Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D315/00—Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups C07D303/00 - C07D313/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/88—Unsaturated compounds containing keto groups containing halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
  • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
  • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

• R is an aryl radical, either unsubstituted or substituted
• R is an aralkyl radical, also either unsubstituted or substituted, particularly in the aryl moiety of the radical.
• Salts, esters, enol-lactones and amides of the above compounds are also contemplated within the scope of this invention as they are considered to be the equivalents of the acids because many of the derivatives exhibit the same therapeutic activity as the corresponding acid. It is hypothesized that the activity exhibited by the derivatives results from their conversion to the corresponding acid upon administration and that the free acid actually produces the therapeutic effect observed.
• ester, enol-lactone and amide derivatives will be described in more detail hereinafter.
• the only limitation to the type of salt is that it be non-toxic. Both Water soluble and Water insoluble salts are useful, depending upon the purpose for which salts of the compounds are to be employed. Insoluble salts are sometimes most useful when it is desired to take advantage of the repository efiects produced by compounds of this type, whereas soluble salts, especially water soluble salts, are usually better suited for use in oral preparations and other dosage forms designed for more rapid absorption into the blood stream.
• all of the compounds of this invention contain an asymmetric carbon atoms, that is, the 4-position carbon atom to which the variable radicals R and R are attached. This is true not only of the hexanoic acids but also of the hexanenitrile intermediates and of each of the derivatives of the hexanoic acids hereinafter described. Because of the presence of this asymmetric carbon atom in the molecule, the racemic modification of the various products are obtained as the end products of the syntheses described.
• the optically active isomers can be separated by well known methods, if desired, and these individual antipodes can be employed to make subsequent derivatives having the same optical configuration if this is desired.
• the compounds of this invention have utility as therapeutic agents, for example, as bactericidal, bacteriostatic, virucidal, and virustatic agents. Some of the novel compounds have shown marked activity as virustatic agents, particularly against organisms causing virus infections in the respiratory tract of man and animals.
• substituents suitable for attachment to the aryl portion of the phenyl and/ or the benzyl radical are halogens, e.g., chlorine, bromine, iodine or fluorine; lower alkyl, e.g., methyl, ethyl, propyl and the like; lower alkoxy, as methoxy, ethoxy, propoxy; nitro; carboxy; hydroxy; and hydroxy-alkyl groups.
• the phenyl and/ or the benzyl radicals can be substituted in the nuclear portion of either or both of them in ortho-, metaor para position, and monoor poly-substitution can be made in either or both of these radicals.
• each of the aryl and aralkyl groups is monoor poly-substituted, or when either is poly-substituted, the substituents need not necessarily be the same. Any combination of substitution is suitable so long as it is chemically possible to introduce the selected radicals into the same nucleus.
• Ortho-substitution particularly solely in the aryl portion of the benzyl radical, generally produces compounds having a high order of virustatic activity and, surprisingly, ortho-halogen substitution substantially increases the virustatic activity of these compounds.
• Especially marked virustatic activity is exhibited by the compound 4-(ortho-chlorobenzyl)-4-phenyl-5-oxohexanoic acid particularly against the PR8 strains of influenza.
• This compound, as well as others embraced by this invention is also efiective against other strains of influenza virus as well as other viruses such as the infectious agent in mumps.
• the compounds generally, and in particular 4-(orthochlorobenzyl)-4-phenyl-5-oxohexanoic acid, are effective upon oral administration. This is a distinct advantage especially in the treatment of virus infections of the upper respiratory tract. Administration is not restricted to the oral route, however, as the compounds can be administered parenterally if this is indicated.
• the compounds of this invention are prepared by alkylation of phenylacetone or a nuclear-1y substituted derivative thereof to introduce the desired benzyl radical. Reaction readily occurs at the carbon atom which carries the phenyl radical. Cyanoethylation of the end product thus obtained produces the corresponding 4-phenyl-4-benzyl-5-oxohexanenitrile which, on hydrolysis, is converted to the desired 4-phenyl-4-benzyl-S-oxohexanoic acid.
• the individual reaction procedures are those conventionally employed to effect the same type of substitution in other compounds.
• the salts are prepared by the action of an alkali metal hydroxide, an alkali'metal carbonate or bicarbonate, an amine or ammonia or the like on the 0x0- hexanoic acid.
