US2527293A - Thomas f - Google Patents
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- US2527293A US2527293A US2527293DA US2527293A US 2527293 A US2527293 A US 2527293A US 2527293D A US2527293D A US 2527293DA US 2527293 A US2527293 A US 2527293A
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- United States
- Prior art keywords
- acid
- salt
- nitro
- barbituric acid
- salts
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 56
- 239000002253 acid Substances 0.000 claims description 48
- 150000007513 acids Chemical class 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 description 118
- 150000003839 salts Chemical class 0.000 description 110
- HNYOPLTXPVRDBG-UHFFFAOYSA-N Barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 238000000034 method Methods 0.000 description 34
- 125000004432 carbon atoms Chemical group C* 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 125000000217 alkyl group Chemical group 0.000 description 24
- 150000007656 barbituric acids Chemical class 0.000 description 24
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 24
- 235000019441 ethanol Nutrition 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 22
- 229910052700 potassium Inorganic materials 0.000 description 22
- 239000011591 potassium Substances 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000007792 addition Methods 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 18
- YOUGRGFIHBUKRS-UHFFFAOYSA-N benzyl(trimethyl)azanium Chemical compound C[N+](C)(C)CC1=CC=CC=C1 YOUGRGFIHBUKRS-UHFFFAOYSA-N 0.000 description 16
- -1 monosubstituted barbituric acid Chemical class 0.000 description 16
- 159000000001 potassium salts Chemical class 0.000 description 16
- 210000004940 Nucleus Anatomy 0.000 description 14
- 230000000875 corresponding Effects 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- PFYZFXSXSIFUTF-UHFFFAOYSA-N CC1(C(NC(NC1=O)=S)=O)CC(CC)[N+](=O)[O-] Chemical compound CC1(C(NC(NC1=O)=S)=O)CC(CC)[N+](=O)[O-] PFYZFXSXSIFUTF-UHFFFAOYSA-N 0.000 description 6
- RVBUGGBMJDPOST-UHFFFAOYSA-N Thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 6
- KJSRUIVCAJSVTF-UHFFFAOYSA-N [N+](=O)([O-])C(CC1C(NC(NC1=O)=S)=O)CC.[K] Chemical compound [N+](=O)([O-])C(CC1C(NC(NC1=O)=S)=O)CC.[K] KJSRUIVCAJSVTF-UHFFFAOYSA-N 0.000 description 6
- 238000007259 addition reaction Methods 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 159000000009 barium salts Chemical class 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 159000000007 calcium salts Chemical class 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- BTYNVOQLMBUUMS-UHFFFAOYSA-N 2-amino-1H-pyrimidine-4,6-dione Chemical compound NC1=NC(=O)CC(=O)N1 BTYNVOQLMBUUMS-UHFFFAOYSA-N 0.000 description 4
- XMBCIDWARZDYSD-UHFFFAOYSA-N 2-nitrobut-1-ene Chemical compound CCC(=C)[N+]([O-])=O XMBCIDWARZDYSD-UHFFFAOYSA-N 0.000 description 4
- FMTLDVACNZDTQL-UHFFFAOYSA-N 5-ethyl-1,3-diazinane-2,4,6-trione Chemical compound CCC1C(=O)NC(=O)NC1=O FMTLDVACNZDTQL-UHFFFAOYSA-N 0.000 description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N Benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 4
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M Benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 4
- SHJBUJFUQWZXCF-UHFFFAOYSA-N C(C)C1(C(NC(NC1=O)=O)=O)CC(CC)[N+](=O)[O-] Chemical compound C(C)C1(C(NC(NC1=O)=O)=O)CC(CC)[N+](=O)[O-] SHJBUJFUQWZXCF-UHFFFAOYSA-N 0.000 description 4
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N Calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N Chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 125000004429 atoms Chemical group 0.000 description 4
- 229910052788 barium Inorganic materials 0.000 description 4
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 4
- 229940073608 benzyl chloride Drugs 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 230000001264 neutralization Effects 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 230000000630 rising Effects 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 230000002557 soporific Effects 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- LDKGEUAGEISBIX-WAYWQWQTSA-N (Z)-3-nitrohex-3-ene Chemical compound CC\C=C(\CC)[N+]([O-])=O LDKGEUAGEISBIX-WAYWQWQTSA-N 0.000 description 2
- RJKGJBPXVHTNJL-UHFFFAOYSA-N 1-nitronaphthalene Chemical compound C1=CC=C2C([N+](=O)[O-])=CC=CC2=C1 RJKGJBPXVHTNJL-UHFFFAOYSA-N 0.000 description 2
- WCVOGSZTONGSQY-UHFFFAOYSA-N 2,4,6-Trichloroanisole Chemical compound COC1=C(Cl)C=C(Cl)C=C1Cl WCVOGSZTONGSQY-UHFFFAOYSA-N 0.000 description 2
