CN106032362A - Preparation method of Anacetrapib - Google Patents
Preparation method of Anacetrapib Download PDFInfo
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- CN106032362A CN106032362A CN201510104458.6A CN201510104458A CN106032362A CN 106032362 A CN106032362 A CN 106032362A CN 201510104458 A CN201510104458 A CN 201510104458A CN 106032362 A CN106032362 A CN 106032362A
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- 0 CC(C)c(c(F)c1)cc(*)c1OC Chemical compound CC(C)c(c(F)c1)cc(*)c1OC 0.000 description 1
- LMILMSJBMSEFIG-FVMDXXJSSA-N C[C@@H]([C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)O1)N(Cc(cc(C(F)(F)F)cc2)c2I)C1=O Chemical compound C[C@@H]([C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)O1)N(Cc(cc(C(F)(F)F)cc2)c2I)C1=O LMILMSJBMSEFIG-FVMDXXJSSA-N 0.000 description 1
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Abstract
The invention relates to a preparation method of a compound represented by the formula (I). The preparation method comprises the following steps: (1) reacting 2-chloro-5-trifluoromethyl-aniline (II) with (4-fluoro-5-isopropyl-2-methoxyphenyl)boric acid (III) to obtain 2-(4-fluoro-5-isopropyl-20methoxyphenyl)-5-trifluoromethyl-aniline (formula IV); (2) reacting the compound (formula IV) with tert-butyl nitrite, acetaldehyde, and alkalis to obtain 2-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol (formula V); (3) reacting the compound (formula V) with a halogenation reagent, and then adding (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2-one (VI) into the reaction mixture to carry out reactions so as to obtain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoproypyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2-one represented by the formula (I), namely Anacetrapib.
Description
Technical field
The present invention relates to bent of Ansai, i.e. (4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-3-{ [4 '-fluoro-5 '-isopropyl-2 '-
Methoxyl group-4-(trifluoromethyl) biphenyl-2-base] methyl }-4-methyl isophthalic acid, the preparation method of 3-oxazolidine-2-ketone.
Background technology
Atherosclerosis and clinical effectiveness, coronary heart disease (CHD), apoplexy and peripheral vascular disease threaten the health of the mankind.
For a long time, it has been recognized that in mammal, change and atherosclerosis and the CHD of lipoprotein distribution are circulated
Danger relevant.HMG-CoA reductase inhibitor, particularly statins, the most successfully reduce coronary artery thing
Part is based on reducing cyclic low-density lipoprotein cholesterol (LDL-C), and LDL-C level is directly related to the atherosclerosis increased
Dangerous.Recently, epidemiological study shows, HDL-C (HDL-C) level and atherosclerosis inversely related,
It is concluded that low Serum HDL-C level is relevant with the CHD danger of increase.
The Metabolism control of lipoprotein levels is to involve the complicated of many factors and dynamic process.One important metabolism of the mankind
Control is cholesterol ester transfer protein (CETP), a kind of plasma glycoprotein, and it is catalyzed cholesteryl ester from HDL to the fat containing apoB
The transfer of albumen (particularly to VLDL) (sees 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, clean reaction be wherein CETP from apoB lipoprotein carry triglyceride to HDL and from
HDL delivery of cholesterol ester exchanges (heteroexchange) to the allos of apoB lipoprotein.
In the mankind, CETP works in reversion cholesterol transport, and by this Umklapp process, cholesterol returns from peripheral tissues
Return liver.
The open CN1980904A (200580022618.7) of Chinese patent discloses (4S, 5R)-5-[3,5-bis-(trifluoromethyl) benzene
Base]-3-{ [4 '-fluoro-5 '-isopropyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone
(i.e. bent of Ansai) and preparation method thereof (seeing embodiment 73).This compound can be used for suppressing cholesterol ester transfer protein (CETP)
And therefore can be used for treating and preventing atherosclerosis.Wherein in embodiment 73, the method that preparation Ansai is bent includes two
Step:
Step 1:(4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-oxazolidine-2-ketone (formula A) and 2-(bromomethyl)-1-
Iodo-4-(trifluoromethyl) benzene (Formula B) reacts, it is thus achieved that (4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-3-[2-iodo-5-(fluoroform
Base) benzyl]-4-methyl isophthalic acid, 3-oxazolidine-2-ketone (formula C):
Step 2:(4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-3-[2-iodo-5-(trifluoromethyl) benzyl]-4-methyl isophthalic acid, 3-oxazolidine-2-
Ketone (formula C) reacts with (4-fluoro-5-isopropyl-2-methoxyphenyl) boric acid (general formula D), it is thus achieved that the bent (formula in end-product Ansai
I):
But, in the said method of CN1980904A, reaction condition is harsher, and uses toxic, expensive urging
Change reagent.Initiation material is not readily available and its preparation cost is higher.In complete reaction scheme, post processing seems and compares
Trouble, byproduct of reaction is more.The yield of end-product is on the low side, and the preparation cost of end-product is higher.
