USH1679H - Process for preparing an optically pure intermediate for a phosphonosulfonate soualene synthetase inhibitor - Google Patents
Process for preparing an optically pure intermediate for a phosphonosulfonate soualene synthetase inhibitor Download PDFInfo
- Publication number
- USH1679H USH1679H US08/748,324 US74832496A USH1679H US H1679 H USH1679 H US H1679H US 74832496 A US74832496 A US 74832496A US H1679 H USH1679 H US H1679H
- Authority
- US
- United States
- Prior art keywords
- carbons
- alkyl
- phosphonate
- enzyme
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- LQHYUUBBIJGBNR-UHFFFAOYSA-N OP(O)(=O)S(O)(=O)=O Chemical compound OP(O)(=O)S(O)(=O)=O LQHYUUBBIJGBNR-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 102000003960 Ligases Human genes 0.000 title 1
- 108090000364 Ligases Proteins 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- -1 phosphonate ester Chemical class 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- SCARISRKCRGDJL-UHFFFAOYSA-N O=P1OSO1 Chemical compound O=P1OSO1 SCARISRKCRGDJL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 102000004190 Enzymes Human genes 0.000 claims description 37
- 108090000790 Enzymes Proteins 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 229940088598 enzyme Drugs 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 244000005700 microbiome Species 0.000 claims description 18
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 13
- 108090000371 Esterases Proteins 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 150000007970 thio esters Chemical class 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 229910021645 metal ion Inorganic materials 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 241000228245 Aspergillus niger Species 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 244000168141 Geotrichum candidum Species 0.000 claims description 7
- 235000017388 Geotrichum candidum Nutrition 0.000 claims description 7
- 108090001060 Lipase Proteins 0.000 claims description 7
- 239000004367 Lipase Substances 0.000 claims description 7
- 102000004882 Lipase Human genes 0.000 claims description 7
- 241000187654 Nocardia Species 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 235000019421 lipase Nutrition 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 6
- 241000235395 Mucor Species 0.000 claims description 6
- 241000589540 Pseudomonas fluorescens Species 0.000 claims description 6
- 240000005384 Rhizopus oryzae Species 0.000 claims description 6
- 235000013752 Rhizopus oryzae Nutrition 0.000 claims description 6
- 241000589516 Pseudomonas Species 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 238000005809 transesterification reaction Methods 0.000 claims description 5
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical group CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 claims description 4
- 241000589776 Pseudomonas putida Species 0.000 claims description 4
- 241000179532 [Candida] cylindracea Species 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 241000589158 Agrobacterium Species 0.000 claims description 3
- 241000589155 Agrobacterium tumefaciens Species 0.000 claims description 3
- 241000588986 Alcaligenes Species 0.000 claims description 3
- 241000186063 Arthrobacter Species 0.000 claims description 3
- 241000228212 Aspergillus Species 0.000 claims description 3
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 3
- 241000221955 Chaetomium Species 0.000 claims description 3
- 241000588881 Chromobacterium Species 0.000 claims description 3
- 241000146387 Chromobacterium viscosum Species 0.000 claims description 3
- 241000222290 Cladosporium Species 0.000 claims description 3
- 241000588914 Enterobacter Species 0.000 claims description 3
- 241000588722 Escherichia Species 0.000 claims description 3
- 241000588724 Escherichia coli Species 0.000 claims description 3
- 241000223198 Humicola Species 0.000 claims description 3
- 241001467578 Microbacterium Species 0.000 claims description 3
- 241000186359 Mycobacterium Species 0.000 claims description 3
- 241000187481 Mycobacterium phlei Species 0.000 claims description 3
- 108010019160 Pancreatin Proteins 0.000 claims description 3
- 241000228143 Penicillium Species 0.000 claims description 3
- 241000228168 Penicillium sp. Species 0.000 claims description 3
- 241000235527 Rhizopus Species 0.000 claims description 3
- 241000235545 Rhizopus niveus Species 0.000 claims description 3
- 241000223252 Rhodotorula Species 0.000 claims description 3
- 241000235070 Saccharomyces Species 0.000 claims description 3
- 241000191940 Staphylococcus Species 0.000 claims description 3
- 241000191967 Staphylococcus aureus Species 0.000 claims description 3
- 241000187747 Streptomyces Species 0.000 claims description 3
- 241000187433 Streptomyces clavuligerus Species 0.000 claims description 3
- 241000223259 Trichoderma Species 0.000 claims description 3
- 241000209140 Triticum Species 0.000 claims description 3
- 235000021307 Triticum Nutrition 0.000 claims description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 3
- MEGHWIAOTJPCHQ-UHFFFAOYSA-N ethenyl butanoate Chemical compound CCCC(=O)OC=C MEGHWIAOTJPCHQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 229940055036 mycobacterium phlei Drugs 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 229940055695 pancreatin Drugs 0.000 claims description 3
- 241000186146 Brevibacterium Species 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 241000187678 Nocardia asteroides Species 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 241000588813 Alcaligenes faecalis Species 0.000 claims 2
- 241000159512 Geotrichum Species 0.000 claims 2
- 241000203790 Kibdelosporangium Species 0.000 claims 2
- 229940005347 alcaligenes faecalis Drugs 0.000 claims 2
- DEXWRCYOMLUJRF-UHFFFAOYSA-N 2,2,2-trifluoroethyl butanoate Chemical compound CCCC(=O)OCC(F)(F)F DEXWRCYOMLUJRF-UHFFFAOYSA-N 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000005133 alkynyloxy group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000004059 squalene synthase inhibitor Substances 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229940123495 Squalene synthetase inhibitor Drugs 0.000 description 6
- 125000004658 aryl carbonyl amino group Chemical group 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 150000003573 thiols Chemical class 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 125000005236 alkanoylamino group Chemical group 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 150000001768 cations Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NSWXWLGELSSYLQ-UHFFFAOYSA-N [1-hydroxy-4-(3-phenoxyphenyl)butyl]phosphonic acid Chemical compound OP(=O)(O)C(O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 NSWXWLGELSSYLQ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 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 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- OFIGVFSAWIBCPW-UHFFFAOYSA-N [1-acetylsulfanyl-4-(3-phenoxyphenyl)butyl]phosphonic acid Chemical compound CC(=O)SC(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 OFIGVFSAWIBCPW-UHFFFAOYSA-N 0.000 description 2
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000000871 hypocholesterolemic effect Effects 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 235000013923 monosodium glutamate Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
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- 229940086542 triethylamine Drugs 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4056—Esters of arylalkanephosphonic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P9/00—Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen
Definitions
- the present invention relates to a process for preparing a substantially optically pure phosphonate ester or phosphonate thioester intermediate(s) via an enzymatically catalyzed enantioselective reaction, and to a process for preparing a substantially optically pure phosphono-sulfonate squalene synthetase inhibitor employing such intermediate(s).
- R 4 is H, alkyl, cycloalkyl, aryl, aryl-alkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
- Z is H, halogen, lower alkyl or lower alkenyl
- R 1 a lipophilic group containing at least 7 carbons, including pharmaceutically acceptable salts thereof.
