GB2131422A - Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones - Google Patents
Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones Download PDFInfo
- Publication number
- GB2131422A GB2131422A GB08317146A GB8317146A GB2131422A GB 2131422 A GB2131422 A GB 2131422A GB 08317146 A GB08317146 A GB 08317146A GB 8317146 A GB8317146 A GB 8317146A GB 2131422 A GB2131422 A GB 2131422A
- Authority
- GB
- United Kingdom
- Prior art keywords
- dione
- oxazolidine
- hydrogen
- product
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000002218 hypoglycaemic effect Effects 0.000 title abstract description 17
- 239000000543 intermediate Substances 0.000 title abstract description 15
- -1 5-substituted oxazolidine-2,4-diones Chemical class 0.000 title description 43
- 239000001257 hydrogen Substances 0.000 claims abstract description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 22
- 229910052760 oxygen Chemical group 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000001301 oxygen Chemical group 0.000 claims abstract description 12
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 12
- 239000011593 sulfur Substances 0.000 claims abstract description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 7
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 19
- 150000002431 hydrogen Chemical class 0.000 claims abstract 9
- 125000001589 carboacyl group Chemical group 0.000 claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 abstract description 2
- 150000002367 halogens Chemical group 0.000 abstract description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 369
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 249
- 239000000047 product Substances 0.000 description 233
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 223
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 181
- 239000003921 oil Substances 0.000 description 143
- 235000019198 oils Nutrition 0.000 description 143
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 135
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 132
- 239000011541 reaction mixture Substances 0.000 description 127
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 117
- 229940093499 ethyl acetate Drugs 0.000 description 115
- 235000019439 ethyl acetate Nutrition 0.000 description 115
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 113
- 238000000034 method Methods 0.000 description 113
- COWNFYYYZFRNOY-UHFFFAOYSA-N oxazolidinedione Chemical compound O=C1COC(=O)N1 COWNFYYYZFRNOY-UHFFFAOYSA-N 0.000 description 111
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 110
- 239000000203 mixture Substances 0.000 description 94
- 238000002360 preparation method Methods 0.000 description 91
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 77
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 67
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 58
- 239000007787 solid Substances 0.000 description 52
- 239000000243 solution Substances 0.000 description 49
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 46
- 239000012267 brine Substances 0.000 description 44
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 41
- 229960000583 acetic acid Drugs 0.000 description 39
- 239000000284 extract Substances 0.000 description 37
- 238000001914 filtration Methods 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- 239000002253 acid Substances 0.000 description 29
- 150000003839 salts Chemical class 0.000 description 29
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 239000010410 layer Substances 0.000 description 27
- 238000001953 recrystallisation Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 22
- 238000004458 analytical method Methods 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 22
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 22
- 239000012043 crude product Substances 0.000 description 21
- 238000001704 evaporation Methods 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 150000001299 aldehydes Chemical class 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 150000001477 2,4-oxazolidinediones Chemical class 0.000 description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- 238000012544 monitoring process Methods 0.000 description 16
- 229910052708 sodium Inorganic materials 0.000 description 16
- 238000001665 trituration Methods 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 15
- 239000008280 blood Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 239000002243 precursor Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
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- 239000008346 aqueous phase Substances 0.000 description 11
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- 239000005457 ice water Substances 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- ZIIHZVKHFWOENY-UHFFFAOYSA-N 5,5-dihydroxy-1,3-diazinane-2,4,6-trione Chemical compound OC1(O)C(=O)NC(=O)NC1=O ZIIHZVKHFWOENY-UHFFFAOYSA-N 0.000 description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
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- DWYFUJJWTRPARQ-UHFFFAOYSA-N phenyl(thiophen-2-yl)methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CS1 DWYFUJJWTRPARQ-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- 230000001376 precipitating effect Effects 0.000 description 1
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- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- AAZYNPCMLRQUHI-UHFFFAOYSA-N propan-2-one;2-propan-2-yloxypropane Chemical compound CC(C)=O.CC(C)OC(C)C AAZYNPCMLRQUHI-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
- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 description 1
- MGESDDNXOPAKNI-UHFFFAOYSA-N propyl 4-propoxythiophene-3-carboxylate Chemical compound CCCOC(=O)C1=CSC=C1OCCC MGESDDNXOPAKNI-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- OVYWMEWYEJLIER-UHFFFAOYSA-N quinolin-6-ol Chemical compound N1=CC=CC2=CC(O)=CC=C21 OVYWMEWYEJLIER-UHFFFAOYSA-N 0.000 description 1
- XCRPPAPDRUBKRJ-UHFFFAOYSA-N quinolin-7-ol Chemical compound C1=CC=NC2=CC(O)=CC=C21 XCRPPAPDRUBKRJ-UHFFFAOYSA-N 0.000 description 1
- JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 1
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- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PURPVYFQAABQLY-UHFFFAOYSA-N sodium;5-thiophen-3-yl-1,3-oxazolidine-2,4-dione Chemical compound [Na].O1C(=O)NC(=O)C1C1=CSC=C1 PURPVYFQAABQLY-UHFFFAOYSA-N 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
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- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
- C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
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- 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
A compound of the formula <IMAGE> wherein R<4> is hydrogen, lower alkanoyl or benzoyl and R<1> is <IMAGE> wherein R' is (C1-C4)alkyl or phenyl, R'' is hydrogen, (C1-C4)alkyl or phenyl and X is halo; <IMAGE> wherein Y is hydrogen or (C1-C3)alkoxy, Y' is hydrogen or (C1-C3)alkyl and Y'' is hydrogen or halo; <IMAGE> wherein Z' is hydrogen, halo or (C1-C3)alkoxy and Z'' is hydrogen or halo; <IMAGE> wherein W is hydrogen or halo, and n is 1 or 2; <IMAGE> wherein Q is sulfur or oxygen and V is hydrogen or (C1-C3)alkyl; <IMAGE> wherein Q is sulfur or oxygen; and V is hydrogen or (C1-C3)alkyl; or <IMAGE> wherein Y is sulfur or oxygen; X is hydrogen, halogen, methyl, phenyl, benzoyl or (C1-C3)alkoxy; X<1> is hydrogen or methyl; and X<2> is hydrogen or halo. The compounds are intermediates for certain hypoglycemic compounds.
Description
1 GB 2 131 422 A 1
SPECIFICATION Intermediates for hypoglycemic 5-substituted oxazolidine-2, 4-diones
This application is a divisional from UK application No. 8122524 filed 22. 07.8 1.
The present invention relates to certain 5-furyl, 5-thienyl, 5-chromanyl, 2,3 dihydrobenzo[b]furanyi, 5-pyridyl, 5-quinoly], 5-pyrrolyl, 5-indolyl, 5- thiazoly], 5-oxazolyl, 5-1sothiazolyl 5 and 5-isoxazoly] derivatives of oxazolidine-2,4-dione having utility as hypoglycemic agents.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g., chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g., phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in a high percentage 10 of diabetics where available synthetic hypoglycemic agents are not effective, requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild,abnormalities in blood glucose to coma, or even death, Where effective, a synthetic hypoglycemic agent is preferred over insulin, being more convenient to 15 administer and less prone to cause severe hypoglycemic reactions. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been 20 reported to possess this type of activity, as reviewed recently by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part 11, John Wiley and Sons, N.Y. 1979), pp. 1057-10801.
The oxazolidine-2,4-diones of the present invention are novel compounds; this in spite of the fact that the oxazolidine-2,4-diones are broadly known as a class of compounds [for an extensive review, see Clark-Lewis, Chem. Rev. 58, pp. 63-99 (1958)1. Among the compounds known in this class are 25 5-phenyloxazolidine-2,4-dione, variously reported as an intermediate to certain beta-lactam antibacterial agents (Sheehan, U.S. Patent 2,721,197), as an antidepressant agent (Plotnikoff, U.S.
Patent 3,699,229) and as an anticonvulsant agent [Brink and Freeman, J. Neuro. Chem. 19 (7), pp.
1783-1788 (1972)1; a number of 5-phenyloxazolidine-2,4-diones substituted on the phenyl ring, e.g., 5-(4-methoxyphenyl)oxazolidine-2,4-dione [King and Clark-Lewis, J. Chem. Soc., pp. 3077- 30 3079 (1 96M, 5-(4-chiorophenyi)oxazolidine-2,4-dione [Najer et aL, Bull. soc. chim. France, pp.
1226-1230 (1961)1, 5-(4-m ethyl phenyl)oxazol idi ne-2,4-dio ne [Reibsomer et aL, J. Am. Chem. Soc.
61, pp. 3491-3493 (1939)1, and 5-(4-aminophenyi)oxazolidine-2,4-dione (German Patent 108,026); and 5-(2-pyrryi)oxazolidine-2,4-dione [Ciamacian and Silber, Gazz. chim. ital. 16, 357 (1886); Ber. 19, 1708-1714 (1886)1. The last-named compound, having no prior known utility, shows only relatively 35 weak hypoglycemic activity (videpost, Table 1).
Oxazolicline-2,4-dione and substituted oxazolidine-2,4-diones (specifically, the 5methyl and 5,5 dimethyl derivatives) have been reported as acid moieties suitable for forming acid-addition salts with the hypoglycemic, basic biguanides (Shapiro and Freedman, U.S. Patent 2, 961,377). We have determined that neither oxazolidine-2,4-dione itself, nor 5,5- dimethyloxazoiidine-2,4-dione possess 40 the hypoglycemic activity of the compounds of the present invention.
Recently, a group of spiro-oxazolidine-2,4-dione derivatives have been reported which are aldose - reductase inhibitors, thus finding utility in the treatment of certain complications of diabetes (Schnur, U.S. Patent 4,200,642).
A process for the synthesis of 3-aryloxazolidine-2,4-diones (wherein said aryl group is 6 to 12 45 carbon atoms, unsubstituted or substituted with one or more halogen atoms, methyl or methoxy) is the subject of another recent U.S. Patent (Schoiz, U.S. 4,220,787). The utility of these compounds is not specified.
The present invention is concerned with compounds of the formula 0, 0 1 RL 5 4 3 IR 50 wherein R is hydrogen, (Cl-c,)-alkanoyl (e.g., formyl, acetyl, isobutyryl), benzoyi, (C,--C4)-carbalkoxy (e.g., carbomethoxy, carbethoxy, carbisopropoxy), (C,-C,)-alkylcarbamoyl (e.g., N-m ethyl ca rba moy], Npropylcarbarnoyl), (C5-CI,)-cycloalkylearbamoyl (e.g., Wcyclohexylcarbarnoyl) or di-(C1-C3)- dialkylcarbamoyl (e.g., N,N-dimethylcarbarnoyl); and R' is:
2 GB 2 131 422 A 2 (a) CY p o or xl AI At A.
wherein R' 'S W,-C4)alkyl or phenyl, W' is hydrogen, (Cl-C4)alkyl or phenyl and X is halo (fluoro, chloro, bromo or iodo); these formulae are intended to encompass 2- or 3-pyrrolyl and indoly] derivatives, with substituents as specified; Y9 (b) Y:ll 1 p 5 tIy wherein Y is hydrogen or (C,-C3)aRoxy, Y' is hydrogen or (Cl-C3)alkyl and Y' is hydrogen or halo; z z (C) Z) or Z)MN wherein Z' is hydrogen, halo or (Cl-C3)alkoxy and Z" is hydrogen or halo; (d) r W 1.9707 2)n wherein W is hydrogen or halo, and n is 1 or 2; these formula are intended to encompass 6- or 7-halo8-chromanyl or 5- or 6-halo-7-benzofuranyl derivatives; v Q (e) or wherein Q is sulfur or oxygen and V is hydrogen or (Cl-C3)alkyl; or v 01- wherein Q is sulfur or oxygen; and V is hydrogen or (Cl-C3)alkyl; these formula are intended to 15 encompass 3-, 4- and 5-isothiazolyl and isoxazolyl derivatives; (f) X 2 (g) or 6 7 Y wherein Y is sulfur or oxygen; X is hydrogen, fluoro, chloro, bromo, iodo, methyl, phenyl, benzoyl or (Cl-C3)alkoxy; X' is hydrogen or methyl; and X' is hydrogen, fluoro, chloro, bromo or iodo; when X' is hydrogen, the first formula is intended to encompass the full gamut of 5- (2-furyl)-, 5-Q-furyl)-, 5-(2 thienyl)and 5-(3-thienyi)-derivatives of oxazolidine-2,4-dione wherein the substituent X can be attached to any vacant carbon position of the furan/thiophene ring, i.e., X X \ OX X I.Q0X Ox Y A I! f 3 GB 2 131 422 A 3 Ox X Ox Ox 0 \ X ', 5\ Y X Y Y wherein X and Y are as defined above and Ox is used as an abbreviation for the oxazolidin-2,4-dione ring attached at the 5-position; when both X and X' are other than hydrogen, the second substituent can be inserted at either vacant position in any one of these six variants; the second formula is intended to encompass those compounds wherein the oxazolidine is substituted at the 2-, 3- or 7-position of the 5 benzo[blfuran/benzo[blthiophene ring system, i.e.
L- jl:: 11(0 X WY 1 Ox 91::
OX The invention also encompasses the pharmaceutically acceptable cationic salts of compounds of the formula (1) when R is hydrogen, as well as the pharmaceutically acceptable acid addition salts thereof when R' contains a basic nitrogen function.
It is believed that the inherent, high activity of these compounds resides primarily in those compounds wherein R is hydrogen, and that those compounds wherein R is one of a variety of carbonyl derivatives defined above represent so-called pro-drugs, i.e., the carbonyl side chain is removed by hydrolysis under physiological conditions, yielding the fully-active compounds wherein R is hydrogen.
The expression "pharmaceutically acceptable cationic salts" is intended to define such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts, (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine KM-di benzyiethylenedia mine), choline, diethanolamine, ethylenediamine, megiumine (N-methyiglucamine), benethamine (N-benzyiphenylethylamine), diethylamine, piperazine, tromethamine (2amino-2-hydroxymethy]-1,3-propanediol), procaine, etc.
The expression "pharmaceutically acceptable acid addition salts- is intended to include such salts as the hydrochloride, hydrobromide, hydroiodide, nitrate, hydrogen sulfate, dihydrogen phosphate, mesylate, maleate, succinate, etc.
The compounds of the present invention possess hypoglycemic activity, reflecting their clinical utility in the lowering of the blood glucose level of hyperglycemic mammals, including man, to normal 25 values.They have special advantage of lowering blood giticose values to a normal range without danger of causing hypoglycemia. The compounds of the present invention are tested for hypoglycemic (anti-hyperglycemic) activity in rats, using the so-called glucose tolerance test, as described in greater detai! hereinafter.
Preferred compounds, because of their better hypoglycemic activity, are those wherein R is hydrogen, or the pharmaceutically acceptable salts thereof. Among those compounds of the formula (1) wherein R is hydrogen, the most preferred compounds, because of their excellent hypoglycemic activity, are:
5-(1 -methyl -2-pyrrolyl) oxazo lidi ne-2,4-dione; 5-(1 -ethyl-2-pyrrolyl)oxazolidine-2,4-dione; 35 5-(1 -phenyi-2-pyrroiyi)oxazolidine-2,4-dione; 5-(2-methoxy-3-pyridyi)oxazolidine-2,4-dione; 5-(2-ethoxy-3-pyridyi)oxazolidine-2,4-dione; 5-(5-chloro-2-methoxy-3-pyridyl)oxazolidine2,4-dione; 5-(5-chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione; 40 5-(8-quinoiyl)oxazolidine-2,4-dione; 5-(7-methoxy-8-quinolyi)oxazolidine-2,4-dione; 5-(6-chloro-8-quinolyi)oxazolidine-2,4-dione; 5-(6-fluoro-8-quinolyi)oxazolidine-2,4-dione; 5-(2-benzthiazoiyi)oxazolidine-2,4-dione; 45 5-(2-thiazolyl)oxazolidine-2,4-dione; 5-(6-chloro-8-chromanyi)oxazolidine-2,4-dione; 5-(6-fluoro-8-chromanyi)oxazolidine-2,4-dione; 5-(5-chloro-2,3dihydro-7-benzofuranyl)oxazolidine-2,4-dione; 5-(3-methyi-5-isoxazoiyi)oxazolidine-2,4-dione; 50 5-(3-thienyl)oxazolidin-2,4-dione; 5-(4-bro mo-3 -thi enyi) oxazo 1 i di n-2,4-di one; 5-(4-ethoxy-3-thienyl)oxazolidin-2,4-dione; 5- (4-eth oxy-2-m ethyl-3-th i e nyl)oxazo 1 i di n-2,4-di one; 5-(4-m ethoxy-2-m ethyl-3-thi enyl)oxazo lidi n-2,4-di one; 55 4 GB 2 131 422 A 4 5-Q-methyl -2-thienyi)oxazolidin-2,4-dione; 5-(3-methoxy-2thienyi)oxazolidin-2,4-dione; 5-(3-furyi)oxazolidin-2,4-dione; 5-(2furyl)oxazolidin-2,4-dione; 5-(3-bromo-2-furyi)oxazolidin-2,4-dione; 5-(5ch 1 oro-2-f uryl) oxazo lidi n2,4-di one; 5(7-benzo [blthienyi)oxazolidin-2,4-dione; and 5-(5-chloro-7benzo[blfuranyi)oxazolidin-2,4-dione. The compounds of the present invention are prepared by a variety of methods, as summarized in 10 Flowsheet Lwherein R' is as defined above; R 2 is lower alkyl (e.g. methyl or ethyl); R' is hydrogen, lower alkyl or phenyl; and R 4 is hydrogen, or acyl such as acetyl or benzoyi.
Flow sheet 1 15 Oxazolidine-2,4-dione precursors OR h OR R 1 'O'y OR 2 R 1 N R 2 NH R 2 (3) (4) (5) A L R 3 4 OR NH 2 R1/( Ri IA"Y NE R' OR 0 0 0 0 R 4 0 NH l> 'IM R H v (9) (1, 2) A L Y,\, 0 __SR 2 4 R 1,1N (6) H R 0 (10) (8) (7) A particularly convenient synthesis for compounds of the present invention is via carboximidate (3). The latter compound is reacted with phosgene in an inert solvent such as tetrahydrofuran in the presence of 2 to 2.3 equivalents of a tertiary amine (e.g. triethylamine, N-methyimorpholine). A further 20 equivalent of tertiary amine is used if the carboximidate is introduced as the acid addition salt (e.g.
hydrochloride salt). The temperature of the reaction is not critical, but lower temperatures (e.g. -100 to 1 OIC) are preferred during the initial stages of the reaction, particularly if it is desired to isolate the intermediate 4-alkoxyoxazol-2-one (4). Isolation of this intermediate is carried out by simple evaporation of the reaction mixture to dryness. On further reaction at higher temperatures (e.g. 200- 25 150IC) or an aqueous work-up the intermediate (4) is converted to the desired oxazolidine-2,4-dione.
When a primary or secondary amine function is desired in the final product, this functionality is introduced via an oxazolidine-2,4-dione containing a group selectively reducible (e.g. by catalytic 4 c GB 2 131 422 A 5 hydrogenation or acid/metal couple) to the primary or secondary amine. For example an N-benzylindole can be used as a precursor for an indole derivative.
The carboximidate (3) is conveniently prepared from the corresponding aldehyde by the sequence:
R'CHO (11) Osi(CH 3)3 (12) 1r OH R1.11cs OH R 1 OR 2 NB (3) (13) The aldehyde (11) is converted to the cyanohydrin (13) by standard procedures (e.g. via the bisulfite adduct, which is reacted with cyanide in a two phase, aqueous-organic solvent system). Alternatively, the aldehyde is converted to the trimethylsilyl cyanohydrin (12) by reaction with trimethyisilylcarbonitrile in the presence of a catalytic quantity of a Lewis acid, e.g., zinc iodide. A reaction inert solvent (e.g. methylene chloride, ether) is generally used when the aldehyde is a solid, but 10 is optional when the aldehyde is a liquid. The temperature of the reaction is not critical, it being conveniently made up at reduced temperature (e.g. 0-50C) and allowed to proceed at room temperature for a matter of hours or days, as necessary to achieve complete reaction. If desired, the trimethylsilyl ether can be hydrolyzed to cyanohydrin, conveniently at reduced temperature (e.g.
-1 OOC) in a two phase strong aqueous acid/organic solvent system.
Either the cyanohydrin (13) or the trimethyisfiy-i ether (1 2)_is converted to the carboximidate (3) by strong acid catalyzed alcoholysis (using strictly anhydrous conditions). A convenient method is to simply dissolve the nitrile in alcohol which has been saturated with hydrogen chloride) and allow the solution to stand until carboximidate formation is complete. Temperature is not critical, although lower temperatures (e.g. 0-25IC) generally lead to more optimal yields.
The aldehydes required for the above syntheses are broadly available either commercially, or by literature methods. For example, Nalkylpyrrole-2-carbaidehydes are obtained by alkylation of pyrrole2carbaldehyde (Weygand, Organic Preparations, Interscience, New York, 1945, p. 403) using conditions specifically exemplified hereinafter for the preparation of N-alkylpyrroles, or by ReimerTieman formulation of Walkylpyrrole (cf Weygand loc. cit.); 3-formylindoles are similarly obtained from 25 indoles [cf Boyd and Robson, Biochem. J. 29, p. 555 (1935); Shabica et al. , J. Am. Chem. Soc. 68, p.
1156 (1946111; Rosenmund hydrogenation of the corresponding acid chloride [e.g. 3-furaldehyde; Hayes, -1. Am. Chem. Soc. 71, 2581 (1949)1, from halomethyl compounds by the Sommelet reaction [e.g. 3-thenaldehyde; Campaigne and LaSuer, J. Am. Chem. Soc. 70,1557 (1948)1, formulation [e.g. 2 thenaldehyde, 3-methyl-2-thenaldehyde, 5-methy]-2-thenaidehyde; Watson and Michaels, J. Am. 30 Chem. Soc. 72, 1422 (1950), Organic Syntheses 31, 108 (1951); 3-bromo-2- thenaldehyde; Elliott et aL, J. Chem. Soc. (C), 2551 (1971)1; reduction of chloromethyl substituted aldehydes [e.g. 5-methyl-2 furaidehyde, Spence and Wild, J. Chem. Soc., 338 (1935)], oxidation of the corresponding alcohol [e.g.
2-thenaldehyde; Emmerson and Patrick, J. Org. Chem., 14, 790 (1949)1, interaction of Grignard reagents with orthoformic esters [e.g. 2-thenaldehyde; Cagniant, Bull. soc. chim. France 16, 849 35 (1949)1, decarboxylation of alpha-keto acids [e.g. 2-thenaldehyde; Barger and Easson, J. Chem. Soc., 2100 (1938)1, and halogenation [e.g., 2-bromo-3-thenaldehyde; Elliot et aL, loc. cit.]; a variety of the presently required aldehydes are further available by the hydrolysis of gem-dihalides, oxidation of primary alcohols, interaction of Grignard reagents with orthoformic esters and other methods known in the art. Additional methods are noted in the Preparations detailed hereinafter.
Another suitable precursor for those oxazolidine-2,4-diones of the present invention lacking a primary or secondary amine function is the alpha-hydroxy amide (5). The latter compound is converted to the desired oxazolidine-24-dione (1), either by reaction with alkyl chloroformate in the presence of a basic catalyst such as potassium carbonate, or by reaction with a dialkyl carbonate in the presence of a more strongly basic catalyst such as sodium methoxide or potassium tert- butoxide. An alcohol is generally suitable as solvent for the latter reaction with 1 to 3 equivalents of both dialkyl carbonate and base employed, preferably 2-3 equivalents of each. When a primary or secondary amine function is 6 GB 2 131 422 A 6 desired in the final product, this functionality is introduced via an oxazolidine-2,4-dione containing a suitable precursor group, as described above.
The required alpha-hydroxy amide is conveniently prepared from cyanohydrin (13) or from alphahydroxy acid or ester 0:
OH R'-')"- W 40.
0 OH 5 Convenient conditions for the hydrolysis of the cyanohydrin (13) are to treat the cyanohydrin in formic acid with excess concentrated hydrochloric acid. A temperature range of 0-751C is generally satisfactory, depending upon the stability of the individual amide in this medium. If desired, an intermediate formate ester of (5) can be isolated under these conditions. Over hydrolysis to the acid can be avoided by tic monitoring of the reaction, as detailed below. Convenient conditions for the 10 aminolysis of ester (6) are to simply heat the ester in hot concentrated ammonium hydroxide.
The alpha-hydroxy ester (6) itself can also be employed as the immediate precursor of the desired oxazolidine-2,4-dione. The ester is reacted with urea (or one of certain substituted ureas, such as phenyl urea or 1 acetyl-3 -methyl u re a) in the presence of a basic catalyst such as sodium ethoxide (suitably 1 equivalent) in alcohol at a temperature of 50-11 OIC. The ester to be used for this purpose 15 is by no means restricted to a simple lower alkyl ester, but can be any one of a broad variety of esters, e.g. phenyl, benzy], etc. Furthermore, the ester can be replaced by a 1,3-dioxolan-4-one, an alphaacyloxy ester or a thioester e.a., CH 3 CH 3 CH 3 H 3 0- =0 C=0 0 or 0 Rl--Voc 2 H 5 ',,-YSCH 3 0 0 and the urea can be replaced by a urethan.
Two other precursors suitable for the synthesis of the desired oxazolidine-2,4-diones are the thio compounds (7) and (8). The 2-thioxo compound (7) is converted to the desired oxazolidine-2,4-diones under oxidative conditions, e.g. mercuric icn, aqueous bromine or chlorine, metaperiodate, or aqueous hydrogen peroxide, usually in excess and in the presence of a co-solvent, such as a lower alcohol. The temperature of reaction is not critical, temperatures in the range 25-1 OOIC being generally satisfactory. Other methods are usually preferred when R' has an amine function, since competing oxidation at the nitrogen tends to reduce yields and complicates isolation of the desired product; it has been found, however, that when the product contains a tert-amine (e.g., pyridine, quinoline), that periodate or bromine are reagents well- suited for this purpose. The oxazolidine-2,4-diones are obtained from the alkylthio compounds (8) by simple acid or base catalyzed hydrolysis. Preferable conditions are aqueous hydrochloric acid in a temperature range of 0-501C.
