GB2235924A - Phosphorus-containing 3-hydroxy-butanoic acid intermediates - Google Patents
Phosphorus-containing 3-hydroxy-butanoic acid intermediates Download PDFInfo
- Publication number
- GB2235924A GB2235924A GB9020929A GB9020929A GB2235924A GB 2235924 A GB2235924 A GB 2235924A GB 9020929 A GB9020929 A GB 9020929A GB 9020929 A GB9020929 A GB 9020929A GB 2235924 A GB2235924 A GB 2235924A
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- United Kingdom
- Prior art keywords
- mmole
- evaporated
- mixture
- solution
- acid
- Prior art date
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- Granted
Links
- 239000000543 intermediate Substances 0.000 title abstract description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 5
- 229910052698 phosphorus Inorganic materials 0.000 title description 5
- 239000011574 phosphorus Substances 0.000 title description 5
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 title 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 63
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 abstract description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 102
- 239000000203 mixture Substances 0.000 description 71
- 239000000243 solution Substances 0.000 description 70
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- 229910052786 argon Inorganic materials 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
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- 210000003494 hepatocyte Anatomy 0.000 description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 10
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 10
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 10
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- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 229940045348 brown mixture Drugs 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
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
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- 229960002424 collagenase Drugs 0.000 description 1
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- MPSZITJFIKCNBV-UHFFFAOYSA-N cyclohexa-2,4-dien-1-imine Chemical compound N=C1CC=CC=C1 MPSZITJFIKCNBV-UHFFFAOYSA-N 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 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
- 125000002704 decyl group Chemical group [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])* 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 description 1
- 125000003438 dodecyl group Chemical group [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])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001278 effect on cholesterol Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011491 glass wool Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic 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
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical class C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 238000000464 low-speed centrifugation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960001961 meglutol Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940057061 mevalonolactone Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000007793 ph indicator Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- XYKIUTSFQGXHOW-UHFFFAOYSA-N propan-2-one;toluene Chemical compound CC(C)=O.CC1=CC=CC=C1 XYKIUTSFQGXHOW-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 238000005584 silyl ether cleavage reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 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 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 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
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 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 PโC bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- 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 PโC bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- 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 PโC bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
-
- 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 PโC 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
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound having the structure <IMAGE> wherein R<a> is lower alkyl or lower alkoxy or a compound having the structure <IMAGE> wherein R<a'> is lower alkyl or OH. The above compounds are intermediates for HMG-COA reductase inhibitors claimed in patent application GB 8811929.2 (GB 2205837).
Description
PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE
INHIBITORS, NEW INTERMEDIATES AND METHOD
The present invention relates to new phosphorus-containing compounds which inhibit the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and thus is useful in inhibiting cholesterol biosynthesis, to hypocholesterolemic compositions containing such compounds, to new intermediates formed in the preparation of such compounds and to a method of using such compounds for such purposes.
F. M. Singer et al., Proc. Soc. Exper.
Biol. Med., 102, 370 (1959) and F. H. Hulcher,
Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U. S. Patents Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactone structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula
in which E represents a direct bond, a C13 alkylene bridge or a vinylene bridge and the various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U. S. Patent No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure
wherein A is H or methyl; E is a direct bond, -CH3-, -CH2-CH2-, -CH2-CH2-CH2- or -CH=CH-; R1, R2 and R3 are each selected from H, halogen, C14 alkyl, C1-4 haloalkyl, phenyl, phenyl substituted by halogen, C1-4 alkoxy, C28 alkanoyloxy, 1-4 alkyl, or C14 haloalkyl, and OR4 in which R4 is H, C2-8 alkanoyl, benzoyl, phenyl, halophenyl, phenyl C1-3 alkyl, C1-9 alkyl, cinmayl, C1-5 haloalkyl, allyl, cycloalkyl-C1-3-alkyl, adamantyl-Cl~3-alkyl, or substituted phenyl
C1-3-alkyl in each of which the substituents are selected from halogen, C14 alkoxy, C1-4 alkyl, or
C1-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the 1-3 alkyl and phenyl, dimethylamino or acetylamino substituted
C1-3-alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the trans racemate shown in the above formula.
WO 84/02131 (PCT/EP83/00308) (based on
U. S. application Serial No. 443,668, filed
November 22, 1982, and U. S. application Serial
No. 548,850, filed November 4, 1983), filed in the name of Sandoz AG discloses heterocyclic analogs of mevalono lactone and derivatives thereof having the structure
wherein one of R and Ro is
and the other is primary or secondary C1-6 alkyl, C3-6 cycloalkyl or phenyl-(CH2)m-,
wherein R4 is hydrogen, C1-4 alkyl, C1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R5 is hydrogen, C13 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R5a is hydrogen, C12 alkyl, C1-2 alkoxy, fluoro or chloro, and
m is 1, 2 or 3,
with the provisos that both R5 and R5a must be hydrogen when R4 is hydrogen, R5a must be hydrogen when R5 is hydrogen, not more than one of
R4 and R5 is trifluoromethyl, not mcr than one of
R4 and R5 is phenoxy and not more than one of R4 and R5 is benzyloxy,
R2 is hydrogen, C14 alkyl, C36 cycloalkyl, C14 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R3 must be hydrogen when R2 is hydrogen, not more than one of
R2 and R3 is trifluoromethyl, not more than one of
R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy.
x is -(CH2)n- or -CH=CE- (n=0, 1, 2 or 3),
wherein R6 is hydrogen or C13 alkyl in free acid form or in the form of a physiologicallyhydrolysable and -acceptable ester or a 8 lactone thereof or in salt form.
GB 2162-179-A discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure
wherein R1 = 1-3C alkyl;
Z is a gp. of formula Z1 or Z2:
R7 = H, a hydrolysable ester gp. or a cation.
European Patent No. 164-698-A discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R5 SO2X, then removing the protecting group Pr.
wherein X = halo;
Pr = a carbinol-protecting group;
R1 = H or CH3;
R3, R4 = H, 1-3C alkyl or phenyl-(1-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo;
R2 = a group of formula (A) or (B):
= = H or OH; R = H or CH3;
a, b, c and d = optional double bonds;
R7 = phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or halo; R8, R9 = 1-3C alkyl or halo;
R5 = 1-3C alkyl, phenyl or mono- or di-(l-3C alkyl)phenyl.
Anderson, Paul Leroy, Ger. Offen.
DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure
wherein R1 is alkyl, Z = Q, Q1; R7 = H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
WO 8402-903 (based on U.S. application
Serial No. 460,600, filed January 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure
wherein the two groups Ro together form a radical of formula
or -(CH2)4
wherein R2 is hydrogen, C1-4 alkyl, C1.4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R2 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy,
R1 is hydrogen, C1-6 alkyl, fluoro, chloro or benzyloxy,
R4 is hydrogen, C1-4 alkyl, C1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R5 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
R5a is hydrogen, C12 alkyl, C12 alkoxy, fluoro or chloro, and with the provisos that not more than one of R4 and R5 is trifluoromethyl, not more than one of R4 and R5 is phenoxy and not more than one of R4 and Pts is benzyloxy,
wherein n is 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1,
Z is
wherein R6 is hydrogen or C13 alkyl, with the general proviso that -X-Z and the R4 bearing phenyl group are ortho to each other;
in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a 6 lactone thereof or in salt form.
European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5thia-w-aryl-alkanoic acids having the structural formula:
wherein Z is:
n is 0, 1 or 2;
E is -CH2-, -CH2-CH2-, -CH2-CH2-CH2 -, -CH=CH-CH2-; or -CH2-CH=CH-; R1, R2 and R3 are, e.g., hydrogen, chloro, bromo, fluoro, C1-alkyl, phenyl, substituted phenyl or OR7 in which R7 is, e.g., hydrogen, C2 8alkanoyl, benzoyl, phenyl, substituted phenyl, C1-9alkyl, cinnamyl, C1-4haloalkyl, allyl, cycloalkyl-C1-3alkyl, adamantyl-C1-3-alkyl, or phenyl C1-3 alkyl; R , R5 and R6 are hydrogen, chloro, bromo, fluoro or C1 3 alkyl; and
X is, e.g., hydrogen, C13 alkyl, a cation derived from an alkali metal or is ammonium.
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French patent application 2,596,393 A filed on April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula:
wherein R1 and R2 = H, lower alkyl or optionally substituted aralkyl;
R3 and R4 = H, lower alkyl or optionally substituted aryl or aralkyl.
These comounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European patent application 142,146-A (Merck & Co., Inc) discloses mevinolin-like compounds of the structural formula:
wherein:
R1 is, e.g., hydrogen or C14alkyl; E is CH2CH2 -CH=CH-, or -(CH2)r-; and
Z is
1)
wherein X is -O- or -NR9 wherein R9 is hydrogen or
C1-3alkyl;
R7 is C2-8alkyl; and R is hydrogen or CH3;
2)
wherein R10, R11 and R12 are independently, e.g., hydrogen, halogen or C1-4alkyl; 3)
In accordance with the present invention, there is provided phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA Reductase) and thus are useful as hypocholesterolemic agents and include the following moiety
wherein X is -o- or -NH-, n is 1 or 2 and Z is a "hydrophobic anchor".
The term hydrophobic anchor as employed herein refers to a lipophilic group which when linked to the HMG-like upper side chain of the molecule by the appropriate linker ("X"), binds to a hydrophobic pocket of the enzyme not utilized in binding the substrate HMG CoA, resulting in enhanced potency relative to compounds where Z=H.
In preferred embodiments, the compounds of the invention have the formula I
including salts thereof, wherein R is OH, lower alkoxy or lower alkyl;
RX is H or lower alkyl;
X is -O- or -NH-;
n is 1 or 2;
Z is a hydrophobic anchor;
and including pharmaceutically acceptable salts thereof.
The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases.
Such salts include ammonium salts, alkali metal salts like, lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, such as amine like salts, e.g., dicyclohexylamine salt, benzathine, N-methyl-Dglucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
Examples of hydros Dbic anchors which may be included in accordance wit the present invention include, but are not limited to
wherein the dotted lines represent optional double bonds, for example,
wherein R, R , R2a and R2b may be the same or different and are each independently selected from
H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or ORY wherein RY is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl.
Where Z is
R5 and R5' are the same or different and are H, lower alkyl or OH;
R6 is lower
such as
or arylCH2-; R6a is lower alkyl, hydroxy, oxo or halogen; q is 0, 1, 2 or 3, and
R7 is H or lower alkyl;;
Thus, the compounds of formula I encompass
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 12 carbons in the normal chain, preferably 1 to 7 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 a halo-substituent, such as F, Br, C1 or I or CF3, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an alkylcycloalkyl substituent, hydroxy, and alkylamino substituent, an alkanoylamino substituent, an arylcarbonylamino substituent, a nitro substituent, a cyano substituent, a thiol substituent or an alkylthio substituent.