- R 3 is alkyl, cycloalkyl, aryl or arylalkyl; which includes the steps of reacting a racemic phosphonate alcohol of the structure II ##STR3## wherein R 1 is as defined above, with an ester of the structure III ##STR4## wherein OR 2 represents a leaving group and R2 is alkyl, aryl, arylalkyl or alkenyl, in the presence of an enzyme or microorganism which is a source for enzyme capable of catalyzing transesterification of an alcohol, to form the substantially optically pure phosphonate I, and recovering the substantially optically pure phosphonate I for use in preparing a phosphonosulfonate squalene synthetase inhibitor as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994 (file HX59c) (which is incorporated herein by reference).
- a process for preparing a substantially optically pure phosphonate thioester of the structure IV ##STR5## wherein R 9 is alkyl, which includes the steps of treating a racemic phosphonate thioester V ##STR6## with an enzyme or microorganism which is a source of enzyme capable of stereoselectively hydrolyzing the thioester bond to form the substantially optically pure phosphonate thioester IV, for use in preparing a phosphonosulfonate squalene synthetase inhibitor as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994 (file HX59c).
- ester of formula III in the presence of lipases or esterases (or microorganisms capable of producing same), is capable of catalyzing the stereoselective transesterification of alcohols such as compound II.
- This process produces alcohols in the undesired enantiomeric form IA ##STR7## and the resulting "by-product" is in fact a high yield of substantially optically pure unreacted desired enantiomers of formula I.
- lipases or esterases employed herein are capable of stereoselectively hydrolyzing racemic thioester V to the desired thioester enantiomer IV.
- the reaction of the racemic phosphonate alcohol II or the racemic phosphonate thioester V and the enzyme or microorganism is carried out at a temperature within the range of from about 15 to about 60° C., preferably from about 20° to about 50° C., for a period of from about 45 to about 250 hours, preferably from about 48 to about 72 hours.
- reaction will be carried out in the presence of an inert organic solvent such as toluene, t-butyl-methyl ether, 1,1,2-trichloro-1,2,2-trifluoroethane, cyclohexane, benzene, hexane, heptane, tetrahydrofuran, dimethylformamide, isooctane and octane, preferably toluene.
- an inert organic solvent such as toluene, t-butyl-methyl ether, 1,1,2-trichloro-1,2,2-trifluoroethane, cyclohexane, benzene, hexane, heptane, tetrahydrofuran, dimethylformamide, isooctane and octane, preferably toluene.
- the processes of the present invention have the advantage of producing an enantiomeric specific result.
- the transformation is catalyzed at ambient temperature and pressure, one obtains high conversion and enantiomeric purity of the desired enantiomer.
- Acylating agents useful in the present invention are organic acids, halides, esters, and acid anhydrides.
- Exemplary acylating agents are acetic acid, isopropenyl acetate, vinyl butyrate, vinyl acetate, various other acetates, and the like. Additional acylating agents are generally known in the art; see, for example, Methoden der Organischen Chemie (Houben-Weil), Vol. XV, part II, p. 1 et seq. (1974). Isopropenyl acetate, vinyl acetate, and vinyl butyrate are preferred.
- ⁇ -phosphonosulfonate compounds employing as starting materials or intermediates the substantially optically pure phosphonate I or IV.
- the ⁇ -phosphonosulfonate product inhibits cholesterol biosynthesis (as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994), and thus is useful as an hypocholesterolemic and antiatherosclerotic agent, and has the following structure ##STR8## wherein R 5 is H, alkyl, arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
- R 5a is H, alkyl, cycloalkyl, aryl, aryl-alkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
- R 1 a lipophilic group containing at least 7 carbons and is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; and where in the above groups alkenyl and/or alkynyl may be substituted or unsubstituted; cycloalkyl; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; aryl; heteroaryl; heteroarylalkyl; cycloalkylalkyl; cycloheteroalkylalkyl; or a group of the structure ##STR9## wherein Ar is aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) and may include one to
- the (CH 2 )p group may contain 1, 2, 3 or more alkyl, alkoxy, alkenyl, alkynyl, hydroxy and/or halogen substituents as well as any of the substituents defined for R 6 .
- the substantially optically pure phosphonate diester I or phosponate thioester IV is employed as the starting material to form the phosphonosulfonate squalene synthetase inhibitor VIA as set out in the following reaction scheme.
- the starting racemic phosphonate alcohol II may be prepared according to the following reaction sequence.
- the starting racemic phosphonate thioester V may be prepared according to the following reaction sequence. ##STR12##
- lower alkyl or “alkyl” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, in the normal chain, more preferably 1 to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as F, Br, C1 or I or CF 3 , alkoxy, aryl, arylalkyl, alkenyl, cycloalkyl, amino,
- cycloalkyl as employed herein alone or as part of another group includes saturated or partially unsaturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R 6 .
- substituents such as halogen, alkyl, alkoxy, hydroxy
- aryl refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, or phenyl or naphthyl substituted with 1 to 4 substituents such as alkyl, halogen (Cl, Br or F), alkoxy, hydroxy, amino, alkanoylamino, arylcarbonylamino, aryl, arylalkyl, cycloalkyl, alkylamido, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R 6 .
- substituents such as alkyl, halogen (Cl, Br or F), alkoxy, hydroxy, amino, alkanoylamino, arylcarbonylamino, aryl, arylalkyl, cycloalkyl, alkylamido, nitro, cyano, thiol and/or alky
- aralkyl refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl.
- lower alkoxy as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
- lower alkylthio as employed herein alone or as part of another group includes any of the above alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.
- lower alkylamino as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
- alkanoyl as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
- lower alkenyl or “alkenyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, preferably 3 to 30 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cyclo
- lower alkynyl or “alkynyl” as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, preferably 2 to 20 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl,
- Examples of suitable (CH2) p groups include ##STR13##
- halogen or "halo” as used herein refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred.
- amino refers to unsubstituted amino as well as monosubstituted amino or disubstituted amino wherein the substituents may be alkyl and/or aryl.
- metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
- cycloheteroalkyl refers to a 5-, 6- or 7-membered saturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked to the carbon "C" of ##STR14## through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) p (which is defined above), such as ##STR15## and the like.
- the above groups may include 1 to 3 substituents such as any of the R 6 groups as defined above.
- any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
- heteroaryl refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, which is linked to the carbon "C" of ##STR16## through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 ) p (which is defined above), such as ##STR17## and the like.
- the above groups may include 1 to 3 substituents such as any of the R 6 groups as defined above.
- any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
- cycloheteroalkylalkyl refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to the "C" of ##STR18## group through a (CH 2 )p chain wherein p is preferably 1 to 8.
- heteroarylalkyl refers to a heteroaryl group as defined above linked through a C atom or heteroatom to the "C" of ##STR19## through a --(CH 2 ) p --chain as defined above, where p is preferably 1 to 8.
- R 5 is a metal ion such as Na or K, or H or a pharmaceutically acceptable salt
- R 5a is a metal ion such as Na or K
- R 1 is Ar 1 --O--Ar 2 --(CH 2 ) p --
- Ar 1 and Ar 2 are independently selected from any of the Ar groups defined hereinbefore, and (CH 2 ) p is as defined hereinbefore.
- Fusion refers to growth of the microbial cells to be used in a transformation process.
- the enzyme or microorganism used in the present processes can be any enzyme or microorganism having the ability to catalyze the enantioselective esterification of alcohols II or hydrolysis of thioester V.
- Various enzymes, such as esterases and lipases, regardless of origin or purity, are suitable for use in the present invention.