The precursor 2-thioxo compound (7) is prepared from the corresponding aldehyde (11), generally accomplished in an aqueous acidic media by the action of thiocyanate (1-1.1 equivalents) and cyanide (1 to 1.2 equivalents) at 0-701C, following the method of Lindberg and Pederson by which method the preparation of 5-(2-thienyl)-2-thiooxazolidin-4-one has been reported [Acta Pharm. 35 Suecica 5 (1), pp. 15-22 (1968); Chem. Abstr. 69, 52050k]. The precursor 2-alkylthio compounds (8) can be prepared by alkylation of the 2-thioxo compounds (7), e.g. with an alkyl halide or dialkyl sulfate, preferably in the presence of at least two equivalents of a base such as a lower alkoxide in a reaction inert solvent such as a lower alkanol. The 3-alkyl derivative can be a by-product of this reaction.
Also suitable as a precursor is the 2-imino-oxazolidine-4-one derivative (9), readily hydrolyzed to the oxazolidine-2,4-dione, preferably under aqueous acid conditions. The required 2-iminooxazolidin-4 one is obtained by condensation of the alpha-hydroxy ester (6) with guanidine or with thiourea in the presence of one equivalent of a strong base such as sodium alkoxide, by ammonolysis of the 2-alkoxy compound (isomeric with 4) or the 2-thioalkyl compound (8), by alkali induced cyclzation of the 45 appropriate alpha-halogenureides (R'CHZCONHCONHR' wherein Z is a halogen such as chloro or bromo), or by the condensation of the appropriate alkyl alpha- haloacetates (RICHWOOR') with urea or a substituted urea WNI-ICONI-1,).
Ammonolysis of the 4-alkoxy derivatives (4) yields 4-imino derivatives (isomeric with 9). The 0.
A 7 GB 2 131 422 A latter compounds are also readily hydrolyzed to oxazolidine-2,4-diones. The 4-alkoxy derivatives themselves are also prepared from the silver salt of the desired oxazolidine-2,4-dione.
Also highly useful as precursors of the oxazolidine-2,4-diones of the present invention are the dialuric acids and acyl dialuric acids (10). These are readily converted, under mildly basic conditions, to 5 the desired oxazolidine-2,4-diones. Methods suitable for the preparation of precursor dialuric acids (10) are shown in Flowsheet 11, wherein the substituents R', R' and R 4 are as defined above, and M is U, MgC1, MgBr, MgI, or other suitable metal.
A general method for preparing dialuric acids appropriate as precursors of the oxazolidine-2,.4diones of the present invention is from the malonic ester derivatives (14), involving the two stages of base catalyzed condensation with urea and oxidation to the hydroxy or acyloxy compounds. When the 10 first stage is oxidation, the intermediate is a so-called tartronic acid derivative (15), while when the first stage is condensation, the intermediate is a so-called barbituric acid (16). When R' contains an amine function (e.g. 2-aminophenyl), it is preferred to carry out oxidation as the first stage, preventing possible complications of nitrogen oxidation. When condensation is the second stage, the dialuric acid is usually not isolated, at least in pure form, and is further converted, under basic conditions of the 15 condensation, to the oxazolidine-2,4-dione.
R 1 H--------------- i Rowsheet 11 NH R ' 0 R 1r M 0 :H COOR 2 19 4 R C-OR 6OR 2 R 1 M (10) (15) A L 0 -NH R 1 _ O NE COOR 2 R' ii 2 COOR (16) (14) The substituted maionic esters required for the above syntheses, when not available commercially, are obtained by literature methods, such as alcoholysis of alpha-cyano esters [cf. Steele, J. Am. Chem. Soc. 53, 286 (1931)1, carbalkoxylation of esters [cf. Homing and Finelli, Org. Syntheses 20 30, 43 (1950)l and decarbonylation of alpha-keto esters obtained by the condensation of dialkyl oxalate with carboxylate esters [Reichstein and Morsman, Heiv. Chim. Acta 17, 1123 (1934); Blicke and Zienty, J. Am Chem. Soc. 63, 2946 (1941)1.
A less general method for the preparation of the appropriate dialuric acid intermediate is to react an electron rich heteroaryl/aryl compound, e.g., G 6 3 Br ,W P, 1 1 1 z, H Q, )0 CH 0 N H CH 3 H N1:1 Bre,A 3 1 i HO M H N H CH 3 H HHO)=C) 0 H 8 GB 2 131 422 A 8 Now available is yet another method for the preparation of certain dialuric acid intermediates. This method, preferred when the appropriate starting materials are readily available, involves the reaction of alloxan (preferably in anhydrous form) with the appropriate organometal derivative (e.g., organolithium, Grignard reagent). For example:
0 L1 110 %N KO a Protection strategies are required when using this method for preparation of certain oxazolidine2,4-diones wherein R' carries a substituent which is not compatible with organometallic reactions, e.g., an acyl group is protected as its ethylenic ketal. In other cases, such as when R' carries a group such as nitro or amino, this method generally lacks utility.
It will be evident to those skilled in the art that the preferred process for the oxazolidine-2,4- 10 diones of the present invention will vary from one given value of R' to another, depending upon such factors as availability of starting materials, yields, ability to remove undesirable impurities from the end- products, the chemical nature of the substituent groups contained in the final products, etc. The pharmaceutically-acceptable cationic salts of the compounds of the present invention which form such salts are readily prepared by reacting the acid forms with an appropriate base, usually one 15 equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, ethylenediamine, megiumine, benethamine, diethylamine, piperazine and tromethamine. Those salts which do not precipitate directly are isolated by concentration to dryness or by addition of a non-solvent. In some cases, salts can be prepared by mixing a solution of the acid with 20 a solution of a different salt of the cation (sodium ethylhexanoate, magnesium oleate), employing a solvent in which the desired cationic salt precipitates, or can be otherwise isolated by concentration and addition of a non-solvent.
The pharmaceutically acceptable acid addition salts of the compounds of the present invention which form such salts are readily prepared by reacting the base forms with an appropriate acid, usually 25 one equivalent, in a cosolvent. Typical acids are hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, methanesuifonic, maleic, succinic, etc. Those salts which do not precipitate directly are isolated by concentration to dryness or by addition of a non-solvent.
3-Acylated derivatives of the present invention are readily prepared by using standard conditions of acylation, e.g. the reaction of the oxazoildine-2,4-dione salt (per se, or conveniently formed in situ by 30 the addition of one equivalent of a tertiary amine such as triethylamine or N-methyl morph ol i ne with an equivalent of the appropriate acid chloride or acid anhydride) or reaction of the oxazolidine-2,4-dione with the appropriate organic isocyanate, optionally in the presence of a catalytic amount of tertiary amine base. In either case, the reaction is carried out in a reaction inert solvent, such as toluene, tetrahydrofuran or methylene chloride. The temperature is not critical, and can be over a broad range 35 (e.g. 0-1 50OC). It will be evident to those skilled in the art that such acylation will be complicated by competing or even selective sidechain (R') acylation when the sidechain contains a primary or secondary amine function.
It will be evident to those skilled in the art that the compounds of the present invention are asymmetric and therefore capable of existing in two optically active enantiomeric forms. The racemic compounds of the present invention, being acids when R is H, form salts with organic amines. These racemic forms are therefore generally capable of resolution into the optically active forms by the classic method of forming diastereomeric salts with optically active amines, now separable by selective crystallization; alternatively those compounds containing a basic amine function can be resolved by forming a salt with an optically active acid, preferably a strong organic acid such as a sulfonic acid. In general, one of the enantiomeric forms is found to have greater activity than the other.
The reactions employed to prepare the compounds of this invention can generally be monitored by standard tic methods, employing commercially available plates. Suitable eluants are common solvents such as chloroform, ethyl acetate or hexane or suitable combinations thereof which will differentiate starting materials, products, by-products, and in some cases intermediates. Applying these methods, which are well known in the art, will permit further improvement in the metodology of the specific examples detailed hereinafter, e.g. the selection of more optimal reaction times and temperatures, as well as aid in the selection of optimal processes. The oxazolidine-2,4-diones of the present invention are readily adapted to
clinical use as antidiabetic agents. The hypoglycemic activity required for this clinical use is defined by the glucose 55 tolerance test procedure which follows. Intact male albino rats are the experimental test animals employed for such purposes. The test animals are fasted approximately 18- 24 hours. The rats are weighed, numbered and recorded in groups of five or six as needed. Each group of animals is then dosed intraperitoneally with glucose (one gram per kilogram) and orally with either water (controls) or 11 1 9 GB 2 131 422 A 9 compound (at a level usually selected from the range 0. 1 to 100 mg/kg). Blood glucose levels (mg/1 00 m]) are measured in tail blood samples over a period of 3 hours in both control and treated groups. With equivalent zero hour blood glucose levels in control and treated groups, the % lowering of blood glucose at 0.5 hour, 1 hour, 2 hours and 3 hours is calculated as:
[Control Blood Glucose]-[Treated Blood Glucose] X100% 5 [Control Blood Glucose] Clinically useful hypoglycemic agents show activity in this test. The hypoglycemic activities determined for compounds of the present invention are summarized in Table 1. This table records % blood glucose lowering at the 0.5 hour and 1 hour time points. A blood glucose lowering of 9% or greater generally reflects statistically significant hypoglycemic activity in this test. Those compounds which show significant activity only at the 2 hour or 3 hour points have such activity recorded in footnotes.
Table 1 Hypoglycemic activity of oxazolidine-2,4-diones in the rat glucose tolerance test NII % Lowering Ar Dose of blood glucose level 15 Ar (mglkg) 0.5 hr 1 hr 2-Thienyl 10 11 8 5-Benzoyl- 25 10 7 3-Bromo- 10 8 6(a) 20 5-Bromo- 100 36 19 5-Chloro- 100 26 17 3-Methoxy 5 13 16 5-Methoxy- 25 9 7 3-Methyl- 100 30 17 25 14 12 $-Methyl 50 18 10 5-Phenyl 50 1 5(b) 3-Thianyl 10 23 20 5 20 17 30 4-Bromo- 100 31 25 14 9 4-Methoxy- 5 11 8 4,.,N4ethoxy-2-methyi- 5 16 14 4-Ethoxy- 5 19 19 35 4-E,thoxy-2-methyl- 5 7 12 4-Propoxy- 5 11 6 2-Furyl 100 27 23 11 7 3-Bromo- 25 is 10 40 11, 11 5-Bromo- 50 19 20 2 11 5-Chloro 25 21 20 3-Mathoxy- 25 10 10 45 5-Methy]100 27 19 5-Phenyi- 25 6 4(c) 3-Furyl 10 17 13 14 8 2,5-Dirtiethyi33(e) 16(f) 50 4-lodo- 25 19(e) Offi 3-Benzeblthienyl 100 11 5 7-Benzo[b]thienyl 100 -4 12(d) 7-Benzo[blfuranyl - - - 5-Chloro- 10 23(e) 1 Offi 55 8-Chromanyl - - 6-Chloro- 10 11 6-Fluoro- 10 9 GB 2 131 422 A 10 Table 1 (contd.) --c Ar NE % Lowering of blood glucose level Dose Ar (mglkg) 0.5 hr 1 hr 5 2,3-Dihydrobenzofuranyl - 5-Chloro- 25 - 23(g) 2-Pyrrolyl 100 11 8 1-Methyl- 100 18 17 1 -Ethyl 100 14 16 10 1 -(1 -Butyi)- 100 4 13 1 -Phenyl 100 30 32 3-1ndolyl - - - 5-Bromo- 100 9 10 1-Methyl- 100 11 8 15 3-Pyridyl - - - 2-Methoxy 10 13 2-Ethoxy- 25 2-Methoxy-5-chloro- 25 22 17 2-Ethoxy-5-chloro- 10 - 24(g) 20 5-Quinolyl 6-Methoxy- 20 - 7(h) 8-Quinolyl 18 19 16 6-Chloro- 10 - 16 6-Fluoro- 10 15 25 7-Methoxy- 10 - -0) 2-Thiazolyl- 75 11 10 2-Benzthiazolyl- 50 8 10 5-isoxazolyl - - - 3-Methyl- 100 4 7(j) 30 (a) 11 at 2 hours.
(b) 9 at 2 hours.
(c) 10 at 3 hours.
(d) 16 at 2 hours; 10 at 3 hours.
(e) At 0.75 hours.
(f) At 1.5 hours.
(g) At 0.75 hours.
(h) 9 at 2 hours.
(i) 12 at 3 hours.
(j) 24 at 2 hours, 14 at 3 hours.
The oxazolidine-2,4-diones of the present invention are clinically administered to mammals, including man, via either the oral or the parenteral route. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0. 10 to about 50 mg/kg body weight of the subject per day, preferably about 0.20 to about 20 mg/kg body weight per day administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage. This will 50 vary according to the particular compound employed and with the subject being treated.
The compounds can be used in pharmaceutical preparations containing the compound, or pharmaceutically acceptable acid salt thereof, in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described above. Thus, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions can if desired, contain additional components such as flavorants, 1 11 GB 2 131 422 A 11 sweeteners, excipients and the like. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable acid addition salts of the compounds. 5 The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly, with intramuscular administration being preferred in man.
The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples.
Example 1 Methyl 2-methoxypyridine-3-carbox.yiate Thionyl chloride (50 mi) was added to 2-methoxypyridine-3-carboxylic acid (5 g) in 50 mi of carbon tetrachloride and the mixture refluxed for 2 hours. The reaction mixture was cooled, evaporated to solids and chased with multiple portions of fresh carbon tetrachloride. The resulting acid chloride hydrochloride was dissolved in excess methanol (50 mi), stirred for 16 hours at room temperature, then evaporated an oil and taken up in chloroform. The chloroform solution was washed with two portions of saturated sodium bicarbonate and then one portion of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [4.63 g; pnmr/CDCI,/delta (ppm): 3.9 and 4.1 (2s, 6H), 6.9 (m, 1 H), 8.2 (m, 2 H)].
By the same procedure, 4-methylpyridine-3-carboxylic acid is converted to methyl 4 methylpyridi n e-3-ca rboxyl ate.
Example 2
3-Methanesuifinyimethylcarbonyl-2-methoxypyridine Sodium hydride (2.69 g, 50% dispersion in oil, 0.056 mole) was washed three times with petroleum ether. Following the third decantation, traces of petroleum ether were removed by evaporation in vacuo. Dimethyisulfoxide (30 mi) was added and the mixture heated in an oil bath at 751C for 45 minutes, by which time hydrogen evolution had ceased. The mixture was cooled in an ice water bath and diluted with 30 mi of dry tetra hydrofu ran. Title compound of the preceding Example (4.63 9, 0.028 mole) in 10 mi of dry tetrahydrofuran was added dropwise over 5 minutes. The reaction mixture was warmed and stirred at room temperature for 30 minutes, poured into 180 mi of water, 30 acidified to pH 4 with 1 N hydrochloric acid and extracted with three portions of chloroform. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to yield title product as an oil [4.97 g; pnmr/,ClDC1,Melta (ppm); 2.8 is, 3H, 4.1 (s, 3H), 4.4 and 4.7 (2d, 2H), 7.0 (m, 1 H), 8.3 (m, 2 K.
By the same procedure the 4-methyl compound of the preceding Example is converted to 3- 35 methanesuifinyimethylcarbony]-4-methyipyridine.
Example 3
S-Methyl 2-acetoxy-2-(2-methoxy-3-pyridyi)thioacetate Title compound of the preceding Example (3.97 g), sodium acetate (3.97 g) and acetic anhydride (40 mi) were combined in 80 mi of toluene and heated at 1151 for 16 hours. The mixture was cooled 40 and evaporated to dryness in vacuo to yield crude product. The latter was chromatographed on 200 g of silica gel with 2:1 chloroform:ethyl acetate as eluant, tic monitoring and collecting 10 mi fractions.
Clean product fractions 58-79 were combined and concentrated to an oil. To remove possible traces of residual acetic anhydride, the oil was taken into wet ethanol, held for 15 minutes, re-evaporated, chased with toluene, taken up in chloroform, dried over anhydrous magnesium sulfate, filtered, and re- 45 evaporated to yield the title product as an oil [3.16 g; Rf 0.60 Q:1 ethyl acetate: methanol); m/e 255; ir (CHIC12) 1748,1686,1582,1460,1205 cm-11.
By the same procedure the methyl compound of the preceding Example is converted to S-methyl 2-acetoxy-2-(4-methyi-3-pyridyi)thioacetate.
Example 4
5-(2-Methoxy-3-pyridyi)oxazolidine-2,4-dione Sodium methoxide (632 mg, 11.7 mmoles) was taken into 50 mi of absolute ethanol and the solution cooled in an ice-water bath. Urea (234 mg, 3.9 mmole) was added, followed by the title compound of the preceding Example (1.0 g, 3.9 mmole) in 5 mi of ethanol. The mixture was heated at reflux for 16 hours, then cooled to room temperature, neutralized with 11. 7 mi of 1 N hydrochloric acid 55 and evaporated to a gum which was chased with toluene. The gum was chromatographed on 40 g of silica gel with 1:2 ethyl acetate:chloroform as eluant, tic monitoring and 10 mi fractions collected.
Product containing fractions 6-15 were combined and evaporated to a viscous oil, which was crystallized from water [75 mg; m.p. 183-1 861C, Rf 0.32 (11:2 ethyl acetate:chloroform)l.
By the same method, the methyl analog of the preceding Example is converted to 5-(4-methyl-3- 60 pyridyl)oxazolidine-2,4-dione.
12 GB 2 131 422 A 12 Example 5 Ethyl 2-ethoxypyridine-3-carboxylate 2-Ethoxypyridine-3- carboxylic acid (4 g) was converted to its acid chloride hydrochloride by refluxing with 8.6 mi of thionyl chloride for 60 minutes. The reaction mixture was evaporated to solids with toluene chase to remove the excess thionyl chloride. The residue was taken in 80 mi of ethanol and held for 16 hours at O"C, then evaporated to solids, which were partitioned between toluene and 1 N sodium hydroxide. The aqueous layer was extracted with fresh toluene and the two organic layers combined, washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [3.2 g; pnmr/CDC13/delta (ppm) 1.6 (2s, 6H), 4.4-5.0 (2q, 4H), 7.2 and 8.2 (m, 3K.
Example 6 2-Ethoxy-3-methanesuifinyl methyl carbonylpyridine Using methylene chloride in place of chloroform in the isolation, the procedure of Example 2 was employed to convert product of the preceding Example (3.0 g) to title product [2.63 g; m.p. 89-91 OC; pnmr/WC1,/delta (ppm), 1.5 (t, 3H), 2.8 (s, 3H), 4.2-4.8 (s and q, 4H), 6. 8-7.1 and 8.0-8.4 (3H)I.15 Example 7 S-Methyl 2-acetoxy-2-(2-ethoxy-3-pyridyl)thioacetate Using a reaction time of 4 hours at 1 OWC and then 48 hours at room temperature, the procedure of Example 3 was employed to convert the product of the preceding Example (2.5 g) to crude product, isolated as an oil by evaporation of the reaction mixture. The oil was taken up in ethyl acetate, washed 20 in sequence with three portions of 1 N sodium hydroxide, one of water and one of brine, dried over anhydrous magnesium sulfate and evaporated to yield title product as an oil [2.96 g; Rf 0.78 (10:1 ethyl acetate:methanol); m/e 2691.
Example 8
2-(2-Ethoxy-3-pyridyi)-2-hydroxyacetamide Product of the preceding Example (2.9 g) was combined with 30 mi of ethanol and 30 mi of conc.
ammonium hydroxide, stirred at room temperature for 3 hours and then evaporated to yield crude product as an oil (2.7 g). The oil was chromatographed on 170 g of silica gel using ethyl acetate as eluant and tic monitoring. Clean product fractions were combined and evaporated to yield title product as an oil [0.9 g; Rf 0.6 (10:1 ethyl acetate:methanol); pnmr/WCVdelta (ppm) 1.4 (t, 3H), 4.5 (q, 2H), 30 5.4 (s, 1 H), 6.2-8.2 (m, 5 W].
Example 9 5-(2-Ethoxy-3-pyridyl)oxazolidine-2,4-dione Product of the preceding Example (900 mg, 4.6 mmole) was combined with 25 m] of tert butanol. Dimethyl carbonate (1.08 g, 9.2 mmole) and then potassium tertbutoxide (1.03 g, 9.2 35 mmole) were added and the reaction mixture refluxed for 3.5 hours. The reaction mixture was cooled, poured into 10 mi of 1 N hydrochloric hydrochloric acid, the pH adjusted to 7.0, and extracted with two portions of ethyl acetate. The aqueous layer was saturated with salt and extracted with additional ethyl acetate. The three organic layers were combined, back-washed with a small portion of water and then brine, dried over anhydrous magnesium sulfate and evaporated to yield crude product as a viscous oil. 40 Purified title product was obtained by crystallization from toluene (295 mg, m.p. 140-143OC; m/e 272).
Anal. Calcd. for: C1.1---11.04N2: C, 54.05; H, 4.54; N, 12.61.
Found: C, 54.34; H, 4.85; N, 12.70.
Example 10 Methyl 5-chloro-2-methoxypyridine-3-carboxylate By the procedure of Example 1, 5-chloro-2-methoxypyridine-3-carboxylic acid [Sarges et aL, J. Med. Chem. 19, 709 (1976); 10 g] was converted to its acid chloride, which was added in one portion to 150 mi of methanol (slight exotherm), then made basic with triethylamine (approximately 1.1 equivalents). The reaction mixture was evaporated to solids and the residue partitioned between ethyl 50 acetate and water. The ethyl acetate layer was washed with fresh water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [9.75 g, m.p. 79-81 OC; pnmr/C1)CVdelta (ppm) 3.8 (s, 3H), 4.1 (s, 3H), 8.1 (d, 1 H), 8.3 (d, 1 H)].
Example 11
5-Chloro-3-methanesuifinyimethylcarbonyl-2-methoxypyridine By the procedure of Example 2, the product of the preceding Example (9.7 g, 0.045 mole) was converted to title product isolated as a viscous oil (10.3 g, m/e 249/247).
Example 12 S-Methyl 2-acetoxy-2-(5-chloro-2-methoxy-3-pyridyi)thioacetate Using a reaction time of 19 hours at 1 OOOC, the procedure of Example 3 and the isolation method60 1 13 GB 2 131 422 A 13 of Example 7 were employed to convert product of the preceding Example (10.3 g) to title product in the form of a viscous oil (8.8 g; pnmr/CDCI, includes singlet at 6.4; m/e 291/289).
Example 13
2-(5-Chloro-2-methoxy-3-pyridyi)-2-hydroxyacetamide Methanol (125 mi) was saturated with anhydrous ammonia at 0-51C. The product of the 5 preceding Example (8.8 9) in 25 mi of methanol was added and the reaction mixture stirred overnight at room temperature, then concentrated to a viscous oil (7.3 g). The oil was chromatographed on 400 g of silica gel using 1:1 chloroform:ethyl acetate as eluant, tic monitoring and 10 mI fractions. Clean product fractions 190-270 were combined and evaporated to yield title product [1.3 g; m.p. 110 1130C;m/e218/216;ir(KBr)3444,3410,1684cm-11.
Example 14 5-(5-Chloro-2-methoxy- 3-pyridyi)oxazolidine-2,4-dione Using a reflux period of 15 hours, the procedure of Example 9 was employed to convert the product of the preceding Example (1.25 g, 5.8 mmoles) to title product. To isolate, the reaction mixture was cooled to room temperature and the pH adjusted to 3 with 1 N hydrochloric acid. The mixture was 15 then evaporated in vacuo to slightly gummy solids, which gave filterable, crude product on stirring with 25 mi of water (1.09 g, m.p. 199-2041C. Recrystallization from 15 mi of ethanol gave purified title product [470 mg; m.p. 212-21141C; m/e 244/242; ir(KBr) 3174,3074,2980,1830,1752 em-'].
Example 15
2-(6-Chloro-8-quinolyl)-2-hydroxyacetamide Ethyl 2-(6-chloro-8-quinoiyi)-2-hydroxyacetate (1.6 g) in 300 mi of cone. ammonium hydroxide was heated to reflux. Since complete dissolution did not result, the reaction mixture was cooled, diluted with 50 mi of ethanol and reheated to reflux for 0.5 hour. The reaction mixture was concentrated to a volume of 100 mi, cooled slowly and a crop of title product (320 mg, m.p. 195 1980C) recovered by filtration. Additional product (145 mg) was recovered by concentration of the 25 mother liquor to 50 mi and extraction into three portions of ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness.
By the same procedure, ethyl 2-(6-chloro-2,3-dihydro-7- benzo[blf uranyi)2-hydroxyacetate is converted to ethyl 2-(6-chloro-2,3-dihydro-7-benzo[blfuranyi)-2- hydroxyacetamide.
Example 16
5-(6-Chloro-8-quinolyi)oxazolidine-2,4-dione Potassium tert-butoxide (292 mg, 2.6 mmoles) was dissolved in 20 mi of tert-butanol. Dimethyl carbonate (234 mg 2.6 mmoles) and then title compound of the preceding Example (300 mg, 1.3 mmoles) were added. The reaction mixture refluxed for 18 hours, then cooled to room temperature, 35 adjusted to pH 3 with 1 N hydrochloric acid and diluted with 1 N hydrochloric acid and ethyl acetate.
The aqueous layer was washed with two additional portions of ethyl acetate. The organic layers were combined, washed with two portions of fresh 1 N hydrochloric acid and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil (130 mg). Crystallization of the oil from isopropyl ether gave purified title product [58 mg, m.p. 207-21 OIC; ir(KBr) 1839, 1825, 1740 em-']. 40 By the same procedure the benzofuran analog of the preceding Example is converted to 5-(6 chloro-2,3-dihydro-7-benzo[blfuranyi)oxazolidine-2,4-dione.
Example 17
2-(6-Fiuoro-8-quinoiyi)-2-hydroxyacetamide Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate (1. 1 g) was refluxed for 10 minutes in 300 mi of 45 cone. ammonium hydroxide. The reaction mixture was cooled slightly, clarified by filtration and evaporated to solids. Trituration of the residue with 25 mi of toluene gave the title product (860 mg, m.p. 169-171 'C).
Example 18
5-(6-Fluoro-8-quinoiyi)oxazolidine-2,4-dione Using a reflux period of 3.5 hours, the product of the preceding Example (840 mg, 3.8 mmoles) was converted to title product by the procedure of Example 16. In this case, a pH of 2 was used in the isolation without addition of excess 1 N hydrochloric acid and the crude product was recrystallized from toluene [120 mg, m.p. 202-2041C; m/e 246; ir(KBr) 1819,1743,1363 em-].
Example 19 5-(8-Quinoiyi)oxazolidin-4-one-2-thione Potassium thiocyanate (484 mg, 4.9 mmoles) and potassium cyanide (370 mg, 5.7 mmoles) were combined in 5 mi of water and cooled to 00 C. Quinoline- 8-carbaidehyde [J. Org. Chem. 4 1, p.
