MXPA98007922A - Enzimative process for the stereoselective preparation of amidas terapeuti - Google Patents
Enzimative process for the stereoselective preparation of amidas terapeutiInfo
- Publication number
- MXPA98007922A MXPA98007922A MXPA/A/1998/007922A MX9807922A MXPA98007922A MX PA98007922 A MXPA98007922 A MX PA98007922A MX 9807922 A MX9807922 A MX 9807922A MX PA98007922 A MXPA98007922 A MX PA98007922A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- carbon atoms
- hydroxy
- compound
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title description 13
- 230000000707 stereoselective Effects 0.000 title description 10
- 241000670727 Amida Species 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 102000004882 lipase Human genes 0.000 claims description 24
- 108090001060 lipase Proteins 0.000 claims description 24
- 239000004367 Lipase Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 23
- 235000019421 lipase Nutrition 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 229940040461 Lipase Drugs 0.000 claims description 21
- 102000004157 Hydrolases Human genes 0.000 claims description 19
- 108090000604 Hydrolases Proteins 0.000 claims description 19
- 229940116369 Pancreatic lipase Drugs 0.000 claims description 19
- 102000019280 Pancreatic lipase Human genes 0.000 claims description 19
- 108050006759 Pancreatic lipase Proteins 0.000 claims description 19
- -1 phenylthio, phenylsulfinyl Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- LVEDGSIMCSQNNX-INIZCTEOSA-N (2S)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide Chemical compound C1=CC(NC(=O)[C@@](O)(C)C(F)(F)F)=CC=C1C(=O)C1=CC=CC=C1 LVEDGSIMCSQNNX-INIZCTEOSA-N 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 12
- CTGJACFEVDCYMC-VKHMYHEASA-N (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid Chemical compound OC(=O)[C@@](O)(C)C(F)(F)F CTGJACFEVDCYMC-VKHMYHEASA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 230000000875 corresponding Effects 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000005842 heteroatoms Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 3
- 239000001301 oxygen Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000005647 linker group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 101710019688 COR4 Proteins 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 claims 1
- 230000003217 anti-cancerogenic Effects 0.000 claims 1
- 230000002255 enzymatic Effects 0.000 abstract description 19
- 239000000543 intermediate Substances 0.000 abstract description 11
- 150000002148 esters Chemical class 0.000 description 71
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 49
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 46
- 102000004190 Enzymes Human genes 0.000 description 36
- 108090000790 Enzymes Proteins 0.000 description 36
- 229940088598 Enzyme Drugs 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- LVEDGSIMCSQNNX-UHFFFAOYSA-N N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide Chemical compound C1=CC(NC(=O)C(O)(C)C(F)(F)F)=CC=C1C(=O)C1=CC=CC=C1 LVEDGSIMCSQNNX-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 125000004185 ester group Chemical group 0.000 description 15
- 238000006460 hydrolysis reaction Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- OBNCKNCVKJNDBV-UHFFFAOYSA-N Ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000002194 synthesizing Effects 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000000758 substrate Substances 0.000 description 11
- CTGJACFEVDCYMC-UHFFFAOYSA-N 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid Chemical compound OC(=O)C(O)(C)C(F)(F)F CTGJACFEVDCYMC-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- RBKHNGHPZZZJCI-UHFFFAOYSA-N (4-aminophenyl)-phenylmethanone Chemical compound C1=CC(N)=CC=C1C(=O)C1=CC=CC=C1 RBKHNGHPZZZJCI-UHFFFAOYSA-N 0.000 description 7
- 239000006184 cosolvent Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000008079 hexane Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- DVECBJCOGJRVPX-UHFFFAOYSA-N Butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000012062 aqueous buffer Substances 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- HUCCJSWZXCFGFK-UHFFFAOYSA-N ethyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate Chemical compound CCOC(=O)C(C)(O)C(F)(F)F HUCCJSWZXCFGFK-UHFFFAOYSA-N 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- XDCMNDCKYSQKAX-VKHMYHEASA-N (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile Chemical compound N#C[C@@](O)(C)C(F)(F)F XDCMNDCKYSQKAX-VKHMYHEASA-N 0.000 description 4
- XDCMNDCKYSQKAX-UHFFFAOYSA-N 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile Chemical compound N#CC(O)(C)C(F)(F)F XDCMNDCKYSQKAX-UHFFFAOYSA-N 0.000 description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M Monopotassium phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 4
- 108091005771 Peptidases Proteins 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000003999 initiator Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- 235000019833 protease Nutrition 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-Hydroxybutyric acid Chemical compound CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 3
- 241000131386 Aspergillus sojae Species 0.000 description 3
- 102000033147 ERVK-25 Human genes 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 239000011942 biocatalyst Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 230000001808 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FHUDAMLDXFJHJE-UHFFFAOYSA-N 1,1,1-trifluoropropan-2-one Chemical compound CC(=O)C(F)(F)F FHUDAMLDXFJHJE-UHFFFAOYSA-N 0.000 description 2
- HYFLWBNQFMXCPA-UHFFFAOYSA-N 1-ethyl-2-methylbenzene Chemical compound CCC1=CC=CC=C1C HYFLWBNQFMXCPA-UHFFFAOYSA-N 0.000 description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- MWFMGBPGAXYFAR-UHFFFAOYSA-N Acetone cyanohydrin Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina pectoris Diseases 0.000 description 2
- 208000006673 Asthma Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 206010046543 Urinary incontinence Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 230000005591 charge neutralization Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 102000004257 potassium channel family Human genes 0.000 description 2
- 108020001213 potassium channel family Proteins 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-Phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- WRADANNQOTZBDC-UHFFFAOYSA-N 1-anthracen-9-ylethanol Chemical compound C1=CC=C2C(C(O)C)=C(C=CC=C3)C3=CC2=C1 WRADANNQOTZBDC-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- HDBGBTNNPRCVND-UHFFFAOYSA-N 3,3,3-trifluoropropan-1-ol Chemical compound OCCC(F)(F)F HDBGBTNNPRCVND-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- 235000002247 Aspergillus oryzae Nutrition 0.000 description 1
- 240000006439 Aspergillus oryzae Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000208199 Buxus sempervirens Species 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- YVPYQUNUQOZFHG-UHFFFAOYSA-N Diatrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N Isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N L-Norpseudoephedrine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000035443 Peptidases Human genes 0.000 description 1
- 229960000395 Phenylpropanolamine Drugs 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N Propanamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SOGXBRHOWDEKQB-UHFFFAOYSA-N benzyl 2-chloroacetate Chemical compound ClCC(=O)OCC1=CC=CC=C1 SOGXBRHOWDEKQB-UHFFFAOYSA-N 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
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- FWPDFCSSQIUIGD-UHFFFAOYSA-N butyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate Chemical compound CCCCOC(=O)C(C)(O)C(F)(F)F FWPDFCSSQIUIGD-UHFFFAOYSA-N 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M caproate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- HUCCJSWZXCFGFK-YFKPBYRVSA-N ethyl (2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoate Chemical compound CCOC(=O)[C@](C)(O)C(F)(F)F HUCCJSWZXCFGFK-YFKPBYRVSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium(0) Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003301 hydrolyzing Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N propyl 3,4,5-trihydroxybenzoate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
The present invention provides enzymatic processes for preparing optically active compounds of formula (I) wherein X, E and * have the meanings defined in the specification. The invention also provides chiral intermediates employed to prepare compounds of Formula (I) and enzymatic processes for preparing such chiral intermediates.
