WO2011040717A2 - Method for preparing intermediate of sitagliptin using chiral oxirane - Google Patents
Method for preparing intermediate of sitagliptin using chiral oxirane Download PDFInfo
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- WO2011040717A2 WO2011040717A2 PCT/KR2010/006346 KR2010006346W WO2011040717A2 WO 2011040717 A2 WO2011040717 A2 WO 2011040717A2 KR 2010006346 W KR2010006346 W KR 2010006346W WO 2011040717 A2 WO2011040717 A2 WO 2011040717A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- trifluorophenyl
- oxirane
- trifluorobenzyl
- trifluorobenzene
- mixture
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 42
- 229960004034 sitagliptin Drugs 0.000 title abstract description 15
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 title abstract description 15
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 title description 5
- WHFKHBXZZAXQOD-UHFFFAOYSA-N 3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid Chemical compound OC(=O)CC(O)CC1=CC(F)=C(F)C=C1F WHFKHBXZZAXQOD-UHFFFAOYSA-N 0.000 claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 32
- -1 2,4,5-trifluorobenzene halide Chemical class 0.000 claims description 26
- BJVWCGAQMZQCGP-LURJTMIESA-N (2s)-2-[(2,4,5-trifluorophenyl)methyl]oxirane Chemical group C1=C(F)C(F)=CC(F)=C1C[C@@H]1OC1 BJVWCGAQMZQCGP-LURJTMIESA-N 0.000 claims description 22
- 239000007818 Grignard reagent Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 14
- 150000004795 grignard reagents Chemical class 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- DCKLQKFJVZGRQA-UHFFFAOYSA-N 3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile Chemical compound N#CCC(O)CC1=CC(F)=C(F)C=C1F DCKLQKFJVZGRQA-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- BJVWCGAQMZQCGP-UHFFFAOYSA-N 2-[(2,4,5-trifluorophenyl)methyl]oxirane Chemical compound C1=C(F)C(F)=CC(F)=C1CC1OC1 BJVWCGAQMZQCGP-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- 238000005669 hydrocyanation reaction Methods 0.000 claims description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims description 9
- AUJSFJXDHMABLJ-UHFFFAOYSA-N 1,2,4-trifluorobenzene hydrobromide Chemical compound Br.FC1=CC=C(F)C(F)=C1 AUJSFJXDHMABLJ-UHFFFAOYSA-N 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000006735 epoxidation reaction Methods 0.000 claims description 6
- QLCMQJLKFJPPIT-UHFFFAOYSA-N 1,2,4-trifluoro-5-prop-2-enylbenzene Chemical compound FC1=CC(F)=C(CC=C)C=C1F QLCMQJLKFJPPIT-UHFFFAOYSA-N 0.000 claims description 5
- 229910052802 copper Inorganic materials 0.000 claims description 5
- 239000010949 copper Substances 0.000 claims description 5
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- HQPDCFVCYVJLPC-UHFFFAOYSA-N 1,2,4-trifluorobenzene;hydrochloride Chemical compound Cl.FC1=CC=C(F)C(F)=C1 HQPDCFVCYVJLPC-UHFFFAOYSA-N 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 22
- WHFKHBXZZAXQOD-LURJTMIESA-N (3s)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid Chemical compound OC(=O)C[C@@H](O)CC1=CC(F)=C(F)C=C1F WHFKHBXZZAXQOD-LURJTMIESA-N 0.000 abstract description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 238000005191 phase separation Methods 0.000 description 8
- DCKLQKFJVZGRQA-SSDOTTSWSA-N (3s)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile Chemical compound N#CC[C@@H](O)CC1=CC(F)=C(F)C=C1F DCKLQKFJVZGRQA-SSDOTTSWSA-N 0.000 description 7
- 229960004592 isopropanol Drugs 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000002081 enamines Chemical class 0.000 description 4
- 229960004115 sitagliptin phosphate Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- XDQLWVSUKUDAEO-UHFFFAOYSA-N methyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound COC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F XDQLWVSUKUDAEO-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WZLOKEZFZKLWIH-LURJTMIESA-N (2s)-1-chloro-3-(2,4,5-trifluorophenyl)propan-2-ol Chemical compound ClC[C@@H](O)CC1=CC(F)=C(F)C=C1F WZLOKEZFZKLWIH-LURJTMIESA-N 0.000 description 1
- 240000005020 Acaciella glauca Species 0.000 description 1
- PLTJAESQHAGXAM-UHFFFAOYSA-N FC1=C(C=C(C(=C1)F)F)C=CC Chemical compound FC1=C(C=C(C(=C1)F)F)C=CC PLTJAESQHAGXAM-UHFFFAOYSA-N 0.000 description 1
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 1
- 101000886868 Homo sapiens Gastric inhibitory polypeptide Proteins 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 235000003499 redwood Nutrition 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/08—Compounds containing oxirane rings with hydrocarbon radicals, substituted by halogen atoms, nitro radicals or nitroso radicals
Definitions
- the present invention relates to a method for preparing 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin.
- Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level.
- Sitagliptin phosphate monohydrate was approved by the US Food and Drug Admimstration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes in October 2006 and is marketed in the United States and Korea under the trade name of JANUVIATM (as a single agent) or JANUMETTM (as an oral combination of sitagliptin/Metformin).
- FDA US Food and Drug Admimstration
- WO 2004/085661 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using a platinum-based catalyst, Pt0 2 .
- WO 2005/097733 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively employing a rhodium-based catalyst, [Rh(cod)Cl] 2 with a chiral diphosphine ligand.
- WO 2004/087650 discloses a method for preparing sitagliptin phosphate from (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid through the five- step processes shown in Reaction Scheme 1 :
- Bn is benzyl
- WO 2004/087650 also discloses a method for preparing (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key sitagliptin intermediate, comprising the steps of: conducting a stereoselective reduction of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutyrate in the presence of (S)-BINAP-RuCl 2 -Et 3 N under a high hydrogen pressure, and hydrolyzing the resulting compound, as shown in Reaction Scheme 2:
- KRED-NADH- 110TM is a trade name of the ketoreductase enzyme (Codexis, Redwood City, CA) and A-KRED-NADH is a recycle mixture containing KRED-NADH.
- the 2-(2,4,5-trifluorobenzyl)-oxirane is (2S)-2-(2,4,5-trifluorobenzyl)- oxirane of formula (lib):
- the present invention is characterized in that 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin, is prepared by using a chiral oxirane with a high yield and at a low cost.
- the inventive method comprises the steps of: subjecting 2-(2,4,5- trifluorobenzyl)-oxirane of formula (11a) to ⁇ -hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia); and hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid of formula (la).
- the inventive method comprises the steps of: subjecting (2S)-2-(2,4,5- trifluorobenzyl)-oxirane of formula (lib) to ⁇ -hydrocyanation in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula
- step 2 hydrolyzing the (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid of formula (lb) (step 2):
- the (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb) is prepared by subjecting (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) to ⁇ - hydrocyanation in the presence of a catalyst.
- (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) is dissolved in a solvent and conducted a ⁇ -hydrocyanation by adding sodium cyanide in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb).
- the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is a novel compound and may be prepared by treating a 2,4,5-trifluorobenzene halide as a starting material with a (S)- epihalohydrin (Route 1); or by treating the 2,4,5-trifluorobenzene halide with a allyl halide (Route 2) as shown in Reaction Scheme 6: Reaction Scheme 6
- m-CPBA is m-chloroperoxybenzoic acid.
- the method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 1 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating a (S)-epihalohydrin using the Grignard reagent in the presence of a copper halide to obtain (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol; and conducting an epoxidation reaction of the (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2- propanol in the presence of a strong base.
- the 2,4,5 -trifluorobenzene halide is treated with magnesium (Mg) and organic alkyl halide (e.g., 1,2-dibromoethane); Mg and I 2 ; or isopropyl magnesium chloride (z ' -PrMgCl) to obtain a Grignard reagent.
- Mg magnesium
- organic alkyl halide e.g., 1,2-dibromoethane
- I 2 e.g., 1,2-dibromoethane
- z -PrMgCl isopropyl magnesium chloride
- 2,4,5-trifluorobenzene halide examples include 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.
- (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol is prepared by arylating the (S)-epihalohydrin using the Grignard reagent.
- the Grignard reagent is mixed with a catalytic amount of the copper halide, and then the (S)-epihalohydrin is added thereto slowly at a low temperature to obtain (2S)-3-(2,4,5-trifluorophenyl)-l- halo-2-propanol.
- Examples of the copper halide include CuBr, Cul, and a mixture thereof, preferably Cul.
- the oxirane such as (S)-epihalohydrin comprises (S) and (R) isomer which are commercially available.
- Examples for the (S)-epihalohydrin include (S)- epichlorohydrin.
- (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by dissolving (2S)-3- (2,4,5-trifluorophenyl)-l-halo-2-propanol into a solvent and conducting an epoxidation reaction of a strong base.
- solvent examples include tetrahydrofuran, diethylether, and the like.
- the strong base examples include a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof, preferably sodium hydroxide.
