WO2011000212A1 - 依泽替米贝的制备方法及其中间体 - Google Patents
依泽替米贝的制备方法及其中间体 Download PDFInfo
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- WO2011000212A1 WO2011000212A1 PCT/CN2010/000953 CN2010000953W WO2011000212A1 WO 2011000212 A1 WO2011000212 A1 WO 2011000212A1 CN 2010000953 W CN2010000953 W CN 2010000953W WO 2011000212 A1 WO2011000212 A1 WO 2011000212A1
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- Prior art keywords
- compound
- formula
- ezetimibe
- preparation
- fluorophenyl
- Prior art date
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- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 26
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000000543 intermediate Substances 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- -1 dimethyl tert-butylsilyl Chemical group 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PQKOAYKQUKHPDB-UHFFFAOYSA-N FC1=CC=C(C=C1)C(CCCC(=O)O)=C=O Chemical compound FC1=CC=C(C=C1)C(CCCC(=O)O)=C=O PQKOAYKQUKHPDB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- BAFYQTLKMCGTPW-UHFFFAOYSA-N 1h-indole;1,3-oxazole Chemical compound C1=COC=N1.C1=CC=C2NC=CC2=C1 BAFYQTLKMCGTPW-UHFFFAOYSA-N 0.000 description 1
- BVQJXQSQRXOCIT-UHFFFAOYSA-N 4-[(4-fluoroanilino)methyl]phenol Chemical compound C1=CC(O)=CC=C1CNC1=CC=C(F)C=C1 BVQJXQSQRXOCIT-UHFFFAOYSA-N 0.000 description 1
- DIGXIPNWNUUZRM-UHFFFAOYSA-N 4-benzyl-3h-1,3-oxazol-2-one Chemical compound O1C(=O)NC(CC=2C=CC=CC=2)=C1 DIGXIPNWNUUZRM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- YVQDFRFWFNKQFT-NSHGMRRFSA-N O[C@@H](CCCC(N([C@H]([C@@H](C1)O2)c3c1cccc3)C2=O)=O)c(cc1)ccc1F Chemical compound O[C@@H](CCCC(N([C@H]([C@@H](C1)O2)c3c1cccc3)C2=O)=O)c(cc1)ccc1F YVQDFRFWFNKQFT-NSHGMRRFSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- GKCOJTRGYAUVSR-UHFFFAOYSA-N chloroboron Chemical compound Cl[B] GKCOJTRGYAUVSR-UHFFFAOYSA-N 0.000 description 1
- DRWMGJONTCWKES-UHFFFAOYSA-N chloroform;hydrochloride Chemical compound Cl.ClC(Cl)Cl DRWMGJONTCWKES-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- VVVPGLRKXQSQSZ-UHFFFAOYSA-N indolo[3,2-c]carbazole Chemical compound C1=CC=CC2=NC3=C4C5=CC=CC=C5N=C4C=CC3=C21 VVVPGLRKXQSQSZ-UHFFFAOYSA-N 0.000 description 1
- 229960005544 indolocarbazole Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000110 microvilli Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the invention belongs to the field of medicinal chemistry, and relates to a preparation method of ezetimibe and an intermediate thereof. More specifically, it relates to a compound of the formula I as shown in the following formula, a process for its preparation and an intermediate in the preparation process, and the use of a compound of the formula I for the preparation of ezetimibe (structured as follows). Background 3 ⁇ 4 ⁇
- Ezetimibe (structure is as follows), chemical name (3R, 4S) -1-4- (4-fluorophenyl)-3-(3S) -3- [3- (4-fluorophenyl) -3-hydroxyphenylpropyl]-4-(4-hydroxyphenyl)-2-azetidinone, a hypolipidemic drug, is a selective cholesterol absorption inhibitor with a small intestine brush border Membrane protein binding on membrane vesicles inhibits the body's absorption of cholesterol, thereby lowering cholesterol levels and lowering blood fat.
- ezetimibe has three chiral centers, which are the 3, 4 positions of azabutanone and the 3' chiral carbon atom attached to the side chain of the 3 position and linked to the hydroxyl group.
