (20ml), ethyl acetate (30ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with silica gel column chromatography separation and purification gained resistates, obtains title product 1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 13b (260mg), directly drop into next step.
MS?m/z(ESI)：447[M-1]
The 3rd step
5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
The nitrogen atmosphere cryosel is bathed down, with 1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 13b (260mg, 0.58mmol) be dissolved in the methylene dichloride of 80ml, add 34mg sodium-chlor, temperature slowly is added dropwise to triphosgene (69mg, methylene dichloride 0.23mmol) (20ml) solution successively less than 0 ℃ in keeping, N, (442mg 3.48mmol), keeps temperature less than 0 ℃ to the N-diisopropyl ethyl amine, behind the stirring reaction 1 hour, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-(3,5-di-trifluoromethyl-phenyl)-and 4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone 13 (erythro form) (0.12g, faint yellow solid), productive rate 87.2%.
MS?m/z(ESI)：473[M-1]
1HNMR(400MHz，CDCl 3)δ?9.04(brs，1H)，7.9(s，1H)，7.73(s，2H)，6.00(d，1H)，5.70(d，1H)，4.65(d，1H)，4.32(d，1H)，4.21(m，1H)，2.25(s，3H)，0.81(d，3H).
Embodiment 14
5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
Figure A200710162642D00571
The first step
5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
Repeat the four-step reaction of the embodiment of the invention 13, use resulting compound 1-(3 among the embodiment 13,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 13b and triphosgene, N, the reaction of N-diisopropyl ethyl amine, with preparative chromatography plate separation and purification gained resistates, obtain title product 5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone 14 (Soviet Union's formula) (0.023g, faint yellow solid), productive rate 17.5%.
MS?m/z(ESI)：473[M-1]
1HNMR(400MHz，CDCl 3)δ?9.14(brs，1H)，7.89(s，1H)，7.74(s，2H)，5.97(d，1H)，5.08(d，1H)，4.63(d，1H)，4.36(d，1H)，3.63(m，1H)，2.23(s，3H)，1.46(d，3H).
Embodiment 15
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl }-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Figure A200710162642D00591
The first step
5-formyl radical-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, with 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (0.361g, 1mmol); phenylo boric acid (135mg; 1.1mmol), tetrakis triphenylphosphine palladium (558mg, 0.5mmol); salt of wormwood (318mg; 2.3mmol) be dissolved in and be dissolved in 2ml/2ml N, in N-dimethyl-formamide/water mixed solution, be heated to make in temperature reach 50～60 ℃; behind the stirring reaction 5 hours, the some plate is followed the tracks of reaction and is finished.In reaction solution, add 20ml water and 50ml ethyl acetate extraction reaction solution.Merge organic phase; with saturated sodium-chloride water solution (20ml * 1) washing organic layer; use anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography separation and purification gained resistates, obtain standard product 5-formyl radical-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 15a (0.074g), productive rate: 23%.
MS?m/z(ESI)：310[M-1]
Second step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, with compound 5-formyl radical-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 15a (0.074g, 0.237mmol); 1-(3,5-di-trifluoromethyl-phenyl)-2-amino-ethanol 5e (97mg, 0.355mmol); be dissolved in 1 of 5ml, in the 2-ethylene dichloride, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction spends the night, slow adding sodium cyanoborohydride under stirring (45mg, 0.71mmol), the stirring at room reaction is spent the night, and end is reacted in the tracking of some plate.With reacting liquid filtering, sodium chloride aqueous solution (30ml * 1) washing, use anhydrous sodium sulfate drying again, filter, filtrate decompression concentrates, and with silica-gel plate chromatography separation and purification gained resistates, obtains title product 5-{[2-(3 altogether, 5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 15b (0.062g), productive rate 46%.
MS?m/z(ESI)：567[M-1]
The 3rd step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 15b (0.062g, 0.11mmol), sodium-chlor (20mg) is dissolved in the methylene dichloride of 2ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (70mg successively, 0.23mmol) methylene dichloride (2ml) solution, stirring reaction added N after 2 hours, N-diisopropyl ethyl amine (84mg, 0.66mmol) methylene dichloride (2ml) solution, stirring reaction rose to room temperature after 2 hours, and stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (20ml * 1), water (5ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 2), merge organic phase, with saturated sodium-chloride water solution (10ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-phenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 15 (0.03g, white solid), productive rate 46%.
MS?m/z(ESI)：595[M+1]
1HNMR(400MHz，CDCl 3)δ?10.70(s，1H)，7.88(s，1H)，7.76(s，2H)，7.36(m，3H)，7.20(m，2H)，5.55(t，1H)，4.48～4.26(m，2H)，4.39(q，2H)，3.72(t，1H)，3.13(t，1H)，1.37(t，3H).
Embodiment 16
(4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-4-methyl-oxazoles-2-ketone
Figure A200710162642D00601
The first step
(4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-4-methyl-oxazoles-2-ketone
The nitrogen atmosphere cryosel is bathed down, sodium hydride (80mg) is dissolved in the tetrahydrofuran (THF) of 5ml, cool the temperature to 0 ℃, slowly be added dropwise to (4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone 13 (0.06g, 0.13mmol) tetrahydrofuran solution (5ml), temperature remains on 0 ℃, and stirring reaction 2 hours adds 70 μ l methyl iodide, after the insulation reaction 1 hour, rise to room temperature, reaction is spent the night, and the some plate is followed the tracks of reaction and finished.Add 20ml water, the concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merges organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica-gel plate chromatography separation and purification gained resistates, obtain title product (R, R) 5-(3,5-di-trifluoromethyl-phenyl)-3-(1,5-dimethyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-4-methyl-oxazoles-2-ketone 16 (0.020g, faint yellow solid), productive rate 68%.
MS?m/z(ESI)：506[M+18]
1HNMR(400MHz，CDCl 3)δ?7.88(brs，1H)，7.77(s，2H)，6.08(s，1H)，5.64(d，1H)，4.84(d，1H)，4.46(d，1H)，4.02(m，1H)，3.55(s，3H)，2.23(s，3H)，0.72(d，3H).
