CN103254107A - Ezetimibe analogue and preparation method thereof - Google Patents
Ezetimibe analogue and preparation method thereof Download PDFInfo
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- CN103254107A CN103254107A CN2013101702863A CN201310170286A CN103254107A CN 103254107 A CN103254107 A CN 103254107A CN 2013101702863 A CN2013101702863 A CN 2013101702863A CN 201310170286 A CN201310170286 A CN 201310170286A CN 103254107 A CN103254107 A CN 103254107A
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Abstract
The invention relates to an ezetimibe analogue and a preparation method thereof. The structure general formula of the ezetimibe analogue is shown in a structural formula, wherein in the formula, R1, R2 and R3 are selected from fluorine atom, hydroxyl, hydrogen atom and methoxy independently. The ezetimibe analogue is an ideal inhibitor for sucking cholesterol, and the cholesterol inhibitor can obviously prevent Caco-2 cells from sucking the cholesterol, so that the ezetimibe analogue has the prospect of becoming the inhibitor for sucking the cholesterol.
Description
Technical field
The invention belongs to cholesterol absorption inhibitor and preparation field thereof, particularly a kind of ezetimibe analogue and preparation method thereof.
Background technology
The primary hazard factor of atherosclerosis and coronary heart disease is hypercholesterolemia.Though dietary adjustments has certain control action kou to hyperlipidemia, Most patients finally still needs pharmacological agent.Though vast amount of clinical confirms that lipid-lowering statins can obviously improve blood fat disorder, and can reduce the M ﹠ M of cardiovascular disorder, but because untoward reaction or patient's sensitivity differences of his heavy dose of spit of fland medicine, a lot of patients do not reach desirable lipopenicillinase target.2002, ezetimibe Ezetimibe (SCH58235) as a kind of novel cholesterol absorption inhibitor at U.S.'s official listing, it can be singly with or with the statins combined utilization, to reduce its drug side effect.
The discovery of Ezetimibe and development are very interesting courses.Because the research that beta-lactam begins in cholesterol absorption inhibition field most is the inhibitor as cholesterol acetyltransferase (ACAT).Show that through more far-reaching experiment lactan can suppress small intestine to the absorption of cholesterol with a peculiar mechanism, but the protein of target is not clear at present.But by the screening of a series of active compound, lactan SCH48461 was in the news because of the cholesteryl ester (LCE) that can reduce significantly in the liver in 1994.The separation of the high reactivity metabolite by SCH48461 and the effort of synthetic chemistry, the structure of active compound is optimised for Ezetimibe(SCH58235).
It is also indeterminate to the mechanism of the absorption of cholesterol that Ezetimibe suppresses small intestine, illustrated substantially but suppress the active structure-activity relationship that concerns Ezetimibe by similar compound and cholesterol.Studies show that lactam nucleus is and important pharmacophore that similarly open chain amino acid and sulphur lactam compound all do not have activity.The length of side chain is that restricted 3 carbon are best, greater than 6 to no effect.The N of lactan goes up phenyl ring and the side chain phenyl ring is pharmacophore, and the replacement of the last phenyl ring of N does not have very big influence, but the replacement of side chain phenyl ring has specificity, only only has or not replacement or C-4 position to be replaced by F and produces effect.The C-4 position of the last phenyl ring of N and side chain phenyl ring C-4 position are replaced by F and can stop or the metabolism of slowing down, thereby strengthen the effect that suppresses.Hydroxyl on the side chain and chirality thereof, the oxygen of the chirality phenyl ring C-4 of lactam nucleus C-4 position is necessary, this may be because oxygen is a good electron donor, thereby can form ADME(absorption, distribution, metabolism, the drainage that hydrogen bond is conducive to medicine greatly with the hydroxyl of side chain).Thus, (J.Med.Chem.2005 such as Carreira in 2005,48,6035-6053) reported that the phenolic hydroxyl group to the contraposition of heterocycle C-4 phenyl ring carries out glycosylation modified, found several up-and-coming small molecules by external intestinal brush border film experiment, expectation finally is applied to the treatment of cardiovascular disorder by cholesterol in the reduction blood.Therefore, C-4 modifies to heterocycle, has become active better that cholesterol absorption is suppressed, side effect effective ways still less.
