US3478049A - Nitrofuryl substituted oxadiazoles - Google Patents
Nitrofuryl substituted oxadiazoles Download PDFInfo
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- US3478049A US3478049A US537707A US3478049DA US3478049A US 3478049 A US3478049 A US 3478049A US 537707 A US537707 A US 537707A US 3478049D A US3478049D A US 3478049DA US 3478049 A US3478049 A US 3478049A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
- C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
- C07D307/73—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by amino or imino, or substituted amino or imino radicals
Definitions
- R represents hydrogen, alkyl, haloalkyl, halophenyl, loweralkylphenyl, haloloweralkylphenyl, aryloxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acetylthiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, aralkyl, haloaralkyl, alkoxyaralkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carboalkoxy, carboalkoxyloweralkyl, carboalkoxyvinyl, loweralkenyl, furyl, furylalkenyl, thienyl,
- R when R is nitro-Z-furyl, R may be any of the enumerated radicals except S-nitro-Z-furyl.
- the terms loweralkyl and alkoxy include the straight and branched alkyl and alkoxy radicals containing from one to five carbon atoms, inclusive, while alkyl includes radicals containing up to 17 carbon atoms.
- the compounds of the present invention have the formulae 0 WW l b OaN-C CCN wherein R in these and succeeding formulae may be any of the previously enumerated radicals except 5-nitro-2- furyl.
- These compounds are useful as antibacterial and antifungal agents and can be employed as active, toxic constituents of disinfectant compositions for the control of a vast array of microorganisms such as Salmonella typlzimurium, Escherichia coli, Chaetomium globosum, Fusarium oxysporum, Proteus mirabilz's, Proteus vulgaris, and Alternario species.
- the compounds are dispersed on an inert solid or in a liquid such as water and applied as a dust or spray.
- the compound wherein R of Formula B was bromomethyl completely inhibited the growth of the above-named organisms when employed as an aqueous composition in a concentration of 25 parts per million.
- novel compounds are useful as anthelmintic agents when administered orally to animals at a dosage of 250 mg. daily.
- the new compounds are effective against Trichomonas vaginalz's in concentrations of parts per million or less when applied topically.
- the compound wherein R of formula C was chloromethyl completely inhibited the growth of the above-named organisms when employed as an aqueous composition in a concentration of 25 parts per million.
- the new compounds of Formula B can be readily prepared by heating at or above the melting point a compound of the formula in the absence or presence of a solvent to liberate water and effect ring closure.
- the preparation of compounds of Formula D will hereinafter be described in detail and is fully described in co-pending application Ser. No. 314,875, filed October 9, 1963, now U.S. Patent 3,272,833.
- the compound thus formed is then crystallized from a suitable solvent such as ethanol, nitromethane or acetonitrile.
- equimolar amounts of 5-nitro-2-furylamidoxime and a compound of the Formula RCOX wherein X is a halogen, preferably chlorine or bromine may be refluxed in an inert solvent such as toluene, Xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula D above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring.
- the reaction mixture is then concentrated and the residue recrystallized to obtain the desired oxadiazole as a crystalline solid.
- an excess of the compound RCOX can be employed as the solvent.
- the new compounds of Formula C can likewise be readily prepared by heating at or above the melting point a compound of the formula I ll N112 o 0 E in the absence or presence of a solvent to liberate Water and effect ring closure.
- the preparation of compounds of Formula B will hereinafter be described in detail and is fully described in co-pending application Serial No. 314,849, now US. Patent 3,272,828, filed October 9, 1963.
- the compound thus formed if a solid, is then crystallized from a suitable solvent such as ethanol nitromethane, or acetonitrile. If the compound is a liquid, it is isolated by distillation under reduced pressure.
- an R-substituted amidoxime and -nitro-2-furoyl chloride or bromide can be refluxed in an inert solvent such as acetone, toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula E above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring.
- the reaction mixture is then concentrated and the residue recrystallized or distilled to obtain the desired oxadiazole.
- R 4-chlorophenyl; M.P.:194 C.
- R:2,5-dichlorophenyl; M.P. 152 C.
- O-(halobenzoyl)-5-nitro-2-furylamidoximes such as O-(2-fluorobenzoyl)-5-nitro-2-furylamidoxime, O (2,4-dibromobenzoyl)-5-nitro-2-furylamidomine, O (3,5 difluorobenzoyl) 5 nitro-2-furylamidoxime, or O-(2-chloro-4bromobenzoyl)-5-nitro-2-furyl amidoxime can be heated at or above their melting points to produce the corresponding 3-,5-nitro-2-furyl)-5-halophenyl-1,2,4-oxadiazoles.