Embodiment 17
(4S, 5R)-5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazoles-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00611
The first step
(S)-[1-(methoxyl group-methyl-carbamyl)-ethyl]-benzyl carbamate
Under the nitrogen atmosphere ice bath, with (S)-2-benzyloxy carbon back amino-propionic acid 17a (13g, 58mmol), 1-hydroxyl-benzene a pair of horses going side by side triazole one water (9.6g, 71mmol), (6.8g 7.1mmol) is dissolved in the tetrahydrofuran (THF) of 200ml methoxyl group-methylamine, is cooled to 0～10 ℃, slowly drip N, the N-diisopropylethylamine (25ml, 15.3mmol), controlled temperature is lower than 25 ℃, slowly drip 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (14g again, 7.3mmol), the stirring at room reaction is after 3.5 hours, and the some plate is followed the tracks of reaction and is finished.In system, slowly drip the dilute hydrochloric acid solution of 70ml3N, with ethyl acetate (80ml * 1) extraction gained reaction solution, water extracts once more with ethyl acetate (50ml * 2), merge organic phase, use the dilute hydrochloric acid solution of 20ml3N successively, saturated sodium bicarbonate (20ml) washing organic phase, use saturated sodium-chloride water solution (20ml * 1) washing again, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product (S)-[1-(methoxyl group-methyl-carbamyl)-ethyl]-benzyl carbamate 17b (14.65g), productive rate 95.0%, and product is as next step reaction.
MS?m/z(ESI)：267[M+1]
Second step
(S)-[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-ketone-ethyl]-benzyl carbamate
Under the nitrogen atmosphere ice bath, with (S)-[1-(methoxyl group-methyl-carbamyl)-ethyl]-benzyl carbamate 17b (14.65g, 55mmol), 3, (11.9ml 68.8mmol) is dissolved in the tetrahydrofuran (THF) of 100ml 5-di-trifluoromethyl-phenyl-bromide, be cooled to-10 ℃, (68.8ml 137.5mmol), keeps temperature to be no more than 1～5 ℃ slowly to drip isopropylmagnesium chloride, after being added dropwise to complete, be warming up to 20 ℃, stirring reaction 2 little clocks, the stirring at room reaction is spent the night.The point plate is followed the tracks of reaction and is finished.The dilute hydrochloric acid solution that adds 60ml5N to system, with ethyl acetate (80ml * 1) extraction gained reaction solution, use saturated sodium-chloride water solution (20ml * 1) washing again, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product (S)-[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-ketone-ethyl]-benzyl carbamate 17c (25.1g), productive rate 100%, product is as next step reaction.
MS?m/z(ESI)：420[M+1]
The 3rd step
(1R, 2S)-1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol
In exsiccant hydrogenation bottle, with (S)-[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-ketone-ethyl]-benzyl carbamate 17c (1.48g, 3.53mmol) be dissolved in the methyl alcohol of 30ml, add 480mg Pd/C, room temperature, behind the 30Psi stirring reaction 4 hours, the some plate is followed the tracks of reaction and is finished.Use diatomite filtration, concentrating under reduced pressure filtrate obtain title product (1R, 2S)-1-(3,5-di-trifluoromethyl-phenyl)-2-amino-propanol 17d (0.85g), productive rate 86.6%.
MS?m/z(ESI)：288[M+1]
The 4th step
(1R, 2S)-5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, will (1R, 2S)-1-(3; 5-di-trifluoromethyl-phenyl)-2-amino-propanol 17d (0.35g; 1.22mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-(0.225g 0.813mmol) is dissolved in the 10ml methyl alcohol 4-carboxylic acid tert-butyl ester 1e.Add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, after the stirring at room reaction was spent the night, (the stirring at room reaction was spent the night for 129mg, methyl alcohol 3.23mmol) (2ml) solution, and the some plate is followed the tracks of reaction and finished to add sodium borohydride.Filter, in filtrate, add 20ml water, concentrating under reduced pressure filtrate.With ethyl acetate (50ml * 3) extraction gained residual solution, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrate obtain title product (1R, 2S)-5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 17e (0.47g), directly drop into next step.
MS?m/z(ESI)：547[M-1]
The 5th step
(4S, 5R)-5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with (1R, 2S)-5-{[2-(3,5-di-trifluoromethyl-phenyl)-1-methyl-2-hydroxyl-ethylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 17e (0.47g, 0.86mmol) be dissolved in the methylene dichloride of 40ml, temperature slowly is added dropwise to triphosgene (509mg less than 0 ℃ in keeping, 1.72mmol) methylene dichloride (4ml) solution, after the insulation reaction 1 hour, add N, N-diisopropyl ethyl amine (655mg, 5.16mmol), keep temperature＜5 ℃, stirring reaction was warming up to 0 ℃ after 2 hours, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 1), water (25ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product (4S, 5R)-5-[5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 17 (0.23g, yellow solid), productive rate 48.6%.
MS?m/z(ESI)：597[M+23]
1HNMR(400MHz，CDCl 3)δ?9.30(s，1H)，7.90(s，1H)，7.73(s，2H)，5.71(d，1H)，4.59(d，1H)，4.45(d，1H)，4.20(m，1H)，2.48(s，3H)，1.57(s，9H)，0.82(d，3H).
Embodiment 18
(4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
Figure A200710162642D00631
The first step
(1R, 2S)-1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl
Under the nitrogen atmosphere, will (1R, 2S)-1-(3; 5-di-trifluoromethyl-phenyl)-and 2-amino-propanol 17d (0.35g, 1.22mmol), 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical 13a (0.144g; 0.813mmol) be dissolved in the methylene dichloride of 10ml, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and is finished.Add the 185mg sodium borohydride, add the methyl alcohol of 2ml again.The stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.Filter, filtrate decompression concentrates, and removes methylene dichloride, methyl alcohol.Use 20ml water, ethyl acetate (30ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (1R, 2S)-1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 18a (410mg), directly drop into next step.