Description
ENZ-QATICO PROCESS FOR THE STEREOSELECTIVE PREPARATION OF THERAPEUTIC AMIDES
Field of the Invention The present invention relates to methods of synthesizing pharmaceutical compounds and intermediates used in the synthesis of such chemical compounds. In particular, the present invention relates to novel enzymatic processes for the stereoselective preparation of N-aryl or pyridyl propanamides having a stereogenic center of tertiary alcohol, and enantiomeric intermediates employed for the synthesis of such compounds.
Background of the Invention It is described in U.S. Patent No. 5,272,163, which was published on December 21, 1993 by Russell et al. N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and other propanamides of N-aryl or -pyridyl. Such compounds are cellular openers of the potassium channel and are also used in the treatment of urinary incontinence and other conditions and conditions that include hypertension, asthma, vascular periphery disease and angina, as
REF. 28507 described in the aforementioned patent. The U.S. 5,272,163 also discloses a method of preparing the (S) - (-) enantiomer of N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide in which the method employs ester formation diastereomeric followed by chromatographic separation, and subsequent elimination of the ester group by treatment with a base.
Brief Description of the Invention The present invention provides a novel enzymatic process for the stereoselective preparation of N-aryl or -pyridyl propanamides having a stereogenic tertiary alcohol center as exemplified by the preparation of (S) - (-) - N - (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. Such compounds are cellular openers of the potassium channel and are also used in the treatment of urinary incontinence and other conditions and conditions that include hypertension, asthma, disorders of the vascular periphery and angina. The novel methods of the invention employ an enzymatic step to selectively split an ester group from an enantiomer of a racemic mixture of esters formed from N-aryl or pyridylpropanamide.
The enzymatic stage can follow from the separation of the remaining ester from the alcohol thus produced. The recovered ester that was not unfolded in the enzymatic step can be hydrolyzed if desired to produce the corresponding alcohol. The present invention also provides methods for synthesizing intermediates employed in the synthesis of the aforementioned N-aryl or -pyridylpropanamides, as exemplified by the preparation of (S) -3,3,3-trifluoro-2-hydroxy-2- acid. methylpropanoic acid used in the preparation of (S) - (-) - N - (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. The methods for the stereoselective synthesis of N-aryl or pyridyl propanamides having a stereogenic tertiary alcohol center, exemplified by (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2 -hydroxy-2-methylpropanamide, and intermediates employed in the synthesis of such compounds that are provided herein. These and other aspects of the present invention as set forth in the appended claims are described in their preferred embodiments in the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION A first aspect of the invention provides a method of preparing an optically active compound of
Formula I
OH
wherein E is selected from nitrogen and CZ wherein C is a carbon ring and Z is a substituent defined below, wherein: when? is CZ, X and Z are selected from the group consisting of: (A) X is ArY wherein Y is a linking group selected from carbonyl, sulfinyl and sulfonyl and Ar is selected from the group consisting of: phenyl substituted with 0 -2 substituents selected from halo, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms; six-membered heteroaryl rings containing 1 to 2 nitrogen atoms only as the heteroatoms; five-membered heteroaryl rings containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; and Z is selected from hydrogen, cyano, halo, hydroxy, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms and (B) X is cyano and Z is selected from the group consisting of phenylthio, phenylsulfinyl, and phenylsulfonyl phenyl rings which are substituted with 0-2 substituents selected from halo, hydroxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms; and when E is nitrogen, X independently is selected from any of the values for X given above in (A); and * is an optically active chiral center, comprising the step of treating a racemic compound of Formula II with a hydrolase enzyme. The compounds of formula II are as defined as follows:
Formula II
where E and X have the meanings previously defined here; and R1 is alkyl optionally substituted by one or more substituents independently selected from hydroxy, halogen, alkoxy of 1 to 4 carbon atoms, cyano, alkylamino of 1 to 4 carbon atoms and dialkylamino of 1 to 4 carbon atoms. Preferably, R1 is optionally substituted alkyl of 1 to 7 carbon atoms, more preferably optionally substituted alkyl of 1 to 5 carbon atoms. A preferred substituent is halogen, more preferably chlorine. In the method of the invention, the hydrolase enzyme cleaves the ester group from an enantiomer of the ester of Formula II to provide the (S) or (R) enantiomer as the alcohol of formula I, depending on the specificity of the enzyme, and driving the other enantiomer into the unreacted substrate. The method of the invention may also comprise the step of separating the product formed during the enzymatic step from the unreacted initiator material, ie, separating the alcohol of Formula I formed during the enzymatic treatment of the unreacted ester compound of Formula II . The selective cleavage of the ester group enzyme from an enantiomer of the racemic mixture of the compound of Formula II produces the alcohol. The compound of Formula I and the unreacted ester initiator material of Formula II can be separated using conventional methods such as silica column chromatography. When the desired enantiomer is the unreacted ester, the method of the invention can further comprise conversion of the ester to the corresponding alcohol. The ester can be converted to the corresponding alcohol by treatment with a base such as sodium hydroxide. A preferred embodiment of this aspect of the invention provides a method for preparing (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Formula I wherein * is the configuration (S), E is CZ, X is ArY, Y is carbonyl, Ar is phenyl, and Z is hydrogen). The racemic N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide can be converted to an ester using conventional methods known in the art. For example, the racemic compound is reacted with an acid chloride of formula III:
Formula III O
II R 1 Cl wherein R 1 has the meaning defined hereinbefore, in the presence of a base such as triethylamine, as shown in Scheme I. Preferred compounds of Formula III include monochloroacetyl chloride and butyryl chloride. The racemic N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide can be prepared, for example, using the method of US Pat. No. 5,382,598 or the method described herein. The resulting ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide is then reacted with a hydrolase enzyme, preferably a lipase, more preferably crude porcine pancreatic lipase, which selectively cleaves the ester group of the (R) enantiomer, leading to the ester of the (S) enantiomer. The reaction preferably takes place in an aqueous buffer solution at about pH 7 with tert-butyl methyl ester (MTBE) as a cosolvent. However, it is well understood that the pH of the aqueous buffer solution will depend on the enzyme used in the reaction. The presence of the cosolvent in the reaction mixture is optional. The reaction is allowed to proceed until the available substrate is reacted, which may be from about one to about three days. The reaction may proceed faster or slower depending on the enzyme used and the reaction conditions. It may also be possible to use an enzyme with the opposite specificity, to unfold the ester group from the (S) enantiomer directly in the enzymatic step.