- the synthesis focus of ezetimibe focuses on how these three chiral centers are formed with high efficiency (including chemical yield and stereoselectivity).
- the first step The compound M is reacted with (5 4-benzyl-2-oxazolone chiral auxiliary to form an amide; the second step: CBS catalyzes the reduction of the carbonyl group to form a 3-hydroxyl chiral center; the third step: re-substituted imine
- the reaction produces a key intermediate N;
- Step 4 Formation of a protective group of ezetimibe catalyzed by BSA (bistrimethylsilyl acetamide, bistrimethylsilyl acetamide) and TBAF (tetrabutylammonium fluoride)
- Step 5 Deprotection base to obtain ezetimibe.
- the inventors tried Two chiral centers of aza-butanone are efficiently produced using a more sterically hindered tricyclic indole oxazole chiral auxiliary.
- the tricyclic indolocarbazole chiral auxiliary selected by the present inventors the full name is (3aS, R)-3, 3a,8, -tetrahydro-2H-indole[l,2-oxazol-2-one , the structure is
- This additive has been used in many complex synthetic strategies such as the antiviral drug Sinefongin (Tetrahedron Lett., 1995, 36, p7619) and the HIV protease Saquinavir inhibitor ( In J. Org. Chem., 1997, 62, p6080), development has been relatively mature, but this additive has never been used in the synthesis of ezetimibe. Summary of the invention
- the present inventors have been striving to find a preparation method of ezetimibe which is mild in conditions, simple in operation, high in stereoselectivity, safe and environmentally friendly, and suitable for large-scale commercial production.
- a common chiral auxiliary (5 4-yl-2-oxazolone is often used, and the present invention uses a sterically hindered tricyclic anthraquinone chiral auxiliary, chemical yield.
- the ee value reached 99.97%, and a compound represented by the following formula I was designed and synthesized in the preparation process, and ezetimibe can be synthesized efficiently and safely.
- a further object of the present invention is to provide intermediate preparation of two compounds of the formula I And a method of preparing the intermediate.
- the present invention provides a compound of the formula I, which is capable of efficiently and safely synthesizing ezetimibe:
- PG ⁇ B PG 2 are each independently hydrogen or a hydroxy protecting group, and preferably PG ⁇ B PG 2 is independently hydrogen, acetyl, propionyl, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, trityl Further, 1,3-methylsilyl, dimethyl-tert-butylsilyl or diphenylmethylsilyl; more preferably PG ⁇ n PG 2 is simultaneously hydrogen, trimethylsilyl or acetyl.
- the invention also provides a preparation method of the compound of the formula I, characterized in that the method comprises: adding a compound hydrazine to the compound m in the presence of a hydroxy protecting group reagent of PG ⁇ n PG 2 while simultaneously Protecting group, to obtain a compound of the formula I, the reaction formula is:
- the compound ⁇ was prepared in accordance with Chinese Patent No. CN1130342.
- the compound oxime can be obtained by the following preparation method: Compound IV is obtained by asymmetric reduction. Material, its reaction formula is:
- the compound IV can be obtained by the following preparation method: 5-(4-fluorophenyl)-5-carbonylpentanoic acid is reacted with a tricyclic indoloxazole to obtain a compound IV having a reaction formula of:
- Ezetimibe The invention provides two intermediate compounds:
- the chemical name of the intermediate compound ⁇ provided by the present invention is: (3aS, 8aR)-3-((S 5-(4-fluorophenyl)-5-hydroxypentanoyl)-3,3a,8,8a-four Hydrogen-2H-indolo[1,2-oxazolyl-2-one.
- the chemical name of Compound IV is: 1-(4-fluorophenyl)-5-((3aS,8aR)-2-carbonyl-2H - ⁇ [l,2-d]oxazolyl-3 (3aH,8H,8aH group) pentose-1,5-dione.
- a method of preparing ezetimibe using a compound represented by Formula I which is different from the method of the prior art, uses a relatively new chiral auxiliary, tricycloindole oxazole, The yield reached 90% and the ee value reached 99.97%, which was higher than that of the previous application (5 4-yl-2-oxazolone).
