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US3257420A - Carboxylic acids alpha-substituted by at least one cyclic radical - Google Patents

Carboxylic acids alpha-substituted by at least one cyclic radical Download PDF

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US3257420A
US3257420A US174684A US17468462A US3257420A US 3257420 A US3257420 A US 3257420A US 174684 A US174684 A US 174684A US 17468462 A US17468462 A US 17468462A US 3257420 A US3257420 A US 3257420A
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naphthyl
acid
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Szarvasi Etienne
Neuvy Liliane
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Merck Sante SAS
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LIPHA SAS
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Priority claimed from FR853642A external-priority patent/FR1289597A/en
Priority claimed from FR860401A external-priority patent/FR80103E/en
Priority claimed from FR862174A external-priority patent/FR1318M/en
Priority claimed from FR885619A external-priority patent/FR81162E/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
    • 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
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • n is an odd number at most equal to 3
  • R is a member of the group comprising the l-naphthyl and l-naphthylmethyl radicals
  • R is a member of the group comprising the furyl and tetrahydrofuryl radicals and-when n denotes the number l and R the naphthyl radicalthe vinyl and 1- propenyl radicals, as also their sodium salts, their alkyl and dialkylaminoethyl esters, their hydrazides and their 2-amidoethanol derivatives, and the corresponding ethyl malonates, nitriles and amides.
  • R and R have the same meanings as before and R is a lower alkyl radical, is saponified and decarboxylated by means of an alkali in the presence of an alcohol, preferably benzyl alcohol.
  • alkyl malonates are preferably obtained by reaction of a sodium alcoholate with an alkyl malonate mono-substituted by one of the radicals R and R (011 followed by condensation of the sodium derivative obtained with the halide of formula R (CH or R X, in which X denotes chlorine or bromine, depending upon whether the radical already attached to the. alkyl malonate is R or R (CH Disubstituted ethyl malonates of the formula in which 11, R and R have the same meanings as before, are new compounds.
  • nitriles are preferably obtained by treatment of nitrile of the general formula R CH CN or with sodamide, followed by condensation of the sodium derivative obtained with the halide of the general formula R (CH X or R X, depending upon whether the nitrile is of formula R CH CN or R,- ;(CH ),,CH CN.
  • Alpha-substituted nitriles of the formula OH-CN R2(CH2)11 in which n, R and R have the same meanings as before, are new compounds.
  • the sodium salts and the alkyl and dialkylaminoethyl esters of the preceding acids are obtained by neutralisa tion or esterification of the corresponding acids, which thus constitute intermediate products in the preparation of their derivatives.
  • the toxicities of the compounds of the invention expressed by the 50% lethal dose orally or intraperitoneally administered in the rat, are the following (in mg./kg.):
  • the above acids and sodium salts, mixed with or dissolved in appropriate excipients and adjuvants, may be administered for the treatment of atherosclerosis in dosages between 0.010 g. and 2 g. per day by the oral, rectal or parenteral route;
  • the dialkylaminoethyl esters possess a therapeutic antiinflammatory activity.
  • the diethylaminoethyl ester of alpha-l-naphthylhexen-delta-4-oic acid possesses psychoenergetic activity which is useful in the treatment of traumatic conditions, which is much greater than that of the dimethylaminoethyl ester of para-chlorophenoxyacetic acid, which is a known therapeutic compound.
  • the diethylaminoethyl ester of 1-naphthylpenten delta-4-oic acid exhibits in the Magnus test on the isolated intestine of the rabbit a spasmolytic activity which is ten times greater than that of papaverine.
  • hydrazides constitute intermediate products in the synthesis of the substituted hydr-azines described in the French patent application of December 11, 1961, in the name of the applicants, which constitute inhibitors of monoa'minooxydase and coronary vasodilators.
  • ethoxide is prepared by introducing 9 g. (0.4 atom) of sodium into 256 cc. of absolute ethanol. There are added thereto 96 g. (0.4 mol.) of ethyl furfurylmalonate, and the mixture is boiled for 5 minutes while being well stirred. After cooling, 70.4 g. (0.4 mol.) of 1-chloromethylnaphthalene are added drop by drop through a dropping funnel, whereafter the mixture is heated under reflux for 24 hours and extracted with 25 benzene.
  • Example 5 Alpha- (1-naphthyl) tctrahydrofurylvaleronitrile
  • Example 6.-Alpha+(1-naphthyl)hexen-delta-4-0ic nitrile C H N. -(M 22-1.28.)
  • Sodium methylate may be employed as condensing agent instead of sodamide.
  • Example 7 Alpha (I-naphthyl)penten-delta- 4-0ic nitrile 11.1 g. of sodamide (0.238 mol. of NaNH in cc. of dry ether are reacted as in Example 3 with 37.5 g. (0.224 mol.) of l-naphthylacetonitrile and 28 g. (0.223 mol.) of allyl bromide.
  • Gravimetric aaalysis --.Calculated: C percent, 8694; H percent, 6.31; N percent, 6.76. Found: C percent, 86.94, 86.87; H percent, 6.29, 6.15; N percent, 7.1-1, 7.04.
  • Example 8 Beta-(1-naphthyl)beta'Jw-ylisobutyric acid The product, covered with a layer of hexane, crystallises rapidly, after scraping of the wall with a rod, into substantially white crystals.