- the method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 2 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating an allyl halide with the Grignard reagent to obtain 3- (2,4,5-trifluorophenyl)-l-propene; conducting an epoxidation reaction of 3-(2,4,5- trifluorophenyl)-l-propene using an oxidant to obtain a racemic 2-(2,4,5- trifluorobenzyl)-oxirane; and carrying out selective hydrolytic kinetic resolution (HKR) of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen.
- HLR hydrolytic kinetic resolution
- a Grignard reagent is prepared using a 2,4,5-trifluorobenzene halide.
- the methods for preparing the 2,4,5-trifluorobenzene halide and the Grignard reagent using the same are the same as described above.
- an allyl halide is arylated using the Grignard reagent at a low temperature to obtain 3-(2,4,5-trifluorophenyl)-l-propene.
- allyl halide examples include allyl bromide and the like.
- solvent examples include tetrahydrofuran, diethylether, and the like.
- oxidant examples include m-ClC ⁇ CCbH, CH 3 C0 3 H, CF 3 C0 3 H, H 2 0 2 , and a mixture thereof, preferably m-ClC 6 H 4 C0 3 H.
- (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by conducting a selective HKR of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen of formula (IV):
- the ⁇ -hydrocyanation of the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is conducted in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or d to C 6 alcohol ⁇ e.g., methanol, ethanol, and isopropanol), preferably DMF.
- a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or d to C 6 alcohol ⁇ e.g., methanol, ethanol, and isopropanol, preferably DMF.
- the ⁇ -hydrocyanation is conducted in the presence of a catalyst such as H4CI, citric acid, acetic acid, formic acid, maleic acid, or a mixture thereof, preferably NH 4 CI.
- a catalyst such as H4CI, citric acid, acetic acid, formic acid, maleic acid, or a mixture thereof, preferably NH 4 CI.
- the 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid preferably (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid is prepared by hydrolyzing (3S)-4-(2,4,5- trifluorophenyl)-3-hydroxybutane nitrile obtained in Step 1 in the presence of a strong base and H 2 0 2 .
- the strong base examples include an alkali metal hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH) or a mixture thereof, preferably sodium hydroxide.
- the strong base is used in a form of aqueous solution.
- the method according to the present invention makes it possible to easily prepare 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key intermediate in the synthesis of sitagliptin, with a high yield and a low cost, which is suitable for mass production of sitagliptin.
- Step 1 preparation of (2S)-3-(2A5-trifluorophenyl -chloro-2-prepanol
- Magnesium (Mg) (1.26 g) was added to tetrahydrofuran (THF) (10 ml) and a drop of 1 ,2-dibromomethane was added thereto.
- THF tetrahydrofuran
- 2,4,5- trifluorobenzene bromide (0.55 g) was added slowly, and then stirred for 30 min.
- 2,4,5-trifluorobenzene bromide (9.0 g) in THF (50 ml) was added dropwise over 30 min and then stirred at room temperature for 1 hr.
- Step 2 Preparation of (2S)-2-(2,4,5-trifluorobenzyl -oxirane (2S)-3-(2,4,5-Trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and an aqueous solution of NaOH (2.3 g) was added thereto dropwise. The resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0 4 , and filtered off MgSO 4 . The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (6.8 g, yield: 80 %).
- (2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and NaOH (2.3 g) was added thereto dropwise. The resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS0 4 , and filtered off MgS0 4 . The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (7.6 g, yield: 85 %).
- allyl bromide (18.0 g) in THF (60 ml) was added dropwise over 20 min and then stirred for 1 hrs. The temperature of the resulting mixture was increased to room temperature and then stirred for 1 hr.
- Dichloromethane (MC) 300 ml was added to the resulting mixture to induce phase separation. The organic layer was isolated, washed with 2 M NH 4 CI (150 ml) and water (150 ml) successively, dried over MgS0 4 , and filtered off MgS0 4 . The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.
- 3-(2,4,5-Trifiuorophenyl)-l-propene obtained in step 1 was dissolved in dichloromethane (300 ml) and m-chloroperoxybenzoic acid (m-CPBA) (35 g) was added thereto dropwise. The resulting mixture was stirred for 17 hr and then saturated NaHC0 3 (300 ml) was added thereto to induce phase separation. The organic layer was isolated, washed with 1 N NaOH (300 ml) and brine (100 ml) successively, dried over MgS0 4 , and filtered off MgS0 4 . The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (19.1 g, yield: 75 %).
- m-CPBA m-chloroperoxybenzoic acid
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Abstract
Disclosed is: a novel, simple and low-cost method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, which is used as a key intermediate in the preparation of sitagliptin.
Description
METHOD FOR PREPARING INTERMEDIATE OF SITAGLIPTIN
USING CHIRAL OXIRANE
FIELD OF THE INVENTION
The present invention relates to a method for preparing 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin. BACKGROUND OF THE INVENTION
Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved by the US Food and Drug Admimstration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes in October 2006 and is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent) or JANUMET™ (as an oral combination of sitagliptin/Metformin).