- the enzyme can be in the form of a mixture of animal and plant enzymes, cells of microorganisms, crushed cells or extracts of cells.
- Typical genuses of microorganism suitable as sources of catalyzing enzymes include Mucor, Escherichia, Staphylococcus, Agrobacterium, Rhizopus, Aspergillus, Nocardia, Streptomyces, Trichoderma, Candida, Rhodotorula, Torulopsis, Humicola, Kibadelosporangium, Bacillus, Alcaligenes, Pseudomonas, Brevibacterium, Enterobacter, Chromobacterium, Arthrobacter, Microbacterium, Mycobacterium, Saccharomyces, Penicillium, Chaetomium, Cladosporium and the like.
- enzymes suitable for use in the present invention include lipases, such as Amano P (Pseudomonas fluorescens) which is preferred, Amano AY-30 (Candida cylindracea), Amano N (Rhizopus niveus), Amano R (Penicillium sp.), Amano FAP (Rhizopus oryzae), Amano AP-12 (Aspergillus niger), Amano MAP (Mucor meihei), Amano CG-4 (Geotrichum candidum), Sigma L-0382 (porcine pancrease), Sigma L-3001 (Wheat germ), Sigma L-1754 (Candida cylindracea), Sigma L-0763 (Chromobacterium viscosum) and Amano K-30 (Aspergillus niger). Additionally, enzymes derived from animal tissue include esterase from pig liver, ⁇ -chymotrypsin and pancreatin from pancreas.
- microorganisms suitable for use in the present process include Pseudomonas fluorescens, Pseudomonas putida, Escherichia coli, Staphylococcus aureus, Alicaligenes faecalis, Streptomyces griseus, Streptomyces clavuligerus, Nocardia erthropolis, Nocardia asteroides, Mycobacterium phlei, Agrobacterium radiobacter, Aspergillus niger, Rhizopus oryzae and the like.
- Geotrichum candidum and esterase (Esterase 30,000 (Gist Brocades)).
- Microbially derived enzymes may be used in free state or immobilized on support.
- Suitable carriers are diatomaceous earth (porous Celite® Hyflo Supercel), microporous polypropylene (Enka Accurel® polypropylene powder), or a nonionic polymeric adsorbent such as Amberlite® XAD-2 (polystyrene), XAD-7 (polyacrylate) and the like.
- a carrier immobilizes the enzyme, which controls the enzyme particle size and prevents aggregation of the enzyme particles when used in an organic solvent.
- Desired enantiomers can be isolated from the reaction mixture and purified by known methodologies such as extraction, distillation, crystallization, column chromatography, and the like.
- the processes of the present invention can be carried out using microbial cells containing an appropriate enzyme.
- the present processes are conveniently carried out by adding the cells and the racemic starting materials to the desired solution.
- Cells may be used in the form of intact cells, dried cells such as lyophilized, spray-dried or heat-dried cells, immobilized cells, or cells treated with organic solvents such as acetone or toluene. Cells may also be used in the form of treated cell material such as ruptured cells or cell extract. Cell extracts immobilized on Celite® or Accurel® polypropylene as described earlier can also be used.
- Appropriate media for growing microorganisms for these processes typically include necessary carbon sources, nitrogen sources, and trace elements. Inducers such as fats or oils may also be added.
- Carbon sources include sugars such as maltose, lactose, glucose, fructose, glycerol, sorbitol, sucrose, starch, mannitol, propylene glycol, and the like; organic acids such as sodium acetate, sodium glutamate and the like; amino acids such as sodium glutamate and the like; alcohols such as ethanol, propanol, and the like; and oils such as soybean oil and the like.
- Nitrogen sources include N-Z amine A, corn steep liquor, soy bean meal, beef extracts, yeast extracts, baker's yeast, tryptone, nutrisoy, peptone, yeastamin, sodium nitrate, ammonium sulfate, and the like.
- Trace elements include phosphates and magnesium, manganese, calcium, cobalt, nickel, iron, sodium, and potassium salts.
- appropriate media may include more than one carbon or nitrogen source and may include a mixture of several.
- a typical medium for growth of such cells is:
- the pH of the medium is adjusted to 6.8 to 7.0 prior to sterilization.
- the temperature of the reaction mixture should be maintained to ensure that there is sufficient energy available for the processes.
- 3-Phenoxy benzaldehyde (9.0 mL, 52.01 mmol) was added drop-wise via syringe and the reaction was allowed to warm slowly to room temperature over twelve hours. The reaction was quenched by adding acetic acid (2 mL) followed by hexane (400 mL) and then cooled to about 0° C. to precipitate as much of the phosphine oxide as possible. The mixture was filtered and the filtrate concentrated and then passed through a pad of Silica gel (2.5 inches by 5 inches diameter) using ethyl acetate-hexane (1:5 ratio, ⁇ 1 L) as the eluent.
- Part A compound (15.42 g, 52.01 mmol) ethyl acetate (114 mL), and 5% Pd/C (1.1 g) were added into a Parr bottle which was connected to the Parr apparatus.
- the system was evacuated and back-filled with hydrogen gas five times and then allowed to shake over night under 50 psi of hydrogen pressure. After twelve hours, the system was again evacuated to remove hydrogen and then the reaction mixture was passed through a 5 inch diameter pad of Silica gel (0.5 inch, top) and Celite®(1 inch, bottom). The filtrate yielded title compound (15.28 g, 99%) as a clear viscous oil after removal of the solvent under reduced pressure.
- Part B compound 15.28 g, 51.28 mmol
- methanol 650 mL
- a catalytic amount of para-toluene-sulfonic acid 0.112 g, 0.589 mmol
- the mixture was refluxed at 75° C. for three hours and then worked-up by adding solid NaHCO 3 (0.5 g) and evaporating the methanol under reduced pressure.
- the residue was then partitioned between water (200 mL) and ethyl acetate (250 mL).
- Part D compound (8.95 g, 37.29 mmol) in dry THF (150 mL) was added diethylphosphite (4.90 mL, 38.04 mmol) and a catalytic amount of sodium ethoxide in ethanol (saturated solution, 0.85 mL). After 20 hours, acetic acid was added to neutralize the sodium ethoxide. Solid NaHCO 3 was used to neutralize any excess acetic acid and the THF was partially removed under reduced pressure.
- Enzymatic transesterification of racemic [1-hydroxy-4-(3-phenoxyphenyl)butyl]phosphonic acid, diethyl ester (prepared as described in Example 1) (1.1 g/L) was conducted in 2.0 L of toluene dried over 4° A molecular sieves, in the presence of 24.2 mL of isopropenyl acetate, 0.55 mL water and 63 g of Geotrichum candidum lipase (Biocatalyst) in a 3L glass reactor, at 35° C. The enzyme was kept suspended by an agitator at 200 rpm. Reactions were monitored for the formation of the acetate and optical purity. After the reaction was complete (after 137 hours), the enzyme was recovered by filtration, washed with toluene and air dried. The recovered enzyme from the first reaction was reused in the second reaction.
- Quantitation of starting racemic alcohol and corresponding acetate was performed by HPLC using a HP Hypersil ODS column, 40% isopropanol in water as eluting solvent at a flow rate of 0.5 ml/min, at 37° C.
- the retention items for the alcohol and the acetate were 18.7 and 25.01 minutes, respectively. Elution of both compounds was monitored at 273 nm.
- the absorption maxiumum was determined using a spectorophotometer.
