CN105541742A - Preparation method of ezetimibe intermediate - Google Patents
Preparation method of ezetimibe intermediate Download PDFInfo
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- CN105541742A CN105541742A CN201510943535.7A CN201510943535A CN105541742A CN 105541742 A CN105541742 A CN 105541742A CN 201510943535 A CN201510943535 A CN 201510943535A CN 105541742 A CN105541742 A CN 105541742A
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- ketone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XXSSRSVXDNUAQX-QGZVFWFLSA-N 1-(4-fluorophenyl)-5-[(4s)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione Chemical compound C1=CC(F)=CC=C1C(=O)CCCC(=O)N1C(=O)OC[C@@H]1C1=CC=CC=C1 XXSSRSVXDNUAQX-QGZVFWFLSA-N 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000002904 solvent Substances 0.000 claims abstract description 22
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims abstract description 20
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910000077 silane Inorganic materials 0.000 claims abstract description 17
- -1 1-(4-fluorophenyl)vinyl Chemical group 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 21
- YICIQMJTTGWOHI-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound [CH2]C(=O)C1=CC=C(F)C=C1 YICIQMJTTGWOHI-UHFFFAOYSA-N 0.000 claims description 18
- 229940094989 trimethylsilane Drugs 0.000 claims description 18
- 150000007530 organic bases Chemical class 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 10
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 10
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 claims description 9
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- ZEMBIEOHPGGQNJ-SNVBAGLBSA-N (4s)-4-phenyl-3-prop-2-enoyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N(C(=O)C=C)[C@H]1C1=CC=CC=C1 ZEMBIEOHPGGQNJ-SNVBAGLBSA-N 0.000 abstract 2
- QDMNNMIOWVJVLY-MRVPVSSYSA-N (4s)-4-phenyl-1,3-oxazolidin-2-one Chemical compound C1OC(=O)N[C@H]1C1=CC=CC=C1 QDMNNMIOWVJVLY-MRVPVSSYSA-N 0.000 abstract 1
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 abstract 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 abstract 1
- FNMONQSXVBNVBW-UHFFFAOYSA-N pentane-1,5-dione Chemical compound O=[C+]CCC[C+]=O FNMONQSXVBNVBW-UHFFFAOYSA-N 0.000 abstract 1
- 239000003223 protective agent Substances 0.000 abstract 1
- 230000001988 toxicity Effects 0.000 abstract 1
- 231100000419 toxicity Toxicity 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 28
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000004886 process control Methods 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 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 description 6
- 229960000815 ezetimibe Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009413 insulation Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 4
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical class Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N Valeric acid Natural products CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 108091007403 Cholesterol transporters Proteins 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002440 hepatic effect Effects 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
Abstract
The invention discloses a preparation method of an ezetimibe intermediate. The intermediate is (S)-1-(4-fluorophenyl)-5-(2-oxo-phenyloxazolidinyl-3-yl)pentane-1, 5-dione. The preparation method comprises that 1-(4-fluorophenyl)ethanone and a silane protective agent undergo a reaction to produce ((1-(4-fluorophenyl)vinyl)oxo)trimethylsilane, (S)-4-phenyloxazolidin-2-one and acryloyl chloride undergo a condensation reaction to produce (S)-3-acrylyl-4-phenyloxazolidin-2-one, and the ((1-(4-fluorophenyl)vinyl)oxo)trimethylsilane and the (S)-3-acrylyl-4-phenyloxazolidin-2-one undergo a condensation reaction to produce the ezetimibe intermediate. The preparation method utilizes a convergent type route, has the total yield of 80% or more, utilizes cheap and easily available raw materials, utilizes less types of solvents, produces small toxicity, has a short production period, utilizes simple production units operated easily, is safe and environmentally friendly and is very suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of ezetimibe intermediate, belong to technical field of medicine synthesis.
Background technology
The chemical name of ezetimibe (Ezetimube) is: 1-(4-fluorophenyl)-3 (R)-[3-(4-fluorophenyl)-3 (S)-hydroxypropyl]-4 (S)-(4-hydroxyphenyl)-2-azetidine (azetidine) ketone, and structural formula is as follows:
Ezetimibe is first is also that only approval is for clinical selectivity cholesterol absorption inhibitor, the anticholesteremic agent of the first new mechanism since being born from 1987, energy Selective depression small intestine cholesterol transporter, effective minimizing enteron aisle inner cholesterol absorbs, and reduces blood plasma cholesterol level and hepatic cholesterol reserves.