Summary of the invention
It is an object of the invention to provide the preparation method of the compound of logical formula (I), the method includes:
Step 1: by (the 4-fluoro-5-isopropyl-2-methoxyl group of the 2-of logical formula (II) chloro-5-trifluoromethyl-aniline Yu logical formula (III)
Phenyl) boric acid reacts, it is thus achieved that midbody compound 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-three of logical formula (IV)
Methyl fluoride-aniline:
Step 2: by compound 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-aniline of logical formula (IV) with sub-
The nitric acid tert-butyl ester, acetaldehyde and alkali (such as potassium hydroxide or sodium hydroxide) carry out reacting (or by the compound of logical formula (IV) and nitrous acid
The tert-butyl ester, acetaldehyde react in the presence of a base), it is thus achieved that 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-of logical formula V
Trifluoromethyl-benzyl alcohol:
Step 3: by compound 2-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol and the halogen of logical formula V
Carry out reacting (i.e. hydroxyl by the reaction of halo, or the reaction that is optionally substituted by halogen of hydroxyl) for reagent and to obtain (containing halogenated product) anti-
Answer mixture, add (4S, 5R)-5-[3,5-bis-(trifluoromethyl) the phenyl]-4-methyl of logical formula (VI) the most in the reactive mixture
-1,3-oxazoles alkane-2-ketone reacts, it is thus achieved that (4S, 5R)-5-[3,5-bis-(trifluoromethyl) the phenyl]-3-{ of logical formula (I) [4 '-
Fluoro-5 '-isopropyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone:
Preferably, the reaction in step 1 is to add aqueous slkali (such as 1-5M concentration, preferred 2-4M concentration, as dense in 3M
The K of degree2CO3Or Na2CO3Aqueous solution) organic solvent (such as acetonitrile) (preferably, aqueous slkali accounts for or is equivalent to the body of organic solvent
Long-pending 20-60%, preferred 30-50%) (that is: two phase liquid system) is carried out.It is further preferred that the reaction of step 1 be
Noble gas (such as nitrogen or argon) protection is lower and adds the catalyst (such as Pd (PPh containing palladium in the reactive mixture3)4) feelings
Carry out under condition.Typically, the reaction of step 1 be reactant mixture or reaction system be warming up to 60-95 DEG C, preferred 70-90 DEG C,
Carry out at a temperature of more preferably 75-85 DEG C.The response time of step 1 is usually 1-10 hour, preferably 2-6 hour, more excellent
Select 3-5 hour.
Preferably, step 1) described in alkali in aqueous slkali selected from NaOH, KOH, LiOH, K2CO3、Na2CO3Or Li2CO3。
Preferably, alkali is selected from K2CO3、Na2CO3。
Preferably, step 1 farther includes: after the completion of reaction, carries out being separated by gained reactant mixture and has obtained
Machine phase, organic facies saturated aqueous common salt washs, and filters, and is dried, it is thus achieved that midbody compound 2-(the fluoro-5-of 4-of logical formula (IV)
Isopropyl-2-methoxyphenyl)-5-trifluoromethyl-aniline.
Preferably, the alkali in step 2 is selected from NaOH, KOH, K2CO3Or Li2CO3；Preferably, alkali selected from NaOH or
KOH.Typically, the reaction of step 2 is to carry out in the presence of described alkali and organic solvent (such as acetonitrile).Preferably, this reaction
Carry out at a temperature of-10～10 DEG C, preferably-5～5 DEG C.