- Example 2 acetate is hydrolyzed to the corresponding alcohol employing conventional procedures such as treating Example 2 acetate with aqueous potassium hydroxide or potassium carbonate in the presence of methanol.
- Formic acid (3.50 ml) and hydrogen peroxide (0.35 ml) are premixed for 1 hour at room temperature under argon, then chilled to 0° C. and Part C thioester in formic acid is added dropwise. The reaction is warmed to room temperature.
- Example 1 racemic alcohol (3.49 g, 9.23 mmol) in dichloro-methane (40 mL) was added para-toluenesulfonyl chloride (2.63 g, 13.80 mmol) and N,N-dimethyl-aminopyridine (0.346 g, 2.84 mmol) using a solid addition funnel under argon atmosphere followed by triethylamine (3.2 mL, 22.95 mmol) via a syringe.
- Example 4 About 10 mg of racemic thioester prepared in Example 4 was dissolved in 10 ml of toluene in a 50 ml flask. To this solution 250 mg of Esterase (Gist-Brocades) enzyme was added along with 0.01 ml of water. The reaction mixture was then shaken on a gyrotary shaker at 200 rpm at 25° C. After 72 hours, the enantomeric composition of the unreacted substrate (obtained at 20% yield) was 65% S-enantiomer and 35% R-enantiomer of the thio-ester.
- Esterase Gist-Brocades
- the substantially optically pure thioester prepared in Example 4 is used as a starting material in carrying out the preparation of (S)-3-phenoxy- ⁇ -phosphonobenzene-butane sulfonic acid, tripotassium salt employing the procedure set out in Example 3 Part D.
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Abstract
A process is provided for preparing a substantially optically pure phosphonate ester or phosphonate thioester intermediate via an enzymatically catalyzed enantioselective reaction, which intermediate is employed in preparing phosphonosulfonate squalene synthetase inhibitors.
Description
The present invention relates to a process for preparing a substantially optically pure phosphonate ester or phosphonate thioester intermediate(s) via an enzymatically catalyzed enantioselective reaction, and to a process for preparing a substantially optically pure phosphono-sulfonate squalene synthetase inhibitor employing such intermediate(s).
U.S. application Ser. No. 266,843, filed Jul. 5, 1994 (file HX59c) discloses α-phosphono-sulfonate compounds which are squalene synthetase inhibitors and thereby inhibit cholesterol biosynthesis, and thus are useful as hypocholes-terolemic and antiatherosclerotic agents. These compounds include those of the following structure ##STR1## wherein R3 and R5 are the same or different and are H, alkyl, arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
R4 is H, alkyl, cycloalkyl, aryl, aryl-alkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
Z is H, halogen, lower alkyl or lower alkenyl;
R1 a lipophilic group containing at least 7 carbons, including pharmaceutically acceptable salts thereof.
In accordance with the present invention, a process is provided for preparing a substantially optically pure phosphonate of the structure ##STR2## wherein R1 is a lipophilic group containing at least 7 carbons as defined hereinafter; and
R3 is alkyl, cycloalkyl, aryl or arylalkyl; which includes the steps of reacting a racemic phosphonate alcohol of the structure II ##STR3## wherein R1 is as defined above, with an ester of the structure III ##STR4## wherein OR2 represents a leaving group and R2 is alkyl, aryl, arylalkyl or alkenyl, in the presence of an enzyme or microorganism which is a source for enzyme capable of catalyzing transesterification of an alcohol, to form the substantially optically pure phosphonate I, and recovering the substantially optically pure phosphonate I for use in preparing a phosphonosulfonate squalene synthetase inhibitor as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994 (file HX59c) (which is incorporated herein by reference).
In addition, in accordance with the present invention, a process is provided for preparing a substantially optically pure phosphonate thioester of the structure IV ##STR5## wherein R9 is alkyl, which includes the steps of treating a racemic phosphonate thioester V ##STR6## with an enzyme or microorganism which is a source of enzyme capable of stereoselectively hydrolyzing the thioester bond to form the substantially optically pure phosphonate thioester IV, for use in preparing a phosphonosulfonate squalene synthetase inhibitor as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994 (file HX59c).
In accordance with the present invention, it has been found that the ester of formula III, in the presence of lipases or esterases (or microorganisms capable of producing same), is capable of catalyzing the stereoselective transesterification of alcohols such as compound II. This process produces alcohols in the undesired enantiomeric form IA ##STR7## and the resulting "by-product" is in fact a high yield of substantially optically pure unreacted desired enantiomers of formula I.
In addition, lipases or esterases employed herein are capable of stereoselectively hydrolyzing racemic thioester V to the desired thioester enantiomer IV.
In forming the substantially optically pure phosphonate I and phosphonate thioester IV, the reaction of the racemic phosphonate alcohol II or the racemic phosphonate thioester V and the enzyme or microorganism is carried out at a temperature within the range of from about 15 to about 60° C., preferably from about 20° to about 50° C., for a period of from about 45 to about 250 hours, preferably from about 48 to about 72 hours. The reaction will be carried out in the presence of an inert organic solvent such as toluene, t-butyl-methyl ether, 1,1,2-trichloro-1,2,2-trifluoroethane, cyclohexane, benzene, hexane, heptane, tetrahydrofuran, dimethylformamide, isooctane and octane, preferably toluene.
Intermediates produced by the processes of this invention may be used in procedures described in the above cited patent application to prepare useful squalene synthetase inhibitors. S enantiomers prepared byprocesses of this invention may also be inverted to the associated R enantiomers. See, for example, Mitsunobu reaction procedures described in Babiak et al., J. Org. Chem. 55, 3377-3378 (1990).
The processes of the present invention have the advantage of producing an enantiomeric specific result. When the transformation is catalyzed at ambient temperature and pressure, one obtains high conversion and enantiomeric purity of the desired enantiomer.
Acylating agents useful in the present invention are organic acids, halides, esters, and acid anhydrides. Exemplary acylating agents are acetic acid, isopropenyl acetate, vinyl butyrate, vinyl acetate, various other acetates, and the like. Additional acylating agents are generally known in the art; see, for example, Methoden der Organischen Chemie (Houben-Weil), Vol. XV, part II, p. 1 et seq. (1974). Isopropenyl acetate, vinyl acetate, and vinyl butyrate are preferred.