The report existing lot of documents report at present of the synthetic method of ezetimibe, we are at periodical " Chinese Journal of Pharmaceuticals " 2004,35 (4), the ezetimibe synthesis scheme reported 251-253) and " Chinese Medicine Technological Economy and management " 2012,5, in literature review in 70-74, the understanding that a ratio can be had more comprehensively to summarize to current reported synthetic route.Wherein main commercial route is as follows, and (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone is also one of important fragment forming ezetimibe parent nucleus.
Wherein at periodical " colleges and universities' chemical engineering journal " 2012; 26 (6); in 1014-1019, the technique of ezetimibe amplifies optimization method; with (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone as the important source material in operational path.Generally, 5-(4-fluorophenyl) 5-oxy pentanoic acid is obtained by reacting by fluorobenzene and Pyroglutaric acid, then at the acyl chlorides being prepared into 5-(4-fluorophenyl) 5-oxy pentanoic acid, obtain with the condensation of (S)-4-oxazolyl phenyl alkane-2-ketone again, needs three step linear response obtains altogether, and reaction scheme is as follows:
The total recovery of the program only has about 60%, and owing to adding the metal based compound such as a large amount of catalyzer aluminum chlorides in the first step Friedel-Crafts reaction, huge trouble is caused to dividing of reaction product, also report the defect of the method in its Patent CN103694111A, and it is dispersed in organic phase to need to improve catalyzer by sieving to the grinding of catalyzer aluminum chloride.
Summary of the invention
The object of this invention is to provide a kind of preparation method of ezetimibe intermediate, be a novel synthetic route, adopt convergent type route, simplify the operation step, and in reaction process, separating step is less, and reaction time is short, total recovery reaches more than 80%, is applicable to large-scale industrial production.
To achieve these goals, the technique means that the present invention adopts is:
The preparation method of ezetimibe intermediate, described ezetimibe intermediate is (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone, and structural formula is as follows:
Comprise the steps:
1) by 1-(4-fluorophenyl) ethyl ketone and silane protectant, organic bases back flow reaction generation ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane in a solvent;
2) (S)-4-oxazolyl phenyl alkane-2-ketone and silane protectant, organic bases are reacted completely in a solvent, add acrylate chloride condensation and obtain (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone;
3) ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane and (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone obtain ezetimibe intermediate by condensation reaction.
Step 1) described in 1-(4-fluorophenyl) ethyl ketone and silane protectant, organic bases mol ratio be 1:(1.1 ~ 1.5): (1.5 ~ 3.0).
Step 1) in back flow reaction temperature be 100 ~ 130 DEG C, the reaction times is 10 ~ 20 hours.
Step 1) described in silane protectant be one in trimethylchlorosilane, bromotrimethylsilane or TERT-BUTYL DIMETHYL CHLORO SILANE; Organic bases is triethylamine or diisopropylethylamine; Solvent is the one in DMF, N,N-dimethylacetamide, toluene or methylene dichloride.
Step 2) described in acrylate chloride, (S)-4-oxazolyl phenyl alkane-2-ketone, organic bases, silane protectant mol ratio be (1.05 ~ 1.50): 1:(1.10 ~ 2.50): (1.1 ~ 2.00).
Step 2) described in solvent be one in toluene, methylene dichloride; Silane protectant is the one in trimethylchlorosilane, bromotrimethylsilane or TERT-BUTYL DIMETHYL CHLORO SILANE; Organic bases is triethylamine or diisopropylethylamine.
Step 3) described in ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane, (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone molar ratio be 1:(1.05 ~ 1.5).Solvent is the one in toluene, methylene dichloride or acetonitrile.
Step 3) in temperature of reaction be 40 ~ 50 DEG C, the reaction times is 30 ~ 60 minutes.
The preparation method of ezetimibe intermediate provided by the invention, synthetic route is as follows:
Adopt convergent type route, step 1) synthesize ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane of obtaining and can be separated or without separation, enter next step reaction, reaction scheme is short, easy to operate, yield is high.