14 GB 2 131 422 A 14 957 (1976); 779 mg, 4.9 mmoles] was added, followed by the dropwise addition of hydrochloric acid (30%, 1.9 m]). After stirring for 25 minutes at OIC, the reaction mixture was heated to 90-1 OOIC for minutes, cooled, quenched into crushed ice, adjusted to pH 8 with sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness (163 mg). The latter was partitioned between 1 N sodium hydroxide and ethyl 5 acetate. The basic layer was acidified and extracted with fresh ethyl acetate. The two ethyl acetate layers were combined, dried, filtered and evaporated to yield title product [72 mg; Rf 0.65 (ethyl acetatefl. The original, pH 8 aqueous layer was salted and extracted with ethyl acetate to yield an additional crop (114 mg). The last aqueous phase was acidified and extracted with ethyl acetate to yield a third crop (115 mg).
By the same method, 7-chloroquinoline-8-carbaidehyde is converted to 5-(7chloro-8 quinoiyi)oxazolidin-4-one-2-thione.
Example 20
5-(13- Quinoiyi)oxazolidine-2,4-dione Title compound of the preceding Example (230 mg, 0.94 mmoie) was taken into 6 mi of 2:1 methanol:water and cooled to OIC. Bromine (0.07 mi, 21.7 mg, 2.7 mmoles) was added and the reaction mixture allowed to warm slowly to room temperature, then stirred for 1 hour. The reaction mixture was evaporated to dryness and the residue partitioned between 1 N sodium hydroxide and ethyl acetate. The aqueous layer was separated, acidified and extracted with two portions of fresh ethyl acetate. The acidic extracts were combined, dried and evaporated to an oil (144 mg). Crystallization 20 from toluene-chloroform and recrystallization from toluene gave purified title product (40 mg, m/e 228).
Anal. Calcd. for: Cl,H,O,N2. 0.33H20: C, 61.54; H, 3.70; N, 11.96.
Found: C, 61.50; H, 3.89; N, 11.52.
By the same method the chloro compound of the preceding Example is converted to 5-(7-chloro- 25 8-quinoiyi)oxazolidine-2,4-dione.
Example 21
5-(6-Methoxy-5-quinoiyi)oxazolidin-4-one-2-thione By the procedure of Example 19, 6-methoxyquinoline-5-carbaidehyde (0.77 g) was converted to title product. After quenching into ice, a first crop (190 mg) was isolated by extraction into ethyl 30 acetate, drying over anhydrous magnesium sulfate and evaporation to dryness. A second crop (176 mg) was isolated in like manner by adjusting the aqueous phase to pH 8 with bicarbonate and extracting with additional ethyl acetate. Both crops had m/e 274. The second crop also had m/e 258, indicating contamination with the product of the next step.
Example 22
5-(6-Methoxy-5-quinolyi)oxazolidine-2,4-dione The combined product crops of the preceding Example (0.36 g, 1.31 mmole) were taken into 15 mi of methanol. Sodium metaperiodiate (0.56 g, 2.62 mmoles) in 7.2 m[ of 5% sodium bicarbonate was added dropwise. After stirring for 3 hours at room temperature, the reaction mixture was quenched with water, acidified and extracted with two portions of ethyl acetate. The organic extracts 40 were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness (110 mg).
The aqueous phase was adjusted to pH 7 and further crude product (100 mg) obtained by extraction with ethyl acetate. The crude crops were combined, taken into 1 N sodium hydroxide, acidified to pH 4 with acetic acid and extracted with fresh ethyl acetate. The latter organic extracts were combined and evaporated to dryness. Trituration of the residue with ether, allowing the mixture to stand until 45 crystallization was complete, gave title product (34 mg; m.p. 144-146IC).
Example 23
5-(7-Methoxy-8-quinolyi)oxazolidin-4-one-2-thione By the procedure of Example 19, but using adjustment to pH 7 with bicarbonate after quench and ethyl acetate for extraction, 7-methoxyquinoline-8-carbaidehyde (2.0 g, 10.7 mmoles) was converted 50 to title product [1.17 g; Rf 0.7 (2:1 ethyl acetate:chloroform)I. This product was not partitioned between aqueous base and ethyl acetate, nor was a second crop isolated by salting the aqueous phase and further extracting.
Example 24
5-(7-Methoxy-8-quinoiyi)oxazolidine-2,4-dione Product of the preceding Example (0.74 g, 2.7 mmoles) was combined with 30 mi of methanol and 15 mi of 5% sodium bicarbonate. Sodium metaperiodate (1. 15 g, 5.4 mmoles) in 15 m] of water was added dropwise. After stirring for 3 hours at room temperature, the reaction mixture was - quenched with water, acidified to pH 2-3 and extracted with two portions of ethyl acetate. The GB 2 131 422 A 15 extracts were combined, dried and evaporated to dryness (360 mg). Recrystallization from water gave purified title product (100 mg; m.p. 207-208OC).
Anal. Calcd. for Cl^l\1103. 1.2H,O: C, 59.40; H, 4.34; N, 10.66.
Found: C, 59.33; H, 4.01; N, 10.66.
Example 25 5-Hydroxy-5-(1 -methyl-2-pyrrolyi)-2,4,6-(1 H,3H, 5H)pyrimidinetrione Alloxan hydrate (3.2 g, 0.02 mole) was dissolved in 50 m] of ethanol by warming. 1 Methylpyrrole (1.6 g, 0.02 mole) was added and the mixture warmed for 5 minutes on a steam bath, while perfusing with hydrogen chloride. After standing at room temperature for 0.5 hour, the reaction mixture was evaporated to dryness and the residue triturated with water to yield title product as a solid 10 [2.9 g; m/e 223; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Example 26 5-(11 -Methyl -2-pyrroiyi)oxazolid i ne-2,4-d ione Product of the preceding Example (2.8 g) was combined with 25 mi of 1 N sodium hydroxide and heated on a steam bath for 30 minutes, by which time complete dissolution had occurred. On acidification, a gum precipitated, which solidified on trituration with water (1.2 g). Recrystallization from methanol-ether afforded purified title product [0.70 g; m.p. 108-114 (dec); m/e 1801.
Anal. Calcd. for CH80,3N2: C, 53.33; H, 4.48; N, 15.55.
Found: C, 5 3.16; H, 4.7 2; N, 15.2 8.
Example 27 5-Hydroxy-5-(1 -ethyl-2-pyrroiyi)-2,4,6-(1 H.3H, 5H)pyrimidinetrione Potassium pyrrole [J. Chem. Soc., p. 52 (1931); 1 g; 0.01 mole] was slurried in 5 mi of tetra hyd rofuran. Ethyl iodide (1 mi, 0.0 12 mole) was added, a slight exotherm being noted. The mixture was stirred for 0.5 hour, heated to reflux for 0.5 hour, cooled to room temperature, diluted with 15 mi of water and extracted with 10 m] of ether. The ether extract was washed with 5 mi of water, then added to alloxan hydrate (1.6 g) which had been dissolved in 25 mi of ethanol by heating. The ether was boiled off and the ethanolic residue refluxed for 0.5 hour, then evaporated to a water- soluble gum. The gum was taken up in 25 mi of ethyl acetate, washed with two 10 mi portions of water and reevaporated to yield title product as a gum (0.6 g, m/e 237).
Example 28 5-(11 -Ethyi-2-pyrroiyi)oxazolidine-2,4-dione The procedure of the preceding Example was repeated on a three times scale. The initially isolated product gum (0.03 mole of the pyrimidinetrione) was stirred with 60 mi of 1 N sodium hydroxide for 0.5 hour, then acidified with cone. hydrochloric acid and extracted with ethyl acetate. The extract was.filtered from insoluble impurities, and concentrated to a gum (2.2 g). The gum was chromatographed on 100 mi of silica gel with (1:1 ethyl acetate:hexane as eluant and tic monitoring. Early fractions contained the desired product; these were combined and evaporated to an oil which crystallized on standing. Trituration with water gave purified title product (170 mg; m.p. 90-93IC; m/e 194).
Anal. Calcd. for C^,O^. 0.25F1,0: C, 5 4.40; H, 5.3 2; N, 14. 10.
Found: C, 5 4.3 7; H, 5.16; N, 13.7 6.
Example 29
5-Hydroxy-5-[11 -0 -butyi)-2-pyrroiyi) 1-2,4,6-(11 H,3H, 5H)pyrimidinetrione Potassium pyrrole (3.0 g, 0.03 mole), 1 -iodobutane (9.2 g, 0.05 moles) and 10 mi of tetrahydrofuran were combined and refluxed for 1.5 hours by which time the reaction mixture had 45 become a thick mass. The reaction mixture was diluted with 30 mi of water and extracted with 35 mi of ether. The ether was backwashed with water, then added to a solution of anhydrous alloxan (4.8 g, 0.03 mole) obtained by heating in 50 mi of ethanol. The ether was distilled away, 6N hydrochloric acid (5 mi, 0.03 mole) was added, and the mixture refluxed for 3 minutes, cooled, evaporated to a gum, and triturated with water to afford title product [5.1 g; m.p. 135 (dec); m/e 2651.
Example 30
5-[11 -(1 -Butyl)-2-furylloxazolidine-2,4-dione Product of the preceding Example (5.1 g, 0.019 mole) was combined with 1 N sodium hydroxide (38 mi, 0.038 mole) and stirred at room temperature for 10 minutes. The reaction mixture was filtered, washed with ether, cooled in an ice-water bath, acidified with cone. hydrochloric acid and extracted 55 with three portions of ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated to gummy solids. The latter was chromatographed on silica 16 GB 2 131 422 A 16 gel with ethyl acetate as eluant and tic monitoring to yield partially purified product isolated as an oil (950 mg). The latter was rechromatographed using 1:1 ethyl acetate:hexane as eluant, yielding purified title productas an oil [0.59 g; mle 222; Rf 0.72 (ethyl acetate)].
Anal. Calcd. for C,,H1,0,N,. 0.5H,O: C, 57.38; H, 6.57; N, 12.17.
Found: C, 5 7.40; H, 6.3 5; N, 12.15. 5 Example 31
Sodium 5411 -0 -butyl)-2-furylloxazolidine-2,4-dione Product of the preceding Example (370 mg, 1.66 mmoles) was dissolved in 5 mi of methanol.
Sodium bicarbonate (90 mg, 1.66 mmoles) was added. The resulting solution was evaporated to dryness and the solid residue triturated with ether to yield the title product [300 mg; m.p. 123 1 260C (dec); tie mobility with 1:1 ethyl acetate:hexane/5% acetic acid as eluant identical with the free base form].
Example 32
5-Hydroxy-5-(1 -phenyl-2-pyrroiYI)-2,4,6-(1 H.3H,5H)pyrimidinetrione 1 -Phenylpyrrole (1.4 g, 0.0 1 mole), alloxan hydrate (1.6 g, 0.0 1 mole) and 50 mI of ethanol were 15 combined and refluxed for 15 minutes. No reaction was noted by tic. 1 N Hydrochloric acid (10 mi, 0.0 1 mole) was added and the acidified mixture refluxed for 15 minutes. Incomplete reaction was noted by tie. A second portion of alloxan hydrate (1.6 g, 0.01 mole) was added and the mixture refluxed another minutes, cooled and evaporated to dryness. Trituration of the residue with water gave title product [2.3 g; m/e 285; m.p. 232-2340C (dec); Rf 0.3 (1:1 ethyl acetate:hexane)l.
Anal. Calcd. for C1,1-11 10^. 0.25H20: C, 58.01; H, 4.00; N, 14.50.
Found: C, 57.84; H, 4.05; N, 14.56.
Example 33
5-(11 -Phenyi-2-pyrroiyi)oxazolidine-2,4-dione The product of the preceding Example (1 g) was heated on a steam bath for 20 minutes with 20 25 mi of 1 N sodium hydroxide. The mixture was then cooled in an ice-water bath, acidified with conc.
hydrochloric acid and the supernatant decanted from the resulting gummy precipitate. The gum was taken up in ethyl acetate, washed with water, and evaporated to an oil (0. 47 g). The aqueous decant was also extracted with ethyl acetate, the extract back washed with water and evaporated to a second oil (0.28 g). The two oils were combined, chromatographed on 150 mi of silica gel with 1:1 ethyl acetate:hexane as eluant and tic monitoring. The early, product fractions were combined, evaporated to an oil (410 mg) and the oil crystallized from ether-hexane to yield purified title product [280 mg; m.p. 130-1321C; m/e 242; Rf 0.47 0:1 ethyl acetate:hexane)l.
Anal. Calcd. for C131-11003N2: C, 64.46; H, 4.16; N, 11. 57.
Found: C, 64.40; H, 4.3 5; N, 11. 5 6. 35 Example 34
5-Hydroxy-5-(1 -methyl-3-indolyi)-2,4,6-(1 H,3H.5H)pyrimidinetrione Alloxan hydrate (1.6 g, 0.0 1 mole) 1 -methylindole (1.3 g, 0.0 1 mole) and ethanol (50 mO were combined and the mixture refluxed for 0.5 hour, then concentrated to half- volume, diluted with water and the resulting product recovered by---filtration [2.7 g, Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic 40 acid)].
Example 35
5-(11 -Methyi-3-indoiyi)oxazolidine-2,4-dione Product of the preceding Example (2 9) was heated on a steam bath for 15 minutes with 35 m] of 1 N sodium hydroxide. The reaction mixture was cooled to room temperature, acidified to pH 1 with conc. hydrochloric acid, and decanted from a small amount of gum (130 mg). The decant was clarified by filtration, cooled in an ice-water bath, and the resulting solids (330 mg) recovered by filtration. The filtrate was extracted with ethyl acetate; the extract was backwashed with water and evaporated to solids (0.61 g). The solid products were combined and recrystallized from ethyl acetate/hexane to yield title product (0.33 g; m.p. 152-153.51C).
Anal. Calcd. for C,,H100^. 0.125H20: C, 61.99; H, 4.45; N, 12.05.
Found: C, 61.99; H, 4.45; N, 12.02.
Example 36
5-Hydroxy-5-(5-bromo-3-indoiyi)-2,4,6-(1 H.3H,5H)pyrimidinetrione Alloxan hydrate (1.6 g, 0.01 mole) was dissolved in 40 m] of ethanol by heating. 5-Bromoindole 55 - 5 17 GB 2 131 422 A 17 (1.96 g, 0.01 mole) was added and heating near reflux continued for 15 minutes. Tic did not indicate that reaction had occurred. 1 N Hydrochloric acid (10 mi) was then added while maintaining the reaction near reflux. After 10 minutes, the reaction was concentrated to wet solids. Trituration of these wet solids with water gave the title product [3.17 9, m.p. 250IC; Rf 0.45 (11:1 ethyl acetate:hexane/5% acetic acid); Rf 0.3 (1:5 ethvl acetate:hexane/5% acetic acid)].
Example 37 5-(5-Bromo-3-indoiyi)oxazolidine-2,4-dione Product of the preceding Example (3.1 g) was heated on a steam bath with 50 mi of 1 N sodium hydroxide for 15 minutes, then cooled and crude product (1.25 g) precipitated by acidification with cone. hydrochloric acid. Chromatography on silica gel, using 1 A ethyl acetate:hexane as eluant and tie 10 monitoring gave purified title product [0.41 g; m.p. 185-1 891C; Rf 0.55 (1:5 ethyl acetate:hexane/5% acetic acid)].
Anal. Calcd. for C111-1,03N2Br: C, 44.76; H, 2.38; N, 9.49.
Found: C, 45.10; H, 2.68; N, 9.58.
Example 38
5-Hydroxy- 5-(2-thiazoiyi)-2,4,6-(1 H,3H,5H)pyrimidinetrione Thiazole (1.7 g, 0.02 mole) was dissolved in tetrahydrofuran (35 m]) and cooled to -600C.
Butyllithium (9 mi of 2.4M in hexane, 0.0216 mole) was added dropwise over 20 minutes, and the reaction mixture stirred for an additional 30 minutes at -601C. In this manner 2-thiazolyllithium was formed. Anhydrous alioxan (3 g, 0.021 mole) was dissolved in 20 mi of tetrahydrofuran and added 20 dropwise over 20 minutes, keeping the temperature at -601C. The stirred reaction mixture was warmed to room temperature over 30 minutes, then recooled to O'C. 1 N Hydrochloric acid (25 m]) was added portion wise and the quenched reaction mixture extracted with 50 m] of ethyl acetate. The ethyl acetate extract was back-washed with 15 m[ of water, dried over anhydrous sodium sulfate, filtered and evaporated to yield title product [1.9 g; m/e 227; Rf 0.4 (11:1 ethyl acetate:hexane/5% 25 acetic acid)].
By the same procedure, oxazole is converted to 5-hydroxy-5-(2-oxazoiyi)-2, 4,6 (1 H,3 H,5 H) pyri midi netri one.
Example 39
5-(2-Th iazoly0oxazo lid ine-2,4-dio ne Title product of the preceding Example (1.37 g) was stirred at room temperature with 24 mi of 1 N sodium hydroxide. The reaction mixture was allowed to stand for 25 minutes, acidified with 3 m] of glacial acetic acid and extracted with two 50 mi portions of ethyl acetate. The extracts were separately dried over sodium sulfate, filtered and evaporated to solids, the first yielding 184 mg, the second 85 mg. These solids were combined and chromatographed on 50 mI of silica gel with 1:1 ethyl acetate:hexane/5% acetic acid as eluant and tie monitoring. Clean product fractions were combined, evaporated to dryness and the residue triturated with hexane to yield purified title product (155 mg; m. p. 150-152 'C).
Anal. Calcd. for C61-1403N.S: C, 3 9.13; H, 2.19; N, 15.2 1.
Found: C, 39.53; H, 2.52; N, 14.95. 40 By the same procedure, the other product of the preceding Example is converted to 5-(2 oxazoiyl)oxazolidine-2,4-dione.
Example 40
5-Hydroxy-5-(2-benzthiazolyl)-2,4,6-(1 H,3H,5H)pyrimidinetrione By the procedure of Example 38, benzthiazole (2.7 g, 0.02 moles) was converted to its 2-lithio 45 derivative and then reacted with anhydrous alloxan to yield title product, initially isolated as an oil. The latter was crystallized from ether-hexane [2.2 g; Rf 0.55 0:1 ethyl acetate:hexane/5% acetic acid)].
Example 41
5-(2-Benzthiazoiyi)oxazolidine-2,4-dione Product of the preceding Example (2.15 g) was stirred with 30 mi of 1 N sodium hydroxide for 30 50 minutes. The reaction mixture was extracted with ether and product (0.46 g) precipitated by acidification of the aqueous layer with 6N hydrochloric acid. Chromatography on 50 mi of silica gel with 1:1 ethyl- acetate: hexa ne/5% acetic acid as eluant and tie monitoring, followed by recrystallization from acetoneisopropyl ether gave purified title product [110 mg, m.p. 214- 2160C (dec)l.
Anal. Caled. for C1.H.03N2S: C, 51.29; H, 2.58; N, 11.96. 55 Found: C, 5 1.5 1; H, 2.9 9; N, 12.2 1.
18 GB 2 131 422 A 18 Example 42
2-(6-Chloro-B-chromanyl)-2-trimethyisiloxyethanenitrile 6-Chlorochroman-8-carbaidehyde (7 g, 0.036 mole) in 70 m] of methylene chloride was cooled to 0-51C. Zinc iodide (100 mg) was added, followed by the dropwise addition of trimethylsilylcarbo nitrile (4.26 9, 0.043 mole). The reaction mixture was stirred at room temperature for 64 hours, then washed in sequence with three portions of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [9.5 g; ir(CHIC12) 2857, 1479, 1215, 1190, 1060 cm-11.
Example 43
Ethyl 1-(6-chloro-8-chromanyi)-1-hydroxymethanecarboximidate hydrochloride To cold W-51C), saturated ethanolic hydrogen chloride (250 mi) there was added, in a dropwise manner, product of the preceding Example (9.29 g) in 15 m] of ethanol, keeping the temperature below 1 OOC. The mixture was stirred at 0-51C for 35 minutes and then evaporated to an oil. Crystallization from ethanolether gave title product [5.7 g; m.p. 125-1270 (dec); m/e 271/2691.
Example 44
5-(6-Chforo-8-chromanyi)oxazolidine-2,4-dione Product of the preceding Example (5.4 9, 18.6 mmoles) was suspended in 250 m] of tetra hydrofuran, cooled in an ice-water bath, and triethyiamine (6.01 g, 0.06 mole) added. The cold mixture was perfused with phosgene for 30 minutes, stirred at room temperature for 1 hour and then poured into 1 liter of crushed ice. The quenched reaction mixture was extracted with three portions of 20 methylene chloride. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and evaporated to solids. The residue was recrystallized from toluene to yield purified title product (3.28 9, m.p. 1 70-1721C, m/e 269/267).
Anal. Calcd. for C1,1-11104NCI: C, 53.84; H, 3.77; N, 5.23.
Found: C, 53.73; H, 3.83; N, 5.48. 25 Example 45 2-(6-Fluoro-8-chromanyl)-2-trimethyisiloxyethanenitrile By the procedure of Example 42, 6-fluorochroman-8-carbaidehyde (3.2 g, 0. 0178 mole) was converted to title product as an oil [4.51 g, m/e 279; ir (CHC12) 1498, 1205, 1066 cm-'].
Example 46 Ethyl 1 -(6-fi uoro-8-chro ma nyi)- 1 -hydroxymethanecarboxi mi date hydrochloride Using a reaction time of 1 hour at 0-51 C, the procedure of Example 43 was employed to convert product of the preceding Example (4.4 g) to title product [4.1 g; m.p. 124-1260C (dec); m/e 2531.
1 Example 47
5-(6-Fluoro-8-chromanyi)oxazolidine-2,4-dione By the procedure of Example 44, product of the preceding Example (3.9 g, 0.0 134 mole) was converted to crude title product. Crude solids were taken into 1 N sodium hydroxide and extracted with two portions of ether. Product was reprecipitated by adding the basic aqueous layer slowly to excess 3N hydrochloric acid. Recrystallization from toluene gave purified title product [2.73 g; m.p. 174- 40 1 761C; m/e 2511.
Anal. Calcd. for C,2H,,0,NF: C, 57.37; H, 4.01; N, 5.58.
Found: C, 57.74; H, 3.91; N, 5.40.
Example 48 45 2-(5-Chloro-2,3-dihydro-7-benzo[blfuranyi)-2trimethyisiloxyethanenitrile 5-Chloro-2,3-dihydrobenzo[blfuran-7-carbaidehyde (900 mg, 4.9 mmoles) was dissolved in 25 m] of ether. Zinc iodide (20 mg) and then trimethylsilylcarbonitrile (970 mg, 9.8 mmoles) were added and the mixture stirred 16 hours at room temperature, then diluted with 50 mi ether, washed with three portions of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [1.4 g; m/e 283/281; ir(CHC12) 1479, 1457,1435,1180, 866, 848 cm-11.
By the same method 5-fluoro-2,3-dihydrobenzo[blfuran-7-carbaidehyde is converted to 2-(5fluoro-2,3-dihydro-7-benzo[blfuranyl)-2trimethyisiloxyethanenitrile.
Example 49
Ethyl 1-(5-chloro-2,3-dihydro-7-benzo[blfuranyl)-1hydroxymethanecarboximidate hydrochloride 55 By the procedure of Example 43, title compound of the preceding Example (1.37 g) was 19 GB 2 131 422 A 19 converted to title product. The initially isolated solids were repulped twice in ether to obtain purified product [1.28 g; m.p. 149-1 521C (dec); m/e 257/255; ir(KBr) 3162,2875, 1650,1524,1458 cm 11.
By the same method the fluoro compound of the preceding Example is converted to ethyl 1-(5fluoro-2,3-dihydro-7-benzo[blfuranyi)-1-hyd roxym etha neca rboxi mi date hydrochloride.
Example 50 5-(5-Chloro-2,3-dihydro-7-benzo[blfuranyl)oxazolidine-2,4dione By the procedure of Example 44, title compound of the preceding Example (1.1 g) was converted to toluene recrystallized title product [630mg; m.p. 197-1 991C; m/e 255/253; ir(KBr) 3084, 1833, 1810, 1746 cm-'].
By the same procedure the fluoro analog of the preceding Example is converted to 5-(5-fluoro2,3-dihydro-7-benzo[blfuranyl)oxazolidine-2,4dione.
Example 51 2-(3-Methyi-5-isoxazoiyi)-2-trimethyisilylethanenitrile By the procedure of Example 42, 3-methylisoxazole-5-carbaldehyde (3.4 g, 0.032 mole) was converted to title product, isolated as an oil (6.5 g, no aldehyde proton by nmr).
By the same method, isothiazole-5-carbaldehyde is converted to 2-(5thiazoiyl)-2-trimethyisiiyiethanenitrile and 5-methylisoxazole-3carbaidehyde (Kane et aL, Japan 62/17,572) is converted to 2(5-methyl-3isoxazolyl)-2-trimethyisilylethanenitrile.
Example 52 Ethyl 1 -hydroxy-1 -(3-methyl-5isoxazoiyi)methanecarboxirnidate hydrochloride Title product of the preceding Example (6.5 9) was dissolved in cold, saturated ethanolic hydrogen chloride (50 mi) and held at 5IC for 16 hours. Title product was recovered by filtration (3.3 g, m.p. 119-121 'C).
By the same method, the other products of the preceding Example are converted to ethyl 1 - 25 hydroxy-1 -(5-isothiazoiyl)methanecarboximidate hydrochloride and ethyl 1 -hydroxy-1 -(5-methyl-3 isoxazoiyi)methanecarboximidate hydrochloride.
Example 53
5-(3-Methyi-5-isoxazoiyi)oxazolidine-2,4-dione By the procedure of Example 44, title product of the preceding Example (2. 2 g), was converted to 30 title product. After quench into crushed ice, the product was extracted into ether, the combined extracts dried and evaporated to an oil (1.4 g). Further extraction with ethyl acetate and evaporation gave additional oil (0.4 g). The oils were combined and partitioned between 25 mi of 1 N sodium hydroxide and 25 mi of ether. The basic aqueous phase was separated, acidified with conc.
hydrochloric acid and extracted with 25 mi of ethyl acetate. The ethyl acetate extract was back- washed with water, evaporated to dryness, the residue triturated with ether (146 mg, m.p. 173 1 751C). The ether triturate was evaporated to dryness and triturated with fresh ether (238 mg, m.p.
175-1 770C).
By the same method, the other products of the preceding Example are converted to 5-(5 isothiazolyl)oxazoildine-2,4-dione and 5-(5-methyl-3isoxazolyl)oxazolidine-2,4-dione.