- USEGQJLHQSTGHW-UHFFFAOYSA-N 3-bromo-2-methylprop-1-ene Chemical compound CC(=C)CBr USEGQJLHQSTGHW-UHFFFAOYSA-N 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N Allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L Barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- HWFOVMMUULYWNO-UHFFFAOYSA-N C(C1=CC=CC=C1)C1(C(NC(NC1=O)=O)=O)CC(CC)[N+](=O)[O-] Chemical compound C(C1=CC=CC=C1)C1(C(NC(NC1=O)=O)=O)CC(CC)[N+](=O)[O-] HWFOVMMUULYWNO-UHFFFAOYSA-N 0.000 description 2
- HXTQTOCPZSMUSC-UHFFFAOYSA-N C(C1=CC=CC=C1)[N+](C)(C)C.N1C(=O)NC(=O)CC1=O Chemical compound C(C1=CC=CC=C1)[N+](C)(C)C.N1C(=O)NC(=O)CC1=O HXTQTOCPZSMUSC-UHFFFAOYSA-N 0.000 description 2
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Diethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 2
- 241000269774 Lates Species 0.000 description 2
- 229940073020 Nitrol Drugs 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Trioxopurine Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- 229940116269 Uric Acid Drugs 0.000 description 2
- RJWFZLXTKMHNIR-UHFFFAOYSA-N [N+](=O)([O-])C(C(CC)C1C(NC(NC1=O)=O)=O)CC.[K] Chemical compound [N+](=O)([O-])C(C(CC)C1C(NC(NC1=O)=O)=O)CC.[K] RJWFZLXTKMHNIR-UHFFFAOYSA-N 0.000 description 2
- KPEORJWXMUVACJ-UHFFFAOYSA-N [N+](=O)([O-])C(CC1C(NC(NC1=O)=O)=O)CC Chemical compound [N+](=O)([O-])C(CC1C(NC(NC1=O)=O)=O)CC KPEORJWXMUVACJ-UHFFFAOYSA-N 0.000 description 2
- NCUYEBBVZZCKNZ-UHFFFAOYSA-N [N+](=O)([O-])C(CC1C(NC(NC1=O)=S)=O)CC Chemical compound [N+](=O)([O-])C(CC1C(NC(NC1=O)=S)=O)CC NCUYEBBVZZCKNZ-UHFFFAOYSA-N 0.000 description 2
- KLXLIRZPZWAHBO-UHFFFAOYSA-N [N+](=O)([O-])CC(C1=CC=CC=C1)C1C(NC(NC1=O)=S)=O Chemical compound [N+](=O)([O-])CC(C1=CC=CC=C1)C1C(NC(NC1=O)=S)=O KLXLIRZPZWAHBO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000002152 alkylating Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 235000020127 ayran Nutrition 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 230000000147 hypnotic Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004971 nitroalkyl group Chemical group 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000001624 sedative Effects 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- VHLDQAOFSQCOFS-UHFFFAOYSA-M tetrakis(2-hydroxyethyl)azanium;hydroxide Chemical compound [OH-].OCC[N+](CCO)(CCO)CCO VHLDQAOFSQCOFS-UHFFFAOYSA-M 0.000 description 2
- PIAOLBVUVDXHHL-VOTSOKGWSA-N β-Nitrostyrene Chemical group [O-][N+](=O)\C=C\C1=CC=CC=C1 PIAOLBVUVDXHHL-VOTSOKGWSA-N 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
- C07D239/64—Salts of organic bases; Organic double compounds
Definitions
- Patented Oct. 24, 1950 1 UNITED STATES PATENT OFFICE -,B-NITROALKYL BARBITURIC ACIDS AND SALTS THEREOF Carl T. Bahner, Jefferson City, Tenn.
- the ring nucleus is of the barbituric acid type and is that which is found in such compounds as barbituric acid, 2- th-iobarbituric acid and malonylguanidine.
- the acid characteristics oflcompounds having this skeletal arrangement are imparted by the hydrogen; atoms attached to the nitrogens in the 1 and/or 3 positions, and the salts of the compounds having the above indicated skeletal configuration are to be considered as falling within the scope of this invention as defined by the appended claims.
- this invention relates to the provision of compounds having a barbituric acid type ring nucleus wherein is provided a 2'-nitroalkyl substituent on the carbon atom in the 5 position.
- this invention relates to compounds (and their salts) having the formula:
- R1 is selected from the group consisting of hydrogen and alkyl
- R2 is selected within the above generalized formula and contemplated within the scope-of this invention are 5-(2nitrol-ethyl-n-butyl) barbituric acid, 5- (2 -nitro-l' phenylethyl)-barbituric acid, 5-12.- nitro-n-butyl) -2-thiobarbituric acid, 5-(2-nitron-butyD-barbituric acid, 5-(2-nitro-l-phenylethyl) -2-thiobarbituric acid, 5-ethy1-5-(2-nitron-butyD- barbituric acid, 5-methyl-5-(2'-nitro n-butyl) 2 thiobarbituric acid, 5 allyl-5-(2'- 'nitio-n-butyl) -barbituric acid, 5 benzyl-5-(2'--
- the compounds of this invention are barbituric acid derivatives butit will be apparent that the oxygen onthecarbon atom in the 2 position of the barbituric acid nucleus may be replaced by sulfur to form the corresponding Z-thiobarbituric acid derivative or its salts, or by an imido group to form the corresponding de rivative of malonylguanidine or its salts.
- the compounds of this invention may be prepared by reacting a nitroolefin directly with a salt of the barbituric acid type compound whereby the nitroolefin is added to the barbituric acid type nucleus at the carbon atom in the 5 position.
