CS271481B2 - Method of new tetrazole compounds production - Google Patents

Info

Publication number

CS271481B2

CS271481B2 CS881180A CS118088A CS271481B2 CS 271481 B2 CS271481 B2 CS 271481B2 CS 881180 A CS881180 A CS 881180A CS 118088 A CS118088 A CS 118088A CS 271481 B2 CS271481 B2 CS 271481B2

Authority

CS

Czechoslovakia

Prior art keywords

tetrazol

formula

fluorophenyl

methyl

mmol

Prior art date

1987-02-25

Links

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• Global Dossier
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• -1 tetrazole compounds Chemical class 0.000 title claims description 122
• 238000000034 method Methods 0.000 title claims description 75
• 238000004519 manufacturing process Methods 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 298
• 238000006243 chemical reaction Methods 0.000 claims description 80
• 125000004432 carbon atom Chemical group C* 0.000 claims description 55
• 230000002829 reductive effect Effects 0.000 claims description 55
• 125000000217 alkyl group Chemical group 0.000 claims description 45
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
• 239000003960 organic solvent Substances 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 150000001768 cations Chemical group 0.000 claims description 18
• 150000003839 salts Chemical class 0.000 claims description 16
• 125000004185 ester group Chemical group 0.000 claims description 14
• 239000007858 starting material Substances 0.000 claims description 14
• 125000005843 halogen group Chemical group 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• 230000008569 process Effects 0.000 claims description 13
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
• 231100000252 nontoxic Toxicity 0.000 claims description 9
• 230000003000 nontoxic effect Effects 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
• 230000007062 hydrolysis Effects 0.000 claims description 6
• 238000006460 hydrolysis reaction Methods 0.000 claims description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
• 150000001718 carbodiimides Chemical class 0.000 claims description 3
• 125000000686 lactone group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 497
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 431
• 239000000243 solution Substances 0.000 description 287
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 232
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 218
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 198
• 229910052739 hydrogen Inorganic materials 0.000 description 188
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
• 239000000203 mixture Substances 0.000 description 159
• 229910052799 carbon Inorganic materials 0.000 description 155
• 229910052757 nitrogen Inorganic materials 0.000 description 128
• 238000005160 1H NMR spectroscopy Methods 0.000 description 122
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 122
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 108
• 239000011541 reaction mixture Substances 0.000 description 99
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 95
• 238000004458 analytical method Methods 0.000 description 95
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 90
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 87
• 239000000047 product Substances 0.000 description 78
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 72
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 67
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• 238000001819 mass spectrum Methods 0.000 description 57
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 51
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 47
• 235000019341 magnesium sulphate Nutrition 0.000 description 47
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
• 239000002904 solvent Substances 0.000 description 43
• 239000003480 eluent Substances 0.000 description 42
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
• 239000012044 organic layer Substances 0.000 description 40
• 238000003756 stirring Methods 0.000 description 40
• 239000007787 solid Substances 0.000 description 39
• 239000000741 silica gel Substances 0.000 description 37
• 229910002027 silica gel Inorganic materials 0.000 description 37
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 36
• 150000001299 aldehydes Chemical class 0.000 description 34
• 238000010898 silica gel chromatography Methods 0.000 description 34
• 239000000725 suspension Substances 0.000 description 33
• 239000010410 layer Substances 0.000 description 30
• 238000002844 melting Methods 0.000 description 30
• 230000008018 melting Effects 0.000 description 30
• 238000010992 reflux Methods 0.000 description 28
• 238000004587 chromatography analysis Methods 0.000 description 26
• 239000000284 extract Substances 0.000 description 26
• 239000001257 hydrogen Substances 0.000 description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 26
• 238000004809 thin layer chromatography Methods 0.000 description 26
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• 229910052786 argon Inorganic materials 0.000 description 22
• 239000011734 sodium Substances 0.000 description 21
• 239000002253 acid Substances 0.000 description 20
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
• 239000012279 sodium borohydride Substances 0.000 description 20
• 229910000033 sodium borohydride Inorganic materials 0.000 description 20