The term "cycloalkyl" as employed herein alone or as part of another group includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, . cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups, and/or 1 or 2 alkylthio groups.
The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be 1, 2 or 3 lower alkyl groups, halogens (Cl, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy group, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 haloalkyl groups, 1, 2 or 3 halophenyl groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cycloalkylalkyl groups, 1, 2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino groups, 1, 2 or 3 arylcarbonylamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, 1, 2 or 3 thiol groups, and/or 1, 2 or 3 alkylthio groups with the aryl group preferably containing 3 substituents.
The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein alone or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.
The term "lower alkoxy", "alkoxy11, or "aryloxy" or "aralkoxy" as employed herein alone or as part of another group includes any of the above lower alkyl, 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 lower alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino" as employed herein alone or as part of another group includes any of the above lower alkyl, alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term "alkanoyl" as used herein as part of another group refers to lower alkyl linked to a carbonyl group.
The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, iodine and
CF3, with chlorine or fluorine being preferred.
Preferred are those compounds of formula I which have the following structure
wherein R is OH, OLi; PtXis Li or H;
X is O or NH; and
Z is
wherein R1 is phenyl which includes an alkyl and/or halo substitutent
or R1 is benzyloxy which includes a halo sub stituent; R2 and R2a are the same and are halogen or lower alkyl;
Z may also preferably be
wherein R and Ri are as defined immediately above with respect to the compound of formula II, or
Z is
wherein R5 is H, CH3 or OH and R6 is
or (substituted)phenylmethyl wherein R7 is H or CH3.
The compounds of formula I of the invention may be prepared according to the following reaction sequence and description thereof.
C6H5 Ra-P(Oalkyl)2 O Osi-C-(CH3)3 Ra-P-CH2-CH-CH2-COalkyl III C6H5 # # Oalkyl OSi-C(CH3)3 I-CH2-C-CH-CH2-CO2alkyl Arzubov Reaction H (Ra = lower alkyl or C6H5 C6H5 A lower alkoxy) IV O 1. (CH3)3-SiBr, CH2Cl2 Ra'-P-CH2-CH-CH2-CO2alkyl IV 2. H2O OH O # Si-C(CH3)3 Phosphorus ester cleavage C6H5 C6H5 VA. - Ra'=lower alkyl where Ra was lower alkyl
VB. - Ra'=OH where Ra was lower alkoxy
VB RbOH-DCC O (Ra' = OH) (Rb = lower alkyl) RbO-P-CH2-CH-CH2CO2alkyl # OH Pyridine O (Esterification) Si-C(CH3)3 C6H5 C6H5 VI
VI 1) (COCl); CH2Cl2 (Acid Cl Formation) O or Z-(CH2)n-XH (coupling reaction) Rc-P-CH2-CH-CH2CO2alkyl VA. # X O (C2H5)3N, DMAP (CH2)n Si-C(CH3)3 Z C6H5 C6H5 VII (Rc = lower alkyl or lower alkoxy) 1) (n-C4H9)4,NF, CH3COOH, THF (silyl O VII ether cleavage) R-P-CH2-CH-CH2-CO2Rx 2) OH-, dioxane (Hydrolysis) X # (CH2)n Z I.
As seen in the above reaction sequence, compounds of Formula I may be prepared by subjecting iodide A to an Arbuzov reaction by heating iodide A
and phosphonite/phosphite III
III Ra-P(Oalkoxy)2 wherein Ra is lower alkyl or lower alkoxy, employing standard Arbuzov conditions and procedures to form phosphinate/phosphonate IV
Phosphinate/phosphonate IV is a novel
compound and as such is a part of the present
invention.
Phosphinate/phosphonate IV is then subjected
to a phosphorus ester cleavage by treating a solution of compound IV in an inert organic solvent,
such as methylene chloride, sequentially with bis(trimethylsilyl )trifluoroacetamide (BSTFA) and
trimethylsilyl bromide, under an inert atmosphere such as argon to form the phosphinic acid VA where "a a in IV is lower alkyl, that is, VA lower
or phosphonic acid VB (wherein Ra in IV is lower alkoxy), that is
Compounds VA and VB are novel intermediates and as such as part of the present invention.
Where phosphonic acid VB is obtained, it is esterified by treating VB in dry pyridine with alcohol
VC RbOH (where b is lower alkyl) and dicyclohexyl carbodiimide and the resulting reaction mixture is stirred under an inert atmosphere, such as argon, to form phosphonic mono alkyl ester VI
Ester VI or phosphinic acid VA is then dissolved in an inert organic solvent, such as, methylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyldiethylamine and stirred under an inert atmosphere such as argon; the mixture is evaporated and then dissolved in methylene chloride (or other appropriate inert organic solvent). The resulting solution is cooled to a temperature within the range of from about q0c to about 250C, treated with oxalyl chloride and then evaporated to give crude phosphonochloridate.
The phosphonochloridate is dissolved in inert organic solvent such as methylene chloride, benzene, pyridine or THF; the solution is cooled to a temperature within the range of from about -200C to about OOC and treated with B Z CH2 XH employing a molar ratio of VI or VA:B of within the range of. from about 0.5:1 to about 3:1 and preferably from about 1:1 to about 2:1, followed by triethylamine and catalytic 4-dimethylaminopyridine (DMAP) to form adduct VII
wherein Roc is lower alkyl or lower alkoxy.
Compound VII is subjected to silyl ether cleavage by treating a VII in an inert organic solvent such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium fluoride to form ester VIII
(PtX = alkyl)
The ester VIII may then be hydrolyzed to the corresponding alkali metal salt or acid, that is, where Ptx is alkali metal or H by treatment with strong base such as lithium hydroxide in the presence of dioxane, tetrahydrofuran or other inert organic solvent, under an inert atmosphere such as argon, at 250C, employing a molar ratio of base:ester VIII of within the range of from about 1:1 to about 1.1:1 to form the corresponding alkali metal salt
wherein R is lower alkyl or lower alkoxy.
Compound VIIIA may then be treated with strong acid such as HC1 to form the corresponding acid VIIIB
The ester VIII wherein R is lower alkoxy may be converted to the corresponding di-alkali metal salt by treating ester VIII with strong base at 50-600C employing a molar ratio of base:ester
VIII of within the range of from about 2:1 to about 4:1 to form VIIIC
VIIIC alkali
0 metalo-b-ca. -CH-CH,-C02alkali metal X 5H (CH 2n z The di-alkali metal salt VI I IC may be converted to the corresponding acid wherein R is
OH by treatment with strong acid such as HC1 to form VIIID
The iodide starting material A may be prepared starting with the bromide C
(prepared employing procedures as described
in Tetrahedron Lett. 26, 2951 (1985)) which is dissolved in solution in dimethylformamide (DMF) with imidazole and 4-dimethylamino pyridine and the resulting solution is treated with t-butyldiphenyl silyl chloride under an inert atmosphere such as argon to form the silyl ether D
A solution of silyl ether D in an inert organic solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere such as argon, to form iodide A.
The starting compound B
B Z (CH2)n XH may be prepared as described below depending upon the definition of Z and X.
Thus, compounds of formula B wherein Z is
and X is 0, that is, compounds of the structure
may be prepared by treating aldehyde E
with a reducing agent such as lithium aluminum hydride or sodium borohydride.
Compounds of formula B where Z is
and X is N, that is compounds of the structure
may be prepared by oxidizing the aldehyde E by treating E in solution with acetone with, for example, Jones reagent to form the acid F
which in suspension with methylene chloride is treated with oxalyl chloride to form the corresponding acid chloride which is dissolved in an inert organic solvent such as tetrahydrofuran, and treated with a mixture of concentrated ammonium hydroxide in tetrahydrofuran to form an amide of the structure
Amide G is then reduced to the corresponding amide
B2 by treating G with a reducing agent such as lithium aluminum hydride.
Starting compounds of formula B wherein Z is
and X is O or -NH-, that is, compounds of the structure
where X,is 0 are disclosed by C. H. Heathcock et al,
J. Org. Chem. 50, 1190 (1985). Compounds of formula H' were X is NH may be prepared by the reductive amination of
(prepared as disclosed by C. H. Heathcock et al, supra) by treating J with ammonium acetate and sodium cyanoborohydride in the presence of an alcohol solvent such as methanol.
Starting compound of formula B wherein Z is
and X is O, that is, compounds of the structure
are disclosed in WO 8402-903-A and GB 2,162,179A both filed in the name of Sandoz.
Starting compounds of formula B wherein Z is
and X is NH, that is, compounds of the structure
may be prepared by the reductive amination of the aldehyde 0
by treating 0 with ammonium acetate and sodium cyanoborohydride in the presence of an alcohol solvent such as methanol.
The compounds of the invention may be prepared as racemic mixtures and may later be resolved to obtain the S-isomer which is preferred. However, the compounds of the invention may be prepared directly in the form of their S-isomers as described herein and in the working examples set out hereinafter.
The compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme
A (HMG-CoA) reductase and thus are useful in inhibiting cholesterol biosynthesis as demonstrated by the following tests.
1) Rat Hepatic HMG-CoA Reductase
Rat hepatic HMG-CoA reductase activity is measured using a modification of the method described by Edwards (Edwards, P.A., et al.,
J. Lipid Res. 20:40, 1979). Rat hepatic microsomes are used as a source of enzyme, and the enzyme activity is determined by measuring the conversion of the 14C-EMG-CoA substrate to 14C-mevalonic acid.
a. Preparation of Microsomes
Livers are removed from 2-4 cholestyramine-fed, decapitated, Sprague Dawley rats, and homogenized in phosphate buffer A (potassium phosphate, 0.04 M, pH 7.2; KCl, 0.05 M; sucrose, 0.1 M; EDTA, 0.03 M; aprotinin, 500 KI units/ml). The homogenate is spun at 16,000 x g for 15 minutes at 40C. The supernatant is removed and recentrifuged under the same conditions a second time. The second 16,000 x g supernatant is spun at 100,000 x g for 70 minutes at 40C.
Pelleted microsomes are resuspended in a minimum volume of buffer A (3-5 ml per liver), and homogenized in a glass/glass homogenizer.