- the over-all reaction may be represented as 1'01- 1OWS:
- a quaternary ammonium salt for example, a benzyltrimethylammonium salt
- the addition of the nitroolefin to the carbon atom in the 5 position will readily occur even though one of the hydrogens on the 5 carbon atom has been previously substituted with another grouping, such as methyl, ethyl, n-butyl or benzyl.
- a method has been devised for the ready preparation of 5-alkyl-5- (2'-nitroalkyl) -barbituric acid type compounds directly from the corresponding 5-alkyl compounds. :Such a process and the resulting product constitute onefeature of the present invention.
- alkyl or aralkyl halides employed in this alkylation reaction maybe any that are Well known in the art to 'beuse'fulforalkylation of readily alkylatedcompounds such as malonic ester.
- thehalide should be a chloride, bromide or iodide, suitable examples being methyl iodide, allyl bromide and benzyl chloride.
- Other halides such as ethyl, propyl, n-butyl, iso-butyl,
- the salt employed is prefrably one which is readily ionized in solution and is readily soluble in the solvent employed.
- the potassium salts are convenient but the presess is not limited to them, since, as above explained, under special conditions, the quaternary ammonium salts, such as the benzyltrimethylammonium salt, are preferred.
- a trace of acid may be used in the reaction mixture to inhibit the polymerization of the nitroolefin.
- the reaction is effected most conveniently in a solution which serves as a solvent for both the salt and the nitroolefin and does not react with or destroy either. For example, mixtures of alcohols and water have been found useful but the process is not to be considered as limited to these particular solvents.
- the metallic salts when employed, it is desirable to carry out the nitroolefin addition reaction at elevated temperatures since the reactants are usually more soluble in hot solvents and since elevated temperatures have a tendency to speed up the reaction. However, lower temperatures are preferred when the quaternary ammonium salts are utilized.
- the resulting 5-(2'-nitroalkyl) derivative may be isolated in the form of its salt by any convenient method. Often the salt form is most convenient for medicinal use or for usein preparing other compounds. If desired, salts containing other cations-may be prepared by metathesis or the corresponding free barbituric acid type derivative may be obtained by cautious acidification of the salt formed in the reaction. As previously indicated, both the salts and the free acids are considered as falling Within the spirit and scope of this invention. 7
- the freeacid may be prepared from the salt by cautious treatment with an acid, such as monochloracetic acid or dilute sulfuric acid.
- EXAMPLE III (2 '-11,z'tro-n-butyl) -2-thiobarbituric acid
- a saturated solution of potassium Z-thiobarbiturate was prepared by boiling a mixture of 275 cc. of 95% ethyl alcohol and 140 cc. of water with 9.4 grams of the potassium salt. The hot solution was decanted and to it was added 6.0 grams (an excess) of 2-nitro-l-butene. The remainder of the undissolved salt was dissolved in 125 cc. of boiling Water and added to the'reaction mixture. The solution was allowed to cool and within a short time the lachrymatory odor of nitroolefin had disappeared.
- the corresponding barium and calcium salts were separately prepared by adding concentrated solutions of barium chloride and calcium nitrate, respectively, to separate concentrated clarified solutions of the potassium salt.
- These alkaline earth metal salts were much less soluble in water than was the potassium salt, but were nevertheless somewhat soluble.
- the free 5-(2-nitro-n-butyl) -2-thiobarbituric acid was prepared (1) by the cautious addition of a very dilute solution of sulfuric acid to an aqueous solution of the barium salt, and (2) by a similar addition of a solution of a solution of the calcium salt.
- the benzyltrimethylammonium salt of 2-thiobarbituric acid was prepared by adding to 2.25
- the free acid was obtained by dissolving 1.0 gram of the salt in 5 cc. water at 60 C. and adding 1 cc. of 3 N. hydrochloric acid dropwise with stirring. The oily droplets of the acid which first separated soon solidifiedin an amount corresponding to 0.62 gram.
- EXAMPLE VIII 5 -ethyl-5- (2'-nitro-n-butyl) -barbituric acid
- the benzyltrimethylammonium salt of 5-ethylbarbituric acid was prepared by dissolving 1.85 grams of 5-ethylbarbituric acid in 4.4 grams of Triton B and 2.5 cc. of 95% ethyl alcohol to form a neutral solution.
- To this solution 1.17 grams of 2-nitro-1-butene were added dropwise with stirring employing an ice bath to prevent the temperature from rising above 50 C. The lachrymatory odor of the nitroolefin disappeared at once. The following day cc.
- tetraethanolammonium salts have been used.
- those quaternary ammonium salts that are preferred for use are those which are soluble to a substantial degree in the solvents employed for the nitro'lefin addition reaction.
- EXAMPLE X 5 -allyZ-5 (-2-m'tro -n-butyl) -barbit'uric acid A solution was prepared containing 105 cc. of ethyl alcohol, 7 .0 grams of allyl bromide and 7.0 grams of potassium 5-(2-nitro-n-butyl) barbiturate, the latter having been prepared in accordance with the method indicated in Example IV above. The resulting solution was refluxed for 24 hours, cooled and filtered to remove byproducts. The filtrate was evaporated to dryness
- EXAMPLE XI 5-benzyZ-5- (2'-nitro-n-butyl) -barbituric acid A solution was prepared containing 104 cc.
