NO853254L - Fremgangsmaate for fremstilling av (4s)-6-fluor-spiro-(kroman-4,4`-imidazolidin)-2`,5`-dion eller (2r) metylderivatet derav. - Google Patents
Fremgangsmaate for fremstilling av (4s)-6-fluor-spiro-(kroman-4,4`-imidazolidin)-2`,5`-dion eller (2r) metylderivatet derav.Info
- Publication number
- NO853254L NO853254L NO853254A NO853254A NO853254L NO 853254 L NO853254 L NO 853254L NO 853254 A NO853254 A NO 853254A NO 853254 A NO853254 A NO 853254A NO 853254 L NO853254 L NO 853254L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- methyl
- spiro
- fluoro
- amino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title description 13
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 title 1
- -1 spiroalkylated azlactone compound Chemical class 0.000 claims abstract description 53
- 239000002253 acid Substances 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 20
- 150000002148 esters Chemical class 0.000 claims abstract description 17
- 239000002585 base Substances 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 10
- LXANPKRCLVQAOG-NSHDSACASA-N sorbinil Chemical compound C12=CC(F)=CC=C2OCC[C@@]21NC(=O)NC2=O LXANPKRCLVQAOG-NSHDSACASA-N 0.000 claims abstract description 10
- 108010027597 alpha-chymotrypsin Proteins 0.000 claims abstract description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 8
- 230000000694 effects Effects 0.000 claims abstract description 8
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims abstract description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 7
- 230000018044 dehydration Effects 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 238000005830 amidoalkylation reaction Methods 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 239000007858 starting material Substances 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 12
- 239000012433 hydrogen halide Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 238000012546 transfer Methods 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 8
- 238000003776 cleavage reaction Methods 0.000 claims description 8
- 230000007017 scission Effects 0.000 claims description 8
- IFJLLYGZXTWBJC-TZRNXQDGSA-N (2r)-4-amino-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylic acid Chemical compound FC1=CC=C2O[C@H](C)CC(N)(C(O)=O)C2=C1 IFJLLYGZXTWBJC-TZRNXQDGSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- GCWCVCCEIQXUQU-UHFFFAOYSA-N alpha-hydroxyhippuric acid Chemical compound OC(=O)C(O)NC(=O)C1=CC=CC=C1 GCWCVCCEIQXUQU-UHFFFAOYSA-N 0.000 claims description 6
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical group [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 claims description 4
- IAPBWJGRISENFI-UTMOJQEPSA-N (2r)-4-amino-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylic acid;hydrochloride Chemical compound Cl.FC1=CC=C2O[C@H](C)CC(N)(C(O)=O)C2=C1 IAPBWJGRISENFI-UTMOJQEPSA-N 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- FATKFOJBJPZZED-UHFFFAOYSA-N 4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylic acid Chemical compound C1=C(F)C=C2C(N)(C(O)=O)CCOC2=C1 FATKFOJBJPZZED-UHFFFAOYSA-N 0.000 claims 1
- WVQYSVLMDHXHOV-UHFFFAOYSA-N 6-fluoro-3,4-dihydro-2h-chromen-4-amine Chemical compound C1=C(F)C=C2C(N)CCOC2=C1 WVQYSVLMDHXHOV-UHFFFAOYSA-N 0.000 claims 1
- HHMAXMUHVFLYEI-LBPRGKRZSA-N ethyl (4S)-4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2[C@@](C(=O)OCC)(N)CCOC2=C1 HHMAXMUHVFLYEI-LBPRGKRZSA-N 0.000 claims 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 abstract description 10
- DTDIIZMYQOKQSO-UHFFFAOYSA-N 4-methyl-2-oxo-1,3-dihydropyrido[1,2-a]pyrimidin-5-ium-4-carboxylate Chemical compound C1=CC=CN2C(C)(C(O)=O)CC(=O)N=C21 DTDIIZMYQOKQSO-UHFFFAOYSA-N 0.000 abstract description 10
- 229950004311 sorbinil Drugs 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 5