Dithiothreitol is added (10 mM), and the preparation is aliquoted, quick frozen in acetone/dry ice, and stored at -80 C. The specific activity of the first microsomal preparation was 0.68 nmole mevalonic acid/mg protein/minute.
b. Enzyme Assay
The reductase is assayed in 0.25 ml which contains the following components at the indicated final concentrations:
0.04 M Potassium phosphate, pH 7.0
0.05 M KCl
0.10 M Sucrose 0.03 M EDTA
0.01 M Dithiothreitol
3.5 mM NaCl 1% Dimethylsulfoxide
50-200 pg Microsomal protein
100 pM 14C-tDL]HMG-CoA (0.05 pCi,
30-60 mCi/mmole)
2.7 mM NADPH (nicotinamide adenine
dinucleotide phosphate)
Reaction mixtures are incubated at 370C. Under conditions described, enzyme activity increases linearly up to 300 pg microsomal protein per reaction mixture, and is linear with respect to incubation time up to 30 minutes. The standard incubation time chosen for drug studies is 20 minutes, which results in 12-15% conversion of
HMG-CoA substrate to the mevalonic acid product.
[DL-]HMG-CoA substrate is used at 100 pM, twice the concentration needed to saturate the enzyme under the conditions described. NADPH is used in excess at a level 2.7 times the concentration required to achieve maximum enzyme velocity.
Standardized assays for the evaluation of inhibitors are conducted according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 370C for 15 minutes. DMSO vehicle with or without test compound is added, and the mixture further incubated for 15 minutes at 370C. The enzyme assay is initiated by adding 14C-HMG-CoA substrate. After 20 minutes incubation at 370C the reaction is stopped by the addition of 25 l of 33% KOH. 3H-mevalonic acid (0.05 Ci) is added, and the reaction mixture allowed to stand at room temperature for 30 minutes. Fifty p1 SN
HC1 is added to lactonize the mevalonic acid.
Bromophenol blue is added as a pH indicator to monitor an adequate drop in pH. Lactonization is allowed to proceed for 30 minutes at room temperature. Reaction mixtures are centrifuged for 15 minutes at 2800 rpm. The supernatants are layered onto 2 grams AG l-X8 anion exchange resin (Biorad, formate form) poured in 0.7 cm (id) glass columns, and eluted with 2.0 ml H2O. The first 0.5 ml is discarded, and the next 1.5 ml is collected and counted for both tritium and carbon 14 in 10.0 ml Opti-fluor scintillation fluid.
Results are calculated as nmoles mevalonic acid produced per 20 minutes, and are corrected to 100% recovery of tritium. Drug effects are expressed as 150 values (concentration of drug producing 50% inhibition of enzyme activity) derived from composite dose response data with the 95% confidence interval indicated.
Conversion of drugs in lactone form to their sodium salts is accomplished by solubilizing the lactone in DMSO, adding a 10-fold molar excess of NaOH, and allowing the mixture to stand at room temperature for 15 minutes. The mixture is then partially neutralized (pH 7.5-8.0) using 1N HCl, and diluted into the enzyme reaction mixture.
2) Cholesterol Synthesis in Freshly Isolated Rat
Hepatocytes
Compounds which demonstrate activity as inhibitors of HMG-CoA reductase are evaluated for their ability to inhibit 14C-acetate incorporation into cholesterol in freshly isolated rat hepatocyte suspensions using methods originally described by
Capuzzi et al. (Capuzzi, D.M. and Margolis, S.,
Lipids, 6:602, 1971).
a. Isolation of Rat Hepatocytes
Sprague Dawley rats (180-220 grams) are anesthetized with Nembutol (50 mg/kg). The abdomen is opened and the first branch of the portal vein is tied closed. Heparin (100-200 units) is injected directly into the abdominal vena cava. A single closing suture is placed on the distal section of the portal vein, and the portal vein is canulated between the suture and the first branching vein. The liver is perfused at a rate of 20 ml/minute with prewarmed (370C), oxygenated buffer A (HBSS without calcium or magnesium containing 0.5 mM EDTA) after severing the vena cava to allow drainage of the effluent.
The liver is additionally perfused with 200 ml of prewarmed buffer B (HBSS containing 0.05% bacterial collagenase). Following perfusion with buffer B; the liver is excised and decapsulated in 60 ml Waymouth's medium allowing free cells to disperse into the medium. Hepatocytes are isolated by low speed centrifugation for 3 minutes at 50xg at room temperature. Pelleted hepatocytes are washed once in Waymouth's medium, counted and assayed for viability by trypan blue exclusion.
These hepatocyte enriched cell suspensions routinely show 70-90% viability.
b. 14C-Acetate Incorporation into
Cholesterol
Hepatocytes are resuspended at 5x106 cells per 2.0 ml in incubation medium (IM) [0.02 M
Tris-HCl (pH 7.4), 0.1 M KC1, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate].
Test compounds are routinely dissolved in
DMSO or DMSO:H2O (1:3) and added to the IM. Final
DMSO concentration in the IM is < 1.0%, and has no significant effect on cholesterol synthesis.
Incubation is initiated by adding 14, acetate (58 mCi/mmol, 2 pCi/ml), and placing the cell suspensions (2.0 ml) in 35 mm tissue culture dishes, at 370C for 2.0 hours. Following incubation, cell suspensions are transferred to glass centrifuge tubes and spun at 50xg for 3 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml E2O, and placed in an ice bath.
Lipids are extracted essentially as described by Bligh, E. G. and W. J. Dyer, Can. J.
Biochem. and Physiol., 37:911, 1959. The lower organic phase is removed and dried under a stream of nitrogen, and the residue resuspended in (100 pl) chloroform:methanol (2:1). The total sample is spotted on silica gel (LK6D) thin-layer plates and developed in hexane:ethyl ether:acetic acid (75:25:1). Plates are scanned and counted using a
BioScan automated scanning system. Radiolabel in the cholesterol peak (RF 0.28) is determined and expressed at total counts per peak and as a percent of the label in the total lipid extract.
Cholesterol peaks in control cultures routinely contain 800-1000 cpm, and are 9-20% of the label present in the total lipid extract; results compatable with Capuzzi, et al., indicating 9% of extracted label in cholesterol.
Drug effects (% inhibition of cholesterol synthesis) are determined by comparing % of label in cholesterol for control and drug treated cultures. Dose response curves are constructed from composite data from two or more studies, and results are expressed as I50 values with a 95% confidence interval.
3) Cholesterol Synthesis in Human Skin Fibrobiasts Compound selectivity favoring greater inhibitory activity in hepatic tissue would be an attribute for a cholesterol synthesis inhibitor.
Therefore, in addition to evaluating cholesterol synthesis inhibitors in hepatocytes, these compounds are also tested for their activity as inhibitors of cholesterol synthesis in cultured fibroblasts.
a. Human Skin Fibroblast Cultures
Human skin fibroblasts (passage 7-27) are grown in Eagles' minimal essential medium (EM) containing 10% fetal calf serum. For each experiment, stock cultures are trypsonized to disperse the cell monolayer, counted, and plated in 35 mm tissue culture wells (5x105 cells/2.0 ml). Cultures are incubated for 18 hours at 370C in 5% CO2/95% humidified room air. Cholesterol biosynthetic enzymes are induced by removing the serum containing medium, washing the cell monolayers, and adding 1.0 ml of EM containing 1.0% fatty acid free bovine serum albumin, and incubating the cultures an additional 24 hours.
b. 14C-Acetate Incorporation into
Cholesterol
Induced fibroblast cultures are washed with
EMEM100 (Earle's minimal essential medium). Test compounds are dissolved in DMSO or DMSO:EM (1:3) (final DMSO concentration in cell cultures < 1.0%), added to the cultures, and the cultures preincubated for 30 minutes at 370C in 5% C02/95% humidified room air. Following preincubation with drugs, [1-14CNa acetate (2.0 pCi/ml, 58 mCi/mmole) is added, and the cultures reincubated for 4 hours.
After incubation, the culture medium is removed, and the cell monolayer (200 pg cell protein per culture) is scraped into 1.0 ml of H2O. Lipids in the lysed cell suspension are extracted into chloroform:methanol as described for hepatocyte suspensions. The organic phase is dried under nitrogen, and the residue resuspended in chloroform:methanol (2:1) (100 p1), and the total sample spotted on silica gel (LK6D) thin-layer plates, and analyzed as described for hepatocytes.
Inhibition of cholesterol synthesis is determined by comparing the percent of label in the cholesterol peak from control and drug-treated cultures. Results are expressed as I50 values, and are derived from composite dose response curves from two or more experiments. A 95% confidence interval for the I50 value is also calculated from the composite dose response curves.
A further aspect of the present invention is a pharmaceutical composition consisting of at least one of the compounds of formula I in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, such dosage forms containing from 1 to 2000 mg of active compound per dosage, for use in the treatment. The dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient.
The compounds of formula I may be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol biosynthesis, such as lovastatin, in mammalian species such as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount from about 4 to 2000 mg in a single dose or in the form of individual doses from 1. to 4 times per day, preferably 4 to 200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in sustained release form.
The following working Examples represent preferred embodiments of the present invention.
Unless otherwise indicated, all temperatures are expressed in degrees Centigrade. Flash chromatography was performed on either Merck 60 or
Whatmann LPS-I silica gel. Reverse phase chromatography was performed on CHP-20 MCI gel resin supplied by Mitsubishi, Ltd.
Example 1 (S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl] 2-yl ]methoxy] methoxyphosphinyl] -3-hydroxy-butanoic acid, monolithium salt
A. N- (2 , 4-Dimethylbenzylidene )benzeneamine Ref. Merck U. S. Patent No. 4,375,475, pg. 39.
A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 ml, 50 mmole) and distilled aniline (Aldrich, 4.56 ml, 50 mmole) in dry toluene (80.0 ml) was refluxed for 3.0 hours under argon in a flask equipped with a
Dean-Stark apparatus. The mixture was cooled, then evaporated in vacuo to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-1800C) to give 8.172 g (78.1%) of desired title benzeneimine as a light yellow oil which crystallized on standing to a low melting solid. TLC (4:1) Hex-acetone, RF=0.67 and 0.77 (geometric isomers), U.V. and 12.
Ref. Merck U.S. Patent No. 4,375,475, pg. 39.
A mixture of Part A benzeneimine (6.0 g, 28.7 mmol) in glacial HOAc (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmole) and the clear, red homogeneous solution refluxed under argon for one hour. The resulting turbid mixture was filtered warm through a packed " bed of Celite into 900 ml of H2 Precipitated orange solid was collected by filtration and dried in vacuo at 650C over P205 for 16.0 hours to give 10.627 g (85.5%) of desired title palladium complex as an orange solid with m.p. = 1940-1960C. (Literature m.p. of a recrystallized analytical sample = 2030-2050C).
C. 4'-Fluoro-3,3' ,5-trimethyl[l,l'- biphenyll-2-carboxaldehyde (1) Bromot4-fluoro-3-methylphenyl]- magnesium
Ref. Merck U. S. Patent No. 4,375,475, pp. 37 and 38.