Summary of the invention
Technical problem to be solved by this invention provides a kind of ezetimibe analogue and preparation method thereof, this product is a kind of desirable cholesterol absorption inhibitor, but such cholesterol inhibitor obvious suppression Caco-2 cell has the prospect that becomes the cholesterol absorption inhibitor medicine to the absorption of cholesterol.
A kind of ezetimibe analogue of the present invention, general structure is shown below:
The structural formula of described ezetimibe analogue is
The synthetic method of Ezetimibe analogue of the present invention comprises the steps:
(1) be starting raw material with trifluoroacetic acid and to amino benzenes compounds, back flow reaction under the effect of triphenyl phosphorus and tetracol phenixin is removed phosphorous oxides and solvent, and through underpressure distillation, preparation 2,2,2-trifluoromethanesulfonyl imide is for Acetyl Chloride 98Min. 3;
(2) 3 tetrahydrofuran solution is added dropwise to (LDA is alkali) in the alkaline environment with Ai Wensi chirality prothetic group, desolventizing, resistates is collected product through the silica gel column chromatography wash-out, and preparation has the fluorine-containing crotonoyl oxazolidone 5 of chirality prothetic group;
(3) fluorine-containing alkene acyl oxazolidone 5 hydrogenations under the catalysis of palladium carbon are revolved and are desolventized recrystallization, prepare optically pure fluorine-containing butyryl oxazolidone 6;
(4) fluorine-containing butyryl oxazolidone 6 removes the chirality prothetic group and obtains β-trifluoromethyl-beta-amino acids 7 under lithium hydroxide and hydrogen peroxide effect;
(5) β-trifluoromethyl-beta-amino acids 7 that is dissolved in the methyl alcohol obtains β-trifluoromethyl-beta-amino ester 8 through the thionyl chloride processing at low temperatures;
(6) make alkali at methyl-magnesium-bromide, ether is that β-trifluoromethyl under the solvent-beta-amino ester 8 is converted into optically pure β-trifluoromethyl-beta-lactam 9;
(7) LHMDS makes alkali, and four furans are solvent, and HMPA is activator, with β-trifluoromethyl-beta-lactam 9 and 10 reactions of side chain 3-iodine propylbenzene, silicon class protecting group and hydrogen fluoride pyridine reactant salt is arranged, and obtains target product ezetimibe analogue 2 through aftertreatment.
Ezetimibe analogue of the present invention is as cholesterol absorption inhibitor, be combined by membranin on intestinal brush border film vesicles, suppress small intestine to being transported to the absorption of the cholesterol in the enteron aisle in the diet and through bile, reduce the cholesterol level in serum and the liver and reach the treatment hyperlipidaemia.
Beneficial effect
(1) the present invention is a kind of desirable cholesterol absorption inhibitor with the phenolic groups that trifluoromethyl replaces Ezetimibe heterocycle C-4, and fluorine atom can play the oxygen of phenolic hydroxyl group as the effect of intramolecular hydrogen bond acceptor.The introducing of trifluoromethyl group can increase the membrane permeability, fat-soluble of active compound, can make that lactam nucleus is stable more to be difficult in vivo by metabolism (be the pharmacophore of this type of medicine because of lactam nucleus), thereby can improve the ADME of this medicine;
(2) find by this type of synthetic cholesterol inhibitor is tested Caco-2 cellular cholesterol assimilating activity, but such cholesterol inhibitor obvious suppression Caco-2 cell has the prospect that becomes the cholesterol absorption inhibitor medicine to the absorption of cholesterol.Can raise a presumption first simultaneously: the phenyl ring of heterocycle C-4 position is not the pharmacophore of Ezetimibe, has proposed the new direction of research for the improvement of this class medicine.