Further, in accordance with the present invention, there is provided a process for preparing α-phosphonosulfonate compounds, employing as starting materials or intermediates the substantially optically pure phosphonate I or IV. The α-phosphonosulfonate product inhibits cholesterol biosynthesis (as described in U.S. application Ser. No. 266,843 filed Jul. 5, 1994), and thus is useful as an hypocholesterolemic and antiatherosclerotic agent, and has the following structure ##STR8## wherein R5 is H, alkyl, arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
R5a is H, alkyl, cycloalkyl, aryl, aryl-alkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester;
R1 a lipophilic group containing at least 7 carbons and is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; and where in the above groups alkenyl and/or alkynyl may be substituted or unsubstituted; cycloalkyl; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; aryl; heteroaryl; heteroarylalkyl; cycloalkylalkyl; cycloheteroalkylalkyl; or a group of the structure ##STR9## wherein Ar is aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) and may include one to three additional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl) and wherein (CH2)p contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R6 ; and R6, R7, R8 and R8a are the same or different and are H, alkyl containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkoxy containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkenyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkenyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkyloxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, cycloheteroalkyl, cyclohetero-alkylalkyl, heteroaryl, cycloalkyl, cycloalkyl-alkyl, Ar-alkyl, (such as arylalkyl), ArO (such as aryloxy), Ar-amino (such as arylamino), hydroxy, halogen, nitro, Ar (such as aryl), amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, alkenyl, aryl or any of the Ar groups mentioned above), thiol, alkylthio, Ar-thio (such as arylthio), alkyl-sulfinyl, Ar-sulfinyl (such as arylsulfinyl), carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, Ar-carbonyloxy (such as arylcarbonyloxy), Ar-carbonylamino (such as arylcarbonylamino) or alkylcarbonylamino, as well as any of the Ar groups as defined above, and preferably wherein the total number of carbons in the substituted Ar--(CH2)p --group exceeds 10 carbons; including pharmaceutically acceptable salts thereof such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other FDA approved cations such as ammonium, choline, diethanolamine, ethylenediamine, and salts of naturally occuring amino acids such as arginine, lysine, alanine and the like or prodrug esters as disclosed in application Ser. No. 266,843.
The (CH2)p group may contain 1, 2, 3 or more alkyl, alkoxy, alkenyl, alkynyl, hydroxy and/or halogen substituents as well as any of the substituents defined for R6.
The substantially optically pure phosphonate diester I or phosponate thioester IV is employed as the starting material to form the phosphonosulfonate squalene synthetase inhibitor VIA as set out in the following reaction scheme. ##STR10## The starting racemic phosphonate alcohol II may be prepared according to the following reaction sequence. ##STR11## The starting racemic phosphonate thioester V may be prepared according to the following reaction sequence. ##STR12##
Unless otherwise indicated, the term "lower alkyl" or "alkyl" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, in the normal chain, more preferably 1 to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as F, Br, C1 or I or CF3, alkoxy, aryl, arylalkyl, alkenyl, cycloalkyl, amino, hydroxy, alkylamido, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R6.
Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of another group includes saturated or partially unsaturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may be substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R6.
Unless otherwise indicated, the term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, or phenyl or naphthyl substituted with 1 to 4 substituents such as alkyl, halogen (Cl, Br or F), alkoxy, hydroxy, amino, alkanoylamino, arylcarbonylamino, aryl, arylalkyl, cycloalkyl, alkylamido, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R6.
The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl.
The term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term "lower alkylthio", "alkylthio", "arylthio" or "aralkylthio" as employed herein alone or as part of another group includes any of the above alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term "lower alkylamino", "alkylamino", "arylamino", or "arylalkylamino" as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term "alkanoyl", as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
Unless otherwise indicated, the term "lower alkenyl" or "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, preferably 3 to 30 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R6.
Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, preferably 2 to 20 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, alkanoylamino, alkyl-amido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, as well as any of the other substituents as defined for R6.
Examples of suitable (CH2)p groups include ##STR13##
The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.
The term "amino" as used herein refers to unsubstituted amino as well as monosubstituted amino or disubstituted amino wherein the substituents may be alkyl and/or aryl.
The term "metal ion" refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
The term "cycloheteroalkyl" as used herein as an R1 substituent refers to a 5-, 6- or 7-membered saturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked to the carbon "C" of ##STR14## through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as ##STR15## and the like. The above groups may include 1 to 3 substituents such as any of the R6 groups as defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term "heteroaryl" as an R1 substituent refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, which is linked to the carbon "C" of ##STR16## through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as ##STR17## and the like. The above groups may include 1 to 3 substituents such as any of the R6 groups as defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term "cycloheteroalkylalkyl" as defined by R1 refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to the "C" of ##STR18## group through a (CH2)p chain wherein p is preferably 1 to 8.
The term "heteroarylalkyl" as defined by R1 refers to a heteroaryl group as defined above linked through a C atom or heteroatom to the "C" of ##STR19## through a --(CH2)p --chain as defined above, where p is preferably 1 to 8.
Preferred are compounds of formula VI wherein R5 is a metal ion such as Na or K, or H or a pharmaceutically acceptable salt;
R5a is a metal ion such as Na or K;
R1 is Ar1 --O--Ar2 --(CH2)p --
wherein Ar1 and Ar2 are independently selected from any of the Ar groups defined hereinbefore, and (CH2)p is as defined hereinbefore.
"Fermentation" as used herein refers to growth of the microbial cells to be used in a transformation process.
The enzyme or microorganism used in the present processes can be any enzyme or microorganism having the ability to catalyze the enantioselective esterification of alcohols II or hydrolysis of thioester V. Various enzymes, such as esterases and lipases, regardless of origin or purity, are suitable for use in the present invention. The enzyme can be in the form of a mixture of animal and plant enzymes, cells of microorganisms, crushed cells or extracts of cells.
Typical genuses of microorganism suitable as sources of catalyzing enzymes include Mucor, Escherichia, Staphylococcus, Agrobacterium, Rhizopus, Aspergillus, Nocardia, Streptomyces, Trichoderma, Candida, Rhodotorula, Torulopsis, Humicola, Kibadelosporangium, Bacillus, Alcaligenes, Pseudomonas, Brevibacterium, Enterobacter, Chromobacterium, Arthrobacter, Microbacterium, Mycobacterium, Saccharomyces, Penicillium, Chaetomium, Cladosporium and the like.
Commercially available enzymes suitable for use in the present invention include lipases, such as Amano P (Pseudomonas fluorescens) which is preferred, Amano AY-30 (Candida cylindracea), Amano N (Rhizopus niveus), Amano R (Penicillium sp.), Amano FAP (Rhizopus oryzae), Amano AP-12 (Aspergillus niger), Amano MAP (Mucor meihei), Amano CG-4 (Geotrichum candidum), Sigma L-0382 (porcine pancrease), Sigma L-3001 (Wheat germ), Sigma L-1754 (Candida cylindracea), Sigma L-0763 (Chromobacterium viscosum) and Amano K-30 (Aspergillus niger). Additionally, enzymes derived from animal tissue include esterase from pig liver, α-chymotrypsin and pancreatin from pancreas.
Specific microorganisms suitable for use in the present process include Pseudomonas fluorescens, Pseudomonas putida, Escherichia coli, Staphylococcus aureus, Alicaligenes faecalis, Streptomyces griseus, Streptomyces clavuligerus, Nocardia erthropolis, Nocardia asteroides, Mycobacterium phlei, Agrobacterium radiobacter, Aspergillus niger, Rhizopus oryzae and the like.
Preferred are Geotrichum candidum and esterase (Esterase 30,000 (Gist Brocades)).
Microbially derived enzymes may be used in free state or immobilized on support. Suitable carriers are diatomaceous earth (porous Celite® Hyflo Supercel), microporous polypropylene (Enka Accurel® polypropylene powder), or a nonionic polymeric adsorbent such as Amberlite® XAD-2 (polystyrene), XAD-7 (polyacrylate) and the like. A carrier immobilizes the enzyme, which controls the enzyme particle size and prevents aggregation of the enzyme particles when used in an organic solvent. This can be accomplished, for example, by precipitating an aqueous solution of the enzyme with cold acetone in the presence of the Celite® Hyflo Supercel followed by vacuum drying, or in the case of a nonionic polymeric absorbent, incubating enzyme solutions with absorbent on a shaker, removing excess solution and drying enzyme-adsorbent resins under vacuum.