Typically, the reaction of step 2 carries out 20 minutes-3 hours, preferably 25 minutes-2 hours, and more preferably 30 minutes-1.5 little
Time.Preferably, after reaction terminates, add volume or weight based on reactant mixture in the reactive mixture
The water of 5-50% (preferably 8-40%, more preferably 12-30%), then, removes organic molten by being dried or evaporating (such as rotary evaporation)
Agent (such as acetonitrile), gained residue organic solvent (such as ethyl acetate) extracts and obtains organic facies, and this organic facies is concentrated,
Then crystallisation by cooling, it is thus achieved that the material of white solid, then washs white solid thing and is dried, and obtains the 2-(4-of logical formula V
Fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol.
Preferably, the reaction of step 3 is that (using " one kettle way ") is carried out as follows: 3.1) first by the 2-(4-of logical formula V
Fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol and halogenating agent carry out reaction and obtain reactant mixture, then
Add the 10-80% of volume or weight based on reactant mixture, preferred 20-60%, more preferably 30-50% in the reactive mixture
Water be stirred, stratification, remove water layer and leave organic layer；3.2) in gained organic layer, logical formula (VI) is added
(4S, 5R)-5-[3,5-bis-(trifluoromethyl) phenyl]-4-methyl isophthalic acid, 3-oxazolidine-2-ketone, quaternary ammonium salt and alkali carry out reacting (such as
10-30 hour, preferably 12-22 hour, more preferably 15-19 hour), it is preferred that this reaction be 40-80 DEG C, preferably
Carry out at 50-70 DEG C, more preferably 55-65 DEG C.
Preferably, halogenating agent is thionyl chloride, phosphorus oxychloride or phosphorus pentachloride.Described quaternary ammonium salt be tetrabutylammonium iodide,
Tetrabutyl ammonium fluoride or tetrabutylammonium chloride.In step 3.2) used in alkali selected from NaOH, KOH, LiOH, K2CO3、Na2CO3
Or Li2CO3；Preferably, alkali is selected from K2CO3、Na2CO3。
Preferably, in step 1, compound (II): the mol ratio of compound (III) is 1:0.9-1.3, preferably 1:
0.95-1.2, more preferably 1:1-1.15.
Preferably, in step 2, compound (IV): nitrite tert-butyl: the mol ratio of acetaldehyde is 1:0.9-2:
1.0-2.5, preferably 1:1-1.8:1.1-2.2, more preferably 1:1.05-1.5:1.15-1.8, more preferably 1:1.1-1.3:
1.2-1.5。
Preferably, in step 2, compound (IV): the mol ratio of potassium hydroxide is 1:0.3-0.7, preferably 1:0.4-0.6,
More preferably 1:0.5.
Preferably, in step 3, compound (V): halogenating agent: the mol ratio of compound (VI) is 1:1.2-5:
1.0-1.4, preferably 1:1.6-4:1.02-1.3, more preferably 1:1.8-3.5:1.03-1.25, more preferably 1:2-3:
1.05-1.2。
Advantages of the present invention
1 compares with the synthetic route of existing patent report, and in route, reaction condition is gentle, it is to avoid toxicity, expensive catalysis examination
Agent.
2, initiation material is cheap and easily-available, and W-response yield is 45%, reduces whole reaction cost.
3, reaction scheme post-processing approach is simple, and byproduct of reaction is few, it is adaptable to industry's enlarging production.
Accompanying drawing explanation
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 end-product I.
Specific embodiment
Embodiment 1
Step 1: the flask being furnished with reflux condenser toward 100mL adds compound II, compound III, acetonitrile and 3M K2CO3。
The two phase liquid of gained nitrogen bubble 5 minutes.Adding catalyst Pd (PPh3) 4 under nitrogen protection, reaction is warming up to 80 DEG C,
Stirred under nitrogen atmosphere 3-4 hour, after TLC monitoring reaction completely, is cooled to reactant mixture room temperature and separates biphase.Point
Layer, collected organic layer, with saturated brine It 1-2 time, in addition activated carbon (0.20g) to organic layer, stirring 1 under room temperature
Hour, then mixture is filtered by kieselguhr.Filtrate is added a small amount of acetonitrile azeotropic drying, obtains pale yellow oil.I.e.