Example 54 5-(5-Chloro-2-ethoxy-3-pyridyl)oxazolidine-2,4-dione 5-(2-Ethoxy-3-pyridyi)oxazolidine-2,4-dione (125 mg) was suspended in 100 mi of water and dissolved by warming to 560C. Chlorine was bubbled into the warm solution for 30 minutes, during which time the temperature slowly dropped to 341C and a precipitate formed. The reaction mixture was flushed with nitrogen for 30 minutes and crude product recovered by filtration (101 mg, m.p.
11 9-124IC). Two recrystallizations from 2:1 ethanol:water gave purified title product [24 mg; m.p.
145-147OC; Rf 0.56 (1:1 ethyl acetate:chloroform); m/e 2561.
By the same procedure, substituting 10% fluorine in nitrogen, 5-(2-ethoxy3-pyridyi)oxazoiidine- 2,4-dione is converted to 5-(5-fluoro-2-ethoxy-3-pyridyi)oxazolidine-2,4- dione.
Example 55
2-(3-Furyl)-2-trimethyisiloxyethanenitrile To a mixture of 3furaldehyde (1.92 g, 20 mmoles) and about 100 mg of zinc iodide in 25 mi of ether, trimethylsilylcarbonitrile (4.74 g, 48 mmoles) was added dropwise. The mixture was stirred about 16 hours at room temperature. The reaction mixture was washed sequentially with saturated 55 sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 2-(3-furyl)-2-trimethyisiloxyethanenitrile [2.2 g; pnmr/CDCI,,/delta: 0.2 (s, 9W; 5.4 (s, 1 W; 6.4 (m, 1 H); 7.3 (m, 1 H; 7.5 (m, 1 W].
GB 2 131 422 A 20 Example 56 Ethyl 1 -hydroxy-1 -(3-furyi)methanecarboximidate hydrochloride 2-(3-Furyl)-2-trimethylsiloxyethanenitrile (1.0 9) was dissolved in 10 mi of saturated ethanolic hydrogen chloride at 0-51C. The resulting solution was held at about 50C for 16 hours. The reaction mixture was concentrated to about half volume and diluted with ether. Filtration, with ether wash, gave ethyl 1 -hydroxy-1 -(3-furyi)methanecarboximidate hydrochloride (746 mg; m.p. 11 3-115OC; m/e 169).
Example 57 5-(3-FuryOoxazol idi ne-2,4-d lone Ethyl 1 -hydroxy-1 -(3-furyi)methanecarboximidate hydrochloride (1.5 g, 7. 5 mmoles) was 10 combined with 50 mi of tetrahydrof uran and triethylamine (2.21 g, 21.9 mmoles) and cooled to 1 OOC. Phosgene was bubbled through the cooled reaction mixture for 20 minutes. After stirring the mixture for an additional 30 minutes, nitrogen was flushed through the mixture for 10 minutes. The reaction mixture was poured slowly into 100 9 of crushed ice. The product was extracted into two portions of ether and crude product isolated as an oil by evaporation. The oil was taken up in 5 mi of 1 N sodium 15 hydroxide and extracted with ether. The basic aqueous phase was acidified and extracted with fresh ether. Product was isolated as a gummy solid (600 mg) by evaporation of the latter ether extract. Trituration with chloroform afforded purified 5-Q-f uryi)oxazolidine-2,4-dione (109 mg; m. p. 8688OC; m/e 167). Addition of hexane to the chloroform triturate gave a second crop of product (66 mg; m.p. 86-88'C, m/e 167).
Analysis: Calcd. for C71-1104N: Found:
Example 58 2-(5-Chloro-2-furyi)-2-trimethyisiloxyethanenitrile C, 50.31; H, 3.01; N, 8.38. C, 4 9.9 7; H, 3.13; N, 8.3 7.
5-Chloro2-furaidehyde (2.7 9, 21 mmoles) was dissolved in 30 m] of ether. Trimethylsilylcarbo- 25 nitrile (6.3 m], 50 mmoles) and zinc iodide (about 50 mg) were added and the mixture stirred for 1.5 hours at room temperature, at which time tic (hexane:ethyl acetate 8:1) indicated complete reaction.
Concentration to dryness afforded 2-(5-chloro-2-furyi)-2trimethyisiloxyethanenitrile as an oil (5.5 g; pnmr/MCVdelta: 0.3 (s, 9H); 5.4 (s, 1 H); 6.1 (d, 11-1); 6.5 (d, 1 H)].
Example 59
Ethyl 1-(5-chloro-2-furyi)-1 -hydroxymethanecarboximidate hydrochloride 2-(5-Chloro-2-furyi)-2-trimethyisiloxyethanenitrile (2.3 g) was dissolved in saturated ethanolic hydrogen chloride (25 m]) at OOC. The solution was held for 2.5 hours at about 51C and then concentrated to oil. Trituration with 20 mi of ether afforded crystalline ethyl 1-(5-chloro-2-furyi)-1 hydroxymethanecarboximidate hydrochloride (1.2 g; m.p. 112-114OC; m/e203).
Example 60
5-(5-Chloro-2-furyi)oxazolidine-2,4-dione Ethyl 1-(5-chloro-2-furyi)-1 -hyd roxymetha neca rboxi mi date hydrochloride (1.2 g, 5 mmoles) was suspended in 50 m] of tetrahydrofuran and cooled in an ice bath. Following the addition of triethylamine (2.1 m], 15 mmoles), phosgene was bubbled into the reaction mixture for 20 minutes, 40 maintaining the temperature at 10 to 201C. The mixture was flushed with nitrogen and poured slowly into 100 mi of crushed ice. The quenched reaction mixture was extracted with 100 mi of ether, and the ether back-extracted with brine and concentrated to an oil. The oil was taken up in 15 mI of fresh ether, the solution clarified and extracted with 10 m] of 1 N sodium hydroxide. The basic extract was acidified with concentrated hydrochloric acid and product extracted into ethyl acetate. After back extracting 45 with water, the ethyl acetate layer was concentrated to an oil (550 mg). A portion of this oil (500 mg) was chromatographed on about 50 mi of silica gel, with 5:1 hexane:ethyl acetate containing 5% acetic acid as eluant. The column was monitored by tic (same eluant). Late eluted, product containing fractions were combined, evaporated to dryness and triturated with hexane, affording 5-(5-chloro-2- fu ryl)oxazo lidi ne-2,4-di one [177 mg; m.p. 112-1 141C; m/e 201; Rf 0. 25 (5:1 hexane:ethyl acetate 50 with 5% acetic acid)].
Analysis: Calcd. for C,H404NCI: C, 41.7 1; H, 2.00; N, 6.9 5.
Found: C, 41.80; H, 2.2 1; N, 6.7 7.
Example 61 55 2-(5-Bromo-2-furyi)-2-trimethyisiloxyethanenitrile 5-Bromo-2-furaidehyde (1.1 g, 6 mmoles) was dissolved in 50 mI of ether. A catalytic quantity (about 50 mg) of zinc iodide was added and then trimethyisilylcarbonitrile (746 mg, 1.2 equiv.) was added dropwise. The reaction was monitored by ir (disappearance of typical carbonyl absorption) and 21 GB 2 131 422 A pnmr (disappearance of typical aldehyde proton peak). After 60 minutes at room temperature, the reaction mixture was washed with saturated sodium bicarbonate, twice with water, and finally with brine, dried over anhydrous sodium sulfate and evaporated to yield 2-(5-bromo-2f uryl)-2- tri methylsiloxyethanenitrile as an oil [1.2 9; pnmr/CDCVdelta: 0.3 (s, 9H); 5.6 (s, 1 Irl); 6.4 (cl, 1 H); 6.6 (cl, 1 H)].
Example 62 Ethyl 1-(5-bromo-2-furyi)-1-hydroxymethanecarboximidate hydrochloride Following the procedure of Example 56, except that the reaction mixture was not concentrated prior to addition of ether, 2-(5-bromo-2-furyi)-2- trimethyisiloxyethanenitrile (1.2 g) was converted to ethyl 1-(5-bromo-2- furyi)-1 -hydroxymethanecarboximidate hydrochloride (480 mg, m.p. 120- 1220C, m/e 247, 249). A less pure second crop (235 mg, m.p. 104-1061C) was recovered by evaporation of mother liquor and trituration of the residue with ether.
Example 63
5-(5-Bromo-2-furyl)oxazolidine-2,4-dione Ethyl 1 -(5-bromo-2-furyl)-1 -hyd roxymetha neca rboxi mi date hydrochloride (982 mg, 3.4 mmoles) was converted to 5-(5-bromo-2-furyi)oxazolidine-2,4-dione [126 mg, m.p. 126-129Q m/e 245, 15 247, Rf 0.2 (5"1 hexane:ethyl acetate with 5% acetic acid)] by the procedure of Example 57.
Example 64
2-(3-Bromo-2-furyi)-2-trimethyisiloxyethanenitrile By the procedure of Example 55, 3-bromo-2-furalclehyde (1.75 g, 10 mmoles) in 50 m] of ether was reacted with tri methyl si lylca rbonitri 1 e (8.8 mi, 70 mmoles) in the presence of about 100 mg of 20 zinc iodide. At the end of the 16 hour reaction period, the ether supernatant was decanted from solids and evaporated to dryness to yield 2-(3-bromo-2-furyi)-2trimethyisiloxyethanenitrile [3 g, Rf 0.7 (3:1 hexane:ethyl acetatefl.
Example 65
* Ethyl 1-(3-bromo-2-furyi)-1 -hydroxymethaneca rboxi mi date hydrochloride 2-(3-Bromo-2-furyi)-2-trimethoxysiiyiethanenitrile (6.8 g) was dissolved in 70 m] of saturated ethanolic hydrogen chloride at OIC and maintained at about 5c1C for 2 hours. Concentration to dryness and trituration with acetone afforded ethyl 1-(3-bromo-2-furyl)-1 -hydroxymethanecarboximidate hydrochloride [4.4 9, m.p. 117- 1190 (dec)l.
Example 66 5-(3-Bromo-2-furyi)oxazolidine-2,4-dione By the procedure of Example 60, except that phosgene was bubbled into the reaction mixture at 0 to 1 OOC, ethyl 1-(3-bromo-2-furyi)-1 - hydroxymethanecarboximidate hydrochloride (4.4 g) was converted to purified 5-(3-bromo-2-furyi)oxazolidine-2,4-dione [847 mg; m.p. 128-1 30IC; Rf 0.20 (5:1 hexane:ethyi acetate containing 5% acetic acid)].
Analysis: Calcd. for C7H404INIBr: C, 34.16; H, 1.63; N, 5.69.
Found: C, 34.30; H, 1.88; N, 5.67.
Example 67
2-(2-Furyi)-2-trimethyisiloxyethanenitrile 2-Furaldehyde (24 g, 0.25 mole) was cooled to 0-51C, zinc iodide (500 mg) was added and the 40 mixture stirred. Tri methylsi lyl carbon itri le (30 mi) was added dropwise. The mixture was allowed to warm to room temperature and stirred for approximately 64 hours at room temperature. The reaction mixture was diluted with methylene chloride, extracted twice with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and evaporated to yield 2 (2-furyi)-2-trimethyisiloxyethanenitrile as an oil [36 g, 74%; pnmr/CDCI, /delta: 0.2 (s, 9F1); 5.6 (s, 1 H); 45 6.4 (m, 1 H); 6.6 (m, 1 F1); 7.4 (d, 1 W].
Example 68
Ethyl 1-(2-furyi)-1-hydroxymethanecarboximidate Following the procedure of Example 56, 2-(2-furyi)-2- trimethyisiloxyethanenitrile (15 g) was reacted with saturated ethanolic hydrogen chloride, except that a reaction time of about two hours was 50 employed. Crude product was isolated by evaporating the reaction mixture to an oil. The oil was partitioned in 400 mI of chloroform and saturated sodium bicarbonate. The chloroform was washed twice with fresh saturated sodium bicarbonate, washed once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield ethyl 1-(2-furyl)-1 -hydroxymethane carboximidate as an oil [10.6 g, 81 %; pnmr/CDCI,/delta: 1.3 (t, 31H1); 4. 1 (q, 2H); 5.1 (s, 1 H); 4.8-5.2 55 (m, 1 W; 6.3 (m, 2 W; 7.3 (d, 1 W].
22 GB 2 131 422 A 22 Example 69 5-(2-Furyi)oxazolidine-2,4-dione Ethyl 1-(2-furyl)-1 -hydroxymethanecarboximidate (10.5 g, 6.2 mmoles) was dissolved in 125 m] of stirring tetrahydrofuran and cooled to 0-51C. Triethylamine (12.5 g, 0. 124 mole) was added and the cold solution then perfused with phosgene for 35 minutes, warmed to room temperature and stirred for an additional 16 hours. The reaction mixture was slowly poured into 1 liter of ice and water. The product was extracted into 3 portions of ethyl acetate. The extracts were combined and product extracted into 4 portions of 1 N sodium hydroxide. The combined aqueous extracts were acidified with 6N hydrochloric acid, and product extracted into 4 portions of chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and 10 evaporated to yield crude product as an oil (2.1 g). Column chromatography on 100 g of silica gel with 2:1 chloroform:ethyl acetate as eluant in 10 mi fractions, monitored by tic, gave, by evaporation of fractions 36-48, purified 5-(2-fu ryl)oxazo lidi ne-2,4-d ion e (281 mg; m.p. 99-102IC; m/e 167). Recrystallization from toluene gave more highly purified product (235 mg, m.p. 101-1 031C).
Analysis: Caled. for CH104M C, 50.3 1; H, 3.02; N, 8.38. 15 Found: C, 5 0.4 1; H, 3.2 5; N, 8.2 8.
Example 70
5-Hydroxy-5-(3-methoxy-2-furyi)-2,4,6(1 11-11,3 H,5 H)-pyri midi netrione 3-Methoxyfuran (3.5 g, approximately 50% pure from Preparation 10), alloxan hydrate [5,5 dihydroxy-2,4,6(1 H,3H,5H)- pyrimidinetrione, 4.8 g] and 75 mi of ethanol were combined and 20 refluxed for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness.
Trituration of the residue with 25 mi of water afforded 5-hydroxy-5-(3methoxy-2-furyi)- 2,4,60 H,3H,5H)-pyrimidinetrione [1,9 g, m.p. 120-130 (dec.), m/e 2401.
Example 71
5-(3-Methoxy-2-furyi)oxazolidine-2,4-dione 5-Hydroxy-5-(3-methoxy-2-furyi)-2,4,6(1 H,3 1-1,5 H)-pyri midi netrione (1.7 g) was stirred with 1 N sodium hydroxide (14 mI, 14 mmoles) for 20 minutes. The reaction mixture was acidified with acetic acid and product extracted into ethyl acetate and isolated in crude form by evaporation to an oil.
Chromatography on ca. 100 mi of silica gel, monitored by tic, afforded 5(3-methoXY-2 furyl)oxazolidine-2,4-dione [470 mg, m.p. 102-1040C, Rf 0.6 (1:1 hexane:ethyl acetate with 5% 30 acetic acid)].
Example 72
2-(5-Phenyi-2-thienyi)-2-trimethyisiloxyethanenitrile 5-Phenyl-2-thenaldehyde (0.9 g) in 35 mi of ether was reacted with 1 m] of trimethylsilylcarbo nitrile in the presence of about 50 mg of zinc iodide. After 1 hour of stirring at room temperature, tic 35 indicated reaction was complete. Evaporation to dryness gave 2-(5-pheny]- 2-thienyi)-2-tri methyl siloxyethanenitrile [1.65 g, Rf 0.5 (5:1 hexane:ethyl acetate with 5% acetic acid)].
Example 73
Ethyl 1 -hydroxy-1 -(5-phenyi-2-thienyi)methanecarboximidate hydrochloride 2-(5-P h enyl-2-th lenyl)-2-tri methyl si loxyetha n en itri 1 e (1.6 g) was dissolved in 30 m[ of cold, saturated ethanolic hydrogen chloride and maintained at 0 to 51C for about 17 hours. The reaction mixture wasevaporated to dryness and triturated with ethyl acetate to yield ethyl 1 -hydroxy-1 -(5 phenyl-2-thienyi)methanecarboximidate hydrochloride [0.9 g; pnmr/DMSO/delta: includes 1.1 (31-1); 4.0 (2H); 5.2 (1 W; 6.5 (1 W.
Example 74
5-(5-Phenyi-2-thienyl) oxazol 1 di ne-2,4-di one Ethyl 1 -hydroxy-1 -(5-phenyl-2-th i enyl) m etha neca rboxi m i date hydrochloride (790 mg, 2.6 mmoles) and triethylamine (1.4 mi, 10 mmoles) were reacted with phosgene and product isolated according to the procedures of Example 12, except that the eluant in the chromatography was 2:1 ethyl acetate:hexane, affording 5-(5-phenyl-2-thienyi)oxazolidine-2,4- dione (172 mg, m.p. 23350 235-C).
Analysis: Calcd. for C,1-1,0,NS:
Found:
Example 75 55 2-(2-Thienyi)-2-trimethyisiloxyethanenitrile C, 60.23; H, 3.50; N, 5.40. C, 59.94; H, 3.65; N, 5.38.
By the procedure of Example 67, 2-thenaldehyde (56.1 g, 46.8 mi, 0.5 mole) was reacted for 16 hours with trimethyisilylcarbonitrile (60 mi) in the presence of zinc iodide (approximately 0.5 g), yielding 2-(2-thienyi)2-trimethyisiloxyethanenitrile as an oil [92 g; m/e 211; pnmr/CDCI, /delta: 0.2 (s, 9 W; 5.8 (s, 11-1); 6.9-7.5 (m, 3 W.
23 GB 2 131 422 A 23 Example 76 Ethyl 1-hydroxy-l-(2-thienyl)methanecarboximidate 2-(2-Thienyi)-2-trimethyisiloxyethanenitrile (45 g) was dissolved in 450 mi of absolute ethanol. The solution was cooled to 0-51C and perfused with hydrogen chloride for 40 minutes. The mixture was kept at about 5IC for 16 hours and evaporated to dryness. The residue was triturated with four 200 mi portions of ether, and then partitioned between 400 mi of methylene chloride and saturated sodium bicarbonate. The organic phase was washed twice with saturated sodium bicarbonate, treated with activated carbon, filtered and concentrated to yield ethyl 1 -hydroxy-1 - (2-thienyl) methane carboximidate as an oil which solidified on standing [10 g; pnmr/CDCI,/delta: 1,2 (t, 31-1); 4.1 (9, 21-1); 5.2 (s, 1 H); 5.9 (s, 1 H); 6.8-7.3 (m, 31-1); 7.3-8.1 (s, 1 H].
Example 77 5-(2-Thienyi)oxazolidine-2,4-dione Ethyl 1 -hydroxy-1 -(2-thienyi)methanecarboximidate (10 g, 5.4 mmoles) and triethylamine (15.1 m], 10.8 mmoles) were dissolved in 100 mi of tetra hydrofura n. The solution was cooled to 0-50C and perfused with phosgene for 45 minutes. Stirring was continued for an additional 5 hours at 0-50C. 15 The reaction mixture was poured slowly over 1500 mi of crushed ice. The product was extracted into 1.1 liter of ethyl acetate in three portions. The combined ethyl acetate extracts were then extracted twice with saturated sodium bicarbonate and once with 1:1 saturated sodium carbon ate:water. The combined bicarbonate and carbonate washes were acidified to pH 1-2 with 6N hydrochloric acid and product extracted into several portions of ether. The combined ether extracts were washed with brine, 20 dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and evaporated to yield product (3.0 g). Recrystallization from toluene afforded 5-(2- thienyi)oxazolidine-2,4-dione (1.8 g; m.p. 138-1401C, m/e 183).
Analysis: Calcd. for C,1-15NO,S: C, 4 5.8 9; H, 2.7 5; N, 7.6 5.
Found: C, 45.99; H, 2.87; N, 7.62. 25 Example 78
2-(3-Methyl-2-thienyi)-2-trimethyisiloxyethanenitrile Following the procedure of Example 67, 3-methyl-2-thenaldehyde (31.6 g, 0. 25 mole) was reacted with trimethylsilylcarbonitrile (30 ml) for 16 hours in the presence of 500 mg of zinc iodide.
The reaction mixture was diluted with 200 mi of methylene chloride and further isolated also according 30 to Example 13, affording 2-(3-methyl-2-thienyi)-2- trimethylsiloxyethanenitrile [52 g, 93%; pnmr/CDCI,/delta: 0.2 (s, 91-1); 2.3 (s, 31-1); 5.7 (s, 1 H); 6.8 (cl, 1 H); 7.25 (d, 1 H)].
Example 79
Ethyl 1-hydroxy-l-(3-methy]-2-thienyi)methanecarboximidate 2-(3-Methyi-2-thienyi)-2-trimethyisiloxyethanenitrile (13 g) was added dropwise to 100 mi of 35 cold ethanol, saturated with hydrogen chloride, keeping the temperature at 0-41C. After 1 hour at 0-40C, the reaction mixture was evaporated to dryness. The residue was triturated three times with mi portions of ether, and then partitioned between 300 mi of methylene chloride and saturated sodium bicarbonate. The separated methylene chloride layer was washed with two additional portions of saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to 40 yield ethyl 1 -hydroxy-1 -(3-methyi-2-thienyi)methanecarboximidate (8.0 g, 69%; m.p. 73-76IC; m/e 199).
Example 80
5-(3-Methyl-2-thienyl)oxazolidine-2,4-dione Ethyl 1 -hydroxy-1 -Q-m ethyl-2-th i enyi) metha neca rboxi mi date (6.0 g, 0.03 mole) was dissolved 45 in 75 mi of tetrahydrofuran and cooled to 0-51C. Triethylamine (6.07 g, 8. 37 mi, 0.06 mole) was added, the solution was perfused with phosgene for 35 minutes, and poured slowly into 1 Nter of ice and water. The product was extracted into three portions of ethyl acetate. The ethyl acetate extracts were combined and product extracted into four portions of saturated sodium bicarbonate. The combined aqueous extracts were acidified with 61M hydrochloric acid and product re-extracted into 3 50 portions of fresh ethyl acetate. The combined fresh organic extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to yield product as an oil (2. 4 g, 41 %), which crystallized on scratching. Recrystallization from toluene gave purified 5-(3-methyl-2- thienyi)oxazolidine-2,4-dione (1.84 g, 31 % overall; m.p. 119-121 'C, m/e 197).
Analysis: Calcd. for C,HANS: C, 48.72; H, 3.58; N, 7.10. 55 Found: C, 48.65; H, 3.58; N, 7.01.
A second crop of product (0.63 g) was obtained by extraction of the initial ethyl acetate extracts with 3 portions of 1 N sodium hydroxide, followed by further isolation as above.
24 GB 2 131 422 A 24 Example 81 2-(5-Methyi-2-thienyi)-2-trimethyisiloxyethanenitrile 5-Methyl-2-thenaldehyde (25 9, 0.2 mole), zinc iodide (266 mg) and 100 mi of ether were combined and stirred at room temperature. Tri methyl si ly] ca rbonitri le (23.5 g, 0.24 mole) was added dropwise and the reaction mixture stirred for an additional 2 hours. The reaction mixture was diluted with 100 m] of ether, washed with two 50 mi portions of 5% sodium bicarbonate, washed with two 25 m[ portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to produce 2-(5-methyi-2-thienyi)-2-trimethyisiloxyethanenitrile [42 g; pnmr/CDCI,/delta: 0.2 (s, 91-1); 2.2 (s, 31-1); 5.6 (s, 11-1); 6.6- 7.4 (m, 2H)].
Example 82 Ethyl 1 -hydroxy-1 -(5-methy]-2-thienyl)methanecarboximidate hydrochloride With cooling to 0-51C, ethanol (550 mi) was saturated with hydrogen chloride. 2-(5-MethVI-2thienyl)-2-tri methyl si loxyethane nitri le (42 9) was dissolved in portions and the solution maintained at OIC for 2.5 hours. The reaction mixture was evaporated to dryness and the residue triturated with diethyl ether to provide ethyl 1 -hydroxy-1 -(5-methyi-2thienyi)methanecarboximidate hydrochloride 15 [33 g; m.p. 122-1231C, pnmr/DMSO/delta: M-1.6 (31-1); 2.5 (31-1); 4.6 (21- 1); 5.9 (1 H). 6.6-7.2 (2H)I.
Example 83
5-(5-Methyi-2-thienyi)oxazol id ine2,4-di one Ethyl 1 -hydroxy-1 -(5-methyi-2-furyi)methanecarboximidate hydrochloride (10 g, 0.042 mole) 20 was combined with triethylamine (14.1 g, 0.14 mole) in 250 mi of tetrahydrofuran and cooled to 0 51C. The cold reaction mixture was perfused with phosgene for 30 minutes, warmed to room temperature and poured portionwise onto about 275 m[ of crushed ice. The product was extracted into two 200 m] portions of ethyl acetate. The ethyl acetate extracts were combined and extracted with two m[ portions of 1 N sodium hydroxide. The combined aqueous extracts were acidified with hydrochloric acid and then extracted with two 250 mi portions of fresh ethyl acetate. The last combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to yield 5-(5-methy]-2-thienyi)oxazolidine-2,4-dione (7.2 g). Recrystallization from chloroform/hexane gave purified product (910 mg; m.p. 108-1 OWC; m/e 197).
Example 84
2-(5-Chloro-2-thienyi)-2-trimethyisiloxyethanenitrile 5-Chlorothenaldehyde (5 g, 34 mmoles) was combined with zinc iodide (50 mg) and 30 mi of diethyl ether and cooled to OIC. Trimethyisilylearbonitrile (4.04 g, 40 mmoles) was added dropwise and the reaction mixture warmed to room temperature and stirred for 4 hours. Additional equal portions of trimethyisilylcarbonitrile and zinc iodide were added and the reaction stirred an additional 35 16 hours. The reaction mixture was diluted with ether, washed with two 30 mi portions of 5% sodium bicarbonate, washed once with 30 m] of brine, dried over anhydrous magnesium sulfate and evaporated to yield 2-(5-chloro-2-thienyi)-2-trimethylsiloxyethanenitrile as an oil [4.0 9, pnmr/CDCI,/delta: 0.3 (s, 91-1); 5.7 (s, 11-1); 7.0 (q, 2H)I.