- the selected chiral auxiliary tricyclic indoloxazole can be conveniently prepared from commercial raw materials ((1R, 2S)-1-amino-2,3-dihydro-1H-indol-2-ol). And can be recovered in 95% yield and recycled. (Chem commun 1992, 1673)
- the method for preparing ezetimibe using the compound of the formula I is mild in conditions, simple in operation, and industrially produced.
- Figure 1 is an HPLC chromatogram of the prepared ezetimibe. Specific implementation
- the invention is further illustrated by the following examples, which are merely intended to illustrate the preferred embodiments of the invention and are not intended to limit the invention.
- the technical solutions of the present invention described above are all technical solutions that can achieve the object of the present invention. That is, the temperature used in the following examples Both the degree and the reagents can be replaced with the corresponding temperatures and reagents described above to achieve the objectives of the present invention.
- nuclear magnetic resonance was measured by Bruker AMX-400 and INVOA-600 nuclear magnetic resonance spectrometers, TMS was an internal standard, and chemical shifts were in ppm; HPLC was determined by Agilent 1100 high performance liquid chromatography; 200-300 mesh silica gel, produced by Qingdao Ocean Chemical Plant; TLC silica gel plate is HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Plant; petroleum ether boiling range is 60-90 °C; UV lamp, iodine cylinder display color.
- the concentration means that the solvent in the preparation compound solution is distilled off by a rotary evaporator; the drying means drying the prepared compound at 60 ° C in a DHG-9240A constant temperature drying oven.
- Example 1 1-(4-Fluorophenyl)-5-((3aS,8aR)-2 oxaindolozolyl-3(3a ⁇ ,8,8aff ⁇ ) 3 ⁇ 4 ⁇ -l,5-dione ( Synthesis of Compound IV)
- reaction mixture was stirred at 0 ° C for about 3 hours, then added (3izS) , R)-3,3iz,8,-tetrahydro-2H-indolo[l,2-oxazol-2-one (ie tricycloindoleazole) (25g, 1.0eq), 4-dimethylamino Pyridine (1.745 g, 0.1 eq) and dry DMF (25 ml) were warmed to reflux and maintained at this temperature for about 4 hours. Then, cooled to 10 ° C, the reaction mixture was slowly added to 2N H 2 SO 4 (160 ml).
- (+)-Diisopinolyl chloroboron ⁇ ⁇ solution (Shanghai Feiteng Chemical Co., Ltd.) (69.1 ml, 1.2 eq, 62%) was added to a solution of compound IV (39 g) in tetrahydrofuran (200 ml), and kept in Stir at 30 ° C for 5 hours, then cool to 10 ° C, add diethylamine (26.5 ml, 2.6 eq), continue stirring for 2 hours, filter off the precipitate, filter cake washed with tetrahydrofuran (20 ml) and then combined with water ( The organic phase was washed with brine and brine (50 ml).
- the oil was added to a previously mixed solution of isopropanol (1.5 ml) and 2N sulfuric acid (0.15 ml), stirred for 2 hours, and the precipitate was filtered.
- the filter cake was washed with isopropyl alcohol and then washed with water to pH less than 5, dried.