• ester derivatives are readily prepared by allowing the selected 4-aryl-41ara1kyl-5-oxohexanoic acid toreact with the appropriate alcohol in the presence of esterificatie 131 catalysts, such as certain mineral acids, e.g., sulfuric acr
• esterificatie 131 catalysts such as certain mineral acids, e.g., sulfuric acr
• the enol-lactone derivatives are prepared advantageously by interaction of the selected hexanoic acid with isopropenyl acetate.
• Basic esters generally are prepared by reacting the enollactone with a (di-substituted-amino)-a1kanol.
• the amides advantageously are prepared by allowing the selected enol-lactone to react with the desired amine preferably with heating under reflux conditions.
• R, R' and R-" respectively is an alkyl radical, advantageously a lower alkyl radical
• X is halogen or a similarly re active radical, e.g., a sulfonate ester radical and the like.
• Substantially all of the compounds illustrated by the structures identified by A to G'above are new compounds.
• a suitable method for preparing it consists in condensing a benzaldehyde having the desired substituent on the phenyl nucleus with nitroethane, then reducing and simultaneou'sly hydrolyz'ing the resulting l-(substituted phenyD-2- nitropropene using iron and aqueous hydrochloric acid.
• Another method which can be employed in preparing the nuclearly substituted phenylacetones consists in heating a phenylacetic acid having the desired substituent' or substituents attached to the phenyl nucleus with sodium: ace tate and acetic anhydride. O ther methodsimay be more suitable depending upon the .substituent or substituents one desires tohave attached to the phenyl nucleus. All
• the novel compounds of this invention are also useful as intermediates in preparing derivatives which have been found to have therapeutic activity.
• Derivatives ofpa'rticular interest in this respect are the heretofore unknown 4 aryl 4 aralkyl-1,3-cyclohexanediones. These compounds are often formed as by-productswhen the 4-ary1- 4-aralkyl-5-oxohexanenitriles are hydrolyzed to the corresponding acid.
• They can also be prepared from an derivatives are contained in the following examples, which are illustrative and in nowise limit the procedures by which they can be prepared to the'particular steps described. ,All physical constants are uncorrected values.
• J ?HQ CH2 COQH+R OH 1.5 mole) and o-chlorobenz yl chloride (282 g., 1.75 mole) were thoroughly mixed and approximately 100' ml. of the H V mixture added to the reaction vessel with vigorous stirring.
• 3CH;OH2COOR The temperature rose to 5560 C.
• Example 2 (0 biomobenzyl) -1-phenyl-2-propanone.--Potassium (3-1.6 g., 0.81 mole) wasadded to sodium-dried tertiary-butyl alcohol (700 ml.) in a twoliter, four-necked, round-bottom flask equipped with a mechanically driven Hirshberg stirrer, dropping funnel, thermometer, and reflux condenser. The potassium was dissolved by warming andviolently agitating the mixture. The mixture was cooled and phenylacetone (108.8 g., 0.81 mole) was added in one portion.
• o-Bromobenzyl bromide (214.5 g., 0.86-mole) was dissolved in dry benzene ml.) and the mixture added dropwise over a period of 40 minutes, while thetemperature was main-+ .tained at 3540 C.
• the reaction mixture was stirred
• the solvent then was removed by distillation at reduced pressure and the residue treated with benzene (200 ml.) and water (200 ml.).
• the two layers were separated, and the aqueous layer was washed with benzene (50 ml.)
• the organic layers were combined and dried over sodium sulfate, and the solvent was removed by distillation. Fractional distillation of the residueat reduced pressure gave 205.3 g.
• Example 4 1-(3,4-dichl0r0benzyl) -1-(4-chl0r0phen yl)-2-propanone.-By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by p-chlorophenylacetone and 3,4-dichlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-( 3,4-dichlorobenzyl) l-(4-chlorophenyl) -2-prop anone.
• Example 5 1-benzyl-1-(3,4-dichl0rophenyl)-2-propanone.--By replacing the phenylacetone and the o-bromobenzyl bromide reactants in Example 2 by 3,4-dichlorophenylacetone and benzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-benzyl-l-(3,4-dichlorophenyl) -2-prop anone.
• Example 7 3,4,5 -trich lorobenzyl -phenyl-2 -pr0- pan0ne.By replacing the o-bromobenzyl bromide reactant employed in Example 2 by 3,4,5-trichlorobenzyl chloride (prepared by chlorination of the corresponding toluene), and following substantially the same procedure described in Example 2, there was obtained 1-(3,4,5-trichlorobenzyl)-l-phenyl-2-propanone.