Scheme I
The ester (S) can be separated from the (R) -enantiomer of N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide by standard methods such as chromatography on a silica column or by any other convenient method. When the ester is the (S) enantiomer, it is then treated with a base such as sodium hydroxide in aqueous methanol or other solvent to remove the ester group and provide (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. This aspect of the present invention has been exemplified by the synthesis of (S) - (-) - N - (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. Other N-aryl or pyridyl propanamides of formula I can be prepared by replacing racemic mixtures of such compounds with N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide in the described method in Scheme 1. The use of protecting groups may be necessary for some substituents. Racemic mixtures of the compounds of Formula I can be prepared in accordance with the methods of U.S. Pat. 5,382,598. Scheme 2 shows the preparation of (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide wherein the (S) -3 acid intermediate, 3, 3-trifluoro-2-hydroxy-2-methylpropanoic is prepared by selective crystallization with a resolving agent instead of an enzymatic process. As shown in Scheme 2, 1,1,1-trifluoroacetone (1) is reacted with a cyanide such as sodium cyanide in the presence of an acid such as hydrochloric acid to form 3,3,3-trifluoroacetate. Racemic 2-hydroxy-2-methylpropanonitrile (2). The racemic 3, 3, 3-trifluoro-2-hydroxy-2-methylpronanonitrile (2) is then hydrolyzed with, for example, hydrochloric acid to provide 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3). ). The racemate is then selectively crystallized with a resolving agent such as (IR, 2S) -norephedrine (4) to form a salt (5) which can be recrystallized to diastereomeric purity. The purified salt (6) contains (S) -3, 3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7). The (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid after liberation from the salt is reacted with 4-aminobenzophenone (8) and S0C12 using an organic base such as triethylamine or a Hunig base to form in (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (9), which can then be purified by recrystallization. For the preparation of other N-aryl or pyridyl propanamides of formula I which have the S configuration, an amine of formula IV as defined herein above is substituted by 4-aminobenzophenone (8) in the synthesis shown in Scheme 2. Amine is reacted with:
Scheme 2 1 1, 1, 1 -trffl? Oroacßtoru- 3.3.3-tfMlu? I? -2-ltidxo > i- 3,3,3-txifluoro-2- 2-aatilpropanonltrilo 2- «• tllpropanoic acid
(1 R, 2S) - Mor • fadrína
aal da ñor «initial fadrína
• to the "nox." F "raelled diat« reoat «ricaa« nt «pure
4-Aminober-zsf anona -------- do (S- -3,3,3-trtn? ---? - ™ ------- i .-- ro ----- - l-aa-tilp-rapaaolco
9 Purified tom--. ?-" to. ethyl (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid in a similar manner to produce the amide product which may optionally be purified by conventional methods. The amines of Formula IV are also described in US Pat. No. 5,272,163. The compounds of Formula IV are defined as follows:
Formula IV
where X and E have the meanings defined herein above. Such amines of Formula IV can be prepared according to the methods described in U.S. Pat. 5,272,163. In addition to the methods shown in Scheme 2, the coupling of a compound of Formula IV with (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid can be conducted in other suitable solvents and in the presence of other suitable coupling reagents. Convenient coupling reagents generally known in the art can be employed as standard peptide coupling reagents, for example thionyl chloride (see Morris et al., J. Med. Chem., 34, 447, (1991), carbonyldiimimidazole (CDI) and dicylohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine (DMAP) or -pyrrolidinopyridine Convenient solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide.The coupling reaction can be conducted in a temperature range of about
-40 ° to 40 ° C. In a further aspect, the present invention provides stereoselective methods of preparing (S) -enantiomer intermediates employed in the synthesis of (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2- hydroxy-2-methylpropanamide and other N-aryl or pyridylpropanamides described in the US Pat. 5,272,163. Intermediates of (S) -enantiomers allow (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide or other N-aryl or pyridylpropanamide of Formula I to be prepared without the tedious steps of stereoselective salt formation using resolving agents such as α-methylbenzylamine or norephedrine. The present invention provides stereoselective processes, each containing an enzymatic step, to prepare the acid (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanonitrile and (S) -3,3,3-trifluoromide. 2-hydroxy-2-methylpropanoic. In the first stereoselective process for preparing such intermediates of (S) -3,3,3-trifluoro-2-hydroxy-2-methylpentanoic acid, it is prepared by selective cleavage of a 3, 3, 3-trifluoromethyl ester. Racemic 2-hydroxy-2-methylpropanoic using a hydrolase, preferably a lipase such as the Antarctic Candida lipase. The method comprises treating an ester of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid which preferably has Formula V:
Fopnula V
I ii CH3 - C - C- or - R2 OH
wherein R2 is alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl with a hydrolase enzyme. The ester can be prepared using conventional methods, such as the preparation of the racemic acid with a mineral acid and appropriate alcohol. For example, butyl and propyl esters can be prepared by reacting racemic 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoic acid and propanol or butanol in the presence of a small amount of concentrated sulfuric acid or chloride of dry hydrogen to form the respective butyl or propyl ester. The ester of Formula V can also be prepared by hydrolysis of 3,3,3-trifluoro-2-hydroxy-2-methylpropanonitrile with a sulfuric acid in the presence of the appropriate alcohol. The ester of Formula V is selectively split by a hydrolase enzyme, preferably a lipase such as an Antarctic Candida lipase, to form a mixture of the ester product and acid. The reaction with the hydrolase enzyme is preferably carried out in an aqueous buffer solution at a pH acceptable for the enzyme used to provide a good reaction ratio, usually between about 5 and approximately pH 9. Co-solvents can also be used. such as methyl-tert-butyl ether (MTBE). The reaction is allowed to proceed until a satisfactory amount of the ester has reacted, usually after about one to three days. The current reaction time will depend on factors such as the enzyme, substrates and solvents used. The acid and ester can then be separated using silica gel chromatography or any other suitable method known in the art. Depending on the selectivity of the enzyme, the desired enantiomer (S) can be present as the recovered unreacted ester or as the free acid. In the case where the unreacted ester contains the (S) -enantiomer, the ester group can then be removed to generate the (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid by the reaction with a base such as sodium hydroxide, followed by neutralization. To prepare (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, (S) -3,3,3-trifluoro-2- acid hydroxy-2-methylpropanoic is then reacted with the 4-aminobenzophenone in accordance with the methods herein. Other N-aryl or pyridyl propanamides of formula I can be prepared using (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid and substituting an amine of Formula IV for 4-aminobenzophenone in the synthesis shown in Scheme 2, as described here. The compounds of Formula V