- Optical purity test method Agilent 1100 high performance liquid chromatograph; Mobile phase: 800 ml hexane + 200 ml isopropanol, flow rate: 0.5 mL/min, detection: 254 nm UV, column: CHIRALPAK AD-H 150*4.6 mm, injection Volume: 10 uL, concentration: 0.5 mg/mL, solvent: ethanol, temperature: ambient temperature.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Indole Compounds (AREA)
Description
依泽替米贝的制备 ^及其中间体
¾^领域
本发明属于药物化学领域, 涉及依泽替米贝的制备方法及其中间体。 更具体而言,涉及结构式如下文所示的通式 I化合物及其制备方法和在制 备过程中的中间体,以及通式 I化合物用于制备依泽替米贝 (结构式如下) 的用途。 背景 ¾^
依泽替米贝(Ezetimibe, 结构式如下), 化学名为(3R, 4S) -1-4- (4- 氟苯基) -3- (3S) -3- [3- (4-氟苯基) -3-羟苯基丙基] -4- (4-羟苯基) -2-氮 杂环丁酮, 是一种降血脂药物, 属于选择性胆固醇吸收抑制剂,其与小肠 刷状缘膜小囊泡上膜蛋白结合,抑制机体对于胆固醇的吸收,从而降低胆 固醇水平, 起到降血脂的作用。
依泽替米贝结构
从结构上看, 依泽替米贝有三个手性中心, 分别是氮杂丁酮的 3、 4 位和与 3位相连侧链上的并与羟基相连的 3'位手性碳原子。 依泽替米贝 的合成重点即在如何高效率 (包括化学产率和立体选择性)地形成这三个 手性中心上。
在现有文献中,基本的合成策略是引入 (S)-4-苄基 -2-噁唑酮手性助剂, 在碱和催化剂存在下环合成 (3R,4S 氮杂丁酮,一步生成两个手性中心, 3' 位羟基的手性则由前手性酮用 CBS催化的不对称还原得到。 例如, 根据 如下所示反应路线 (WO0034240、 US6207822和 CN1130342等), 第一步: 即为化合物 M与 (5 4-苄基 -2-噁唑酮手性助剂反应生成酰胺;第二步: CBS 催化还原羰基生成 3,位羟基手性中心; 第三步: 再与取代亚胺反应生成 关键中间体 N; 第四步: 在 BSA(bistrimethylsilyl acetamide, 双三甲基甲 硅垸基乙酰胺)和 TBAF (四丁基氟化铵)催化下生成带保护基的依泽替米 贝; 第五步: 脱保护基即得到依泽替米贝。
由于助剂的位阻对立体选择性影响很大,在本发明中,本发明人尝试
用位阻更大的三环茚并噁唑手性助剂来高效地生成氮杂丁酮的两个手性 中心。
本发明人选用的三环茚并噁唑手性助剂, 全名为 (3aS, R)-3,3a,8, - 四氢 -2H-茚并 [l,2- 噁唑 -2-酮, 结构为
, 该助剂已经被用于许 多复杂的全合成策略中, 如抗病毒药物西奈芬净 (Sinefongin) (Tetrahedron Lett., 1995, 36, p7619)以及 HIV蛋白酶沙奎那韦 (Saquinavir)抑制剂 (J. Org. Chem.,1997,62,p6080)中, 发展已比较成熟, 但是该助剂从未应用于依泽 替米贝的合成中。 发明内容
本发明人致力于寻找条件温和、操作简便、立体选择性高、安全环保、 适合大规模商业化生产的依泽替米贝的制备方法。 在以往的专利文献中, 往往采用常见的手性助剂 (5 4- 基 -2-噁唑酮, 本发明改用位阻更大的三 环茚并噁唑手性助剂, 化学产率达到 90%, ee值达到 99.97%, 并在制备 过程设计合成了如下通式 I所示的化合物, 由其可以高效而安全地合成依 泽替米贝。
因此, 本发明的目的在于提供一种如下通式 I所示的化合物; 本发明的另一个目的在于提供一种通式 I所示化合物的制备方法; 本发明的还一目的在于提供通式 I所示化合物用于制备依泽替米贝 的用途;