• 238000012360 testing method Methods 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 19
• 150000002431 hydrogen Chemical class 0.000 description 19
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
• 230000015572 biosynthetic process Effects 0.000 description 18
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 18
• 235000012000 cholesterol Nutrition 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 16
• 238000001816 cooling Methods 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• 229910052708 sodium Inorganic materials 0.000 description 16
• 239000012312 sodium hydride Substances 0.000 description 16
• 229910000104 sodium hydride Inorganic materials 0.000 description 16
• 229910052938 sodium sulfate Inorganic materials 0.000 description 16
• 235000011152 sodium sulphate Nutrition 0.000 description 16
• CQCAYWAIRTVXIY-UHFFFAOYSA-N 2-(triphenyl-$l^{5}-phosphanylidene)acetaldehyde Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC=O)C1=CC=CC=C1 CQCAYWAIRTVXIY-UHFFFAOYSA-N 0.000 description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
• 150000002596 lactones Chemical group 0.000 description 15
• 230000009467 reduction Effects 0.000 description 15
• LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 15
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
• 239000003153 chemical reaction reagent Substances 0.000 description 13
• 239000006185 dispersion Substances 0.000 description 13
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• 238000002425 crystallisation Methods 0.000 description 12
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
• 239000000463 material Substances 0.000 description 12
• HWHNFJYQDMSYAF-UHFFFAOYSA-N 1,5-dimethyltetrazole Chemical compound CC1=NN=NN1C HWHNFJYQDMSYAF-UHFFFAOYSA-N 0.000 description 11
• 238000005481 NMR spectroscopy Methods 0.000 description 11
• 230000008025 crystallization Effects 0.000 description 11
• 238000000354 decomposition reaction Methods 0.000 description 11
• 150000002148 esters Chemical class 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• 230000005764 inhibitory process Effects 0.000 description 11
• 239000002480 mineral oil Substances 0.000 description 11
• 235000010446 mineral oil Nutrition 0.000 description 11
• 239000012074 organic phase Substances 0.000 description 11
• XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 10
• 239000012965 benzophenone Substances 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
• LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 10
• 238000001953 recrystallisation Methods 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 239000012300 argon atmosphere Substances 0.000 description 9
• 239000000460 chlorine Substances 0.000 description 9
• 229910052731 fluorine Inorganic materials 0.000 description 9
• WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
• 239000000843 powder Substances 0.000 description 9
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
• 102000004190 Enzymes Human genes 0.000 description 8
• 108090000790 Enzymes Proteins 0.000 description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 8
• 241000700159 Rattus Species 0.000 description 8
• 229930182558 Sterol Natural products 0.000 description 8
• XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 8
• 239000001569 carbon dioxide Substances 0.000 description 8
• 229910002092 carbon dioxide Inorganic materials 0.000 description 8
• 238000004440 column chromatography Methods 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 239000011737 fluorine Substances 0.000 description 8
• 239000011343 solid material Substances 0.000 description 8
• 150000003432 sterols Chemical class 0.000 description 8
• 235000003702 sterols Nutrition 0.000 description 8
• 239000000126 substance Substances 0.000 description 8
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
• 241001465754 Metazoa Species 0.000 description 7
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
• 150000001298 alcohols Chemical class 0.000 description 7
• 239000012298 atmosphere Substances 0.000 description 7
• 238000007796 conventional method Methods 0.000 description 7
• 239000013256 coordination polymer Substances 0.000 description 7
• 239000013078 crystal Substances 0.000 description 7
• 238000003818 flash chromatography Methods 0.000 description 7
• 239000006260 foam Substances 0.000 description 7
• 239000000543 intermediate Substances 0.000 description 7
• 210000004185 liver Anatomy 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 6
• HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 6
• NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• 230000029936 alkylation Effects 0.000 description 6
• 238000005804 alkylation reaction Methods 0.000 description 6
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
• 238000012435 analytical chromatography Methods 0.000 description 6
• 239000007864 aqueous solution Substances 0.000 description 6
• 150000008366 benzophenones Chemical class 0.000 description 6
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
• 239000003795 chemical substances by application Substances 0.000 description 6
• 229910052801 chlorine Inorganic materials 0.000 description 6
• 229910052736 halogen Inorganic materials 0.000 description 6
• 150000002367 halogens Chemical class 0.000 description 6
• 238000010438 heat treatment Methods 0.000 description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• 239000011368 organic material Substances 0.000 description 6
