CN106032362B - The preparation method of Ansai Qu - Google Patents
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Abstract
The preparation method of the compound of formula (I), it includes：1) it is reacted by 2 chlorine, 5 5-trifluoromethylaniline (II) with (4 fluorine, 5 isopropyl, 2 methoxyphenyl) boric acid (III), obtains 2 (4 fluorine, 5 isopropyl, 2 methoxyphenyl) 5 5-trifluoromethylanilines (general formula IV)；2) it is reacted by logical formula (IV) compound with nitrite tert-butyl, acetaldehyde and alkali, obtains 2 (4 fluorine, 5 isopropyl, 2 methoxyphenyl) 5 trifluoromethyl benzyl alcohol (general formula V)；3) it is reacted by logical formula (V) compound with halogenating agent, then (4S is added in the reactive mixture, 5R) 5 [3,5 two (trifluoromethyl) phenyl] 4 methyl 1,3 oxazolidine, 2 ketone (VI) is reacted, (the 4S of acquisition formula (I), 5R) 5 [3,5 two (trifluoromethyl) phenyl] 3 { [4 ' fluorine, 5 ' isopropyl 2 ' methoxyl group 4 (trifluoromethyl) biphenyl, 2 base] methyl } 41,3 oxazolidine of methyl, 2 ketone (i.e. Ansai Qu).
Description
Technical field
The present invention relates to Ansai Qu, i.e. (4S, 5R) -5- [3,5- bis- (trifluoromethyl) phenyl] -3- [4 '-fluoro- 5 '-different
Propyl -2 '-methoxyl group -4- (trifluoromethyl) biphenyl -2- bases] methyl } -4- methyl-1s, the preparation method of 3- oxazolidine -2- ketone.
Background technology
Atherosclerosis and its clinical effectiveness, coronary heart disease (CHD), apoplexy and peripheral vascular disease threaten the strong of the mankind
Health.
For a long time, it has been recognized that in mammals, variation and the atherosclerosis of cycle lipoprotein distribution and
The danger of CHD is related.HMG-CoA reductase inhibitor, particularly statins clinically successfully reduce coronary artery thing
Part is based on reduction cyclic low-density lipoprotein cholesterol (LDL-C), and LDL-C levels are directly related to increased atherosclerosis
It is dangerous.Recently, epidemiological study is shown, high-density lipoprotein cholesterol (HDL-C) level and atherosclerosis inversely related,
It is concluded that low Serum HDL-C level is related with increased CHD danger.
The Metabolism control of lipoprotein levels is the complicated and dynamic process for involving many factors.One of the mankind is important
Metabolism control be cholesterol ester transfer protein (CETP), a kind of plasma glycoprotein, catalysis cholesteryl ester is from HDL to containing apoB
Lipoprotein (particularly to VLDL) transfer (referring to Hesler, C.B. et al., (1987) Purification and
Characterization of human plasma cholesteryl ester transfer protein.,
J.Biol.Chem.262 (5), 2275-2282)).In physiological conditions, net reaction is that wherein CETP is carried from apoB lipoprotein
Heterologous exchange (heteroexchange) of the triglycerides to HDL and from HDL delivery of cholesterol ester to apoB lipoprotein.
In the mankind, CETP works in cholesterol transport is inverted, and by the Umklapp process, cholesterol is from peripheral tissues
Return to liver.
Chinese patent discloses CN1980904A (200580022618.7) and discloses (4S, 5R) -5- [3,5- bis- (fluoroforms
Base) phenyl] -3- { [4 '-fluoro- 5 '-isopropyl -2 '-methoxyl group -4- (trifluoromethyl) biphenyl -2- bases] methyl } -4- methyl-1s,
3- oxazolidine -2- ketone (i.e. Ansai Qu) and preparation method thereof (referring to embodiment 73).The compound can be used for inhibiting cholesterol
Therefore transesterify albumen (CETP) simultaneously can be used for treating and preventing atherosclerosis.Wherein in embodiment 73, Ansai is prepared
The method of bent includes two steps：
Step 1：(4S, 5R) -5- [3,5- bis- (trifluoromethyl) phenyl] -4- methyl-1s, 3- oxazolidine -2- ketone (general formula A)
It is reacted with 2- (bromomethyl) -1- iodo- 4- (trifluoromethyl) benzene (Formula B), obtains (4S, 5R) -5- [3,5- bis- (fluoroforms
Base) phenyl] -3- [2- iodo- 5- (trifluoromethyl) benzyl] -4- methyl-1s, 3- oxazolidine -2- ketone (general formula C)：
Step 2：(4S, 5R) -5- [3,5- bis- (trifluoromethyl) phenyl] -3- [2- iodo- 5- (trifluoromethyl) benzyl] -4- first
Base -1,3-oxazoles alkane -2- ketone (general formula C) is reacted, is obtained with (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) boric acid (general formula D)
Obtain final product Ansai Qu (general formula I)：
However, in the above method of CN1980904A, reaction condition is harsher, and using toxic, expensive
Catalytic reagent.Starting material is not readily available and its manufacturing cost is higher.In complete reaction route, the ratio that seems is post-processed
Cumbersome, byproduct of reaction is more.The yield of final product is relatively low, and the manufacturing cost of final product is higher.