  • the recrystallisation is effected as follows:
  • Its sodium salt has a melting point of 260-262 C.
  • W /OH-COOCH3 LO CHz 25 g. (0.089 mol.) of beta-(1-naphthyl)heta-furylisobutyric acid are esterified by heating under reflux with 150 cc. of absolute methanol in the presence of 0.5 cc.
  • the redistilled product has the following constants:
  • the sodium salt has a melting point of 261 C. with decomposition (on the capillary tube). It is a hygroscopic product.
  • Example 13 Methyl alpha- (1 Jmph thylm'ethyl deltatetrahydrofury lvalerate 26.5 g. (0.0845 mol.) of alpha-(1-naphthylmethyl)deltatetrahydrofuryl valeric acid are esterified by the procedure of Example 9.
  • the redistilled product has the following constants:
  • the sodium salt takes the form of white crystals which V are insoluble in cold water and soluble in boiling water,
  • the alpha-( l-naphthyl)furylpropionic amide is obtained alone by the procedure described in the following Example 15, which consists in hydrolysing nitrile in ethanol in the presence of the stoichiometric quantity of potassium hydroxide and limiting the duration of the reaction to half that necessary for producing the acid.
  • Example 16 Methyl alpha-(1-naphthyl)farylpr0pionate C ONHz 27 g. (0.101 mol.) of alpha-(l-naphthyDfurylpropionic acid, 150 cc. of absolute methanol and 0.5 cc. of concentrated sulphuric acid are heated under reflux for 6 hours. After the usual treatment, distillation gives 19 g. of pale yellow oil distilling at 172 172.5 C./1 mm. Hg.
  • the redistilled product has the following constants:
  • the preceding distillate is taken up in 25 cc. of ethyl acetate, and white crystals are formed on the addition of hexane. After three recrystallisations, the product takes the form of white crystals having a melting point of 135 C. (heating stage). 7
  • the sodium salt has a melting point of 250-25 1 C. (capillary tube).
  • Example 22 Methyl alpha-(l-naphthyl)tetrahydrofurylprapionate o 1.1- 00cm
  • U 22 g. (0.0812 mol.) of alpha-(1-naphthyl)tetrahydrofurylpropionic acid are esterified as in Example 9. There are obtained 17.5 g. of pale yellow viscous liquid (yield 75.5%).
  • the redistilled product has a boiling point of 157-158 C./0.36 mm. Hg.
  • Example 23 --Ne0pentyl alpha-(1 -naplzthyl)tetrahydrofurylpropionale 27 (0.1 mol.) of alpha-(l-naphthyl)tetrahydrofurylpropionic acid, prepared as described in Example 20, are esterified with neopentyl alcohol. Distillation gives 20 g. (yield about 59%) of viscous yellow liquid distilling at 182-185 C./1 mm. Hg.
  • the redistilled product has the following constants:
  • the redistilled product which has a honey-yellow color, has a melting point of 191 C./0.36 mm. Hg.
  • Example 25 --Alpha (1-naphthyl)delta tetrahydrofurylvaleric acid L /'0 11-0 0 OH h (01 2)::
  • Example 26 Diethylaminoethyl alpha-(1 -naphthyl)- delta-retrahydrofurylvalerate 29.8 g. (0.1 mol.) of alpha-(l-naphthyDtetrahydrofurylvaleric acid, prepared as described in Example 22, are esterified with diethylaminoethanol 'by the procedure described in Example 11.
  • the redistilled product has the following constants:
  • CH-OONH2 CH3CH CHCI I2 22 g. (0.1 mol.) of alpha-(l-naphthyl)hexen-delta-4- oic nitrile are hydrolysed by the procedure of Example 15. There are obtained 21 g. of yellow product (yield 87.7%). After four recrystallisations from ethyl acetate, the product has a melting point of 1121-122" C. It sublimates in the neighbourhood of this temperature.
  • Example 30 Methyl alpha-(I-naplztlzyl)hexen-delta- 24 g. (0.1 mol.) of alpha-(l-naphthyl)hexen-delta-4- oic acid, prepared as described in Example 28, are esterified with methyl alcohol by the procedure of Example 9.
  • the redistilled product has the following constants:
  • Example 31 --Dietl1ylamin0ethyl alpha-(1 -naphthyl) hexen-delta-4-0ate 24 g. (0.1 mol.) of alpha-(l-naphthyl)hexen delta-4-oic acid are e-sterified with d'iethylaminoethyl alcohol by the procedure described in Example 11.
  • This compound may be solubilised by salification with an acid, more especially hydrochloric acid. It can be directly obtained in the form of its chloride by heating the starting acid with beta-chloroethyl-N-diethylamine in isopropanol.
  • M.P. 125-127 C. (heating stage), with sublimation starting at 100 C.
  • Example 33 Alpha-(1-naphthyl)penten-delta-4-0ic acid
  • Example 34 Diethylaminoethyl ester of alpha-(1 -naphthyl)penten-delta-4-0ic acid
  • Empirical formula C21H27NO2. M 325.42.
  • the redistilled product has the following physical constants:
  • Y 1 A compound of the formula CH-C O OH R2( 2)n in which n, is an odd number at most equal to 3, R is a member of the group consisting of the l-naphthyl and l-naphthylmethyl radicals, and R is a member of the group consisting of the furyl and tetrahydrofuryl radicals andwhen n denotes the number 1 and R the naphthyl radical-the vinyl and l-propenyl radicals. 2.