- Formula A is trifluoromethyl; a,u;y-trichloropropyl; u,0c-
- O-nicotinoyl-5-nitro-2-furylamidoxime (8 grams) was heated at its melting point of 210 C. for 30 minutes.
- EXAMPLE 51 By heating O-(S-nitro 2 furoyl) picolinicamidoxime above its melting point of 217 C. for 5 minutes, water 45 was liberated and the desired 5-(5-nitro-2-furyl)-3-(2- Analyses Calculated Found 5 5 -nitro-2-fury1) -3 O-(S-nitro-Z-furoyl) 2 ly above their melting points for about 5 minutes there is obtained the following oxadiazoles, respectively, wherein R in Formula C is 3-chlorophenyl, 4-chlorophenyl, or
- EXAMPLE 46 5 5 -nitro-2-furyl -3 -(4-sulfonamidophenyl) -1,2,4- oxadiazole he desired oxadiazole
- EXAMPLE 47 5 (5 -nitro -2-furyl) -3-methyl-l ,2,4-oxadiazole 5 -nitro-2-furoyl) butyramidoxime, or O-(5-nitro-2-furoyl)-valeramidoxime compounds as O (5 nitro 2 furoyl) nitro-2-furoy1)-dichloroacetamidoxime, or O tained the following oxadiazoles, respectively, wherein R in Formula C is bromomethyl, iodomethyl methyl, or -chloropropyl.
- R of Formula C O-(5-nitro-2-furoyl) in R of Formula C is trifiuorornethyl, propyl, a,a-dibromobutyl,
- R sulfonamidophenyl in Formula C
- p-sulfonamidobenzarnidoxime To 11 grams (0.05 mole) of p-sulfonamidobenzarnidoxime and 3.53 grams (0.025 mole) of potassium carbonate in 150 ml. of acetone was added with stirring 8.96 grams (0.05 mole) of 5-nitro-2-furoyl chloride in 25 25 ml. of acetone. The mixture was refluxed for 4 hours, and the solid which formed upon cooling was separated by filtration and recrystallized from a dimethylformamide-Water mixture to obtain t which melted at 247 C.
- R methyl in Formula C O-(S nitro 2-furoyl)-acetamidoxime is heated above its melting point for 15 minutes. The reaction mixture is then crystallized from ethanol to obtain the desired oxadiazole having a molecular weight of 195.
- R-substituted amidoximes employed as one of the starting materials are known compounds or can be pre pared by refluxing equimolar amounts of an alkali metal 73 2-quinoly1 above their melting points, there is obtained the corre sponding oxadiazoles wherein R of Formula C is hy- 75 drogen, ethyl, propyl, or butyl, respectively.
- R of the Formula C is aryloxyloweralkyl, aminophenyl, mercaptophenyl, loweralkylthiophenyl, halosulfonamidophenyl, halopyridyl, carboxamido, carboalkoxy, carboalkoxyloweralkyl, carboalkoxyvinyl, loweralkenyl, furylalkenyl, thienylalkenyl, pyridylalkenyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, thienylloweralkyl, oxazyl, imidazyl, or pyr
- the compound wherein R is acetylthiomethyl was made by methods herein disclosed and found to have a melting point of 112-114 C. Upon analysis, the compound was found to contain 40.17% carbon, 2.72% hydrogen, 15.69% nitrogen, and 11.76% sulfur compared to the calculated values of 40.14% carbon, 2.62% hydrogen, 15.61% nitrogen, and 11.91% sulfur.
- R is 5-nitro-2-furyl and R is a member of the group consisting of hydrogen, alkyl, mono or di haloalkyl, mono or dihalophenyl, mono or di methylphenyl, halomethylphenyl, phenoxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acety thiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, phenylalkyl, halophenylalkyl, alkoxyphenylalkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carbomethoxy, carbomethoxyloweralkyl, propenyl, furyl, thienyl, pyrimidyl,
- R is a member of the group consisting of mono and di halophenyl.
- R is a member of the group consisting of mono and di loweralkoxyphenyl.
- R is 5-nitro-2-furyl and R is a member of the group consisting of hydrogen, alkyl, mono or di haloalkyl, mono or dihalophenyl, mono or di methylplhenyl, halomethylphenyl, phenoxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acetylthiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, phenylalkyl, halophenylalkyl, alkoxyphenylalkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carbomethoxy, carbomethoxyloweralkyl, propenyl, furyl, thienyl, pyrimidyl
- R is a member of the group consisting of mono or di haloloweralkyl.
- R is a member of the group consisting of mono or di halophenyl.
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Description
United States Patent 3,478,049 NITROFURYL SUBSTITUTED OXADIAZOLES Anne Mary Von Esch, North Chicago, and Aldo J. Crovetti, Lake Forest, IlL, assignors to Abbott Laboratories, North Chicago, III., a corporation of Illinois No Drawing. Continuation-impart of applications Ser. N 0.