- th invention contemplates compounds and processes wherein the barbituric acid type ring nucleus is substituted in the 5 position by a B-nitroalkyl group.
- the invention contemplates not only the derivatives of barbituric acid, but also .the derivatives of 2-thiobarbituric acid, malonyl- N-alkyl derivative salts in the manner indicated in the foregoing.
- R1 is selected from the group consisting of hydrogen and alkyl
- R2 is selected from the group consisting of hydrogen, alkyl and aryl
- R3 is selected from the group consisting of hydrogen, alkyl and aralkyl
- X is selected from the group consisting of oxygen and sulfur; and the salts of said acids.
- a barbituric acid derivative selected from the class consisting of compounds having the formula:
- R1 is selected from the group consisting of hydrogen and alkyl
- R2 is selected from the group consisting of hydrogen, alkyl and V aryl
- R3 is selected from the group consisting of hydrogen, alkyl, and aralkyl
- a process of preparing a compound having a barbituric acid type ring nucleus substituted in the 5 position with afi-nitroalkyl group which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of a compound it) selected from the group consisting of barbituric acid and Z-thiobarbituric acid to produce the said compound having a barbituric acid ring type nucleus substituted in the five-position with a B-nitro alkyl group.
- a process of preparing a 5-(2-nitroalkyl) barbituri-c acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of barbituric acid to produce a 5-(2' nitroalkyl) barbituric acid derivative.
- Aprocess of preparing a 5-(2'-nitroalkyl) Z-thiobarbituric acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubl bound carbon atoms with a salt of Z-thiobarbituric acid to produce a 5- (2-nitroalkyl) -2-thiobarbituric acid derivative.
- a process for the preparation of a 5-(2'- nitroalkyl)-5-alkyl derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a quaternary ammonium salt of a 5-alkyl derivative of said compound to produce a 5-(2'- nitroalkyl) -5-alkyl'derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid.
- a process of alkylating in the 5 position a compound selected from the group consisting of the salts of 5-(2-nitroalkyl) -barbituric acid and of 5-(2'-nitroalky1) -2-thiobarbituric acid which 1 comprises reacting said compound with an alkyl No references cited.
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Description
Patented Oct. 24, 1950 1 UNITED STATES PATENT OFFICE -,B-NITROALKYL BARBITURIC ACIDS AND SALTS THEREOF Carl T. Bahner, Jefferson City, Tenn.
No Drawing. Application August 5, 1948, Serial No. 42,741
hypnotic, sedative or soporific activity, and as intermediates in the preparation of other pharmaceuticalsand chemical compounds. 7
The compounds that are contemplated within the scope of this invention are those which have the following skeletal configuration:
It will be noted from (1) that the ring nucleus is of the barbituric acid type and is that which is found in such compounds as barbituric acid, 2- th-iobarbituric acid and malonylguanidine. As is well known in the art, the acid characteristics oflcompounds having this skeletal arrangement are imparted by the hydrogen; atoms attached to the nitrogens in the 1 and/or 3 positions, and the salts of the compounds having the above indicated skeletal configuration are to be considered as falling within the scope of this invention as defined by the appended claims. Stated in another way, this invention relates to the provision of compounds having a barbituric acid type ring nucleus wherein is provided a 2'-nitroalkyl substituent on the carbon atom in the 5 position.
More specifically, this invention relates to compounds (and their salts) having the formula:
Norm" o H Rat -5H MI wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected within the above generalized formula and contemplated within the scope-of this invention are 5-(2nitrol-ethyl-n-butyl) barbituric acid, 5- (2 -nitro-l' phenylethyl)-barbituric acid, 5-12.- nitro-n-butyl) -2-thiobarbituric acid, 5-(2-nitron-butyD-barbituric acid, 5-(2-nitro-l-phenylethyl) -2-thiobarbituric acid, 5-ethy1-5-(2-nitron-butyD- barbituric acid, 5-methyl-5-(2'-nitro n-butyl) 2 thiobarbituric acid, 5 allyl-5-(2'- 'nitio-n-butyl) -barbituric acid, 5 benzyl-5-(2'- niti'o-n-butyl) barbituric acid, and the salts thereof. Specific salts that may be mentioned are those of potassium, barium,: calcium and those formed from a quaternary ammonium hydroxide, such as benzyltrimethylammoniumv hydroxide or tetraethanolammonium hydroxide.
' These latter salts are important as intermediates formed When one phase of this invention is carried out in accordance with a preferred embodiment, as will be hereinafter mor fully explained.
As above indicated, the compounds of this invention are barbituric acid derivatives butit will be apparent that the oxygen onthecarbon atom in the 2 position of the barbituric acid nucleus may be replaced by sulfur to form the corresponding Z-thiobarbituric acid derivative or its salts, or by an imido group to form the corresponding de rivative of malonylguanidine or its salts.
The compounds of this invention may be prepared by reacting a nitroolefin directly with a salt of the barbituric acid type compound whereby the nitroolefin is added to the barbituric acid type nucleus at the carbon atom in the 5 position. The over-all reaction may be represented as 1'01- 1OWS:
l ino;
O C=X (salt) 40 (1311 Rs CN NOrRr- O H" na l am ,l r C=X (salt) The salts of; fl cpbarbituric acid type compounds which have been foundto be particularly ffective for carrying out the reaction are those of potassium and of benzyltrimethylammonium V hydroxide. However, in most instances, other salts may readily be used, such as those of sodium,
lithium, calcium, magnesium, barium, tetra- 3 ethanolaminonium hydroxide and the like, the desirability being that such salts be soluble in the solution in which the reaction is efiected.