The title Part C(1) Grignard reagent was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmole, Fairfield Chemical Co.) dropwise at a rate sufficient to maintain the reaction at reflux to stirred magnesium turnings (1.35 g, 55.4 mmole, 8.0 eq.) in dry Et20 (70.0 ml). The reaction was initiated in an ultrasound device.
After bromide addition was complete, the mixture was stirred for one hour under argon at room temperature, refluxed for 15 minutes and then allowed to cool to room temperature.
(2) 4'-Fluoro-3,3',5-trimethyl[l,l'- biphenyl]-2-carboxaldehyde In a second flask, a mixture of the Part B dipalladium complex (3.0 g, 6.92 mmole) and triphenylphosphine (14.52 g, 55.4 mmole, 8.0 eq.) in dry benzene (100 ml) was stirred at room temperature under argon for 30 minutes. Freshly prepared and filtered (glass wool plug) Part C (1)
Grignard reagent was then added in one portion by means of a cannula to this solution and the mixture was stirred for 1.5 hours at room temperature under argon. 6.0 N HCl (35 ml) was added, the mixture stirred an additional hour at room temperature, then filtered through packed
Celite (" bed). The filtrate was extracted with
Et2O (250 ml), the extract washed with brine (2 x 100 ml), dried over anhydrous MgSO4 and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on standing. The crude orange solid was purified by flash chromatography on silica gel (700 g) eluting with hexane, followed by (95:5) hexane-Et2O. Product fractions were evaporated to give 1.507 g (89.9%) of desired title aldehyde as a light yellow solid with m.p. = 720-750C) (Literature reports m.p. = 730-740C).
TLC: (95:5) Hex-Et20, Rf = 0.40, U.V. and PMA.
D. 4'-Fluoro-3,3',5-trimethyl[1,1' biphenyl -2-methanol A cooled (0 C, ice bath) solution of dry
Et2O (15.0 ml) was treated with LiAlH4 (259 mg, 6.82 mmole, 0.55 eq.) and the gray suspension treated dropwise over 15 minutes with a solution of the Part C aldehyde (3.0 g, 12.4 mmole) in dry
Et2O (15 ml). The mixture was stirred at room temperature under argon for 30 minutes, then cooled back to 0 C and quenched by sequential dropwise addition of 260 pl H2O, 260 p1 of 15%
NaOH and 780 p1 H2O. The suspension was diluted with EtOAc, filtered through anhydrous Na2S over packed Celite (" bed) and the colorless filtrate evaporated in vacuo to give 2.99 g (98.8%) of a white solid.Trituration of the crude solid with cold hexane and drying in vacuo afforded 2.467 g (81.6%) of desired title alcohol as a white solid with m.p. 102-1030C. TLC: (9:1) Hex-EtOAc, Rf = 0.24, U.V. and PMA.
E. (S)-3-[[(1,1-Dimethylethyl)diphenyl
silyl]oxy]-4-(hydroxymehoxyphosphinyl)
butanoic acid, methyl ester
(1) (S)-4-Bromo-3-hydroxybutanoic acid,
methyl ester (l)(a) [R-(R*,R*)]-2,3,4-trihydroxy- butanoic acid, calcium salt,
hydrate
Ref. Carbohydrate Research 72, pp. 301-304 (1979).
Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid (44.0 g, 250 mmol) in H20 (625 ml), tMe suspension cooled to OOC (ice bath) and treated portionwise with 30% H202 (100 ml). The mixture was stirred at 300-400C (oil bath) for 30 minutes. Darco (10 g) was added and the black suspension heated on a steam bath until evolution of 02 ceased. The suspension was filtered through Celite, evaporated in vacuo (bath temperature 400C). The residue was taken up in
H20 (50 ml), warmed on a steam bath and CH3OH was added until the solution was turbid. The gummy precipitated solid was collected by filtration and air dried to give 30.836 g (75.2%) of desired calcium salt as a powdery white solid.
TLC (7:2:1) iPrOH-NE4OH-H2Ow Rf = 0.19, PMA.
(l)(b) [S-(R*,S*)]-2,4-Dibromo-3- hydroxybutanoic acid, methyl
ester
Ref. Bock, K. et al., Acta Scandinavica (B) 37, pp. 341-344 (1983)
Part (l)(a) calcium salt (30 g) was dissolved in 30-32% HBr in acetic acid (210 ml) and stirred at room temperature for 24 hours.
Methanol (990 ml) was then added to the brown solution and it was stirred overnight. The mixture was evaporated to an orange oil, taken up in CH3OH (75 ml), refluxed for 2.0 hours and evaporated.
The residue was partitioned between EtOAc (100 ml) and H20, the organic phase washed with H20 (2x) and brine then dried over anhydrous Na2 SO4 and evaporated to give 22.83 g (90.5%) of crude dibromide as a light orange oil. TLC (1:1)
EtOAc-Hex, Rf = 0.69, UV & PMA.
(1) (c) (S)-4-Bromo-3-hydroxybutanoic
acid, methyl ester
Ref. the same as for preparation of (1)(b).
An argon purged solution of the dibromide (20.80 g, 75.4 mmol) and anhydrous NaOAc (21.0 g) in
EtOAc (370 ml) and glacial HOAc (37 ml) was treated with 5% Pd/C (1.30 g) and the black suspension stirred under of H2 (1 atm) while monitoring H2 uptake. After 2.0 hours H2 uptake was complete, the mixture was filtered through Celite, the filtrate washed with saturated NaHCO3 and brine then dried over anhydrous MgS04 and evaporated to give crude dibromoester as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of the dibromide) and vacuum distilled to give 25.77 g (61.3%) of desired title bromoester as a clear oil with b.p. = 790-800C (1.0 mm Hg).
TLC (1:1) EtOAc-Hex, Rf = 0.44, PMA.
Anal Calcd for C5H903Br: C, 30.48; H, 4.60;
Br, 40.56
Found: C, 29.76; H, 4.50; Br, 39.86
(2) (S)-4-Bromo-3-[ [(1,1-dimethylethyl) diphenylsilylloxylbutanoic acid, methyl
ester
A solution of part E(1) bromohydrin (4.0 g, 20.4 mmol), imidazole (6.94 g, 5.0 eq.), and 4-dimethylamino pyridine (4-DMAP) (12 mg, 0.005 eq.) in dry DMF (40 ml) was treated with t-butyldiphenylsilyl chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture stirred overnight under argon at room temperature. The mixture was partitioned between 5% KHSO4 and EtOAc, the organic phase washed with H2O and brine, dried over anhydrous Na SO and evaporated to give 9.32 g (100%) of crude silyl ether as a clear, viscous oil. TLC (3:1) Hex-EtOAc, Rf silyl ether = 0.75, U.V. and
PMA.
(3) (S)-4-Iodo-3-[[(1,l-dimethylethyl)- diphenylsilyl] oxy]butanoic acid,
methyl ester
A solution of the crude Part E(2) bromide (9.32 g, 201 mmole) in methyl ethyl ketone (60 ml, dried over 4A sieves) was treated with sodium iodide (15.06 g, 100.5 mmole, 5.0 eq.) and the yellow suspension refluxed for 5.0 hours under argon. The mixture was cooled, diluted with EtOAc, filtered, the filtrate washed with dilute NaHSO3 (until colorless) and brine then dried over anhydrous Na2 SO4 and evaporated in vacuo to give 10.17 g of a yellow oil.The crude oil was purified by flesh chromatography on silica gel (600 g) eluting with (3:1) Hexane-CS2C12. Product fractions were combined and evaporated to give 7.691 g (74.2%, overall yield for both steps) of desired title iodide as a clear, colorless, viscous oil. TLC (3:1) Hex-EtOAc, product. Rf = 0.75, U.V.
and PMA. (Note: product iodide co-spots with starting bromide).
(4) (S)-4-(Diethoxyphosphinyl)-3-[[(1,1- dimethylethyl )diphenylsilyl) oxy] - butanoic acid, methyl ester
A solution of the iodide (7.691 g) in triethyl phosphite (20 ml) was heated at 1550C (oil bath) for 3.5 hours under argon. The mixture was cooled and excess phosphite distilled off in vacuo (0.5 mm Hg, 750C) to leave a yellow oil (~8.0 g). The crude oil was purified by flash chromatography on silica gel (400 g) eluting with (4:1) Hexane-acetone. Product fractions were evaporated to give 3.222 g (41.1%) of desired title phosphonate as a clear, colorless, viscous oil
TLC (1:1) Hex-acetone, Rf = 0.51, U.V. and PMA.
Additionally 2.519 g (61.1% corrected yield) of starting Part (3) iodide was recovered.
(5) (S)-3-[[(1,1-Dimethylethyl)diphenyl silyl ] oxy] -4-phosphonobutanoic acid,
methyl ester
A solution of the Part (4) phosphonate (9.85 g, 20.0 mmole) in dry CH2C12 (60 ml) was treated sequentially with bistrimethylsilyltrifluoroacetamide (BSTFA) (5.31 ml, 32.0 mmole, 1.6 eq.) and trimethylsilyl bromide (TMSBr) (6.60 ml 50.0 mmole, 2.5 eq.) and the clear mixture stirred overnight under argon at room temperature. 5% KHSO4 (80 ml) was added and the mixture was extracted with EtOAc. The aqueous phase was saturated with NaCl and re-extracted with EtOAc.
The combined organic layers were washed with brine, dried over anhydrous Na SO and evaporated in vacuo to give crude title phosphonic acid as a viscous oil. TLC (7:2:1) iPrOH-NH4OH-H2O, Rf = 0.30, U.V. and PMA.
(6) (S)-3-[[(1,1-Dimethylethyl)diphenyl silyl]oxy]-4-(hydroxymethoxyphosphinyl)- butanoic acid, methyl ester
Part (5) crude phosphonic acid ("'20.0 mmole) in dry pyridine (25 ml) was treated with dried
CH3OH (over 3A sieves, 1.62 ml, 40.0 mmole, 2.0 eq.) and dicyclohexyl carbodiimide (DCC) (4.54 gm, 22.0 mmole, 1.10 eq.) and the resulting white suspension stirred under argon at room temperature overnight. Pyridine was removed in vacuo, then azeotroped with benzene (2 x 15 ml). The residual oil was dissolved in EtOAc, filtered and washed with 1.0 N HC1 and brine, dried over anhydrous Na2 SO4 and evaporated in vacuo to give 8.272 g of crude title ester as an oil containing a small amount of precipitated dicyclohexyl urea (DCU).TLC (7:2:1) iPrOH-NH4-OH H20, Rf = 0.60,
U.V. and PMA.
