WO1993002089A1 - Ketophosphanate coupling procedure - Google Patents
Ketophosphanate coupling procedure Download PDFInfo
- Publication number
- WO1993002089A1 WO1993002089A1 PCT/GB1992/001290 GB9201290W WO9302089A1 WO 1993002089 A1 WO1993002089 A1 WO 1993002089A1 GB 9201290 W GB9201290 W GB 9201290W WO 9302089 A1 WO9302089 A1 WO 9302089A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- general formula
- alkyl
- methyl
- hydroxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000005859 coupling reaction Methods 0.000 title description 17
- 230000008878 coupling Effects 0.000 title description 9
- 238000010168 coupling process Methods 0.000 title description 9
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims abstract description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- -1 alkylsiloxy Chemical group 0.000 claims abstract description 15
- 125000006239 protecting group Chemical group 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- BJXFCYHVICCYIU-UHFFFAOYSA-N naphthalene-1-carbaldehyde Chemical compound C1=CC=C[C]2C(C=O)=CC=C=C21 BJXFCYHVICCYIU-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- ZJMZECYKXSVVQP-UHFFFAOYSA-N 3-benzyl-2-phenyl-5-propan-2-ylimidazole-4-carbaldehyde Chemical compound C=1C=CC=CC=1CN1C(C=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZJMZECYKXSVVQP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 3
- BOZILQFLQYBIIY-INTXDZFKSA-N mevinic acid Chemical class C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)CCC=C21 BOZILQFLQYBIIY-INTXDZFKSA-N 0.000 abstract description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 abstract 1
- 150000001299 aldehydes Chemical class 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 0 CCC(C)(C)C(O[C@@](C[C@](CC1C=CC2*)C=CC)C1[C@]2C=CC(C[C@](C*=C)O)=O)=O Chemical compound CCC(C)(C)C(O[C@@](C[C@](CC1C=CC2*)C=CC)C1[C@]2C=CC(C[C@](C*=C)O)=O)=O 0.000 description 3
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 3
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 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 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- IHTNRDIBNXBSIF-UHFFFAOYSA-N 2-ethyloxane Chemical group CCC1CCCCO1 IHTNRDIBNXBSIF-UHFFFAOYSA-N 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- WLOVDTCTWZCJKC-IPMBQSRPSA-N CCC(C)(C)C(O[C@@H](C[C@H](CC1C=CC2C)/[I]=C/C)C1[C@H]2C=O)=O Chemical compound CCC(C)(C)C(O[C@@H](C[C@H](CC1C=CC2C)/[I]=C/C)C1[C@H]2C=O)=O WLOVDTCTWZCJKC-IPMBQSRPSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 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 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 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
- 238000007068 beta-elimination reaction Methods 0.000 description 1
- 150000005350 bicyclononyls Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000005843 halogen group Chemical group 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
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000011084 recovery 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
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- This invention relates primarily to novel synthetic procedures of compounds which are useful intermediates in the synthesis of a range of mevinic acids.
- HMG-CoA 3-hydroxy -3- methylglutaryl coenzyme A reductase
- EP-A-0251625 discloses compounds of structure
- R 1 is a group of formula CH 2 OH, CH 2 OCOR 3 , CO 2 R 4 or CONR 6 R 7 wherein R 3 , R 4 , R 6 , and R 7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
- the compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations.
- a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
- ketophosphonate reagent corresponding to the substituted ethyl tetrahydropyran moiety:
- WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids.
- the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4 , R,6'R)-6'- ⁇ 2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-napthalenyl) ethyl ⁇ -tetrahydro-4'- hydroxy-2H-pyran-2'-one which has the structure:
- Z is a bulky organic substituent
- Y is a hydroxy, alkylsiloxy, a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or CO 2 R group;
- X is a hydroxy, alkylsiloxy, -CN, a CO 2 R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; and R is C 1-8 alkyl, C 3-8 cyclcalkyl, C 3-8 cycloalkylC 1-8 alkyl, C 2-8 alkenyl or a C 1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
- a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
- C 1-8 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
- C 2-8 alkenyl refers to straight chain or branched chain. hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2-methyl-2- propenyl.
- C2 -8 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl.
- C1 -8 alkoxy refers to straight chain or branched chain alkoxy groups having from one to eight carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
- hydroxy C 1-8 alkyl refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group.
- alkoxy groups are hydroxyethyl and hydroxyn-propyl.
- C 3-8 cycloalkyl refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- C 4-8 cycloalkenyl refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds IIlustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
- halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
- substituted alkyl refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl.