Invention content
The object of the present invention is to provide the preparation method of the compound of logical formula (I), this method includes：
Step 1：By leading to the chloro- 5- trifluoromethyl-anilines of 2- of formula (II) and (the fluoro- 5- isopropyls -2- of 4- of logical formula (III)
Methoxyphenyl) boric acid reacted, obtain midbody compound 2- (the fluoro- 5- isopropyls -2- methoxybenzenes of 4- of logical formula (IV)
Base) -5- trifluoromethyl-anilines：
Step 2：By compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of the 4-) -5- trifluoromethyls-benzene for leading to formula (IV)
Amine reacted with nitrite tert-butyl, acetaldehyde and alkali (such as potassium hydroxide or sodium hydroxide) (or by lead to formula (IV) chemical combination
Object is reacted in the presence of a base with nitrite tert-butyl, acetaldehyde), obtain 2- (the fluoro- 5- isopropyls -2- methoxies of 4- for leading to formula (V)
Base phenyl) -5- trifluoromethyl-benzyl alcohols：
Step 3：By compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of the 4-) -5- romethyl-benzies for leading to formula (V)
Alcohol is reacted (reaction that i.e. hydroxyl is optionally substituted by halogen by halogenated reaction or hydroxyl) with halogenating agent and is obtained (containing halogenated
Product) reaction mixture, then adds (4S, 5R) -5- [3,5- bis- (trifluoromethyls) for leading to formula (VI) in the reactive mixture
Phenyl] -4- methyl-1s, 3- oxazolidine -2- ketone reacted, and obtains (4S, 5R) -5- [3,5- bis- (trifluoromethyls) of logical formula (I)
Phenyl] -3- { [4 '-fluoro- 5 '-isopropyl -2 '-methoxyl group -4- (trifluoromethyl) biphenyl -2- bases] methyl } -4- methyl-1s, 3- dislikes
Oxazolidine -2- ketone：
Preferably, the reaction in step 1 is that (such as 1-5M concentration, preferably 2-4M concentration, such as 3M are dense in addition aqueous slkali
The K of degree2CO3Or Na2CO3Aqueous solution) organic solvent (such as acetonitrile) (preferably, aqueous slkali accounts for or is equivalent to organic solvent
The 20-60% of volume, preferably 30-50%) (i.e.：Two phase liquid system) in carry out.It is further preferred that the reaction of step 1 is
Add under inert gas (such as nitrogen or argon gas) protection and in the reactive mixture catalyst (such as the Pd containing palladium
(PPh3)4) in the case of carry out.Generally, the reaction of step 1 be reaction mixture or reaction system be warming up to 60-95 DEG C, it is excellent
Select 70-90 DEG C, it is 75-85 DEG C more preferable at a temperature of carry out.The reaction time of step 1 is usually 1-10 hours, and preferably 2-6 is small
When, it is 3-5 hours more preferable.
Preferably, the alkali described in step 1) in aqueous slkali is selected from NaOH, KOH, LiOH, K2CO3、Na2CO3Or
Li2CO3.Preferably, alkali is selected from K2CO3、Na2CO3。
Preferably, step 1 further comprises：After the completion of reaction, gained reaction mixture is separated and is obtained
Obtain organic phase, organic phase saturated common salt water washing, filtering and dry, the midbody compound 2- (4- of the logical formula (IV) of acquisition
Fluoro- 5- isopropyls -2- methoxyphenyls) -5- trifluoromethyl-anilines.