Various methods for preparing sitagliptin phosphate have been developed. For example, WO 2004/085661 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using a platinum-based catalyst, Pt02. WO 2005/097733 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively employing a rhodium-based catalyst, [Rh(cod)Cl]2 with a chiral diphosphine ligand.
The document [J. Am. Chem. Soc, 2009, 131, p.l 1316-11317] discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using a ruthenium-based catalyst, Ru(OAc)2 with a chiral diphosphine ligand, and WO 2009/064476 discloses a method for preparing sitagliptin by reducing an enamine stereoselectively using Ru(OAc)2 and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent such as NaBH4.
On the other hand, there has been developed a method for preparing sitagliptin phosphate by using 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, (3S)-3-hydroxy-4- (2,4,5-trifluorophenyl)-butyric acid in particular, as a key intermediate.
For example, WO 2004/087650 discloses a method for preparing sitagliptin phosphate from (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid through the five- step processes shown in Reaction Scheme 1 :
Reaction Scheme 1
wherein, Bn is benzyl.
WO 2004/087650 also discloses a method for preparing (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key sitagliptin intermediate, comprising the steps of: conducting a stereoselective reduction of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutyrate in the presence of (S)-BINAP-RuCl2-Et3N under a high hydrogen pressure, and hydrolyzing the resulting compound, as shown in Reaction Scheme 2:
Reaction Scheme 2
Yield : 83% Ee : 94%ee wherein, Me is methyl and BINAP is 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl.
Further, WO 2009/045507 discloses methods for preparing methyl (S)- and (R)- enantiomers of 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyrate, a key sitagliptin intermediate, via the stereoselective enzymatic reduction of methyl 4-(2,4,5- trifluorophenyl)-3-oxobutyrate using an enzyme, as shown in Reaction Schemes 3 and 4:
Reaction Scheme 3
Yield : 86%<
Ee : 96.6%ee
wherein, KRED-NADH- 110™ is a trade name of the ketoreductase enzyme (Codexis, Redwood City, CA) and A-KRED-NADH is a recycle mixture containing KRED-NADH.
However, the above methods must be carried out under a high hydrogen pressure in the presence of a ruthenium catalyst, or using a ketone reducing enzyme to obtain (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid having a chiral center at the 3- position.
The present inventors have therefore endeavored to develop a novel method for preparing sitagliptin which is free from the above-mentioned problems associated with the conventional methods and unexpectedly found that (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid can be prepared by a simple and low-cost method using (2S)-2-(2,4,5-trifluorobenzyl)-oxirane prepared from the commercially available (S)- epichlorohydrin.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a novel method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid, which is a key intermediate in the synthesis of sitagliptin.
It is another object of the present invention to provide (2S)-2-(2,4,5- trifluorobenzyl)-oxirane and 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile which are used in the preparation of 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid.
In accordance with an aspect of the present invention, there is provided a method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)butyric acid of formula (la), comprising the steps of:
subjecting 2-(2,4,5-trifluorobenzyl)-oxirane of formula (Ila) to β-hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia); and
hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base:
Preferably, the 2-(2,4,5-trifluorobenzyl)-oxirane is (2S)-2-(2,4,5-trifluorobenzyl)- oxirane of formula (lib):
In accordance with an aspect of the present invention, there is provided (2S)-2- (2,4,5-trifluorobenzyl)-oxirane of formula (lib) and 4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile of formula (Ilia), which are used in the preparation of 3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is characterized in that 3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)- butyric acid, which is a key intermediate in the synthesis of sitagliptin, is prepared by using a chiral oxirane with a high yield and at a low cost.
The inventive method comprises the steps of: subjecting 2-(2,4,5- trifluorobenzyl)-oxirane of formula (11a) to β-hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia); and hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid of formula (la).
Preferably, the inventive method comprises the steps of: subjecting (2S)-2-(2,4,5- trifluorobenzyl)-oxirane of formula (lib) to β-hydrocyanation in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula
(Illb) (step 1); and hydrolyzing the (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base to obtain (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid of formula (lb) (step 2):
The method for preparing (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid using (2S)-2-(2,4,5-trifluorobenzyl)-oxirane as a starting material according to the present invention is shown in Reaction Scheme 5, but not limited thereto.
Reaction Scheme 5
(Illb) (lb)
Hereinafter, description of the preparation method illustrated in Reaction Scheme 5 by each step will be given in detail.
<Step 1>
The (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb) is prepared by subjecting (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) to β- hydrocyanation in the presence of a catalyst.