MS?m/z(ESI)：447[M-1]
Second step
(4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
The nitrogen atmosphere cryosel is bathed down, with (1R, 2S)-1-(3,5-di-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-(410mg 0.915mmol) is dissolved in the methylene dichloride of 40ml propane-1-hydroxyl 18a, adds small amount of sodium chloride, temperature is less than 0 ℃ in keeping, (insulation reaction is after half hour for 217mg, methylene dichloride 0.732mmol) (10ml) solution slowly to be added dropwise to triphosgene, add N again, (697mg 5.49mmol), keeps temperature less than 0 ℃ to the N-diisopropyl ethyl amine, behind the stirring reaction 1 hour, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product (4S, 5R)-5-(3,5-di-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone 18 (0.18g, yellow solid), productive rate 42%.
MS?m/z(ESI)：473[M-1]
1HNMR(400MHz，CDCl 3)δ?9.03(brs，1H)，7.9(s，1H)，7.73(s，2H)，6.00(s，1H)，5.70(d，1H)，4.65(d，1H)，4.32(d，1H)，4.22(m，1H)，2.25(s，3H)，0.81(d，3H).
Embodiment 19
3-[1-(3,5-di-trifluoromethyl-phenyl)-5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl]-5-(3,5-di-trifluoromethyl-phenyl)-oxazoles-2-ketone
Figure A200710162642D00651
Repeat the reaction of the embodiment of the invention 12 the first steps, different be to use resulting compound 5-[5-(3 among the embodiment 8,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles 8 and 3,5-di-trifluoromethyl-benzyl bromine is made raw material, obtain title product 3-[1-(3,5-di-trifluoromethyl-phenyl)-5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl]-5-(3,5-di-trifluoromethyl-phenyl)-oxazoles-2-ketone 19 (92mg, white solid), productive rate: 61.7%.
MS?m/z(ESI)：685[M-1]
1HNMR(400MHz，CDCl 3)δ?8.1(s，1H)，7.925(d，3H)，7.374(s，2H)，6.303(s，1H)，5.468(s，2H)，5.367(t，1H)，4.486(m，2H)，3.774(t，1H)，3.093(t，1H)，2.094(s，3H).
Embodiment 20
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl }-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Figure A200710162642D00652
The first step
5-formyl radical-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, with 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (0.361g, 1mmol); to toluene boric acid (150mg; 1.1mmol), tetrakis triphenylphosphine palladium (558mg, 0.5mmol); salt of wormwood (318mg; 2.3mmol) be dissolved in and be dissolved in 2ml/2mlN, in dinethylformamide/water mixed liquid, be heated to make in temperature reach 50～60 ℃; stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.In reaction solution, add 20ml water and 50ml ethyl acetate extraction reaction solution.Merge organic phase; with saturated sodium-chloride water solution (20ml * 1) washing organic layer; use anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography separation and purification gained resistates, obtain standard product 5-formyl radical-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 20a (0.11g), productive rate: 34%.
MS?m/z(ESI)：323[M-1]
Second step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere; with compound 5-formyl radical-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 20a (0.11g; 0.338mmol); 1-(3; 5-di-trifluoromethyl-phenyl)-(139mg 0.507mmol), is dissolved in 1 of 5ml to 2-amino-ethanol 5e; in the 2-ethylene dichloride, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction spends the night, slow adding sodium cyanoborohydride under stirring (64mg, 1.014mmol), the stirring at room reaction is spent the night, and end is reacted in the tracking of some plate.With reacting liquid filtering, with the ethyl acetate of 50ml and the saturated sodium-chloride water solution extraction filtrate of 25ml, organic phase is used anhydrous sodium sulfate drying again, filter, filtrate decompression concentrates, and with silica-gel plate chromatography separation and purification gained resistates, obtains title product 5-{[2-(3 altogether, 5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 20b (0.069g), productive rate 35%.
MS?m/z(ESI)：583[M+1]
The 3rd step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 20b (0.069g, 0.118mmol), sodium-chlor (20mg) is dissolved in the methylene dichloride of 2ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (35mg successively, 0.118mmol) methylene dichloride (2ml) solution, stirring reaction added N after 2 hours, N-diisopropyl ethyl amine (90mg, 0.711mmol) methylene dichloride (2ml) solution, stirring reaction rose to room temperature after 2 hours, and stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.With ethyl acetate (50ml * 1), water (20ml * 1) extractive reaction liquid, water extracts once more with ethyl acetate (20ml * 2), merge organic phase, with saturated sodium-chloride water solution (10ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-p-methylphenyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 20 (0.036g, white solid), productive rate 50%.
MS?m/z(ESI)：609[M+1]
1HNMR(400MHz，CDCl 3)δ?10.73(s，1H)，7.88(s，1H)，7.77(s，2H)，7.17(d，2H)，7.08(d，2H)，5.56(t，1H)，4.48～4.26(m，2H)，4.35(q，2H)，3.72(t，1H)，3.14(t，1H)，2.37(s，3H)，1.36(t，3H).
Embodiment 21
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazole 3-base-methyl }-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Figure A200710162642D00671
The first step
5-formyl radical-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere, with 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c (0.554g, 1.53mmol); 5-sec.-propyl-2-methoxyl group-phenylo boric acid (327mg; 1.68mmol), tetrakis triphenylphosphine palladium (853mg, 0.765mmol); salt of wormwood (486mg; 3.52mmol) be dissolved in and be dissolved in 2ml/2ml N, in dinethylformamide/water mixed liquid, be heated to make in temperature reach 50～60 ℃; stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.In reaction solution, add 20ml water and 50ml ethyl acetate extraction reaction solution.Merge organic phase; with saturated sodium-chloride water solution (20ml * 1) washing organic layer; use anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography separation and purification gained resistates, obtain standard product 5-formyl radical-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 21a (0.14g), productive rate: 23%.
MS?m/z(ESI)：382[M-1]
Second step
5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Under the nitrogen atmosphere; with compound 5-formyl radical-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 21a (0.14g; 0.365mmol); 1-(3; 5-di-trifluoromethyl-phenyl)-(150mg 0.547mmol), is dissolved in 1 of 3ml to 2-amino-ethanol 5e; in the 2-ethylene dichloride, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring reaction spends the night, slow adding sodium cyanoborohydride under stirring (69mg, 1.1mmol), the stirring at room reaction is spent the night, and end is reacted in the tracking of some plate.With reacting liquid filtering, with the ethyl acetate of 50ml and the saturated sodium-chloride water solution extraction filtrate of 25ml, organic phase is used anhydrous sodium sulfate drying again, filter, filtrate decompression concentrates, and with silica-gel plate chromatography separation and purification gained resistates, obtains title product 5-{[2-(3 altogether, 5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 21b (0.153g), productive rate 66%.