本发明的再一目的在于提供两种制备所述通式 I所示化合物的中间
体, 以及所述中间体的制备方法。
根据本发明的一方面,本发明提供一种结构式如下通式 I所示的化合 物, 它可高效且安全地合成依泽替米贝:
其中, PG^B PG2各自独立地为氢或羟基保护基, 优选 PG^B PG2各 自独立地为氢、 乙酰基、 丙酰基、 叔丁氧羰基、 苄基、 苄氧羰基、 三苯甲 基、 三甲基硅基、 二甲基叔丁基硅基或二苯基甲基硅基; 更优选 PG^n PG2同时为氢、 三甲基硅基或乙酰基。
本发明还提供所述通式 I所示化合物的制备方法, 其特征在于, 该方 法包括: 在 PG^n PG2的羟基保护基试剂存在下, 化合物 Π与化合物 m 进行加成反应, 同时上保护基, 得到通式 I所示化合物, 其反应式为:
其中, PG^n PG2的定义如上所述。
化合物 ΙΠ按照中国专利 CN1130342制备。
化合物 Π可按如下制备方法制得: 化合物 IV经不对称还原得到化合
物 Π, 其反应式为:
本发明提供的中间体化合物 Π 的化学名称为: (3aS,8aR)-3-((S 5-(4- 氟苯基 )-5-羟基戊酰基) -3,3a,8,8a-四氢 -2H-茚并 [1,2- 噁唑基 -2-酮。化合物 IV的化学名称为: 1-(4-氟苯基 )-5-((3aS,8aR)-2-羰基 -2H-茚并 [l,2-d]噁唑基 -3(3aH,8H,8aH 基)戊垸 -1,5-二酮。
本发明实现的技术效果如下:
(1)在本发明中,采用通式 I所示的化合物来制备依泽替米贝的方法, 不同于已有文献的方法,采用了较新的手性助剂三环茚并噁唑,产率达到 90%, ee值达到 99.97%, 高于以往应用的 (5 4- 基 -2-噁唑酮。
(2)所选择的手性助剂三环茚并噁唑可由商业化原料 ((1R,2S)-1-氨基 -2,3-二氢 -1H-茚 -2-醇)很方便地制备, 且能以 95%的收率回收, 循环利用。 (Chem commun 1992, 1673)
总之, 采用通式 I所示的化合物制备依泽替米贝的方法, 条件温和, 操作简便, 可以实现工业化生产。 附图说明
图 1为制备的依泽替米贝的 HPLC谱图。 具体实施力式
通过以下实施例进一步说明本发明,以下实施例仅用于更具体地说明 本发明的优选实施方案,不用于对本发明的技术方案进行限定。上述本发 明的技术方案均为可实现本发明目的之技术方案。即以下实施例所采用温
度和试剂, 均可用上文所述相应温度和试剂替代以实现本发明之目的。 在下述制备实施例中,核磁共振由 BrukerAMX-400型和 INVOA-600 型核磁共振仪测定, TMS为内标,化学位移单位为 ppm; HPLC由 Agilent 1100高效液相色谱仪测定;柱层析用硅胶 200-300目,青岛海洋化工厂生 产; TLC硅胶板为烟台化工厂生产的 HSGF-254型薄层层析预制板; 石 油醚沸程为 60—90°C ; 采用紫外灯, 碘缸显色。 制备例中若未特别指出 操作方法,所述浓缩指用旋转蒸发仪将制备化合物溶液中的溶剂蒸出;所 述干燥指用 DHG-9240A恒温干燥箱在 60 °C将制备化合物烘干。 实施例 1 1-(4-氟苯基 )-5-((3aS,8aR)-2 基 茚并 噁唑基 -3(3a^,8 , 8aff^) ¾^-l,5-二酮 (化合物 IV)的合成
在氮气保护下, 在 (TC将 5-(4-氟苯基 )-5-羰基戊酸 (上海凯路化工有 限公司) (30g)、 二异丙基乙胺 (40.8mL, 1.73eq) 溶解于二氯甲垸中 (150ml), 然后在 30分钟内向反应液中逐滴加入三甲基乙酰氯 (17.6mL, 1.0eq)。 保持 0°C继续搅拌反应液约 3小时后, 加入 (3izS, R)-3,3iz,8, -四 氢 -2H-茚并 [l,2- 噁唑 -2-酮 (即三环茚并噁唑) (25g, 1.0eq), 4-二甲氨基 吡啶(1.745g,0.1eq)和干燥DMF (25ml), 升温至回流, 该温度下保持约 4 小时。 然后, 冷却至 10°C, 将反应液缓慢加入 2N H2SO4 (160ml) 中, 有 固体析出, 过滤沉淀, 干燥, 得到 44.5g 的 1-(4-氟苯基 )-5-((3aS,8aR)-2- 羰基 -2H-茚并 [l,2-d]噁唑基 -3(3aH,8H,8aH 基)戊垸 -1,5-二酮 (化合物 IV),