By the same method, 3-fluoro-2-thenaldehyde, 4-fluoro-2-thenaldehyde, 5fluoro-2 thenaldehyde, 5-fluoro-3-thenaldehyde [Gronowitz and Rosen, Chem. Ser. 1, pp. 33-43 (197 1); Chem. Abstracts 75, 20080c], 4-fluoro-3-thenaldehyde, 4-methoxy-3- thenaldehyde, and 4 methylthio-3-thenaldehyde are converted, respectively to 2-(3-fluoro-2thienyi)-2-trimethyisiloxy- ethanenitrile, 2-(4-fluoro-2-thienyi)-2-trimethyisiloxyethanenitrile, 2- (54 1 uoro-2-th ie nyl)-2tri m ethyl siloxyethanenitrile, 2-(5-fluoro-3-thienyi)-2trimethyisiloxyethanenitrile, 2-(4-fluoro-3-thienyi)-2-tri methyisiloxyethanenitrile, 2-(4-methoxy-3-thienyi)-2trimethylsiloxyethanenitrile, 2-(4-methylthio-3 thienyi)-2-trimethyisiloxyethanenitrile.
Example 85 Ethyl 1-(5-chloro-2-thienyi)-1 -hydroxymethanecarboximidate hydrochloride 2-(5-Chloro-2-thienyi)-2-trimethyisiloxyethanenitrile (4 g) was dissolved in absolute ethanol 50 (100 mO. The solution was cooled to 0-50C and saturated with hydrogen chloride. The reaction mixture was held for 16 hours at O'C, evaporated to dryness and triturated with ether to yield solid ethyl 1 -(5-chloro-2-thienyi)-1 -hydroxymetha neca rboxi mi date hydrochloride [3 g, pnmr/DIVISO/delta:
1.2 (31-1); 4.2 (21-1); 5.3 (1 H); 6.6 (11-1); 6.9 (1 H); 7.4 (11-1); 8.4 (1 H)].
By the same method, the other nitriles of the preceding Example are converted to ethyl 1-(3 fluoro-2-thienyl)-1 -hydroxymethanecarboximidate hydrochloride, ethyl 1- (4-fluoro-2-thienyi)-1 hydroxymethanecarboximidate hydrochloride, ethyl 1 -(5-fluoro-2-thienyl)1 -hydroxymethane carboximidate hydrochloride, ethyl 1-(5-fluoro-3thienyl)-1 - hydroxymethanecarboximidate hydrochloride, ethyl 1-(4-fluoro-3-thienyi)-1 - hydroxymethanecarboximidate hydrochloride, ethyl 1 - hydroxy-1 -(4-meth oxy-3-th i e nyi) meth a neca rboxi m i date hydrochloride and 1 -hydroxy-1 -(4-methylthio3-thienyimethanecarboximidate hydrochloride.
GB 2 131 422 A 25 Example 86 5-(5-Chloro-2-thienyi)oxazolidine-2,4-dione Ethyl 1-(5-chloro-2-thienyl)-1-hyd roxym etha n eca rboxi mi date hydrochloride (3.0 g, 12 mmoles) and triethylamine (4.0 g, 39 mmoles) were combined in 90 mi of tetrahydrofuran and cooled to OOC.
The slurry was perflused with phosgene for 30 minutes, warmed to room temperature and stirred for 16 5 hours. The reaction mixture was poured slowly into 100 mi of crushed ice and product extracted into two 100 m] portions of ethyl acetate. The combined ethyl acetate extracts were backwashed with two 50 mi portions of water and one 50 mi portion of saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated to a semi-solid (2.5 g). Recrystallization from toluene provided purified 5-(5-chloro-2-thienyl)oxazolidine2,4-dione(O.6g, m.p. 126-130IC).
Analysis: Caled. for C7H403NCIS: C, 3 8.64; H, 1. 84; N, 6.44.
Found: C, 38.17; H, 2.07; N, 6.91.
By the same method the other imino ethers of the preceding Example are converted to 5-Qfluoro-2-thienyi)oxazolidine-2,4-dione, 5-(4-fluoro-2thienyi)oxazolidine-2,4-dione, 5-(5-fluoro2thienyi)oxazolidine2,4-dione, 5-(5-fluoro-3-thienyl)oxazolidine-2,4-dione, 5-(4-fluoro3thienyi)oxazolidine-2,4-dione, 5-(4-methoxy-3-thienyi)oxazolidine-2,4dione and 5-(4-methyithio-3thienyi)oxazolidine-2,4-dione.
Example 87 2-(4-Bromo-3-thienyi)-2-trimethyisitoxyethanenitrile 4-Bromo-3-thenaldehyde (5.5 g, 29 mmoles) in 75 mi of methylene chloride was cooled to 0- 20 50C. Zinc iodide (50 mg) was added, followed by the dropwise addition of trimethylsilylcarbonitrile (3.47 g, 35 mmoles) over a 3 minute period. The mixture was warmed to room temperature, stirred for 16 hours, washed twice with saturated sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(4-bromo-3-thienyi)- 2-trimethyisiloxyethane- nitrile as an oil (7.6 g, 90%, m/e 291/289).
Example 88 Ethyl 1-(4-bromo-3-thienyl)-1-hydroxymethanecarboximidate 2-(4Bromo-3-thienyi)-2-tri methyl si loxyetha nen itri le (7.5 g) in 200 mi of ethanol, cooled in an ice bath, was perfused with hydrogen chloride for 45 minutes. After an additional 20 minutes at 0-5'C the reaction mixture was evaporated to dryness and triturated with ether to yield the hydrochloride salt 30 of the product as a hygroscopic solid. The salt was taken up in a mixture of methylene chloride and saturated sodium bicarbonate. The separated methylene chloride layer was washed twice with saturated sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield ethyl 1-(4bromo-3-thienyi)-1 -hyd roxym etha neca rboxi m i date as an oil (6.1 9, 89%, m/e 265/263).
Example 89 5-(4-Brorno-3-thienyl)oxazolidine-2,4-dione Ethyl 1-(4-bromo-3thienyi)-1 -hydroxymethanecarboximidate (6.0 g, 23 mmoles) and triethylamine (5.15 g, 51 mmoles) were combined in 250 mI of tetrahydrofuran, cooled in an ice-water bath and perfused with phosgene for 35 minutes. The reaction mixture was warmed to room temperature, stirred for 1.5 hours, poured slowly over 1 liter of crushed ice, and product extracted into 3 portions of methylene chloride. The combined methylene chloride extracts were evaporated to an oil, crystallized by the addition of a small amount of ether and hexane, and triturated in about 40 m] of ether to yield 5-(4-bromo-3-thienyl)oxazolidine-3,4-dione (3.4 g, 56%; m. p. 158-161 OC).
Recrystallization from 40 mi of toluene afforded purified product (2.51 g; m.p. 164-1 660C; m/e 263/261).
Alternatively, the ether solution of the lithium derivative of 3,4dibromothiophene is reacted with a 1.05 equivalent of alioxan according to the procedure of Example 54, yielding 5-(4-bromo-3-thienyi) 5-hydroxy-2,4,60 H,3H,5H)-pyrimidinetrione. Following the procedure of Example 55, the latter is converted to the desired 5-(4-bromo-3thienyi)oxazolidine-2,4-dione.
Example 90
2-(3-Thienyi)-2-trimethyisiloxyethanenitrile 3-Thenaldehyde (10 g, 0.089 moles), zinc iodide (120 mg) and ether (60 mi) were combined and stirred. Trimethyisilylcarbonitrile (10.6 g, 0. 107 mole) was added dropwise over 10 minutes and the reaction mixture stirred for 16 hours, diluted with 60 mi of ether, washed with two 30 mi portions of 55 5% sodium bicarbonate, washed with 30 mi of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(3-thienyi)-2-trimethyisiloxyethanenitrile as an oil [14.3 g, pnmr/CDCI,/delta:
0.2 (9H); 5.6 (1 H; 7.0-7.5 (3H)I.
26 GB 2 131 422 A 26 Example 91 Ethyl 1-hydroxy-l-(3-thienyi)methanecarboximidate At 0-50C, 2-(3-thienyi)2-trimethyisiloxyethanenitrile (14.3 g) was dissolved portionwise in 500 mi of ethanol, previously saturated with hydrogen chloride at 0-50C. The solution was held at OIC for 16 hours, and the product isolated as the hydrochloride salt by evaporation of the reaction mixture to dryness and trituration of the residue with ether. The salt was taken up in 400 m] of chloroform and 100 mi of saturated sodium bicarbonate. The separated chloroform layer was washed with an additional 100 mi of saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered and evaporated to yield ethyl 1 - hydroxy-1 -(3-thienyl)methanecarboximidate [12.5 g, 10 pnmr/CDCI,/delta: 1.0-1.3 (31-1); 4.8-5.3 (2H); 5.0 (1 H); 6.9-7.2 QW; 7.3-8.0 (1 H)].
Example 92 5-(3-Thi enyl)oxazol idi ne-2,4-d lone Ethyl 1 -hydroxy-1 -(3-thienyi)methanecarboximidate (12.5 g, 0.067 mole) and triethylamine (16.1 g, 0. 159 mole) were combined in 600 mi of tetrahydrofuran and cooled to OOC. The mixture was perfused with phosgene for 30 minutes, warmed to room temperature and allowed to stand for 16 15 hours. The mixture was poured slowly into 600 mi of ice and water (foaming of excess phosgene), and extracted twice with 600 m] portions of ethyl acetate. The combined extracts were washed with two 300 mi portions of 1 N sodium hydroxide. The combined basic extracts were acidified with hydrochloric acid and product re-extracted into two fresh 300 mi portions of ethyl acetate. The combined fresh 20 extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to solids (8.0 g). Recrystallization from hot toluene gave purified 5-(3-thienyi)oxazolidine2,4-dione (5.5 g, m.p. 1331361C). A second recrystallization, from ethyl acetate/hexane, provided additional purification (first crop: 2.352 g; m. p. 136-1 381C, m/e 183; ir (KBr): 5.5, 5.8 microns).
Example 93 Ethyl 2-hydroxy-2-(3-thienyi)acetate 3-Thenaldehyde (10 g, 0.089 mole) and sodium bisulfite (13.8 g, 0.133 mole) were heated at 50-601C, in 152 mI of water for 2 hours, forming the bisulfite adduct in situ. The reaction mixture was cooled to 51C, and 200 mi of ethyl acetate was added. To the stirred, two phase system, potassium cyanide (17.4 g, 0.267 mole) in 75 mi of water was added dropwise over 30 minutes. The reaction mixture was warmed to 201C and held for 1 hour. Additional potassium cyanide (5.7 g, 0.088 30 mole) was added and the mixture stirred an additional 10 minutes at 2WC. The layers were separated and the aqueous layer-washed with 50 m[ of ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride, providing a clean solution of the cyanohydrin of 3 thenaldehyde in ethyl acetate.
The solution of the cyanohydrin of 3-thenaldehyde in ethyl acetate was stirred at room temperature and charged with 41.6 g (52.7 m[, 10 equiv.) of ethanol and concentrated hydrochloric acid (15.2 mi, 0.182 mole) and the mixture refluxed for 17 hours. The reaction mixture was cooled to 251C, washed with 100 mi of water and then with saturated sodium bicarbonate to a pH>7.0, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and evaporated to an oil (approximately 11.5 g) which upon addition of 46 m] of 1: 1 toluene/isooctane afforded crystalline ethyl 40 2-hydroxy-2-(3-th ienyi) acetate (7.4 g, 45%, m.p. 55-5710.
Example 94
2Hydroxy-2-(3-thienyi)acetamide Ethyl 2-hydroxy-2-(3-thienyl)acetate (168 g, 0.903 mole) was slurried in 15N ammonium hydroxide (420 m], 6.3 moles) and heated to reflux for 2.5 hours. The resulting solution was cooled to 45 701C and toluene (840 mi) was added. The stirred mixture was allowed to cool to 200C and granulated for 1 hour. Filtration, with toluene wash, gave 2-hydroxy-2-(3- thienyi)acetamide (105.9 g, 75%, m.p. 120-126IC). A second crop (10.3 g, m.p. 1 14-120IC) was obtained by evaporating the aqueous layer of the filtrate to 50 mi and granulating with 100 mi of toluene. Recrystallization of the 50. first and second crops from ethyl-acetate afforded a 77-79% recovery of purified product (m.p. 50 127-130OC).
Example 95
5-(3-Thienyl)oxazolidine-2,4-dione At 251C, 2-hydroxy-2-(3thienyl)acetamide (10.0 g, 0.064 mole) was added to a solution of sodium methoxide (10 9, 0.185 mole) and diethyl carbonate (22.0 m], 0.182 mole) in 200 mi of ethanol. The reaction mixture was heated to reflux for 3 hours, cooled to 200C, and slowly diluted with mi of water. Ethanol was removed by evaporation and the aqueous residue treated with activated carbon and filtered. The filtrate was layered with ethyl acetate and the pH adjusted to 1.0 with concentrated hydrochloric acid. The aqueous layer was separated and washed with 100 m] of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate. The ethyl 60 acetate was removed by distillation in vacuo with displacement by toluene to a final volume of 150 mi.
27 GB 2 131 422 A 27 The resulting slurry was heated to reflux (solution), cooled to OOC, and filtered to yield 5-Qthienyi)oxazolidine-2,4-dione (8.92 g, 76.5%, m.p. 135-138OC).
Example 96
Sodium 5-(3-thienyl)oxazolidine-2,4-dione 5-(3-Thienyi)oxazolidine-2,4-dione (3.0 g, 16.4 mmole) was dissolved in 60 mi of ethyl acetate and treated with 300 mg of activated carbon. After stirring at 201C for 10 minutes, the mixture was filtered with ethyl acetate wash. Methanolic sodium hydroxide (3.78N, 4.2 m]) was added and the sodium salt was allowed to crystallize. After about 30 minutes, 0.3 m] of water was added. The slurry was granulated for 30 minutes at room temperature, then cooled to 51C and granulated for an additional 30 minutes. Filtration gave sodium 5-(3-thienyi)oxazolidine-2, 4-dione as the monohydrate (3.37 g, 95%, m.p. 208-21 OIC).
Analysis: Calcd. for C7HANSNa. H20:
C, 37.67; H, 2.7 1; N, 6.28; 0, 28.67; S, 14.37; Na, 10.30; H201 8.07.
Found:
C, 37.35; H, 3.03; N, 6.24; 0, 27.83; S, 14.33; Na, 10.76; H,O, 8.30.
Sodium hydroxide is substituted with an equivalent of potassium hydroxide, diethanolamine, meglumine or piperazine to produce the corresponding salts. The solvent is removed by evaporation or a non-solvent such as ether or hexane is added as necessary to facilitate precipitation of the product.
The same methods are employed to produce the pharmaceutical ly acceptable salts of the other oxazolidine-2,4-diones of the present invention.
Example 97
2-(3-Bromo-2-thienyi)-2-trimethyisiloxyethanenitrile 3-Brom o-2-the n aldehyde (6 g, 31 mmoles) and zinc iodide (50 mg) were combined with 180 mi of methylene chloride. Trimethyisilylearbonitrile (4.0 g, 5.2 mi, 41 mmoles) were added dropwise. The reaction mixture was stirred for 24 hours at room temperature, diluted with 50 m] of methylene chloride, washed with 60 m] of 5% sodium bicarbonate and then with 50 m] of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(3-bromo2-thienyl)-2-tri m ethyl siloxyethanenitrile (7.2 g, oil, mle 291/289).
Example 98
Ethyl 11-( 3-bromo-2-thienyi)-1 -hydroxymethanecarboximidate hydrochloride At OIC, 2-Q-brom o-2-thie nyl)-2-tri methyl si loxyetha ne nitri le (7.0 g, 24 moles) was dissolved in 210 mi of ethanol saturated at OIC with hydrogen chloride. After stirring for 30 minutes at the same temperature, the reaction mixture was evaporated to dryness. Trituration of the solid residue with ether afforded ethyl 1-(3-bromo-2-thienyi)-1 -hydroxymethanecarboximidate hydrochloride (7.0 g, m.p.
120-122OC).
Example 99
5-(3-Bromo-2-thienyl)oxazolidine-2,4-dione Ethyl 1-(2-bromo-2-thienyl)-1-hydroxymethanecarboximidate hydrochloride (6.8 g, 23 mmoles) and triethylamine (7.6 9, 10.5 mi, 76 mmoles) were combined in 250 ml of tetrahydrofuran. The mixture was cooled to 0-51C, perfused with phosgene for 30 minutes, warmed to room temperature, 40 stirred for 16 hours, and poured slowly into 300 mi of crushed ice. The quenched reaction mixture was extracted twice with 200 m] portions of chloroform. The combined chloroform extracts were washed with 60 mi of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil.
Addition of hexane and ether afforded crystalline product. Recrystallization from toluene gave 5-(3 bromo-2-thienyi)oxazolidine-2,4-dione (2.25 g; m.p. 138-139<>C).
Analysis: Calcd. for CHANSBr: C, 32.09; H, 1.59; N, 5.34; S, 12.21.
Found: C, 3 2.4 1; H, 1. 7 5; N, 5.49; S, 12.6 1.
Example 100
5-(5-Bromo-2-thienyi)-2-thioxooxazolidin-4-one Potassium cyanide (7.9 g, 0. 123 mole) and potassium thiocyanate (10 g, 0. 104 mole) were 50 combined in 8.5 m 1 of water and stirred at 0 1 C. 5-Bromo-2-thena Idehyde (20 g, 0. 104 mole) was added, yielding a slurry. Hydrochloric acid (30%, 50.7 mO was added, producing an oil ball. The reaction mixture was diluted with 104 mi of water and stirred for 48 hours, by which time a granular solid had formed. Solids were recovered by filtration and distributed between chloroform and 5% sodium bicarbonate. The mixture was filtered, and the aqueous layer separated, acidified and the 55 precipitated product recovered by filtration. Recrystallization from toluene gave purified 5-(5-bromo-2 thienyl)-2- thioxooxazolidin-4-one (2.08 g, m.p. 119-1 2WC, m/e 279/277).
28 GB 2 131 422 A 28 Analysis: Calcd. for C,HAM0,S,: Found:
C, 30.23; H, 1.95; N, 5.04. C, 30.54; H, 1.72; N, 5.26.
Example 101
5-(5-Bromo-2-thienyi)oxazolidine-2,4-dione 5-(5-Bromo-2-thienyi)-2-thioxooxazolidin-4-one(1.5 g) was dissolved in 1:1 watenethanol (10 mi) at 501C. Hydrogen peroxide (30%, 7.0 m]) was added to the stirred solution, which became somewhat turbid. Turbidity was reduced by the addition of 1 m] of ethanol. The mixture was heated at 701C for 30 minutes, cooled somewhat, diluted with 100 m] water and extracted with chloroform. The chloroform extract was washed with two 50 mi volumes of sodium bicarbonate. The combined aqueous extracts were clarified by filtration, acidified with hydrochloric acid to pH 1.0, and filtered to 10 yield 5-(5-bromo-2-thienyi)oxazolidine-2,4-dione (0.51 g, 36%; m.p. 139139.5'C; m/e 263/261).
Analysis: Calcd. for C^BrNO3S: C, 32.08; H, 1.54; N, 5.34.
Found: C, 32.16; H, 1.69; N, 5.47.
Example 102
5-Hydroxy-5-(3-methoxy-2-thienyi)-2,4,6(1 H,3H,5H)-pyrimidinetrione 3-Methoxythlophene [2.4 g, crude material prepared according to Arkiv. Kemi. 12, 239-246 (1958); Chem. Abstr. 52, 20115d] and alloxan hydrate (3.2 g) were dissolved by heating in 25 mi of ethanol. Hydrochloric acid (1 N, 3 mi 3 mmoles) was added and the mixture refluxed for 3 minutes. The mixture was cooled to room temperature and diluted with 15 mi of waterto induce further crystallization of product. Filtration with 1:1 ethanol:water and then water wash gave 5-hydroxy-5-(3methoxy-2-thienyi)2,4,6(1 H,3H,5H)pyrimidinetrione [1.5 g, m.p. 190-21 OOC, (dec.); R, 0.3 (1:1 hexane:ethyl acetate with 5% acetic acid); m/e 2561.
Example 103
5-(3-Methoxy-2-thienyl)oxazolidine-2,4-dione 5-Hydroxy-5-(3-methoxy-2-thienyl)-2,4,6(1 H,3H,5H)pyrimidinetrione (1 g) was dissolved in 1 N 25 sodium hydroxide (20 mi) and stirred for 1 hour. The mixture was acidified, clarified, extracted twice with 50 m] portions of ethyl acetate. The combined ethyl acetate extracts were back-washed with water and evaporated to dryness (0.5 g of solids). Chromatography on about 85 m[ of silica gel, monitored by tic, afforded 5-(3-methoxy-2-thienyi)oxazolidine-2,4-dione (300 mg, m.p. 156-1 58IC).
Analysis: Calcd. for C^04NS: C, 45.08; H, 3.3 1; N, 6.57. 30 Found: Q 4 5.2 1; H, 3.3 9; N, 6.47.
Example 104
5-Hydroxy-5-(5-phenyi-2-furyi)-2,4,6(1 H,3H,5H)-pyrimidinetrione 2-Phenyifuran (5.76 g, 40 mmoles) was combined with 100 mi of tetrahydrofuran and cooled to -301C. Butyl lithium in hexane (2.3M, 19.1 mi) was added dropwise over 5 minutes, keeping the temperature between -201 and -301C. The reaction mixture was allowed to warm to room temperature and then recooled to -301C. Sublimed alloxan (5.96 9, 42 mmoles) in 40 mi of tetrahydrofuran was added over 5 minutes, again keeping the temperature - 201 to -301C. The reaction mixture was again allowed to warm to room temperature, then recooled to OIC and 50 m] of 1 N hydrochloric acid added portionwise over 2-3 minutes. The quenched reaction mixture was extracted with 100 mi of ethyl acetate. The extract was filtered through a bed of anhydrous magnesium sulfate, and evaporated to yield 5-hydroxy-5-(5-pheny]-2furyl)2,4,6(1 H,3H,5H)pyrimidinetrione [9. 4 g, gummy solid, R, 0.75 0:1 hexane ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.45).
Example 105
5-(5-Phenyi-2-furyi)oxazolidine-2,4-dione 5-Hydroxy-5-(5-phenyl-2-furyl)-2,4,6(1 H,3H,5H)pyrimidinetrione (0.7 g)was dissolved in 15 m[ of 1 N sodium hydroxide, stirred at room temperature for 15 minutes, extracted with ethyl acetate, made slightly acidic with about 1 mi of glacial acetic acid, and extracted with 25 mi of ethyl acetate.
The latter ethyl acetate extract was back washed with about 6.5 mi of water, filtered over a bed of 50 anhydrous magnesium sulfate and evaporated to yield solid 5-(5-phenyi-2- furyi)oxazolidine-2,4-dione [100 mg; m.p. 21 6-218IC; Rf 0.6 (1:1 hexane:ethyl acetate/5% acetic acid)].
Example 106 5-Hydroxy-5-(5-methyi-2-furyi)-2.4.6(1 H,3H, 5H)pyrimidinetrione 2-Methylfuran (3.28 g, 3.58 mi, 40 mmoles) was combined with 100 mi of tetra hydrofu ran. The 55 reaction mixture, flushed with nitrogen, was cooled to -300C and butyl lithium (19.1 mi of 2.3M in hexane) was added over a period of 10 minutes, maintaining the temperature at -20 to -300C. The 1 29 GB 2 131 422 A 29 reaction mixture was warmed to room temperature and then back to -301C. Sublimed alloxan (5.96 g) in 40 mi of tetrahydrofuran was added dropwise over 10 minutes, keeping the temperature at -20 to -30'C. The reaction mixture was warmed to room temperature, cooled to OIC and 50 mi of 1 N hydrochloric acid added portionwise, keeping the temperature at 0 to 50C. The reaction mixture was extracted with 100 mi of ethyl acetate. The extract was back washed with 25 mi of water, filtered through a bed of anhydrous magnesium sulfate and evaporated to yield solid 5-hydroxy-5-(5methyi-2furyl)-2,4,6(1 H,3H,5H)pyrimidinetrione (6.3 g; mle 224).
Example 107 5-(5-Methy]-2-furyi)oxazolidine-2,4-dione 5-Hydroxy-5-(5-methy]-2-furyi)2,4,6(1 H,3H,5ffipyrimidinetrione (6.3 g) was dissolved in 50 mi10 of 1 N sodium hydroxide and stirred at room temperature for 15 minutes. The reaction mixture was extracted with 50 mi of ethyl acetate, and acidified with glacial acetic acid. Product was then extracted into fresh ethyl acetate (three 30 mi portions). The combined ethyl acetate extracts were filtered through a bed of anhydrous magnesium sulfate and evaporated to an oil. The oil was chromatographed on 50 mi of silica gel, with 1:1 hexane:ethyl acetic acid as eluant. The column was monitored by tic using the same eluant. Clean product containing fractions were combined, evaporated to dryness and triturated with hexane (311 mg, m.p. 135-138OC). Recrystallization from methanol/water afforded purified 5-(5- methyi-2-furyi)oxazolidine-2,4-dione (142 mg, m.p. 136.5-137.5IC).
Analysis: Caled. for C,11,1\10,: C, 53.04; H, 3.90; N, 7.73.
Found: C, 52.82; H, 4.03; N, 7.65. 20 Example 108
5-Hydroxy-5-(3-thienyi)-2,4,6(1 H,3H,5H)pyrimidinetrione lsopropyl ether (40 mi) was cooled to -700C. Butyl lithium in hexane (2. 4M, 10 mi, 24 mmoles) was added over 10 minutes, keeping the temperature -700 to -601C. 3- Bromothiophene (1.9 mi, 20 mmoles) was added over 20 minutes, keeping the temperature -721 to -68'C. The mixture was 25 stirred for an additional 30 minutes at -721 to -700C. Sublimed alloxan (3 g, 21 mmoles) in 25 mi of tetrahydrofuran was added over 40 minutes, keeping the temperature -700 to -651C. Stirring at this temperature was continued for 15 minutes. The cooling bath was removed and the reaction mixture stirred for one hour at room temperature, then cooled to 51C. Hydrochloric acid (1 N, 40 mi) was added slowly, and the organic phase separated. The aqueous phase was extracted with 35 mi of ethyl acetate. The combined organic phase/extract was washed with 10 mI of water, dried over anhydrous sodium sulfate and concentrated to yield solid 5-hydroxy-5-(3-thienyi)-2,4,6(1 H,3H, 5H)pyrimidinetrione (1.41 9, 3 1 %; m/e 226).
When this reaction was carried out in tetrahydrofuran with reverse addition of the 3- bromothiophene to butyl lithium, with immediate addition of 0.5 equivalent of alloxan hydrate in place 35 of 1 equivalent of anhydrous alloxan, the product was a mixture of the above trione and 5-(3-bromo- 2thienyi)-5-hydroxy-2,4,6(1 H,3H,5H)pyrimidinetrione, which in turn was converted to a mixture of 5-Qbromo-2-thienyi)oxazolidine-2,4-dione and 5(3-thienyi'loxazolidine-2,4-dione by the method of Example 55.