Preferably, the alkali in step 2 is selected from NaOH, KOH, K2CO3Or Li2CO3；Preferably, alkali be selected from NaOH or
KOH.Generally, the reaction of step 2 is carried out in the presence of the alkali and organic solvent (such as acetonitrile).Preferably, the reaction
It is carried out at a temperature of -10~10 DEG C, preferably -5~5 DEG C.
Generally, the reaction of step 2 carries out -3 hours 20 minutes, preferably -2 hours 25 minutes, more preferable 30 minutes -1.5 small
When.Preferably, after reaction terminates, the 5- of the volume or weight based on reaction mixture is added in the reactive mixture
Then the water of 50% (preferably 8-40%, more preferable 12-30%), is removed organic by dry or evaporation (such as rotary evaporation)
Solvent (such as acetonitrile), gained residue organic solvent (such as ethyl acetate) extract and obtain organic phase, the organic phase quilt
Concentration, then crystallisation by cooling, obtains the substance of white solid, then white solid object is washed and dried, and obtains logical formula (V)
2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- trifluoromethyl-benzyl alcohols.
Preferably, the reaction of step 3 is that (using " one kettle way ") carries out as follows：3.1) first by the 2- (4- of logical formula (V)
Fluoro- 5- isopropyls -2- methoxyphenyls) -5- trifluoromethyl-benzyl alcohols and halogenating agent react and obtain reaction mixture,
Then add in the reactive mixture the volume or weight based on reaction mixture 10-80%, preferably 20-60%, more preferably
The water of 30-50% is stirred, stratification, is removed water layer and is left organic layer；3.2) general formula is added in gained organic layer
(VI) (4S, 5R) -5- [3,5- bis- (trifluoromethyl) phenyl] -4- methyl-1s, 3- oxazolidine -2- ketone, quaternary ammonium salt and alkali carry out
Reaction (such as 10-30 hours, preferably 12-22 hours, 15-19 hours more preferable), it is preferred that the reaction be 40-80 DEG C,
It is preferred that 50-70 DEG C, it is 55-65 DEG C more preferable at carry out.
Preferably, halogenating agent is thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.The quaternary ammonium salt is tetrabutyl iodate
Ammonium, tetrabutyl ammonium fluoride or tetrabutylammonium chloride.Alkali used in step 3.2) is selected from NaOH, KOH, LiOH, K2CO3、
Na2CO3Or Li2CO3；Preferably, alkali is selected from K2CO3、Na2CO3。
Preferably, in step 1, compound (II):The molar ratio of compound (III) is 1:0.9-1.3, preferably 1:
0.95-1.2, more preferable 1:1-1.15.
Preferably, in step 2, compound (IV)：Nitrite tert-butyl:The molar ratio of acetaldehyde is 1:0.9-2:1.0-
2.5, preferably 1:1-1.8:1.1-2.2, more preferable 1:1.05-1.5:1.15-1.8, more preferable 1:1.1-1.3:1.2-1.5.
Preferably, in step 2, compound (IV)：The molar ratio of potassium hydroxide is 1:0.3-0.7, preferably 1:0.4-
0.6th, more preferable 1:0.5.
Preferably, in step 3, compound (V):Halogenating agent:The molar ratio of compound (VI) is 1:1.2-5:
1.0-1.4 preferably 1:1.6-4:1.02-1.3, more preferable 1:1.8-3.5:1.03-1.25, more preferable 1:2-3:1.05-1.2.
Advantages of the present invention
1st, compared with the synthetic route of existing patent report, reaction condition is mild in route, avoids toxicity, expensive urges
Change reagent.
2nd, starting material is cheap and easily-available, and W-response yield is 45%, reduces entire reaction cost.
3rd, reaction route post-processing approach is simple, and byproduct of reaction is few, suitable for industry's enlarging production.
Description of the drawings
Fig. 1 is the reacting flow chart of the present invention.
Fig. 2 is the collection of illustrative plates of intermediate V.
Fig. 3 and Fig. 4 is the spectrogram of final product I.