For 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) 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: take 100mL round-bottomed flask, adds intermediate compound IV, nitrite tert-butyl, acetaldehyde, potassium hydroxide and acetonitrile.
After stirring 30min-1h, TLC monitoring reaction completely at 0 DEG C, add 20ml water and stir 1 hour, then acetonitrile rotation is removed, use
Ethyl acetate extracts 3 times, merges organic facies, concentrates organic facies, obtains pale yellow oily liquid body, adds normal heptane, is transferred to
Refrigerator stands crystallize.Sucking filtration obtains white (off-white color) solid, washs 1-2 time with frozen water and cold normal heptane, 40 degree of bakings
Dry, obtain white (off-white color) pressed powder, wash 1-2 time with frozen water and cold normal heptane, 40 degree of drying, obtain white
(off-white color) pressed powder, is 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=12.0
Hz, 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: take 100ml round mouth flask, adds intermediate V and dichloromethane, is cooled to less than 5 DEG C, and stirring is lower slowly
Dropping thionyl chloride.By gained reactant mixture insulation reaction 2-3 hour at 15-20 DEG C, TLC monitoring reaction completes.To
Mixture adds water stir 10 minutes, stratification, removes water layer, compound VI is joined in 100ml round-bottomed flask,
Add tetrabutylammonium iodide, K2CO3, heating up and stir 16-18 hour at 60 DEG C, TLC monitors response situation, and reaction completes
After, insulation is lower adds normal heptane and water.Discard water layer, organic layer is washed with water (3 times), obtain yellow liquid after concentration, add
Enter ethanol: water (volume ratio is 1:20), standing crystallizes, obtains white powder, be final products (compound of Formula I).Receive
Rate 72%.
Step 3 reacts rate of charge
The sign 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 (11)
1. leading to the preparation method of the compound of formula (I), the method includes:
Step 1: by (the 4-fluoro-5-isopropyl-2-methoxyphenyl) of the 2-of logical formula (II) chloro-5-trifluoromethyl-aniline Yu logical formula (III)
Boric acid reacts, it is thus achieved that and midbody compound 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl of logical formula (IV)-
Aniline:
Step 2: by compound 2-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-aniline and the nitrous acid of logical formula (IV)
The tert-butyl ester, acetaldehyde and alkali react, it is thus achieved that 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-benzyl of logical formula V
Base alcohol:
Step 3: tried with halo by compound 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-benzyl alcohol of logical formula V
Agent carries out reacting and obtaining reactant mixture, then adds (4S, 5R)-5-[3,5-bis-(three of logical formula (VI) in gained reactant mixture
Methyl fluoride) phenyl]-4-methyl isophthalic acid, 3-oxazolidine-2-ketone reacts, it is thus achieved that (4S, 5R)-5-[3,5-bis-(trifluoromethyl) benzene of logical formula (I)
Base]-3-{ [4 '-fluoro-5 '-isopropyl-2 '-methoxyl group-4-(trifluoromethyl) biphenyl-2-base] methyl }-4-methyl isophthalic acid, 3-oxazolidine-2-ketone:
Method the most according to claim 1, wherein, the reaction in step 1 is that (such as 1-5M is dense adding aqueous slkali
Degree, preferred 2-4M concentration, K such as 3M concentration2CO3Or Na2CO3Aqueous solution) organic solvent (such as acetonitrile) (preferably, alkali
Solution accounts for the 20-60% of the volume of organic solvent, preferred 30-50%) in carry out.
Method the most according to claim 2, wherein the reaction of step 1 is to protect at noble gas (such as nitrogen or argon)
Add down and in the reactive mixture catalyst (such as Pd (the PPh containing palladium3)4Carry out in the case of).
The most according to the method in claim 2 or 3, wherein the reaction of step 1 is to heat up at reactant mixture or reaction system
To 60-95 DEG C, carry out at a temperature of preferred 70-90 DEG C, more preferably 75-85 DEG C, and/or, the response time of step 1 is
1-10 hour, preferably 2-6 hour, more preferably 3-5 hour.