Formula V
wherein R2 is alkyl of 3 to 6 carbon atoms, alkoxy, or phenyl, form another aspect of the invention. The compounds of Formula VI
Formula VI CF3 O CH ^ - C - C - or - OH wherein * is an optically active chiral center and R2 is alkyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl forms an additional aspect of the invention. Preferably, * is an optically active chiral center having the (S) configuration. In the second stereoselective method for preparing such intermediates, (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid is prepared by treating or reacting a compound of Formula VII,
wherein A is CN, COH, CH (ORJ) 2, COR ", COOR3, C0NH2, CONHR6 or CONRV; R3, R4, R5, R6, R7 and R8 are independently selected from alkyl, aryl, and aralkyl; and R9 is alkyl, aryl or aralkyl, any of which may be optionally independently substituted with substituents selected from a hydroxy, halogen, alkoxy of 1 to 4 carbon atoms, cyano, alkylamino of 1 to 4 carbon atoms or dialkylamino of 1 to 4 carbon atoms, with a hydrolase enzyme, preferably a lipase such as a crude porcine pancreatic lipase, which selectively cleaves the ester group to provide the corresponding alcohol of Formula VIII
Formula VIII
wherein * is an optically active chiral center and A has the previously defined meaning herein, and converting group A of the compound of Formula VIII to an acid (i.e., to a COOH group). R9 is preferably optionally substituted with alkyl of 1 to 10 carbon atoms, more preferably alkyl of 1 to 5 carbon atoms. A is preferably CN. Preferably, R3, R4, R5, R6, R7 and R8 are independently alkyl of 1 to 10 carbon atoms, more preferably alkyl of 1 to 5 carbon atoms. The reaction with the hydrolase can be carried out in an aqueous buffer, with the pH of the solution adjusted to an acceptable value for the enzyme used, generally between pH 7 and approximately pH 7.5. Cosolvents such as MTBE can also be used. The reaction is usually allowed to proceed until a satisfactory amount of the ester has reacted. The reaction is usually left to proceed for about three days, but the current time will depend on factors such as the enzyme, substrates and solvents used. The mixture of alcohol and ester can then be separated by conventional methods such as chromatography on a silica column. Depending on the selectivity of the enzyme, the desired enantiomer (S) may be present as the ester or alcohol recovered (unreacted). When the desired (S) enantiomer is the recovered ester, the ester can then be treated with a base such as sodium hydroxide to remove the ester group. Group A is converted to a carboxyl group by standard methods to provide (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid. Optionally, depending on the nature of A, the ester removed and the hydrolysis steps of the nitrile can be combined. In a preferred embodiment, (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid is prepared by reacting (S) -3,3,3-trifluoro-2-hydroxy-2- methylpropanonitrile with the acid. (S) -3,3,3-trifluoro-2-hydroxy-2-propanenitrile can be prepared by reacting 1,1-trifluoroacetate with sodium cyanide in the presence of hydrochloric acid to form 3,3 , Racemic 3-trifluoro-2-hydroxy-2-methylpropanonitrile. The racemic 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanenitrile is then reacted with an acid chloride such as butyryl chloride to form the ester. The racemic ester is reacted with a lipase enzyme such as crude porcine pancreatic lipase which selectively cleaves the ester group from the enantiomer (R) leaving the ester of enanomer (S). The ester group of the (S) enantiomer is then removed using standard procedures to provide (S) -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanonitrile, which returns treated with acid such as sulfuric acid or hydrochloric acid to form the acid (S) -3,3,3-trifluoro-2-hydroxy-2- methylpropanoic A further aspect of the invention provides a method for preparing (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanonitrile, wherein the method comprises treating a compound of Formula VII wherein A is CN with a hydrolase enzyme preferably a lipase such as a crude porcine pancreatic lipase. The present invention thus also provides compounds of Formula VII Formula VII CF, CH, -C-A i, OCORwhere A and R9 have the previously defined meanings here; and the compounds of Formula IX
Formula IX CF3 CH, - C - A i, OCOR
wherein * is an optically active chiral center and A and R9 have the meanings previously defined herein. Preferably, * denotes an optically active chiral center having the configuration (S). The present invention also provides compound of Formula VIII
Formula VIII
The enzymatic step of the methods described herein can be performed using any type of hydrolase enzyme that is capable of selectively cleaving an ester group to form an alcohol, such as a lipase, esterase, peptidase or protease. The enzyme can be obtained from microbial cultures of plants or animals. Such enzymes are commercially available or can be prepared by methods known in the art. It has been found that lipase preparations can selectively split out esters formed from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and other esters described herein, to effect the resolution of the enantiomers in acceptable yields. It has been found that commercially available lipase preparations preferentially split the ester group from the (R) enantiomer, from the (S) -enantiomer in the form of an ester. A preferred lipase is the crude porcine pancreatic lipase which is readily available commercially. Lipases from other species can also be used. Porcine pancreatic lipase provides good specificity and reaction rate. The enzymes employed in the present invention are commercially available and can be used in the reaction mixture as they are received without further treatment or the enzymes