Particularly, (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib) is dissolved in a solvent and conducted a β-hydrocyanation by adding sodium cyanide in the presence of a catalyst to obtain (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile of formula (Illb).
The (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is a novel compound and may be prepared by treating a 2,4,5-trifluorobenzene halide as a starting material with a (S)- epihalohydrin (Route 1); or by treating the 2,4,5-trifluorobenzene halide with a allyl halide (Route 2) as shown in Reaction Scheme 6:
Reaction Scheme 6
wherein, m-CPBA is m-chloroperoxybenzoic acid.
Route 1
The method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 1 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating a (S)-epihalohydrin using the Grignard reagent in the presence of a copper halide to obtain (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol; and conducting an epoxidation reaction of the (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2- propanol in the presence of a strong base.
Particularly, the 2,4,5 -trifluorobenzene halide is treated with magnesium (Mg) and organic alkyl halide (e.g., 1,2-dibromoethane); Mg and I2; or isopropyl magnesium chloride (z'-PrMgCl) to obtain a Grignard reagent.
Examples of the 2,4,5-trifluorobenzene halide include 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.
Next, (2S)-3-(2,4,5-trifluorophenyl)-l-halo-2-propanol is prepared by arylating the (S)-epihalohydrin using the Grignard reagent. Preferably, the Grignard reagent is mixed with a catalytic amount of the copper halide, and then the (S)-epihalohydrin is added thereto slowly at a low temperature to obtain (2S)-3-(2,4,5-trifluorophenyl)-l- halo-2-propanol.
Examples of the copper halide include CuBr, Cul, and a mixture thereof, preferably Cul.
The oxirane such as (S)-epihalohydrin comprises (S) and (R) isomer which are
commercially available. Examples for the (S)-epihalohydrin include (S)- epichlorohydrin.
Then, (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by dissolving (2S)-3- (2,4,5-trifluorophenyl)-l-halo-2-propanol into a solvent and conducting an epoxidation reaction of a strong base.
Examples of the solvent include tetrahydrofuran, diethylether, and the like.
Examples of the strong base include a alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof, preferably sodium hydroxide.
Route 2
The method for preparing (2S)-2-(2,4,5-trifluorobenzyl)-oxirane according to Route 2 comprises the steps of: preparing a Grignard reagent using a 2,4,5- trifluorobenzene halide; arylating an allyl halide with the Grignard reagent to obtain 3- (2,4,5-trifluorophenyl)-l-propene; conducting an epoxidation reaction of 3-(2,4,5- trifluorophenyl)-l-propene using an oxidant to obtain a racemic 2-(2,4,5- trifluorobenzyl)-oxirane; and carrying out selective hydrolytic kinetic resolution (HKR) of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen.
Particularly, a Grignard reagent is prepared using a 2,4,5-trifluorobenzene halide. The methods for preparing the 2,4,5-trifluorobenzene halide and the Grignard reagent using the same are the same as described above.
Then, an allyl halide is arylated using the Grignard reagent at a low temperature to obtain 3-(2,4,5-trifluorophenyl)-l-propene.
Examples for the allyl halide include allyl bromide and the like.
Next, a reacemic 2-(2,4,5-trifluorobenzxyl)-oxirane is prepared by dissolving 3-
(2,4,5-trifluorophenyl)-l-propene in a solvent and adding an oxidant thereto to induce an epoxidation.
Examples of the solvent include tetrahydrofuran, diethylether, and the like.
Examples of the oxidant include m-ClC^CCbH, CH3C03H, CF3C03H, H202, and a mixture thereof, preferably m-ClC6H4C03H.
Then, optionally (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is prepared by conducting a selective HKR of the racemic 2-(2,4,5,-tifluorobenzyl)-oxirane using (S,S)-Co-salen of
formula (IV):
The method for preparing the desired chiral oxirane via selective HKR of the terminal oxirane has been disclosed in the documents [see Tetrahedron Asymmetry, 2003, 14, 1407-1446, and J Am. Chem. Soc, 2002, 124, 1307-1315].
The β-hydrocyanation of the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane is conducted in a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or d to C6 alcohol {e.g., methanol, ethanol, and isopropanol), preferably DMF.
The β-hydrocyanation is conducted in the presence of a catalyst such as H4CI, citric acid, acetic acid, formic acid, maleic acid, or a mixture thereof, preferably NH4CI.
<Step 2>
The 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, preferably (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid is prepared by hydrolyzing (3S)-4-(2,4,5- trifluorophenyl)-3-hydroxybutane nitrile obtained in Step 1 in the presence of a strong base and H202.
Examples of the strong base include an alkali metal hydroxide such as sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH) or a mixture thereof, preferably sodium hydroxide. Preferably, the strong base is used in a form of aqueous solution.
