NO310683B1 - 3-pyrazol-karboksamid-derivater med cannabinoid reseptor- affinitet, anvendelse derav, farmasöytisk preparat, samtfremgangsmåte for fremstilling - Google Patents

Info

Publication number

NO310683B1

NO310683B1 NO19982589A NO982589A NO310683B1 NO 310683 B1 NO310683 B1 NO 310683B1 NO 19982589 A NO19982589 A NO 19982589A NO 982589 A NO982589 A NO 982589A NO 310683 B1 NO310683 B1 NO 310683B1

Authority

NO

Norway

Prior art keywords

formula

compound

compounds

hydrogen

pyrazole

Prior art date

1995-12-08

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• 238000000034 method Methods 0.000 title claims description 137
• 238000002360 preparation method Methods 0.000 title claims description 20
• 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
• BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical class NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 title description 27
• 102000018208 Cannabinoid Receptor Human genes 0.000 title description 9
• 108050007331 Cannabinoid receptor Proteins 0.000 title description 9
• 150000001875 compounds Chemical class 0.000 claims description 485
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 243
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 111
• 239000002904 solvent Substances 0.000 claims description 95
• 229910052739 hydrogen Inorganic materials 0.000 claims description 63
• 239000001257 hydrogen Substances 0.000 claims description 63
• 150000003839 salts Chemical class 0.000 claims description 51
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
• -1 1,3,3-trimethylbicyclo-[2,2,1]hept- 2-yl residue Chemical group 0.000 claims description 30
• 125000000217 alkyl group Chemical group 0.000 claims description 28
• KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical class OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 claims description 27
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 150000002367 halogens Chemical class 0.000 claims description 22
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 21
• 239000004480 active ingredient Substances 0.000 claims description 21
• 239000002253 acid Substances 0.000 claims description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
• 238000006243 chemical reaction Methods 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
• 238000011282 treatment Methods 0.000 claims description 15
• 238000010992 reflux Methods 0.000 claims description 14
• 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 claims description 12
• 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 claims description 12
• 150000002431 hydrogen Chemical class 0.000 claims description 12
• 125000001424 substituent group Chemical group 0.000 claims description 12
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 201000010099 disease Diseases 0.000 claims description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 150000001450 anions Chemical class 0.000 claims description 4
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• 125000003118 aryl group Chemical group 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
• 239000005977 Ethylene Substances 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 230000003301 hydrolyzing effect Effects 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
• 239000000243 solution Substances 0.000 description 208
• 239000000543 intermediate Substances 0.000 description 195
• 239000000047 product Substances 0.000 description 186
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
• 239000000203 mixture Substances 0.000 description 138
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 120
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 117
• 239000011541 reaction mixture Substances 0.000 description 102
• 229910001868 water Inorganic materials 0.000 description 100
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 93
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
• 239000012074 organic phase Substances 0.000 description 63
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 55
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 50
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 47
• 239000003480 eluent Substances 0.000 description 47
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 46
• 239000002244 precipitate Substances 0.000 description 45
• 239000000377 silicon dioxide Substances 0.000 description 45
• 239000011734 sodium Substances 0.000 description 44
• 229910000104 sodium hydride Inorganic materials 0.000 description 38
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 36
• 239000012312 sodium hydride Substances 0.000 description 36
• 238000005481 NMR spectroscopy Methods 0.000 description 35
• 239000006185 dispersion Substances 0.000 description 34
• 229920006395 saturated elastomer Polymers 0.000 description 34
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 32
• 238000001816 cooling Methods 0.000 description 31
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• 239000000706 filtrate Substances 0.000 description 26
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
• 239000000725 suspension Substances 0.000 description 23
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 18
• 239000002198 insoluble material Substances 0.000 description 17
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 16
• 239000007853 buffer solution Substances 0.000 description 16
• 239000000460 chlorine Substances 0.000 description 16
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• 230000000694 effects Effects 0.000 description 15
• 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 13
• WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 13
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• 239000005457 ice water Substances 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• 229910052708 sodium Inorganic materials 0.000 description 10
• 239000011780 sodium chloride Substances 0.000 description 10
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 159000000000 sodium salts Chemical class 0.000 description 9
• XLWSBDFQAJXCQX-UHFFFAOYSA-N 4-(bromomethyl)-1,2-dichlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1Cl XLWSBDFQAJXCQX-UHFFFAOYSA-N 0.000 description 8
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
• 150000008064 anhydrides Chemical class 0.000 description 8
• 238000002425 crystallisation Methods 0.000 description 8