- alkylsiloxy refers to a siloxy group substituted with from one to three alkyl groups, each alkyl group independently being straight or branched and having from one to eight carbon atoms. Illustrative of such groups are trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.
- suitable protecting group refers to a group temporarily attached to a reactive centre in a multi-functional molecule.
- the protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites.
- Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from a C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, hydroxy C 1-8 alkyl, hydroxy, halogen, OCOR or CO 2 R group.
- Z containing two or more 5 or 6 membered saturated rings fused together include decahydronaphthalenyl, and [4,3,0] bicyclononyl.
- Z containing two or more 5 or 6 membered rings fused together each ring being independently saturated, unsaturated or aromatic, include octahydronapthalenyl, hexahydronapthalenyl, benzocyclohexyl, benzocyclopentyl, and benzocyclohexenyl.
- Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, and each optionally containing one or more heteroatoms include benzimidazolyl, quinolinyl and isoquinolinyl.
- Z containing two or more 5 or 6 membered rings joined via a single bond each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include cyclohexylbenzyl, biphenyl, phenylpyridyl and phenyl pyrazolyl.
- Z containing two or more 5 or 6 membered rings joined via a single carbon bridge each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include 2,2-diphenylvinyl.
- the coupling reaction may be performed at a temperature between 20°C and 40°C.
- the reaction temperature is preferably room temperature.
- a further advantage of the invention is that base sensitive moieties of the substrate, reagent or product, or base labile protecting groups on the substrate, reagent or product, are stable under the reaction conditions.
- the nature of the solvent of a given reaction is important, for example on grounds of solubility of substrate, reagents and products, or for ease of working up the reaction products.
- the reaction of the invention is particularly adaptable since it may be carried out in either a water miscible solvent, for preference t-butanol or isopropanol, or a water immiscible solvent, for preference diethyl ether.
- the solvent will be chosen according to the reactants and products in each case.
- Lithium hydroxide and caesium carbonate have been found to be particularly effective bases for use in the coupling reaction. It is preferable to carry out the reaction in an aprotic solvent such as diethyl ether if lithium hydroxide is used as a base but when the base is caesium carbonate, the reaction proceeds more efficiently in a protic solvent such as t-butanol.
- aprotic solvent such as diethyl ether
- caesium carbonate may be used without drying, and lithium hydroxide may be used as the commercially available monohydrate.
- the coupling reaction may be carried out with a ratio of compound of formula III:base of from 0.9:1 to 1.5:1 and it is preferred that the ratio is 1:1.
- the ratio of compound of formula II: compound formula III may be from 0.5:1 to 1:1.
- reaction is especially suitable for the preparation of a compound of general formula I
- R 3 represents a hydrogen atom, COC 1-8 alkyl, COC 3-8 cycloalkyl, COC 3-8 cycloalkylC 1-8 alkyl, COC 2-8 alkenyl, COC 1- 6 alkyl substituted phenyl group, or a suitable protecting group;
- R 4 represents a hydrogen atom, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, or a C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C 1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
- R 5 represents a hydrogen atom or a C 1-8 alkyl group
- R 6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
- Y is hydroxy or alkylsiloxy; and X is a CO 2 R C 1-8 alkyl group.
- Examples of compounds of general formula III are: methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate; and methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate.
- Compounds of general formula II which are suitable for use in the coupling reaction include:
- R 3 , R 4 , R 5 and R 6 are as defined in general formula IV;
- R 7 represents a hydrogen atom or a substituent R 8 or M
- R 8 represents a C 1-5 alkyl group, or a C 1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
- M represents a cation capable of forming a pharmaceutically acceptable salt
- Preferred compounds which can be made by this method are:
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Abstract
Compounds of general formula (I), wherein Z is a bulky organic substituent; Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO2R group; X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; R is C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; may be prepared in good yield and with minimal side reactions by reacting a compound of general formula (II), wherein Z is as defined as in general formula (I), with a compound of general formula (III), wherein X and Y are as defined in general formula (I); in the presence of a weak hydroxylic base such as lithium hydroxide (but excluding strong bases such a sodium hydroxide or potassium hydroxide), or a Group (I) or Group (II) carbonate, in a substantially anhydrous solvent. The reaction is useful for the preparation of mevinic acid derivatives which are HMG-CoA reductase inhibitors and avoids the low temperatures necessary in prior art methods.
Description
Ketophosphanate coupling procedure
This invention relates primarily to novel synthetic procedures of compounds which are useful intermediates in the synthesis of a range of mevinic acids.