The method according to the present invention makes it possible to easily prepare 3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid, particularly (3S)-3-hydroxy-4-(2,4,5- trifluorophenyl)-butyric acid, a key intermediate in the synthesis of sitagliptin, with a high yield and a low cost, which is suitable for mass production of sitagliptin.
Further, the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane and 4-(2,4,5-trifluorophenyl)- 3 -hydroxy butane nitrile which are used in preparing (3S)-3-hydroxy-4-(2,4,5-
trifluorophenyl)-butyric acid as a intermediate, are novel compound. Accordingly, the present invention provides the (2S)-2-(2,4,5-trifluorobenzyl)-oxirane and 4-(2,4,5- trifluorophenyl)-3-hydroxybutane nitrile. The following preparative examples and examples illustrate the embodiments of the present invention in more detail. However, the following preparative examples and examples of the present invention are merely examples, and the present invention is not limited thereto. Preparation Example 1: Preparation of (2S)-2-(2,4,5-trifluorobenzyI)-oxirane
Step 1: preparation of (2S)-3-(2A5-trifluorophenyl -chloro-2-prepanol Magnesium (Mg) (1.26 g) was added to tetrahydrofuran (THF) (10 ml) and a drop of 1 ,2-dibromomethane was added thereto. To the resulting mixture, 2,4,5- trifluorobenzene bromide (0.55 g) was added slowly, and then stirred for 30 min. To the reaction mixture thus obtained, 2,4,5-trifluorobenzene bromide (9.0 g) in THF (50 ml) was added dropwise over 30 min and then stirred at room temperature for 1 hr. Cul (0.72 g) was added thereto and the temperature of the resulting reaction mixture was lowered to 0 °C. To the cooled reaction mixture, (S)-epichlorohydrin (4.1 ml) in THF (40 ml) was added dropwise over 30 min, and then stirred for 2 hrs at room temperature. Saturated NH4CI (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS04, and filtered off MgS04. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.
Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl -oxirane
(2S)-3-(2,4,5-Trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and an aqueous solution of NaOH (2.3 g) was added thereto dropwise. The resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS04, and filtered off MgSO4. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (6.8 g, yield: 80 %).
'H-NMR(300MHz, CDC13) : δ 7.17-7.05 (2H, m), 6.96-6.88 (2H, m), 3.16-3.13 (1H, m) 3.14 (1H, dd, J=4.68, 14.7), 2.82-2.77 (2H, m), 2.54-2.47 (1H, m).
Preparation Example 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane
Step 1 : Preparation of (2SV3-(2.4,5-trifluorophenvn-l-chloro-2-propanol
2N -PrMgCl in THF (26 ml) was added to 2,4,5-trifluorobenzene bromide (9.55 g) in THF (30 ml) dropwise at -15 °C for lhr. Cul (0.72 g) was added thereto at -15 °C and raised the temperature of the resulting mixture to -10 °C. To the resulting mixture, (S)-epichlorohydrin (4.1 ml) in THF (40 ml) was added dropwise over 30 min and then stirred at 0 °C for 1 hr. Saturated N¾C1 (50 ml) and ethyl acetate (50 ml) were added to the resulting reaction mixture to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS04, and filtered off MgS04. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.
Step 2: preparation of (2S -2-(2,4,5-trifluorobenzylVoxirane
(2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml) and NaOH (2.3 g) was added thereto dropwise. The
resulting mixture was stirred for 1 hr and condensed under a reduced pressure to remove methanol. The residue was mixed with water (50 ml) and ethyl acetate (50 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (50 ml), dried over MgS04, and filtered off MgS04. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (7.6 g, yield: 85 %).
Preparation Example 3: Preparation of 2-(2,4,5-trifluorobenzyl)-oxirane
Step 1: Preparation 3-(2A5-trifluorophenyl -l-propene
Mg (1.26 g) was added to THF (30 ml) and a drop of 1 ,2-dibromomethane (0.2 g) was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (3.6 g) was added slowly and then stirred for 30 min. To the reaction mixture thus obtained, 2,4,5-trifluorobenzene bromide (25 g) in THF (60 ml) was added dropwise over 60 min and then stirred at room temperature for 1 hr. The temperature of the resulting mixture was lowered to -10 °C . To the cooled mixture, allyl bromide (18.0 g) in THF (60 ml) was added dropwise over 20 min and then stirred for 1 hrs. The temperature of the resulting mixture was increased to room temperature and then stirred for 1 hr. Dichloromethane (MC) (300 ml) was added to the resulting mixture to induce phase separation. The organic layer was isolated, washed with 2 M NH4CI (150 ml) and water (150 ml) successively, dried over MgS04, and filtered off MgS04. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound.