  • R is a member of the group consisting of the l-naphthyl .and l-naphthylmethyl radicals, and R is a member of the group consisting of the furyl and tetrahydrofuryl radicals and-when n denotes the number 1 and R the naphthyl radical-the vinyl and l-propenyl radicals. 3. Beta-(l-naphthyl) beta'-furylisobutyric acid.

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Description

United States Patent CARBOXYLIC ACIDS ALPHA-SUBSTITUTED BY AT LEAST ONE CYCLIC RADICAL Etienne Szarvasi, Lyon, and Liliane Neuvy, Paris, France,
assignors to Lipha, Lyonnaise Industrielle Pharmaceutique No Drawing. Filed Feb. 21, 1962, Ser. No. 174,684 Claims priority, application France, Feb. 23, 1961, 853,642, Patent 1,289,597; Apr. 28, 1961, 860,401, Patent 80,103; May 16, 1961, 862,174, Patent 1,318; Jan. 23, 1962, 885,619, Patent 1,289,597 26 Claims. (Cl. 260-3474) CH-O 0 OH eat in which:
n is an odd number at most equal to 3,
R is a member of the group comprising the l-naphthyl and l-naphthylmethyl radicals, and
R is a member of the group comprising the furyl and tetrahydrofuryl radicals and-when n denotes the number l and R the naphthyl radicalthe vinyl and 1- propenyl radicals, as also their sodium salts, their alkyl and dialkylaminoethyl esters, their hydrazides and their 2-amidoethanol derivatives, and the corresponding ethyl malonates, nitriles and amides.
These acids may be prepared in accordance with the invention by either of the following two methods, whereby they are obtained in good yields.
In the first method, a disubstituted alkyl malonate of the general formula i ice In the second method, alpha-substituted aliphatic acids of the formula CHCOOH R2(CHz);l in which n, R and R have the same meanings as before,
, are prepared by hydrolysing an alpha-substituted nitrile in which 11, R and R have the same meanings as before and R is a lower alkyl radical, is saponified and decarboxylated by means of an alkali in the presence of an alcohol, preferably benzyl alcohol.
The above disubstituted alkyl malonates are preferably obtained by reaction of a sodium alcoholate with an alkyl malonate mono-substituted by one of the radicals R and R (011 followed by condensation of the sodium derivative obtained with the halide of formula R (CH or R X, in which X denotes chlorine or bromine, depending upon whether the radical already attached to the. alkyl malonate is R or R (CH Disubstituted ethyl malonates of the formula in which 11, R and R have the same meanings as before, are new compounds.
of the formula CH-ON Rnom) by means of 'an alkali in the presence of an alcohol, preferably benzyl alcohol. In a preferred variant of the invention, in the case of the use of benzyl alcohol, alkali and nitrile are employed in equimolecular quantities. The above nitriles are preferably obtained by treatment of nitrile of the general formula R CH CN or with sodamide, followed by condensation of the sodium derivative obtained with the halide of the general formula R (CH X or R X, depending upon whether the nitrile is of formula R CH CN or R,- ;(CH ),,CH CN.
Alpha-substituted nitriles of the formula OH-CN R2(CH2)11 in which n, R and R have the same meanings as before, are new compounds.
The sodium salts and the alkyl and dialkylaminoethyl esters of the preceding acids are obtained by neutralisa tion or esterification of the corresponding acids, which thus constitute intermediate products in the preparation of their derivatives.
In addition, it is possible to obtain by hydrolysis of the nitriles, not the above-mentioned acids, but the corresponding amides of formula CH-CONH: R2(CH2)n the hydrolysis of the nitrile being effected by a substantially equimolecular quantity of an alkali in the presence of alcohol. Amides of the formula CH-C ON Hz in which n, R and R have the same meanings as above, themselves constitute new compounds.
Hydrazides of the formula o HC ONH-NHz RA E) in which n, R, and R have the same meanings as before,
are also new compounds. They are obtained by reacting an ester of the corresponding acid with hydrazine.
Finally, Z-amidoethanol derivatives of the formula amine.
The above-defined acids, their sodium salts and their The administration of the product by the oral route in a dosage of 300 mg./kg. gives substantially identical results.
It will be seen that the first of the above-designated new compounds are notably more active than alpha-biphenylylbutyric acid. The others, while being less active, still have interesting efiicacity.
The toxicities of the compounds of the invention, expressed by the 50% lethal dose orally or intraperitoneally administered in the rat, are the following (in mg./kg.):
Oral Intraroute peritoneal route Sodium alpha- (l-naphthyl) -iurylpropionate 1, 500 300 Sodium beta-(l-naphthyl)-beta-iurylisobutyrate 1, 500 300 Sodium alpha(l-naphthyl)-tetrahydrofury1- propionate 750 300 Sodium alpharfl-naphthylmethyl) tetrahydroiuryl-valerate 1, 500 350 Sodium a1pha- (1-naphthyl)-hexen-de1ta-4- oate 1, 500 250 By Way of comparison, the toxicity of alpha-biphenylylbutyric acid is 1500 mg./ kg. by the oral route.