It will be apparent that the above indicated generalized equation indicates that a convenient method has been devised in accordance with this invention for adding a finitroalkyl group to a compound of the barbituric acid type wherein the carbon atom in the 5 position has attached at least one unsubstituted hydrogen atom. The metallic salts of the barbituric acid type compound are very satisfactory for use in the cases where neither hydrogen on the 5 carbon atom is substituted. However, in those cases where one of the hydrogens on the 5 carbon atom has already been substituted, such as by an alkyl or an aryl group, then it is preferred to employa quaternary ammonium salt of such a 5 monosubstituted barbituric acid derivative in the reaction with the nitroolefin. When a quaternary ammonium salt is employed (for example, a benzyltrimethylammonium salt), the addition of the nitroolefin to the carbon atom in the 5 position will readily occur even though one of the hydrogens on the 5 carbon atom has been previously substituted with another grouping, such as methyl, ethyl, n-butyl or benzyl. Thus by the use of the quaternary ammonium salts, a method has been devised for the ready preparation of 5-alkyl-5- (2'-nitroalkyl) -barbituric acid type compounds directly from the corresponding 5-alkyl compounds. :Such a process and the resulting product constitute onefeature of the present invention.
In accordance with a further and alternative embodiment of this invention where it is desired to provide an alkyl substituent on the carbon atom in the 5 position together with the fi-nitroalkyl substituent, it has been found that this may be accomplished by the direct alkylation of a 5- (2',-nitroall yl) -barbituric acid type compound with an alkyl halide. Thus an alkyl group is added to the nucleus at the carbon atom in the 5 position. The alkylation reaction is preferably carried out with the salt of the 5-(2-nitroalkyl) barbituric acid type compound, and the over-all reaction may be represented as follows:
The alkyl or aralkyl halides employed in this alkylation reaction maybe any that are Well known in the art to 'beuse'fulforalkylation of readily alkylatedcompounds such as malonic ester. Generally thehalide should be a chloride, bromide or iodide, suitable examples being methyl iodide, allyl bromide and benzyl chloride. Other halides, such as ethyl, propyl, n-butyl, iso-butyl,
benzyl, etc. may be used.
In carrying out the addition ofa nitroolefin to a'salt of barbituric acid type compound as indicated'in the foregoing, the salt employed is prefrably one which is readily ionized in solution and is readily soluble in the solvent employed.
4 The potassium salts are convenient but the presess is not limited to them, since, as above explained, under special conditions, the quaternary ammonium salts, such as the benzyltrimethylammonium salt, are preferred. If desired, a trace of acid may be used in the reaction mixture to inhibit the polymerization of the nitroolefin. The reaction is effected most conveniently in a solution which serves as a solvent for both the salt and the nitroolefin and does not react with or destroy either. For example, mixtures of alcohols and water have been found useful but the process is not to be considered as limited to these particular solvents. Generally speaking, when the metallic salts are employed, it is desirable to carry out the nitroolefin addition reaction at elevated temperatures since the reactants are usually more soluble in hot solvents and since elevated temperatures have a tendency to speed up the reaction. However, lower temperatures are preferred when the quaternary ammonium salts are utilized. After the addition reaction has taken place, the resulting 5-(2'-nitroalkyl) derivative may be isolated in the form of its salt by any convenient method. Often the salt form is most convenient for medicinal use or for usein preparing other compounds. If desired, salts containing other cations-may be prepared by metathesis or the corresponding free barbituric acid type derivative may be obtained by cautious acidification of the salt formed in the reaction. As previously indicated, both the salts and the free acids are considered as falling Within the spirit and scope of this invention. 7
For a more complete understanding of this invention, reference will now be made to certain specific examples wherein are indicated certain of the new compounds herein contemplated together with their method of preparation. It will be understood, however, that this invention is not to be restricted in any way by these specific examples since they are merely illustrative and not definitive of the broad aspects of the present invention.
EXAMPLE I 5- (2-m'tro-1 '-ethyl-n-butyl) -barbituric acid v A mixture of 0.78 gram of 3-nitro-3-hexene, 1.0 gram of potassium barbiturate containing a trace of free barbituric acid, 5 cc. of ethyl alcohol and 2 cc. of water was refluxed for 3 hours. The nitroolefin and the barbiturate reacted to form potassium 5-(2'-nitro 1-ethyl-n-butyl)- barbiturate. This salt was recovered by coolmg the reacted solution to room temperature and adding 5 cc. of acetone to precipitate unreacted pbtas'siurn barbiturate. The solution was filtered and the filtrate was evaporated to dryness. The residue was washed with acetone. The washed d'ried'p'owde'r was analyzed for posassium. Calculated for potassium 5-'(2-nitro-'1-ethyl-nbutyl)-barbiturate: 13.3%; found, K, 13.4%,
The freeacid may be prepared from the salt by cautious treatment with an acid, such as monochloracetic acid or dilute sulfuric acid.