F. (S)-4-[tt4'-Fluoro-3,3',5-trimethyl- [1,1 '-biphenyl] -2-y1]methoxyphosphinyl] - 3-t-butyldiphenylsilyloxybutanoic acid,
methyl ester
Part E crude phosphonic acid mono methyl ester (6.595 gm, "'14.7 mmole) was dissolved in dry
CH2C12 (30 ml), treated with distilled trimethylsilyldiethylamine (5.60 ml, 29.4 mmole, 2.0 eq.) and stirred under argon at room temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo.
The light yellow viscous oil was dissolved in dry
CH2Cl2 (30 ml) and DMF (dried over 4A sieves, 2 drops), the clear solution cooled to -100C (salt/ice bath) and treated dropwise via syringe with distilled oxalyl chloride (1.41 ml, 16.2 mmole, 1.1 eq.). Vigorous gas evolution was evident and the solution became deeper yellow in color. The mixture was stirred under argon at -100C for 15 minutes then allowed to stir at room temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo-to give crude phosphonochloridate as a yellow oil.
To a solution of the crude phosphonochloridate (~ 14.7 mmole) in dry CH2Cl2 (10 ml) was added dropwise a solution of the Part D biphenyl alcohol (2.06 g, 8.43 mmole) in dry pyridine (15 ml) and the resulting mixture stirred at room temperature under argon for 16 hours.
The mixture was evaporated to dryness and the residue partitioned between 5% KHSO4 and EtOAc.
The organic phase washed with saturated NaHCO3 and brine then dried over anhydrous Na2 SO4 and evaporated in vacuo to give 8.290 g of a brown oil. The crude product was purified by flash chromatography on silica gel (370 g) eluting with (70:30) Hexane-acetone. Product fractions were combined and evaporated to give 3.681 g (66%) of the desired title phosphonate as a pale yellow oil. TLC (3:2) Hexane-acetone, Rf = 0.59, U.V. and
PMA.
G. (S)-4-[[(4'-Fluoro-3,3' ,5-trimethyl- [1,1' -biphenyl]-2-y1]methoxyphosphinyl] - 3-hydroxybutanoic acid, methyl ester
A mixture of the Part F silyl ether (1.103 g, 1.66 mmole) in dry THF (20.0 ml) was treated with glacial acetic acid (380 pl, 6.64 mmole, 4.0 eq.) and a 1.0 M tetrabutylammonium fluoride solution (4.98 ml, 4.98 mmole, 3.0 eq.) and the clear yellow solution stirred overnight at room temperature under argon. The mixture was partitioned between cold H2O and EtOAc, the organic phase washed with saturated NaHCO3 and brine, dried over anhydrous Na2 SO4 and evaporated to a viscous yellow oil (1.174 g). The crude oil was purified by flash chromatography on silica gel (47 g) eluting with (85:15)
CH2C12-Acetone.Product fractions were evaporated to give 679 mg (93.1%) of desired title alcohol as a clear viscous oil. TLC (1:1) Hexane-acetone, Rf = 0.41, U.V. and PMA.
H. (S)-4-[[(4'-Fluoro-3,3' ,5-trimethyl- tlfl'-biphenyl]-2-yl]methoxy]methoxy- phosphinyl]-3-hydroxy-butanoic acid,
monolithium salt
A solution of the Part G methyl ester (184 mg, 0.420 mmole) in dioxane (5.0 ml) was treated with 1.0 N LiOH (0.50 ml, 1.2 eq.) and the mixture stirred at room temperature under argon for 3 hours. The mixture was diluted with H2O, filtered through a 0.4 pm polycarbonate membrane and evaporated in vacuo. The residue dissolved in H20 (75 ml), frozen and lyophilized. The crude acid was dissolved in a minimum amount of H2O and chromatographed on a 100 ml bed of CHP-20 resin eluting with aH2O/CH3CN linear gradient system.
Product fractions were evaporated, dissolved in
H2O (50 ml), filtered through 0.4 m polycarbonate membrane and lyophilized to give 174 mg (89.1% based on weight of hydrate) of desired title mono-lithium salt as a white solid. TLC (7:2:1) iPrOH-NH4OH-E2O, Rf = 0.58 , U.V. and PMA.
Anal Calcd for C21H25O6PFLi + 1.95 moles H20 (MW 465.46): C, 54.19; H, 6.26; F, 4.08; P. 6.65
Found: C, 54.19; H, 6.21; F, 4.29; P, 6.43 H1 NMR (400 HMz):
6 1.74-2.08 ppm (2H, m, -PO(OCH3)CH2-) 2.30 (3H, s, aromatic methyl)
2.32 (3H, d, aromatic methyl a to
fluorine, JHF2.2 Hz)
2.35-2.62 (2H, m, -CH2CO2Li) 2.46 (3H, s, aromatic methyl)
3.57 & BR<
3.63 (3H, 2 doublets, -OP(OCH3)-,
2 diastereomers, JH p= 10.3
Hz)
4.28 (lH, m, -CH2CH(OH)CH2CO2Li) 4.97
6.87-7.25 (5H, m, aromatic H's)
Example 2 (S)-4-IIC4'-Fluoro-3,3',5-trimethylll,l' biphenyl]-2-yl]methoxy]hydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt
A solution of the Example 1 diester (374 mg, 0.853 mmole) in dioxane (8.0 ml) was treated with 1.0 N LiOH (2.6 ml, 3.0 eq.) and heated at 500C (oil bath) for 5.0 hours under argon. A white precipitate was evident. The mixture was diluted with H20 and filtered. The aqueous solution was extracted once with Et2O, filtered through a 0.4 pm polycarbonate membrane and concentrated in vacuo. The crude product was chromatographed on CHP-20 resin (100 ml bed) eluting with a H20/CH3CN linear gradient system.
Product fractions were evaporated in vacuo, taken up in H2O (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 260 mg (67.1% based on hydrate weight) of desired title di-lithium salt as a white solid. TLC (7:2:1).
PrOH-NH4OH-H20, Ref=0.47, U.V. and PMA.
Anal Calcd for C2og2206pFLi2 + 1.77 moles H20: C, 52.88, H, 5.67; F, 4.18; P, 6.82
Found: C, 52.88; H, 5.26; F, 4.24; P, 6.43
H1 NMR (400 MHz, CD30D): 6 1.69 ppm
2.26-2.42 (2H, m, CE2CO2Li) 2.30 (3H, s, aromatic methyl)
2.31 (3H, d, aromatic methyl a
to F, JEF=1.9 Hz) 2.38 (3H, s, aromatic methyl) 4.22 (1H, m, -CH(OH)CH2-) 4.75 (2H, m,
6.86-7.23 (5H, m, aromatic protons)
Example 3 (3S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]2-yl]methoxy]methylphosphinyl]-3-hydroxybutanoic acid, monolithium salt
A. (S)-4-[(Chloro)methylphosphinyl]-3
[[(1,l-dimethylethyl)diphenylsilyl]oxy]
butanoic acid, methyl ester
The title phosphinochloridate compound is prepared as described in Example 6 Part B first three paragraphs.
B. (3S)-4-[[[4'-Fluoro-3,3',5-trimethyi- [1,1' -biphenyl] -2-yl]methoxy]methyl-
phosphinyl]-3-t-butyldiphenylsilyloxy- butanoic acid, methyl ester
A cooled (0 C, ice bath) solution of Part A phosphinochloridate ("'2.2 mmole) and Example 1
Part C(2) biphenyl alcohol (429 mg, 2.2 mmole, 1.0 eq) in dry CH2Cl2 (10 ml) was treated with Et3N (425 pl, 3.04 mmole, 1.4 eq) and 4-DMAP (27 mg, 0.22 mmole) and the orange solution stirred at room temperature overnight under argon. The mixture was partitioned between 5% KHSO4 and EtOAc, the organic layer washed with brine, dried over anhydrous
Na2SO4 and evaporated to give 1.1 g of an orange oil. The crude oil was purified by flash chromatography on LPS-1 silica gel (44 g) eluting with (1:1) EtOAc:Hexane.Product fractions were combined and evaporated to give 298 mg (21%) of desired coupled title product as a pale yellow oil. Also 460 mg (67% corrected yield) of starting
Example 1 Part C(2) biphenyl alcohol was recovered.
TLC (1:1) EtOAc:Hex, Rf=0.18 W and PMA.
C. (3S)-4-[[[4'-Fluoro-3,3',5-trimethyl [1,1' -biphenyl]-2-yl]methoxy]methyl- phosphinyl] -3-hydroxybutanoic acid,
methyl ester
A solution of the Part B silyl ether (298 mg, 0.46 mmole) in dry THF (6.0 ml) was treated with glacial HOAc (110 p1, 1.84 mmole, 4.0 eq) and a 1.0 M in THF solution of tetrabutylammonium fluoride (1.43 ml, 3.1 eq) and the resulting solution stirred overnight under argon at room temperature. The mixture was partitioned between cold H20 and EtOAc, the organic phase washed with saturated NaHCO3 and brine, dried over anhydrous Na2 SO4 and evaporated to a yellow oil (273 mg). The crude oil was purified by flash chromatography on LPS-1 silica gel (11 g) eluting with (3:2) Hex-acetone.Product fractions were combined and evaporated to give 150 mg (80%) of desired title alcohol as a viscous oil.
TLC (1:1) Hex:acetone, Rf=0.23, W and PMA.
D. (3S)-4-([[4'-Fluoro-3,3' ,5-trimethyl- [1,1'-biphenyl]-2-yl]methoxy]methyl
phosphinyl]-3-hydroxybutanoic acid,
monolithium salt
A solution of the Part C methyl ester (150 mg, 0.367 mmole) in dioxane (3.0 ml) was treated with 1.0 N LiOH (0.44 ml, 1.2 eq.) and the resulting white suspension was stirred at room temperature under argon for 2 hours. The mixture was diluted with H2O, filtered through a 0.4 pm polycarbonate membrane and evaporated in vacuo to a colorless glass.
The crude product was taken up in a minimum amount of H20 and chromatographed on HP-20 (100 ml bed) eluting with a H2O/CH3CN linear gradient.
Product fractions were evaporated, taken up in H2O (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 130 mg (79% based on hydrate weight) of desired title lithium salt as a white solid. TLC (8:1:1) CH2C12-CH3OH-HOAc,
Rf=0.52, UV and PMA.