314,863 and Ser. No. 314,891, Oct. 9, 1963. This application Mar. 28, 1966, Ser. No. 537,707
Int. Cl. C07d 85/06; A01n 9/22 US. Cl. 260-307 10 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:
The present application is a continuation-in-part of copending applications Ser. Nos. 314,863 and 314,891, both filed October 9, 1963 and now abandoned.
This invention relates to compounds of the formula In this formula, when R is S-nitro-Z-furyl, R represents hydrogen, alkyl, haloalkyl, halophenyl, loweralkylphenyl, haloloweralkylphenyl, aryloxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acetylthiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, aralkyl, haloaralkyl, alkoxyaralkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carboalkoxy, carboalkoxyloweralkyl, carboalkoxyvinyl, loweralkenyl, furyl, furylalkenyl, thienyl, thienylalkenyl, pyridylalkenyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, thienylloweralkyl, oxazyl, isoxazyl, quinolyl, isoquinolyl, pyrazyl, imidazyl, pyrazinyl, or thiazyl. Likewise, when R is nitro-Z-furyl, R may be any of the enumerated radicals except S-nitro-Z-furyl. The terms loweralkyl and alkoxy include the straight and branched alkyl and alkoxy radicals containing from one to five carbon atoms, inclusive, while alkyl includes radicals containing up to 17 carbon atoms.
More particularly, the compounds of the present invention have the formulae 0 WW l b OaN-C CCN wherein R in these and succeeding formulae may be any of the previously enumerated radicals except 5-nitro-2- furyl.
These compounds are useful as antibacterial and antifungal agents and can be employed as active, toxic constituents of disinfectant compositions for the control of a vast array of microorganisms such as Salmonella typlzimurium, Escherichia coli, Chaetomium globosum, Fusarium oxysporum, Proteus mirabilz's, Proteus vulgaris, and Alternario species. In such use, the compounds are dispersed on an inert solid or in a liquid such as water and applied as a dust or spray. In a typical. application, the compound wherein R of Formula B was bromomethyl completely inhibited the growth of the above-named organisms when employed as an aqueous composition in a concentration of 25 parts per million. Additionally, these novel compounds are useful as anthelmintic agents when administered orally to animals at a dosage of 250 mg. daily. Likewise, the new compounds are effective against Trichomonas vaginalz's in concentrations of parts per million or less when applied topically. In another typical application, the compound wherein R of formula C was chloromethyl completely inhibited the growth of the above-named organisms when employed as an aqueous composition in a concentration of 25 parts per million.
The new compounds of Formula B can be readily prepared by heating at or above the melting point a compound of the formula in the absence or presence of a solvent to liberate water and effect ring closure. The preparation of compounds of Formula D will hereinafter be described in detail and is fully described in co-pending application Ser. No. 314,875, filed October 9, 1963, now U.S. Patent 3,272,833. The compound thus formed is then crystallized from a suitable solvent such as ethanol, nitromethane or acetonitrile. If desired, equimolar amounts of 5-nitro-2-furylamidoxime and a compound of the Formula RCOX wherein X is a halogen, preferably chlorine or bromine, may be refluxed in an inert solvent such as toluene, Xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula D above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring. The reaction mixture is then concentrated and the residue recrystallized to obtain the desired oxadiazole as a crystalline solid. Alternatively, an excess of the compound RCOX can be employed as the solvent.
The new compounds of Formula C can likewise be readily prepared by heating at or above the melting point a compound of the formula I ll N112 o 0 E in the absence or presence of a solvent to liberate Water and effect ring closure. The preparation of compounds of Formula B will hereinafter be described in detail and is fully described in co-pending application Serial No. 314,849, now US. Patent 3,272,828, filed October 9, 1963. The compound thus formed, if a solid, is then crystallized from a suitable solvent such as ethanol nitromethane, or acetonitrile. If the compound is a liquid, it is isolated by distillation under reduced pressure. If desired, equimolar amounts of an R-substituted amidoxime and -nitro-2-furoyl chloride or bromide can be refluxed in an inert solvent such as acetone, toluene, xylene, dimethylformamide, or benzene in the presence of a hydrohalide acceptor such as pyridine, potassium carbonate, or triethylamine or in acetic acid without acid acceptor to form the intermediate compound designated in Formula E above in situ and without actually isolating said intermediate continuing the reaction at reflux temperature to close the ring. The reaction mixture is then concentrated and the residue recrystallized or distilled to obtain the desired oxadiazole.
The examples which follow are presented as illustrations rather than limitations of the invention.