Specific embodiment
Embodiment 1
Step 1：Compound II, compound III, acetonitrile and 3M are added in toward flasks of the 100mL equipped with reflux condenser
K2CO3.The two phase liquid of gained nitrogen bubbling 5 minutes.Catalyst Pd (PPh3) 4 is added under nitrogen protection, and reaction is warming up to
80 DEG C, stirred under nitrogen atmosphere 3-4 hours, TLC monitorings are after the reaction was complete, and reaction mixture is cooled to room temperature and detaches two
Phase.Layering, collected organic layer, with brine It 1-2 time of saturation, in addition activated carbon (0.20g) to organic layer, at room temperature
Stirring 1 hour, is then filtered mixture by diatomite.Filtrate is added in into a small amount of acetonitrile azeotropic drying, obtains faint yellow oil
Shape object.As intermediate compound IV.Yield 70%.
Step 1 coupling reaction rate of charge
Intermediate compound IV1H NMR：
LCMS=328.1 (M+1)+。1H NMR(CDCl3, 400MHz) and δ 7.73 (s, 1H), 7.47 (s, 1H), 7.12 (s,
1H), 7.04-7.01 (m, 2H), 6.27 (s, 2H), 3.83 (s, 3H), 2.87 (m, 1H), 1.20 (d, 6H)
Step 2：100mL round-bottomed flasks are taken, add in intermediate compound IV, nitrite tert-butyl, acetaldehyde, potassium hydroxide and acetonitrile.0
Stir 30min-1h at DEG C, TLC monitoring adds in 20ml water and stirs 1 hour, then remove acetonitrile rotation, use acetic acid after the reaction was complete
Ethyl ester extracts 3 times, merges organic phase, concentrates organic phase, obtains pale yellow oily liquid, adds in normal heptane, is transferred in refrigerator
Stand crystallization.Suction filtration obtains white (off-white color) solid, is washed 1-2 times with ice water and cold normal heptane, and 40 degree of drying obtain white
Color (off-white color) solid powder, is washed 1-2 times with ice water and cold normal heptane, and 40 degree of drying obtain white (off-white color) solid
Powder, as intermediate V.Yield 90%.
Step 2 rate of charge
Intermediate V's1H NMR：
mp 93.5-95.5℃；LCMS=343.1 (M+1)+；1H NMR(CDCl3, 400MHz) δ 1.24 (d, J=6.9Hz,
6H), 1.95 (t, J=6.1Hz, 1H), 3.21 (sept, J=6.9Hz, 1H), 3.73 (s, 3H), 4.49 (m, 2H), 6.67 (d, J
=12.0Hz, 1H), 6.99 (d, J=8.6Hz, 1H), 7.30 (d, J=7.9Hz, 1H), 7.60 (dd, J1=8.0Hz, J2=
1.3Hz, 1H), 7.84 (d, J=0.7Hz, 1H)
Step 3：100ml round mouth flasks are taken, add in intermediate V and dichloromethane, are cooled to 5 DEG C hereinafter, slow under stirring
Thionyl chloride is added dropwise.By gained reaction mixture insulation reaction 2-3 hours at 15-20 DEG C, TLC monitoring reactions are completed.To mixed
It closes and water stirring 10 minutes is added in object, stratification removes water layer, compound VI is added in 100ml round-bottomed flasks, then adds
Enter tetrabutylammonium iodide, K2CO3, stirred 16-18 hours at 60 DEG C of heating, TLC monitoring response situations, after the completion of reaction, under heat preservation
Add in normal heptane and water.Water layer is discarded, (3 times) are washed with water in organic layer, yellow liquid is obtained after concentration, adds in ethyl alcohol：Water (body
Product is than being 1:20) it, stands still for crystals, obtains white powder, as final products (compound of Formula I).Yield 72%.