The synthesis of ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane, is specially:
1-(4-fluorophenyl) ethyl ketone, silane protectant, organic bases are dissolved in solvent; stirring reaction under nitrogen protection; be warming up to 100 ~ 130 DEG C of reactions 10 ~ 20 hours; then room temperature is cooled to; use sherwood oil dilute reaction solution; the throw out triethylamine hydrochloride that suction filtration removing is separated out, collects filtrate, after alkali cleaning, washing, underpressure distillation, obtains product ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane.
(S) synthesis of-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone, is specially:
(s)-4-phenyl-2-azolactone is added in solvent; be cooled between 0 ~ 10 DEG C; add silane protectant; stir 30 ~ 60 minutes at remaining on 0 ~ 10 DEG C; drip organic bases, drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising; continue stirring reaction at 0 ~ 10 DEG C, until (s)-4-phenyl-2-azolactone raw material TLC detection reaction complete (TLC testing conditions: petrol ether/ethyl acetate=2/1).Then acrylate chloride is dripped, drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, add anhydrous tetrabutyl ammonium fluoride (TBAF), reaction solution at room temperature stirs 2-5 hour, after reaction terminates, reaction solution is poured in frozen water, at room temperature stirs 30 ~ 60 minutes, be separated organic phase, organic phase alkali liquid washing, is separated organic phase, obtains thick product after evaporate to dryness organic phase.In thick product, add Virahol, stir 2 hours at 20 ~ 25 DEG C, suction filtration, obtains white solid powder, obtains product (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone after drying.The mol ratio of wherein said acrylate chloride, (S)-4-oxazolyl phenyl alkane-2-ketone, organic bases, silane protectant is (1.05 ~ 1.50): 1:(1.10 ~ 2.50): (1.1 ~ 2.00).
The synthesis of ezetimibe intermediate (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone, is specially:
(S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone, ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane, iodine are added in solvent, stir until react completely at 40 ~ 50 DEG C, then add Sulfothiorine to stir 30 ~ 60 minutes, be separated organic phase, gained organic phase washes twice with water again, evaporated under reduced pressure solvent obtains crude product, crude product uses recrystallisation from isopropanol again, obtain product (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone; Wherein, the molar ratio of ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane, (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone and iodine is 1:(1.05 ~ 1.5): (0.05 ~ 0.15), solvent is the one in toluene, methylene dichloride, acetonitrile.
Beneficial effect: this operational path adopts convergent type route, ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane generated can be separated or without separation, directly enter next step reaction, real reaction step is only two steps, total recovery can reach more than 80%, at least improves 10% than existing methods.In addition this operational path is simple to operate, and raw material is industrialized product, and Chemical market is cheaply easy to get, and in reaction process, separating step is less, and the cycle in reaction times is short, is applicable to suitability for industrialized production.
Embodiment
1-(4-fluorophenyl) ethyl ketone is purchased from Aladdin Reagent Company, s ()-4-phenyl-2-azolactone is from Jiangsu Senxuan Pharmaceutical Co., Ltd., N-(4-fluorophenyl)-4-benzyloxy benzene methylene amine is from Jiangsu Hansyn Pharmaceutical Co., Ltd., and trimethylchlorosilane (TMSCl) is from Aladdin Reagent Company.
The preparation of embodiment 1 ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane
Structural formula is as follows:
In 500ml there-necked flask, add 1-(4-fluorophenyl) ethyl ketone 20g (0.145mol, 1eq.), triethylamine 22g (0.217mol, 1.5eq), trimethylchlorosilane 18.90g (0.174mol, 1.2eq) and 100mlN, dinethylformamide, reaction is stirred under nitrogen protection, be warming up to 100 DEG C of insulations 10 hours, then room temperature (25 DEG C) is cooled to, with sherwood oil 150ml dilute reaction solution, the throw out triethylamine hydrochloride of separating out removes with Büchner funnel suction filtration, collect filtrate, use 10% (wt) sodium hydrogen carbonate solution washing organic phase of 200ml ice again, organic phase uses 200ml water washing twice again, solvent is fallen in underpressure distillation, obtain solid 27.1g, yield 90%.