5., according to the method in any of the one of claim 2-4, wherein the alkali in the described aqueous slkali in step 1 is selected from
NaOH、KOH、LiOH、K2CO3、Na2CO3Or Li2CO3；Preferably, alkali is selected from K2CO3、Na2CO3。
6. according to the method in any of the one of claim 1-5, wherein step 1 farther includes: after the completion of reaction,
Carrying out gained reactant mixture being separated and obtaining organic facies, organic facies saturated aqueous common salt washs, and filters, and is dried, and obtains
Obtain midbody compound 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-aniline of logical formula (IV).
7., according to the method in any of the one of claim 1-6, wherein the alkali in step 2 is selected from NaOH, KOH, K2CO3
Or Li2CO3；Preferably, described alkali is selected from NaOH or KOH；Preferably, wherein the reaction of step 2 is in organic solvent (example
Such as acetonitrile) in the presence of, carry out at a temperature of-10～10 DEG C, preferably-5～5 DEG C.
Method the most according to claim 7, wherein the reaction of step 2 carries out 20 minutes-3 hours, preferably 25 minutes
-2 hours, more preferably 30 minutes-1.5 hours；Preferably, after reaction terminates, add in the reactive mixture based on
The water of the 5-50% (preferably 8-40%, more preferably 12-30%) of the volume or weight of reactant mixture, then, by being dried or steaming
Sending out (such as rotary evaporation) and remove organic solvent (such as acetonitrile), gained residue is with organic solvent (such as ethyl acetate) extraction
Obtaining organic facies, this organic facies is concentrated, then crystallisation by cooling, it is thus achieved that the material of white solid, then by white solid thing
Wash and be dried, obtain 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-benzyl alcohol of logical formula V.
9. according to the method in any of the one of claim 1-8, wherein the reaction of step 3 is carried out as follows: 3.1) first
Carried out reacting acquisition by 2-(4-fluoro-5-isopropyl-2-the methoxyphenyl)-5-trifluoromethyl-benzyl alcohol of logical formula V and halogenating agent to contain
The reactant mixture of halogenated product, add the most in the reactive mixture volume or weight based on reactant mixture 10-80%,
The water of preferably 20-60%, more preferably 30-50% is stirred, stratification, removes water layer and leaves organic layer；3.2) in institute
Obtain (4S, 5R)-5-[3,5-bis-(trifluoromethyl) the phenyl]-4-methyl isophthalic acid adding logical formula (VI) in organic layer, 3-oxazolidine-2-ketone, quaternary ammonium salt
Carry out with alkali reacting (such as 10-30 hour, preferably 12-22 hour, more preferably 15-19 hour), it is preferred that this reaction is
40-80 DEG C, carry out at a temperature of preferred 50-70 DEG C, more preferably 55-65 DEG C.
Method the most according to claim 9, wherein, halogenating agent is thionyl chloride；And/or
Quaternary ammonium salt is tetrabutylammonium iodide；And/or
In step 3.2) used in alkali selected from NaOH, KOH, LiOH, K2CO3、Na2CO3Or Li2CO3；Preferably, alkali
Selected from K2CO3、Na2CO3。
11. according to the method in any of the one of claim 1-10, the most in step 1, and compound (II): compound
(III) mol ratio is 1:0.9-1.3, preferably 1:0.95-1.2, more preferably 1:1-1.15；And/or,
In step 2, compound (IV): nitrite tert-butyl: the mol ratio of acetaldehyde is 1:0.9-2:1.0-2.5, excellent
Select 1:1-1.8:1.1-2.2, more preferably 1:1.05-1.5:1.15-1.8, more preferably 1:1.1-1.3:1.2-1.5；
And/or
In step 3, compound (V): halogenating agent: the mol ratio of compound (VI) is 1:1.2-5:1.0-1.4,
Preferably 1:1.6-4:1.02-1.3, more preferably 1:1.8-3.5:1.03-1.25, more preferably 1:2-3:1.05-1.2.
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| CAMERON J. SMITH等: "Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester Transfer Protein Inhibitors: Modifications of the Oxazolidinone Ring Leading to the Discovery of Anacetrapib", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| JEFFREY T. KUETHE等: "Synthesis of stable isotope labeled anacetrapib, its major metabolites and [14C]anacetrapib", 《J. LABEL COMPD. RADIOPHARM》 * |
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| CN106032362B (en) | 2018-06-19 |
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