A number of mevinic acids have been reported to be potent inhibitors of the enzyme 3-hydroxy -3- methylglutaryl coenzyme A (HMG-CoA) reductase, the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolaemia and hyperlipidaemia.
Thus W F Hoffman et al (J. Med. Chem., 29, 849-852 (1986)) have reported the synthesis and testing of a compound now known as simvastatin, having the structure
EP-A-0251625 (Inamine) discloses compounds of structure
where R is similar to the corresponding group in the compounds described above, R1 is a group of formula CH2OH, CH2OCOR3, CO2R4or CONR6R7 wherein R3, R4, R6, and R7 can cover a range of alkyl, alkoxy or aryl groups, and the dotted lines represent single or double bonds.
The compounds disclosed have been generally obtained by fermentation of a suitable microorganism, or derived chemically from compounds obtained from such fermentations. However, a procedure based totally on chemical synthesis would have significant advantages over a fermentation procedure on grounds of flexibility, yield, ease of purification and hence cost.
Accordingly, Heathcock and Rosen disclosed in US 4,950,775 the total synthesis of compactin, which also possesses HMG-CoA reductase inhibitory activity, and which has the structure
The synthetic procedure disclosed therein involved a key step involving a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:
Similarly, WO-A-9100280 discloses the total synthesis of a group of HMG-CoA reductase inhibiting mevinic acids. In particular the document describes the synthesis of (1S,2S,4aR,6S,8S,8aS,4,R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]-
6-[(E)-prop-1-enyl]-1-napthalenyl) ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one which has the structure:
The synthetic procedure disclosed in WO-A-9100280 also utilised as a key step a Horner Wadsworth Emmons coupling between an aldehyde, corresponding to the decalin portion of the target compound:
and a ketophosphonate:
Horner Wadsworth Emmons couplings have also been described in the art, a typical description being contained in Synthesis, Commun, 884, (1979) wherein simple aldehydes, such as benzaldehydes, were converted in good yield to alkenes in the presence of sodium or potassium hydroxide in a solvent such as tetrahydrofuran or dichloromethane:H2O by treatment with a reagent such as
(CH3O)2P(O) CN
With more complex substrates and reagents, however, lower yields were obtained.
Similarly, in both US 4,950,775 and WO-A-9100280 only moderate yields of product were obtained at this step. The reaction conditions described therein involved using lithium salts of strong bases, such as lithium hexamethyldisilazide, or lithium salts such as lithium chloride in the presence of bases of moderate strength, such as DBU, to catalyse the coupling. It was found that side reactions occurred, including beta- elimination reactions involving reagent and product, and epimerisation of the starting aldehyde. Moreover, these side products were difficult to remove, thus lowering the isolated yields still further and adversely affecting the economic advantages of the totally synthetic route referred to above.
Therefore, although the prior art and the work disclosed in US 4,950,775 and WO-A-9100280 are pioneering, there is still room for further improvement in the synthetic
methodology used, net laast to enable coupling of large, bulky substrates and reagents and in particular those containing a variety of reactive centres capable of side reactions and especially those labile under basic conditions, in order to optimise yield and facilitate recovery of products.
It has now been found that other conditions and reactants may be used to expedite such couplings to prepare, inter alia intermediates of mevinic acids in high yield.
According to a first aspect of the invention there is provided a process for the preparation of a compound of general formula I
wherein Z is a bulky organic substituent;
Y is a hydroxy, alkylsiloxy, a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or CO2R group;
X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group; and
R is C1-8 alkyl, C3-8 cyclcalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
As used herein the term "C1-8 alkyl" refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
As used herein the term "C2-8 alkenyl" refers to straight
chain or branched chain. hydrocarbon groups having from two to eight carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2- butenyl and 2-methyl-2- propenyl.
As used herein the term "C2-8 alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one or more double bonds, each of either E or Z stereochemistry where applicable. This term would include for example, propynyl, butynyl and pentynyl. As used herein the term "C1-8 alkoxy" refers to straight chain or branched chain alkoxy groups having from one to eight carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
As used herein the term "hydroxy C1-8alkyl" refers to straight chain or branched chain alkyl groups having from one to eight carbon atoms and carrying a hydroxy group. Illustrative of such alkoxy groups are hydroxyethyl and hydroxyn-propyl.
As used herein, the term "C3-8 cycloalkyl" refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term "C4-8 cycloalkenyl" refers to an alicyclic group having from 4 to 8 carbon atoms and
having in addition one or more double bonds IIlustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
As used herein the term "halogen" or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
As used herein the term "substituted alkyl" refers to a straight or branched chain hydrocarbon group of one to three carbon atoms substituted with one or more aryl groups. Illustrative of such groups are benzyl and diphenyl methyl. As used herein, the term "alkylsiloxy" refers to a siloxy group substituted with from one to three alkyl groups, each alkyl group independently being straight or branched and having from one to eight carbon atoms. Illustrative of such groups are trimethylsiloxy, triisopropylsiloxy and t-butyldimethylsiloxy.