• Example 8 I-(p-propylbenzyl)-1-phenyl-2-pr0pan0ne.-By replacing the o-bromobenzyl bromide reactant employed in Example 2 by p-propylbenzyl cldoride (prepared by chloromethylation of propylbenzene), and following substantially the same procedure described in Example 2, there was obtained l-(p-propylbenzyl)-1-phenyl-2-propanone.
• Example 9 J-(chlorobenzyl)-1-(p-ethylphenyl)-2- propanone-By replacing the phenylacetone and the o-bromobenzyl bromide reactants employed in Example 2 by p-ethylphenylacetone and p-chlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained l-(pchlorob enzyl) l- (p-ethyl) -2-prop anone.
• Example 10 1-(0-chl0robenzyl) -1-(p-methoxyphenyl)-2-propanone.-By replacing the phenylacetone and the o-bromobenzyl bromide employed in Example 2 by p-methoxyphenylacetone and o-chlorobenzyl chloride respectively, and following substantially the same procedure described in Example 2, there was obtained 1-(0- chlorobenzyl) -1- (p-methoxyphenyl) -2-propanone.
• Example, 25 4-(o chlorobenxyl)-4-phenyl- -oxohxanenitrile.
• the catalyst benzyltrimethylammoniumg hydroxide (2 fml.
• phenyl-Z-propanon'e employed in Example 25 by an equimolecular quantity of lbenzyl-l-(3,4-dichlorophenyl) -2- propanone, prepared as described in Exam'pIeQS, and tol- .-hexanenirrile.-'-By replacing the 1 (o chlorobenzyl) 1 oxohexanenitrile.-.By replacing the l-(o-chlorobenzyl) -1: phenyl-2propanone employed inExa'mple 25 by an'equimolecular quantity of1-(3,4,5-trichlorobenzyl)-l-phenyl- 2-propanone, prepared as described in-Example 7, and following substantially the same procedure described in Example 25, there was obtained 4-(3,4,5-t1richlorobenzyl)- 4-phenyl-5-oxohexanenitrile.
• Example 30.-4 (p-chlorobenzyl) -4-'(p-ethylphenyl)- 5 -ox0hexanenit rile.By replacing the l-(o-chlorobenzyD- l-pheny-Lpropanone employed in Example 25 by an equimolecular quantity of l-(p-chlorobenzyl)el-(p-ethylphenyD-Z-propanone,prepared asp-described in Example 9, and following substantially the same procedure described in Example 25, there was obtained 4-(p-chlorobenzyl)- 4-(p-ethylphenyl)-5-oxohexanenitrile. a
• Example 31 4-(0-chl0r0benzyl)-4(p meth0xyphen- 'yl)-5-oxohexanenitrile.--By replacing the l-(o-chlorobenzyl)-1-phenyl-2-propanone employed in Example 25 by an equimolecular quantity of 51-(p-ethoxybenzyl)-lmethoxyphenyl)-2-propanone, prepared as described in Example 10, and following substantially the same procedure described in Example 25, there was obtained 4-(0- chlorob enzyl) -4 (p-methoxyphenyl) -5-oxohexanenitrile.
• Example 32 -4-(p-eth0xybenzyl)-4 (m-meth0xyphentvl)-5-0xohexanenit rile.---By replacing the vl-(o-chloro- .benzyl)-l-phenyl-2-propanone employed in Example 25 by an equimolecular quantity of l- (p-ethoxybenzyl)-l- (m-methoxyphenyl)-2-propanone, prepared as described in Example 11, and following substantially the same procedure described in Example 25, there was obtained 4-(pethoxybenzyl) -4 (m-methoxyphenyl) -5 -oxohexanenitrile.
• the hexanenitriles of this invention contain an asymmetric carbon atom; therefore the racemic modification is produced in the synthesis. Hydrolysis of these hexanenitriles produces the corresponding racemic modification of the hexanoic acids.
• the following example describes a preferred method for hydrolyzing the hexanenitriles to the DL-hexanoic acids.
• Example 50 -4-(3,4-dichlorobenzyl)-4-(4-chl0rophenyl)-5-ox0hexan0z'c acid-By replacing the 4-(0-c'nlorobenzyl)-4-phenyl-5-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(3,4-dichlor0- benzyl)-4-(4-chlorophenyl)-5-oxohexanenitrile, prepared as described in Example 26, and following substantially the same procedure described in Example 49, there was obtained 4-(3,4-dichlorobenzy1) 4 (4 chlorophenyl)-5 oxohexanoic acid.