Description of drawings
Fig. 1 is the development synoptic diagram of Ezetimibe;
Fig. 2 (a) and (b) be respectively intermediate that embodiment 1 step 2 obtains
1H NMR with
13C NMR figure;
Fig. 3 (a) and (b) be respectively intermediate that embodiment 1 step 3 obtains
1H NMR with
13C NMR figure;
Fig. 4 (a) and (b) be respectively intermediate that embodiment 1 step 4 obtains
1H NMR with
13C NMR figure;
Fig. 5 (a) and (b) be respectively intermediate that embodiment 1 step 5 obtains
1H NMR with
13C NMR figure;
Fig. 6 (a) and (b) be respectively intermediate that embodiment 1 step 6 obtains
1H NMR with
13C NMR figure;
Fig. 7 (a) and (b) be respectively intermediate that embodiment 1 step 7 obtains
1H NMR with
13C NMR figure.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
1. intermediate 3d(2,2,2-trifluoro-N-(4-fluorophenyl) acetimidoyl chloride) synthetic:
In a dry there-necked flask of the 25mL nitrogen protection that prolong is housed, add Ph
3P (33mmol, 8.655g), Et
3N (13.2mmol, 1.825mL), CCl
4(55mmol, 5.275mL) and trifluoroacetic acid (11mmol 1.254g), reaction flask stirs 10 minutes in ice bath after, adds para-fluoroaniline (11mmol, CCl 1.221g) in reaction flask
4(55mmol, 5.275mL) solution, behind the reaction 3h, solvent under reduced pressure revolves and removes mixture under refluxing, and the solid mixture that obtains is washed and filtered with normal hexane, filtrate concentrates the back underpressure distillation, obtain product 3d, ((E)-4-fluoro-N-trifluoro acetal) aniline, this compound gets nuclear magnetic data and document (J.Org.Chem.1993,58,32) report is consistent.
2. intermediate 5d's is synthetic:
(S,Z)-4-benzyl-3-(4,4,4-trifluoro-3-(4-fluorophenylamino)but-2-enoyl)oxazolidin-2-one(5d).
In the there-necked flask of a 25mL nitrogen protection anhydrous and oxygen-free, add anhydrous THF (4mL) and be cooled to-60 ° of C; add LDA(2.5mL; 2Min THF) after; again to wherein dripping compound 4(2.5mmol; 0.513g; (S)-3-ethanoyl-4-benzyl oxazolidine-2-ketone); reaction flask is after this temperature stirs two hours; temperature of reaction is down to-78 ° of C; and to wherein dropwise dripping compound 3d (2.5mmol, THF(6mL 0.563g)) solution, the TLC monitoring; disappear until raw material, with saturated ammonium chloride solution quencher reaction.With ethyl acetate extraction three times, anhydrous sodium sulfate drying, revolve and desolventize, silica gel column chromatography separates and obtains compound 5d, (S, Z)-4-benzyl-3-(4,4,4-, three fluoro-3-((4-fluoroaniline) but-2-ene acyl) oxazolidine-2-ketone.Productive rate 63%, Z:E=27:1 (head product fluorine spectrum determines).
mp110–111℃;[α]
D24.3-58.2(c0.67,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ10.80(s,1H),7.36(t,J=7.2Hz,2H),7.31(d,J=6.9Hz,1H),7.28–7.20(m,4H),7.07(t,J=8.1Hz,2H),6.92(s,1H),4.78(d,J=6.9Hz,1H),4.31–4.13(m,2H),3.39(d,J=13.3Hz,1H),2.83(dd,J=10.0,2.4Hz,1H).
13C?NMR(101MHz,CDCl
3)δ167.4,161.6(d,J=247.2Hz),153.1,149.2(q,J=31.1Hz),135.5,133.6(d,J=3.1Hz),129.4,129.0,128.5(d,J=8.4Hz),127.4,120.2(q,J=276.4Hz),115.9(d,J=22.8Hz).86.9(q,J=5.6Hz),66.2,55.1,38.2.
19F?NMR(377MHz,CDCl
3)δ-63.16(s,3F),-114.23(d,1F).IR(KBr)
max3155,3064,3023,2982,2921,1776,1637,1506,1311,1191,1142,842,703cm
-1;MS(EI)m/z409.0M
+;HRMS(EI)m/z[M+Na]
+calcd?for?C
20H
16F
4N
2Na
1O
3,431.0989;Found,431.0984.
3. intermediate 6d's is synthetic:
(S)-4-benzyl-3-((S)-4,4,4-trifluoro-3-(4-fluorophenylamino)butanoyl)oxazolidin-2-one(6d).