As used herein the term "suitable protecting group" refers to a group temporarily attached to a reactive centre in a multi-functional molecule. The protecting group should ideally be able to be introduced specifically at the group to be protected, should be stable throughout all subsequent reaction conditions involving manipulations at other reactive sites, and be able to be removed under conditions that do not affect other reactive sites. For a good review of protecting groups, see "Protective Groups in Organic Synthesis", Greene, T W Ed., John Wiley and Sons, 1981.
Preferably, Z comprises two or more 5 or 6 membered rings
either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from a C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, hydroxy C1-8alkyl, hydroxy, halogen, OCOR or CO2R group. Examples of Z containing two or more 5 or 6 membered saturated rings fused together include decahydronaphthalenyl, and [4,3,0] bicyclononyl.
Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, include octahydronapthalenyl, hexahydronapthalenyl, benzocyclohexyl, benzocyclopentyl, and benzocyclohexenyl. Examples of Z containing two or more 5 or 6 membered rings fused together, each ring being independently saturated, unsaturated or aromatic, and each optionally containing one or more heteroatoms include benzimidazolyl, quinolinyl and isoquinolinyl.
Examples of Z containing two or more 5 or 6 membered rings joined via a single bond, each ring being independently saturated, unsaturated or aromatic,and each optionally containing one or more heteroatoms include cyclohexylbenzyl, biphenyl, phenylpyridyl and phenyl pyrazolyl.
Examples of Z containing two or more 5 or 6 membered rings joined via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic,and each
optionally containing one or more heteroatoms include 2,2-diphenylvinyl.
One advantage of the invention is that the coupling reaction may be performed at a temperature between 20°C and 40°C. The reaction temperature is preferably room temperature. Clearly therefore, this is an advantage since, with the coupling reaction used previously, it was often necessary to use temperatures as low as -70°C which, of course presents great problems if the reaction is to be used on a large scale.
Furthermore, using the process of the invention, it is possible to obtain the product in yields of 80-90% whereas with previous methods, yields were, at the most, about 66% and were often a great deal lower than this. The invention represents, in this respect, a significant improvement over prior art methods. A further advantage of the invention is that base sensitive moieties of the substrate, reagent or product, or base labile protecting groups on the substrate, reagent or product, are stable under the reaction conditions.
It will be appreciated by those skilled in the art that the nature of the solvent of a given reaction is important, for example on grounds of solubility of substrate, reagents and products, or for ease of working up the reaction products. The reaction of the invention is particularly adaptable since it may be carried out in either a water miscible solvent, for preference t-butanol or isopropanol, or a water immiscible solvent, for preference diethyl ether. The solvent will be chosen
according to the reactants and products in each case.
Lithium hydroxide and caesium carbonate have been found to be particularly effective bases for use in the coupling reaction. It is preferable to carry out the reaction in an aprotic solvent such as diethyl ether if lithium hydroxide is used as a base but when the base is caesium carbonate, the reaction proceeds more efficiently in a protic solvent such as t-butanol.
Although it is preferable to use previously dried solvents for the coupling reaction, the reaction itself is unaffected by small amounts of water. Thus caesium carbonate may be used without drying, and lithium hydroxide may be used as the commercially available monohydrate.
The coupling reaction may be carried out with a ratio of compound of formula III:base of from 0.9:1 to 1.5:1 and it is preferred that the ratio is 1:1. The ratio of compound of formula II: compound formula III may be from 0.5:1 to 1:1.
The reaction is especially suitable for the preparation of a compound of general formula I
wherein X and Y are as defined above and
Z is a fused ring system of general formula IV
R3 represents a hydrogen atom, COC1-8 alkyl, COC3-8 cycloalkyl, COC3-8 cycloalkylC1-8 alkyl, COC2-8 alkenyl, COC1- 6 alkyl substituted phenyl group, or a suitable protecting group;
R4 represents a hydrogen atom, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl group, or a C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
R5 represents a hydrogen atom or a C1-8 alkyl group;
R6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
These compounds of general formula I are mevinic acid
derivatives which, as has been discussed, are potent inhibitors of HMG-CoA reductase.
It is particularly preferred to use the method of the invention to prepare compounds of general formula I wherein:
Y is hydroxy or alkylsiloxy; and X is a CO2R C1-8 alkyl group.