can be pretreated, for example, by dissolution in buffers at about pH 7 to 7.5 and the . absorption on a support such as sugar beds, diatomaceous earths, activated carbon, ion exchange resins or silica gel or covalently bound to a polymeric support. Typically, the enzymatic step of the methods of the present invention can be performed at a ratio of 1:10 to 100: 1 (weight: weight) substrate: enzyme. Enzyme proportions: substrates from 5: 1 to 1: 1 have been found to provide satisfactory results. The ratio of the substrate to enzyme may need to be varied to produce a satisfactory proportion of reaction depending on such factors as initiator materials, the enzyme used and the reaction conditions such as temperature and solvent. The enzymatic reaction is allowed to proceed until satisfactory amounts of the alcohol are formed by cleavage of the ester group from starting materials. In general, the enzymatic reaction will be allowed to proceed for about twenty hours to about four to five days, preferably about one to three days. The pH of the reaction mixture is generally from about 5 to about 9, preferably from about 7 to about 8. The enzymatic step is generally carried out at a temperature of about 15 to about 40 ° C, preferably about 25 to about 38 ° C. The reaction conditions may need to vary within (or even outside) the aforementioned ranges to provide a satisfactory ratio depending on such factors as initiator materials, enzymes and solvents employed. The solvent and any cosolvent used in the reaction mixture will vary depending on such factors as the enzyme and substrate used in the reaction. The solvent may also influence the selectivity and / or proportion of the enzymatic reaction and in such cases the solvent may be selected to increase the reaction ratio (relative to other solvents) and / or influence the selectivity of the enzyme to the enantiomer. wanted. The solvent of the reaction mixture can be any conventional aqueous buffer such as a potassium dihydrogen phosphate buffer. Suitable cosolvents for the reaction include MTBE. The enzymatic resolution reaction has been taken to complement it (ie, reaction of all of the ester (R)) in two days using a substrate: enzyme ratio of 1: 1 w / w with the racemic ester derived from N- (4-benzoylphenyl) -3,3, 3 -trifluoro-2-hydroxy-2-methylpropanamide and butyric acid and pancreatic lipase from raw porcine. A substrate: enzyme ratio of 5: 1 w / w of the same materials produces approximately 25% ester hydrolysis in two days. The reaction of the porcine pancreatic lipase with the racemic ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and butyric acid, after the hydrolysed recovered ester, provides an enantiomeric excess of the 98.5% isomer (S) in 35% yield (70% of available ester (S)). As used herein, the alkyl and alkyl portions of alkoxy and aralkyl include both straight or branched chain radicals. Particular values of alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, sec-butyl and tert-butyl. Particular values of alkoxy include methoxy, ethoxy, propoxy and butoxy. Particular values of aralkyl include benzyl, phenylethyl and phenylpropyl. Particular values of aryl include phenyl. Particular values of alkylamino include methylamino, ethylamino, propylamino and butylamino. Particular values of dialkylamino include dimethylamino and diethylamino.
Particular values of Ar as a six-membered heteroaryl ring containing 1-2 nitrogen atoms include 2-, 3-, and 4-pyridyl, 2-pyrazinyl, 2- and 4-pyrimidinyl and 3-and 4-pyridazinyl. Particular values of Ar as a five-membered heteroaryl ring containing from 1-2 heteroatoms selected from nitrogen, oxygen and sulfur include 3,4- and 5-isothiazolyl, 2-, 4- and 5-oxazolyl, 2,4- and 5-thiazolyl, 2- and 3-furyl, and 2- and 3-furyl. The term "halogen" refers to fluoro, chloro, bromo, and iodo unless otherwise indicated * denotes an optically active chiral center in the R or S configuration. The invention is further illustrated by reference to the following examples which do not limit the scope of the invention.
EXAMPLES
Example 1 - Synthesis of (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide
A. Preparation of racemic butyric ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.
The N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (25 g) and triethylamine (15 ml) were stirred in acretonitrile (150 ml) at 0-5 ° C and butyryl chloride (10 ml) was added for 15 minutes at < 10 ° C. After 2 hours 45 minutes at < 10 ° C, triethylamine (2 ml) and butyryl chloride (1 ml) were further added and the reaction was stirred at 20 ° C for 1 hour 30 minutes, when in addition butyryl chloride (1 ml) was added. The reaction was completed after about 30 more minutes. Water (450 ml) and then ethyl acetate (175 ml) were added, the mixture was stirred for 15 minutes, then separated. The aqueous layer was extracted again with lime acetate (175 ml), then the combined organic extracts were washed with 50% brine (150 ml), filtered and evaporated. The oil was recrystallized by the solution in warm tert-butyl methyl ether (MTBE) (60 ml), slowly adding hexane (400 ml) for 10 minutes, then cooling at 5 ° C for 21 hours. After 30 minutes, at 5 ° C, the racemic butyric ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was completely filtered, washed with hexane ( 50 ml) and dried in vacuo at 40 ° C. Yield: 26 g (86%).
B. Enzymatic hydrolysis of the butyric ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. 7.1 mmol of a solution of potassium dihydrogen phosphate (50 ml) was adjusted to pH 7.1 with 0.1 N of a sodium hydroxide solution (2 ml), the porcine pancreatic lipase (Biocatalyst, Treforest, UK) (2.0 g), was added and the pH was again adjusted to 7.1 with a 0.1N sodium hydroxide solution (2 ml). The racemic butyric ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1 g) was dissolved in MTBE (10 ml) and added to the reaction, washing in MTBE (2 ml) additional. The reaction was stirred at 38 ° C under the pH control initially exposed to 7.05 max / 7.50 min. After 24 hours, the additional porcine pancreatic lipase (0.8 g) was added and the pH adjusted to 7.05 max / 7.00 min and left for an additional 42 hours when a total of 10 ml of 0.1 N sodium hydroxide was added. The reaction mixture was acidified to pH 3.5 with 2N HCl (2 ml), stirred for 15 minutes, then ethyl acetate (30 ml) was added and the mixture was stirred for an additional 10 minutes. The mixture was then filtered and the residue was washed with ethyl acetate (20 ml). The aqueous phase was separated and extracted with ethyl acetate (30 ml). The combined organic extracts were washed with 50% saline (20 ml), filtered and evaporated to an oil which was partially crystallized. Yield: 0.95 g. The product is a mixture of alcohol- (R) (99% enantiomeric excess) and ester ,.