The preparation of embodiment 2 ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane
Structural formula is as follows:
In 500ml there-necked flask, add 1-(4-fluorophenyl) ethyl ketone 20g (0.145mol, 1eq.), diisopropylethylamine 26.18g (0.203mol, 1.4eq), trimethylchlorosilane 19.69g (0.181mol, 1.25eq) with 100ml toluene, reaction is stirred under nitrogen protection, be warming up to 100 DEG C of insulations 8 hours, then room temperature is cooled to, with sherwood oil 150ml dilute reaction solution, the throw out triethylamine hydrochloride of separating out removes with Büchner funnel suction filtration, collect filtrate, use 10% (wt) sodium hydrogen carbonate solution washing organic phase of 200ml ice again, organic phase uses 200ml water washing twice again, solvent is fallen in underpressure distillation, obtain solid 25.59g (yield 85%).
The preparation of embodiment 3 ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane
Structural formula is as follows:
In 500ml there-necked flask, add 1-(4-fluorophenyl) ethyl ketone 20g (0.145mol, 1eq.), diisopropylethylamine 26.18g (0.203mol, 1.4eq), bromotrimethylsilane 27.70g (0.181mol, 1.25eq) with 100ml toluene, reaction is stirred under nitrogen protection, be warming up to 100 DEG C of insulations 12 hours, then room temperature is cooled to, with sherwood oil 150ml dilute reaction solution, the throw out triethylamine hydrochloride of separating out removes with Büchner funnel suction filtration, collect filtrate, use 10% (wt) sodium hydrogen carbonate solution washing organic phase of 200ml ice again, organic phase uses 200ml water washing twice again, solvent is fallen in underpressure distillation, obtain solid 26.50g, yield 88%.
The preparation of embodiment 4 (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone
Structural formula is as follows:
In 500ml there-necked flask, add (s)-4-phenyl-2-azolactone 20g (0.122mol, 1eq.) with methylene dichloride 200ml, be cooled between 0 ~ 10 DEG C, add bromotrimethylsilane 16g (0.146mol, 1.2eq.), stir 30 minutes at remaining on 0 ~ 10 DEG C, drip triethylamine 15.4g (0.152mol, 1.25eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, continue at 0 ~ 10 DEG C, to stir 2 hours until (s)-4-phenyl-2-azolactone raw material TLC detection reaction complete (TLC testing conditions: petrol ether/ethyl acetate=2/1).Then add 13.22g acrylate chloride (0.146mol, 1.2eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, add 1.6g anhydrous tetrabutyl ammonium fluoride (TBAF, 6.1mmol, 0.05eq.), reaction solution at room temperature stirs 2 hours.After reaction terminates, reaction solution is poured in 200ml frozen water, at room temperature stirs 30 minutes, is separated organic phase, and organic phase 10% (wt) sodium hydrogen carbonate solution washing, is separated organic phase, obtains thick product after evaporate to dryness organic phase.In thick product, add Virahol 100ml, stir 2 hours at 25 DEG C, suction filtration, obtains white solid powder, obtains product compound 23.8g after drying, yield 90%.
1HNMR(400MHz,CDCl
3)δ7.51(dt,J＝26.2,13.1Hz,1H),7.36(ddd,J＝15.6,11.2,6.8Hz,4H),6.49(dd,J＝17.0,1.4Hz,1H),5.89(dd,J＝10.5,1.4Hz,1H),5.50(dd,J＝8.7,3.9Hz,1H),4.73(t,J＝8.8Hz,1H),4.31(dd,J＝8.9,3.9Hz,1H)。
The preparation of embodiment 5 (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone
Structural formula is as follows:
In 500ml there-necked flask, add (s)-4-phenyl-2-azolactone 20g (0.122mol, 1eq.) with methylene dichloride 200ml, be cooled between 0 ~ 10 DEG C, add trimethylchlorosilane 15.86g (0.146mol, 1.2eq.), stir 30 minutes at remaining on 0 ~ 10 DEG C, drip diisopropylethylamine 39.30g (0.305mol, 2.50eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, continue at 0 ~ 10 DEG C, to stir 2 hours until (s)-4-phenyl-2-azolactone raw material TLC detection reaction complete (TLC testing conditions: petrol ether/ethyl acetate=2/1).Then add 15.46g acrylate chloride (0.171mol, 1.4eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, add 1.6g anhydrous tetrabutyl ammonium fluoride (TBAF, 6.1mmol, 0.05eq.), reaction solution at room temperature stirs 2 hours.After reaction terminates, reaction solution is poured in 200ml frozen water, at room temperature stirs 30 minutes, is separated organic phase, and organic phase 10% (wt) sodium hydrogen carbonate solution washing, is separated organic phase, obtains thick product after evaporate to dryness organic phase.In thick product, add Virahol 100ml, stir 2 hours at 25 DEG C, suction filtration, obtains white solid powder, obtains product compound 24.6g after drying, yield 93%.