Desired enantiomers can be isolated from the reaction mixture and purified by known methodologies such as extraction, distillation, crystallization, column chromatography, and the like.
As will be apparent to those skilled in the art, the processes of the present invention can be carried out using microbial cells containing an appropriate enzyme. When using a microorganism to perform the resolution, the present processes are conveniently carried out by adding the cells and the racemic starting materials to the desired solution. Cells may be used in the form of intact cells, dried cells such as lyophilized, spray-dried or heat-dried cells, immobilized cells, or cells treated with organic solvents such as acetone or toluene. Cells may also be used in the form of treated cell material such as ruptured cells or cell extract. Cell extracts immobilized on Celite® or Accurel® polypropylene as described earlier can also be used.
Appropriate media for growing microorganisms for these processes typically include necessary carbon sources, nitrogen sources, and trace elements. Inducers such as fats or oils may also be added.
Carbon sources include sugars such as maltose, lactose, glucose, fructose, glycerol, sorbitol, sucrose, starch, mannitol, propylene glycol, and the like; organic acids such as sodium acetate, sodium glutamate and the like; amino acids such as sodium glutamate and the like; alcohols such as ethanol, propanol, and the like; and oils such as soybean oil and the like.
Nitrogen sources include N-Z amine A, corn steep liquor, soy bean meal, beef extracts, yeast extracts, baker's yeast, tryptone, nutrisoy, peptone, yeastamin, sodium nitrate, ammonium sulfate, and the like.
Trace elements include phosphates and magnesium, manganese, calcium, cobalt, nickel, iron, sodium, and potassium salts.
It is within the scope of this invention that appropriate media may include more than one carbon or nitrogen source and may include a mixture of several.
A typical medium for growth of such cells is:
______________________________________ Material Name Concentration (% w/v) ______________________________________ Cerelose hydrate 4.4 Ammonium sulfate 0.75 Yeast extract 0.10 Uncon antifoam 0.04 Corn steep liquid 3.3 ______________________________________
The pH of the medium is adjusted to 6.8 to 7.0 prior to sterilization.
The temperature of the reaction mixture should be maintained to ensure that there is sufficient energy available for the processes.
The following examples represent preferred embodiments of the present invention. Unless indicated otherwise, all temperatures are expressed in degrees Centigrade (° C.).
Preparation of Racemic Starting Material [1-Hydroxy-4-4(3-phenoxyphenyl)butyl]phosphonic acid, diethyl ester ##STR20##
A magnetically stirred suspension of ##STR21## (25.10 g, 54.88 mmol) in THF (400 mL) under argon was cooled to about -45° C. (dry ice-methanol). After temperature equilibration (˜15 minutes), 1.6 M n-butyllithium (33.5 mL, 53.60 mmol) was added drop-wise via syringe. The reaction mixture became pale yellow in color. The reaction was allowed to warm to 0° C. and was stirred for 30 minutes and then cooled to about -78° C. (dry ice-acetone). 3-Phenoxy benzaldehyde (9.0 mL, 52.01 mmol) was added drop-wise via syringe and the reaction was allowed to warm slowly to room temperature over twelve hours. The reaction was quenched by adding acetic acid (2 mL) followed by hexane (400 mL) and then cooled to about 0° C. to precipitate as much of the phosphine oxide as possible. The mixture was filtered and the filtrate concentrated and then passed through a pad of Silica gel (2.5 inches by 5 inches diameter) using ethyl acetate-hexane (1:5 ratio, ˜1 L) as the eluent. Evaporation of the solvent under reduced pressure yielded title compound (5.96 g, 99%) as a clear yellow oil. TLC: Rf =0.40 and 0.48 (mixture of E and Z isomers). [Silica gel, ethyl acetate-hexane, 1:5, visible with UV and PMA staining] ##STR22##
Part A compound (15.42 g, 52.01 mmol) ethyl acetate (114 mL), and 5% Pd/C (1.1 g) were added into a Parr bottle which was connected to the Parr apparatus. The system was evacuated and back-filled with hydrogen gas five times and then allowed to shake over night under 50 psi of hydrogen pressure. After twelve hours, the system was again evacuated to remove hydrogen and then the reaction mixture was passed through a 5 inch diameter pad of Silica gel (0.5 inch, top) and Celite®(1 inch, bottom). The filtrate yielded title compound (15.28 g, 99%) as a clear viscous oil after removal of the solvent under reduced pressure.
TLC: Rf =0.48, [Silica gel, ethyl acetate-hexane, 1:5, visible with UV and PMA staining]. ##STR23##
To a magnetically stirred solution of Part B compound (15.28 g, 51.28 mmol) in methanol (650 mL), was added a catalytic amount of para-toluene-sulfonic acid (0.112 g, 0.589 mmol). The mixture was refluxed at 75° C. for three hours and then worked-up by adding solid NaHCO3 (0.5 g) and evaporating the methanol under reduced pressure. The residue was then partitioned between water (200 mL) and ethyl acetate (250 mL). The aqueous layer was extracted once more with ethyl acetate (250 mL) and then the organic layers were combined and dried over MgSO4, filtered, and evaporated under reduced pressure producing a viscous residue. To a magnetically stirred solution of the resulting residue in methanol (500 mL), was added para-toluenesulfonic acid (0.072 g, 0.379 mmol). The mixture was refluxed at 75° C. for four hours and then worked up exactly as before resulting in the title compound (14.1 g crude, >80% NMR yield) as a clear slightly yellow oil. TLC: Rf =0.58, [Silica gel, ethyl acetate-hexane, 1:5 visible with UV and PMA staining]. ##STR24##
A magnetically stirred solution of Part C 5 compound (2.13 g, 7.44 mmol) in a mixture of acetic acid-water (5:1 volume ratio, 70 mL) was placed under house vacuum periodically (once an hour) for a few minutes to drive the reaction to completion by removing methanol. After about five hours, hexane was used to extract the reaction mixture 7 times with a total of 500 mL. The organic layers were combined and washed with saturated NaHCO3 solution (350 mL) until all the acetic acid in the organic layer was neutralized. The organic layer was then dried over MgSO4, filtered and evaporated under reduced pressure affording title compound (1.72 9, 96%) as a clear viscous oil, which was used immediately in the next step. TLC: Rf =0.48, [Silica gel, ethyl acetate-hexane, 1:5, visible with UV and PMA staining].
To a magnetically stirred solution of Part D compound (8.95 g, 37.29 mmol) in dry THF (150 mL) was added diethylphosphite (4.90 mL, 38.04 mmol) and a catalytic amount of sodium ethoxide in ethanol (saturated solution, 0.85 mL). After 20 hours, acetic acid was added to neutralize the sodium ethoxide. Solid NaHCO3 was used to neutralize any excess acetic acid and the THF was partially removed under reduced pressure. The residue was partitioned between water (150 mL) and ethyl acetate (200 mL), separated, and the resulting aqueous layer extracted twice more with ethyl acetate (200 mL each). The organic layers were combined, dried over MgSO4, filtered and the solvent evaporated under reduced pressure to give 14.03 g of crude material. Purification of a fraction of the resulting residue (10.96 g) by column chromatography (Silica gel, eluted with methanol: methylene chloride, 5:95 ratio) afforded the title compound (8.74 g, 80%) as a clear viscous oil.