• Example 51 4 benzyl-4-(3,4-diclzlorophenyl) -5-oxohexanoic acid.By replacing the 4-(o-chlorobenzyl)-4- phenyl-S-oxohexaneuitrile employed in Example 49 by an equimolecular quantity of 4-benzyl-4-(3,4-dichlorophenyl) -5-oxohexanenitrile, prepared as described in Example 27, and following substantially the same procedure described in Example 49, there was obtained 4-benzyl-4- (3,4-dichlorophenyl) -5-oxohexanoic acid.
• Example 54 -4-(p-clzl0r0benzyl)-4-(p-ethylphenyl)-5- oxolzexanoz'c acid.-By replacing the 4-(o-chlorobenzyl)- 4-phenyl-5-oxohexanenitri1e employed in Example 49 by an equimolecular quantity of 4-(p-chlorobenzyl)-4-(pethylphenyl)-5-oxohexanenitrile, prepared as described in Example 30, and following substantially the same procedure described in Example 49, there was obtained 4-(pchlorobenzyl) -4- (p-ethylphenyl) -5-oxohexanoic acid.
• Example 55 -4-(0-chl0r0benzyl) -4-(p melhoxyphenyl)-5-0x0hexan0ic acid.-By replacing the 4-(o-chlorobenzyl)-4-phenyl-5-oxohexanenitrile employed in Example 49 by an equirnolecular quantity of 4-(o-chlorobenzyl)-4- (p-methoxyphenyl)-5-oxohexanenitrile, prepared as described in Example 31, and following substantially the same procedure described in Example 49, there was obtairied 4-(o-chlorobenzyl)-4-(p-methoxyphenyl) 5 0x0- hexanoic acid.
• Example 57.4-(m-methylbenzyl)-4-(0-meth0xyphenyl)-5-0xohexanoic acid By replacing the 4-(0-chlorobenzyl) -4-phenyl-5-oxohexanenitrile employed in Example 49 by an equimolecular quantity of 4-(m-methylbenzyl)-4- (o-methoxyphenyl)-5-oxohexanenitrile, prepared as described in Example 33, and following substantially the same procedure described in Example 49, there was obtained 4-(n1-methylbenzyl)-4-(o-methoxyphenyl)-5 OX0- hexanoic acid.
• hexanoic acids prepared by hydrolyzing the hexanenitriles described in the preceding examples by the process described in Example 49, are identified in Table Ill.
• An exception occurs when either or both of the radicals R and R contain a group, such as a cyano group, which is hydrolyzed under the conditions described in Example 49.
• Example 72 -Levo-4-'(o-chloroljenzyl -4-phenyl-5 -0x0- hexanoic acid.Racemic-4-(o-chlorobenzyl)-4-phenyl-5- 'oxohexanoic acid (354.4 'g., 1.07 mole), prepared as de-' scribed in Example 49, and brucine alkaloid (422.6 g., 1.07 mole) were dissolved in warm methanol, seeded, and cooled for 24hours at room temperature andthen 24 hours at 5 C. The solid was'filtered ofi'and'dried. (The *me thanolic mother liquor was set aside for recovery, by
• Example 73 -Dextro'-4-(o-chlorobenzyl)-4-phenyl-5- oxohexzmoic acid-The methanolic mother liquor from which the brucine salt of the levo-acid separated (de scribed in Example 72) was evaporated to dryness at reduced pressure on a steam bath. The resulting oil was dissolved in chloroform (500 ml.) and extracted with an excess of aqueous sodium hydroxide solution ('1 liter containing 28 g., 0.7 mole, of sodium hydroxide). Two more extractions of the chloroformphase with 100 m1. portions of aqueous sodium hydroxide of the same strength were made. The combined aqueousextracts were acidified with excess concentrated hydrochloric acid and the mixture then extracted with benzene (500 mil). Two more extractions with benzene (100ml. portions) were made,
• benzene extracts were extracted with aqueous sodium hydroxide solution (1 liter containing 28 g., 0.7 mole, of sodium hydroxide).
• aqueous sodium hydroxide solution (1 liter containing 28 g., 0.7 mole, of sodium hydroxide).