1HNMR(400MHz,CDCl
3)δ7.51(dt,J＝26.2,13.1Hz,1H),7.36(ddd,J＝15.6,11.2,6.8Hz,4H),6.49(dd,J＝17.0,1.4Hz,1H),5.89(dd,J＝10.5,1.4Hz,1H),5.50(dd,J＝8.7,3.9Hz,1H),4.73(t,J＝8.8Hz,1H),4.31(dd,J＝8.9,3.9Hz,1H)。
The structural formula of preparing of embodiment 6 (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone is shown below:
10g (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone (0.046mol is added in 250ml there-necked flask, 1eq), 10.6g ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane (0.051mol, 1.1eq), 0.6g iodine (0.0023mol, 0.05eq) with toluene 100ml, stir until react completely at 40 DEG C, then 100ml water is added and 0.5g Sulfothiorine stirs 30 minutes, be separated organic phase, gained organic phase uses 200ml water washing twice again, evaporated under reduced pressure solvent obtains crude product, crude product uses 50ml recrystallisation from isopropanol again, obtain product 14.7g, yield 89%.
1HNMR(400MHz,CDCl
3)δ8.01-7.879m,1H),7.34(ddd,J＝14.9,11.0,6.7Hz,3H),7.10(t,J＝8.6Hz,1H),5.43(dd,J＝8.7,3.6Hz,1H)4.70(t,J＝8.8Hz,1H),4.28(dd,J＝8.9,3.6Hz,1H),3.15-3.01(m,1H),2.97(t,J＝7.2Hz,1H),2.05(p.J＝7.1Hz,1H)。
The structural formula of preparing of embodiment 7 (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone is shown below:
10g (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone (0.046mol is added in 250ml there-necked flask, 1eq), 14.3g ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane (0.069mol, 1.5eq), 0.12g iodine (0.0046mol, 0.10eq) with toluene 100ml, stir until react completely at 40 DEG C, then 100ml water is added and 0.5g Sulfothiorine stirs 30 minutes, be separated organic phase, gained organic phase uses 200ml water washing twice again, evaporated under reduced pressure solvent obtains crude product, crude product uses 50ml recrystallisation from isopropanol again, obtain product 15.5g, yield 94%.
1HNMR(400MHz,CDCl
3)δ8.01-7.879m,1H),7.34(ddd,J＝14.9,11.0,6.7Hz,3H),7.10(t,J＝8.6Hz,1H),5.43(dd,J＝8.7,3.6Hz,1H)4.70(t,J＝8.8Hz,1H),4.28(dd,J＝8.9,3.6Hz,1H),3.15-3.01(m,1H),2.97(t,J＝7.2Hz,1H),2.05(p.J＝7.1Hz,1H)
The one kettle way preparation of embodiment 8 (S)-1-(4-fluorophenyl)-5-(2-oxygen-4-oxazolyl phenyl alkane-3-base) pentane-1,5-diketone
In 500ml there-necked flask; add 1-(4-fluorophenyl) ethyl ketone 18.0g (0.130mol; 1eq.), triethylamine 19.8g (0.195mol, 1.5eq), trimethylchlorosilane 17.0g (0.157mol, 1.2eq) and 100ml toluene; reaction is stirred under nitrogen protection; be warming up to 100 DEG C of insulations 15 hours; then be cooled to room temperature (25 DEG C), retain the reaction solution of (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone.
In 500ml there-necked flask, add (s)-4-phenyl-2-azolactone 15g (0.091mol, 1eq.) with toluene 100ml, be cooled between 0 ~ 10 DEG C, add trimethylchlorosilane 11.90g (0.110mol, 1.2eq.), stir 30 minutes at remaining on 0 ~ 10 DEG C, drip triethylamine 27.5g (0.273mol, 3.0eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, continue at 0 ~ 10 DEG C, to stir 2.5 hours until (s)-4-phenyl-2-azolactone raw material TLC detection reaction complete (TLC testing conditions: petrol ether/ethyl acetate=2/1).Then add 10.7g acrylate chloride (0.118mol, 1.3eq.), drip process control temperature of charge between 0 ~ 10 DEG C, after dropwising, add 1.6g anhydrous tetrabutyl ammonium fluoride (TBAF, 6.1mmol, 0.05eq.), reaction solution at room temperature stirs 2 hours.After reaction terminates, reaction solution is poured in 200ml frozen water, at room temperature stir 30 minutes, be separated organic phase, organic phase 10% sodium carbonate solution washs, and is separated organic phase, after organic phase distills dry solvent, add fresh toluene 100ml, retain the reaction solution of (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone.