EXAMPLE II M 5-;(2' ni tro- 1'-phenyletliyl) -barbitmzc dam A mixture of 2.69 grams of w-nitros'tyrene, 3.00 grains'of'potassium barbiturate, 5.4 cc, of water and 15 cc. 'of ethyl alcohol was refluxed for 1'7 hours and then diluted with 15 cc. of acetone. The precipitate obtained on cooling to room temperature and filtering weighed 0.708- gram and contained some unreacted potassium barbiturate. The filtrate on evaporation yielded 323 grams of crude potassium '5- (2-nitro-1-phenylethyl) barbiturate from which the purified salt was obtained by recrystallization from absolute ethyl alcohol. The free acid was liberated by treatment of an aqueous solution of the potassium salt with a solution of monochloracetic acid.
EXAMPLE III (2 '-11,z'tro-n-butyl) -2-thiobarbituric acid A saturated solution of potassium Z-thiobarbiturate was prepared by boiling a mixture of 275 cc. of 95% ethyl alcohol and 140 cc. of water with 9.4 grams of the potassium salt. The hot solution was decanted and to it was added 6.0 grams (an excess) of 2-nitro-l-butene. The remainder of the undissolved salt was dissolved in 125 cc. of boiling Water and added to the'reaction mixture. The solution was allowed to cool and within a short time the lachrymatory odor of nitroolefin had disappeared. On evaporation of the solution to drynessa nearlytheoretical yield of crude potassium 5-(2-nitro-n-butyl)-2-thiobarbiturate was obtained. Impurities were removed by dissolving a 3.0 g. portion of the crude salt'in 25 ml. of boiling absolute methyl alcohol, allowing to stand with 0.2 g. activated charcoal at 65 C., fitering, adding 40 ml. of dry ether-to the filtrate, cooling, filtering again to remove dark-colored impurities, then evaporating the filtrate to obtain the purified salt.
Analysis: Calculated for potassium 5-(2-nitro n-butyl) -2-thiobarbiturate: K, 13.79%; found, K, 13.56%, 13.53%. i
The corresponding barium and calcium salts were separately prepared by adding concentrated solutions of barium chloride and calcium nitrate, respectively, to separate concentrated clarified solutions of the potassium salt. The barium and calcium salts, respectively, precipitated out. These alkaline earth metal salts were much less soluble in water than was the potassium salt, but were nevertheless somewhat soluble.
The free 5-(2-nitro-n-butyl) -2-thiobarbituric acid was prepared (1) by the cautious addition of a very dilute solution of sulfuric acid to an aqueous solution of the barium salt, and (2) by a similar addition of a solution of a solution of the calcium salt.
5- (z'mitro-n-butyl') -barbitm'ic acid oxalic acid to tion yielded 18.6 grams of crude potassium 5- (2-'nitro-n-butyl-) -ba .rbiturate. In order to obtain the free acid, 7.0 grams of this crude'saltwere dissolved in 20 cc. of water and thesolution. was acidified by the addition of a solution of 2.0 grams ofconcentrated sulfuric acid-in 20 cc. of water over a period of 30 minutes; keeping the solution cooled and wel-listirred. During this period the weight of free acid which separated in the form of white crystals was 2.7 grams. An additional quantity of the free acid was recovered by extracting the aqueous mother liquor with ethyl ether. After recrystallization, the acid small amount of solid matter.
.melted at C. Analysis: Calculated for5- (2'-nitro-n-butyl) -barbituric acid: C, 41.92%, H, 4.33%; found: C, 41.97%, H, 4.91%.
In the foregoing examples an embodiment of this invention has been illustrated wherein the potassium salts of barbituric acid were employed. As previously indicated, and in accordance with one preferred embodiment of this invention, it has been found under certain conditions advantageous to use a quaternary ammonium salt of the barbituric acid type compound instead of the alkali metal salt. When such quaternary ammonium salts are employed, the reaction may then be carried out in more concentrated solutions and at lower temperatures. Likewise the use of these salts is particularly desirable when it is desired to react a nitroolefin with a barbituric acid type derivative which already has one alkyl or aryl substituent on the carbon atom in the 5 position since very much improved yields are obtained (see particularly Example VIII). The next four examples are illustrative of processes in which a quaternary ammonium salt of the barbituric acid type compound is employed in reactions involving nitroolefins.
EXAMPLEV 5-(2'-m'tro-n-butyl)-bdrbituric acid 7 tion which is sold and distributed by Rohm &'
Haas Co., of Philadelphia, Pa.). To this solution was added 5.06 grams of -nitro-1-butene in small portions with stirring, employing a water bath to prevent the temperature from rising above about 40 C. The odor of the nitroolefin-was no longer observed after a short period.
After the solution had been allowed to stand for four days (this period of standing not being necessary), it was centrifuged to remove a Thereafter the 5- (2' -nitro-n-butyl) Y barbituric acid benzyltrimethylammonium saltwas treated in the supernatant liquid by the addition of 4.0 grams of concentrated sulfuric acid dissolved in 20 cc. of water. The dilute acid was added dropwise with stirring over a 30 minute period, keeping the solution cooled. The weight of crude product which separated in the form of tan crystals was 13.3
grams. A single recrystallization from isopropyl alcohol was sufficient to yield nearly pure 5-(2- nitro-n-butyl)-barbituric acid melting at, 152 to 154 C.