EXAMPLE 1 O-nicotinoyl-S-nitro-2-furylamidoxime To grams (0.08 mole) of 5-nitro-2-furylamidoxime, 6.05 grams (0.04 mole) of potassium carbonate in 175 ml. of acetone was added slowly with stirring and cooling a solution of 12.4 grams (0.08 mole) of nicotinoyl chloride (B.P.= C. at 15 mm. pressure) in 50 ml. of acetone. The mixture was then stirred at room temperature for 5 hours. The solid which formed was filtered off and crystallized from a dimethylformamide-water mixture to obtain the desired product which melted at 211 C.
Analysis.-Calculated: C=47.83%; H=2.92%; N: 20.32%. Found: C=48.09%; H=2.90%; N=20.75%.
A 2.5 gram portion of the above product was heated with 1.3 grams of methyl iodide in nitromethane on a steam bath for 2.5 hours. The methiodide salt which formed was separated by filtration and after crystallization from a dimethylformamide-alcohol mixture was found to melt at 200 C.
EXAMPLE 2 O-(5-nitro-2-furoyl)-p-sulfonamidobenzamidoxime HCCH NH: O 0
To 4 grams (0.02 mole) of p-sulfonamidobenzamidoxime melting at 210 C. was added 1.28 grams (0.01 mole) of anhydrou potassium carbonate and ml. of anhydrous acetone. The mixture was cooled to 0 C. and 3.26 grams (0.02 mole) of 5-nitro-2-furoyl chloride melting at 40 C. dissolved in 25 ml. of anhydrous acetone was added with stirring over a period of 15 minutes. The mixture was then stirred at room temperature for an additional 7 hours. The solid which formed was removed by filtration, washed successively with water and ethanol, and recrystallized from a dimethylformamide-water mixture at 100 C. to obtain the desired product as a crystalline yellow solid melting at 230 C. (sealed capillary) with decomposition.
Analysis.-Calculated: C=40.68%; H=2.84%; N= 15.82%. Found: C:40.84%; H=2.86%; N=15.99%.
EXAMPLE 3 3-(5-nitro-2-furyl)-5-methyl-1,2,4-oxadiazole R=methyl in Formula B O-acetyl-S-nitro-2-furylamidoxime (5.3 grams, 0.025 mole) melting at C. was heated at C. for 15 minutes. Upon cooling, a brown oil formed which was crystallized from ethanol to obtain the desired oxadiazole. M.P.=105 C.
Analysis.Calculated: C=43.08%; H:2.58%; N: 21.54%. Found C=43.30%; H=2.67; N=2l.66%.
By heating O-formyl-5-nitro-2-furylamidoxime, O-propionyl 5 nitro-2-furylamidoxime, O-butyryl-S-nitro-Z- furylamidoxime or O-valeryl-5-nitro-2-furylamidoxime above their melting point, there is obtained the corresponding oxadiazoles wherein R of Formula B is hydrogen, ethyl, propyl, or butyl, respectively. The compound wherein R is ethyl melted at 98 C. and contained 20.28% nitrogen compared to the calculated value of 20.09% nitrogen.
EXAMPLE 4 3-(5-nitro-2-furyl)-5-phenyl-1,2,4-oxadiazo1e R=phenyl in Formula B O-benzoyl-5-nitro-2-furylamidoxime (8 grams, 0.029 mole) melting at 210 C. was heated at 215 C. on an oil bath for about 30 minutes. The residue resulting was crystallized from boiling ethanol to yield the desired oxadiazole as a cream-colored solid melting at 200 C.
Analysis.Calculated: C=56.03%; H=2.74%; N: 16.34%. Found: C:55.93%; H=2.65%; N=16.13%.
By heating 0 (3 chlorobenzoyl)-5-nitro-2-furylamidoxime (M.P.=162 C.), O-(4-chlorobenzoyl)-5-nitro2- furylamidoxime (M.P.:194 C.) or O-(2,5-dichlorobenzoyl) 5 nitro 2 furylamidoxime (M.P.= C.) slightly above their melting point for about 5 minutes, there is obtained the following oxadiazoles respectively wherein R in Formula B is as shown below:
R=3-chlorophenyl; M.P.=150 C. R=4-chlorophenyl; M.P.:194 C. R:2,5-dichlorophenyl; M.P.=152 C.
In like manner, other O-(halobenzoyl)-5-nitro-2-furylamidoximes such as O-(2-fluorobenzoyl)-5-nitro-2-furylamidoxime, O (2,4-dibromobenzoyl)-5-nitro-2-furylamidomine, O (3,5 difluorobenzoyl) 5 nitro-2-furylamidoxime, or O-(2-chloro-4bromobenzoyl)-5-nitro-2-furyl amidoxime can be heated at or above their melting points to produce the corresponding 3-,5-nitro-2-furyl)-5-halophenyl-1,2,4-oxadiazoles.