The above acids and sodium salts, mixed with or dissolved in appropriate excipients and adjuvants, may be administered for the treatment of atherosclerosis in dosages between 0.010 g. and 2 g. per day by the oral, rectal or parenteral route;
The dialkylaminoethyl esters possess a therapeutic antiinflammatory activity. In addition, the diethylaminoethyl ester of alpha-l-naphthylhexen-delta-4-oic acid possesses psychoenergetic activity which is useful in the treatment of traumatic conditions, which is much greater than that of the dimethylaminoethyl ester of para-chlorophenoxyacetic acid, which is a known therapeutic compound. The diethylaminoethyl ester of 1-naphthylpenten delta-4-oic acid exhibits in the Magnus test on the isolated intestine of the rabbit a spasmolytic activity which is ten times greater than that of papaverine.
The hydrazides constitute intermediate products in the synthesis of the substituted hydr-azines described in the French patent application of December 11, 1961, in the name of the applicants, which constitute inhibitors of monoa'minooxydase and coronary vasodilators.
Finally, the Z-amidoethanol derivatives possess therapeutic hypoglycemic properties.
There are hereinafter described as non-limiting ex- 4 amples the preparations and physical properties of various compounds of the invention.
Example 1.-Ethyl alpha-(1-naphthylmethyl)alphafurfurylmalonate Empirical formula: C HQ O (Molecular mass: M: 3 80.42.) Developed formula:
- CHz COOC2H5 C 5 mojc OOOCZH5 Sodium ethoxide is prepared by introducing 9 g. (0.4 atom) of sodium into 256 cc. of absolute ethanol. There are added thereto 96 g. (0.4 mol.) of ethyl furfurylmalonate, and the mixture is boiled for 5 minutes while being well stirred. After cooling, 70.4 g. (0.4 mol.) of 1-chloromethylnaphthalene are added drop by drop through a dropping funnel, whereafter the mixture is heated under reflux for 24 hours and extracted with 25 benzene.
Distillation of the extract gives 105 g. of a honey-yellow viscous liquid, B.P.=202203 C./1.5 mm. Hg. The yield is 69% (theoretical quantity 152 g.).
Example 2.Ethyl alpha-(1 -naphthylmethyl )alphatetmhydrofurylpropylmalonate C H O (M=41 2.51.) Developed formula:
35 o H. 0 02C 2115 I I LQJ-(CHDa C 02C 2115 Example 3.-A[pha-(1-naphthyl)furylpropionitrile C H NO. (M=247.27.)
Into a well-dried spherical flask are introduced 580 cc. of dry ether, 57 g. of 90% sodamide (1.26 mol. of r NaNH and 196 g. (1.17 mol.) of alpha-l-naphthylacetonitrile, whereafter the mixture is heated under reflux for one hour. The flask is cooled in an ice bath and there are added dropaby-drop 157 g. (1.34 mol.) of furf-uryl chloride dissolved in 157 cc. of dry ether. After heating under reflux for 6 hours, the product is carefully poured into water and acidula-ted with hydrochloric acid. On distillation, there are obtained 208 g. of pale yellow viscous liquid distilling at 193196 C./ 3 mm. Hg. Yield 71.8% (theoretical quantity 289.2 g). After redistillation, the product has the following constants:
B.P.=194195 c./2 mm. Hg.
Refractive index: n =1.'6 11.
It crystallises at ambient temperature.
After two recrystallisations from a mixture of ethanol and hexane in equal volumes, there is obtained a white -solid having a melting point of 46.548 C. (on the heating-stage microscope).
Gravimetric analysis gives.-Calculated: C percent, 82.58; H percent, 5.29; N percent, 5.66. Found C percent, 82.21, 82.99; H percent, 5.33, 5.33; N percent,
Example 4.Alpha-.(1-naphthyl) tetrahydrofurylpropionitrile C1'1H1'10N- (M='2-51.31.)
41.2 g. (0.25 mol.) of tetrahydrofurylbromide are condensed with 37.5 g. (0.224 mol.) of alpha (1-naph-thyl)- acetonitrile by the same procedure as in Example 3. 1
After distillation, there are obtained 37.5 g. of pale yellow viscous liquid distilling at 184-187 C./1 mm. Hg.
Yield 67% (theoretical quantity 56.4 g.). After redistillation, the product has a boiling point of 154 C./ 0.4 mm. Hg.
Gravimetric analysis-Calculated: C percent, 81.29; H percent, 6.82; N percent, 5.57. Found: C percent 81.01, 81.14; H percent, 6.63, 6.79; N percent 6.05, 6.10.
Example 5.Alpha- (1-naphthyl) tctrahydrofurylvaleronitrile Example 6.-Alpha+(1-naphthyl)hexen-delta-4-0ic nitrile C H N. -(M=22-1.28.)
11.1 g. of 90% sodamide (0.238 mol. of NaNH in 110 cc. of dry ether are reacted as in Example 3 with 37.5 g. (0.224 mol.) of alpha-i1-naphthyl)acetonitrile and 33 g. (0.244 mol.) of crotyl 'bromide. There are obtained 32.5 g. of viscous yellow liquid. Yield 65.7%
6 (theoretical quantity 49.5 g.). After two redistillations, the product has the following constants:
B.:P. /0.9 mm. Hg=138 C. Gravimetric analysis.Calcul-ated: C percent, 86.88; H percent, 6.83; N percent, 6.33. Found: C percent, 86.52; H percent, 6.97; N percent, 6.69.
Sodium methylate may be employed as condensing agent instead of sodamide.