The reaction solution of above-mentioned (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone, reaction solution, the 0.14g iodine (0.004mol, 0.10eq) of ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane is added in 500ml there-necked flask, stir until react completely at 40 DEG C, then 200ml water is added and 0.5g Sulfothiorine stirs 30 minutes, be separated organic phase, gained organic phase uses 300ml water washing twice again, evaporated under reduced pressure solvent obtains crude product, crude product uses 70ml recrystallisation from isopropanol again, obtain product 13.8g, total recovery 84%.
1HNMR(400MHz,CDCl
3)δ8.01-7.879m,1H),7.34(ddd,J＝14.9,11.0,6.7Hz,3H),7.10(t,J＝8.6Hz,1H),5.43(dd,J＝8.7,3.6Hz,1H)4.70(t,J＝8.8Hz,1H),4.28(dd,J＝8.9,3.6Hz,1H),3.15-3.01(m,1H),2.97(t,J＝7.2Hz,1H),2.05(p.J＝7.1Hz,1H)。
Claims (9)
1. the preparation method of ezetimibe intermediate, described ezetimibe intermediate structure formula is as follows:
It is characterized in that, comprise the steps:
1) by 1-(4-fluorophenyl) ethyl ketone and silane protectant, organic bases back flow reaction generation ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane in a solvent;
2) (S)-4-oxazolyl phenyl alkane-2-ketone and silane protectant, organic bases are reacted completely in a solvent, add acrylate chloride condensation and obtain (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone;
3) ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane and (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone obtain ezetimibe intermediate by condensation reaction.
2. the preparation method of ezetimibe intermediate according to claim 1; it is characterized in that, step 1) described in 1-(4-fluorophenyl) ethyl ketone and silane protectant, organic bases mol ratio be 1:(1.1 ~ 1.5): (1.5 ~ 3.0).
3. the preparation method of ezetimibe intermediate according to claim 1, is characterized in that, step 1) in back flow reaction temperature be 100 ~ 130 DEG C, the reaction times is 10 ~ 20 hours.
4. the preparation method of ezetimibe intermediate according to claim 1, is characterized in that, step 1) described in silane protectant be one in trimethylchlorosilane, bromotrimethylsilane or TERT-BUTYL DIMETHYL CHLORO SILANE; Organic bases is triethylamine or diisopropylethylamine.
5. the preparation method of ezetimibe intermediate according to claim 1; it is characterized in that, step 2) described in acrylate chloride, (S)-4-oxazolyl phenyl alkane-2-ketone, organic bases, silane protectant mol ratio be (1.05 ~ 1.50): 1:(1.10 ~ 2.50): (1.1 ~ 2.00).
6. the preparation method of ezetimibe intermediate according to claim 1, is characterized in that, step 2) described in solvent be toluene or methylene dichloride; Silane protectant is the one in trimethylchlorosilane, bromotrimethylsilane or TERT-BUTYL DIMETHYL CHLORO SILANE; Organic bases is triethylamine or diisopropylethylamine.
7. the preparation method of ezetimibe intermediate according to claim 1, is characterized in that, step 2) in (S)-4-oxazolyl phenyl alkane-2-ketone, silane protectant and organic bases in a solvent temperature of reaction be 0 ~ 10 DEG C.
8. the preparation method of ezetimibe intermediate according to claim 1, it is characterized in that, step 3) described in ((1-(4-fluorophenyl) vinyl) oxygen) trimethyl silane, (S)-3-acryloyl-4-oxazolyl phenyl alkane-2-ketone molar ratio be 1:(1.05 ~ 1.5).
9. the preparation method of ezetimibe intermediate according to claim 1, is characterized in that, step 3) in temperature of reaction be 40 ~ 50 DEG C, the reaction times is 30 ~ 60 minutes.
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| WO2005049592A1 (en) * | 2003-11-24 | 2005-06-02 | Hetero Drugs Limited | A novel process for ezetimibe intermediate |
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