- SEAQTHCVAGBRFY-INWYIAFRSA-N (2r,4s)-6-fluoro-2-methylspiro[2,3-dihydrochromene-4,5'-imidazolidine]-2',4'-dione Chemical compound C([C@H](OC1=CC=C(F)C=C11)C)[C@@]21NC(=O)NC2=O SEAQTHCVAGBRFY-INWYIAFRSA-N 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 230000001684 chronic effect Effects 0.000 abstract description 2
- 208000002249 Diabetes Complications Diseases 0.000 abstract 1
- 206010012655 Diabetic complications Diseases 0.000 abstract 1
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 49
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 239000010410 layer Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- SWBBIJZMIGAZHW-UHFFFAOYSA-N 6-fluoro-2,3-dihydrochromen-4-one Chemical compound O1CCC(=O)C2=CC(F)=CC=C21 SWBBIJZMIGAZHW-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000002274 desiccant Substances 0.000 description 8
- 239000012362 glacial acetic acid Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- ICRFTBHKBZHNBZ-NSHDSACASA-N methyl (4s)-4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2[C@@](C(=O)OC)(N)CCOC2=C1 ICRFTBHKBZHNBZ-NSHDSACASA-N 0.000 description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 6
- 150000003512 tertiary amines Chemical class 0.000 description 6
- 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 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- BGIJXHNCUBTVDQ-KRTXAFLBSA-N methyl (2r,4s)-4-amino-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2[C@@](C(=O)OC)(N)C[C@@H](C)OC2=C1 BGIJXHNCUBTVDQ-KRTXAFLBSA-N 0.000 description 5
- ICRFTBHKBZHNBZ-UHFFFAOYSA-N methyl 4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)(N)CCOC2=C1 ICRFTBHKBZHNBZ-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000012044 organic layer 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
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- DBEYNBHRSXVDML-ZJGHLTBISA-N (2r)-4-(carbamoylamino)-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylic acid Chemical compound FC1=CC=C2O[C@H](C)CC(NC(N)=O)(C(O)=O)C2=C1 DBEYNBHRSXVDML-ZJGHLTBISA-N 0.000 description 3
- DBEYNBHRSXVDML-INWYIAFRSA-N (2r,4s)-4-(carbamoylamino)-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylic acid Chemical class FC1=CC=C2O[C@H](C)C[C@@](NC(N)=O)(C(O)=O)C2=C1 DBEYNBHRSXVDML-INWYIAFRSA-N 0.000 description 3
- QAHZIGHCEBUNGT-QMGFNSACSA-N (5r,6s,7s,8r,9r)-6,7,8-trihydroxy-9-(hydroxymethyl)-1,3-diazaspiro[4.5]decane-2,4-dione Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)C[C@]11C(=O)NC(=O)N1 QAHZIGHCEBUNGT-QMGFNSACSA-N 0.000 description 3
- JXSPKRUNMHMICQ-UHFFFAOYSA-N 1-(2-bromoethoxy)-4-fluorobenzene Chemical compound FC1=CC=C(OCCBr)C=C1 JXSPKRUNMHMICQ-UHFFFAOYSA-N 0.000 description 3
- PNXWJPITIBTSLJ-UHFFFAOYSA-N 1-(2-chloroethoxy)-4-fluorobenzene Chemical compound FC1=CC=C(OCCCl)C=C1 PNXWJPITIBTSLJ-UHFFFAOYSA-N 0.000 description 3
- VEJVMXDLMISMQY-UHFFFAOYSA-N 1-fluoro-4-(2-iodoethoxy)benzene Chemical compound FC1=CC=C(OCCI)C=C1 VEJVMXDLMISMQY-UHFFFAOYSA-N 0.000 description 3
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- NIXWJKXCCFECGN-UHFFFAOYSA-N 4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylic acid;hydrochloride Chemical compound Cl.C1=C(F)C=C2C(N)(C(O)=O)CCOC2=C1 NIXWJKXCCFECGN-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 235000012501 ammonium carbonate Nutrition 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- NMITXSPJSHCLIK-SSDOTTSWSA-N 1-[(2r)-1-bromopropan-2-yl]oxy-4-fluorobenzene Chemical compound BrC[C@@H](C)OC1=CC=C(F)C=C1 NMITXSPJSHCLIK-SSDOTTSWSA-N 0.000 description 2
- KMSVANWURMHBAC-UHFFFAOYSA-N 2-acetamido-2-hydroxyacetic acid Chemical compound CC(=O)NC(O)C(O)=O KMSVANWURMHBAC-UHFFFAOYSA-N 0.000 description 2
- PHNLPIKGAKYXOX-UHFFFAOYSA-N 2-benzamido-2-[2-(2-bromoethoxy)-5-fluorophenyl]acetic acid Chemical compound C(C1=CC=CC=C1)(=O)NC(C1=C(C=CC(=C1)F)OCCBr)C(=O)O PHNLPIKGAKYXOX-UHFFFAOYSA-N 0.000 description 2
- FYWDUQCSMYWUHV-UHFFFAOYSA-N 3-chloro-5-hydroxypentan-2-one Chemical compound CC(=O)C(Cl)CCO FYWDUQCSMYWUHV-UHFFFAOYSA-N 0.000 description 2