Examples of compounds of general formula III are: methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate; and methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate. Compounds of general formula II which are suitable for use in the coupling reaction include:
{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde);
{(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methyl-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6-
dimethyl-8-[(2"-(S)-methy1-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde);
{ (1S,2S,4aR,6R,8S,8aS)-6-(t-butyldiphenylsiloxy)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl-
1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);
{(1S,2S,6S,8S,8aS)-1,2,6,7,3,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6- dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene1- carbaldehyde); or
1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde.
Compounds of general formulae II and III are known in the art or can be prepared by methods analogous to those in the art.
In a second aspect of the invention there is provided a process for the preparation of a methyl (1S,2S, 4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyl- oxy-5'- oxohept-6'-enoate, the method comprising reacting a methyl (R) -3-[ (trialkylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.
In a further aspect of the invention, there is provided a process for the preparation of compounds of general formulae V and VI
R3, R4, R5 and R6 are as defined in general formula IV;
R7 represents a hydrogen atom or a substituent R8 or M;
R8 represents a C1-5 alkyl group, or a C1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
M represents a cation capable of forming a pharmaceutically acceptable salt;
Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by the process of the invention and subsequently converting the compound of general formula
I to a compound of general formula V or VI by any suitable method.
A suitable method for this conversion is described in WO- A-9100280.
Preferred compounds which can be made by this method are:
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; and
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8, 8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl)- tetrahydro-4'-hydroxy-2H-pyran-2'-one.
The following examples, which are for the purposes of illustration only, show the synthesis of a compound of general formula I from a compound of general formula II and a compound of general formula III using two alternative routes. Organic solutions were dried over anhydrous magnesium sulphate. Ether refers to diethyl ether. NMR spectra aquired at 250MHz (proton) or 62.9MHz (carbon) in deuteriochloroform unless noted otherwise. Coupling constants are given in Hertz.
Example l
Methyl (1S,2S,4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6-
[ (E) -prop-1-enyl ] -1-naphthalenyl ) -3 , -t-butyldimethylsilyl-oxy-5 ' -oxohept-6 '-enoate.
USING LITHIUM HYDROXIDE
A mixture of methyl (R)-3-[(tert-butyldimethylsilyl) oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (241 mg, 0.63 mmol) and lithium hydroxide monohydrate (26.5 mg, 0.63 mmol) in anhydrous ether (3 mL) was stirred at room temperature under argon for 35 minutes. The aldehyde
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a- octahydro-2- methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-
1-enyl]naphthalene-1-carbaldehyde) (131 mg, 0.40 mmol) in ether (3 mL) was added and the resulting solution stirred for 7 days. The solution was then diluted with more ether
(10 mL), washed with ammonium chloride solution (3 mL) and brine (2 mL). Column chromatography eluting with hexane:ethyl acetate (12:1) gave the unreacted starting aldehyde (12 mg) followed by the required enone (193 mg,
82%; 92% with respect to unrecovered aldehyde).
delta H 6.77 (1H, dd, J = 17.5 and 10), 6.01 (1H, d, J = 17.5), 5.75 (1H, ddq, J = 15, 7.5 and 2.5), 5.65 (1H, dq, J = 10.5 and 2.5), 5.50 - 5.30 (2H, m), 4.95 (1H, m), 4.62 (1H, m), 3.68 (3H, s), m.83 (1H, dd, J = 17.5 and 5), 2.74 (1H, dd, J = 17.5 and 5), 2.65 - 2.2 (6H, m), 2.05 - 1.2 (10H, m), 1.14 (3H, s), 1.12 (3H, s), 0.95 (3H, d, J = 7.5), 0.88 - 0.72 (12H, m), 0.08 (3H, s), 0.03 (3H, s)
delta C 195.77 175.15, 170.05, 147.05, 134.46, 130.73, 130.54, 129.51, 121.68, 68.77, 64.55, 49.99, 46.09, 41.33, 41.23, 41.11, 41.01, 40.03, 35.70, 34.53, 34.44, 34.00, 31.56, 29.31, 24.30, 23.23, 23.05, 16.47, 15.03, 7.77, -6.13, -6.47 Using the above method with 7.0 g of aldehyde (21 mmol), 11.29 g of keto-phosphonate (6a) (29.5 mmol) and 1.24 g of lithium hydroxide gave 0.92 g of recovered aldehyde and 9.45 (76%; 88% with respect to unrecovered aldehyde) of enone.
Example 2
Methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-triisopropyl-silyl- oxy-5'-oxohept-6'-enoate.