EXAMPLE 5 3- (5-nitro-2-furyl) -5-chloromethyl-1,2,4-oxadiazole R chloromethyl in Formula B O-chloroacetyl-5-nitro-2-furylamidoxime (1.10 grams, 0.004 mole) was heated at 185 C. for 5 minutes. Water was liberated and the resulting brown oil was cooled to 120 C. at which temperature a solid formed. Upon crystallization from ethanol, the desired oxadiazole was obtained as a cream-colored, crystalline solid which melted at 110 C. and contained 18.25% nitrogen compared to the calculated value of 18.31% nitrogen.
Similarly, by heating at or slightly above their melting points such compounds as O-bromoacetlyl-S-nitro-Z- furylamidoxime, O iodoacetyl-5-nitro-2-furylamidoxime, O-dichloroacetyl-5-nitro-2-furylamidoxime, O a bromopropionyl-5-nitro-2-furylamidoximc or O-y-chlorobutyryl- 5-nitro-2-furylamidoxime, there is readily obtained the following oxadiazoles respectively wherein R in formula B is as indicated:
R=bromomethy1; M.P.=131 C. R=idomethyl; M.P.=129 C. R=dichloromethyl; M.P.==40 C. R=a-bromoethyl; M.P.=79 C. R='y-chloropropyl; M.P.=68 C.
\ Formula A is trifluoromethyl; a,u;y-trichloropropyl; u,0c-
dibromobutyl; oc'y-dii0dObl1tyl; a-chloro-fl-bromovaleryl trichloromethyl, or a-bromovaleryl and similar haloloweralkyl radicals.
EXAMPLE 6 3-(5-nitro-2-furyl)-5-(3-pyridyl)-1,2,4-oxadiazole obtained which melted at 107 C. Upon analysis, the prodnot was found to contain 15.69% nitrogen compared to R=3 pyridyl in Formula B the calculated value of 15.73% nitrogen.
O-nicotinoyl-5-nitro-2-furylamidoxime (8 grams) was heated at its melting point of 210 C. for 30 minutes.
Using methods exemplified in the foregoing examples, the following compounds, wherein R refers to substitutions in Formula B, were made.
Analyses Found Calculated Melting Point Example C QQQQQQO QQQQQQQQQQQQQQQQQQQQQQQQQQO .131... .1 1 1 r y 1 "m2K356171QL1221202211221210013 34 44 1 y 1 1 1 r y v 1 1 1 I 1 1 y 1 7 1 1 1 1 v 1 y 1 1 v HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHI p nitrophenyl,
chlorothienyl, oxazyl, isoxazyl, quinolyl, isopyrazyl, carboethoxy, carbomethoxyvinyl, furyl- 9 l y .w n 1 U V S y X m O bk 3 m w. w 8 hon w mh a a n r m wm y P n 2 M e a A h d wamm X n mi E mm] a 01W. h 0 m m kL YO nh 6 m 1 ew 1 flmmm m m o .I 8.3 0 G e 1 0 Z a i d m m B m m 00 1 V. 0 E m P u m M m m m e P v .w r u D. JR 0 r .n m 5 3 This compound was prepared by heating O-crotonyl- S-nitrofurylamidoxime melting at 184 C. to a tempera- 5 (5 mtro'z'furyl)'3'ch1oromethyll24oxadlzolfi Rzchloromethyl in Formula C A solution of 10.26 grams of O- chloroacetamidoxime in 175 ml. of n-butanol was heated ture of 190 C. for minutes. After recrystallization C. Identity was 5-nitro-2-furoyl) from ethanol, the product melted at 145 confirmed by elemental analysis.
EXAMPLE 9 under reflux for 2 hours. The reaction mixture was then 3-(5-nitro-2-furyl)-5-carbomethoxyethy1-1,2,4-oxadiazo1e V concentrated and distilled under reduced pressure to obtain the desired oxadiazole which boiled at 149 C. at
0.25 mm. pressure and had a refractive index n 1.6038. Upon analysis R=carbomethoxyethyl in Formula B Three grams of O-carbomethoxypropionyl-S-nitrofurylamidoxime melting at C. was heated at C. to
25 f the product was found to contain 18.35% nitrogen compared to the calculated value of liberate water and close the ring. The brown liquid formed 18.30% nitrogen. solidified upon the addition of ethanol and after recrystal- Similarly, by heating at or slightly above their meltlization from boiling ethanol the desired oxadiazole was 75 ing points in the presence or absence of a solvent such L2 Zom 22222422om322232 EXAMPLE 48 -halophenyl-1,2,4-oxadiazoles R=halophenyl in Formula C By heating nitro 2 furoyl)-3-chlorobenzamidoxime, O-(5-nitro-2-furoyl)-4-chlorobenzamidoxime, or ,S-dichlorobenzamidoxime slight- -(5-nitro-2-furoyl)-halo benz- 5 -nitro-2-furoyl) -fluoro benzami- EXAMPLE 49 5-(5-nitro-2-furyl)-3-benzyl-1,2,4-oxadiazole R benzyl in Formula C A quantity of O-(5-nitro-2-furoyl)-benzacetamid0xime is heated at its melting point for 15 minutes to liberate EXAMPLE 50 5- S-nitro-Z-furyl -3 -(p-nitrophenyl) -1,2,4-oxadiaz0le R=nitrophenyl in Formula C O-(S-nitro 2-furoyl)-p-nitrobenzamidoxime (5.56 g., 0.017 mole) was heated at 230 C. under reduced pressure for 5 minutes. The resulting product was crystallized from nitromethane and melted at 212 C.