Separation of the Product The product was separated by column chromatography using silica gel 60 (Fluka, Buchs, Switzerland), eluting with 5% ethyl acetate / toluene to remove the ester, then 50% ethyl acetate / toluene to remove the ester. eliminate alcohol. Alcohol yield: 338 mg; enantiomer- (R) with 97.6% enantiomeric excess. Ester yield: 415 mg.
C. Hydrolysis of the recovered Ester The recovered ester (415 mg) was dissolved in methanol (25 ml), a 100 ° Tw sodium hydroxide solution was added and stirred for 30 minutes at 20 ° C. Water (70 ml) was added, the mixture was acidified to pH 2 with 2N HCl (2 ml) and then extracted with ethyl acetate (2x30 ml). The organic extracts were washed with 50% saline (20 ml), filtered and evaporated to a white solid. Yields of (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide: 297 mg (71.7%, 98.5% enantiomeric excess).
Example 2 - Effect of the Portion of the acid in proportion to the hydrolysis of the ester and specificity of the reaction. A range of esters were prepared from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and the corresponding acid chlorides. These were subjected to cleavages porcine pancreatic lipase and analyzed after 24 hours. The phosphate buffer (50 ml) was adjusted to pH
7. 6 to 38 ° C, the enzyme was added (0.2 g) and the pH was again adjusted to 7.6. The racemic ester derived from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.0 g) was added in MTBE, followed by a wash of MTBE (total 12 ml), and the mixture was then stirred at about 38 ° C under a pH control using an auto-titrator and 0.1 N NaOH. At the end of the reaction, the pH of the mixture was adjusted to < 5 with 2N HCl and the product was extracted into ethyl acetate. The ester and the alcohol can be separated by chromatography and the recovered ester hydrolyzed using NaOH in methanol. Alcohols (R) (S) were analyzed by high pressure liquid chromatography (HPLC) using a Quiracel OJ column (Daicel Chemical Industries) to determine the enantiomeric purity. The degree of conversion was determined along with the enantiomeric excess of the alcohol product (R) after it has been separated from the unreacted ester, except for the benzoate and phenylacetate reactions which are extremely slow. The results are shown in Table 1:
Table 1 Ester Conversion after 24 Selectivity ee (excess hours using 1: 5 p / p enantiomyric enzyme: ester product of the (R) isomer
Acetate 2.5% 86% ee Propionate 6% 87% ee Butyrate 10% 99% ee Hexanoate 4.7% 98% ee Benzoate < l% N / A Phenylacetate < 1% N / A Monocloroacetate approx. 65% approx. 30% ee
The monochloroacetate was hydrolyzed substantially faster than any of the other experienced esters; this reaction continued well beyond 50% of the label and the (R) isomer was not detected in (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy -2-methylpropanamide recovered from the residual ester indicating good selectivity.
Example 3 - Hydrolysis of racemic Ester formed from N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and Butyric acid
A. The racemic N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpro-anamide was prepared from 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid racemic and 4-aminobenzophenone in accordance with Scheme 2 and converted to the butyric ester. The butyric ester was screened against a range of esterases and lipases. The racemic butyric ester of N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (0.5 g) in DMSO (0.3 ml) was added to the enzyme (0.1 g) in a buffer maintained at pH 7.5 at 30 ° C. The results are shown in Table 2.
Table 2 Enzyme Amplitude of the reaction Proportion (S): (R) of the alcohol product
Quirazima L5 < 20% 1: 1. { boehringer) (lipase) acetone powder from < 2% 2: 1 ram liver (sigma) acetone powder from < 2% 1.1.3 pig liver (sigma) pancreatic lipase < 10% 1:10 (biocatalyst) Quirazyme 7 (Boehringer < 10% 1: 3.6 (lipase) pancreatic lipase < 5% 1: 15.6 (fluka)
B. The racemic N- (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide was prepared from racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid and 4-aminobenzophenone according to scheme 2 and converted to the butyric ester. The butyric ester was hydrolyzed using porcine pancreatic lipase (Biocatalyst). The racemic butyric ester of N- (4-benzoylphenyl) -3, 3, 3-trifluoro-2-hydroxy-2-methylpropanamide (0.5 g) in MTBE (5 ml) was added to the enzyme (0.1) in buffer maintained at pH 7.5 at 3.0 ° C. Using the porcine pancreatic lipase, the reaction proceeded at approximately 25% conversion in two days and showed very little hydrolysis of the desired (S) enantiomer. Adding more porcine pancreatic lipase (0.2g) gave 35% of the reaction after an additional three hours and the experiment gave the alcohol (R) with an enantiomeric excess of about 99%. The product was chromatographed to give the alcohol (R) of 99% enantiomeric excess, with the ester recovered after the hydrolysis having an enantiomeric excess of 50%. The reaction was taken to complete it in two days using 1: 1 (w / w) of the enzyme: substrate to give (S) - (-) - N- (4-benzoylphenyl) -3,3,3-trifluoro-2 -hydroxy-2-methylpropanamide after hydrolyzing the recovered ester, with an enantiomeric excess of 98.5% in 35% yield based on the entry of the racemic butyric ester of N- (4-benzoylphenyl-3, 3, 3-trifluoro- 2-hydroxy-2-methylpropanamide (ie, 70% of the ester (S) available).
Example 4 - Enzymatic resolution of the esters of 3, 3, 3-trifluoro-2-hydroxy-2-methyl propanic acid. The reactions were carried out at 38 ° C using a pH controller exposed to 7.10 max / 7.07 min. A solution of 5 millimolar potassium dihydrogen phosphate (100 ml) and the immobilized Candida antarctia lipase (Novozyme® SP435, Boehringer Mannheim) (2g) were stirred together and the pH was adjusted to 7.1 with a 0.5N aqueous sodium hydroxide solution. (2 ml) at 38 ° C. Racemic methyl, or 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid butyl ester (5 g), optionally dissolved, was added in tert-butyl methyl ether (MTBE) (50 ml) or ter- butanol (50 ml). The reaction mixture was stirred until an amount of 0.5 N sodium hydroxide solution had been added with a corresponding to approximately 50% hydrolysis. Optionally, more of the enzyme can be added to increase the proportion of the hydrolysis. Further, (MTBE) was added, the reaction mixture was stirred for 15 minutes then filtered, and the residue was washed with MTBE (15 ml). The aucose layer was separated and extracted with MTBE (30 ml). The combined organic extracts were washed with saline (30 ml) and filtered and evaporated to obtain the unreacted ester. The enantiomeric proportion of the ester can be determined by NMR analysis using a chiral axis reagent such as 2,2,2-trifluoro-l (9-anthryl) ethanol (tfae). The aqueous layer from the separation was acidified to approximately pH 2 and extracted with either MTBE or ethyl acetate (2 x 50 ml). The organic extracts were filtered through diatomaceous earth (2 g), washed with saline solution, filtered and evaporated to obtain the solution of 3,3, 3-trifluoro-2-hydroxy-2-methylpropanoic acid which can be crushed with hexane before completely filtering the solid. The enantiomeric purity of the acid can be determined by the
NMR in the presence of L (-) -a-methylbenzylamine.