Step 3 reacts rate of charge
The characterization of compound of Formula I：
LCMS=638.18 (M+1)+。1H NMR(CDCl3, 400MHz) and δ 7.87 (s, 1H), 7.71-7.60 (m, 4H),
7.38 (s, 1H), 7.08 (t, 1H), 7.02-6.98 (m, 1H), 5.60 (d, J=8.0Hz, 0.5H), 5.40 (d, J=7.8Hz,
0.5H), 4.86 (d, 1H), 3.23-3.15 (m, 1H), 4.14 (d, 0.5H), 3.92 (d, 0.5H), 3.78 (m, 4H), 3.23-
3.21 (m, 1H), 1.26 (m, 6H), 0.54 (d, J=6.7Hz, 1.5H), 0.36 (d, J=6.7Hz, 1.5H)
Claims (19)
1. the preparation method of the compound of logical formula (I), this method include：
Step 1：By leading to the chloro- 5- trifluoromethyl-anilines of 2- of formula (II) and (the fluoro- 5- isopropyls -2- methoxies of 4- of logical formula (III)
Base phenyl) boric acid reacted, obtain the midbody compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) of logical formula (IV) -
5- trifluoromethyl-anilines：
Step 2：By lead to formula (IV) compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- trifluoromethyl-anilines with
Nitrite tert-butyl, acetaldehyde and alkali are reacted, and obtain 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- of logical formula (V)
Trifluoromethyl-benzyl alcohol：
Step 3：By lead to formula (V) compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- trifluoromethyl-benzyl alcohols with
Halogenating agent is reacted and obtains reaction mixture, then added in gained reaction mixture (4S, the 5R) of logical formula (VI)-
5- [3,5- bis- (trifluoromethyl) phenyl] -4- methyl-1s, 3- oxazolidine -2- ketone are reacted, obtain (4S, the 5R) of logical formula (I) -
5- [3,5- bis- (trifluoromethyl) phenyl] -3- { [4 '-fluoro- 5 '-isopropyl -2 '-methoxyl group -4- (trifluoromethyl) biphenyl -2- bases]
Methyl } -4- methyl-1s, 3- oxazolidine -2- ketone：
2. according to the method described in claim 1, wherein, the reaction in step 1 be in the organic solvent of addition aqueous slkali into
Capable.
3. according to the method described in claim 2, wherein, aqueous slkali is the K of 1-5M concentration2CO3Or Na2CO3Aqueous solution.
4. according to the method described in claim 2, wherein, aqueous slkali occupies the 20-60% of the volume of solvent.
5. according to the method described in claim 2, the reaction of wherein step 1 is mixed under inert gas shielding and in reaction
It is carried out in the case of the catalyst containing palladium is added in object.
6. the reaction of the method according to claim 2 or 5, wherein step 1 is in reaction mixture or reaction system heating
And/or, the reaction time of step 1 is 1-10 hours to carrying out at a temperature of 60-95 DEG C.
7. according to the method described in claim 6, wherein, the reaction of wherein step 1 is in reaction mixture or reaction system liter
Temperature to carrying out at a temperature of 75-85 DEG C and/or, the reaction time of step 1 is 3-5 hours.
8. the alkali in the aqueous slkali in the method according to claim 2 or 5, wherein step 1 selected from NaOH, KOH,
LiOH、K2CO3、Na2CO3Or Li2CO3。
9. method according to claim 1 or 2, wherein step 1 further comprise：After the completion of reaction, gained is reacted
Mixture is separated and obtains organic phase, organic phase saturated common salt water washing, filtering and dry, the logical formula (IV) of acquisition
Midbody compound 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- trifluoromethyl-anilines.
10. according to the method described in claim 1, the alkali wherein in step 2 is selected from NaOH, KOH, K2CO3Or Li2CO3。
11. according to the method described in claim 10, the reaction of wherein step 2 is in the presence of an organic, at -10~10 DEG C
At a temperature of carry out.
12. the reaction of the method according to claim 10 or 11, wherein step 2 carries out -3 hours 20 minutes.
13. the method according to claim 10 or 11, wherein, after reaction terminates, base is added in the reactive mixture
In the water of the 5-50% of the volume or weight of reaction mixture, then, pass through dry or evaporating organic solvent, gained residual
Object organic solvent extracts and obtains organic phase, which is concentrated, then crystallisation by cooling, obtains the object of white solid
Then white solid object is washed and dried by matter, obtain 2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- of logical formula (V)
Trifluoromethyl-benzyl alcohol.
14. the reaction of method according to claim 1 or 2, wherein step 3 carries out as follows：3.1) first by leading to formula (V)
2- (the fluoro- 5- isopropyls -2- methoxyphenyls of 4-) -5- trifluoromethyl-benzyl alcohols and halogenating agent react obtain it is halogen
For the reaction mixture of product, the 10-80% of the volume or weight based on reaction mixture is then added in the reactive mixture
Water be stirred, stratification, remove water layer and leave organic layer；3.2) logical formula (VI) is added in gained organic layer
(4S, 5R) -5- [3,5- bis- (trifluoromethyl) phenyl] -4- methyl-1s, 3- oxazolidine -2- ketone, quaternary ammonium salt and alkali are reacted.