Using the method of Example 1 with 25 mg of aldehyde (0.075 mmol), methyl (R)-3-[triisopropyl- silyloxy]-6- (dimethoxyphosphonyl)-5-oxohexanoate (35 mg, 0.083 mmol) and lithium hydroxide (3.5 mg, 0.083 mmol) gave a 60% yield of enone after 4 days.
Example 3
Methyl (1S,2S,4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethγl-1"-oxobutyl)oxy]6- [(E)-prop-1-enyl]-1-naphthalenyl)-3'-t-butyldimethyl- silyl-oxy-5'-oxohept-6'-enoate
USING CAESIUM CARBONATE tert-Butanol (14 mL) was added to a mixture of methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (1.26 g, 3.30 mmol) and caesium carbonate (1.07 g, 3.28 mmol) and the resulting solution stirred at room temperature for 40 minutes under argon. A solution of the aldehyde (l.Og, 3.01mmol) in t- butanol (6 mL) was added and the reaction stirred for 4 days. The resulting dark yellow solution was diluted with ether (40 mL) and washed with ammonium chloride solution
(20 mL). The aqueous layer was extracted with more ether
(2 x 20 mL) and the combined organic layers washed with brine (2 x 15 mL), dried and evaporated to give a dark yellow solid. Chromatography on silica eluting with firstly dichloromethane gave unreacted aldehyde (220 mg), and then with hexane: ethyl acetate (4:1) gave the desired enone as a pale yellow solid (930 mg, 53%; 68% with respect to unrecovered aldehyde).
Example 4
Methyl ( 3 ,R) - (E) -7 ' - (l-benzyl-2-phenyl-4-isopropyl- imidazol-5-yl) -3 'tert-butyldimethylsilyloxy-S'-oxohepte'- enoate
A mixture of the methyl (R)-3-[(tert-butyldimethyl- silyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate (369 mg; 0.97 mmol) and lithium hydroxide monohydrate (40 mg; 0.97 mmol) in ether (5 mL) was stirred under argon for 30 minutes at room temperature. A solution of 1- benzyl-2- phenyl-4-isopropylimidazole-5-carbaldehyde (184 mg; 0.60 mmol in ether (5 mL) was added and stirring continued for 5 days after which time the reaction was diluted with ether (10 mL). The organic solution was washed with ammonium chloride solution (10 mL) and brine (5 mL), dried and evaporated to an orange semi-solid. Chromatography on silica eluting with hexane-ethyl acetate (4:1) gave the product (116mg, 34%; 89% with respect to recovered aldehyde).
deltah 7.55 - 7.23 (9H m), 7.1 - 7.05 (2H m), 6.27 (1H d J = 16), 5.3 (2H s), 4.55 (1H m), 3.65 (3H m), 3.27 (1H m), 2.70 (1H dd J = 15 and 6), 2.62 (1H J = 15 and 6), 2.52 (dd J = 14.7 and 5.5), 2.42 (dd J = 14.7 and 5.5), 1.41 (3H s), 1.38, (3H s), 0.81 (9H s), 0.03 (3H s), -0.03
(3H s). deltaC 195.83, 170.07, 153.61, 150.00, 135.20, 128.56, 128.09, 127.84, 127.59, 127.37, 127.28, 126.47, 124.18, 122.27, 121.04, 65.00,50.04, 47.46, 47.26, 41.11, 25.95,
24.27, 20.78, 16.46, -6.41.
From the above Examples, it can be seen that the coupling reaction of the invention can be carried out at room temperature and it is not necessary to use the extreme conditions which were essential for prior art coupling reactions.
Claims
1. A process for the preparation of a compound of general formula I
wherein
Z is a bulky organic substituent;
Y is a hydroxy, alkylsiloxy or a hydroxy function protected by a suitable protecting group, -CN, a halogen, oxo, or a CO2R group;
X is a hydroxy, alkylsiloxy, -CN, a CO2R group, a hydroxymethyl or an alkylsiloxymethyl group, or a hydroxy function, hydroxymethyl function or carboxyl function protected by a suitable protecting group;
R is C1-8 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylC1-8 alkyl, C2-8 alkenyl or a C1-8 alkyl substituted phenyl group; the process comprising reacting a compound of general formula II
wherein Z is as defined as in general formula I, with a compound of general formula III
wherein X and Y are as defined in general formula I; in the presence of a weak hydroxylic base such as lithium hydroxide or a Group I or Group II carbonate, in a suitable solvent.