EXAMPLE 51 By heating O-(S-nitro 2 furoyl) picolinicamidoxime above its melting point of 217 C. for 5 minutes, water 45 was liberated and the desired 5-(5-nitro-2-furyl)-3-(2- Analyses Calculated Found 5 5 -nitro-2-fury1) -3 O-(S-nitro-Z-furoyl) 2 ly above their melting points for about 5 minutes there is obtained the following oxadiazoles, respectively, wherein R in Formula C is 3-chlorophenyl, 4-chlorophenyl, or
2,5-dichlorophenyl.
In like manner, other 0 amidoximes such as O doxime, O- (S-nitro-Z-furoyl) -2,4-dibromobenzamidoxime, O (5 nitro-Z-furoyl)-3,S-difluorobenzamidoxime, O-(5'- nitro 2 furoyl)-2-iodobenzamidoxime, or O-(5-nitro-2- furoyl)-2-chloro-4-bromobenzamidoxime can be heated at or above their melting points to produce the corresponding 5 (5 -nitro-2-furyl)-3-halophenyl-1,2,4-oxadiazoles.
water and obtain the above-named oxadiazole having a molecular weight of 273.
Analysis.Calculated: C, 47.69%; H, 2.00%; N, 40 18.54%. Found: C, 47.65%; H, 2.26%; N, 18.72%.
pyridyl)-1,2,4-oxadiazole which formed was crystallized from nitromethane. M.P.=l99 C.
Analysis.Calculated: C, 51.17%; H, 2.34%; N, 21.70%. Found: C, 51.19%; H, 2.50%; N, 21.87%.
Using methods exemplified in the foregoing examples, the following compounds, wherein R refers to substitutions in Formula C, were made.
-(5-nitro-2- furoyl)-- -chlorobutyramidoxime, there is readily ob- 5 d1chl0r0- oc-ChlOIO-fi- Melting Point CHzQl (chloromethyl) 5658 bromo-acetamidoxime, O-(5-nitro-2-furoyl)-iodoacetamidoxime, O-(S- -haloloweralkylamidoximes can be heated at or above their melting points to liberate water and produce the corresponding 5-(5- nitro 2-furyl)-3-haloloweralkyl-1,2,4-oxadiazoles whereot,oc,'y-[IiChlOrO- a,' -diiodobutyl, bromovaleryl, trichloromethyl, or a-bromovaleryl and similar haloloweralkyl radicals.
EXAMPLE 46 5 5 -nitro-2-furyl -3 -(4-sulfonamidophenyl) -1,2,4- oxadiazole he desired oxadiazole EXAMPLE 47 5 (5 -nitro -2-furyl) -3-methyl-l ,2,4-oxadiazole 5 -nitro-2-furoyl) butyramidoxime, or O-(5-nitro-2-furoyl)-valeramidoxime compounds as O (5 nitro 2 furoyl) nitro-2-furoy1)-dichloroacetamidoxime, or O tained the following oxadiazoles, respectively, wherein R in Formula C is bromomethyl, iodomethyl methyl, or -chloropropyl.
If desired, other O-(5-nitro-2-furoyl) in R of Formula C is trifiuorornethyl, propyl, a,a-dibromobutyl,
R=sulfonamidophenyl in Formula C To 11 grams (0.05 mole) of p-sulfonamidobenzarnidoxime and 3.53 grams (0.025 mole) of potassium carbonate in 150 ml. of acetone was added with stirring 8.96 grams (0.05 mole) of 5-nitro-2-furoyl chloride in 25 25 ml. of acetone. The mixture was refluxed for 4 hours, and the solid which formed upon cooling was separated by filtration and recrystallized from a dimethylformamide-Water mixture to obtain t which melted at 247 C.