Anal Calcd for C21H2505FLiP + 1.73 moles H2O (MW 445.49): C, 56.61; H, 6.44; F. 4.26; P, 6.95
Found: C, 56.67; H, 6.36; F, 4.31; P, 7.43
H1 NMR (400 MHz): 6 1.49 ppm (3H, d,
JH-P=14.7 Hz) 1.83-2.0 (2H, m,
2.27-2.40 (2H, m, cH2cO2Li) 2.30 (6H, s, 2 aromatic methyl's)
2.44 (3H, s, aromatic methyl)
4.26 (lH, m, -CH2CH(OH)CH2CO2Li) 4.87 (2H, m,
6.90-7.20 (5H, m, aromatic H's)
Example 4 (S)-4-[[[2,4-Dichloro-6-[[4-fluorophenyl)methoxy]phenyl]methoxy]methoxyphosphinyl]-3-hydroxybu @ic acid, monolithium salt
A. 2,4-Dichloro-6-(4-fluorophenylmethoxy) benzaldehyde (Ref.: J.Med Chem., 1986, 29, 167)
Absolution of 13.77 g (72.5 mmol) of 4,6-dichloro-2-hydroxybenzaldehyde in 100 ml of
DMF was stirred and 12.02 g (87 mmol) of K CO was added. This mixture was heated to "'700C for 60 minutes, then 11.7 ml of 4-fluorobenzyl bromide was added. The resulting solution was stirred at 700C for 3.5 hours, then this was poured onto ice
H20 (1.5 1), filtered and washed with H20, and recrystallized from Et2O/petroleum ether.
Yield: 17.88 g (83%) of off-white crystals, m.p.
107-1080C.
B. 2,4-Dichloro-6-[(4-fluorophenyl)
methoxy]benzemethanol
Cold (0 C, ice bath), dry Et2O (10.0 ml) was treated with LiA1H4 (158 mg, 4.16 mmole, 0.6 eq.) and the grey suspension treated dropwise with a solution of Part A aldehyde (2.06 g, 6.93 mmole) in 10 ml dry THF. The mixture was warmed to room temperature and stirred for an hour under argon. The mixture was cooled back to 0 C (ice bath) and quenched by sequential dropwise addition of H20 (160 p1), 15% NaOH (160 p1) and H2O (475 l).
Precipitated salts were removed by filtration through anhydrous Na2 SO4 over packed Celite (h" bed). The clear filtrate was evaporated to give w.052 g (98.9%) of crude alcohol as white crystals. One trituration with cold hexane afforded 1.892 g (91.2%) of pure title alcohol as a white crystalline solid with m.p. = 72-730C.
TLC (4:1) Hex-acetone, Rf=0.31, UV and
PMA.
Anal Calcd for C14HO2Cl2F (MW 301.142):
C, 55.84; H, 3.68; C1, 23.55; F, 6.31
Found: C, 55.97; H, 3.71; Cl, 23.42; F, 6.30
C. (S)-4-[[[2,4-Dichloro-6-[(4-fluoro
phenyl)methoxy]phenyl]methoxy]methoxy
phosphinyl]-3-t-butyldiphenylsilyloxy
butanoic acid, methyl ester
A solution of the Example 1 Part E(6) methyl ester ("'3.84 mmole) in dry CH2C12 (10 ml) was treated with distilled trimethylsilyl diethylamine (1.46 ml, 7.68 mmole, 2.0 eq.) and the resulting solution stirred at room temperature under argon for 1.0 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 20 ml) and dried in vacuo to give crude silylated phosphonic acid mono methyl ester as a colorless oil.
A solution of the crude ester ("'3.84 mmole) in dry CH2Cl2 (10 ml) and dry DMF (1 drop) was cooled to -10 C (salt, ice bath) and treated dropwise with distilled oxalyl chloride (368 wi, 4.22 mmole, 1.1 eq.). Gas evolution was evident from the clear yellow mixture. The mixture was stirred at room temperature under argon for one hour, evaporated in vacuo, chased with benzene (2 x 20 ml) to give crude phosphonochloridate as a viscous yellow oil.
The crude phosphonochloridate ("'3.84 mmole) in dry CH2Cl2 (10 ml) at 0 C (ice bath) was treated with Part B alcohol (1.15 g, 3.84 mmole, 1.0 eq.) followed by Et3N (805 pl, 5.76 mmole, 1.5 eq.) and 4-DMAP (47 mg, 0.384 mmole, 0.1 eq.) and the brown mixture stirred overnight at room temperature under argon. The mixture was partitioned between 5% KESO4 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2SO4 and evaporated to give 3.197 g of a dark brown oil. The crude product was purified by flash chromatography on silica gel (160 g) eluting with (7:3) Hex-EtOAc.
Product fractions were combined and evaporated to give 594 mg (21.1%) of desired title phosphonate as a yellow oil. Additionally, 688 mg (52.4% corrected yield ) of starting Part B alcohol was recovered.
TLC (1:1) Hex-acetone, Rf=0.29, UV and PMA.
D. (S)-4-! [(2,4-Dichloro-6-((4-fluoro- phenyl)methoxyZphenyl]methoxy]methoxy- phosphinyl] -3-hydroxy butanoic acid,
methyl ester
A solution of the Part C silyl ester (578 mg, 0.788 mmole) in dry TEF (8 ml) was treated with glacial HOAc (180 pl, 3.2 mmole, 4.0 eq.) followed by 1.0 M solution of n-Bu4NF in THF (2.36 ml, 2.36 mmole, 3.0 eq.) and the resulting pale yellow solution stirred overnight under argon at room temperature. The mixture was poured into cold H2O rnd extracted with EtOAc (2X). The organic phase was washed with saturated NaHCO3 and brine, dried over anhydrous Na2 SO4 and evaporated to give 625 mg of a yellow oil.The crude product was purified by flash chromatography on silica gel (31 g) eluting with (7:3) Hexane-acetone.
Product fractions were combined and evaporated to give 339 mg (86.9%) of desired title alcohol as a clear, colorless, viscous oil.
TLC (1:1) Hex-acetone, Rf = 0.25, UV and PMA.
E. (S)-4-[[[2,4-Dichloro-6-[(4-fluoro
phenyl)methoxy]phenyl]methoxy]methoxy
phosphinyl]-3-hydroxybutanoic acid,
monolithium salt
A solution of the Part D phosphonate (132 mg, 0.267 mmole) in dioxane (2.5 ml) was treated with 1.0 N LiOH (0.32 ml, 1.2 eq.) and the mixture stirred under argon at room temperature for 4.0 hours.. A white precipitate was noted. The mixture was diluted with H2O, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on HP-20 resin (100 ml bed) eluting with a H2O/CH3CN linear gradient system. Product fractions were combined and evaporated, taken up in H20, filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 108 mg (79% based on hydrate weight) of desired title lithium salt as a white solid.
TLC (20:1:1) CH2C12- CH3OH-HOAc, Rf = 0.41,
W and PMA.
Anal Calcd for C19H18O7C12F1i2P + 1.42 moles H2O (MW 511.72): C, 44.59; H, 4.10; C1, 13.86;
F, 3.71; P, 6.05
Found: C, 44.22; H, 4.09; C1, 13.91; F, 3.72;
P, 6.11
H1 NMR (400 MHz): 6 1.98-2.11 ppm (2H, m,
2.26-2.45 ppm (2H, m, -CH(OH)CH2CO2Li) 3.63 & BR<
3.62 (3H, 2 doublets, 2 diastereomers,
JHP-11 Hz)
4.23 (lH, m, (-CH2CH(OH)CH2CO2Li) 5.16 (2H, s, F-PhCH2O) 5.24 (2H, d, ArCH2OP, JHp=6.2 Hz)
7.13-7.53 (6H, m, aromatic H's)
Example 5 (3S)-4-[[[2,4-Dichloro-6-[(4-fluorophenyl)- methoxy]phenyl]methoxy]hydroxyphosphinyl]-3hydroxybutanoic acid, dilithium salt
A mixture of the Example 4 Part D diester (210 mg, 0.424 mmole) in dioxane (4.0 ml) was treated with 1.0 N LIOH (1.30 ml, 3.0 eq.) and the colorless solution heated at 500C (oil bath) under argon for 3.5 hours. A white precipitate was evident after 15 minutes. The mixture was diluted with H20, filtered and the filtrate evaporated in vacuo. The residue was dissolved in a minimum amount of H2O and chromatographed on HP-20 resin (100 ml bed) eluting with a H2O/CH3CN linear gradient. Product fractions were combined and evaporated. The residue was taken up in H20 (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 175 mg (81% based on hydrate weight) of desired title dilithium salt as a white solid.
TLC (8:1:1) CH2Cl2-CH3OH-HOAc, Rf = 0.07, W and PMA.
Anal Cacld for C18H16O7Ci2FLi2P + 1.70 moles H20 (MW 509.62): C, 42.42; H, 3.84; F, 3.73;
Cl, 13.91; P, 6.08
Found: C, 42.46; H, 3.90; F, 3.93; C1, 13.42;
P, 5.66 H1NMR (400 MHz): 6 1.73-1.92 ppm (2H, m,
2.27 (1H, dd, -CH(OH)CH2CO2Li, JHH=8.8
Hz) 2.39 (1H, dd, -CH(OH)CH2CO2Li, JHH=4.4
Hz) 4.26 (1H, m, CH2CH(OH)CH2CO2Li) 5.08 (2H, s, F-Ph-CH2OAr) 7.03-7.53 (6H, m, aromatic H's).
ExamPle 6 (3S)-4-[[2,4-Dichloro-6-[(4-fluorophenyl)methoxy] phenyl ]methoxy)methylphosphinyl]-3-hydroxybutanoic acid, methyl ester
A. (S)3-[[(l,l-Dimethylethyl)diphenylsilJ1] oxy]-4-(ethoxymethylphosphinyl)butanoic
acid, methyl ester
A mixture of the Example 1 Part E(3) iodide (4.68 g, 9.18 mmole) in methyl diethoxyphosphine (Strem Chemicals, 5.0 g, 36.7 mmole) was heated at 1000C (oil bath) for 2.5 hours, then at 1500C for three additional hours under argon. A white precipitate slowly formed in the yellow solution. Excess phosphine was distilled off in vacuo (0.5 mm Hg) and the crude product purified by flash chromatography on silica gel eluting with (65:35) Hexane-acetone. Product fractions were combined and evaporated to give 1.590 g (38%) of desired title phosphinic ester (mixture of diastereomers) as a clear viscous oil.
TLC (3:2) Hex-acetone, Rf (2 diastereomers) = 0.19 and 0.22, W and PMA.
B. (3S)-4-[[2,4-Dichloro-6-[(4-fluoro
phenyl)methoxy]phenyl]methoxy]methyl phosphinyl]-3-t-butyldiphenylsilyl- butanoic acid, methyl ester
A solution of Part A phosphinic ester (605 mg, 1.3 mmole) in dry CH2C12 (6.0 ml) was treated with bis(trimethylsilyl)trifluoroacetamide (BSTFA) (280 p1, 1.05 mmole, 0.8 eq.) and trimethylsilyl bromide (TMSBr) (210 pl, 1.57 mmole, 1.2 eq.) and the resulting solution stirred at room temperature under argon overnight. 5% KHSO4 (15 ml) was added and the mixture extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2 SO4 and evaporated in vacuo to give crude phosphinic acid as a colorless oil.