TLC: Rf =0.23, [Silica gel, ethyl acetate, visible with UV and PMA staining].
Preparation of S-(+)-[1-(Acetyloxy)-4-(3-phenoxy-phenyl)butyl]-phosphonic acid diethyl ester Via Enzymatic Transesterification of [1-Hydroxy-4-(3-phenoxyphenyl)butyl]phosphonic acid, diethyl ester
Enzymatic transesterification of racemic [1-hydroxy-4-(3-phenoxyphenyl)butyl]phosphonic acid, diethyl ester (prepared as described in Example 1) (1.1 g/L) was conducted in 2.0 L of toluene dried over 4° A molecular sieves, in the presence of 24.2 mL of isopropenyl acetate, 0.55 mL water and 63 g of Geotrichum candidum lipase (Biocatalyst) in a 3L glass reactor, at 35° C. The enzyme was kept suspended by an agitator at 200 rpm. Reactions were monitored for the formation of the acetate and optical purity. After the reaction was complete (after 137 hours), the enzyme was recovered by filtration, washed with toluene and air dried. The recovered enzyme from the first reaction was reused in the second reaction.
After the preparative scale resolutions, the reaction mixture was filtered to remove the enzyme, after which toluene was removed under reduced pressure to produce a light brown liquid (2.41 gm). Chromatography on this material on 100 gm of silica gel, which was pre-washed with 400 mL of ethyl acetate-hexane (80:20) mixture, afforded 0.85 grams of S-(+)-[1-(acetyloxy)-4-(3-phenoxyphenyl)butyl]-phosphonic acid, diethyl ester, when eluted with ethyl acetate-hexane-triethyl amine (80:17:3) as a colorless oil. Eluting further with 300 mL of eluant recovered 0.85 gm (38% yield) of alcohol. Isolated acetate (yield 38%): HPLC HI was <98% and optical purity was 95%. [A]D =+7.5 =1 in CH2 Cl2. Recovered alcohol: HPLC HI of the material was <97% and optical purity was 87%.
Quantitation of starting racemic alcohol and corresponding acetate was performed by HPLC using a HP Hypersil ODS column, 40% isopropanol in water as eluting solvent at a flow rate of 0.5 ml/min, at 37° C. The retention items for the alcohol and the acetate were 18.7 and 25.01 minutes, respectively. Elution of both compounds was monitored at 273 nm. The absorption maxiumum was determined using a spectorophotometer.
The substantially optically pure acetate prepared in Example 2 was used as a starting material in carrying out the preparation of (S)-(+)-3-phenoxy-α-phosphonobenzenebutane sulfonic acid, tripotassium salt as follows:
The Example 2 acetate is hydrolyzed to the corresponding alcohol employing conventional procedures such as treating Example 2 acetate with aqueous potassium hydroxide or potassium carbonate in the presence of methanol.
To a stirred solution of Part A alcohol (216 rag, 0.57 mmol) and pyridine (125 μL) in CH2 Cl2 (2 mL) at 0° C. under argon is added trifluoromethane sulfonic anhydride (100 μL, 0.59 mmol) over about 10 min. After another 15 min., the reaction mixture is warmed to room temperature, stirred for 20 min., diluted with diethyl ether, washed with 1M HC1, and then with brine, dried over MgSO4, filtered and stripped to give title triflate.
To stirred solution of Part B triflate (195 mg, 0.38 mmol) in DMF (2 mL) at room temperature under argon is added ##STR29## (96 mg, 0.84 mmol, 2.2 eq) to form title thioester.
Formic acid (3.50 ml) and hydrogen peroxide (0.35 ml) are premixed for 1 hour at room temperature under argon, then chilled to 0° C. and Part C thioester in formic acid is added dropwise. The reaction is warmed to room temperature.
1M K2 SO3 is added until presence of peroxide is negative. The reaction is neutralized with 1M KOH (100 ml) (for pH 1.8 to 3.0) and concentrated to title compound.
Preparation of Racemic Starting [1-(Acetylthio)-4-(3-phenoxyphenyl)butyl]phosphonic acid, diethyl ester ##STR31##
To a magnetically stirred solution of Example 1 racemic alcohol (3.49 g, 9.23 mmol) in dichloro-methane (40 mL) was added para-toluenesulfonyl chloride (2.63 g, 13.80 mmol) and N,N-dimethyl-aminopyridine (0.346 g, 2.84 mmol) using a solid addition funnel under argon atmosphere followed by triethylamine (3.2 mL, 22.95 mmol) via a syringe. After six hours of stirring at room temperature the reaction mixture was poured into 0.1 N HC1 (40 mL), extracted with dichloromethane (40 mL) and the organic layer was washed with water (40 mL), dried over magnesium sulfate, filtered and concentrated to afford 5.01 g (˜99% yield) of crude title trosylate. The material was carried on to the next step without any further purification: TLC Rf=0.48 (product) and Rf=0.23 (starting material), [Silica gel; ethyl acetate], visualization with UV and PMA.
B. Racemic [1-(Acetylthio)-4-(3-phenoxy-phenyl)butyl]phosphonic acid, diethyl ester
To a magnetically stirred solution of the Part A tosylate (4.91 g, 9.23 mmol) in acetonitrile (45 mL) was added solid potassium thioacetate (3.00 g, 26.32 mmol) in one portion. The reaction mixture was heated for 14 hours at 60° C. to complete the reaction. Acetonitrile was removed under vacuum and the residue partitioned between ethyl acetate (125 mL) and water (75 mL). The layers were separated and the aqueous layers were extracted with ethyl acetate (75 mL). The organic layers were then combined and washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated to afford 3.94 g of a crude dark red viscous oil. Purification by column chromatography (Silica gel; 3:1 ethyl acetate:hexanes) and treatment with decolorizing charcoal gave 2.31 g (57% yield) of title compound as a clear viscous oil. TLC Rf=0.27 (product) and Rf =0.34 (starting material) [Silica gel; ethyl acetate: hexanes (3:1)], visualization by UV and PMA.
About 10 mg of racemic thioester prepared in Example 4 was dissolved in 10 ml of toluene in a 50 ml flask. To this solution 250 mg of Esterase (Gist-Brocades) enzyme was added along with 0.01 ml of water. The reaction mixture was then shaken on a gyrotary shaker at 200 rpm at 25° C. After 72 hours, the enantomeric composition of the unreacted substrate (obtained at 20% yield) was 65% S-enantiomer and 35% R-enantiomer of the thio-ester.
The substantially optically pure thioester prepared in Example 4 is used as a starting material in carrying out the preparation of (S)-3-phenoxy-α-phosphonobenzene-butane sulfonic acid, tripotassium salt employing the procedure set out in Example 3 Part D.
Claims (17)
1. A method for preparing a substantially optically pure phosphonate of the structure ##STR34## wherein R1 is a lipophilic group containing at least 7 carbons;
R3 is alkyl, cycloalkyl, aryl or arylalkyl; which comprises reacting a racemic phosphonate of the structure ##STR35## wherein R1 is as defined above, with an ester of the structure ##STR36## wherein R3 is as defined above; and
OR2 represents a leaving group and R2 is alkyl, aryl, arylalkyl or alkenyl, in the presence of an enzyme or microorganism which is a source for enzyme capable of catalyzing trans- esterification of an alcohol, to form the substantially optically pure phosphonate, and recovering the substantially optically pure phosphonate.