- PLFOGGJHQOVQAF-UHFFFAOYSA-N 4-(carbamoylamino)-6-fluoro-2,3-dihydrochromene-4-carboxylic acid Chemical compound C1=C(F)C=C2C(NC(=O)N)(C(O)=O)CCOC2=C1 PLFOGGJHQOVQAF-UHFFFAOYSA-N 0.000 description 2
- REPDIIJXIFGHIO-UHFFFAOYSA-N 4-acetamido-6-fluoro-2,3-dihydrochromene-4-carboxylic acid Chemical compound C1=C(F)C=C2C(NC(=O)C)(C(O)=O)CCOC2=C1 REPDIIJXIFGHIO-UHFFFAOYSA-N 0.000 description 2
- RPAIBTVEPAACRP-UHFFFAOYSA-N 6-fluoro-2-methyl-2,3-dihydrochromen-4-one Chemical compound FC1=CC=C2OC(C)CC(=O)C2=C1 RPAIBTVEPAACRP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
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- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
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- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- IGMKHLRKJOTJCQ-UHLUBPPHSA-N methyl (2r,4s)-4-(carbamoylamino)-6-fluoro-2-methyl-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2[C@@](C(=O)OC)(NC(N)=O)C[C@@H](C)OC2=C1 IGMKHLRKJOTJCQ-UHLUBPPHSA-N 0.000 description 1
- IYGDYBHXXNMSHY-LBPRGKRZSA-N methyl (4s)-4-(carbamoylamino)-6-fluoro-2,3-dihydrochromene-4-carboxylate Chemical compound C1=C(F)C=C2[C@@](C(=O)OC)(NC(N)=O)CCOC2=C1 IYGDYBHXXNMSHY-LBPRGKRZSA-N 0.000 description 1
- MWYQEQGGDBAVQA-UHFFFAOYSA-N methyl 4-amino-6-fluoro-2,3-dihydrochromene-4-carboxylate;hydrochloride Chemical compound Cl.C1=C(F)C=C2C(C(=O)OC)(N)CCOC2=C1 MWYQEQGGDBAVQA-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 1
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- 150000002825 nitriles Chemical class 0.000 description 1
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- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910000601 superalloy Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/74—Benzo[b]pyrans, hydrogenated in the carbocyclic ring
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Pyrane Compounds (AREA)
- Orthopedics, Nursing, And Contraception (AREA)
- Pens And Brushes (AREA)
- Coloring (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Cosmetics (AREA)
- Compounds Of Unknown Constitution (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US64200884A | 1984-08-20 | 1984-08-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO853254L true NO853254L (no) | 1986-02-21 |
Family
ID=24574782
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853254A NO853254L (no) | 1984-08-20 | 1985-08-19 | Fremgangsmaate for fremstilling av (4s)-6-fluor-spiro-(kroman-4,4`-imidazolidin)-2`,5`-dion eller (2r) metylderivatet derav. |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4716113A (ja) |
| EP (1) | EP0172719B1 (ja) |
| JP (2) | JPS6157588A (ja) |
| KR (1) | KR870000628B1 (ja) |
| AT (1) | ATE37371T1 (ja) |
| AU (1) | AU556793B2 (ja) |
| DD (2) | DD240207A5 (ja) |
| DE (1) | DE3565105D1 (ja) |
| DK (1) | DK374985A (ja) |
| EG (1) | EG17060A (ja) |
| ES (1) | ES8700259A1 (ja) |
| FI (1) | FI853183L (ja) |
| GR (1) | GR851993B (ja) |
| HU (3) | HU201042B (ja) |
| IL (1) | IL76131A (ja) |
| NO (1) | NO853254L (ja) |
| NZ (1) | NZ213128A (ja) |
| PH (1) | PH26782A (ja) |
| PL (2) | PL148572B1 (ja) |
| PT (1) | PT80985B (ja) |
| YU (1) | YU43879B (ja) |
| ZA (1) | ZA856267B (ja) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4952694A (en) * | 1988-07-27 | 1990-08-28 | Pfizer Inc. | Novel resolution process for racemic spiro-hydantoins |
| US5006657A (en) * | 1988-07-27 | 1991-04-09 | Pfizer Inc. | Intermediates in a resolution process for racemic spiro hydantoins |
| US5151544A (en) * | 1990-05-25 | 1992-09-29 | Alcon Laboratories, Inc. | Intermediates in the preparation of chiral spirofluorenehydantoins |
| US5206367A (en) * | 1992-02-18 | 1993-04-27 | Pfizer Inc. | Preparation of optically active spiro-hydantoins |
| US5508466A (en) * | 1994-04-13 | 1996-04-16 | G.D. Searle & Co. | Synthesis of N-protected-α-substituted-glycine racemic esters by zinc-mediated addition of organic halide to glycine cation equivalent |