• 230000008025 crystallization Effects 0.000 description 8
• 230000007062 hydrolysis Effects 0.000 description 8
• 238000006460 hydrolysis reaction Methods 0.000 description 8
• 239000008346 aqueous phase Substances 0.000 description 7
• 229940121376 cannabinoid receptor agonist Drugs 0.000 description 7
• 239000003537 cannabinoid receptor agonist Substances 0.000 description 7
• 238000010908 decantation Methods 0.000 description 7
• 150000003217 pyrazoles Chemical class 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
• PXEODPDCEHMCKE-UHFFFAOYSA-N 2-chloro-4-(iodomethyl)-1-methylbenzene Chemical compound CC1=CC=C(CI)C=C1Cl PXEODPDCEHMCKE-UHFFFAOYSA-N 0.000 description 6
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
• RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
• 229910052801 chlorine Inorganic materials 0.000 description 6
• 239000012442 inert solvent Substances 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
• WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 description 5
• IRSVDHPYXFLLDS-UHFFFAOYSA-N 2,4-dichloro-1-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1Cl IRSVDHPYXFLLDS-UHFFFAOYSA-N 0.000 description 5
• YNZFFALZMRAPHQ-SYYKKAFVSA-N 2-[(1r,2r,5r)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol Chemical compound OC1=CC(C(C)(C)CCCCCC)=CC=C1[C@H]1[C@H](CCCO)CC[C@@H](O)C1 YNZFFALZMRAPHQ-SYYKKAFVSA-N 0.000 description 5
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
• HQVHOQAKMCMIIM-HXUWFJFHSA-N WIN 55212-2 Chemical compound C([C@@H]1COC=2C=CC=C3C(C(=O)C=4C5=CC=CC=C5C=CC=4)=C(N1C3=2)C)N1CCOCC1 HQVHOQAKMCMIIM-HXUWFJFHSA-N 0.000 description 5
• 235000019445 benzyl alcohol Nutrition 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 210000004027 cell Anatomy 0.000 description 5
• 239000003153 chemical reaction reagent Substances 0.000 description 5
• 238000001035 drying Methods 0.000 description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
• 102000005962 receptors Human genes 0.000 description 5
• 108020003175 receptors Proteins 0.000 description 5
• OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• 229920000858 Cyclodextrin Polymers 0.000 description 4
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
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• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
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• 239000012298 atmosphere Substances 0.000 description 4
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• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
• 150000002148 esters Chemical class 0.000 description 4
• 239000007903 gelatin capsule Substances 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• 229910052744 lithium Inorganic materials 0.000 description 4
• 239000012299 nitrogen atmosphere Substances 0.000 description 4
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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• 125000006239 protecting group Chemical group 0.000 description 4
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• ZBEIEMMSBLROPG-UHFFFAOYSA-N 1-bromo-5-chloro-2,3-dihydro-1h-indene Chemical compound ClC1=CC=C2C(Br)CCC2=C1 ZBEIEMMSBLROPG-UHFFFAOYSA-N 0.000 description 3
• HUAAXEGWVZBZHR-UHFFFAOYSA-N 2,2,6,6-tetramethylcyclohexan-1-amine Chemical compound CC1(C)CCCC(C)(C)C1N HUAAXEGWVZBZHR-UHFFFAOYSA-N 0.000 description 3
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
• JTMYLQKKQFLIGV-UHFFFAOYSA-N 2-chloro-4-(chloromethyl)-1-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1Cl JTMYLQKKQFLIGV-UHFFFAOYSA-N 0.000 description 3
• BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
• OCJBMQKQAOSSKM-UHFFFAOYSA-N 4-(bromomethyl)-1H-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1CBr OCJBMQKQAOSSKM-UHFFFAOYSA-N 0.000 description 3
• YOACSNDETIDTAY-UHFFFAOYSA-N 4-(bromomethyl)-2-fluoro-1-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1F YOACSNDETIDTAY-UHFFFAOYSA-N 0.000 description 3
• 101710187022 Cannabinoid receptor 2 Proteins 0.000 description 3
• 102100036214 Cannabinoid receptor 2 Human genes 0.000 description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
• 241000282412 Homo Species 0.000 description 3
• 102000043136 MAP kinase family Human genes 0.000 description 3
• 108091054455 MAP kinase family Proteins 0.000 description 3
• 101100229907 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) GPP2 gene Proteins 0.000 description 3
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
• 229910052783 alkali metal Inorganic materials 0.000 description 3
• 229910052794 bromium Inorganic materials 0.000 description 3
• 125000001309 chloro group Chemical group Cl* 0.000 description 3
• 238000007796 conventional method Methods 0.000 description 3
• 238000010828 elution Methods 0.000 description 3
• 238000001914 filtration Methods 0.000 description 3
• 150000004678 hydrides Chemical class 0.000 description 3
• 239000013067 intermediate product Substances 0.000 description 3
• 229910003002 lithium salt Inorganic materials 0.000 description 3
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• 210000004698 lymphocyte Anatomy 0.000 description 3
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• 235000019341 magnesium sulphate Nutrition 0.000 description 3
• 238000002844 melting Methods 0.000 description 3
• 230000008018 melting Effects 0.000 description 3
• 229910052759 nickel Inorganic materials 0.000 description 3
• 229910052757 nitrogen Inorganic materials 0.000 description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 description 3
• 230000020477 pH reduction Effects 0.000 description 3
• 230000002093 peripheral effect Effects 0.000 description 3
• 229920001223 polyethylene glycol Polymers 0.000 description 3
• 238000002953 preparative HPLC Methods 0.000 description 3
• 239000012047 saturated solution Substances 0.000 description 3
• 239000000741 silica gel Substances 0.000 description 3
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• IAIHUHQCLTYTSF-OYNCUSHFSA-N (1s,3r,4r)-2,2,4-trimethylbicyclo[2.2.1]heptan-3-ol Chemical compound C1C[C@@]2(C)[C@@H](O)C(C)(C)[C@@H]1C2 IAIHUHQCLTYTSF-OYNCUSHFSA-N 0.000 description 2
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
• YYPPFEKHXPADAV-UHFFFAOYSA-N 1-(bromomethyl)-4-ethylbenzene Chemical compound CCC1=CC=C(CBr)C=C1 YYPPFEKHXPADAV-UHFFFAOYSA-N 0.000 description 2
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