2. A process as claimed in claim 1, wherein Z comprises two or more 5 or 6 membered rings either fused together or joined together via a single bond or via a single carbon bridge, each ring being independently saturated, unsaturated or aromatic, and each ring optionally containing one or more heteroatoms, and, in addition, optionally carrying one or more side chains each independently selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkoxy, hydroxy C1-8alkyl, hydroxy, halogen, OCOR or a CO2R group.
3. A process as claimed in claim 1 or claim 2 wherein the reaction is carried out at a temperature of from 20°C to 40°C.
4. A process as claimed in claim 3, wherein the reaction is carried out at room temperature.
5 A process as claimed in any one of claims 1 to 4 wherein the solvent is aprotic, for example diethyl ether.
6. A process as claimed in any one of claims 1 to 4 wherein the solvent is protic, for example t-butanol or isopropanol.
7. A process as claimed in any one of claims 1 to 6 wherein the base is lithium hydroxide or caesium carbonate.
8. A process as claimed in any one of claims 1 to 7 wherein the ratio of the compound of formula III:base is from 0.9:1 to 1.5:1.
9. A process as claimed in any one of claims 1 to 8 wherein the ratio of compound of formula II:compound of formula III is from 0.5:1 to 1:1.
10. A process as claimed in any one of claims 1 to 9, wherein Z is a fused ring system of general formula IV wherein
R3 represents a hydrogen atom, COC1-8 alkyl, COC3-8 cycloalkyl, COC3-8 cycloalkylC1-8 alkyl, COC2-8 alkenyl, COC1- 6 alkyl substituted phenyl group, or a a suitable protecting group;
R4 represents a hydrogen atom, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl group, or a C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl group substituted with a substituted phenyl group, or a hydroxy C1-8 alkyl group, or a hydroxy group, alkylsiloxy group or a hydroxy group protected by a suitable protecting group;
R5 represents a hydrogen atom or a C1-8 alkyl group;
R6 represents a hydrogen atom, or a methyl or ethyl group; each of a, b,and c, is independently a single or double bond except that when a and c are double bonds then b is a single bond.
11. A process as claimed in any one of claims 1 to 10 wherein:
Y is hydroxy or alkylsiloxy; and X is a CO2 C1-8 alkyl group.
12. A process as claimed in any preceding claim, wherein the compound of general formula III is
Methyl (R)-3-[(tert-butyldimethylsilyl)oxy]-6- (dimethoxyphosphonyl)-5-oxonexanoate; or
Methyl (R)-3-[triisopropylsilyloxy]-6-(dimethoxy- phosphonyl)-5-oxohexanoate.
13. A process as claimed in any preceding claim wherein the compound of general formula II is {(1S, 2S, 4aR, 6S, 8S, 8aS)-1,2,4a,5,6,7,8,8a-octahydro- 2-methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]- 6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S, 2S, 4aR, 6S, 8S, 8aS) -1,2,4a,5, 6,7,8, 8a- octahydro- 2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)- prop-1-enyl]naphthalene-1-carbaldehyde};
{(1S,2S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2-methyl-8-[(2"- (S)-methy1-1"-oxobutyl)oxy]naphthalene-1-carbaldehyde};
{(1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-2,6- dimethyl-8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalene- 1-carbaldehyde); {(1S,2S,4aR,6R,8S,8aS)-6-(t-butyldimethylsiloxy)-
1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-(S)-methyl- 1"-oxobutyl)oxy]-naphthalene-1-carbaldehyde);
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl8- [(2",2"-dimethy1-1"-oxobutyl)oxy]naphthalene-1- carbaldehyde};
{(1S,2S,6S,8S,8aS)-1,2,6,7,8,8a-hexahydro-2,6-dimethyl- 8-[(2"-(S)-methyl-1"-oxobutyl)oxy]naphthalenel- carbaldehyde); or 1-benzyl-2-phenyl-4-isopropylimidazole-5-carbaldehyde. 13. A process for the preparation of a methyl (1S,2S,
4aR,6S,8S,8aS,3,R)-7'-(1,2,4a,5,6,7,8,8a-octahydro- 2- methyl-8-[(2",2"-dimethy1-1"-oxobutyl)oxy]-6-[(E)-prop- 1-enyl]-1-naphthalenyl)-3'-trialkylsilyloxy-5'-oxohept- 6'-enoate, the method comprising reacting a
methyl (R)-3-[(trialkylsilyl)oxy]-6-(dimethoxyphosphonyl)-5-oxohexanoate with {(1S,2S,4aR,6S,8S,8aS)- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2",2"-dimethyl- 1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl] naphthalene-1- carbaldehyde} and either lithium hydroxide or caesium carbonate in a substantially anhydrous solvent.