(0.31mmol 0.34g), adds the afterreaction bottle with hydrogen exchange three times, to wherein adding compound 5d(3.1mmol, methyl alcohol 1.27g) (15mL) solution to add Pd/C in the 25mL there-necked flask of the nitrogen protection of a drying.Be reflected to stir in hydrogen (1atm) atmosphere and spend the night.Filter, methyl alcohol is washed, and filtrate is spin-dried for, and uses the mixed solvent sherwood oil: ethyl acetate=4:1 recrystallization obtains compound 6d, (4S)-and 4-benzyl-3-(4,4,4-trifluoromethyl-3-(4-fluoroaniline) butyryl) oxazolidine-2-ketone.Productive rate 73%, dr〉99:1.
mp164–166℃;[α]
D26.0-354.7(c0.21,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ7.28(s,3H),7.14(d,J=5.8Hz,2H),6.93(t,J=8.1Hz,2H),6.73(s,2H),4.62(s,2H),4.18(d,J=3.9Hz,2H),3.92(s,1H),3.63(dd,J=15.5,9.5Hz,1H),3.18(dd,J=25.4,14.7Hz,2H),2.73–2.60(m,1H).
13C?NMR(101MHz,CDCl
3)δ169.1,156.9(d,J=237.7Hz),153.6,142.07(d,J=2.2Hz),134.8,129.4,129.0,127.5,125.5(q,J=282.0Hz),116.0(d,J=22.6Hz),115.4(d,J=7.6Hz),66.4,55.4,54.2(q,J=30.2Hz),37.5,35.4.
19F?NMR(377MHz,CDCl
3)δ-75.89(d,J=6.6Hz,3F),-125.26(s,1F).IR(KBr)
max3346,3023,2982,2921,1762,1689,1512,1399,1221,1175,1117,990,833,756,707cm
-1;MS(EI)m/z411.0M
+;HRMS(EI)m/z?M
+calcd?for?C
20H
19F
4N
2O
3,411.1326;Found,411.1343.
4. intermediate 7b's is synthetic:
(S)-4,4,4-trifluoro-3-(4-fluorophenylamino)butanoic?acid(7b).
With compound 6d (7.3mmol, THF:H 3.0g)
2(4:1,29mL) mixing solutions joins in the there-necked flask of a 100mL O, slowly dropping H under 0 ° of C
2O
2(30%, 4.3mL), slowly add LiOHH subsequently
2(12.2mmol, aqueous solution 4mL 0.513g) are reflected at 0 ° of C and kept two hours O.After finishing, the TLC monitoring reaction adds Na
2SO
3Consume remaining H
2O
2, conditioned reaction liquid pH value to 12, with ethyl acetate extraction three times, discard organic phase after, water layer is regulated the pH value to 1-2, uses ethyl acetate extraction again three times, organic phase concentrates, silica gel column chromatography gets 7b, 4,4,4-, three fluoro-3-((4-fluorobenzene) amido) butyric acid.Productive rate 99%.
mp98–99℃;[α]
D27.4+326.8(c0.41,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ7.54(s,1H),6.92(t,J=8.1Hz,2H),6.70(s,2H),4.40(s,1H),2.89(d,J=16.1Hz,1H),2.65(dd,J=16.0,9.0Hz,1H).
13C?NMR(101MHz,CDCl
3)δ175.7,157.1(d,J=237.9Hz,),141.7(d,J=2.0Hz),125.4(q,J=283.8Hz),115.9,(d,J=22.6Hz)115.7(d,J=7.6Hz),54.2(q,J=30.2Hz),34.8.
19F?NMR(377MHz,CDCl
3)δ-76.02(d,J=6.4Hz,3F),-124.88(s,1F).IR(KBr)
max3393,3055,2933,1714,1517,1041,1265,1173,1123,822,632cm
-1;MS(EI)m/z250.1[M–H]
-;HRMS(EI)m/z[M–H]-calcd?for?C
10H
8F
4N
1O
2,250.0497;Found,250.0493.
5. intermediate 8b's is synthetic:
(S)-methyl4,4,4-trifluoro-3-(4-fluorophenylamino)butanoate(8b).