The benzyltrimethylammonium salt of 2-thiobarbituric acid was prepared by adding to 2.25
grams of Triton B enough 2-thiobarbituric acid (about 0.760 grams) to produce a neutral solu- Ition. After 30 minutes a solution of 0.70 gram of 1-nitro-2-phenylethylene in 2.5 cc. of absolute ethyl alcohol was added. The solution remained clear on standing overnight but upon seeding deposited crystals of the benzyltrimethylammonium salt of 5-( '-nitro-l-phenylethyl) -2-5thiobarbituric acid. The crystals were washed with 5 cc. of ethyl alcohol and were dried. The crystals had a melting point of to 191 C. and 1.45 grams were recovered. The corresponding. free i alcohol and water.
acid was obtained by dissolving 0.80 gram of the salt in 50 cc. of water to form a saturated solution and then adding 1 cc. of 3 N. hydrochloric acid at room temperature. The free acid separated out in the form of white crystals.
EXAMPLE VII (2 -m'tro-1 -phenylethyl) -barbituric acid.
,5-(2 nitro-l phenylethyl)-barbituric acid began to precipitate. This salt was recovered by filtration and washed with a mixture of ethyl It weighed 30 grams and decomposed at 175 C. An additional 0.9 gram of the salt was recovered from the mother liquor.
The free acid was obtained by dissolving 1.0 gram of the salt in 5 cc. water at 60 C. and adding 1 cc. of 3 N. hydrochloric acid dropwise with stirring. The oily droplets of the acid which first separated soon solidifiedin an amount corresponding to 0.62 gram.
EXAMPLE VIII 5 -ethyl-5- (2'-nitro-n-butyl) -barbituric acid The benzyltrimethylammonium salt of 5-ethylbarbituric acid was prepared by dissolving 1.85 grams of 5-ethylbarbituric acid in 4.4 grams of Triton B and 2.5 cc. of 95% ethyl alcohol to form a neutral solution. To this solution 1.17 grams of 2-nitro-1-butene were added dropwise with stirring employing an ice bath to prevent the temperature from rising above 50 C. The lachrymatory odor of the nitroolefin disappeared at once. The following day cc. of water were added to the reaction mixture and it was centrifuged to remove some gummy material which separated. The resulting clear solution of the benzyltrimethylammonium salt of 5-ethyl-5-(2- nitro-n-butyl)-barbituric acid was acidified by the addition of 1.0 gram of concentrated sulfuric acid dissolved in 8 cc. of water dropwise with stirring and cooling over a 10 minute period.
Additional gummy material formed was separated and the clarified solution was allowed to evaporate until crystals formed which were recovered by filtration, washed with water and h monium salts may be employed if desired. For
example,tetraethanolammonium salts have been used. As will be apparent to one skilled in the art, those quaternary ammonium salts that are preferred for use are those which are soluble to a substantial degree in the solvents employed for the nitro'lefin addition reaction.
In order to demonstrate that aspect of this inven ion when r lates to the preparation of? 5- alkyl-5- 2-nitroall yl) barbituric acid type combarbiturate.
pounds by alkylation in accordance with this invention, the following three examples are given:
EXAMPLE IX 5-m'ethyl-5-(2-nitro-n-butyl) -2 thiobarbituric acid A solution was prepared comprising 73 cc. of absolute methyl alcohol, 14.5 cc, of methyl iodide and 7.0 grams of potassium 5-(2-nitro-n-butyl) 2-thiobarbiturate, the latter being prepared in accordance with the method indicated in Example III. The solution was refluxed for 24 hours, then filtered and the filtrate evaporated to dryness. The crude product was purified by dissolving in 24 ml. of hot alcohol, then throwing out of solution by addition of water and cooling. After two further crystallizations from isopropyl alcohol it was obtained in the form of crystals melting at 203 C. with decomposition. Analysis: Calculated for 5-methyl-5-(2-nitro-n-butyl) -2- thiobarbituric acid: C, 41.69, H, 5.05; found: C, 41.85, H, 5.02.
EXAMPLE X 5 -allyZ-5 (-2-m'tro -n-butyl) -barbit'uric acid A solution was prepared containing 105 cc. of ethyl alcohol, 7 .0 grams of allyl bromide and 7.0 grams of potassium 5-(2-nitro-n-butyl) barbiturate, the latter having been prepared in accordance with the method indicated in Example IV above. The resulting solution was refluxed for 24 hours, cooled and filtered to remove byproducts. The filtrate was evaporated to dryness EXAMPLE XI 5-benzyZ-5- (2'-nitro-n-butyl) -barbituric acid A solution was prepared containing 104 cc. of 91% ethyl alcohol, 5.0 grams of benzyl chloride and 4.5 grams of potassium 5-(2-nitro-n-butyl) The solution was refluxed for 24 hours, cooled and filtered to'remove potassium chloride. The filtrate was evaporated to dryness and the residue was recrystallized first from hot absolute alcohol, by addition of water and cooling, then from 95% alcohol to form white crystals which melted with decomposition at 225 to 227 C. The acid prepared showed upon analysis: Calculated: C, 56.38, H, 5.36; found: C, 56.42, H, 5.41.