A solution of the crude phosphinic acid (s1.3 mmole) in dry CH2C12 (6.0 ml) was treated with distilled trimethylsilyl diethylamine (270 pl, 1.44 mmole, 1.1 eq.) and the clear mixture was stirred at room temperature under argon for 1.0 hour. The mixture was evaporated in vacua, chased with benzene (1 x 15 ml), and dried in vacuo.
A cooled (0 C, ice bath) solution of the crude silylated phosphinic acid (รง1.3 mmole) in dry
CH2Cl2 (6.0 ml) and DMF (1 drop) was treated dropwise via syringe with distilled oxalyl chloride (130 p1, 1.44 mmole, 1.1 eq.). Gas evolution was evident. The mixture was stirred at room temperature under argon for one hour then evaporated in vacua, chased with benzene (2 x 15 ml) and dried in vacuo to give crude phosphinochloridate as a yellow oil.
A cooled (0 , ice bath) solution of phosphinochoridate (~1.3 mmole) and Example 1 Part
E(6) alcohol (392 mg, 1.3 mmole) in dry CH2Cl2 (6.0 ml) was treated with Et3N (275 pl, 1.97 mmole, 1.5 eq.) and 4-DMAP (16 mg, 0.13 mmole, 0.1 eq) and the resulting yellow mixture stirred under argon at room temperature overnight. The mixture was partitioned between 5% KHSO4 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2SO4 and evaporated to give 908 mg of crude product as a dark yellow oil. The crude product was purified by flash chromatography on silica gel (45 g) eluting with (3:2) Hex-EtOAc.
Product fractions were combined and evaporated to give 266 mg (28.3%) of desired title product as a clear, colorless oil. Also 197 mg (57%, corrected yield) of the starting alcohol was recovered.
C. (3S)-4-t[2,4-Dichloro-6-[(4-fluoro- phenyl )methoxy)phenyl ]methoxy]methyl- phosphinyl]-3-hydroxybutanoic acid,
methyl ester
A solution of the Part B silyl ester (275 mg, 0.38 mmole) in dry THF (6.0 ml) was treated with glacial HOAc (90 pl, 1.53 mmole, 4.0 eq.) and a 1.0 M solution in TEF of tetrabutylammonium fluoride (1.2 ml, 3.1 eq.). The resulting solution was stirred overnight under argon at room temperature. The mixture was partitioned between cold H20 and EtOAc, the organic phase washed with saturated NaHCO3 and brine, dried over anhydrous Na2 SO4 and evaporated to give 258 mg of a yellow oil. The crude product was purified by flash chromatography on LPS-1 silica gel (8 g) eluting with (1:1) Hexane-acetone.Product fractions were combined and evaporated to give 142 mg (77%) of desired title alcohol as a clear, colorless, oil.
TLC (1:1) Hexane-acetone, Rf = 0.20, W and PMA.
D. (3S)-4-[ [2,4-Dichloro-6-[(4-fluoro- phenyl)methoxy]phenyl]methoxy]methyl
phosphinyl]-3-hydroxybutanoic acid,
monolithium salt ~~~~~~~~~~~~ A solution of the Part C methyl ester (142 mg, 0.296 mmole) in dioxane (3.0 ml) was treated with 1.0 N LiOH (0.36 ml, 1.2 eq.) and the resulting white suspension stirred under argon at room temperature for 2.0 hours. The mixture was diluted with H2O, filtered through a 0.4 ijm polycarbonate membrane and the filtrate evaporated in vacuo;
The crude product was dissolved in a minimum amount of H20 and chromatographed on a 100 ml bed of HP-20 resin eluting with a H2O/CH3CN linear gradient. Product fractions were combined and evaporated.The residue was taken up in H2O, filtered through a polycarbonate membrane and lyophilized to give 93 mg (63% based on hydrate weight) of desired title lithium salt as a white solid.
TLC (8:1:1) CH2C12- CH30H-HOAc, Rf = 0.51, W and
PMA.
Anal Calcd for C19H19O7Cl2Flip + 1.38 moles H2O (MW 495.94): C, 46.01; H, 4.42; F, 3.83; C1, 14.30;
P, 6.24
Found: C, 46.10; H, 4.49; F, 3.82; Cl, 14.32;
P, 6.43
H1 NMR (400 MHz): a 1.53 ppm (3H, d,
JH-P 14.6 Hz) 1.87-2.10 (2H, m,
2.27 (1H, dd, -CH(OH)CH2CO2Li, JH-H=8.4 Hz, JH-P=1.1 Hz)
2.38 (1H, dd, -CH(OH)CH2CO2Li,
JH-H=4.7 Hz, JH-P=1.1 Hz)
4.29 (1H, m, -CF2CH(OH)CH2CO2Li)
5.16+5.18 (4H, m, ArCH2OP and F-PhCH2O)-)
7.11-7.52 (6H, m, aromatic)
Example 7 (S)-4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl2-yl]methyl]amino]methoxyphosphinyl]-3-hydroxybutanoic acid, monolithium salt
A. 4'-Fluoro-3,3',5-trimethyl[l,l'- biphenyll-2-carboxylic acid
A solution of the Example 1 Part C(2) aldehyde (1.0 g, 4.13 mmole) in acetone (10.0 ml) at 0 C (ice bath) was treated dropwise with 8.0 N Jones reagent (4.1 ml, excess) and the resulting brown-green suspension stirred overnight under argon at room temperature. Excess oxidant was destroyed by adding isopropanol (10.0 ml) and precipitated chromium salts removed by filtration through a h" pad of Celite. The filtrate was evaporated, taken up in EtOAc, washed with 1.0 N
HCl (2X), saturated NH4Cl (2X) and brine, then dried over anhydrous Na2 SO4 and evaporated to give 1.011 g of a green solid with m.p. 153-1540C.
The crude acid was purified via the dicyclohexylamine salt. To a solution of the crude acid in EtOAc (5.0 ml) was added dicyclohexyl amine (DCHA) (823 pl, 1.0 eq.). The solution diluted with hexane and precipitated crystalline salt was collected to give 997 mg (55% from aldehyde, m.p. 181-183 C) of desired product as an off-white crystalline DCHA salt.
The title free acid was regenerated from the DOHA salt by partitioning the salt between 5%
KHSO4 and EtOAc. The organic phase was washed with brine, dried over anhydrous Na2 SO4 and evaporated in vacuo to give 554 mg (52% from aldehyde) of desired title acid.
TLC (9:1) CH2C12-CH3OH, Rf=0.37, W and PMA.
B. 4'-Fluoro-3,3',5-trimethyl[l,l'- biphenyl 1 -2-carboxamide A suspension of the Part A acid (554 mg, 2.14 mmole) in dry CH2C12 (6.0 ml) and dry DMF (1 drop) at 0 C (ice bath) was treated dropwise via syringe with distilled oxalyl chloride (205 p1, 2.35 mmole, 1.1 eq.) and the clear yellow solution stirred under argon at room temperature for one hour. The mixture was evaporated in vacuo, chased with benzene (2X) and dried in vacuo to give crude acid chloride as a yellow oil.
A cooled (0 C, ice bath) mixture of THF (3.0 ml) and concentrated NH4OH (2.0 ml, excess) was treated dropwise with a THF solution (3.0 ml) of the crude acid chloride and the bright orange solution stirred at room temperature under argon for 1.0 hour. The mixture was partitioned between H20 and EtOAc, the organic phase washed with saturated NaHCO3, H2O and brine, then dried over anhydrous Na2SO4 and evaporated to give 528 mg (96.1%) of crude amrde as a light orange solid. One recrystallization from EtOAc-hexane afforded 435 mg (79.1%) of purified title amide as pale yellow needles with m.p. 197-1980C. TLC (1:1)
Et20-Acetone Rf=0.83, W and PMA.
C. 4Z-Fluoro-3,3',5-trimethyl[1,1'- biphenyl]-2-methanamine
A cooled (0 C, ice bath) solution of dry
THF (5.0 ml) was treated with solid LiAlH4 (125 mg, 3.3 mmole) and the gray suspension treated dropwise over five minutes with a solution of-the Part B amide (424 mg, 1.65 mmole) in ThF (5.0 ml).
The resulting suspension was stirred at room temperature under argon for 2.5 hours, then refluxed for 45 minutes. The mixture was cooled to 0 C (ice bath) and quenched by sequential dropwise addition of 125 pl H20, 125 p1 of 15% NaOH and 375 pl H2O Precipitated aluminum salts were removed by filtration through anhydrous Na2 SO4 over packed
Celite. The clear filtrate was evaporated in vacuo to give the crude amine as a clear oil.
TLC (7;3) Et2O-acetone, Rf=3.60, W and PMA. The amine was purified as the HCl salt.
A solution of the crude amine (~1.65 mmole) in absolute EtOH (8.0 ml) was treated with concentrated HC1 (152 pl, 1.82 mmole) and the mixture stirred for 15 minutes at room temperature under argon. The mixture was evaporated in vacuo to a white crystalline solid.
The solid was triturated with cold Et2O, collected by filtration and dried in vacuo to give 426 mg (92.4%) of title amine-HCl as fine white crystals.
D. (S)-4-[[[[4'-Fluoro-3,3',5-trimethyl [1,1' -biphenyl] -2-yl]methyl] amino] -
methoxyphosphinyl] -3-t-butyldiphenyl- silyloxy butanoic acid, methyl ester
A solution of Example 1 Part E(6) methyl ester ("'2.0 mmole) in dry CH2C12 (5.0 ml) was treated with distilled trimethylsilyl diethylamine (758 pl, 4.0 mmole, 2.0 eq.) and the clear mixture stirred at room temperature under argon for one hour. The mixture was evaporated in vacuo, chased with benzene (l x 15 ml) and dried in vacuo.
A cooled (OOC) solution of the crude silyl phosphonate in dry CH2Cl2 (7.0 ml) and DMF (1 drop) was treated dropwise with distilled oxalyl chloride (192 pl, 2.2 mmole, 1.1 eq.). Gas evolution was evident from the clear yellow mixture. The solution was stirred at room temperature for one hour, evaporated in vacuo, chased with benzene (2 x 15 ml), and dried in vacuo to give the crude phosphonochloridate as a yellow, viscous oil.