| EP2957556B1 (en) * | 2013-02-12 | 2020-01-15 | Osaka University | Aromatic amino acid derivative and positron emission tomography (pet) probe using the same |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3878043A (en) * | 1973-01-02 | 1975-04-15 | Univ Southern Illinois | Method for preparing L-dopa and novels compounds useful therein |
| DE2336718A1 (de) * | 1973-07-19 | 1975-02-06 | Basf Ag | Verfahren zur herstellung von substituierten oxazolinon-(5)-verbindungen |
| US4117230A (en) * | 1976-10-18 | 1978-09-26 | Pfizer Inc. | Hydantoin derivatives as therapeutic agents |
| US4130714A (en) * | 1977-05-23 | 1978-12-19 | Pfizer Inc. | Hydantoin therapeutic agents |
| DE2807286A1 (de) * | 1978-02-21 | 1979-08-23 | Bayer Ag | Stereoselektive spaltung von phenylglycinderivaten und 4-hydroxyphenylglycinderivaten mit enzymharzen |
| US4267342A (en) * | 1978-08-21 | 1981-05-12 | Pfizer Inc. | Spiro-oxazolidindiones |
| US4262092A (en) * | 1979-05-08 | 1981-04-14 | Ethyl Corporation | Process for producing N-acyl-D-phenylalanine ester |
| DE2927535A1 (de) * | 1979-07-07 | 1981-01-08 | Bayer Ag | Stereoselektive spaltung von phenylglycinderivaten mit enzymharzen |
| DE2927534A1 (de) * | 1979-07-07 | 1981-01-08 | Bayer Ag | Optisch reine heterocyclische aminosaeuren, verfahren zu ihrer herstellung und ihre verwendung |
| US4248882A (en) * | 1980-02-12 | 1981-02-03 | Pfizer Inc. | Treating diabetes-associated complications with hydantoin amines |
| JPS5745185A (en) * | 1980-07-21 | 1982-03-13 | Eisai Co Ltd | Hydantoin derivative and its preparation |
| GB2098212B (en) * | 1981-05-12 | 1984-11-14 | Ici Plc | Process for preparing 1'-substituted-spiro(imidazolidine)-4,3'-indoline-2,2',5-triones |
| US4435578A (en) * | 1982-11-10 | 1984-03-06 | Pfizer Inc. | Sorbinil by optical resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid |
| US4474967A (en) * | 1983-04-27 | 1984-10-02 | Pfizer Inc. | 8-Deutero and 8-tritio-substituted derivatives of D-4S-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione |
| US4464380A (en) * | 1983-05-25 | 1984-08-07 | Pfizer Inc. | Imidazolidinedione derivatives |
-
1985
- 1985-08-13 EP EP85305724A patent/EP0172719B1/en not_active Expired
- 1985-08-13 AT AT85305724T patent/ATE37371T1/de not_active IP Right Cessation
- 1985-08-13 DE DE8585305724T patent/DE3565105D1/de not_active Expired
- 1985-08-16 GR GR851993A patent/GR851993B/el unknown
- 1985-08-16 JP JP60180396A patent/JPS6157588A/ja active Granted
- 1985-08-16 NZ NZ213128A patent/NZ213128A/en unknown
- 1985-08-17 HU HU864033A patent/HU201042B/hu not_active IP Right Cessation
- 1985-08-17 HU HU87630A patent/HU194857B/hu not_active IP Right Cessation
- 1985-08-17 HU HU853185A patent/HU193127B/hu not_active IP Right Cessation
- 1985-08-19 ZA ZA856267A patent/ZA856267B/xx unknown
- 1985-08-19 YU YU1319/85A patent/YU43879B/xx unknown
- 1985-08-19 KR KR1019850005969A patent/KR870000628B1/ko not_active IP Right Cessation
- 1985-08-19 DK DK374985A patent/DK374985A/da not_active Application Discontinuation
- 1985-08-19 EG EG516/85A patent/EG17060A/xx active
- 1985-08-19 PL PL1985255065A patent/PL148572B1/pl unknown
- 1985-08-19 IL IL76131A patent/IL76131A/xx unknown
- 1985-08-19 PL PL1985260564A patent/PL147253B1/pl unknown
- 1985-08-19 DD DD85279813A patent/DD240207A5/de not_active IP Right Cessation
- 1985-08-19 PT PT80985A patent/PT80985B/pt not_active IP Right Cessation
- 1985-08-19 AU AU46414/85A patent/AU556793B2/en not_active Ceased
- 1985-08-19 NO NO853254A patent/NO853254L/no unknown
- 1985-08-19 FI FI853183A patent/FI853183L/fi not_active Application Discontinuation
- 1985-08-19 DD DD85295403A patent/DD254005A5/de not_active IP Right Cessation
- 1985-08-20 PH PH32670A patent/PH26782A/en unknown
- 1985-08-20 ES ES546294A patent/ES8700259A1/es not_active Expired
-
1986
- 1986-03-31 US US06/846,383 patent/US4716113A/en not_active Expired - Lifetime
-
1988
- 1988-04-26 JP JP63103727A patent/JPS63290873A/ja active Pending
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