It will be apparent from the foregoing examples that a new series of compounds has been prepared which are particularly useful as intermediates in the preparation of certain pharmaceuticals related to barbituric acid and itsanalogues. Broadly speaking, th invention contemplates compounds and processes wherein the barbituric acid type ring nucleus is substituted in the 5 position by a B-nitroalkyl group. In its I broadest aspects the invention contemplates not only the derivatives of barbituric acid, but also .the derivatives of 2-thiobarbituric acid, malonyl- N-alkyl derivative salts in the manner indicated in the foregoing.
While several particular embodiments of this invention are shown above, it will be understood, of course, that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated, therefore, by the ap pended claims, to cover any such modifications 'as fall within the true spirit and scope of this invention.
What is claimed is:
1. A compound selected from the class consisting of acids having the formula:
wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected from the group consisting of hydrogen, alkyl and aryl, wherein R3 is selected from the group consisting of hydrogen, alkyl and aralkyl; and wherein X is selected from the group consisting of oxygen and sulfur; and the salts of said acids.
2. A barbituric acid derivative selected from the class consisting of compounds having the formula:
wherein R1 is selected from the group consisting of hydrogen and alkyl, wherein R2 is selected from the group consisting of hydrogen, alkyl and V aryl and wherein R3 is selected from the group consisting of hydrogen, alkyl, and aralkyl; and
the salts of said compounds.
4. A compound selected from the group consisting of the 5-(2-nitroalkyl) barbituric acids and their salts.
5. A compound selected from the group consisting of the 5-(2-nitroalkyl) Z-thiobarbituric acids and their salts.
6. 5-Benzyl 5 (2-nitro-n-butyl) -barbituric acid.
7. 5-Methyl 5 (2'-nitro-n-butyl) -2thiobarbituric acid.
8. 5-Ethyl-5-(2'-nitro n butyl) barbituric acid.
9. A process of preparing a compound having a barbituric acid type ring nucleus substituted in the 5 position with afi-nitroalkyl group which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of a compound it) selected from the group consisting of barbituric acid and Z-thiobarbituric acid to produce the said compound having a barbituric acid ring type nucleus substituted in the five-position with a B-nitro alkyl group.
10. A process of preparing a 5-(2-nitroalkyl) barbituri-c acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a salt of barbituric acid to produce a 5-(2' nitroalkyl) barbituric acid derivative.
11. The process recited in claim 10 wherein said salt is a quaternary ammonium salt of barbituric acid.
12. The process recited in claim 10 wherein said salt is a benzyltrimethylammonium salt of barbituric acid.
13. The process recited in claim 10 wherein said salt is an alkali metal salt.
1 1. The process recited in claim 10 wherein said salt is a potassium salt. 7
15. Aprocess of preparing a 5-(2'-nitroalkyl) Z-thiobarbituric acid derivative which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubl bound carbon atoms with a salt of Z-thiobarbituric acid to produce a 5- (2-nitroalkyl) -2-thiobarbituric acid derivative.
16. The process recited in claim 15 wherein said salt is a quaternary ammonium salt of barbituric acid.
17. The process recited in claim 15 wherein said salt is a benzyltrimethylammoniumsalt of barbituric acid.
18. The process recited in claim 15 wherein said salt is an alkali metal salt.
19. The process recited in claim 15 wherein said salt is a potassium salt.
20. A process for the preparation of a 5-(2'- nitroalkyl)-5-alkyl derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid which comprises reacting a nitroolefin in which the nitro group is attached to one of the doubly bound carbon atoms with a quaternary ammonium salt of a 5-alkyl derivative of said compound to produce a 5-(2'- nitroalkyl) -5-alkyl'derivative of a compound selected from the group consisting of barbituric acid and Z-thiobarbituric acid.
21. The process recited in claim 20 wherein said salt is a benzyltrimethylammonium salt of said derivative.
22. A process of alkylating in the 5 position a compound selected from the group consisting of the salts of 5-(2-nitroalkyl) -barbituric acid and of 5-(2'-nitroalky1) -2-thiobarbituric acid which 1 comprises reacting said compound with an alkyl No references cited.
Certificate of Correction Patent No. 2,527,293 October 24, 1950 CARL T. BAHNER It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:
Column 1, line 9, for soporifices read sopom'fics; column 5, line 30, for fitering read filtering; column 6, line 60, for nitrol read m'tro;
and that the said Letters Patent. should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice. Signed and sealed this 2nd day of January, A. D. 1951.
THOMAS F. MURPHY,
Assistant Commissioner of Patents.
Claims (1)
1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF ACIDS HAVING THE FORMULA:
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3271402A (en) * | 1966-09-06 | Carbon-z-thiobarbituric acids | ||
US3511838A (en) * | 1965-09-07 | 1970-05-12 | Chevron Res | 1,5-di-(1-halo-1-nitroalkylthio)-2,6-dioxy pyrimidines |
-
0
- US US2527293D patent/US2527293A/en not_active Expired - Lifetime
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Cited By (2)
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US3271402A (en) * | 1966-09-06 | Carbon-z-thiobarbituric acids | ||
US3511838A (en) * | 1965-09-07 | 1970-05-12 | Chevron Res | 1,5-di-(1-halo-1-nitroalkylthio)-2,6-dioxy pyrimidines |
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