In the 25mL there-necked flask of an anhydrous and oxygen-free nitrogen protection, add compound 7b(6.77mmol; 1.7g) anhydrous methanol (12.2mL) solution; under 5 ° of C, react 0.5h; subsequently thionyl chloride (8.13mmol, 0.967g) by joining in the reaction flask slowly, holding temperature is at 10-15 ° of C; add the afterreaction bottle and be warming up to 60 ° of C; continue reaction 1.5h, be cooled to room temperature and add toluene (12mL), add NaHCO under the ice bath
3(17mmol reacts 1h after 1.428g) again, the reaction solution ethyl acetate extraction, and anhydrous sodium sulfate drying concentrates the back silica gel column chromatography and obtains 8b, 4,4,4-, three fluoro-3-((4-fluorobenzene) amido) methyl-butyrate.Productive rate 96%.
mp58–59℃;[α]
D26.8-15.0(c0.30,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ6.92(t,J=8.1Hz,2H),6.71(d,J=4.0Hz,2H),4.40(dd,J=6.7,4.4Hz,1H),3.70(s,3H),3.68(s,1H),2.84(dd,J=15.8,3.3Hz,1H),2.63(dd,J=15.8,8.9Hz,1H).
13C?NMR(101MHz,CDCl
3)δ169.9,156.9(d,J=237.6Hz),142.0(d,J=1.9Hz),125.5(q,J=283.7Hz),115.9(d,J=22.6Hz),115.5(d,J=7.6Hz),54.5(q,J=30.2Hz),52.3,34.7.
19F?NMR(377MHz,CDCl
3)δ-76.11(d,J=6.7Hz,3F),-125.28(s,1F).IR(KBr)
max3375,3121,3047,2959,1743,1519,1438,1364,1291,1109,988,905,820,659cm
-1;MS(EI)m/z266.1M
+;HRMS(EI)m/z?M
+calcd?for?C
11H
10F
4N
1O
2,264.0653;Found,264.0654.
6. intermediate 9b's is synthetic:
(S)-1-(4-fluorophenyl)-4-(trifluoromethyl)azetidin-2-one(9b).
In the 50mL there-necked flask of an anhydrous and oxygen-free nitrogen protection; add compound 8b(5.7mmol; 1.51g) anhydrous ether solution (14mL); after reaction flask being cooled to-12 ° of C; drip MeMgBr (11.4mmol; 2.8M/L) anhydrous diethyl ether (6mL) solution, add the back and continue reaction at-12 ° of C, disappear until raw material.Put out reaction with saturated ammonium chloride solution, extracted with diethyl ether three times, the saturated NaHCO of organic phase
3Wash, anhydrous sodium sulfate drying concentrates the back silica gel column chromatography and obtains 9b, (S)-and 1-(4-fluorophenyl)-4-(trifluoromethyl) nitrogen heterocyclic din-2-ketone.Productive rate 62%.
mp49–50℃;[α]
D28.5-240.5(c0.21,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ7.42(dd,J=7.2,4.7Hz,2H),7.07(t,J=8.0Hz,2H),4.63–4.46(m,1H),3.38(dd,J=15.5,5.7Hz,1H),3.22(d,J=15.5Hz,1H).
13C?NMR(101MHz,CDCl
3)δ162.4,159.8(d,J=244.9Hz),132.8(d,J=2.9Hz),124.2(q,J=280.0Hz),119.2(d,J=8.0Hz),116.1(d,J=22.9),50.9(q,J=35.7Hz),38.7.
19FNMR(377MHz,CDCl
3)δ-73.66(d,J=5.0Hz,3F),-116.35–-116.37(m,1F).IR(KBr)
max3080,2974,1774,1512,1390,1281,1223,1147,943,830,658cm
-1;MS(EI)m/z234.1M
+;HRMS(EI)m/z[M-H]
-calcd?for?C
10H
6F
4N
1O
1,232.0391;Found,232.0393.
7. target product 2d's is synthetic:
(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(trifluoromethyl)azetidin-2-one(2d).