(I) The results of the hydrolysis without the cosolvent of the methyl, ethyl and butyl esters of 3,3,3-trifluoro-2-hydroxy-2-methyl-ropanoic acid are shown below in Table 3.
Table 3 Products (ee%) Ester (R) - Acid (S) -Estet Methyl 30 Ethyl 50 43 Butyl 67
(ii) The results of the hydrolysis of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid ethyl ester with several cosolvents are shown in Table 4.
Table 4
Example 5 - Enzymatic resolution of the esters of 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoic acid.
Example 5A Reactions were performed either: (a) in a 7 ml glass vessel containing a buffer of 50 mM citric acid / sodium phosphate, pH 7.6 (4 ml). 3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid ethyl ester (40 mg) was suspended in the buffer and the enzyme (10 mg) was added at the start of the reaction. The reactions were vigorously stirred at 22 ° C. or (b) in a glass container with a threaded reaction cap containing 5 mM of the citric acid / sodium phosphate buffer, pH 7.6 (30 ml). 3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid ethyl ester (300 g) was suspended in the buffer and the pH adjusted to 7.6 using a 0.1 M sodium hydroxide solution. The enzyme was added at the start of the reaction (75 mg). The reactions were stirred at 28 ° C and the pH maintained at 7.6 by automatic titration with 0.1 M sodium hydroxide solution.
Samples of the reaction mixtures (0.2 ml) were taken at intervals and extracted with hexane (1.8 ml) The samples were analyzed for the extent of the hydrolysis by measuring the residual ester concentration by gas chromatography. The reactions were carried out in an eigenvalue, the amplitude of the hydrolysis could also be determined from the consumption of the sodium hydroxide solution.The concentration of the ester was determined by gas chromatography under the following conditions: chromatograph: 'Perkin Elmer 8500; column: DB5 (30 meters), J & Scientific; oven: 120 ° C; detector: 250 ° C, injector: 250 ° C; carrier gas: helium gas; pressure: 8 psi; detector: FDI. The retention time for ethyl ether was 2.8 minutes. The enantiomeric excess of the residual ester was also determined by gas chromatography under the following conditions: chromatograph: Perkin Elmer 8500; column: CP Chirasil-Dex CB (25 meters), Chrompak; oven: isothermal gradient temperature 1-80 ° C for 3 minutes, ramp - 20 ° C / minute for 2 minutes, isothermal 2-120 ° C for 6 minutes; other regulators as for non-chiral analysis. The retention time for the (S) -enantiomer was 4.0 minutes and for the (R) enantiomer was 4.1 minutes. The results are shown in Table 5. As shown in Table 5, the hydrolysis of 3, 3, 3-trifluoro-2-hydroxy-2-methylpropanoic acid ethyl ester for Aspergillus oryzae, Bacillus li chenif ormis, Aspergillus Sojae and SP539 enzymes provide good selectivity for the (R) -enantiomer of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid ethyl ester.
Example 5B The enzymes of Aspergillus sojae
(Sigma) (protease) and SP539 (Novo) (protease) were also used to hydrolyse the butyl ester of 3,3,3-trifluoro-2-hydroxy-2-propanoic acid. The analytical procedures were the same as those used for the ethyl ester in Example 5A. The retention time for the butyl ester was 4.6 minutes (column DB5). The retention time for the (S) enantiomer was 6.1 minutes. The retention time for the (R) enantiomer was 6.3 minutes (CP Column Quirassil-Dex CB). The experiments were carried out in a pH auto-titrator as described for the ethyl ester in Example 5A. The samples were taken over a period of time. The results are shown in Tables 6 and 7.
Table 5
Table 6
Aspergillus sojae (Sigma)
Table7
EXAMPLE 6- Enzymatic resolution of the butyl ester 3,3,3-trifluoro-2-hydroxy-2-methylpropionitrile.
The reaction was carried out at 38 ° C using a pH controller placed at 7.50 max / 7.45 min. A solution of potassium dihydrogen phosphate 5 millimolar (100 ml) and a crude porcine pancreatic lipase (PPL) (lg) were stirred together and the pH was adjusted to 7.5 with an aqueous 0.1 N sodium hydroxide solution (5 ml) at 38 ° C. The racemic butyric ester of 3,3,3-trifluoro-2-hydroxy-2-methylpropanonitrile (5 g) was added, dissolved in MTBE (20 ml), washed with more MTBE (5 ml). After an additional 7 hours the PPL (1 g) was added and the reaction was allowed to stir overnight, then 30 ml of NaOH was added. After an additional 7 hours and an additional 14 ml of 0.1 N NaOH have been added, more PP1 (2g) is added, requiring 10 ml of 0.1N NaOH for neutralization. The reaction was stirred for an additional 2 days after which an additional 69 ml of 0.1N NaOH was added (a total of 113 ml consumed by the hydrolysis of the catalyzed enzyme against a theoretical of 119 ml). MTBE (50 ml), diatomaceous earth (2 g) and 2N hydrochloric acid (5 ml) were added adjusting the pH to 5, and the reaction mixture was stirred for 15 minutes after filtering. The aqueous layer was separated and extracted with MTBE (50 ml). The combined organic extracts were washed with 50% saline, then filtered and evaporated to dryness. The resulting oil (3.3 g) was chromatographed on a flash column of silica gel using dichloromethane as the eluent. The unreacted ester
(950 mg) was recovered and shown to be a single enantiomer by NMR in the presence of a reactive axis. The recovered ester (100 mg), water (1 ml) and concentrated hydrochloric acid (2 ml) were heated together at 100 ° C for 6 hours, then stirred at 20 ° C overnight. The saturated saline solution (2 ml) was added and the mixture was extracted with MTBE (2x5 ml). The MTBE solution was filtered and evaporated to obtain a somewhat solid oil which was triturated with hexane (2 ml). The solid (14.5 ml) was filtered off completely and washed with hexane (5 ml). NMR in the presence of L (-) -a-methylbenzylamine showed the (S) -ser enantiomer of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.