MS?m/z(ESI)：639[M-1]
The 3rd step
5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Cryosel is bathed down, with 5-{[2-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-4-(5-sec.-propyl-2-methoxyl group-phenyl)-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 21b (0.153g, 0.239mmol), sodium-chlor (10mg) is dissolved in the methylene dichloride of 9ml, temperature is less than 0 ℃ in keeping, slowly be added dropwise to triphosgene (71mg successively, 0.239mmol) methylene dichloride (2ml) solution, stirring reaction added N after 2 hours, N-diisopropyl ethyl amine (182mg, 1.434mmol) methylene dichloride (2ml) solution, stirring reaction rose to room temperature after 2 hours, and stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.With ethyl acetate (50ml * 1), water (20ml * 1) extractive reaction liquid, water extracts once more with ethyl acetate (20ml * 2), merge organic phase, with saturated sodium-chloride water solution (10ml * 1) washing organic layer, the organic layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[5-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-4-(5-sec.-propyl-2-methoxyl group-phenyl) base-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 21 (0.095g, thick liquid), productive rate 60%.
MS?m/z(ESI)：667[M+1]
1HNMR(400MHz，CDCl 3)δ?10.52(d，1H)，7.87(s，1H)，7.74(s，2H)，7.18(m，1H)，6.97～6.92(d，1H)，6.84(m，1H)，5.52(t，1H)，4.50～4.33(m，2H)，4.35(q，2H)，3.76～3.62(m，1H)，3.75(s，1.5H)，3.64(s，1.5H)，3.21～3.09(m，1H)，2.86～2.83(m，1H)，1.38(t，3H)，1.23～1.21(m，6H).
Embodiment 22
5-(4-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
Figure A200710162642D00691
The first step
1-(4-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl
Under the nitrogen atmosphere, (0.35g, 1.22mmol), (0.144g 0.813mmol) is dissolved in the methylene dichloride of 10ml 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical 13a, adds a small amount of 4 with 1-(4-trifluoromethyl-phenyl)-2-amino-propanol 10b
Figure A200710162642D0077151852QIETU
Molecular sieve, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and is finished.Add the 185mg sodium borohydride, add the methyl alcohol of 2ml again.The stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.Filter, filtrate decompression concentrates, and removes methylene dichloride, methyl alcohol.Use 20ml water, ethyl acetate (30ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 1-(4-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 22a (300mg), directly drop into next step.
MS?m/z(ESI)：447[M-1]
Second step
(4S, 5R)-5-(4-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone
The nitrogen atmosphere cryosel is bathed down, with 1-(4-trifluoromethyl-phenyl)-2-[(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-ylmethyl)-amino]-propane-1-hydroxyl 22a (300mg, 0.79mmol) be dissolved in the methylene dichloride of 10ml, add small amount of sodium chloride, temperature is less than 0 ℃ in keeping, (insulation reaction is after half hour for 470mg, methylene dichloride 1.58mmol) (10ml) solution slowly to be added dropwise to triphosgene, add N again, (697mg 5.49mmol), keeps temperature less than 0 ℃ to the N-diisopropyl ethyl amine, behind the stirring reaction 10 minutes, rise to room temperature, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product (4S, 5R)-and 5-(4-trifluoromethyl-phenyl)-4-methyl-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-oxazoles-2-ketone 22 (0.018g, yellow solid), productive rate 11.2%.
MS?m/z(ESI)：405[M-1]
1HNMR(400MHz，CDCl 3)δ?7.67(d，2H)，7.40(d，2H)，5.98(s，1H)，5.63(d，1H)，4.58(s，1H)，4.28(d，1H)，4.10(m，1H)，2.23(d，3H)，0.80(d，3H).
Embodiment 23
5-[6-(3,5-di-trifluoromethyl-phenyl)-2-ketone-[1,3] oxazine-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
Figure A200710162642D00701
The first step
2-(3,5-di-trifluoromethyl-phenyl)-oxyethane
With sodium hydride (3.6g, 90mmol) be dissolved in the DMSO of 180ml, be added dropwise to Trimethylsulfoxonium Iodide (23.1g, 105mmol), the stirring at room reaction is added dropwise to 3 after 8 minutes again in reaction solution, 5-di-trifluoromethyl-phenyl aldehyde 23a (7.26g, DMSO solution (30ml) 30mmol), stirring at room reaction are after 50 minutes, and the some plate is followed the tracks of reaction and finished.Reaction solution is poured in the frozen water of 800ml, with Skellysolve A (300ml * 3) extraction gained mixed solution, merge organic phase, with saturated sodium-chloride water solution (50ml * 1) washing organic layer, the organic layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 2-(3,5-di-trifluoromethyl-phenyl)-and oxyethane 23b (1.6g, yellow oil), productive rate 21%.