Example 109
5-(3-Thienyi) oxazolidine-2,4-dione 5-Hydroxy-5-(3-thienyi)-2,4,6(1 H,3H,5H)pyrimidinetrione (1. 16 g, 5.1 mmoles) was dissolved in 1 N sodium hydroxide (11 mi, 11 mmoles) and allowed to stand at room temperature for 15 minutes.
The solution was acidified with acetic acid, and product allowed to crystallize over 35 minutes.
Filtration gave 5-(3-thienyi)oxazolidine-2,4-dione (480 mg, 51%; m.p. 133135IC). An additional 45 crop of product was obtained by extracting the mother liquor with ethyl acetate. The extract was back washed with water, and evaporated to dryness (80 mg, contaminated with starting material).
Example 110 5-(3-Furyl)-5-hydroxy-2,4,6(1 11-11,3 H, 5H) pyri midi netrione The detailed procedure of Example 108, but substituting 3-bromofuran (2. 94 9, 1.8 m[, 20 50 mmoles) for the 3-bromothiophene, was employed to produce 5-(3-furyi)-5- hydroxy 2,4,6(1 H,3H,5H)pyrimidinetrione (1.62 g, oil, m/e 2 10).
Example 111
5-(3-Furyi)oxazolidine-2,4-dione 5-(3-Furyi)-5-hydroxy-2,4,6(1 H,3H,5H)pyrimidinetrione (1.62 g) was dissolved in 15 mi of 1 N sodium hydroxide, and allowed to stand for 15 minutes at room temperature, and then extracted with mI of ethyl acetate. The aqueous layer was acidified with glacial acetic acid (about 1.5 mi) and product extracted into 25 mi of ethyl acetate. The extract was back washed with 5 mi of water, filtered through a bed of anhydrous sodium sulfate, and evaporated to yield crude product as an oil (470 mg, GB 2 131 422 A 30 m/e 167). Crystallization from chloroform gave purified 5-(3- furyi)oxazolidine-2,4-dione (129 mg, m.p. 88-900C, m/e 167). A second, lower melting crop was obtained from mother liquor.
Example 112
3-Thenaldehyde cyanohydrin Sodium bisulfite (30.2 g, 0.29 mole) was dissolved in 190 mi of water and warmed to 501C. 3 Thenaldehyde (25 g, 0.22 mole) was added and the reaction mixture held at 50-551C for 35 minutes, by which time all but a small amount of gummy solids were in solution. The mixture was cooled to 5IC and layered with 190 mI of isopropyl ether. With stirring, sodium cyanide (24.8 g, 0.25 mole) in 190 mi of water was added dropwise over 20 minutes, keeping the temperature below 1 O'C.
Stirring was continued at room temperature for 1 hour. The organic layer was separated, and the aqueous phase extracted with fresh isopropyl ether (300 mi). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield 3thenaldehyde cyanohydrin as an oil (28.3 g, 92%).
Example 113
2-Hydroxy-2-(3-thienyl)acetamide Formic acid (0.5 mO was cooled in an ice-water bath. 3-Thienaldehyde cyanohydrin (1.0 9) and then concentrated hydrochloric acid (0.5 mi) were added. The reaction mixture was stirred at room temperature for 1 hour, poured over crushed ice, and extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil, which partially crystallized on scratching. Recrystallization from ethyl acetate 20 gave 2-hydroxy-2-(3thienyi)acetamide (389 mg, 35%, m.p. 123-1261C, m/e 157).
Example 114
Mixed methyllethyl esters of 2-benzoyi-2-(3-thienyi)malonic acid Commercially available mixed esters of 2-(3-thienyi)malonic acid (47% diethyl, 43% methyl/ethyl, 10% dimethyl; 11.4 g) were added portionwise to a dispersion of sodium hydride in oil (50%,2.4 g) slurried in 70 mi of toluene. An exotherm was noted, the temperature rising to 450C. The reaction mixture was stirred for 3 hours at room temperature, and then cooled in an ice-water bath. Benzoyl peroxide (8 g) in 100 mi of toluene was added over a period of 1 hour, maintaining the temperature 10-200C. The mixture was stirred for 30 minutes at room temperature, diluted dropwise with 50 mi of water (initial foaming noted), and finally diluted with 50 m] of ether. The organic phase was separated, back washed with three 25 mi portions of water, and evaporated to yield mixed methyl/ethyl esters of 2- benzoyloxy-2-(3-thienyi)malonic acid as an oil (15.5 g containing about 1. 2 g of oil from the sodium hydride dispersion).
Example 115
5-(3-Thienyi)oxazolidine-2,4-dione Sodium (0.46 g, 20 mmoles) was dissolved in 50 mI of absolute ethanol. To the resulting warm solution of sodium ethoxide (about 60OC), crude mixed esters of 2-benzoyloxy-2-(3-thienyi)malonic acid (7 g, approximately 20 mmoles, as prepared in Example 60) were added, followed by urea (1.2 g, 20 mmoles) dissolved in 20 m] of hot ethanol. The reaction mixture was heated in an oil bath at 105- 11 O"C for 4.5 hours. The reaction mixture was cooled, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was back washed with water and concentrated to an oil. Trituration with 20 mI of 1:1 ether:hexane gave a mixture of 5-(3thienyl)oxazolidine-2,4-dione and intermediate 5-benzoyloxy-5-(3thienyl)2,4,6(1 H,3H,5H)pyrimidinetrione (0.8 g). A portion of this mixture (0.3 g) was dissolved in 1 N sodium hydroxide (5 mi) and allowed to stand for 20 minutes at room temperature. The reaction mixture was clarified by filtration, and acidified with acetic acid to precipitate 5(3-thienyi)oxazolidine-2,4- dione (100 mg, m.p. 136-138'C).
Example 116
2-(3-Benzo[blthienyl)-2-trimethyisiloxyethanenitrile Benzo[blthiophene-3-carbaidehyde [1.8 9, 11 mmoles, J. Chem. Soc. C., pp. 339-340 (1969)l and about 100 mg of zinc iodide were combined in 35 mi of ether. Trimethylsilylcarbonitrile (1.98 g, 50 mmoles) was added dropwise. After approximately 1 hour, the reaction mixture was washed in sequence with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield 2-(3-benzo[blthienyi)-2trimethyisiloxyethanenitrile [2.5 g, oil, Rf 0.7 (12 ethyl acetate:hexane)].
Example11117 Ethyl 1-(3-benzo[blthienyi)-1-hydroxym etha necarboxi m i date hydrochloride With cooling in an ice-water bath, 2-(3-benzo[blthienyi)-2- trimethyisiloxyethanenitrile (2.3 9) was dissolved in 10 mi of saturated ethanolic hydrogen chloride, and held for 16 hours at about 51C.
The reaction mixture was evaporated to dryness and triturated with ether to yield l-Q benzo[blthienyi) 1-hydroxymethanecarboximidate hydrochloride (2.2 g, m.p. 128-131 OC, m/e 235).60 31 GB 2 131 422 A 31 Example 118 5-(3-Benzo[blthienyi)oxazolidine-2,4-dione Ethyl 1-(3-benzo[blthienyl)-1-hydroxymethanecarboximidate hydrochloride (2.36 g, 8.7 mmoles) and triethylamine (2.64 9, 26 mmoles) were combined in 50 rril of tetrahydrofuran and cooled to 1 OOC. Phosgene was bubbled through the cooled reaction mixture for 30 minutes, followed by a 10 minute flush with nitrogen. The reaction mixture was slowly poured into 100 mi of ice and extracted twice with ether. The combined ether extracts were back-washed with water and then brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield a gummy solid (1.7 g). This crude product was dissolved in 1 N sodium hydroxide, washed twice with ether and acidified with 6N hydrochloric acid, affording purified 5(3-benzo[blthienyi)oxazolidine-2,4-dione (950 mg, m.p. 202-2051'C, m/e 10 233).
Analysis: Calcd. for Cl, H,O,NS: C, 56.64; H, 3.02; N, 6.00.
Found: C, 56.74; H, 3.18; N, 5.69.
1, 25 Example 119
2-(7-Benzo[blthienyl)-2-trimethyisiloxyethanenitrile Benzo[blthiophene-7-carbaidehyde [1.3 g, 8 mmoles, J. Org. Chem. 39, 2829 (1974)l was dissolved in 35 mi of ether. Trimethyisilylcarbonitrile (1.5 mi, 12 mmoles) and zinc iodide (about 50 mg) were added and the mixture stirred for 1 hour at room temperature, at which time tic indicated conversion was complete. The reaction mixture was evaporated to dryness, yielding 2-(7 benzo[blthienyl)-2-trimethyisiloxyethanenitrile [2.2 g, oil; Rf 0.6 (1:5 ethyl acetate:hexane/5% acetic 20 acid)].
Example 120
Ethyl 1-(7-benzo[blthienyl)-1-hydroxymethanecarboxi mi date hydrochloride By the procedure of Example 112, 2-(7-benzo[blthienyl)-2trimethyisiloxyethanenitrile (2.1 g), using 35 mi of saturated ethanoUc hydrogen chloride, was converted to ethyl 1-(7-benzo[blthienyi-lhydroxymethanecarboximidate hydrochloride (1.1 g, m.p. 1 20-122OC), after crystallization from acetone.
Example 121
5-(7-Benzo[blthienyi)oxazolidine-2,4-dione Following the procedure of Example 118, ethyl 1-(7-benzo[blthienyi)-1 - hydroxymethane carboximidate hydrochloride (1.1 g, 4 mmoles) and triethylamine (1.7 mi, 12 mmoles) were reacted with phosgene. The crude product, isolated as an oil, was dissolved in 25 mi ether and product extracted into 50 ml of 1 N sodium hydroxide. This aqueous extract was acidified with concentrated hydrochloric acid and product extracted into fresh ether, which was back washed with water and evaporated in vacuo to a solid residue (670 mg). This residue was recrystallized to yield 5-(7 benzo[blthienyi)oxazolidine2,4-dione (0.45 9, m.p. 1 30-132OC).
Analysis: Calcd. for C111-1103NS: C, 56.64; H, 3.02; K 6.00.
Found: C, 5 6.42; H, 3.18; N, 5.9 1.
Example 122 40 5-Hydroxy-5-(5-methoxy-2-thienyi)-2,4,6(1 H,3H,5H)pyrimidinetrione 2-Methoxythiophene (2.3 g, 20 mmoles) was dissolved in 35 mi of ether. With cooling, butyl lithium in hexane (2.4M, 9 mI, 21.6 mmoles) was added dropwise over 15 minutes, the temperature rising as high as 351C during this addition. The reaction mixture was stirred for 1 hour at room temperature. While maintaining the temperature between -201 and -1 5IC, sublimed alloxan (3 g, 21 mmoles) in 20 mi of tetrahydrofuran was added during 10 minutes. The mixture was warmed to room 45 temperature, stirring for 0.5 hour, cooled to WC and quenched by adding 35 mi of 1 N hydrochloric acid in portions. The organic phase was separated and the aqueous phase extracted with 25 m] of ethyl acetate. The combined organic phase and extract were back-washed with water, concentrated to dryness and triturated with hexane to yield solid 5-hydroxy-5-(5-methoxy- 2-thienyl)2,4,6(1H,3H,5H)pyrimidinetrione(l.4g,m/e256).
Example 123
5-(5-Methoxy-2-thienyl)oxazolidine-2,4-dione 5-Hydroxy-5-(5-methoxy-2-thienyl)-2,4,6(1 H,3H,5H)pyrimidinetrione (1.1 g) was dissolved in 10 mi of 1 N sodium hydroxide, allowed to stand for 1.5 hours at room temperature, extracted with ether, acidified with acetic acid, diluted with 15 ml of water and filtered to yield product [567 mg, m.p. 55 144-1460C (dec.)]. Recrystallization from acetone-hexane gave purified 5- (5-methoxy-2 thienyi)oxazolidine-2,4-dione in two crops [487 mg, m.p. 147-148'C (dec. )].
Analysis: Calcd. for C,H704NS: C, 45.08; H, 3.31; N, 6.57.
Found: C, 45.08; H, 3.41; N, 6.39.
32 GB 2 131 422 A 32 Example 124 5-[5-(2-Phenyi-1,3-dioxolan-2-yi)-2-thienyll-2,4,6(1 H,3H,5H)pyrimidinetrione At room temperature, 2-phenyl-2-thienyi)-1,3-dioxolane (3.26 9,14 mmoles) was dissolved in 35 m[ of ether. Butyl lithium in hexane (2.4M, 6.25 m], 15 mmoles) was added dropwise over 15 minutes, the temperature rising to 331C. The mixture was stirred for 75 minutes at room temperature and then cooled. Maintaining the temperature between -151 and -201C, sublimed alloxan (2.13 g, 15 mmoles) in 20 mi of tetrahydrofuran was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes, cooled to 51C, quenched with 35 mi of 1 N hydrochloric acid, added in small portions, and extracted with 25 mi of ethyl acetate. The organic layer was back washed with 15 m] of water, filtered through a bed of anhydrous sodium sulfate, and 10 evaporated to yield 5-[5-(2-p henyi- 1,3-d loxola n-2-y1)thi enyll-2,4, 6(1 H,3 H,5 H)-pyri midi n etri one [oil, Rf 0.25 0:1 hexane:ethyl acetate/5% acetic acid)] contaminated with starting material (Rf 0.8).
Example 125 5-[5-(2-Phenyi-1,3-dioxolan-2-yi)- 2-thienylloxazolidine-2,4dione The entire crude product from the preceding Example was taken into 35 mi of 1 N sodium hydroxide and allowed to stand for 30 minutes. After acidification the product was extracted into isopropyl ether. The extract was back washed with water and evaporated to yield 5-[5-(2-pheny]-1,3dioxolan- 2yi)thienylloxazolidine-2,4-dione [0.40 g, Rf 0.65 (1:1 ethyl acetate:hexane/5% acetic acid)].
Example 126
5-(5-Benzoyi-2-thienyi)oxazolidine-2,4-dione 5-[5-(2-Pheny]-1,3-dioxolan-2-yl)-2-thienylloxazolidine-2,4-dione (0.40 g) was dissolved in 30 mI of ether and stirred with 10 m] of 6N hydrochloric acid at room temperature for 1 hour. Ethyl acetate (10 mi) was added, and the organic layer was separated and evaporated in vacuo to dryness (0.388 g). Chromatography on 50 m[ of silica gel, eluted with 1:1 hexane:ethyl acetate/5% acetic acid and monitored by tie, gave in early fractions purified 5-(5-benzoy]-2- thienyi)oxazolidine-2,4-dione 25 (0.22 g, m.p. 1153-1551'C, m/e 287).
Analysis: Calcd. for C14H104NS:
Found:
Example 127 30 5-(3-Thienyl)oxazolidine-2,4-dione capsules C, 58.52; H, 3.16; N, 4.87. Q 58.69; H, 3.50; N, 4.94.
The following ingredients were combined and blended for 30 minutes:
Sodium 5-(3-thienyi)oxazolidine-2,4-dione monohydrate Lactose, anhydrous, U.S.P. Corn starch, dried, U.S.P.
30.46 14.05 g 5.00 g Equivalent to 25 g of active drug (unsolvated free acid).
The mixture was milled (0.040 inch plate) and blended for an additional 30 minutes. Magnesium stearate, sodium laury] sulfate, 90/10 blend (1.00 g) was added and the mixture blended for 20 minutes. The blend was filled into 0 gelatin capsules (505 mg fill weight) so as to obtain capsules of 250 mg potency.
Larger capsules are employed to prepare capsules of higher potency.
The same procedure was employed to prepare capsules of 100 mg potency from the following ingredients:
Sodium 5-(3-thienyi)oxazolidine-2,4-dione monohydrate Lactose, anhydrous, U.S.P. Corn starch, dried, U.S.P. Magnesium stearate/lauryl sulfate (90/10 blend) Equivalent to 10 g of activated ingredient (unsolvated free acid).
12.18 9 32.32 g 5.00 g 0.50 g A lower level of active ingredient in the blend is used to prepare capsules of lower potency.
Example 128 50 Tablets A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:
4 Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5 33 GB 2 131 422 A 33 Into this tablet base there is blended sufficient sodium 5-(3- thienyi)oxazolidine-2,4-dione monohydrate to form tablets containing 50 mg, 100 mg or 250 mg of active drug (weight equivalent to the free acid). The portion of blend to active drug is within the limits of 1-0.167 to 1- 1, e.g., in the extremes, 60.2 mg of sodium salt monohydrate and 300 mg of blend in a 50 mg tablet or 304.6 mg of sodium salt monohydrate and 250 mg of blend in a 250 mg tablet.
Example 129 Injectable preparation Sterile sodium 5-(3-thienyi)oxazolidine-2,4-dione is dry filled into vials so as to contain 670.1 mg of the sodium salt monohydrate per via] (equivalent to 550 mg of free acid). Prior to use, sterile water for injection (11 mi) is added, and the mixture shaken to form a solution, containing 50 mg/m] of active 10 drug, which is suitable for intravenous, intramuscular or subcutaneous injection.
Alternatively vials are filled by a freeze drying procedure. Two mi of a sterile, aqueous solution containing 335 mg/mi of sodium salt monohydrate is introduced into each vial. The vials are freeze dried on trays.
Example 130
3-Ethoxycarbonyi-5-(3-thienyi)oxazolidine-2,4-dione Sodium 5-(3-thienyi)oxazolidine-2,4-dione monohydrate is stripped of water by drying in vacuo at elevated temperature (50-70OC). The anhydrous salt (2.05 9, 10 mmoles) is suspended in 35 mi of 1,2-dichloroethane. Ethyl chloroformate (1.41 g, 10 mmoles) is added and the mixture refluxed for about 2 hours. The reaction mixture is cooled to room temperature, byproduct sodium chloride 20 removed by filtration and the filtrate concentrated to dryness to yield 3- ethoxycarbonyi-5-(3 thie nyl) oxazo lid in-2,4-dione.
Substitution of the ethyl chloroformate with an equivalent quantity of acetyl chloride, isobutyryl chloride, N,N-dimethylearbamoyl chloride, or benzoyl chloride produces, respectively, 3-acetyl-5-Qthienyi)oxazolidine-2,4-dione, 3isobutyroyl-5-(3-thienyl)oxazolidine-2,4dione, 3-(N,N-di m ethylcarbamoyl)-5-(3-thienyi)oxazolidine-2,4-dione and 3-benzoyl-5-(3-thienyi)oxazolidine-2,4-dione.
Example 131 3-Acetyl-5-(3-thienyi)oxazolidine-2,4-dione Method A 5-(3-Thienyi)oxazolidine-2,4-dione (1.83 9, 10 mmoles) and triethylamine (0.14 mi, 10 mmoles) 30 are combined with 2 5 mi of 1,2-dichloroethane at room temperature. Acetyl chloride (0.72 mi, 10 mmoles) is added dropwise over a few minutes and the reaction mixture stirred for 3 hours. The reaction mixture is evaporated to dryness and the residue distributed between saturated sodium bicarbonate and chloroform. The chloroform layer is washed with water, and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 3-acetyi-5(3-thienyi)oxazolidine-2,4- 35 dione.
Method B 5-(3-Thienyi)oxazolidine-2,4-dione (1.83 g, 10 mmoles) and acetic anhydride (1.14 mi, 12 mmoles) are combined with 20 mi of tetrahydrofuran and stirred for 40 hours. The reaction mixutre is evaporated to dryness and 3-acetyl-5-(3-thienyl)oxazolidine-2,4-dione further isolated as in method A. 40 The same procedure, but substituting acetic anhydride with an equiviaent of acetoformic acid reagent [a solution of acetic-formic anhydride in acetic acid; cf. Blackwood et aL, J. Am. Chem. Soc., 82, 5194 (1960)1, propionic anhydride or benzoic anhydride, allows formation of corresponding 3 formyi-5-(3-thienyi)oxazolidine-2,4-dione, 3-propionyi-5-(3- thienyi)oxazolidine-2,4-dione and 3benzoyi-5-(3-thienyi)oxazolidine-2,4-dione.
Example 132 3-(N-M ethyl carba moyl)-5-(3-thienyi)oxazol idi ne-2,4-dione 5-(3-Thienyi)oxazolidine-2,4-dione (1.83 9, 10 moles) and one drop of triethylamine are combined in 35 mi of 1,2-dichioroethane. Methyl isocyanate (0.58 mi, 10 mmoles) is then added and the reaction mixture stirred for 4 hours at room temperature. The reaction is diluted with 35 mi of 1,2- 50 dichloroethane, washed with saturated sodium bicarbonate and then brine, dried over magnesium sulfate, filtered and concentrated to yield 3-(N-m ethyl)- 5-Q-thie nyl)oxazo lid i ne-2,4-d io ne.
Example 133
3-(4-Methoxy-3-thienyl)-2-trimethyisiloxyethanenitrile By the procedure of Example 55, 4-methoxy-3-thenaldehyde (2.6 g, 18.3 mmole) and trimethylsilylcarbonitrile (2.15 g, 21.7 mmole) in 250 mi of ether in the presence of 50 mg of zinc iodide was converted to title product as an oil (3.9 g, m/e 241).
Example 134
Methyl 1 -hydroxy-1 -(4-methoxy-3-thienyi) methaneca rboxi mi date hydrochloride Saturated methanolic hydrogen chloride (100 mO was maintained at 0-50C in an ice bath. Title60 34 GB 2 131 422 A 34 product of the preceding Example (3.9 g) in 20 mi of methanol was added dropwise and the mixture held for 1 hour at 0-5'C. The reaction mixture was concentrated to solids and the residue triturated with ether to yield the title product [2.76 g, m.p. 94-991C (dec.)]. Recrystallization from methanolether gave purified title product [1.51 g; m.p. 112-114 (dec.); m/e 2011.
Example 135 5-(4-Methoxy-3-thienyi)oxazolidine-2,4-dione By the procedure of Example 57, the product of the preceding Example (1.3 g, 5.5 mmoles) and triethylamine (1.7 g, 17 mmoles) in 50 mi of tetrahydrofuran were reacted with phosgene for 30 minutes at 0-5'C. The reaction mixture was stirred overnight at room temperature. The reaction 10mixture was poured slowly into 500 mi of crushed ice and extracted with three 50 m] portions of chloroform. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. Recrystallization from toluene gave purified title product [510 mg; m.p. 120-222IC; ir (KBr) 1377, 1732,1767,1808 em-'].
Analysis: Calcd. for C,H704NS: C, 4 5.06; H, 3.3 1; N, 6.5 7.
Found: C, 45.3 1; H, 3.4 1; N, 6.85.
Example 136
3-(4-Ethoxy-3-thienyi)-2-trimethyisiloxyethanenitrile By the procedure of Example 55, 4-ethoxy-3-thenaidehyde (8.1 g, 0.052 mole) and trimethyl silylearbonitrile (6.13 g, 0.062 mole) in 300 mi of ether, in the presence of 50 mg of zinc iodide, were converted to title product (13 g) as a viscous oil; pnmr indicated absence of the aldehyde proton. 20 Example 137 Ethyl 1 -hydroxy-1 -(4-ethoxy-3-thienyi)nlethanocarboximidate hydrochloride Using ethanol in place of methanol, but otherwise the procedure of Example 134, product of the preceding Example (13 g) was converted to title compound [9.23 9, m.p. 126-1281 (dec.)].
Example 138
5-(4-Ethoxy-2-thienyl)oxazolidine-2,4-dione Using a phosgene perfusion time of 1 hour at 0-5'C and a further reaction time of 1 hour at room temperature, product of the preceding Example (9.2 g) was converted to title product. To isolate the product, the reaction was poured in 1.5 1 of crushed ice and extracted with three 200 mi portions of chloroform. The organic layers were combined and extracted with three 150 mi portions of 1 N sodium 30 hydroxide. The basic extracts were combined, back-washed with 200 mI of fresh chloroform, reacidified with 3N hydrochloric acid and extracted with three 200 mi portions of chloroform. The last three organic extracts were combined, washed with brine, dried over magnesium suifate, filtered, evaporated to solids, and the residue crystallized from toluene to yield title compound [4.06 g, m.p.
144-146'C,m/e227;ir(KBr)1822,1737,1568cm-11.
Analysis: Calcd. for C^O,NS: C, 47.57; H, 3.99; N, 6.17.
Found: C, 47.18; H, 4.04; N, 6.06.
The chloroform back-wash was re-extracted with three 150 mi portions of fresh 1 N sodium hydroxide. These basic extracts were combined and additional product (980 mg, m.p. 144-146OC) 40 recovered in like manner.
Example 139 2-[4-(n-Propoxy)-3-thienyll-2-trimethyisiloxyethanenitrile By the procedure of Example 55, 4-(n-propoxy)-3-thenaidehyde (3.1 g, 18 mmoies) and tri methylsilylcarbonitrile (2.28 g, 2.9 mi, 23 mmoles) in 250 mi of ether, in the presence of 50 mg of zinc iodide, were converted to title product as an oil [4.6 g; m/e 269; ir (CH2C12) 2936,1558 em-']. 45 Example 140
Ethyl 1 -hydroxy-1 -[4-(n-propoxy)-3-thienyll metha necarboxi mi date hydrochloride Using a reaction time of 20 minutes after completion of the addition, the procedure of Example 137 was used to convert the product of the preceding Example (4.5 g) into title product of the present Example [3.05 g, m.p. 127-1291C (dec.)].
Example 141
5-[4-(n-Pro poxy)-3-th ienyloxazol idi ne-2,4-di one By the procedure of Example 135, the product of the preceding Example (2. 8 g, 0.01 mole) was converted to toluene recrystallized 5-[4-(n-propoxy)-3thienylloxazolidine-2,4-dione [1.63 g; m.p.
134-136OC;m/e241;ir(KBr)1827,1747,1564cm-11.
W GB 2 131 422 A 35 Example 142
2-(4-Methoxy-2-methyl-3-thienyl)-2-trimethyisiloxyethanenitrile By the procedure of Example 55, 4-methoxy-2-methyl-3-thenaidehyde (5.2 g, 33.3 mmoles) and trim ethylsilylcarbonitri le (3.96 g, 40 mmoles) in 350 mi of ether, in the presence of 50 mg of zinc iodide, were converted to title product, isolated as a viscous oil [7.3 g; m/e 255; ir (CH2C11) 1575, 5 1204,1075 em-'].