Example 7.Alpha (I-naphthyl)penten-delta- 4-0ic nitrile 11.1 g. of sodamide (0.238 mol. of NaNH in cc. of dry ether are reacted as in Example 3 with 37.5 g. (0.224 mol.) of l-naphthylacetonitrile and 28 g. (0.223 mol.) of allyl bromide.
The addition of allyl bromide takes place in an ice bath, and the reaction is violent.
Distillation of the final product gives 39.5 g. of pale yellow liquid distilling at C./ 1.5 mm. Yield 85.6%. The redistilledproduct has the following constants:
B.P./0.5 mm.=132 0.
Density: D =:1.0520.
Refractive index: n =1.603.
Gravimetric aaalysis.--.Calculated: C percent, 8694; H percent, 6.31; N percent, 6.76. Found: C percent, 86.94, 86.87; H percent, 6.29, 6.15; N percent, 7.1-1, 7.04.
Example 8.Beta-(1-naphthyl)beta'Jw-ylisobutyric acid The product, covered with a layer of hexane, crystallises rapidly, after scraping of the wall with a rod, into substantially white crystals. The recrystallisation is effected as follows:
18 g. of crystals are dissolved in 18 cc. of tepid ethyl acetate. After filtration, 90 cc. of hexane are added to the solution and the mixture is placed in the refrigerator.
7 The oil which precipitates is converted, after initiation of the crystallisation, in the form of a white crystalline mass having a melting point of 72-74 C. (heating stage) and an acid number of 198 (theoretical number 199).
Its sodium salt has a melting point of 260-262 C.
, (capillary tube).
Gravimetric analysis of the acid-Calculated: C percent, 77.11; H percent, 5.75. Found: C percent 7721, 7704; H percent 5.63, 5.78.
7 Example 9.Methyl beta-(1 -naphthyl )beta-furylisobutyrate 1 C H O (M=294.33.)
01E, W /OH-COOCH3 LO CHz 25 g. (0.089 mol.) of beta-(1-naphthyl)heta-furylisobutyric acid are esterified by heating under reflux with 150 cc. of absolute methanol in the presence of 0.5 cc.
-of concentrated sulphuric acid.
Distillation of the product obtained gives 19.5 g. of pale yellow viscous liquid distilling at 197-200 C./ 4 mm. Hg. After redistillation, the ester possesses the following constants:
B.'P./2 mm. Hg=193-195 C.
-Sapnification number.Calculated: 190. Found: 182.
Example 10.--Neopentyl beta-(1 -naphthyl) beta'-fu=rylisobutyrate 21 g. (0.075 mol.) of beta-(l-naphthyl)beta'-fu-rylisobutyric acid, which is a compound prepared as described in Example 8, in solution in 150 cc. of dry benzene is heated under reflux for 17 hours with 7 g. (0.0805 mol.) of neopentyl alcohol in the presence of 0.5 g. of paratoluenesulphonic acid. After the usual treatment of the reaction mixture, distillation gives 0.5 g. (yield about 32%) of very viscous yellow liquid distilling at 187192 C./2 mm. Hg. 7
The redistilled product has the following constants:
B.P./2 mm. Hg=179-180 C.
Refractive index n =1.5585
Saponification number.C-alculated: 163.
Example 11.N-diethylamin0ethyl beta-(1-naphthyl)- beta'-furylis0butyrate C H O N. (M=379.47.)
159. Found:
In a spherical flask provided with a Dean and Stark decanting device, 28 g. (0.1 mol.) of beta-(l-naphthyD- betaafurylisoh-utyric acid in 170 cc. of dry xylene, 12 g.
(0.1025 mol.) of diethylaminoethanol and 0.5 g. of paratoluenesulphonic acid are heated under reflux for 5 hours. After the usual treatment, distillation gives 21 g. of very viscous dark yellow liquid distilling at 195-196" C./1
Gravimetric analysis-Calculated: C'percent, 75.98;-
H percent, 7.70; N percent, 3.69. Found: C percent, 74.74, 74.86; H percent, 7.32, 7.38; N percent, 3.49, 3.54.
Example 12.Alpha-(I-naphthylmethyl) delta-tetra- .hydrofurylvaleric acid C H O (M=312.39.)
' 40.5 g. (0.098 mol.) of ethyl alpha-(l-naphthylmethyl) alpha-tetrahydrofurylpropylmalonate are saponified by a procedure similar to that of Example 8. There are obtained 23.5 g. of very viscous pale yellow oil distilling at 220222 C. under less than 1 mm. (Yield 77% Acid number.Calculated: 179. Found: 177.
Gravimetric analysis.Calculated: C%, 76.89; H%, 7.74. Found: C%, 76.60, 76.50; H%, 7.38, 7.32.
The sodium salt has a melting point of 261 C. with decomposition (on the capillary tube). It is a hygroscopic product.
Example 13.Methyl alpha- (1 Jmph thylm'ethyl deltatetrahydrofury lvalerate 26.5 g. (0.0845 mol.) of alpha-(1-naphthylmethyl)deltatetrahydrofuryl valeric acid are esterified by the procedure of Example 9.
Distillation of the product obtained gives 16 g. of viscous yellow oil distilling at 188188.5 C. under about 1mm. Hg. Yield: 57.7%.