Second step
3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxyl-propionitrile
With 2-(3,5-di-trifluoromethyl-phenyl)-oxyethane 23b (1.39g, 5.1mmol), (1.0g 10.2mmol) is dissolved in the tetrahydrofuran (THF) of 20ml the cyano group trimethyl silane, adds tetrabutylammonium fluoride (2.0g) under the stirring at room, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with aqueous acetic acid (20ml * 1) washing organic layer, use saturated sodium bicarbonate aqueous solution (20ml * 1) more successively, saturated sodium-chloride water solution (20ml * 1) washing, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 3-(3,5-di-trifluoromethyl-phenyl)-and 3-hydroxyl-propionitrile 23c (430mg, yellow oil), productive rate 29%
MS?m/z(ESI)：282[M-1]
The 3rd step
3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine
Under the nitrogen atmosphere, with 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxyl-propionitrile 23c (430mg, 1.52mmol) be dissolved in the tetrahydrofuran (THF) of 20ml, under the room temperature, drip the tetrahydrofuran solution (6.08ml of borine, 6.08mmol), stirring reaction spends the night, and the some plate is followed the tracks of reaction and is finished.In reaction solution, add 10ml methyl alcohol, the concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, use saturated sodium bicarbonate aqueous solution (20ml * 1) successively, saturated sodium-chloride water solution (20ml * 1) washing, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 3-(3,5-di-trifluoromethyl-phenyl)-and 3-hydroxy-propylamine 23d (150mg, light yellow oil), productive rate 34.4%
MS?m/z(ESI)：288[M+1]
The 4th step
5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid tert-butyl ester
Under the nitrogen atmosphere, with 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-carboxylic acid tert-butyl ester 1e (132mg, 0.476mmol); 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine 23d (150mg, 0.523mmol); be dissolved in the methylene dichloride of 10ml, add a small amount of 4
Figure A200710162642D0077151852QIETU
Molecular sieve, stirring at room reaction are after 2 hours, and the some plate is followed the tracks of reaction and finished.Add the 114mg sodium borohydride, add the methyl alcohol of 2ml again.The stirring at room reaction is after 2 hours, and the some plate is followed the tracks of reaction and finished.Filter, filtrate decompression concentrates, and removes methylene dichloride, methyl alcohol.Use 20ml water, ethyl acetate (30ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid tert-butyl ester 23e (150mg, light yellow oil), productive rate 57%
MS?m/z(ESI)：549[M+1]
The 5th step
5-[6-(3,5-di-trifluoromethyl-phenyl)-2-ketone-[1,3] oxazine-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid tert-butyl ester 23e (150mg, 0.274mmol) be dissolved in the methylene dichloride of 10ml, add small amount of sodium chloride, temperature slowly is added dropwise to triphosgene (163mg less than 0 ℃ in keeping, 0.548mmol) methylene dichloride (10ml) solution, insulation reaction adds N after half hour again, N-diisopropyl ethyl amine (208.6mg, 1.64mmol), keep temperature less than 0 ℃, stirring reaction rose to room temperature after 10 minutes, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with preparative column chromatography separation and purification gained resistates, obtain title product 5-[6-(3,5-di-trifluoromethyl-phenyl)-2-ketone-[1,3] oxazine-3-base-methyl]-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-carboxylic acid, ethyl ester 23 (0.015g, yellow solid), productive rate 9.6%.
MS?m/z(ESI)：574[M-1]
1HNMR(400MHz，CDCl 3)δ?9.6(s，1H)，7.88(s，1H)，7.83(s，1H)，5.40(m，1H)，4.69(d，1H)，4.51(d，1H)，3.61(m，1H)，3.40(m，1H)，2.46(s，3H)，2.32(m，1H)，2.17(m，1H)，1.55(s，9H).
Embodiment 24
6-(3,5-di-trifluoromethyl-phenyl)-3-(4-iodo-5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine
Figure A200710162642D00721
The first step
5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine
Under the nitrogen atmosphere, (116mg, 0.381mmol), (164mg 0.571mmol), is dissolved in the methyl alcohol of 10ml 3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine 23d, adds a small amount of 4 with 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical-4-iodine 8b
Figure A200710162642D0077151852QIETU
Molecular sieve, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and is finished.Add 2ml sodium cyanoborohydride (49.5mg, methanol solution 0.762mmol).The stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and finished.Filter, filtrate decompression concentrates, and removes methyl alcohol.Use 20ml water, ethyl acetate (30ml * 3) extraction gained resistates, merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 24a (170mg, white solid), directly drop into next step reaction.
Second step
6-(3,5-di-trifluoromethyl-phenyl)-3-(4-iodo-5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine
Under the nitrogen atmosphere, with 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-(170mg 0.296mmol) is dissolved in the N of 10ml, in the dinethylformamide to 2-methyl-4-Trifluoromethyl-1 H-pyrroles-3-iodine 24a, drip 20ml N under the stirring at room, N-carbonyl dimidazoles (53mg, N 0.326mmol), dinethylformamide solution, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica-gel plate chromatography separation and purification gained resistates, obtain title product 6-(3,5-di-trifluoromethyl-phenyl)-3-(4-iodo-5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine, 24 (0.022g, yellow solid), productive rate 12.4%.
MS?m/z(ESI)：599[M-1]
1HNMR(400MHz，CDCl 3)δ?9.57(s，1H)，7.88(s，1H)，7.83(s，2H)，5.40(m，1H)，4.68(d，1H)，4.46(d，1H)，3.61(m，1H)，3.47(m，1H)，2.26(s，3H)，2.35(m，1H)，2.16(m，1H).
Embodiment 25
5-[4-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
Figure A200710162642D00731
Figure A200710162642D00741
The first step
5-aminomethyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
(600mg, 1.66mmol), (238mg, 3.57mmol), (293mg 3.57mmol) is dissolved in the methyl alcohol of 15ml sodium-acetate oxammonium hydrochloride, reflux stirring reaction 2 hours with 5-formyl radical-4-iodo-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 5c.In a single port flask, add the 10ml concentrated hydrochloric acid successively in addition, the water of 30ml, (906mg 13.94mmol), adds small amount of methanol it is dissolved zinc powder again.Be added dropwise in the above-mentioned hydrochloric acid reaction liquid under stirring, normal-temperature reaction 3 hours, the some plate is followed the tracks of reaction and is finished.Reaction solution is poured in the uncovered beaker, added saturated sodium bicarbonate solution, filter to there being a large amount of white solids to generate.Filtrate extracts with ethyl acetate (200ml * 2), the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-aminomethyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25a (0.27g, white solid), productive rate 69%.
MS?m/z(ESI)：235[M-1]
Second step
(3,5-di-trifluoromethyl-phenyl)-hydroxyl-methyl acetate
(1.44g 5.0mmol) is dissolved in the benzene of 25ml with (3,5-di-trifluoromethyl-phenyl)-hydroxyl-acetate 25b, adding methyl alcohol (4.0ml, 100mmol), TMSA (613mg, 6.0mmol), stirring at room reaction 3 hours, the some plate is followed the tracks of reaction and is finished.In reaction solution, dropwise drip acetic acid, make solution from light yellow become the clarification colourless, the concentrating under reduced pressure reaction solution, with silica gel column chromatography separation and purification gained resistates, obtain title product (3,5-di-trifluoromethyl-phenyl)-and hydroxyl-methyl acetate 25c (1.493g, colorless oil), productive rate 98.8%.