14. A process for the preparation of a compound of general formula V or VI
R3, R4, R5 and R6 are as defined in general formula IV;
R7 represents a hydrogen atom or a substituent R8 or M; R8 represents a C1-5 alkyl group, or a C1-5 alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino;
M represents a cation capable of forming a pharmaceutically acceptable salt;
Q represents C=O or CHOH; and each of a, b, c, and d is independently a single or double bond except that when a and c are double bonds then b is a single bond; the process comprising preparing a compound of general formula I by a process as claimed in anyone of claims 1 to 11 and subsequently converting the compound of general formula I to a compound of general formula V or VI by any suitable method. 16. A process as claimed in claim 15 for the preparation of:
(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2-methyl-8-[(2",2"-dimethyl-1"-oxobutyl)-oxy]- 6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'- hydroxy-2H-pyran-2'-one; or
(1S,2S,4aR,6S,8S,8aS,4,R,6,R)-6'-{2-(1,2,4a,5,6,7,8,8a- octahydro-2,6-dimethyl-8-[(2",2"-dimethyl-1"-oxobutyl)- oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}- tetrahydro-4'-hydroxy-2H-pyran-2'-one.
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GB919115773A GB9115773D0 (en) | 1991-07-22 | 1991-07-22 | Synthetic process |
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GB (1) | GB9115773D0 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1993022321A1 (en) * | 1992-04-23 | 1993-11-11 | British Bio-Technology Limited | Phosphorus containing alkynyl derivatives |
US5677455A (en) * | 1994-09-06 | 1997-10-14 | Ube Industries, Ltd. | Preparation of 3-oxy-5-oxo-6-heptenoic acid derivatives |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0369288A1 (en) * | 1988-11-14 | 1990-05-23 | F. Hoffmann-La Roche Ag | Pyranyl ethyl naphthalene derivatives, their preparation and use as medicines |
US4950775A (en) * | 1985-10-11 | 1990-08-21 | University Of California | Antihypercholesterolemic compounds and synthesis thereof |
WO1991000280A1 (en) * | 1989-07-04 | 1991-01-10 | British Bio-Technology Limited | 6-(hydronaphtyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones and the corresponding hydroxy acids |
US5049577A (en) * | 1990-01-29 | 1991-09-17 | E. R. Squibb & Sons, Inc. | 2-pyrrolidone substituted dihydroxy alkanoic, alkenoic and alkynoic acids, compositions and HMG-CoA reductase inhibition therewith |
US5049778A (en) * | 1990-08-13 | 1991-09-17 | Zenith Electronics Corporation | Mask support structure for tension mask color cathode ray tubes |
-
1991
- 1991-07-22 GB GB919115773A patent/GB9115773D0/en active Pending
-
1992
- 1992-07-15 WO PCT/GB1992/001290 patent/WO1993002089A1/en active Application Filing
- 1992-07-15 AU AU23126/92A patent/AU2312692A/en not_active Abandoned
- 1992-07-22 ZA ZA925525A patent/ZA925525B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4950775A (en) * | 1985-10-11 | 1990-08-21 | University Of California | Antihypercholesterolemic compounds and synthesis thereof |
EP0369288A1 (en) * | 1988-11-14 | 1990-05-23 | F. Hoffmann-La Roche Ag | Pyranyl ethyl naphthalene derivatives, their preparation and use as medicines |
WO1991000280A1 (en) * | 1989-07-04 | 1991-01-10 | British Bio-Technology Limited | 6-(hydronaphtyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-ones and the corresponding hydroxy acids |
US5049577A (en) * | 1990-01-29 | 1991-09-17 | E. R. Squibb & Sons, Inc. | 2-pyrrolidone substituted dihydroxy alkanoic, alkenoic and alkynoic acids, compositions and HMG-CoA reductase inhibition therewith |
US5049778A (en) * | 1990-08-13 | 1991-09-17 | Zenith Electronics Corporation | Mask support structure for tension mask color cathode ray tubes |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993022321A1 (en) * | 1992-04-23 | 1993-11-11 | British Bio-Technology Limited | Phosphorus containing alkynyl derivatives |
US5677455A (en) * | 1994-09-06 | 1997-10-14 | Ube Industries, Ltd. | Preparation of 3-oxy-5-oxo-6-heptenoic acid derivatives |
US5744604A (en) * | 1994-09-06 | 1998-04-28 | Ube Industries, Ltd. | Preparation of 3-oxy-5-oxo-6-heptenoic acid derivatives |
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ZA925525B (en) | 1994-01-24 |
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