It is noted that, in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the manufacture of the objects to which it relates. Having described the invention as above, the content of the following is claimed as property.
Claims (18)
1. A method of preparing an optically active compound of Formula I where E is selected from nitrogen and CZ, where C is a carbon ring and Z is a substituent defined below, wherein: (A) X is ArY where Y is a selected carbonyl bonding group, sulfinyl and sulfonyl and Ar is selected from the group consisting of: phenyl substituted with 0-2 substituents selected from halo, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, and alkoxy of 1 to 4 carbon atoms; six-membered heteroaryl rings containing 1 to 2 nitrogen atoms only as the heteroatoms; five-membered heteroaryl rings containing 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur; and Z is selected from hydrogen, cyano, halo, hydroxy, alkyl of 1 to 4 carbon atoms and alkoxy of 1 to 4 carbon atoms and (B) X is cyano and Z is selected from the group consisting of phenylthio, phenylsulfinyl, and phenylsulfonyl phenyl rings which are substituted with 0-2 substituents selected from halo, hydroxy, cyano, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms; and when E is nitrogen, X independently is selected from any of the values for X given above in (A); v * is an optically active chiral center, characterized in the process because it comprises the step of treating to bind a racemic compound of Formula II with a hydrolase enzyme. The compounds of Formula II are as defined above as follows: Fopnula II wherein X and E are as previously defined and R1 is alkyl optionally substituted by one or more substituents independently selected from hydroxy, halogen, alkoxy of 1 to 4 carbon atoms, cyano, alkylamino of 1 to 4 carbon atoms and dialkylamino of 1 to 4 carbon atoms, with a hydrolase enzyme.
2. The method according to claim 1, characterized in that it further comprises the step of separating the unreacted compound of Formula II from the optically active compound of Formula I.
3. The method according to claim 1, characterized in that it further comprises the step of converting the unreacted compound of Formula II to the corresponding alcohol of Formula I.
4. The method according to claim 1, characterized in that the hydrolase enzyme is a lipase.
5. The method according to claim 4, characterized in that the lipase is the porcine pancreatic lipase.
6. The method according to claim 1, characterized in that R1 is optionally substituted by alkyl of 1 to 7 carbon atoms.
7. The method according to claim 1, characterized in that said optically active compound of Formula I is (S) - (-) - (4-benzoylphenyl) -3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and said step of treating a racemic mixture of a compound of Formula II with a hydrolase enzyme is carried out with a compound of Formula II wherein E is CZ, X is ArY, Y is carbonyl, Ar is phenyl and Z is hydrogen.
8. A method of preparing (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid characterized in that it comprises treating a racemic compound of formula V Fopnula V? F3 O Ct- - I ?? C - C- O - R 'I OH wherein R2 is alkyl of 1 to 6 carbon atoms, alkoxy or phenyl, with a hydrolase enzyme.
9. The method according to claim 8, characterized in that said hydrolase enzyme is a lipase.
10. The method according to claim 9, characterized in that said lipase is a Candida anticarcinogenic lipase.
11. A compound of formula V or formula VI Formula V Fopnula VI CH3 - - O - R "characterized in that R2 is alkyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, or phenyl and * is an optically active chiral center, providing that when said compounds have the formula V, R2 is not ethyl.
12. A method of preparing (S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid characterized in that it comprises the steps of treating a compound of Formula VII Formula VII CF3 CH-, - C - A wherein A is CN, COH, CH (OR3) 2, COR4, COOR5, CONH2, CONHR6 or CONR7R8, R3, R4, R5, R6, R7 and R8 are independently selected from alkyl, aryl, and aralkyl; and R9 is alkyl, aryl or aralkyl, wherein R3, R4, R5, R6, R7 and R8 and R9 may be optionally independently substituted with substituents selected from a hydroxy, halogen, alkoxy of 1 to 4 carbon atoms, cyano , alkylamino of 1 to 4 carbon atoms or dialkylamino of 1 to 4 carbon atoms; with a hydrolase enzyme to provide the corresponding of formula VIII Fopnula HIV wherein A has the meaning defined above and * is an optically active chiral center; and converting the compound of Formula VIII to an acid.
13. The method according to claim 12, characterized in that the enzyme hydrolase is a lipase.
14. The method according to claim 13, characterized in that said lipase is the porcine pancreatic lipase.
15. The method according to claim 12, characterized in that in Formula VIII, A is CN.
16. A compound of formula VIII Fopnula VIII wherein * is an optically active chiral center characterized in that A is CN, COH, CH (OR3) 2, COR4, COOR5 'CONH2, CONHR6 or CONR7R8; R3, R4, R5, R6, R7 and R8 are independently selected from alkyl, aryl, and aralkyl; and wherein R3, R4, R5, R6, R7, and R8 can be optionally independently substituted with substituents selected from hydroxy, halogen, alkoxy of 1-4 carbon atoms, cyano, alkylamino of 1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms
17. A compound according to claim 16, characterized in that A is CN.
18. A compound of Formula VII or Formula IX Formula VII Formula IX CF3 CF, | l3 - C - A CH3 - * C - A OCOR9. OCO $ characterized because * is an optically active chiral center, and A is CN, COH, CH (OR3) 2, COR4, COOR5, CONH2, CONHR6 or CONR7R8, R3, R4, R5, R6, R7 and R8 are independently selected from alkyl, aryl, and aralkyl; and R9 is alkyl, aryl or aralkyl, and wherein R3, R4, Rs, R6, R7, R8 and R9 may be optionally independently substituted with substituents selected from hydroxy, halogen, alkoxy of 1 to 4 carbon atoms, cyano , alkylamino of 1 to 4 carbon atoms; providing that when A is CN, R9 is not methyl.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9607458.8 | 1996-04-10 |
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MXPA98007922A true MXPA98007922A (en) | 1999-04-06 |
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