Example 143
Ethyl 1 -hydroxy-1 -Wrn - ethoxy-2-methyl-3-thienyl) metha necarboxi mi date hydrochloride The procedure of Example 137 was applied to the product of the preceding Example (7.2 g) to produce 5.8 g of a mixture of title compound and the corresponding ethoxy ether (estimated by pnmr 10 to be about 40% methyl ether and 60% ethyl ether; showing both m/e 243 and 229).
A portion of this mixture (2.5 g) was taken into 100 mi of methanol, cooled to 0-51C, and perfused with hydrogen chloride for 1 hour. After 1 hour additional stirring at OIC, the reaction mixture was evaporated to a viscous oil. Crystallization from ether gave title product [2.1 g; m.p. 1 23-1251C (dec.); m/e 2291. The corresponding methyl imidate ester of the title product is obtained by
directly reacting the product of the preceding Example with methanolic hydrogen chloride according to the procedure of Example 134.
Example 144
Ethyl 1 -(hydroxy)-1 -(4-ethoxy-2-methyi-3-thienyl)methanecarboximidate hydrochloride 20 A portion of the mixed methyl and ethyl ethers of the preceding Example (2.5 9) was taken into mi of ethanol and cooled to OIC. The cold solution was perfused with hydrogen chloride for 1 hour, stirred for an additional hour at OOC and evaporated to an oil. The oil was crystallized by trituration with ether. Repulping in ether gave title product [2.07 g, m. p. 105-1071C (dec.); m/e 2431.
Example 145 5-(4-Methoxy-2-methyi-3-thienyl)oxazolidine-2,4-dione Using a reaction time of 3.5 hours at room temperature, but otherwise following the procedure of Example 57, the product of Example 143 (2.0 g, 7.5 mmoles) was converted to toluene recrystallized title product [0.52 g, m.p. 179-181 'C; m/e 227; ir (KBr) 1820,1750,1727,1583 em-'].
Example 146 5-(4-Ethoxy-2-methyl-3-thienyl)oxazolidine-2,4-dione By the procedure of the preceding Example, the product of Example 144 (1. 9 g) was converted to title product [245 mg, m.p. 136-138OC; m/e 241; ir (KBr) 1824,1743 em-'].
Example 147
5-Hydroxy-(2,5- dimethyi-3-furyl)-2,4,G(1 H,3H.5H)pyrimidinetrione lsopropyl ether (35 mi) was cooled to -681C. Butyl lithium (5 mi of 2.1 M in hexane, 10.5 mmoles) was added, allowing the temperature to rise to -60'C. 2,5- Dimethyl-3-iodofuran [J. Am.
Chem. Soc. 70, p. 739 (1948); 1.2 mi, 9 mmoles] was then added dropwise keeping the temperature between -65 and -681C. After stirring for 0.5 hour at -68'C, anhydrous alloxan (1.5 g, 10.6 mmoles) dissolved in 15 mi of tetrahydrofuran was added dropwise over 30 minutes, keeping the 40 temperature -65 to -601C. The stirred reaction mixture was warmed over 15 minutes to OIC, 1 N hydrochloric acid (25 mi) was added and the organic phase separated. The aqueous phase was extracted with 20 mi of ethyl acetate. The combined organic layers were washed with 10 m] of water and evaporated to yield title product [1 g, Rf 0.005 (1:5 ethyl acetate:hexane/5% acetic acid)].
Example 148 5-(2,5-Dimethyi-3-furyi)oxazolidine-2.4-dione Product of the preceding Example (1 g) was taken into 10 mi of 1 N sodium hydroxide and held foi minutes. The solution was extracted with 5 mi of ethyl acetate, acidified with acetic acid and extracted with 25 mi of ethyl acetate. The acidic extract was back-washed with 5 m] of water and evaporated to solids (340 mg), which were chromatographed on 50 mi of silica gel, using 1:1 ethyl 50 acetate:hexane as eluant and tIc monitoring. Clean fractions were combined, evaporated to dryness and the residue recrystallized from ether-hexane to yield purified title product [170 mg; m.p. 144 1451; m/e 195; Rf 0.3 (1:5 ethyl acetate:hexane/5% acetic acid); Rf 0.55 0:1 ethyl acetate:hexane)] Analysis: Calcd. for C^04M C, 5 5.3 8; H, 4.6 5; N, 7.18.
Found: C, 55.15; H, 4.76; N, 7.04. 55 Example 149 5-Hydroxy-5-(4-iodo-3-furyl)-2,4,6(1 H,3H,5H)pyrimidinetrione 3,4-Diiodofuran (0.96 g, 3 mmoles) in 5 mi of ether was added slowly to a cold (-WC) solution 36 GB 2 131 422 A of butyl lithium (2 m[ of 2.3M in hexane, 4.6 mmoles) in 15 mi of ether. The mixture was stirred for 20 minutes at -651C. Anhydrous alloxan (0.57 g, 4 mmoles) was dissolved in 10 mi of tetrahydrofuran and added slowly to the 4-lodo-3-furyl lithium solution at -650 C. After 10 minutes at the same temperature, the reaction mixture was warmed to 1 5IC, acidified with 15 m] of 1 N hydrochloric acid and extracted with ether. The ether extract was back-washed with 10 mi of water, concentrated to dryness and the residue triturated with 2 mi of hexane to yield title product [108 mg; m/e 336; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Example 150 5-(4-lodo-3-furyi)oxazolidine-2,4-dione Product of the preceding Example (100 mg) was allowed to stand with 1 m] of 1 N sodium 10 hydroxide for 15 minutes at room temperature. The reaction mixture was acidified with acetic acid and extracted with 3 mi of ethyl acetate. The organic extract was back-washed with 1 mi of water and evaporated to a gum (63 mg). Crude material (120 mg) prepared in this manner was chromatographed on 50 mI of silica gel using 1:1 ethyl acetate:hexane as eluant and tic monitoring. The first fractions from the column were combined and evaporated to a gum (78 mg) which crystallized from chloroform to yield purified title product (45 mg; m.p. 140-144OC).
Analysis: Calcd. for C^04NI: Found:
Example 151
5-(5-Chloro-7-benzo[blfuranyi]oxazolidine-2,4-dione Title product of Example 50 (100 mg, 0.39 mmole) was suspended in 6 m] of chloroform and bis(trimethyisiiyi)trifluoroacetamide (100 mg, 0. 104 mi, 0.39 mmole) added in one portion. After stirring for 1 minute, N-bromosuccinimide (69 mg, 0.39 mmole) was added together with a trace (a single crystal) of benzoyl peroxide. The mixture was heated to reflux for 2 hours, cooled to room temperature, filtered from insolubles and evaporated to semisolids under a stream of nitrogen. The residue was partitioned between 1 N sodium hydroxide and ethyl acetate. The aqueous layer was separated, washed with fresh ethyl acetate, acidified with 1 N hydrochloric acid and extracted with three portions of chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, filtered, concentrated to an oil, and title product crystallized from toluene (44 mg; m.P.154-157OC;m/e251,253).
By the same method the fluoro analog of Example 50 is converted to 5-(5fluoro-7benzo[blfuranylloxazolidine-2,4-dione.
C, 28.69; H, 1.38; N, 4.78. C, 28.37; H, 1.62; N, 4.74.
Preparation 1 2-Ethoxy-3-pyridinecarboxylic acid Sodium ethoxide was prepared by adding sodium (1.4 g, 0.06 mole) portion wise to 50 mi of 35 anhydrous ethanol. The solution was diluted with 20 mi of ethanol and 4.5 g of 2-chloropyridine-3 carboxylic was added. The reaction mixture was heated in a steel pressure vessel at 1 700C for 6 hours.
The vessel was cooled and the contents evaporated to dryness in vacuo. The residue was taken up in mi of water and acidified to constant pH 4.5. The water solution was saturated with salt and extracted with four portions of ethyl acetate. The combined ethyl acetate layers were back washed 40 with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product (4.33 g, m.p. 85-88OC).
Preparation 2 2-Methoxy-3-pyridinecarboxylic acid A stainless steel stirred autoclave was charged sequentially with methanol (2.8 1), sodium methoxide (259 g) (in portions, keeping the temperature less than 351C), and 2-chloro-3-pyridine carboxylic acid (190 g). The autoclave was sealed and the reaction mixture heated at 11 OIC (50 psig) for 48 hours. The reaction mixture was cooled to 251C and discharged from the autoclave. Solids were recovered by filtration. Concentration of the filtrate gave a second crop. These process steps were repeated until virtually all of the methan& had been removed. The several crops of solids were combined, taken up in 2.5 liters of water and acidified with conc. hydrochloric acid to pH 2.7 keeping the temperature below 201C. The precipitated product was granulated for 30 minutes at 1 50C and recovered by filtration (141 g). Purified title product was obtained by recrystallization from ethyl acetate-hexane (120.5 g, m.p. 148-150OC).
Preparation 3 Ethyl 2-(6-chloro-8-quinoiyl)-2-oxoacetate 8-Bromo-6chloroquinoline [J. Het. Chem. 6, pp. 243-245 (1969); 6 g, 0.025 mole] in 50 mi of tetrahydrofuran was added dropwise over a 10 minute period to a mixture of butyl lithium (2.3M in hexane, 12.2 mi, 0.028 mole) and 40 mi of tetrahydrofuran held at -701C. After an additional 30 37 GB 2 131 422 A 37 minutes at this temperature, a cold (00 C) solution of diethyl oxa late (14.6 g, 0.10 mole) in 50 mi of tetrahydrofuran was added dropwise. The reaction mixture was maintained at OIC for 1 hour, then quenched at 0-51C with glacial acetic acid (17 mi) in 50 m] of tetrahydrofuran. After warming to room temperature the quenched mixture was poured into 500 mi of water and then diluted with 500 mi of ethyl acetate and 500 mi of saturated sodium bicarbonate. The organic layer was separated, washed with 500 mi of fresh bicarbonate, dried over anhyd-ous magnesium sulfate, filtered, and evaporated to an oil. Trituration with two 100 mi portion J hexane gave the title product (2.3 g, m.p. 107-11 OIC; m/e 265/263).
Preparation 4 10 Ethyl 2-(6-chloro-8-quinoiyi)-2-hydroxyacetate Sodium borohydride (2.5 g, 0.066 mole) was dissolved in 300 mi of ethanol at 1 OIC and added in one portion to a 1 OIC solution of product of the preceding Preparation (2.0 g, 0.0076 mole) in 200 mi of ethanol. After a few minutes, the reaction mixture was diluted with 750 mi of ethyl acetate and 750 mi of water. The aqueous layer was extracted with 250 mi of fresh ethyl acetate. The organic layers were combined, washed with three 250 mi portions of brine, dried over anhydrous magnesium 15 sulfate, filtered and evaporated to yield title product, initially an oil which crystallized on standing (1.87 g; m.p. 121-1241C, m/e 267/265).
Preparation 5 Ethyl 2-(6-fluoro-8-quinoiyi)-2-oxoacetate By the procedure of Preparation 3, 8-bromo-6-fluoroquinoline [J. Het. Chem., 6, pp. 243-245 20 (1969); 4.5 g, 0.02 mole] was converted to hexane triturated title product (1.6 g; m.p. 1 14-117OC).
Preparation 6 Ethyl 2-(6-fiuoro-8-quinoiyi)-2-hydroxyacetate By the procedure of Preparation 4, product of the preceding Preparation (1.5 g, 6.1 mmoles) was converted to title product. The product, initially obtained as a turbid oil, was taken backup in ethyl 25 acetate, washed with brine, dried, filtered and evaporated to an oil which rapidly crystallized (1.23 g, m.p. 84-8710.
Preparation 7 6-Hydroxyquinoline-5-carbaidehyde Sodium hydroxide (25 9) was dissolved in 35 m] of water with cooling, 6- hydroxyquinoline (5 9) 30 in 15 mi of chloroform was added and the reaction mixture heated to reflux (about 90IC) for 12 hours, during which two further 15 mi portions of chloroform were added - one after 2 hours and the other after 6 hours. The reaction mixture was cooled and crude product recovered by filtration. The crude was dissolved in 125 m] of hot water treated with activated carbon, filtered hot, cooled and acidified with acetic acid and filtered to yield title product [2.5 g; m.p. 1 36- 137IC; m/e 173; pnmr/C13C'3 35 shows aldehyde proton at 10.5 ppm and aromatic protons at 7.2-9.4 ppm].
Preparation 8 6-Methoxyquinoline-5-carbaidehyde Product of the preceding Preparation (1.7 g, 9.8 mmoles) in 85 mi of acetone was combined with potassium carbonate (1.21 g, 8.8 mmoles). Dimethyl sulfate (0.83 m], 8.8 mmoles) was added and the 40 mixture stirred at room temperature for 16 hours. Additional potassium carbonate (0.34 g, 2.5 mmole) and dimethyl sulfate (0.23 mi, 2.5 mmole) were added and the mixture stirred 4 more hours at room temperature and then 3 hours at 601C. The reaction mixture was cooled to room temperature, salts removed by filtration, and the filtrate evaporated to dryness. The residue was taken up in ethyl acetate, washed sequentially with two portions of 1 N ammonium hydroxide, one of water and one of brine, 45 dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [0.78 g; Rf 0.35 (2:1 ethyl acetate:chloroform); pnmr/C1DO,/delta (ppm): 4.2 (s, 3H), 7.4- 9.1 (m, 5H), 10.3 (s, 1 Hfl.
Preparation 9 7-Hydroxyquinoline-8-carbaidehyde By the procedure of the Preparation 7, 7-hydroxyquinoline (5 g) was converted to title product 50 (3.3 g, m.p. 127-130IC; m/e 173; pnmr/CDCI, shows aldehyde proton at 10.8 ppm, aromatic protons at 7.0-8.9 ppm.
Preparation 10 7-Methoxyquinoline-8-carbaidehyde By the procedure of Preparation 8, the product of the preceding Preparation (3.3 g, 19 mmoles) 55 was converted to title product [2.1 g, pnmr/CDCI,/delta (ppm): 4.1 (s, 3H), 7.5-9.0 (m, 5H), 11.2 (s, 1 W].
38 GB 2 131 422 A 38 Preparation 11 6-Chlorochroman Mossy zinc (75 g), 7.5 g of mercuric chloride, 125 mi of water and 4 m] of conc. hydrochloric acid were combined, shaken for 5 minutes, allowed to settle, and liquids decanted from the resulting amalgamated zinc. A mixture of 100 mi of water and 126 m] of conc. hydrochloric acid and then 6 ch loro-4-chom a none (15 g) were added to the metal, and the mixture refluxed for 1.5 hours, cooled to room temperature, decanted from the zinc and the decant extracted with three portions of ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (14 g). The oil was chromatographed on 400 g of silica gel using 9: 1 hexane:ether as eluant tic monitoring and 15 mi fractions. Clean product fractions were combined and evaporated to yield title 10 product as an oil [8.72 g; pnmr/CDCI,/delta (ppm) 2.0 (m, 2H), 3.7 (t, 2H), 4.1 (t, 2H), 6.9 (m, 3H); m/e 170/168; Rf 0.88 (2:1 hexane:ether)l.
Preparation 12 6-Chlorochroman-8-carbaidehyde Product of the preceding Preparation (8.6 g, 0.051 mole) in 75 mi of methylene chloride was 15 cooled in an ice-water bath. Titanium tetrachloride (19.34 g, 11.2 mi, 0. 102 mole) was added, followed by the dropwise addition of 1,1 dichloromethyl methyl ether (6.2 g, 0.054 mole). The reaction mixture was stirred at 01 for 30 minutes, then slowly poured into 400 mI of saturated sodium bicarbonate. The aqueous phase was extracted with three fresh portions A methylene chloride. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [7.9 g; m.p. 83-86IC; pnmr/CiDC1. /delta (ppm) 2.0 (m, 2H), 2.8 (t, 2 H), 4.2 (t, 2 H), 7.1 -7.5 (m, 2 H), 10.2 (s, 1 H), m/e 19 8/19 61.
Preparation 13 6-Fluorochroman By the procedure of Preparation 11, 6-f 1 uoro-4-chroma none (15 g) was converted to chromatographed 6-fluorochroman [5.7 g; oil; pnmr/C1DO,/delta (ppm) 2.0 (m, 2H), 3.8 (t, 2H), 4.1 (t, 2H), 6.8 (m, 3H); Rf 0.68 (2:1 hexane:ether); m/e 152].
* Preparation 14 6-Fluorochroman-8-carbaidehyde By the procedures of Preparation 12, the product of the preceding Preparation (5.5 9, 0.036 30 mole) was converted to title product initially isolated as a viscous oil which was crystallized from hexane (3.4 g; m.p. 54-57IC; m/e 180).
Preparation 15 3-Methyl-5-isoxazolecarboxamide 3-Methyl-5-isoxazolecarboxylic acid (20 g) was refluxed for 10 hours in 350 mi of thionyl 35 chloride, then stirred at room temperature for 16 hours, clarified by filtration and evaporated to an oil.
The oil was multiply triturated with hot hexane, and the combined hexane triturates evaporated to yield acid chloride (16.2 to 21 g) as a solid.
With stirring, acid chloride prepared in the manner (35 g) was added portionwise to 300 mi of conc. ammonium hydroxide at room temperature. After granulating for 1 hour, title product was 40 recovered by filtration (24.2 g, m.p. 180-182IC).
Preparation 16 3-Methyl-5-isoxazolecarbonitrile Product of the preceding Preparation (5 g) was mixed thoroughly with phosphorus pentoxide (10 9) and placed in an oil bath preheated to 1401. The bath temperature was increased to 2001C and 45 title product recovered by distillation in vacuo [2.9 9, ir (film) nitrile band at 2220 cml, no amide peak in the 1700 cm-1 region].
Preparation 17 3-Methyi-5-isoxazolecarbaidehyde Product of the preceding Preparation (1.08 9, 0.01 mole) was dissolved in 25 mI of ether and 50 cooled to -401C. Diisobutylaluminum hydride (12 mi of 1 M in hexane, 0. 012 mole) was added at -40'C over a 15 minute period. The mixture was stirred at -30' to -351C for 10 minutes. Keeping the temperature at -201C, 60 mi of ethyl acetate was added. Keeping the temperature at -251C, methanol (15 mi) was added dropwise, and keeping the temperature below 20'C, 3 mi of 6N hydrochloric acid was added. The reaction mixture was warmed to 51C and the organic phase washed with 25 mi of water and evaporated to an oil. The oil was chromatographed on 50 mi of silica gel using 1:1 ether:hexane as eluant. Product fractions were combined and evaporated to yield title product (0.42 g; m.p. 39-41 'C). A small sample further purified by sublimation had m.p. 43-451C.
39 GB 2 131 422 A 39 Preparation 18 5-Chlorobenzo[blfuran-2-carboxylic acid 5-Chlorosalicylaidehyde (31.3 g, 0.2 mole) was dissolved in 200 mi of 2- butanone. Potassium carbonate (82.9 9, 0.6 mole) and then diethyl 2bromomalonate (95.6 g, 0.4 mole) were added and the mixture heated to refluxfor five hours, then cooled, filtered from salts, and concentrated to an oil. The oil was partitioned between 500 mi of 10% sulfuric acid and 500 mi of ether. The aqueous layer was extracted with two 250 mi portions of fresh ether. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a second oil. The second oil was dissolved in 400 mi of 10% ethanolic potassium hydroxide, heated at reflux for 1 hour and concentrated to solids. The solids were dissolved in 1500 mi of water, filtered from trace insoluble 10 matter, acidified with 6N hydrochloric acid and precipitated solids recovered by filtration. Purified title product was obtained by repulping the solids in 1 liter of water (19 g, m.p. 259-2621C, m/e 198/196).
By the same procedure, 5-fluorosalicyaldehyde and 6-chlorosalicylaidehyde are converted, respectively, to 5-fluot-obenzo[blfuran-2-carboxylic acid and 6- chlorobenzo[blfuran-2-carboxylic acid.15 Preparation 19 5-Chlorobenzo[blfuran Title compound of the preceding Preparation (7.8 g) was combined with copper powder (700 ring) and quinoline (50 mi) and the mixture heated to reflux for 50 minutes, then cooled to room temperature and diluted with 500 mi of ether. Insolubles were removed by filtration and the filtrate washed in sequence with five 200 mI portions of 2N hydrochloric acid and one of brine, dried over anhydrous magnesium suffate and concentrated to an oil (6.2 g). The oil was chromatographed through 200 g of silica gel using ether as eluant and 300 m] fractions. Fractions 1 and 2 were combined and evaporated to yield title product as an oil (6.1 g).
By the same procedure the other benzofurancarboxylic acids of the preceding Preparation are 25 converted to 5-fluorobenzo[blfuran and 6-chlorobenzo[blf u ran.
Preparation 20 5-Chloro-2,3-dihydrobenzo[blfuran Pd/C (5%, 12.2 g) in 400 mi of acetic acid was prehydrogenated at atmospheric pressure and 250C. Title compound of the preceding Preparation (6.1 9) in 100 mi of acetic acid was added and hydrogenation continued until slightly more than 1 equivalent of hydrogen had been consumed.
Catalyst was recovered by filtration over diatomaceous earth. The filtrate was neutralized with saturated potassium carbonate and extracted with four 200 mi portions of ether. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was chromatographed on 400 g silica gel using hexane-3% ether as eluant, 15 m] fractions and tic monitoring. Pure product fractions 70-90 were combined and evaporated to yield title product [2.15 g; oil; Rf 0.32 (hexane); m/e 156/1541.
By the same procedure, the other benzofurans of the preceding Preparation are converted to 5 fluoro-2,3-dihydrobenzo[b]furan and 6-ch loro-2,3-di hyd robe nzo [blf u ran.
Preparation 21 5-Chloro-2,3-dihydrobenzo[b]furan-7-carbaidehyde By the procedure of Preparation 12, title compound of the preceding Preparation (2.1 g) was converted to crude product contaminated with an isomeric aldehyde. Purified title product was obtained by digesting the crude product in 50 mi of boiling hexane, filtering and cooling the filtrate [0.93 g; m.p. 79-81 'C; Rf 0.55 (chloroform); m/e 184/1821.
By the same method the 5-fluoro compound of the preceding Preparation is converted to 5fluoro-2,3-dihydrobenzo[blfuran-7-carbaidehyde.
By the method of Preparation 3, the 6-chloro compound is converted to ethyl 2-(6-chloro-2,3dihydro-7-benzo[blfuranyi)-2-oxoacetate; then by the method of Preparation 4 to ethyl 2-(6-chloro2,3-dihydro-7-benzo[b]furanyl)-2-hydroxyacetate.
Preparation 22 7-Chloroquinoline-8-carbaidehyde 7-Chloro-8-methyiquinoline (1 9) [Bradford et aL, J. Chem. Soc. p. 437 (1947)] is dissolved in 20 mi of benzene and brominated with one equivalent of N-bromosuccinimide in the presence of catalytic amounts of peroxide. The product, 7-chloro-8-(bromomethyl)quinoline is isolated by evaporation. 55 The bromo compound is solvolyzed to 7-chloro-8-(hydroxymethyi)quinoline by warming with excess alcoholic potassium hydroxide. To isolate the product, the reaction mixture is neutralized with hydrochloric acid, salts separated by filtration and the filtrate evaporated to dryness.
The alcohol (1 g) is dissolved in 10 mi of methylene chloride and added dropwise to a slurry of 1.5 equivalents of pyridinum chlorochromate in 20 mi of methylene chloride. The exothermic reaction 60 is controlled by rate of addition, use of a reflux condenser and occasional cooling in a cooling bath. The GB 2 131 422 A 40 reaction mixture is diluted with ether, and the supernatant separated by decantation and filtration. The product is purified by filtration through a short magnesium silicate column with ether as eluant and isolated by removal of the solvent in vacuo.
Preparation 23 3-Furaldehyde 3-Furyimethanol (19.6 g, 0.2 mole) in 50 m] of methylene chloride was added dropwise to a slurry of pyridinium chlorochromate (64.5 g, 0.3 mole) in 450 m] of methylene chloride. The exothermic reaction, which led to vigorous reflux, was controlled by occasional cooling with an ice bath. By the end of 60 minutes, gummy solids had precipitated. The reaction mixture was diluted with 600 mi of ether and the supernatant separated by a combination of decantation and filtration. The 10 filtrate was passed through Florisil (synthetic magnesium silicate) contained in a short column, with ether as eluant. Collected fractions were combined and evaporated to an oil. Distillation of the oil provided 3-furaldehyde (7.6 g; b.p. 68-721C/40-45 mm).
Alternatively, this aldehyde is prepared by Rosenmund reduction of 3furoic acid chloride [Hayes, J. Am. Chem. Soc. 71, 2581 (1949)1.
Preparation 24 2-(2-Furyi)-1,3-dioxolane 2-Furaldehyde (42 mi, 0.5 mole), ethyleneglycol (50 mi, 0.9 moles) and p- toluenesuifonic acid (about 200 mg) were combined in 150 mi of toluene and the mixture refluxed for 6 hours while collecting byproduct water in a Dean-Stark trap. The mixture was cooled, diluted with 500 m] of ether, 20 and clarified by filtration. The filtrate was washed with 200 mi of saturated sodium bicarbonate and the organic phase again clarified by filtration. This second filtrate was washed with 200 m] of water, and the organic layer concentrated to dryness, affording 2-(2-furyi)-1,3- dioxolane as an oil (45 g).
Preparation 25 2-(5-Chloro-2-furyi)-1,3-dioxolane 2-(2-Furyi)1,3-dioxolane (14 g, 0. 1 mole) was dissolved in 100 mi of tetrahydrofuran and the solution cooled to -251 to -201C. Maintaining this temperature range, butyl lithium in hexane (45 m] of 2.2M, 0.1 mole) was added over a period of 10 minutes. The mixture was allowed to warm to OIC over 25 minutes and rechilled to -301C. While maintaining a temperature range of -30l> to -251C, hexachloroethane (23.7 g, 0. 1 mole) in 50 mi of tetrahydrofuran was added over 5 minutes. The reaction mixture was warmed to room temperature, stirred for 1.5 hours, recooled to 50C, and diluted slowly with 500 mi of water. Product was extracted into ether (2x500 mi) and recovered as an oil (15.8 g) by evaporation to dryness. The oil was chromatographed on a 200 mi volume of silica gel, using 8:1 hexane:ethyl acetate as eluant and monitoring by silica gel tic with the same eluant. The early, product containing fractions were combined and evaporated to yield purified 2-(5-chloro-2fury])- 1 3-dioxolane as an oil [5 g; Rf 0.6 (8:1 hexane:ethyl acetatefl.
Preparation 26 5-Chloro-2-furaidehyde 2-(5-Chloro-2-furyi)-1,3-dioxolane (4.8 9) was dissolved in 20 mi of ether. 6N Hydrochloric acid (10 mO was added and the two-phase mixture stirred for 1 hour at room temperature. The ether phase 40 was separated, washed with water and evaporated to yield 5-chloro-2- furaldehyde as an oil (2.8 g).