In the 25mL there-necked flask of an anhydrous and oxygen-free nitrogen protection; add compound 9b (0.3mmol; anhydrous tetrahydrofuran solution 70mg) (2mL); after reaction flask being cooled to-78 ℃; be dissolved with LHMDS (0.36mmol; 1M in THF) anhydrous tetrahydrofuran solution (2mL) is added dropwise in the reaction flask; after continuing reaction 0.5h; to wherein adding HMPA (2.16mmol; 0.388g), after continuing to stir 0.5h, compound 10b (1.2mmol; 0.451g, (S)-tert-butyl (3-iodo-1-phenyl propoxy-) dimethylsilane) anhydrous tetrahydrofuran solution (2mL) be added dropwise in the reaction flask.The TLC monitoring disappears until raw material, puts out reaction with saturated ammonium chloride solution.Ethyl acetate extraction three times, saturated sodium-chloride is washed, anhydrous sodium sulfate drying, the decompression backspin is dissolved in tetrahydrofuran (THF) (8.5mL) with residuum after desolventizing and joins in the 25mL there-necked flask of anhydrous and oxygen-free nitrogen protection.To wherein adding anhydrous pyridine (1.65mL), hydrogen fluoride pyridine salt (1.65mL) reacts until finishing under the room temperature.After watering down reaction mixture with ether, extracted with diethyl ether, saturated sodium bicarbonate is washed, and silica gel column chromatography separates and obtains target product 2d, (3R, 4S)-1-(4-fluorobenzene)-3-((S)-3-(4-fluorobenzene)-3-hydroxypropyl)-4-(trifluoromethyl) nitrogen heterocyclic din-2-ketone.Two step productive rates 46%.
[α]
D28.3-239.8(c0.80,CHCl
3);
1H?NMR(400MHz,CDCl
3)δ7.40–7.34(m,2H),7.32–7.27(m,2H),7.08–6.98(m,4H),4.71(t,J=5.9Hz,1H),4.19(qd,J=5.4,2.2Hz,1H),3.39(td,J=7.3,2.0Hz,1H),2.49(s,1H),1.90(dtt,J=9.8,6.6,3.4Hz,4H).
13C?NMR(101MHz,CDCl
3)δ166.0,162.3(d,J=245.9Hz),159.8(d,J=245.1Hz),139.8(d,J=3.1Hz),132.7(d,J=2.8Hz),127.3(d,J=8.1Hz),124.1(q,J=280.1Hz),119.3(d,J=8.0Hz),116.1(d,J=22.9Hz),115.4(d,J=21.4Hz),72.8,57.1(q,J=34.8Hz),51.9,36.1,24.3.
19F?NMR(377MHz,CDCl
3)δ-72.51(d,J=5.1Hz,3F),-114.52–-114.70(m,1F),-116.17–-116.33(m,1F).IR(KBr)
max3442,3068,2945,2851,1763,1634,1511,1407,1356,1281,1226,1153,834cm
-1;MS(EI)m/z430.0[M+HCOOH]
-;HRMS(EI)m/z[M-H]
-calcd?for?C
19H
15F
5N
1O
2,384.1028;Found,384.1036.
Embodiment 2
1.Ezetimibe analogue is in the inhibition activity of cell levels to external source type cholesterol absorption.
Subject cell: Caco-2
Experiment material: [
3H] cholesterol: Perkin-Elmer; Cholesterol, cholyltaurine salt, oleic acid, glyceryl monooleate and positive drug Zetia: sigma
Experimental technique
The Caco-2 cell inoculation in 24 orifice plates, 1 * 10
4The cells/ hole is in 37 ° of C, 5%CO
2After cultivating 7d in the incubator, cell forms individual layer closely.Every 48h changes liquid between incubation period.
Experiment is preceding with adding compound or equivalent DMSO(contrast behind the hungry cell 16h of serum free medium), DMSO final concentration 0.1%, compound arrange three concentration: 25,50,100 μ M, two multiple holes.After compound is hatched 3h, discard nutrient solution, add the little glue of cholesterol (5mM cholyltaurine salt, 0.5mM oleic acid, 0.3mM glyceryl monooleate, 5 μ M cholesterol, 12.3kBq/mL[
3H] cholesterol) hatch 2h.Discard nutrient solution, wash twice with the PBS that contains 5mM cholyltaurine salt, contain the PBS lysing cell of 0.25%SDS with 100 μ l.Add scintillator, measure DPM with liquid scintillation counter.Inhibiting rate %=(A-B) * and 100/A, A, B are respectively the DMP in control wells and test-compound hole.
Experimental result
The result is as shown in the table:
Table: compound 2d suppresses Caco-2 cellular cholesterol assimilating activity
Annotate: above-mentioned data represent that with mean ± SD experiment repeats twice.The positive medicine of Ezetimibe.