• 238000000926 separation method Methods 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 5
• IBZBXKKSBMPSJO-UHFFFAOYSA-N 3,3-bis(4-fluorophenyl)-2-(1-methyltetrazol-5-yl)prop-2-enal Chemical compound CN1N=NN=C1C(C=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 IBZBXKKSBMPSJO-UHFFFAOYSA-N 0.000 description 5
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
• 208000031226 Hyperlipidaemia Diseases 0.000 description 5
• PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 5
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
• 239000004480 active ingredient Substances 0.000 description 5
• 150000001336 alkenes Chemical class 0.000 description 5
• 239000008346 aqueous phase Substances 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
• 239000003638 chemical reducing agent Substances 0.000 description 5
• 239000013058 crude material Substances 0.000 description 5
• 238000010828 elution Methods 0.000 description 5
• 238000001704 evaporation Methods 0.000 description 5
• 230000008020 evaporation Effects 0.000 description 5
• 239000012456 homogeneous solution Substances 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• 230000002401 inhibitory effect Effects 0.000 description 5
• 238000002955 isolation Methods 0.000 description 5
• 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 5
• 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 5
• 239000000155 melt Substances 0.000 description 5
• VZWNYVYPLLHODU-UHFFFAOYSA-N nona-6,8-dienoic acid Chemical compound OC(=O)CCCCC=CC=C VZWNYVYPLLHODU-UHFFFAOYSA-N 0.000 description 5
• 239000008194 pharmaceutical composition Substances 0.000 description 5
• 229910052700 potassium Inorganic materials 0.000 description 5
• CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 5
• 159000000000 sodium salts Chemical class 0.000 description 5
• 238000001228 spectrum Methods 0.000 description 5
• 125000001424 substituent group Chemical group 0.000 description 5
• 238000003786 synthesis reaction Methods 0.000 description 5
• 239000006188 syrup Substances 0.000 description 5
• 235000020357 syrup Nutrition 0.000 description 5
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
• 239000008096 xylene Substances 0.000 description 5
• CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 4
• FGNHBDHQAUDQCH-UHFFFAOYSA-N (4-fluorophenyl) 6-(2-ethyltetrazol-5-yl)-3,5-dihydroxyhept-6-enoate Chemical compound FC1=CC=C(C=C1)OC(CC(CC(C(=C)C=1N=NN(N=1)CC)O)O)=O FGNHBDHQAUDQCH-UHFFFAOYSA-N 0.000 description 4
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 4
• OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
• HZFRQMOECFLXIV-UHFFFAOYSA-N 5,5-bis(4-fluorophenyl)-4-(1-methyltetrazol-5-yl)penta-2,4-dienal Chemical compound CN1N=NN=C1C(C=CC=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 HZFRQMOECFLXIV-UHFFFAOYSA-N 0.000 description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
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• NTDIRNUKAZNMSW-STYNFMPRSA-M sodium;(3r,5s)-9,9-bis(4-fluorophenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound [Na+].CN1N=NN=C1C(C=C[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 NTDIRNUKAZNMSW-STYNFMPRSA-M 0.000 description 1
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• 230000002269 spontaneous effect Effects 0.000 description 1
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• 238000010561 standard procedure Methods 0.000 description 1
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• 239000000758 substrate Substances 0.000 description 1
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• RCWOYGUJLXGCOP-UHFFFAOYSA-N tert-butyl 9,9-bis(2-fluoro-4-methylphenyl)-3,5-dihydroxy-8-(1-methyltetrazol-5-yl)nona-6,8-dienoate Chemical compound FC1=CC(C)=CC=C1C(C=1C(=CC(C)=CC=1)F)=C(C=CC(O)CC(O)CC(=O)OC(C)(C)C)C1=NN=NN1C RCWOYGUJLXGCOP-UHFFFAOYSA-N 0.000 description 1
• LWGWDKMHPJJYAD-UHFFFAOYSA-N tert-butyl 9,9-bis(2-fluoro-4-methylphenyl)-5-hydroxy-8-(1-methyltetrazol-5-yl)-3-oxonona-6,8-dienoate Chemical compound FC1=CC(C)=CC=C1C(C=1C(=CC(C)=CC=1)F)=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)C1=NN=NN1C LWGWDKMHPJJYAD-UHFFFAOYSA-N 0.000 description 1
• IGUIXAMGBRYHBV-UHFFFAOYSA-N tert-butyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1-methyltetrazol-5-yl)-3-oxonona-6,8-dienoate Chemical compound CN1N=NN=C1C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 IGUIXAMGBRYHBV-UHFFFAOYSA-N 0.000 description 1
• RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
• YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
• CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
• 150000003536 tetrazoles Chemical class 0.000 description 1
• 230000001225 therapeutic effect Effects 0.000 description 1
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• 125000003944 tolyl group Chemical group 0.000 description 1
• 125000005270 trialkylamine group Chemical group 0.000 description 1
• 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
• FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
• CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
• 229910052722 tritium Inorganic materials 0.000 description 1
• 229910052721 tungsten Inorganic materials 0.000 description 1
• JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
• 210000002700 urine Anatomy 0.000 description 1
• 229920002554 vinyl polymer Polymers 0.000 description 1
• 238000010792 warming Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1