Analysis.Calculated: C, 42.84%; H, 2.40%; N, 16.66%. Found: C, 42.93%; H, 2.44%; N, 16.61%.
In like manner, the reaction of 5-nitro-2-furoyl chloride with an R-substituted amidoxime wherein R is phenoxymethyl, hydroxyphenyl, methoxyphenyl, acylaminophenyl, methylthiophenyl, furyl, thienyl, pyrimidyl, oxazyl, bromofuryl, chlorothienyl, isoxazyl, quinolyl, isoquinolyl, pyrazyl, carbethoxy, pyrazinyl, thiazyl, carbomethoxyethyl, or earboxamidomethyl, the corresponding R-substituted oxadiazoles of Formula C are obtained.
R=methyl in Formula C O-(S nitro 2-furoyl)-acetamidoxime is heated above its melting point for 15 minutes. The reaction mixture is then crystallized from ethanol to obtain the desired oxadiazole having a molecular weight of 195.
By heating O-(5-nitro-2-furoyl)-formamidoxime, O-(5- 5O nitro-2-furoyl)-propionamidoxime, 0
Example QQQQQQQQQQQQQQQQQQQQO p-Sulfonamidophenyl p-Nitrobonzyl.
2-furyl B-picoly 71 72.. l-isoquinoly The R-substituted amidoximes employed as one of the starting materials are known compounds or can be pre pared by refluxing equimolar amounts of an alkali metal 73 2-quinoly1 above their melting points, there is obtained the corre sponding oxadiazoles wherein R of Formula C is hy- 75 drogen, ethyl, propyl, or butyl, respectively.
hydroxide, hydroxylamine hydrochloride, and a nitrile of the formula R-CEN in ethanol. The solution is filtered and the filtrate concentrated to recover the desired amidoxime as a residue which can be purified by recrystallization from a suitable solvent.
In like manner, other O-(S-nitro-Z-furoyl) amidoximes can be heated at or above their melting points, in the absence or presence of a suitable solvent, to liberate Water and effect ring closure to obtain the corresponding oxadiazoles wherein R of the Formula C is aryloxyloweralkyl, aminophenyl, mercaptophenyl, loweralkylthiophenyl, halosulfonamidophenyl, halopyridyl, carboxamido, carboalkoxy, carboalkoxyloweralkyl, carboalkoxyvinyl, loweralkenyl, furylalkenyl, thienylalkenyl, pyridylalkenyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, thienylloweralkyl, oxazyl, imidazyl, or pyrazinyl.
Referring to Formula B, the compound wherein R is acetylthiomethyl Was made by methods herein disclosed and found to have a melting point of 112-114 C. Upon analysis, the compound was found to contain 40.17% carbon, 2.72% hydrogen, 15.69% nitrogen, and 11.76% sulfur compared to the calculated values of 40.14% carbon, 2.62% hydrogen, 15.61% nitrogen, and 11.91% sulfur.
While the invention has been illustrated by the foregoing examples, it will be apparent that various equivalent changes and modifications may be resorted to without departing from the spirit thereof.
What is claimed is:
1. A compound of the formula wherein when one of R and R is 5-nitr0-2-furyl, the other is a member of the group consisting of hydrogen, alkyl, mono or di haloalkyl, mono or di halophenyl, mono or di methylphenyl, halomethylphenyl, phenoxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acetylthiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, phenylalkyl, halophenylalkyl, alkoxyphenylalkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carbomethoxy, carbomethoxyloweralkyl, propenyl, furyl, thienyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, quinolyl, isoquinolyl, and pyrazinyl; the terms loweralkyl and alkoxy including the straight and branched alkyl and alkoxy radicals containing from one to five carbon atoms, inclusive, while alkyl includes radicals containing up to 17 carbon atoms.
2. A compound as claimed in claim 1 wherein R is 5-nitro-2-furyl and R is a member of the group consisting of hydrogen, alkyl, mono or di haloalkyl, mono or dihalophenyl, mono or di methylphenyl, halomethylphenyl, phenoxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acety thiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, phenylalkyl, halophenylalkyl, alkoxyphenylalkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carbomethoxy, carbomethoxyloweralkyl, propenyl, furyl, thienyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, quinolyl, isoquinolyl, and pyrazinyl; the terms loweralkyl and alkoxy including the straight and branched alkyl and alkoxy radi- :als containing from one to five carbon atoms, inclusive, while alkyl includes radicals containing up to 17 carbon atoms.