产率 85%。 NMR (300MHZ, CDC13): δ 2.16 (q, 2H), 3.05 (t, 5H), 3.41 (s, 3H), 5.29 (m, 1H), 5.95 (s+s, 1H), 7.15 (t, 2H), 7.22-7.38 (m, 5H), 7.63 (s+s, 1H), 8.00 (m, 1H)。 实麵 2 (3aS,8aR)-3-((5)-5-(4-氟苯基 )-5 ¾基戊藤 )-33a,8,8a-四 氢 -2 -茚并 [1J ^噁喊 -2-酮(化合物 Π)的合成
将 (+)-二异松蒎基氯硼垸庚垸溶液 (上海飞腾化工有限公司) (69.1 ml, 1.2eq, 62%)加入到化合物 IV(39g)的四氢呋喃 (200ml)溶液中,保持在 30°C 搅拌 5小时, 然后冷却至 10°C, 加入二乙胺 (26.5ml, 2.6eq), 继续搅拌 2 小时, 滤去沉淀, 滤饼用四氢呋喃 (20ml)洗后合并有机相, 用水 (100ml) 洗和盐水 (50ml)洗涤有机相, 浓缩后得到黄色油状物。 用 110ml石油醚 / 乙酸乙酯 =10:l(V/v)溶解油状物, 搅拌 14小时, 有白色固体析出, 过滤, 干燥,得到 33.5g的标题化合物 Π,产率 86%。 rfNMR (300MHz, CDC13) : δ 1.82 (m, 5H), 2.98 (t, 2H), 3.41 (s, 3H), 4.68 (m, 1H), 5.24 (m, 1H), 5.85 (m, 1H), 7.02-7.38 (m, 5H), 7.63 (m, 1H)。
实麵 3 (3a5)-3-((2R,55)-5-(4-氟雜) -2-((5)-(4-氟雜氨基) (4- (三 甲^^基)苯基)甲基) -5- (三甲 ¾ ^基)戊 ¾¾)-3,3a,8,8a-四氢 -2 -茚并
[1,2^噁唑 -2-酮 (化合物 I, Ρ =Ρ02=三甲 基)的合成
在氮气保护下, 实施例 2 制备的化合物 Π (2.06g, 5.58mmol) 和 ( ― 4-((4-氟苯基氨基)甲基)苯酚 (化合物 ΠΙ) (2.401g, 11.15mmol, 2.0eq)
加入干燥的二氯甲垸(20ml) 中, 将反应液冷却至 -5°C, 缓慢加入二乙胺 (4.9ml, 29.28mmol, 5.25eq), 然后加入三甲基氯硅垸 (2.7ml, 20.97mmol, 3.76eq), 加完后将反应液冷却至 -25 °C到 -30 °C, 缓慢加入 TiC (0.67ml, 6.13mmol, l . leq), Ti(OCH(CH3)2)4 (0.6ml, 0.37mmol), 搅拌半小时后, 保持 温度在 -25°C到 -30°C, 加入醋酸(1.611 1,27.8811 11 01,5.060), 继续搅拌半小 时。 将反应液倾入 7%酒石酸水溶液 (32ml)中, 0°C搅拌 1.5小时, 然后将 反应液逐渐升至室温。 将 20%的 NaHSO3加至反应液中, 搅拌 1.5小时, 分离有机相并用水洗, 干燥, 浓缩至小体积后加入二 (三甲基)甲酰胺 (2.7mL,2.0eq)。将上述得到的混合物加热至回流, 保温 1小时, 然后浓缩 至干, 得到粘稠油状物, 用乙酸乙酯 /石油醚重结晶得到固体的 (3aS)-3-((2R,5S)-5-(4-氟苯基 )-2-((5 (4-氟苯基氨基) (4- (三苯甲基硅氧基)苯 基)甲基) -5- (三苯甲基硅氧基)戊酰基 )-3,3a,8,8a-四氢 -2H-茚并 [l,2- 噁唑 -2-酮 (化合物 I, PG尸 PG2=三甲基硅基), 2 g, 产率 52%。