MS?m/z(ESI)：301[M-1]
The 3rd step
(3,5-di-trifluoromethyl-phenyl)-bromo-methyl acetate
During cryosel was bathed, (1.493g 4.94mmol) was dissolved in the methylene dichloride of 30ml with (3,5-di-trifluoromethyl-phenyl)-hydroxyl-methyl acetate 25c.(1.799g, 5.43mmol), all after the dissolving, add triphenylphosphine (1.425g, 5.43mmol), stirring reaction 4 hours is put plate tracking reaction and is finished in batches to add carbon tetrabromide.The concentrating under reduced pressure reaction solution with silica gel column chromatography separation and purification gained resistates, obtains title product (3,5-di-trifluoromethyl-phenyl)-bromo-methyl acetate 25d (0.812g, colourless liquid), productive rate 45%.
MS?m/z(ESI)：285[M-80]
The 4th step
5-({ [(3,5-di-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino }-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
With 5-aminomethyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25a (0.082g, 0.347mmol) be dissolved in the tetrahydrofuran (THF) of 20ml, add (3,5-di-trifluoromethyl-phenyl)-bromo-methyl acetate 25d (0.507g, 1.388mmol), triethylamine (350mg, 3.47mmol), spend the night by the stirring at room reaction.The point plate is followed the tracks of reaction and is finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (50ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with silica gel column chromatography separation and purification gained resistates, obtains title product 5-({ [(3,5-di-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino }-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25e (0.1g), productive rate 55%.
MS?m/z(ESI)：519[M-1]
The 5th step
5-{[1-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
In the dry ice bath, with Li-Al hydrogen (170mg, 4.47mmol) be dissolved in the tetrahydrofuran (THF) of 50ml, add 5-({ [(3,5-di-trifluoromethyl-phenyl)-methoxycarbonyl-methyl]-amino }-methyl-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25e (0.1g, 0.192mmol) tetrahydrofuran solution (10ml), stirring reaction is after half hour.Add 1ml water stopped reaction.The point plate is followed the tracks of reaction and is finished.The concentrating under reduced pressure reaction solution boils off most of tetrahydrofuran (THF).With ethyl acetate (30ml * 3), water (15ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[1-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25f (0.025g, light yellow solid), productive rate 27%.
MS?m/z(ESI)：491[M-1]
The 6th step
5-[4-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester
The nitrogen atmosphere cryosel is bathed down, with 5-{[1-(3,5-di-trifluoromethyl-phenyl)-2-hydroxyl-ethylamino]-methyl }-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25f (25mg, 0.05mmol) be dissolved in the methylene dichloride of 2ml, add small amount of sodium chloride, temperature slowly is added dropwise to triphosgene (15mg less than 0 ℃ in keeping, 0.05mmol) methylene dichloride (2ml) solution, insulation reaction adds N after half hour again, N-diisopropyl ethyl amine (38mg, 0.3mmol), keep temperature less than 0 ℃, stirring reaction rose to room temperature after 10 minutes, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (10ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-[4-(3,5-di-trifluoromethyl-phenyl)-2-ketone-oxazoles-3-base-methyl]-3-Trifluoromethyl-1 H-pyrroles-2-carboxylic acid, ethyl ester 25 (0.012g, white solid), productive rate 46%.
MS?m/z(ESI)：517[M-1]
1HNMR(400MHz，CDCl 3)δ?10.14(s，1H)，7.90(s，1H)，7.70(s，2H)，6.00(s，1H)，4.89～4.71(m，2H)，4.47～4.43(d，1H)，4.35(q，2H)，4.175～4.136(m，2H)，1.37(t，3H).
Embodiment 26
6-(3,5-di-trifluoromethyl-phenyl)-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine
The first step
5-{[3-(3,5-di-trifluoromethyl-phenyl)-3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles
Under the nitrogen atmosphere, (143mg, 0.808mmol), (300mg 1.05mmol), is dissolved in the methyl alcohol of 10ml 3-(3,5-two trifluoromethyls-phenyl)-3-hydroxy-propylamine 23d, adds a small amount of 4 with 5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-formyl radical 13a
Figure A200710162642D0077151852QIETU
Molecular sieve, the stirring at room reaction is spent the night, and the some plate is followed the tracks of reaction and is finished.(315mg, 4.848mmol), the stirring at room reaction is spent the night, and puts plate tracking reaction and finishes to add sodium cyanoborohydride.Filter, filtrate decompression concentrates, and removes methyl alcohol.Use 20ml water, ethyl acetate (30ml * 3) extraction gained resistates merges organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles 26a (170mg, light yellow solid), productive rate 47.2%
Second step
6-(3,5-di-trifluoromethyl-phenyl)-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine
The nitrogen atmosphere cryosel is bathed down, with 5-{[3-(3,5-di-trifluoromethyl-phenyl)-the 3-hydroxy-propylamine]-methyl }-2-methyl-4-Trifluoromethyl-1 H-pyrroles 26a (145mg, 0.323mmol) be dissolved in the methylene dichloride of 20ml, add small amount of sodium chloride, temperature slowly is added dropwise to triphosgene (193mg less than 0 ℃ in keeping, 0.648mmol) methylene dichloride (20ml) solution, insulation reaction adds N after half hour again, N-diisopropyl ethyl amine (164mg, 1.3mmol), keep temperature less than 0 ℃, stirring reaction rose to room temperature after 10 minutes, stirring reaction spends the night, and the some plate is followed the tracks of reaction and finished.The concentrating under reduced pressure reaction solution, with ethyl acetate (30ml * 3), water (20ml * 1) extraction gained resistates, water extracts once more with ethyl acetate (20ml * 3), merge organic phase, with saturated sodium-chloride water solution (20ml * 1) washing organic layer, the ethyl acetate layer anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography separation and purification gained resistates, obtain title product 6-(3,5-di-trifluoromethyl-phenyl)-3-(5-methyl-3-Trifluoromethyl-1 H-pyrroles-2-base-methyl)-2-ketone-[1,3] oxazine, 26 (0.1g, faint yellow solid), productive rate 67%.