Step 2: Preparation of 2-(2,4,5-trifluorobenzyl')-oxirane
3-(2,4,5-Trifiuorophenyl)-l-propene obtained in step 1 was dissolved in dichloromethane (300 ml) and m-chloroperoxybenzoic acid (m-CPBA) (35 g) was added
thereto dropwise. The resulting mixture was stirred for 17 hr and then saturated NaHC03 (300 ml) was added thereto to induce phase separation. The organic layer was isolated, washed with 1 N NaOH (300 ml) and brine (100 ml) successively, dried over MgS04, and filtered off MgS04. The residue was condensed under a reduced pressure to remove the organic solvent to obtain the title compound (19.1 g, yield: 75 %).
Preparation Example 4: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane
(AcOH) (120 uL) and THF(1 mL) were mixed in a reactor at room temperature. The temperatue of the resulting mixture was lowered to 0 °C and H20 (1.0 ml) was added thereto. The mixture thus obtained was stirred at room temperature for 24 hrs and condensed under a reduced pressure to remove THF. The residue was subjected to column chromatography to obtain the title compound (7.71 g, yield: 41 %).
Preparation Example 5: Preparation of (3S)-4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile
To a solution of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (5.30 g) in MeOH (25 ml), NaCN (2.07 g) in water (10 ml) and NH4C1 (1.96 g) were added successively and warmed up to 50 °C . The resulting mixture was stirred for 3 hrs and condensed under a reduced pressure to remove the solvent. The residue was mixed with water (25 ml) and ethyl acetate (25 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (25 ml) twice, dried over MgS04, filtered off MgS04, and condensed under a reduced pressure to remove the organic
solvent. The residue was subjected to column chromatography to obtain the title compound (5.59 g, yield: 92 %).
'H-NMR(300MHz, CDC13) : δ 7.19-7.08 (2H, m), 6.99-6.90 (2H, m), 4.24-4.15 (1H, m), 2.96-2.83 (2H, m), 2.65-2.48 (2H, m)
Example 1: Preparation of (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid
(3S)-4-(2,4,5-Trifluorophenyl)-3-hydroxybutane nitrile (5.59 g) obtained in Preparation Example 5 was dissolved in MeOH (20 ml) in a reactor at room temperature and 30 % H202 (5.31 mL) and NaOH (2.60 g) were added thereto successively. The resulting mixture was warmed up 70 °C and refluxed for 6 hrs with stirring. The temperature of the resulting mixture was lowered to 0 °C and 2N HCl (aq) (28.0 mL) was added slowly thereto. The mixture thus obtained was extracted with ethyl acetate (30 ml) to induce phase separation. The organic layer was isolated, washed with aq. saturated sodium chloride solution (30 ml) twice, dried over MgS04, filtered off MgS04, and condensed under a reduced pressure to remove the organic solvent. The residue was subjected to column chromatography to obtain the title compound (5.48 g, yield: 90 %).
'H-NMR(300MHz, CDC13) : δ 7.27-7.07 (2H, m), 6.96-6.86 (2H, m), 6.0 (1H, br), 4.30-4.22 (m, 1H), 2.79 (2H, d, J=6.3), 2.61-2.44 (m, 2H)
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.
Claims
1. A method for preparing 3-hydroxy-4-(2,4,5-trifluorophenyl)butyric acid of formula (la), comprising the steps of:
subjecting 2-(2,4,5-trifluorobenzyl)-oxirane of formula (Ila) to β- hydrocyanation in the presence of a catalyst to obtain 4-(2,4,5-trifluorophenyl)-3- hydroxybutane nitrile of formula (Ilia); and
hydrolyzing the 4-(2,4,5-trifluorophenyl)-3-hydroxybutane nitrile in the presence of a strong base:
F (Ilia).
2. The method of claim 1, wherein the 2-(2,4,5-trifluorobenzyl)-oxirane is (2S)-2- (2,4,5-trifluorobenzyl)-oxirane of formula (lib):
3. The method of claim 1, wherein the catalyst is selected from the group consisting of NH4CI, citric acid, acetic acid, formic acid, maleic acid, and a mixture thereof.
4. The method of claim 1, wherein the β-hydrocyanation is conducted by using sodium cyanide.
5. The method of claim 1, wherein the strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof.
6. The method of claim 1, wherein the 2-(2,4,5-trifluorobenzyl)-oxirane is prepared by a method comprising the steps of:
preparing a Grignard reagent using a 2,4,5-trifluorobenzene halide;
arylating a (S)-epihalohydrin in the presence of a copper halide to obtain (2S)-3- (2,4,5-trifluorophenyl)-l-halo-2-propanol using the Grignard reagent; and
conducting an epoxidation reaction of the (2S)-3-(2,4,5-trifluorophenyl)-l-halo- 2-propanol in the presence of a strong base.