The redistilled product has the following constants:
B.P./0.6 mm. Hg=178 c. D, =1.1s2
Saponification numberCalculated: 171. Found: 170. Example l4.Alpha-(I-naphthyl)furylpropionic acid 40 g. (0.705 mol.) of potassium hydroxide in 1660 cc. of benzyl alcohol are heated under reflux for 15 hours with 79 g. (0.32 mol.) of l-naphthyl-alpha-(furfuryl) acetonitrile. When the reaction is complete, the benzyl alcohol is driven off in vacuo and the solid residue is dissolved in water. The product is made acid with hydrochloric acid until it changes the colour of Congo red and is then extracted with benzene. Distillation gives 56.5 g. of viscous yellow liquid, B.P./2 mm. Hg 218-2l9 C. Yield 71.3% Saponification gives the same yield if equimolecular quantities of nitrile and potassium hydroxide are employed.
The pasty product, covered with a layer of ether, crystallises after several hours in a refrigerator, to give almost white crystals. After threerecrystallisations from ethyl acetate or a mixture of ethyl acetate and hexane, the product has the following constants:
M.P.=80-82 C. (heating stage).
Acid number.Calculated: 210. Found: 212.
Gravimetric analysis.Calculated: C%, 76.70; H%, 5.30. Found: C%, 76.71, 76.78; H%, 4.94, 5.18.
The sodium salt takes the form of white crystals which V are insoluble in cold water and soluble in boiling water,
and which have a melting point of 302-303 C. (heating stage).
Saponification in ethanol, with stoichiometric quantities of nitrile and potassium hydroxide is longer (about a hundred hours). It gives a mixture of the same acid and of the corresponding amide.
The alpha-( l-naphthyl)furylpropionic amide is obtained alone by the procedure described in the following Example 15, which consists in hydrolysing nitrile in ethanol in the presence of the stoichiometric quantity of potassium hydroxide and limiting the duration of the reaction to half that necessary for producing the acid.
Example 15.Alpha-(1-naphthyl) furylp ropionamide C17H15NO2.
4.4 g. (0.079 mol.) of caustic potash in 5 cc. of water and 120 cc. of alcohol are heated under reflux for 50 hours with 19.5 g. (0.79 mol.) of l-naphthyl-alpha-(furfuryDacetonitrile. When the reaction is complete, the ethanol is evaporated in vacuo. The cooled mixture is acidulated with hydrochloric acid. The oily product is extracted with ether; After evaporation of the ether, there remains a solid residue, which is recrystallised from ethanol. There are obtained as the first fraction 2 g. of slightly yellow crystals, and then as the second fraction 1.5 g. of slightly brown crystals (total yield 50.2%). After two further recrystallisations, the product takes the form of White crystals having a melting point of 107- 108 C. (heating-stage microscope).
Gravimetric analysis.Calculated: C%, 77.00; H%, 5.70; N%, 5.28. Found: C%, 77.26, 77.11; H%, 5.85, 5.74; N%, 5.37, 5.43.
Example 16.Methyl alpha-(1-naphthyl)farylpr0pionate C ONHz 27 g. (0.101 mol.) of alpha-(l-naphthyDfurylpropionic acid, 150 cc. of absolute methanol and 0.5 cc. of concentrated sulphuric acid are heated under reflux for 6 hours. After the usual treatment, distillation gives 19 g. of pale yellow oil distilling at 172 172.5 C./1 mm. Hg.
Yield 67% The redistilled product possesses the following constants:
B.P./0.7 mm. Hg: 158 C. B.P./0.75 mm. Hg=159 C. D *=1.1375
10 Saponification number.Calculated: 199. Found: 199.
Example 17.-Ne0pentyl alpha-(I-naphthyl)furylpropionate C H O (M=336.41.)
27 g. (about 0.1 mol.) of alpha-(1-naphthyl)furylpropionic acid, prepared as described in Example 14, is treated as in Example 10 with neopentyl alcohol. Distillation gives 16.5 g. (yield 49%) of a pale yellow oil distilling at 184-185 C./2 mm. Hg.
The redistilled product has the following constants:
B.P./1 mm. Hg=171-172 C.
Density: d =1.0652
Saponification number.-Calculated: 166. Found:
Example 18.-N-diethylam'in0ethyl alpha-(1 -naphlhyl) fzu'ylpropionate (M=365.45.)
(The
27 g. (0.101 mol.) of alpha-(l-naphthyl)furylpropionic acid in cc. of dry xylene are esterified as in Example 11 with 12 g. (0.1025 mol.) of diethylaminoethanol in the presence of 0.5 g. of p-toluenesulp'honic acid.
Distillation gives 17 g. of reddish-yellow viscous liquid distilling at 210-4212" C./1 mm. Hg. Yield 46%. The
redistilled product is pale yellow. Its constants are:
B.P./1.5 mm. Hg=215216 C. n =1.5745
Gravi-metric analysis.Calculated: C%, 75.60; H%, 7.44; N%, 3.83. Found: C%, 75,61, 75.30; H%, 7.08, 7.09; N%, 3.73, 3.70.
Example 19.2-alpha-(1-naphtlzyl)farylpr0pi0namid0- ethanol C19H19NO3. (M=309.34.
constants:
M.P.=122123 C. (heating stage).
11 Acetyl number.-Calculated: 181. Found: 181. Analysis.Calculated: C%, 73.77; H%, 6.19; N%, 4.52. Found: C%, 73.59; H%, 6.11; N%, 4.62.