Preparation 27 5-Bromo-2-furylcarboxamide 5-Bromo-2-furoic acid (20 g) was refluxed for 3 hours with 60 mi of thionyl chloride, and the corresponding acid chloride isolated as an oil by concentration. The acid chloride was added dropwise 45 to 150 mi of stirring, concentrated ammonium hydroxide. Filtration afforded 5-bromo-2furylcarboxamide (17.0 g, m.p. 140-143OC).
Preparation 28 5-Bromo-2-furylcarbonitrile 5-Bromo-2-furylcarboxamide (10 g) was combined with 50 mi of phosphorus oxychloride and 50 refluxed for 24 hours. The mixture was poured onto ice, the product extracted into ether, which on evaporation gave 5-bromo-2-furylcarbonitrile as an oil (6.4 g).
Preparation 29 5-Bromo-2-furaidehyde 5-Bromo-2-furylcarbonitrile (2.3 g, 13 mmoles) was dissolved in 50 mi of ether and cooled, 55 under nitrogen, to -1 OIC. Diisobutylaluminum hydride (1.9 g, 13 mmoles) as a 25% solution in toluene was added dropwise, maintaining the temperature near -1 OIC. The reaction was allowed to warm to room temperature and allowed to stir about 6 hours. The reaction mixture was cooled to 00 to 2.
41 GB 2 131 422 A 41 5'C, diluted with 1 mi of methanol, acidified with 3N hydrochloric acid, washed with water, and evaporated to yield 5-bromo-2-furaldehyde (1.2 g, m.p. 74-76OC).
Preparation 30 3-Bromo-2-furaidehyde Phosphorus oxychloride (6.5 g, 70 mmoles) was added to dimethylformamide (5.4 g, 70 mmoles) 5 at 01 to 1 O1C. The resulting slurry was diluted with 10 mi of ethylene dichloride. Maintaining the mixture near 1 O1C, 3-bromofuran (9.2 g, 63 mmoles) was added. The reaction mixture was then heated to 58-600C for 1 hour and then recooled to 1 O'C. Sodium acetate trihydrate (15 g) dissolved in 25 m] of water was added slowly, with good stirring, keeping the temperature 101 to 301C. The mixture was reheated to 68-720C for 20 minutes, cooled to room temperature, and diluted with 20 10 mi of water. Product was extracted into 75 mi of ether, and the ether back-washed with water and concentrated to yield 3-bromo-2-furaldehyde as an oil [0.9 g, Rf 0.65 Q:1 hexane:ethyl acetate)].
Preparation 31 3-lodofuran 3-Bromofuran (14.7 g, 0.1 mole) in 100 m[ of ether was cooled to -701C. Butyl lithium (42 mi of 15 2.4M, 0.1 mole) in hexane was added dropwise over 0.5 hour, maintaining the temperature from -700 to -650C. Iodine (25 g, 0. 1 mole) in 200 m] of ether was then added over 1 hour maintaining the same temperature range. The reaction mixture was warmed to room temperature and then back to 21C.
Water (100 mi) was added dropwise. The ether layer was separated, washed with aqueous thiosulfate and then water, dried over anhydrous sodium sulfate, evaporated to an oil and distilled to yield 3- 20 iodofuran (15.7 g, b.p. 481/28 mm).
Preparation 32 3-Methoxyfuran Sodium metal (5.6 g, 0.24 mole) was dissolved in 150 mi of dry methanol. 3-lodofuran (15.7 9, 0.08 mole) and cuprous oxide (8 9, 0.1 mole) were added and the mixture was refluxed with vigorous stirring for 42 hours. The reaction mixture was cooled to room temperature, diluted with 200 m] of water, and product extracted into 100 mi of ether. The ether extract was back-washed with 15 mi of water, dried over anhydrous sodium sulfate and evaporated to yield crude 3-methoXyfuran (approximately 3-4 g of approximately 50% purity) suitable for further processing.
Preparation 33 5-Phenyl-2-thenaidehyde 1 -Phenylthiophene [1.6 g, 0.01 mole, prepared according to J. Am. Chem. Soc. 46, 2339 (1 924)l was dissolved in 20 mi of tetrahydrofuran and cooled to -401C. Butyl lithium in hexane (4.5 mi of 2.2M) was added over 3 minutes, maintaining the temperature -401 to -300C. The mixture was warmed to OIC and then cooled to -400C. Dimethylformamide (1.2 mi, 15 mmole) was added, 35 maintainingthe temperature -400 to -301C. The mixture was warmed to room temperature and held for 0.5 hour, recooled to O1C, quenched with 6 m] of 6N hydrochloric acid, diluted with 10 mi of water, and extracted with 20 mi of ether. Evaporation of the ether extract to dryness gave crude product (1.9 g). Recrystallization from about 35 mi of hexane gave purified 5-phenyl-2- thenaldehyde (0.9 g, m.p.
90-92OC).
Preparation 34 4-Bromo-3-thenaidehyde 3,4-Dibromothiophene [15 g, 0.062 mole, J. Org. Chem. 36,2690 (197 M in 20 mi of ether was cooled to -701C and butyl lithium in hexane (34.8 m] of 2.1 M, 0.073 mole) added dropwise over 5 minutes. After stirring for 5 minutes at -701C, the solution was transferred, via nylon tubing under_ 45 nitrogen pressure, to a solution of dimethylfornnamide (6.8 g, 0.093 mole) in 35 mi of ether. The resulting mixture was heated to reflux for 2 hours, cooled to room temperature, washed in sequence with two portions of 1 N hydrochloric acid, one of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was twice distilled to yield 4-bromo-3-thenaldehyde (5.7 g, b.p. 81-840C/0.8 mm, m/e 192/190).
Preparation 35 2-Phenyllfuran Aniline (46.5 g, 0.5 mole) was combined with 500 m] of water and 100 mi of concentrated hydrochloric acid and cooled to -51C. Sodium nitrite (36.2 g, 0.525 mole) in 100 mi of water was added dropwise over 45 minutes, keeping the temperature -31 to -50C. After addition was complete, 55 the mixture was stirred for 30 minutes at -51C, and zinc chloride (68 g) was added. Maximal precipitation of the diazonium salt was obtained by the addition of 100 g of sodium chloride. The mixture was stirred for 5 minutes, with the cooling bath removed and cautiously filtered, without wash, and air dried for 2 hours. (Previous vacuum drying of this product led to explosive decomposition). The 42 GB 2 131 422 A 42 intermediate diazonium salt was suspended in 750 mi of furan at OIC. With vigorous stirring, powdered sodium hydroxide (5 g) was added, followed by anhydrous sodium acetate (10 g). The reaction mixture was stirred for 5 hours at OIC and then for 16 hours at room temperature. Solids were removed by filtration and the filtrate evaporated to crude product (25 mi of oil). Distillation afforded 1 phenylfuran (9.2-9.6 g, b.p. 87-951/15 mm, b.p. 501/1 mm).
Preparation 36 2-Phenyi-2-(2-thienyi)-1,3-dioxolane 2-Benzoylthiophene (19 g, 0. 1 moid), ethylene glycol (11 mi, 0.2 mole), toluene (150 mi) and ptoluenesuifonic acid (about 0.2 g) were combined and refluxed for 6 hours. By-product water was cooled in a Dean-Stark trap. Tic (1:8 ethyl acetate:hexane) indicated reaction to be about 40% complete. More ethylene glycol (30 mi) was added and reflux continued for 35 hours. Reaction was still incomplete. The reaction mixture was diluted with 200 mi of ether, washed twice with 150 mi portions of water and concentrated to dryness. The residue was chromatographed on about 500 mi of si!ica gel, with 1:8 ethyl acetate:hexane as eluant, monitored by tic. Faster moving, product containing fractions were combined and evaporated to yield 2-phenyl-2-(2-thienyi)-1,3-dioxolane [8 g, oil, Rf 0.6 (1:8 ethyl 15 acetate: hexa nefl. - Preparation 37 Methyl 4-methoxy-3-thenoate Methyl 4-acetoxy-3-thenoate (U.S. Patent 3,144,235; 10 g) was dissolved in 20 mi of methanol and added to 100 mi of methanol containing 0.31 m] of concentrated sulfuric acid. The mixture was 20 refluxed for 4 days, then neutralized with 0.6 g of sodium acetate and solvent removed by evaporation.
The residue was taken up in 200 m] of ether. The ether solution was washed sequentially with two 50 m] portions of water, two 50 mi portions of 1 N sodium hydroxide and two 50 mi portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil which crystallized on standing (4.35 g; m.p. 64-66OC).
When this reaction was worked up after only 1 day only a low yield of the desired product (2.2 g) was isolated. The two 1 N sodium hydroxide extracts were combined and acidified, precipitating methyl 4-hydroxy-3-thenoate (5.13 g). When this alcohol was dissolved in 100 mi of methanol containing 0.3 mi of concentrated suifuric acid and refluxed for 3 days, the above work- up afforded title product (2.10 g, m.p. 64-66IC).
Preparation 38 1 -(4-Methoxy-3-thienyi) methanol Methyl 4-methoxy-3-thenoate (U.S. Patent 4,144,235; 3.9 g, 23 mmoles) was dissolved in 50 m] of toluene and cooled in an acetone-dry ice bath. Diisobutyi aluminum hydride (46 mI of 1 M in hexane, 46 mmoles) was added dropwise over 30 minutes. The mixture was stirred for an additional 2 35 hours at the bath temperature and then allowed to warm to room temperature. Keeping the temperature below 300C, methanol (14.7 g, 18.6 mi, 0.46 mole) was slowly added. The mixture was then stirred for 16 hours at room temperature, by which time a granular precipitate had formed. The mixture was filtered over diatomaceous earth with methanol wash. The combined filtrate and washes were concentrated to yield the title product as an oil (2.8 g, m/e 144).
Preparation 39 4-Methoxy-3-thenaldehyde Pyridinium chlorochromate (6.4 g), 29.7 mmoles) was dissolved in 100 mi of methylene chloride and added in one portion to a solution of the product of the preceding Example (2.8 g, 19.8 mmoles) also in 100 mi of methylene chloride. The reaction mixture was stirred at room temperature for three 45 hours, diluted with 200 mi of ether and decanted from the black precipitate. The precipitate was washed with two 100 mi portions of ether. The combined decant and washes were filtered, washed in sequence with two portions of 1 N hydrochloric acid, one portion of water, two portions of 1 N sodium hydroxide and one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield title product as an oil [2.6 g; m/e 142; ir (CH2C12) 1688, 1544 cm- Preparation 40 Ethyl 4-ethoxy-3-thenoate Following the approximate procedure of U.S. 4,144,235, methyl 4-acetoxy-3- thenoate (20 9) was dissolved in 240 mi of ethanol and 0.62 mi of concentrated sulfuric acid was added. The reaction mixture was gently refluxed for 79 hours, then neutralized with sodium acetate (1.2 g) and evaporated 55 to an oil. The latter was partitioned between 400 m[ of ether and 50 m] of water. The organic layer was separated and washed in sequence with 75 mI of water, three 50 mi portions of 1 N sodium hydroxide and two 75 mi portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [14.9 g, pnmr indicates entirely ethyl ester, no methyl ester].
7k i 9 43 GB 2 131 422 A 43 Preparation 41 1-(4-Ethoxy-3-thienyi)methanol By the procedure of Preparation 38, the product of the preceding Preparation (14 g) was converted to title product as an oil (9.15 g).
Preparation 42 4-Ethoxy-3-thenaidehyde By the procedure of Preparation 39, the product of the preceding Preparation (9.15 g) was converted to the title product, initially isolated as an oil which quickly crystallized on cooling [8.18 g; m.p. 42- 45IC; m/e 156; ir (KBr) 3090,2977 1688 cm-1].
Preparation 43 n-Propyl 4-(n-propoxy)-3-thenoate By the procedure of Preparation 40, using a reaction reflux time of 10 days, methyl 4-acetoxy-3thenoate (6 g) in 750 mi of 1 -propanoi containing 0.19 mi of concentrated sulfuric acid was converted to title product as an oil (5.4 g; m/e 228).
Preparation 44 1-[4-(n-Propoxy)-3-thienyl) methanol By the procedure of Preparation 38, the product of the preceding Preparation (5.4 g) was reduced to title compound, isolated as an oil (3. 44 g; m/e 172).
Preparation 45 20 4-(n-Propoxy)-3-thenaidehyde) By the procedure of Preparation 39, the product of the preceding Preparation (3.34 g) was converted to title compound [3.19 g; m/e 170; ir (CH,Clj 1689, 1539 cm-11.
Preparation 46 Ethyl 4-methoxy-2-methyl-3-thenoate Ethyl 4-hydroxy-2-methyi-3-thenoate [Chem. Ber. 48, p. 593 (1915); 7.8 g] was combined with 25 600 mi of methanol and 0.25 mi concentrated sulfuric acid and refluxed for 21 hours. The reaction mixture was evaporated to an oil, taken up in 500 mi of ether, washed with two 50 mi portions of 1 N sodium hydroxide and then one of brine, dried over anhydrous magnesium sulfate, and evaporated to yield title product as an oil (7.8 9; m/e 200; pnmr/CIDC13 includes singlet OCH3 protons at 3.9 ppm). The product is contaminated with a minor portion of the corresponding methyl ester.
Preparation 47 (4-Methoxy-2-methyl-3-thienyi) methanol The product of the preceding Preparation (7.8 g, 0.039 mole) was dissolved in 100 mI of hexane and 75 mi of toluene and cooled to -781C. Diisobutyl aluminum hydride (78 mi of 1 M in hexane, 0.078 mole) was added dropwise over 40 minutes. The mixture was stirred for 2 hours at -780C, warmed to room temperature and stirred for an additional 16 hours. Methanol (25.0 g, 31.6 mi, 0.78 mole) was added dropwise to the reaction mixture, keeping the temperature below 301C. After stirring 1.5 hours at room temperature, the reaction mixture was clarified by filtration over diatomaceous earth, with thorough methanol wash and repulp of the cake and finally methylene chloride wash. The combined filtrate and washes were dried over anhydrous magnesium suffate, filtered and evaporated to 40 yield title product as an oil (5.56 g; m/e 158; ir (CH,Clj 3598, 1582, 1708 cm-1.
Preparation 48 4-Methoxy-2-methyi-3-thenaidehyde By the procedure of Preparation 39, the product of the preceding Preparation (5.4 g, 0.034 mole) was converted to title compound isolated as an oil [5.23 g; Rf 0.36 (chloroform)].
Claims (2)
1. A compound of the formula 0 R 4 0 NH R: 1 wherein R 4 is hydrogen, lower alkanoyl or benzoyl and R' is 44 GB 2 131 422 A 44 (a) CN-- A, p a N3 or A - X "I A, wherein R' 'S (C,-C4)alkyl or phenyl, C is hydrogen, (C,-CJalkyl or phenyl and X is halo; 2 (b) Y11:o, 1 kll J 'N Y wherein Y is hydrogen or (C,-C,)alkoxy, Y' is hydrogen or (C,-CJalkyl anrl Y is hydrogen or halo; (c) z to lz::
Z 1 p Z', or z J: $ wherein Z' is hydrogen, halo or (C,-CJalkoxy and Z" is hydrogen or halo; (d) wherein W is hydrogen or halo, and n is 1 or 2; v (e) W 70Y H 2) n Q 1 A, or N wherein Q is sulfur or oxygen and V is hydrogen or (Cl-CJalkyl; v E: Q3- (f) wherein Q is sulfur or oxygen; and V is hydrogen or (C,-C.)alkyl; or (g) X 1 X V.. Y, c
2. Y X 2 3 or 15 a z G wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (Cl-CJalkoxy; X' is 15 hydrogen or methyl; and X' is hydrogen or halo.
New claims or amendments to claims filed on 10-1 -84. Superseded claims 1 New or amended claims:- 1. A compound of the formula 0 R 4 0 NH R:N wherein R' is hydrogen, lower alkanoyl or benzoyl and R' is 1 Y1 i P GB 2 131 422 A 45 (a) CN- A.
r a N3- A - X or ",a 1 A.
wherein R' is (C,-CJalkyl or phenyl, C is hydrogen, (C,-C,)akyl or phenyl and X is halo; 0 (b) -- 1 NY wherein Y is hydrogen or (C,-C,)aikoxy, Y' is hydrogen or W,-CJalkyl and Y' is hydrogen or halo; (C) z z Zz P::
I wherein Z' is hydrogen, halo or (C,-C,)afkoxy and Z" is hydrogen or halo; (d) wherein W is hydrogen or ha.lo; and n is 1 or 2; v Q or (e) W H 2)n C;I 05 wherein Q is sulfur or oxygen and V is hydrogen or (Cl-C3)alkyl; v (f) R Q3- wherein Q is sulfur or oxygen; and V is hydrogen or (C,-IC,)alkyl; X (g) 1 XY4. ty 1 2.
Y X 2 wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C,-C3)alkoxy; X' is hydrogen or methyl; and X2 is hydrogen or halo; or (h) 5-(2-phenyi-1,3- dioxolan-2-yi)thien-2-yl; with 15 the proviso that when R' is as defined in (h), R' is hydrogen.
Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17320680A | 1980-07-28 | 1980-07-28 | |
US06/222,202 US4367234A (en) | 1980-07-28 | 1981-01-02 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
US06/252,962 US4342771A (en) | 1981-01-02 | 1981-04-23 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
US06/252,961 US4332952A (en) | 1980-07-28 | 1981-04-23 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8317146D0 GB8317146D0 (en) | 1983-07-27 |
GB2131422A true GB2131422A (en) | 1984-06-20 |
GB2131422B GB2131422B (en) | 1984-12-05 |
Family
ID=27497044
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8122524A Expired GB2080803B (en) | 1980-07-28 | 1981-07-22 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
GB08317146A Expired GB2131422B (en) | 1980-07-28 | 1983-06-24 | Intermediates for hypoglycemic 5-substituted oxazolidine-2 4-diones |
GB08317143A Expired GB2134105B (en) | 1980-07-28 | 1983-06-24 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
GB08317142A Expired GB2134104B (en) | 1980-07-28 | 1983-06-24 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
GB08317147A Expired GB2128184B (en) | 1980-07-28 | 1983-06-24 | Aljyl 2-hydroxy-and-acyloxy-thioacetates |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8122524A Expired GB2080803B (en) | 1980-07-28 | 1981-07-22 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08317143A Expired GB2134105B (en) | 1980-07-28 | 1983-06-24 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
GB08317142A Expired GB2134104B (en) | 1980-07-28 | 1983-06-24 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
GB08317147A Expired GB2128184B (en) | 1980-07-28 | 1983-06-24 | Aljyl 2-hydroxy-and-acyloxy-thioacetates |
Country Status (29)
Country | Link |
---|---|
JP (1) | JPS5764692A (en) |
AR (3) | AR230281A1 (en) |
AU (2) | AU526733B2 (en) |
CA (1) | CA1161843A (en) |
CH (1) | CH653029A5 (en) |
CS (1) | CS237320B2 (en) |
DD (1) | DD202555A5 (en) |
DE (1) | DE3129275A1 (en) |
DK (1) | DK152650C (en) |
ES (4) | ES8301976A1 (en) |
FI (1) | FI75820C (en) |
FR (1) | FR2487350B1 (en) |
GB (5) | GB2080803B (en) |
GR (1) | GR75303B (en) |
HK (1) | HK43886A (en) |
IE (1) | IE51662B1 (en) |
IL (1) | IL63424A (en) |
IT (1) | IT1138111B (en) |
KE (1) | KE3624A (en) |
LU (1) | LU83513A1 (en) |
MY (1) | MY8600596A (en) |
NO (1) | NO812559L (en) |
NZ (1) | NZ197854A (en) |
PH (2) | PH21172A (en) |
PL (1) | PL133220B1 (en) |
PT (1) | PT73436B (en) |
SE (1) | SE461039B (en) |
SG (1) | SG56656G (en) |
YU (2) | YU185481A (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4695634A (en) * | 1981-01-02 | 1987-09-22 | Pfizer Inc. | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
US4689336A (en) * | 1981-01-02 | 1987-08-25 | Pfizer Inc. | Hypoglycemic 5-substituted oxazolidine 2,4-diones |
GR78120B (en) * | 1982-03-01 | 1984-09-26 | Pfizer | |
DE3233089A1 (en) * | 1982-09-07 | 1984-03-08 | Basf Ag, 6700 Ludwigshafen | CHINOLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR CONTROLLING UNWANTED PLANT GROWTH |
JPS59152382A (en) * | 1983-02-18 | 1984-08-31 | Tanabe Seiyaku Co Ltd | Furyloxazolylacetic acid derivative and its preparation |
US4968707A (en) * | 1987-06-10 | 1990-11-06 | Pfizer Inc. | Oxazolidin-2-one derivatives as hypoglycemic agents |
TW403748B (en) | 1994-11-02 | 2000-09-01 | Takeda Chemical Industries Ltd | An oxazolidinedione derivative, its production and a pharmaceutical composition for lowering blood sugar and lipid in blood comprising the same |
IL117208A0 (en) * | 1995-02-23 | 1996-06-18 | Nissan Chemical Ind Ltd | Indole type thiazolidines |
ES2567135T3 (en) * | 2003-08-29 | 2016-04-20 | The Brigham And Women's Hospital, Inc. | Hydantoin derivatives as inhibitors of cell necrosis |
EP2520561B1 (en) * | 2007-06-08 | 2016-02-10 | MannKind Corporation | IRE-1A Inhibitors |
BRPI0923126A2 (en) | 2008-12-23 | 2021-09-08 | President And Fellows Of Harvard College | SMALL MOLECULE NECROPTOSIS INHIBITOR COMPOUNDS, USE AND COMPOSITION COMPRISING THE SAME AND METHOD OF LOWERING NECROPTOSIS |
JP2016514693A (en) | 2013-03-15 | 2016-05-23 | プレジデント アンド フェローズ オブ ハーバード カレッジ | Hybrid necrotosis inhibitor |
TW201632516A (en) | 2014-12-11 | 2016-09-16 | 哈佛大學校長及研究員協會 | Inhibitors of cellular necrosis and related methods |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE729852C (en) * | 1939-07-06 | 1943-01-04 | Carl Nachtigall | Process for the preparation of 2,4-dioxooxazolidines |
DE834992C (en) * | 1946-09-16 | 1952-03-27 | British Schering Res Lab Ltd | Process for the preparation of N-alkyl or N-aralkyl derivatives of oxazolidine-2, 4-dynes |
US2721197A (en) * | 1953-01-05 | 1955-10-18 | Bristol Lab Inc | Bicyclic lactams |
US2954381A (en) * | 1958-12-03 | 1960-09-27 | Us Vitamin Pharm Corp | Heteroaryloxazolidinediones |
US3699229A (en) * | 1970-12-18 | 1972-10-17 | Abbott Lab | 2-oxo-5-phenyl-4-oxazolidinone as an anti-depressant agent |
DE2813873A1 (en) * | 1978-03-31 | 1979-10-11 | Basf Ag | PROCESS FOR THE PRODUCTION OF OXAZOLIDINE-2,4-DIONEN |
US4200642A (en) * | 1978-08-21 | 1980-04-29 | Pfizer Inc. | Spiro-oxazolidindiones |
-
1981
- 1981-07-22 SG SG305/86A patent/SG56656G/en unknown
- 1981-07-22 GB GB8122524A patent/GB2080803B/en not_active Expired
- 1981-07-23 CS CS815646A patent/CS237320B2/en unknown
- 1981-07-23 PL PL1981232330A patent/PL133220B1/en unknown
- 1981-07-24 DE DE19813129275 patent/DE3129275A1/en active Granted
- 1981-07-24 SE SE8104543A patent/SE461039B/en not_active IP Right Cessation
- 1981-07-27 CA CA000382568A patent/CA1161843A/en not_active Expired
- 1981-07-27 IE IE1696/81A patent/IE51662B1/en unknown
- 1981-07-27 DD DD81232129A patent/DD202555A5/en unknown
- 1981-07-27 NO NO812559A patent/NO812559L/en unknown
- 1981-07-27 FR FR8114542A patent/FR2487350B1/en not_active Expired
- 1981-07-27 AU AU73436/81A patent/AU526733B2/en not_active Ceased
- 1981-07-27 IL IL63424A patent/IL63424A/en unknown
- 1981-07-27 LU LU83513A patent/LU83513A1/en unknown
- 1981-07-27 PT PT73436A patent/PT73436B/en unknown
- 1981-07-27 ES ES504321A patent/ES8301976A1/en not_active Expired
- 1981-07-27 YU YU01854/81A patent/YU185481A/en unknown
- 1981-07-27 CH CH4878/81A patent/CH653029A5/en not_active IP Right Cessation
- 1981-07-27 DK DK334781A patent/DK152650C/en not_active IP Right Cessation
- 1981-07-27 PH PH25966A patent/PH21172A/en unknown
- 1981-07-27 NZ NZ197854A patent/NZ197854A/en unknown
- 1981-07-27 IT IT23176/81A patent/IT1138111B/en active
- 1981-07-27 GR GR65638A patent/GR75303B/el unknown
- 1981-07-27 FI FI812339A patent/FI75820C/en not_active IP Right Cessation
- 1981-07-27 JP JP56117572A patent/JPS5764692A/en active Granted
-
1982
- 1982-04-27 AR AR289216A patent/AR230281A1/en active
- 1982-04-27 AR AR289218A patent/AR230053A1/en active
- 1982-04-27 AR AR289217A patent/AR229958A1/en active
- 1982-07-23 ES ES514316A patent/ES514316A0/en active Granted
- 1982-07-23 ES ES514315A patent/ES514315A0/en active Granted
- 1982-07-23 ES ES514314A patent/ES514314A0/en active Granted
- 1982-11-02 AU AU90100/82A patent/AU548932B2/en not_active Ceased
-
1983
- 1983-01-03 PH PH28343A patent/PH18925A/en unknown
- 1983-04-22 YU YU00919/83A patent/YU91983A/en unknown
- 1983-06-24 GB GB08317146A patent/GB2131422B/en not_active Expired
- 1983-06-24 GB GB08317143A patent/GB2134105B/en not_active Expired
- 1983-06-24 GB GB08317142A patent/GB2134104B/en not_active Expired
- 1983-06-24 GB GB08317147A patent/GB2128184B/en not_active Expired
-
1986
- 1986-04-04 KE KE3624A patent/KE3624A/en unknown
- 1986-06-09 HK HK438/86A patent/HK43886A/en unknown
- 1986-12-30 MY MY596/86A patent/MY8600596A/en unknown
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