2. The process as defined in claim 1 wherein the microorganism employed as a source for enzyme is of the genus Mucor, Escherichia, Staphylococcus, Agrobacterium, Rhizopus, Aspergillus, Nocardia, Streptomyces, Trichoderma, Candida, Rhodotorula, Torulopsis, Humicola, Kibdelosporangium, Bacillus, Alcaligenes, Pseudomonas, Brevibacterium, Enterobacter, Chromobacterium, Arthrobacter, Microbacterium, Mycobacterium, Saccharomyces, Penicillium, Chaetomium, Cladosporium or Geotrichum.
3. The process as defined in claim 2 wherein the enzyme employed is Candida cylindracea, Pseudomonas fluorescens, Rhizopus niveus, Penicillium sp., Rhizopus oryzae, Aspergillus niger, Mucor meihei, Geotrichum candidum, porcine pancreas, wheat germ, Chromobacterium viscosum, Novo Lipolase, Pseudomonas lipase, esterase, α-chymotrypin and pancreatin.
4. The process as defined in claim 1 wherein the microorganism employed is Pseudomonas fluorescens, Pseudomonas putida, Escherichia coli, Staphylococcus aureus, Geotrichum candidum, Alcaligenes faecalis, Steptomyces griseus, Streptomyces clavuligerus, Nocardia erthropolis, Nocardia asteroides, Mycobacterium phlei, Agrobacterium radiobacter, Aspergillus niger, Rhizopus oryzae or Esterase 30000 enzyme.
5. The process as defined in claim 1 where in the starting racemic phosphonate R1 is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing from 7 to 25 carbons on the chain and from 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; or aryl; and where in the above groups alkenyl, alkynyl and/or aryl may be substituted or unsubstituted; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; cycloalkyl; heteroarylalkyl; cycloalkylalkyl; heteroaryl; cycloheteroalkylalkyl; or a group of the structure ##STR37## wherein Ar is aryl or heteroaryl, and Ar may include one to three additional rings fused to Ar, and wherein (CH2)p contains from 1 to 15 carbons in the chain and may include 0, 1, 2 or 3 double bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R6 ; and R6, R7, R8 and R8a are the same or different and are H, alkyl containing 1 to 40 carbons, alkoxy containing 1 to 40 carbons, alkenyl containing 2 to 40 carbons, alkenyloxy containing 2 to 40 carbons, alkynyl containing 2 to 40 carbons, alkynyloxy containing 2 to 40 carbons, hydroxy, halogen, nitro, amino, thiol, alkylthio, alkyl-sulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkyl-carbonyloxy, alkylcarbonyl-amino, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, cycloalkylalkyl, Ar-alkyl, ArO, Ar-amino, Ar, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, cyano, Ar-carbonyloxy, or Ar-carbonylamino.
6. The process as defined in claim 1 wherein the starting racemic phosphonate R1 is Ar1 --O--Ar2 -(CH2)p --wherein Ar1 is an aryl group and Ar2 is an aryl group, and p is 1 to 15.
7. The process as defined in claim 6 wherein the starting racemic phosphonate Ar1 --O--Ar2 --(CH2)p --is ##STR38## where n is 2, 3 or 4.
8. The process as defined in claim 1 wherein the starting racemic phosphonate is ##STR39## and the product is ##STR40##
9. The process as defined in claim 1 wherein the reaction of the racemic phosphonate and enzyme or microorganism is carried out at a temperature within the range of from about 15° to about 60° C., in the presence of an ester source of the structure R3 COOR2.
10. The process as defined in claim 9 wherein the inert organic solvent is toluene, hexane, or t-butylmethyl ether and the ester source is isopropenyl acetate, trifluoroethyl butyrate, vinyl butyrate or vinyl acetate.
11. A process for preparing a substantially optically pure phosphonate thioester of the structure ##STR41## wherein R9 is alkyl'
R1 is a lipophilic group containing at least 7 carbons;
which comprises treating a racemic phosphonate thioester of the structure ##STR42## wherein R1 is as defined above, and
R9 is alkyl; with an enzyme or microorganism which is a source of enzyme capable of stereoselectively hydrolyzing the thioester bond to form the substantially optically pure phosphonate thioester, and recovering the substantially pure phosphonate thioester.
12. The process as defined in claim 11 wherein the microorganism employed as a source for enzyme is of the genus Mucor, Escherichia, Staphylococcus, Agrobacterium, Rhizopus, Aspergillus, Nocardia, Streptomyces, Trichoderma, Candida, Rhodotorula, Torulopsis, Humicola, Kibdelosporangium, Bacillus, Alcaligenes, Pseudomonas, Brevebacterium, Enterobacter, Chromobacterium, Arthrobacter, Microbacterium, Mycobacterium, Saccharomyces, Penicillium, Chaetomium, Cladosporium or Geotrichum.
13. The process as defined in claim 12 wherein the enzyme employed is Candida cylindracea, Pseudomonas fluorescens, Rhizopus niveus, Penicillium sp., Rhizopus oryzae, Aspergillus niger, Mucor meihei, Geotrichum candidum, porcine pancreas, wheat germ, Chromobacterium viscosum, Novo Lipolase, and Pseudomonas lipase, esterase, α-chymotrypin and pancreatin.
14. The process as defined in claim 13 wherein the microorganism employed is Pseudomonas fluorescens, Pseudomonas putida, Pseudomonas ovalis, Escherichia coli, Staphylococcus aureus, Geotrichum candidum, Alcaligenes faecalis, Steptomyces griseus, Streptomyces clavuligerus, Nocardia erthropolis, Nocardia asteraides, Mycobacterium phlei, Agrobacterium radiobacter, Aspergillus niger, Rhizopus oryzae or Esterase 30000 enzyme.
15. The process as defined in claim 11 where in the starting racemic thioester R1 is Ar1 --O--Ar2 --(CH2)p --wherein Ar1 is an aryl group and Ar2 is an aryl group, and p is 1 to 15.
16. The process as defined in claim 11 wherein the starting racemic phosphonate is ##STR43## and the product is ##STR44##
17. A process for preparing a phosphono-sulfonate of the structure ##STR45## wherein R1 is a lipophilic group containing at least 7 carbons; R5 is H, alkyl, arylalkyl, aryl or cycloalkyl; or a metal ion or other pharmaceutically acceptable salt, or prodrug ester;
R5a is H, alkyl, arylalkyl, aryl or cycloalkyl, or a metal ion or other pharmaceutically acceptable salt, or prodrug ester;
which comprises
providing a substantially optically pure phosphonate thioester of the structure ##STR46## wherein R1 and R5 are as defined above and R9 is alkyl, and employing the thioester to form the phosphonosulfonate.
Priority Applications (1)
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US08/748,324 USH1679H (en) | 1996-11-13 | 1996-11-13 | Process for preparing an optically pure intermediate for a phosphonosulfonate soualene synthetase inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US08/748,324 USH1679H (en) | 1996-11-13 | 1996-11-13 | Process for preparing an optically pure intermediate for a phosphonosulfonate soualene synthetase inhibitor |
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US08/748,324 Abandoned USH1679H (en) | 1996-11-13 | 1996-11-13 | Process for preparing an optically pure intermediate for a phosphonosulfonate soualene synthetase inhibitor |
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1996
- 1996-11-13 US US08/748,324 patent/USH1679H/en not_active Abandoned
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