15. according to the method for claim 14, wherein, the reaction of step 3.2) carries out 10-30 at a temperature of 40-80 DEG C
Hour.
16. according to the method for claim 14, wherein, halogenating agent is thionyl chloride；And/or
Quaternary ammonium salt is tetrabutylammonium iodide；And/or
Alkali used in step 3.2) is selected from NaOH, KOH, LiOH, K2CO3、Na2CO3Or Li2CO3。
17. method according to claim 1 or 2, wherein in step 1, compound (II):Mole of compound (III)
Than being 1:0.9-1.3；And/or
In step 2, compound (IV)：Nitrite tert-butyl:The molar ratio of acetaldehyde is 1:0.9-2:1.0-2.5；And/or
In step 3, compound (V):Halogenating agent:The molar ratio of compound (VI) is 1:1.2-5:1.0-1.4.
18. the method according to claim 11, wherein, in step 1, compound (II):The molar ratio of compound (III)
It is 1:0.95-1.2；And/or
In step 2, compound (IV)：Nitrite tert-butyl:The molar ratio of acetaldehyde is 1:1.05-1.5:1.15-1.8；And/or
In step 3, compound (V):Halogenating agent:The molar ratio of compound (VI) is 1:1.8-3.5:1.03-1.25.
19. the method according to claim 11, wherein, in step 1, compound (II):The molar ratio of compound (III)
It is 1:1-1.15；And/or
In step 2, compound (IV)：Nitrite tert-butyl:The molar ratio of acetaldehyde is 1:1.1-1.3:1.2-1.5；And/or
In step 3, compound (V):Halogenating agent:The molar ratio of compound (VI) is 1:2-3:1.05-1.2.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101374817A (en) * | 2006-01-31 | 2009-02-25 | 田边三菱制药株式会社 | Trisubstituted amine compound as inhibitors of cholesteryl ester transfer protein cetp |
| US20100167986A1 (en) * | 2005-09-30 | 2010-07-01 | Amjad Ali | Cholesteryl Ester Transfer Protein Inhibitors |
| EP2468735A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
| WO2013066768A1 (en) * | 2011-10-31 | 2013-05-10 | Merck Sharp & Dohme Corp. | Process for a cetp inhibitor |
| CN103384663A (en) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
| CN104557757A (en) * | 2004-07-02 | 2015-04-29 | 默沙东公司 | CETP inhibitors |
| CN104649993A (en) * | 2014-06-12 | 2015-05-27 | 广东东阳光药业有限公司 | Method for preparing cholesteryl ester transfer protein (CETP) inhibitor |
-
2015
- 2015-03-10 CN CN201510104458.6A patent/CN106032362B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557757A (en) * | 2004-07-02 | 2015-04-29 | 默沙东公司 | CETP inhibitors |
| US20100167986A1 (en) * | 2005-09-30 | 2010-07-01 | Amjad Ali | Cholesteryl Ester Transfer Protein Inhibitors |
| CN101374817A (en) * | 2006-01-31 | 2009-02-25 | 田边三菱制药株式会社 | Trisubstituted amine compound as inhibitors of cholesteryl ester transfer protein cetp |
| EP2468735A1 (en) * | 2010-12-23 | 2012-06-27 | LEK Pharmaceuticals d.d. | Synthesis of intermediates for preparing anacetrapib and derivates thereof |
| CN103384663A (en) * | 2010-12-23 | 2013-11-06 | 力奇制药公司 | Synthesis of intermediates for preparing anacetrapib and derivatives thereof |
| WO2013066768A1 (en) * | 2011-10-31 | 2013-05-10 | Merck Sharp & Dohme Corp. | Process for a cetp inhibitor |
| CN104649993A (en) * | 2014-06-12 | 2015-05-27 | 广东东阳光药业有限公司 | Method for preparing cholesteryl ester transfer protein (CETP) inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib;Cameron J. Smith等;《Journal of Medicinal Chemistry》;20110617;第54卷;全文 * |
| Synthesis of stable isotope labeled anacetrapib, its major metabolites and [14C]anacetrapib;Jeffrey T. Kuethe等;《J. Label Compd. Radiopharm》;20130609;第56卷;全文 * |
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