MS?m/z(ESI)：475[M+1]
1HNMR(400MHz，CDCl 3)δ?9.26(s，1H)，7.88(s，2H)，7.83(s，1H)，5.99(s，1H)，5.40(m，1H)，4.65(d，1H)，4.39(d，1H)，3.61(m，1H)，3.48(m，1H)，2.34(m，1H)，2.23(s，3H)，2.15(m，1H).
Test case:
Biological assessment
Example 1 CETP suppresses the cell proliferation test
Following in vitro tests is to be used for measuring the active vitro inhibition effect of the CETP of The compounds of this invention in whole plasm.
Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism, it can the catalysis cholesterol ester by the transfer of high-density lipoprotein (HDL) (HDL) to apolipoprotein B (apoB).The principle of this experimental applications CETP inhibitor screening is as follows: in reaction system, the donor molecule of neutral lipid that contains fluorescence oneself cancellation is under the mediation of CETP, and its lipid is transferred in the acceptor molecule, thereby loses inhibition, causes system fluorescence to raise.Can suppress the transfer of lipid to the inhibition of CETP, thereby reduce the system fluorescence intensity.
Reagent and method
Adopting CETP inhibitor screening reagent to form comprises: donor molecule, acceptor molecule, reaction buffer, rabbit anteserum (CETP enzyme source).
Experimental procedure:
1. all testing compounds are dissolved by DMSO, and concentration is 1mM (end reaction concentration is 50uM).
2. according to the form below preparation feedback system adopts 200uL PCR pipe, and sealing was placed 5 minutes
Table 1. mixture 1
Figure A200710162642D00781
With donor molecule, acceptor molecule, reaction buffer with an amount of mixed solution of the proportional arrangement of 1:1:2, mixing, every pipe 20uL is added in the mixture 1.Sealing, mixing.
4.37 ℃ hatched 45 minutes.
5. every pipe is drawn the 95uL reaction solution and is placed 96 orifice plates, measures fluorescence (excitation wavelength 465nm; Wavelength of transmitted light 535nm).
By comparison, calculate the inhibiting rate of each compound to pipe to be measured and positive control pipe fluorescence intensity.
The activity of The compounds of this invention
The biochemical activity of The compounds of this invention is measured by above test, and the inhibiting rate ratio that records sees the following form.
The embodiment numbering Inhibiting rate ratio (CETP)
16 31.10％
18 30.20％
19 94.60％
22 31.10％
24 58.50％
26 24.60％

Claims (27)

1. compound, its prodrug or its pharmacy acceptable salt by general formula (I) expression:
Figure A200710162642C00021
Wherein:
R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, trifluoromethyl or Heterocyclylalkyl;
R 3Be selected from hydrogen atom, alkyl, aryl, aralkyl or heteroaryl, wherein alkyl, aryl, aralkyl or heteroaryl are further replaced by one or more substituting groups that are selected from halogen or trifluoromethyl;
R 4Be selected from hydrogen atom, alkyl, cycloalkyl, aryl, heteroaryl or-C (=O) OR 7
R 5Be selected from hydrogen atom, halogen, alkyl, cycloalkyl, trifluoromethyl or-C (=O) OR 7
R 6Be selected from hydrogen atom, halogen, alkyl, cycloalkyl, trifluoromethyl, Heterocyclylalkyl, aryl, aralkyl or heteroaryl, wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters;
R 7Be selected from hydrogen atom, alkyl, thiazolinyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl;
N is 1～2.
2. compound according to claim 1, its prodrug or its pharmacy acceptable salt, comprising:
Figure A200710162642C00022
Figure A200710162642C00031
3. pharmaceutical composition, its comprise medicine effective dose as claim 1 or 2 any one described compound, its prodrug or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
4. compound according to claim 1, the preparation method of its prodrug or its pharmacy acceptable salt, this method may further comprise the steps:
Under the room temperature, polysubstituted pyrroles's aldehyde, reduction amination obtain polysubstituted pyrroles's methylamine;
Figure A200710162642C00041
Under the argon atmospher, polysubstituted pyrroles's methylamine and triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan or six-ring carbamate respectively;
Figure A200710162642C00042
Under the nitrogen atmosphere, five yuan of general formulas or six-ring carbamate obtain five yuan or the six-ring carbamate compounds that the target compound N shown in the general formula (1) replaces with the haloalkane reaction in tetrahydrofuran (THF) with after the tetrahydrofuran solution effect of sodium hydride;
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
5. compound according to claim 1, the preparation method of its prodrug or its pharmacy acceptable salt, this method may further comprise the steps:
Pyrroles's aldehydo-ester that halogen replaces in methyl alcohol with oxammonium hydrochloride, the sodium-acetate reflux obtains polysubstituted hygron ester;
Figure A200710162642C00052
Under the room temperature, the Arylacetic acids that hydroxyl replaces in benzene with methyl alcohol, the TMSA reaction obtains the aryl ethyl ester that hydroxyl replaces;
Figure A200710162642C00053
Under the room temperature, the aryl ethyl ester that hydroxyl replaces in methylene dichloride with carbon tetrabromide, triphenylphosphine obtains the aryl ethyl ester of bromo;
Figure A200710162642C00054
Polysubstituted hygron ester obtains the hygron diester of aryl replacement with the aryl ethyl ester reaction of bromo in tetrahydrofuran (THF);
Figure A200710162642C00055
The hygron diester that aryl replaces obtains the hygron alcohol ester of aryl replacement with the tetrahydrofuran solution reduction reaction of Li-Al hydrogen in tetrahydrofuran (THF);
Under the nitrogen protection, the hygron alcohol ester that aryl replaces in methylene dichloride with triphosgene, N, N-diisopropyl ethyl amine ring-closure reaction obtains five yuan and six-ring carbamate compounds;
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
6. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure
Figure A200710162642C00062
7. intermediates preparation according to claim 6, this method may further comprise the steps:
Under the ice bath, 4,4, the reactant aqueous solution of 4-three fluoro-3-carbonyl-ethyl butyrates and Sodium Nitrite obtains 4,4,4-three fluoro-2-oximido 3-carbonyl-ethyl butyrates, again with 3-carbonyl-butyric acid-tert-butyl ester in Glacial acetic acid under the heating condition zinc powder reduction obtain cyclization product trifluoromethyl pyrpole diester;
Figure A200710162642C00063
Under argon shield, the trifluoromethyl pyrpole diester reduces under tetrahydrofuran (THF) and Li-Al hydrogen room temperature and obtains the trifluoromethyl pyrpole alcohol ester;
Figure A200710162642C00064
Under the room temperature, the trifluoromethyl pyrpole alcohol ester obtains the trifluoromethyl pyrpole aldehydo-ester with the pyridinium chloro-chromate oxidation in methylene dichloride.