Wherein, the structural formula of 2a is
Name be called (3R, 4S)-1-(4-p-methoxy-phenyl)-3-(3-phenyl propyl)-4-(trifluoromethyl) nitrogen heterocyclic din-2-ketone;
The structural formula of 2b is
Name be called (3R, 4S)-1-(4-fluorophenyl)-3-(3-phenyl propyl)-4-(trifluoromethyl) nitrogen heterocyclic din-2-ketone;
The structural formula of 2c is
Name be called (3R, 4S)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-p-methoxy-phenyl)-4-(trifluoromethyl) nitrogen heterocyclic din-2-ketone.
Conclusion:
1) the positive drug Zetia significantly suppresses the Caco-2 cell to exogenous when 50 μ M
3The absorption of H cholesterol.
2) activity of test-compound 2d and positive drug approach.
Claims (4)
1. ezetimibe analogue, it is characterized in that: general structure is shown below:
2. a kind of ezetimibe analogue according to claim 1, it is characterized in that: the structural formula of described ezetimibe analogue is
3. the preparation method of an ezetimibe analogue comprises:
(1) be starting raw material with trifluoroacetic acid and to amino benzenes compounds, react under the effect of triphenyl phosphorus and tetracol phenixin, remove phosphorous oxides and solvent, through underpressure distillation, preparation 2,2,2-trifluoromethanesulfonyl imide is for Acetyl Chloride 98Min.;
(2) tetrahydrofuran solution of above-mentioned product is added dropwise in the alkaline environment with Ai Wensi chirality prothetic group reacts, desolventizing, resistates is collected product through the silica gel column chromatography wash-out, and preparation has the fluorine-containing alkene acyl oxazolidone of chirality prothetic group;
(3) hydrogenation under the catalysis of palladium carbon is revolved and is desolventized recrystallization, prepares optically pure fluorine-containing butyryl oxazolidone;
(4) under lithium hydroxide and hydrogen peroxide effect, remove the chirality prothetic group and obtain β-trifluoromethyl-beta-amino acids;
(5) β-trifluoromethyl-beta-amino acids 7 that is dissolved in the methyl alcohol obtains β-trifluoromethyl-beta-amino ester through the thionyl chloride processing;
(6) make alkali with methyl-magnesium-bromide, ether is under the solvent, and β-trifluoromethyl-beta-amino ester is converted into optically pure β-trifluoromethyl-beta-lactam;
(7) make alkali with LHMDS, tetrahydrofuran (THF) is solvent, and HMPA is activator, and β-trifluoromethyl-beta-lactam is reacted with side chain 3-iodine propylbenzene respectively, obtains target product through aftertreatment.
4. the preparation method of a kind of ezetimibe analogue according to claim 1, it is characterized in that: the alkaline environment in the described step (2) is alkali with LDA.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348213A (en) * | 2015-09-22 | 2016-02-24 | 武汉理工大学 | Preparation method for beta-fluoroalkyl-beta-amino acids compound |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
| CN109369491A (en) * | 2018-12-10 | 2019-02-22 | 无锡福祈制药有限公司 | A new class of ezetimibe derivative and preparation method thereof |
| CN109384700A (en) * | 2018-12-10 | 2019-02-26 | 无锡福祈制药有限公司 | A new class of Ezetimibe analog and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1069024A (en) * | 1991-07-23 | 1993-02-17 | 先灵公司 | As 'beta '-lactam compounds that reduces the replacement of cholesterol medicament in the blood and preparation method thereof |
-
2013
- 2013-05-09 CN CN201310170286.3A patent/CN103254107B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1069024A (en) * | 1991-07-23 | 1993-02-17 | 先灵公司 | As 'beta '-lactam compounds that reduces the replacement of cholesterol medicament in the blood and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| JOHN W.CLADER.ET AL: "《2-Azetidinone Cholesterol Absorption Inhibitors: Structure-Activity Relationships on the Heterocyclic Nucleus》", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105348213A (en) * | 2015-09-22 | 2016-02-24 | 武汉理工大学 | Preparation method for beta-fluoroalkyl-beta-amino acids compound |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
| CN109369491A (en) * | 2018-12-10 | 2019-02-22 | 无锡福祈制药有限公司 | A new class of ezetimibe derivative and preparation method thereof |
| CN109384700A (en) * | 2018-12-10 | 2019-02-26 | 无锡福祈制药有限公司 | A new class of Ezetimibe analog and preparation method thereof |
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