7. The method of claim 6, wherein the 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.
8. The method of claim 6, wherein the copper halide is selected from the group consisting of CuBr, Cul, and a mixture thereof.
9. The method of claim 6, wherein the strong base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and a mixture thereof.
10. The method of claim 1, wherein 2-(2,4,5-trifluorobenzyl)-oxirane is prepared by a method comprising the steps of:
preparing a Grignard reagent using a 2,4,5-trifluorobenzene halide;
arylating an allyl halide with the Grignard reagent to obtain 3-(2,4,5- trifluorophenyl)- 1 -propene; conducting an epoxidation reaction of the 3-(2,4,5-trifluorophenyl)-l-propene using an oxidant to obtain a racemic 2-(2,4,5,-tifluorobenzyl)-oxirane; and
carrying out selective hydrolytic kinetic resolution of the racemic 2-(2,4,5,- tifluorobenzyl)-oxirane.
11. The method of claim 10, wherein the 2,4,5-trifluorobenzene halide is selected from the group consisting of 2,4,5-trifluorobenzene bromide, 2,4,5-trifluorobenzene chloride, and a mixture thereof.
12. The method of claim 10, wherein the oxidant is selected from the group consisting of m-ClCetLtCOsH, CH3CO3H, CF3CO3H, H202, and a mixture thereof.
13. The method of claim 10, wherein the selective hydrolytic kinetic resolution is conducted using (S,S)-Co-salen of formula (IV):
14. (2S)-2-(2,4,5-trifluorobenzyl)-oxirane of formula (lib):
F (lib).
15. 4-(2,4,5-Trifluorophenyl)-3-hydroxybutane nitrile of formula (Ilia):
(Ilia).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2009-0093894 | 2009-10-01 | ||
| KR1020090093894A KR101253106B1 (en) | 2009-10-01 | 2009-10-01 | Method for preparing intermediate of sitagliptin using chiral oxirane |
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| Publication Number | Publication Date |
|---|---|
| WO2011040717A2 true WO2011040717A2 (en) | 2011-04-07 |
| WO2011040717A3 WO2011040717A3 (en) | 2011-10-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/KR2010/006346 WO2011040717A2 (en) | 2009-10-01 | 2010-09-16 | Method for preparing intermediate of sitagliptin using chiral oxirane |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR101253106B1 (en) |
| AR (1) | AR079102A1 (en) |
| TW (1) | TW201118101A (en) |
| WO (1) | WO2011040717A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838511A (en) * | 2011-06-24 | 2012-12-26 | 浙江海翔药业股份有限公司 | Sitagliptin intermediates as well as preparation method and application of intermediate |
| CN113979853A (en) * | 2021-11-24 | 2022-01-28 | 上海科利生物医药有限公司 | Preparation method of (S) -3-hydroxy-4- (2,4, 5-trifluorophenyl) butyric acid |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2108767A2 (en) * | 1970-10-02 | 1972-05-26 | Synthelabo | 2-carbamyloxy-3-phenylbutyronitriles - with hypnotic activity |
| WO2004087650A2 (en) * | 2003-03-27 | 2004-10-14 | Merck & Co. Inc. | Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors |
| TW200936764A (en) * | 2007-10-03 | 2009-09-01 | Teva Pharma | Processes for preparing an intermediate of sitagliptin via enzymatic reduction |
| US20090192326A1 (en) | 2007-11-13 | 2009-07-30 | Nurit Perlman | Preparation of sitagliptin intermediate |
-
2009
- 2009-10-01 KR KR1020090093894A patent/KR101253106B1/en active Active
-
2010
- 2010-09-16 WO PCT/KR2010/006346 patent/WO2011040717A2/en active Application Filing
- 2010-09-29 AR ARP100103536A patent/AR079102A1/en not_active Application Discontinuation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838511A (en) * | 2011-06-24 | 2012-12-26 | 浙江海翔药业股份有限公司 | Sitagliptin intermediates as well as preparation method and application of intermediate |
| CN113979853A (en) * | 2021-11-24 | 2022-01-28 | 上海科利生物医药有限公司 | Preparation method of (S) -3-hydroxy-4- (2,4, 5-trifluorophenyl) butyric acid |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20110036308A (en) | 2011-04-07 |
| WO2011040717A3 (en) | 2011-10-13 |
| KR101253106B1 (en) | 2013-04-10 |
| AR079102A1 (en) | 2011-12-28 |
| TW201118101A (en) | 2011-06-01 |
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