A cooled (OOC) solution of the phosphonochloridate and Part C biphenyl amine HCl (416 mg, .1.49 mmole) in dry CH2C12 (10 ml) was treated with Et3N (641 pl, 4.6 mmole, 2.3 eq.) and 4-DMAP (24 mg, 0.2 mmole, 0.1 eq.) and the clear yellow mixture stirred overnight at room temperature under argon. The mixture was partitioned between 5% KHSO4 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2 SO4 and evaporated in vacuo to give 1.19 g of a yellow oil. The crude product was purified by flash chromatography on silica gel (60 g) eluting with (7:3) hexane-acetone.
Product fractions were evaporated to give 588 mg (59.5%) of desired title phosphonamide as a pale yellow, viscous oil.
TLC (7:3) Hexane-acetone, Ref=0.20, W and PMA.
E. (S)-4-[[[[4'.-Fluoro-3,3',5-trimethyl- [l,1'-biphenyl)-2-yl]methyl]amino]
methoxyphosphinyl ] -3 -hydroxybutanoic acid, methyl ester
A solution of Part D silyl ether (588 mg, 0.888 mmole) in dry THF (10.0 ml) was treated with glacial HOAc (203 p1, 3.55 mmole, 4.0 eq.) and a 1.0 M solution in ThF of tetrabutylammonium fluoride (2.66 ml, 2.66 mmole, 3.0 eq.) and the resulting solution stirred overnight under argon at room temperature. The mixture was poured into cold H2O and extracted with EtOAc. The organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2 SO4 and evaporated in vacuo to give 605 mg of an orange oil.The crude product was purified by flash chromatography on silica gel (36 g) eluting with (1:1) Hexaneacetone. Product fractions were combined and evaporated to give 196 mg (50.4%) of desired title alcohol as a light orange oil.
TLC (1:1) Hexane-acetone, Rf=0.16, W and PMA.
F. (S)-4-[[[[4'-Fluoro-3,3',5trimethyl- [l,1'-biphenyl]-2-yl]methyl]amino]- methoxyphosphinyl]-3-hydroxybutanoic
acid, monolithium salt
A solution of the Part E diester (105 mg, 0.240 mmole) in dioxane (2.0 ml) was treated with 1.0 N LiOH (288 pl, 1.2 eq.) and the white suspension stirred under argon at room temperature for 4.0 hours. The mixture was diluted with H2O, filtered, the filtrate evaporated in vacuo. The residue was chromatographed on HP-20 (100 ml bed) resin eluting with a H2O/CH3CN linear gradient.
Product fractions were combined and evaporated.
The residue was taken up in H20 (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 70 mg (62.7% based on weight of hydrate) of desired title lithium salt as a white solid.
TLC (20:1:1) CH2Cl2-CH3OH-HOAc, Rf=0.19, W and
PMA.
Anal Calcd for C21H26NO5PFLi + 2.41 moles H2O (MW 472.75): C, 53.35; H, 6.57; N, 2.96; F, 4.02;
P, 6.55
Found: C, 53.35; H, 6.52; N, 2.98; F, 4.05;
P, 6.59
H1 NMR (400 MHz): 6 1.79-1.97 ppm (2H, m,
2.26-2.44 ppm (2H, m, -CH2CO2Li
2.29 (3H, s, aromatic methyl)
2.31 (3H, d, aromatic methyl a
to fluorine, JHF=1.4 Hz)
2.47 (3H, aromatic methyl)
3.46 & BR<
3.50 (3H, 2 doublets, 2
diastereomers, Jew=10.5 Hz) 3.96 (2H, m,
4.17 (1H, m, (-CH2CH(oH)CH2CO2Li) 6.84-i.21 (5H, m, aromatic protons)
Examples 8 to 20
Following the procedures as outlined heretofore and as described in the previous working Examples, the following additional compounds may be prepared.
Ex. No. ~~~~~~ R Z n X RX 8. OH (0 0CN2 c, 1 O H c1 3 9. 5 CHy 2 NH CH3 CH3 Cl 10. C 3H7 G z 1 0 Li C1 < C2H5 11. CH30 CH2- l 2 NH H 3 12. OH t 2 0 H oQ 0 13. C4H90 > CH2- 1 0 Li (CH 25
Ex. No. R Z n X R 14. C5Hll 1 NH > CE2 CH 15. OK C H -CE 2 0 OK I CIO H stCH3 CH3 16. ONa POH2 2 0 H (FCH3 17. CH30 FCH2 -0 1 NH H * CH3 HO H
Ex. x No. R Z n X R C2H5-C-c-O 2 5, v 11 1 0 H 18. CH3 C/ 1 O H 3 3 CH3 OH. 19. HO S 2 0 Li 01 20. Cm30 < 1 NH H C
Example 21 (S )-4-Diisopropyloxyphosphinyl )-3- [[(1, 1-dimethyl- ethyl)diphenylsilyl] oxy] -butanoic acid, methyl ester
The Example 1 Part E(3) iodide (45.1 mmol., 21.70 g) was stirred under high vacuum for 30 minutes. Freshly distilled triisopropyl phosphite (0.451 mol., 93.92 g, 113.37 ml.) was added in one portion and the reaction mixuture was stirred under argon and heated in a 1550C oil bath for 16.5 hours. The mixture was then cooled to room temperature. Excess triisopropyl phosphite and volatile reaction products were removed by short path distillation (10 mm Hg) followed by Kugelrohr distillation (0.50 mm Hg, 1000C, 8 hours).The product was further purified via flash chromatography (95 mm diam. column, 6"/Merck silica gel, 6/3/1 Hexane/acetone/toluene eluent, 2"/min flow rate, 50 ml fractions) to afford 17.68 g (33.96 mmol, 75% yield) of the title isopropylphosphonate as a clear viscous oil.
TLC: Silica gel Rf=0.32 (6:3:1 Hexane/acetone
toluene) 1HNMR: (270 MHz, CDC13) 8 7.70-7.65 (m,4H)
7.45-7.35 (m,6H)
4.57-4.44 (m,3H)
3.59 (s,3H)
2.94 and 2.88 (2xd, 1H J=3.7 Hz)
2.65 and 2.60 (2xd, 1H J=7.4 Hz)
2.24-1.87 (Series of m, 2H)
1.19 and 1.12 (2xd, 12H J=6.3 Hz)
1.01 (s, 9H)
Example 22
S)-4-(Hydroxymethoxyphosphinyl)-3- [[(1,1-dimethyl- ethyl )diphenylsiiyl )oxy]butanoic acid, methyl ester, dicyclohexylamine (1::1) salt
The Example 21 isopropyl phosphonate (30.5 mmol, 10.66 g) was stirred under argon, at room temperature, in 80 ml of dry CH2Cl2. This solution was treated dropwise (5 min) with bistrimethylsilyltrifluoroacetamide (BSTFA) (32.8 mmol, 8.44 g, 8.71 ml), followed by dropwise addition (10 min) of trimethylsilylbromide (TMSBr) (51.3 mmol, 7.84 g, 6.75 ml). After stirring at room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% aqueous KHSO4 and stirred vigorously for 15 minutes. The aqueous layer was extracted 3 times with ethylacetate. The organic extracts were combined, washed once with brine, dried over Na2SO4 and concentrated in vacuo. The residue was azeotroped 2 times with 50 ml of toluene. The precipitate which formed was suspended in toluene and filtered.The filtrate was concentrated and the azeotrope/filter process repeated. The resulting filtrate was evaporated in vacuo and then pumped under high vacuum for 5 hours. The resulting viscous clear oil was stirred under argon, at room temperature, in 50 ml of dry pyridine. This solution was treated in one portion with dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g), followed by addition of methanol (41.0 mmol, 1.31 g, 1.67 ml). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a celite pad in a sintered glass funnel.
The celite was washed with ethyl acetate and the combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed 2 times with 5% aqueous KHSO4 and once with brine. The organic extract was dried over Na2SO4, filtered, the filtrate concentrated and azeotroped 2 times with toluene, suspended in toluene and filtered. The resulting filtrate was again concentrated, azeotroped, filtered and the filtrate evaporated in vacuo and placed under high vacuum for 6 hours to afford the phosphonate monoester as a clear viscous oil (10.2 g, > 100% yield).TLC: silica gel Rf=0.50 (7:2:1 nPrOH/NH40H/H2O). The phosphonate monoester [1.21 g was pumped under high vacuum for 4 hours, affording 1.16 g (2.57 mmol)] was dissolved in 10 ml of dry ethyl ether and treated dropwise with dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml).
The resulting homogeneous solution sat at room temperature for 7 hours resulting in significant crystal formation. The mixture was stored at -200C for 16 hours and then warmed to room temperature and filtered. The crystals were washed with cold, dry ethyl ether and then pumped under high vacuum over P205 for 18 hours. The crystals were subsequently pumped under high vacuum at 450C for 4 hours, affording 1.25g (1.98 mmol, 77% yield) of the title dicyclohexylamine salt as a white powdery solid, m.p. 155-1560C.
TLC: Silica gel Ref=0.57 (20% MeOH/CH2C12) 'H NMR: (270 MH2, CDC13) 6 7.71-7.65 (m, 4H)
7.40-7.32 (m, 6H)
4.02 (m, 1H)
3.52 (s, 3H)
3.28 and 3.22 (m, 1H)
3.11 (d, 3H J=11 Hz)
2.77-2.64 (m, 2H)
2.62-2.56 (m, 1H) 1.92-1.08 (Series of m, 22H)
1.00 (S, 9H) Mass Spec: (FAB) 632 (M & ) IR:(KBr) 3466-3457 (broad) 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 820 CM-1
Anal Calcd for C22R31 O6PSi.C12H23N:
C,64.63; H,8.61; N,2.22
Found: C, 64.51; H, 8.49; N, 2.18
Claims (2)
- CLAIMS 1. A compound having the structurewherein Ra is lower alkyl or lower alkoxy, including all stereoisomers thereof.
- 2. A compound having the structurewherein Ra is lower alkyl or OH, including all stereoisomers thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US5328187A | 1987-05-22 | 1987-05-22 | |
US10968087A | 1987-10-19 | 1987-10-19 | |
GB8811929A GB2205837B (en) | 1987-05-22 | 1988-05-20 | Phosphorus-containing hmg-coa reductase inhibitors |
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Publication Number | Publication Date |
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GB9020929D0 GB9020929D0 (en) | 1990-11-07 |
GB2235924A true GB2235924A (en) | 1991-03-20 |
GB2235924B GB2235924B (en) | 1991-11-20 |
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GB9020929A Expired - Fee Related GB2235924B (en) | 1987-05-22 | 1990-09-26 | Phosphorus-containing hmg-coa reductase inhibitors,new intermediates and method |
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GB (1) | GB2235924B (en) |
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1990
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GB2235924B (en) | 1991-11-20 |
GB9020929D0 (en) | 1990-11-07 |
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