Figure A200710162642C00065
8. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Wherein X is a halogen.
9. intermediates preparation according to claim 8, this method may further comprise the steps:
Under the room temperature, the trifluoromethyl pyrpole diester obtains three with trifluoroacetic acid selective reduction reaction in methylene dichloride
Methyl fluoride pyrroles acid esters;
The trifluoromethyl pyrpole acid esters obtains the methylpyrrole ester that halogen replaces with the halogen reaction under heating condition;
Under the methylpyrrole ester that halogen replaces heat in tetrahydrofuran (THF)/water/acetic acid with ceric ammonium nitrate generation oxidizing reaction, pyrroles's aldehydo-ester of halogen replacement;
Wherein X is a halogen.
10. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Figure A200710162642C00075
Wherein X is a halogen.
11. an intermediates preparation according to claim 10, this method may further comprise the steps:
Under the room temperature, the trifluoromethyl pyrpole aldehydo-ester obtains trifluoromethyl pyrpole aldehydic acid with trifluoroacetic acid generation reduction reaction in methylene dichloride;
Figure A200710162642C00081
Trifluoromethyl pyrpole aldehydic acid obtains halo trifluoromethyl pyrpole aldehyde with the potassium halide reaction under heating condition;
Figure A200710162642C00082
Wherein X is a halogen.
12. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Figure A200710162642C00083
13. an intermediates preparation according to claim 12, this method may further comprise the steps:
Trifluoromethyl pyrpole aldehydic acid obtains trifluoromethyl pyrpole aldehyde with copper chromite generation reduction reaction under heating condition
Figure A200710162642C00084
14. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Figure A200710162642C00085
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
15. an intermediates preparation according to claim 14, this method may further comprise the steps:
Under the nitrogen atmosphere, the SuZuKi linked reaction takes place and obtains the aryl-pyrrolidine aldehydo-ester in the boric acid that pyrroles's aldehydo-ester that halogen replaces and aryl replace;
Figure A200710162642C00091
Wherein X is a halogen; Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more alkyl, aryl, alkoxyl group, carboxylic acid, carboxylicesters.
16. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Figure A200710162642C00092
Wherein, R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, trifluoromethyl or Heterocyclylalkyl.
17. one kind according to the described intermediates preparation of claim 16, this method may further comprise the steps:
Cryosel is bathed down, replaces the nitrated nitro substitution compound that obtains under the aldehyde room temperature;
Figure A200710162642C00093
Under the room temperature, the nitro-compound hydro-reduction obtains amino substitution compound
Wherein, R 1, R 2Be selected from hydrogen atom, aryl or heteroaryl separately respectively, wherein aryl or heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, trifluoromethyl or Heterocyclylalkyl.
18. the intermediate of the described general formula of synthetic claim 1 (I) compound, it is represented by following general structure:
Figure A200710162642C00095
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
19. an intermediates preparation according to claim 18, this method may further comprise the steps:
Under the nitrogen atmosphere ice bath, (S) benzyloxy carbon back alanine obtains the amino substitution compound of methoxyl group of (S) configuration with methoxyl group-methylamine generation reductive amination process in tetrahydrofuran (THF);
Figure A200710162642C00101
Under the nitrogen atmosphere ice bath, (S) amino substitution compound of the methoxyl group of configuration and aryl bromide linked reaction obtain (S) configuration aryl substitution compound;
Figure A200710162642C00102
Under the room temperature, (S) configuration aryl substitution compound and Pd/C reduction reaction obtain (1R, aryl substituted propanol 2S);
Figure A200710162642C00103
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
20. the intermediate of the compound of the described general formula of synthetic claim 1 (I), it is represented by following general structure:
Figure A200710162642C00104
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
21. an intermediates preparation according to claim 20, this method may further comprise the steps:
Under the room temperature, aryl formaldehyde and sodium hydride, Trimethylsulfoxonium Iodide generation ring-closure reaction obtains the aryl rings oxidative ethane;
Figure A200710162642C00105
The aryl rings oxidative ethane in tetrahydrofuran (THF) with the cyano group trimethyl silane, the tetrabutylammonium fluoride ring-opening reaction obtains the aryl propionitrile that hydroxyl replaces;
Figure A200710162642C00111
Under the nitrogen atmosphere, aryl propionitrile that hydroxyl replaces and the reaction of the tetrahydrofuran solution of borine obtain the aryl propyl amine that hydroxyl replaces;
Figure A200710162642C00112
Wherein: Ar is aryl, aralkyl or heteroaryl, and wherein aryl, aralkyl, heteroaryl are further replaced by one or more substituting groups that are selected from alkyl, aryl, alkoxyl group, carboxylic acid or carboxylicesters.
22. the purposes of composition according to claim 3 in the preparation cetp activity inhibitors.
23. the purposes of composition according to claim 3 in the medicine of preparation prevention or treatment hyperlipidaemia.
24. composition according to claim 3 is in preparation prevention or treat purposes in the atherosclerotic medicine.
25. the purposes of a compound according to claim 1 in the preparation cetp activity inhibitors.
26. the purposes of a compound according to claim 1 in the medicine of preparation prevention or treatment hyperlipidaemia.
27. a compound according to claim 1 is in the preparation prevention or treat purposes in the atherosclerotic medicine.
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