3. A compound as claimed in claim 2 wherein R is mono or di haloalkyl.
4. A compound as claimed in claim 2 wherein R is loweralkyl.
5. A compound as claimed in claim 2 wherein R is a member of the group consisting of mono and di halophenyl.
6. A compound as claimed in claim 2 wherein R is a member of the group consisting of mono and di loweralkoxyphenyl.
7. A compound as claimed in claim 1 wherein R is 5-nitro-2-furyl and R is a member of the group consisting of hydrogen, alkyl, mono or di haloalkyl, mono or dihalophenyl, mono or di methylplhenyl, halomethylphenyl, phenoxyloweralkyl, hydroxyphenyl, aminophenyl, nitrophenyl, loweralkoxyphenyl, mercaptophenyl, acetylthiomethyl, loweralkylthiophenyl, halosulfonamidophenyl, sulfonamidophenyl, phenylalkyl, halophenylalkyl, alkoxyphenylalkyl, pyridyl, pyridylloweralkyl, halopyridyl, carboxamido, carbomethoxy, carbomethoxyloweralkyl, propenyl, furyl, thienyl, pyrimidyl, halopyrimidyl, halofuryl, halothienyl, furylloweralkyl, quinolyl, isoquinolyl, and pyrazinyl; the terms loweralkyl and alkoxy including the straight and branched alkyl and alkoxy radicals containing from one to five carbon atoms, inclusive, while alkyl includes radicals containing up to 17 carbon atoms.
8. A compound as claimed in claim 7 wherein R is a member of the group consisting of mono or di haloloweralkyl.
9. A compound as claimed in claim 7 wherein R is loweralkyl.
10. A compound as claimed in claim 7 wherein R is a member of the group consisting of mono or di halophenyl.
References Cited UNITED STATES PATENTS 3,337,541 8/1967 Haraoka et al. 26O307 ALEX MAZEL, Primary Examiner R. I. GALLAGHER, Assistant Examiner US. Cl. X.R.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31486363A | 1963-10-09 | 1963-10-09 | |
| US53770766A | 1966-03-28 | 1966-03-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3478049A true US3478049A (en) | 1969-11-11 |
Family
ID=26979599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US537707A Expired - Lifetime US3478049A (en) | 1963-10-09 | 1966-03-28 | Nitrofuryl substituted oxadiazoles |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US3478049A (en) |
| BR (1) | BR6463315D0 (en) |
| FR (1) | FR4273M (en) |
| GB (1) | GB1025439A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3857843A (en) * | 1972-09-11 | 1974-12-31 | American Cyanamid Co | Cyclopropyl 1,2,4-oxadiazolyldiazines |
| US3907809A (en) * | 1967-01-31 | 1975-09-23 | Abbott Lab | 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts |
| US3991067A (en) * | 1971-05-19 | 1976-11-09 | Glaxo Laboratories Limited | Mono- or disubstituted 1,2,4,oxadiazoles which are substituted by at least 1-N-substituted carbamoyl group |
| US4007185A (en) * | 1967-01-31 | 1977-02-08 | Abbott Laboratories | 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3493565A (en) * | 1966-03-14 | 1970-02-03 | Squibb & Sons Inc | 3-amino-5-(nitrofuryl)-1,2,4-oxadiazole derivatives |
| EP1047425A4 (en) * | 1997-12-17 | 2009-04-22 | Merck & Co Inc | Integrin receptor antagonists |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3337541A (en) * | 1964-12-28 | 1967-08-22 | Fujisawa Pharmacentical Co Ltd | 5-[2-(5-nitro-2-furyl) vinyl]-1, 3, 4-oxadiazole derivatives |
-
1964
- 1964-10-07 GB GB40925/64A patent/GB1025439A/en not_active Expired
- 1964-10-09 BR BR163315/64A patent/BR6463315D0/en unknown
-
1965
- 1965-01-05 FR FR808A patent/FR4273M/fr not_active Expired
-
1966
- 1966-03-28 US US537707A patent/US3478049A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3337541A (en) * | 1964-12-28 | 1967-08-22 | Fujisawa Pharmacentical Co Ltd | 5-[2-(5-nitro-2-furyl) vinyl]-1, 3, 4-oxadiazole derivatives |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3907809A (en) * | 1967-01-31 | 1975-09-23 | Abbott Lab | 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts |
| US4007185A (en) * | 1967-01-31 | 1977-02-08 | Abbott Laboratories | 3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts |
| US3991067A (en) * | 1971-05-19 | 1976-11-09 | Glaxo Laboratories Limited | Mono- or disubstituted 1,2,4,oxadiazoles which are substituted by at least 1-N-substituted carbamoyl group |
| US3857843A (en) * | 1972-09-11 | 1974-12-31 | American Cyanamid Co | Cyclopropyl 1,2,4-oxadiazolyldiazines |
Also Published As
| Publication number | Publication date |
|---|---|
| FR4273M (en) | 1966-07-11 |
| GB1025439A (en) | 1966-04-06 |
| BR6463315D0 (en) | 1973-07-17 |
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