HJNM (300MHz, CDC13): δ 0.02 (s, 9Η), 0.22 (s, (Η), 1.56 (dd, 4Η), 3.38 (s, 2Η), 4.41 (m, 4H), 5.21 (q, 1H), 5.91 (s+s, 1H), 6.28 (m, 1H), 6.71-7.31 (m, 15H)。 鎌例 4 依泽替米贝的合成
在氮气保护下, 将实施例 3制备的化合物 I (PGfPG^三甲基硅
¾)(0.2g)加入到 2ml甲苯中, 然后加入 BSA (双三甲基甲硅垸基乙酰胺) (0.12ml,0.72mmol,1.75eq)。 将反应液加热到 30°C, 在该温度下搅拌 20分 钟后, 加入四丁基氟化铵(4mg,0.05eq), 继续搅拌 1小时后, 加入醋酸 (0.02ml)再继续搅拌 15分钟。将反应液冷却到 10°C,加入 lml的二异丙基胺,
继续搅拌 10分钟, 加入 0.5ml水, 浓缩反应液, 得到油状物。 将油状物加 入事先混合好的异丙醇 (1.5ml)和 2N硫酸 (0.15ml)溶液中, 搅拌 2小时, 过 滤沉淀, 滤饼用异丙醇洗涤, 再用水洗涤至 pH值小于 5, 干燥, 得到 98mg 依泽替米贝,产率 90%,光学收率为 99.9696% c rfNMR (300MHz, DMSO): δ 9.54 (s, 1Η), 7.32 (dd, 2Η), 7.21 (m, 4H), 7.35 (m, 4H), 6.77 (d, 2H), 5.3 (d, 1H), 4.82 (d, 1H), 4.50 (m, 1H), 3.10 (m, 1H), 1,70-1.9 (m, 4H).
光学纯度测试方法: Agilent 1100高效液相色谱仪; 流动相:800ml正 己垸 +200ml 异丙醇, 流速: 0.5mL/min, 检测: 254 nm UV, 柱: CHIRALPAK AD-H 150*4.6mm,注射体积: 10uL,浓度: 0.5mg/mL,溶剂: 乙醇, 温度.:周围温度。
光学纯度 HPLC谱图见图 1。
Claims
1、 如下通式 I所示的化合物:
其中, PG^n PG2各自独立地为氢或羟基保护基。
2、 根据权利要求 1所述通式 I所示的化合物, 其中, PG^n PG2各 自独立地为氢、 乙酰基、 丙酰基、 叔丁氧羰基、 苄基、 苄氧羰基、 三苯甲 基、 三甲基硅基、 二甲基叔丁基硅基或二苯基甲基硅基。
3、根据权利要求 1或 2所述通式 I所示的化合物, 其中, PG^n PG2 同时为氢、 三甲基硅基或乙酰基。
4、 一种权利要求 1所述的通式 I所示的化合物的制备方法, 其特征 在于, 在 PG1和 PG2的羟基保护基试剂存在下, 化合物 Π与化合物 m 进行加成反应, 同时上保护基, 得到通式 I所示化合物, 其反应式为:
5、 如权利要求 4所述的制备方法, 其中, 所述化合物 Π按如下制备
方法制得: 化合物 IV经不对称还原得到化合物 π, 其反应式为:
6、 如权利要求 5所述的制备方法, 其中, 所述化合物 IV通过 5-(4- 氟苯基 5-羰基戊酸与三环茚并噁唑反应制得, 其反应式为:
5-(
7、 权利要求 1所述的通式 I所示的化合物用于制备依泽替米贝的用 途, 其特征在于, 通式 I所示的化合物在强碱和催化剂作用下上保护基、 环合和脱保护基得到依泽替米贝:
依泽替米贝
其中, PG^n PG2如权利要求 1所述。
其化学名称为 (3aS,8a )-3-((S)-5-(4-氟苯基 )-5-羟基戊酰基) -3,3a,8,8a- 四氢 -2H-茚并 [1,2-d]噁唑基 -2-酮。
其化学名称为: 1-(4-氟苯基 )-5-((3aS,8aR)-2-羰基 -2H-茚并 [1,2-d]噁唑 基 -3(3aH,8H,8aH)-基)戊垸- 1 ,5-二酮。
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CN104387308A (zh) * | 2014-11-18 | 2015-03-04 | 武汉福星生物药业有限公司 | 一种控制EZ-zanOH杂质产生制备高纯度依折麦布的方法 |
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