• the aqueous layer was again acidified with excess concentrated hydrochloric acid and extracted with benzene (500 ml).
• the benzene solution was dried over sodium sulfate and then the benzene removed by evaporation. The resulting oil.
• the solid that separated consists mainly of the racemic .modification. This material was removed by filtration,
• Example '69 Fractional scribed in Example '69, and preparing thebrucine salt of this latter product by substantially the same process described'in Example 72, there was obtained a 57% yield of' levo-4-(o-bromobenzyl) -4-phenyl-5-oxohexanoic acid which, after recrystallization from cyclohexane, melted at 85.5'87.5 C.
• the specific rotation of a 2% solution ofi'this product in 95% ethanol was 1 18;5 at 25 C.
• esters of the 4-aryl-4-aralkyl-5-oxohexanoic acids are advantageously prepared by dissolving the selected hexauoic acid in a mixture of absolute alcohol and concentrated sulfuric acid.
• An advantageous ratio is about 1 mole of the hexanoic acid, 2-2.5 liters of alcohol and 70-85 ml. of concentrated sulfuric acid.
• the mixture is then refluxed several hours, generally from 3 to 10 hours, under anhydrous conditions and the excess alcohol removed by distillation or evaporation.
• the residue, containing the crude ester then is dissolved in about 200 ml.
• benzene aqueous sodium bicarbonate.
• the ester may be isolated by pouring the reaction mixture into water and dissolving the material that sep-" arates in benzene.
• the benzene solution is dried advan-' tageously over sodium sulfate, and the solvent removed by distillation or evaporation.
• Example 75 -Methyl 4-benzyl-4-phenyl-5-oxohexan0- ate.4-benzyl-4-phenyl-5-oxohexanoic acid (50 g., 0.169 mole), prepared as described in Example 58, was dissolved in absolute methanol (200 ml.), and concentrated sulfuric acid (14 ml.) was added. The mixture was refluxed under anhydrous conditions for 7%. hours. The solution was cooled and poured into a liter of ice Water. An oil separated which soon solidified. The solid was filtered off, washed in water, and dissolved in benzene. The solution was washed with water, then with sodium bicarbonate solution, and again with Water.
• Example 76 Lev methyl 4 (o chlorobenzyl) 4- phenyl 0x0hexan0ate.Levo-4-(o-chlorobenzyl)-4- phenyl-S-oxohexanoic acid (100 g., 0.3 mole), obtained as described in Example 72, was dissolved in a solution of absolute methanol (400 ml.) and concentrated sulfuric acid (16 ml). The solution was refluxed under anhydrous conditions for seven hours. Most of the solvent was removed by reduced pressure distillation and the residue poured into water. The mixture was extracted three times with toluene (125 ml. portions) and the combined extracts were washed first with water, then saturated sodium bicarbonate solution and finally with water.
• esters of 4-aryl-4-aralkyl-S-oxohexanoic acid identified in column C of Table IV, were prepared by allowing the hexanoic acid, identified in column A,- to react with the alcohol, identified in column 13, according to the procedure D1 and Example 75 above.
• the 1,3-cyclohexanedione derivatives of the 4-aryl-4- aralkyl-S-oxohexanoic acids can be prepared by various methods.
• the 1,3-cyclohexanedione derivative is often formed as a by-product when the 4-aryl-4-aralkyl-5-oxohexanenitriles are hydrolyzed to the corresponding acid.
• the 1,3-cyclohexanedione by-product may be formed regardless of whether the hydrolysis of the nitrile is conducted under acid or alkaline conditions.
• the cyclohexanedione product in general was separated from the hexanoic acid by making use of the difference in their solubility in organic solvents.
• 1,3-cyclohexanedione derivatives can be prepared from an ester of the 4-aryl-4-aralkyl-5-oxo- .hexanoic acid which is readily converted to the 1,3-cyclohexanedione in the presenceof sodium alkoxide or similar basic catalyst.
• 1,3-cyclohexanediones can be prepared is by reaction of the l-aryl-l-aralkyl-Z- propanones with beta-propiolactone in the presence of certain condensing agents, such as potassium tertiarybutoxide.
• certain condensing agents such as potassium tertiarybutoxide.
• Optimum yields are obtained when an excess of beta-propiolactone and of the condensing agent are used.
• Very good yields have been obtained by employing 'a molar ratio of ketone to beta-propiolaotone to condensing agent of 1:25:25.