Example 20.Alpha-(1-naphthyl) tetrahydrofurylpropionic acid C H O (M=270.31.)
65 g. (0.259 mol.) of alpha-(l-naphthyl)tetrahydrofurylpropionitrile are hydrolysed as in Example 14. After the usual treatment of the crude reaction product, an oil separates, which rapidly solidifies in the refrigerator (31.5 g.). The mother liquors are extracted with benzene and the extract is distilled. There are thus recovered 15 g. of viscous product distilling at 217218 C./ 1.5 mm. Hg. The total yield is 66.5%.
The preceding distillate is taken up in 25 cc. of ethyl acetate, and white crystals are formed on the addition of hexane. After three recrystallisations, the product takes the form of white crystals having a melting point of 135 C. (heating stage). 7
Acid number.Calculated: 207. Found: 207.
Gravimetrz'c analysis.-Calculated: C%, 75.53; H%, 6.71. Found: C%, 75.57; H%, 6.62.
The sodium salt has a melting point of 250-25 1 C. (capillary tube).
Example 21 .Alpha-(1-naphthyl) tetrahydrofurylpropionamide C H NO (M=269.32.)
C II-CONHB L H2 15.5 g. (0.0617 mol.) of alpha-(1-naphthyl)tetrahydrofurylpropionitrile are hydrolysed as in Example 15. After the usual treatment and evaporation of the extraction solvent (benzene), there remain 12.5 g. (yield 75%) of a crystalline mass.
After two recrystallisations from ethyl acetate, the product has the following constants:
M.P.=153-153.5 C.
Gravimetric analysis.Calculated: C%, 75.83; H%, 7.11; N%, 5.20. Found: C%, 75.62; H%, 7.14; N%, 5.14.
Example 22.Methyl alpha-(l-naphthyl)tetrahydrofurylprapionate o 1.1- 00cm U 22 g. (0.0812 mol.) of alpha-(1-naphthyl)tetrahydrofurylpropionic acid are esterified as in Example 9. There are obtained 17.5 g. of pale yellow viscous liquid (yield 75.5%). The redistilled product has a boiling point of 157-158 C./0.36 mm. Hg.
Saponification number.Calculated: 196. Found: 200.
Example 23.--Ne0pentyl alpha-(1 -naplzthyl)tetrahydrofurylpropionale 27 (0.1 mol.) of alpha-(l-naphthyl)tetrahydrofurylpropionic acid, prepared as described in Example 20, are esterified with neopentyl alcohol. Distillation gives 20 g. (yield about 59%) of viscous yellow liquid distilling at 182-185 C./1 mm. Hg.
The redistilled product has the following constants:
B.P./1 mm. Hg=182185 C.
Saponification number.-Calculated: 164.
Example 24.N-diethylaminoethyl alplza-(I-naphtl1yl)- tetrahydrofurylpropionate OH-C OOCHzC (CH3):
164. Found:
o H0 0 0' omommcgum 1.4.
27 g. (0.1 mol.) of alpha-(l-naphthyl) tetrahydrofurylpropionic acid are esterified in the manner described in Examples 11 and 12 with 12 g. (0.1 mol.) of diet-hylaminoethanol. There are obtained 19 g. (yield 51.5%) dark yellow oil distilling at 191194 C./ 0.5 mm. Hg.
The redistilled product, which has a honey-yellow color, has a melting point of 191 C./0.36 mm. Hg.
Gravimetric analysis-Calculated: C%, 74.79; H%, 8.46; N%, 3.79. Found: C%,'74.86, 74.57; H%, 8.34, 8.51; N%, 3.98, 3.92.
Example 25.--Alpha (1-naphthyl)delta tetrahydrofurylvaleric acid L /'0 11-0 0 OH h (01 2)::
13 Example 26.Diethylaminoethyl alpha-(1 -naphthyl)- delta-retrahydrofurylvalerate 29.8 g. (0.1 mol.) of alpha-(l-naphthyDtetrahydrofurylvaleric acid, prepared as described in Example 22, are esterified with diethylaminoethanol 'by the procedure described in Example 11.
Distillation gives 20 g. (yield 50.5%) of brownishyellow viscous liquid distilling at 216 C./0.7 mm. Hg and at 218-219 C./0.85 mm. Hg.
The redistilled product has the following constants:
Analysis.--Calculated: C%, 75.53; H%, 8.87; N%, 3.52. Found: C%, 75.33; H%, 8.63; N%, 3.45.
Example 27.--Beta-(1-naphthyl) beta-tetralzydrfurylisobutyric acid B.P./1 mm. Hg= 2l2 C. Acid number.-Calculated: 197. Found: 194.
Analysis.Calculated: C%, 76.05; H%, 7.09. Found: C%, 76.76, 76.72; H%, 6.60, 6.66.
Example 28.--(1-naphthyl) hexen-a eltal-oic acid C R O (M=240.29.)
67 g. (0.3 mol.) of alpha-(l-naphthyl)hexen-de1ta-4- oic nitrile are hydrolysed as in Example 14. Distillation of the product gives 41 g. of pale yellow viscous liquid. After distillation, the product has the following constants:
B.P./0.7 mm. Hg: 167 C. B.P./0.8 mm. Hg: 168 C. Acid number.-Calculated: 233. Found: 234.