• Example 92 4 benzyl 4-(5 ,4-dichl 0r0phenyl)-1,3- byclohexanedione.-By replacing the methyl 4'-benzyl-4- phenyl-S-oxohexanoate employed in Example 90 by an equimolecular quantity of methyl 4-benzyl-4-(3,4-dichlorophenyl)-5-oxohexanoate, product of Example 85, there was obtained 4-benzyl-4-(3,4-dichlorophenyl)-1,3- cyclohexanedione.
• Example 952-4 - (p-chlqrobenzyl)-4-(p-ethylphenyl)f 1,S-cyblohexanedi0ne.By replacing the methyl 4-benz yl- '4-phenyl-5-loxohexanoate employed in Example 90 by an equimolecular quantity of ethyl 4-(p chlorobenzyl)-4-(pethylphenyl)-5-oxohanoate, product of Example 88, there was obtained 4 (p-chlorobenzyl)-4-(p-ethylphenyl)- 'l,3 cyclohexanedione.
• Example 95 -4- (p-ethoxybenz'yl) -4- (m-methoxyphem yl) -1,3-cycl 0hexandi0'ne.-By replacing the methyl 4- 'benzyl-4-pl1enyl-S-oxohexanoate employed in Example 90 by an equimolecular quantity of -1-propyl 4-(p-ethoxybenzyl)-4-(m-methoxyphenyl) 5-oxohexanoate, product of Example 89, there was obtained 4- (p-eth0xybenzyl) 4-
• Example 97 4-(o-me thylben'zyl) -4-ph'enyl-1,3-cycl0- hexanedi0ne.-A solution of potassium tertiary-butoxide was prepared by allowing potassium (6.6 g., 0.169 mole) to'reactwith dry tertiary-butyl alcohol (175
• the enol-lactone can be iso- 17 lated from the undistilled residue or it can be purified by distillation.
• Example 103 Levo-4-(o-chlorobenzyl) -4-phenyl-5- hydroxy-S-hexenoic acid laclne.-lsopropenyl acetate (100 g., 1 mole) and levo-4-(o-chlorobenzyl)-4-phenyl- 5-oxohexanoic acid (80 g., 0.24 mole), obtained as described in Example 72, were placed in a flask equipped with a long fractionating column and concentrated sulfuric acid (3 drops) was added. A downwardly directed condenser was attached to the side arm and the mixture was gently heated so that a slow distillation occurred. A total of 30 ml. of'material, boiling at 56-59 C., was collected during two hours. Another drop of concentrated sulfuric acid was added to the reaction mixture and heating was continued for another 30 minutes; however, only a very little more distillate was collected.
• the enol-lactone can be dissolved in the selected (di-substituted-amino)-alkanol when the alkanol is a liquid, and in the event the alkanol is a solid, then the alkanol can be melted and the enol-lactone dissolved therein or the enollactone and the (di-substituted-amino)-alkanol can be dissolved in a common inert solvent.
• the solution, however made, is then heated preferably under anhydrous conditions and often conveniently refluxed for several hours.
• the excess (di-substituted-amino) -alkanol then is distilled oil and the residue, the basic ester, purified according to conventional methods.
• Example 120 2-dimethylaminoethyl 4-(0-chl0robenzyl)-4-phenyl- -ox0hexanoate hydr0br0mide.4-(ochlorobenzyl)-4-phenyl-S-hydroxy-S-hexenoic acid lactone (36.1 g., 0.115 mole), product of :Example 102, was dissolved in dry Z-dimethylaminoethanol (89 g., 1.0 mole) and the mixture heated under anhydrous conditions for 30 minutes at 95 C. and then refluxed for 2 hours. The excess amine was removed by distillation at reduced pressure and the residue dissolved in benzene (250 1111.). The solution was washed twice with water and then dried over sodium sulfate. The solvent was removed by distillation at reduced pressure and the residue dissolved in cyclohexane (150 ml.)
• a 4,4-disubstituted-5-oxohexanoic acid having the 5 general formula and alkali metal salts thereof wherein R is a mononuclear aryl radical and R is a mononuclear arylmethyl radical;
• CH 5 4-(o-ehlorobenzyl)-4-phenyl-5-oxohexanoic acid.

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• 1954
  • 1954-07-15 US US443695A patent/US3042714A/en not_active Expired - Lifetime
• 1955
  • 1955-07-14 ES ES0223143A patent/ES223143A1/es not_active Expired

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