Grauimetric analysis.Calculated: C%, 80.00; H%,'
6.71. Found: C%, 80.13; H%, 6.75.
Example 29.Alpha-(1-naphthyl) hexen-delfa-4-0ic amide C H NO. (M='239.30.)
CH-OONH2 CH3CH=CHCI I2 22 g. (0.1 mol.) of alpha-(l-naphthyl)hexen-delta-4- oic nitrile are hydrolysed by the procedure of Example 15. There are obtained 21 g. of yellow product (yield 87.7%). After four recrystallisations from ethyl acetate, the product has a melting point of 1121-122" C. It sublimates in the neighbourhood of this temperature.
Gravz'metric analysis.Calculated: C%, 80.30; H%, 7.16; N%, 5.85. Found: C%, 80.43; H%, 7.30; N%, 6.03.
, Example 30.Methyl alpha-(I-naplztlzyl)hexen-delta- 24 g. (0.1 mol.) of alpha-(l-naphthyl)hexen-delta-4- oic acid, prepared as described in Example 28, are esterified with methyl alcohol by the procedure of Example 9.
Distillation gives 19 g. (yield of viscous yellow liquid distilling at 131-134 C./1 mm. Hg.
The redistilled product has the following constants:
Saponification number.Calculated: 224. Found: 224.
Example 31.--Dietl1ylamin0ethyl alpha-(1 -naphthyl) hexen-delta-4-0ate 24 g. (0.1 mol.) of alpha-(l-naphthyl)hexen delta-4-oic acid are e-sterified with d'iethylaminoethyl alcohol by the procedure described in Example 11.
' Distillation gives 15 g. (yield 44%) of honey-yellow viscous liquid distilling at 20 5-207 C./ 3 mm. Hg.
The pale yellow redistilled product has the following constants:'
B.P./2 mm. Hg: 197 C.
. Analysis.Calculated: C%, 77.85; H%, 8.61; N%, I
4.12. Found: C%, 78.10, 78.28; H%, 8.27, 8.24; N%, 3.98, 3.95.
This compound may be solubilised by salification with an acid, more especially hydrochloric acid. It can be directly obtained in the form of its chloride by heating the starting acid with beta-chloroethyl-N-diethylamine in isopropanol.
1 Example 32.A. lpha-(1-napl1thyl) hexen-deltal-oic I ydrazide CIGHIBNZO.
25.5 g. (0.1 mol.) of methyl alpha-(1-naphthyl)hexendelta-4-oate, the preparation of which has been described in the foregoing Example 30, are heated under reflux for 4 /2 hours with 20.4 g. (0.4 mol.) of 98% hydrazine hydrate, in solution in 45 cc. of isopropyl alcohol '(the mixture is heterogeneous in the cold) in the presence of 0.4 cc. of acetic acid.
When the reaction is complete, the volatile products are driven oil in vacuo. The desired product is deposited in the form of a white crystalline mass, which is dried in the air. There are obtained 23.5 g. (yield 92.5%) of white product. After three recrystallisation-s from ethyl acetate, the product has the following constants:
M.P.=125-127 C. (heating stage), with sublimation starting at 100 C.
Analysis.Calculated: C%, 75.58; H%, 7.13; N%, 11.03. Found: C%, 75.81; H%, 7.24; N%, 10.91.
Example 33.Alpha-(1-naphthyl)penten-delta-4-0ic acid Example 34.Diethylaminoethyl ester of alpha-(1 -naphthyl)penten-delta-4-0ic acid Empirical formula C21H27NO2. M=325.42.) Developed formula:
(Molecular mass:
+HCOO(CH2)2N CH2CH=CH2 C2H5 '23 g. (0.1 mol.) of alpha-(1-naphthyl)penten-delta- 4-oic acid, in solution in 230 cc. of isopropanol and 14 g. (0.104 mol.) of beta-chloroethyl-N-diethylamine are heated under reflux for 8 /2 hours. After evaporation of the isopropanol in vacuo on the Water bath, the syrupy residue is taken up in a potassium carbonate solution and the organic product is separated by extraction with ether. Distillation gives 23 g. of a pale yellow viscous liquid distilling under 4 mm. Hg at 194-195 C.
The redistilled product has the following physical constants:
B.P./1 mm. Hg=148149 C.
Density: d =1.O205
Refractive index: :1555
Gravimetric analysis.Calculated: C%, 77.76; H%,
16 8.08; N%, 4.31. Found: 0%; 77.50; H%, 8.04; N%, 4.50.
Example 35.-Dimethylaminoethyl ester of alpha-(lnaphlhyl)penten-delta-4-oic acid Empirical formula c,.,'H No (M=297.37.)
I CH3 0 H-COO 2) 2 C Hz-C H=C Ha C H;
We claim: Y 1. A compound of the formula CH-C O OH R2( 2)n in which n, is an odd number at most equal to 3, R is a member of the group consisting of the l-naphthyl and l-naphthylmethyl radicals, and R is a member of the group consisting of the furyl and tetrahydrofuryl radicals andwhen n denotes the number 1 and R the naphthyl radical-the vinyl and l-propenyl radicals. 2. A sodium salt of a compound of the formula R1 \OHCO OH 2( 2)n in which n is an odd number at most equal to 3,
R is a member of the group consisting of the l-naphthyl .and l-naphthylmethyl radicals, and R is a member of the group consisting of the furyl and tetrahydrofuryl radicals and-when n denotes the number 1 and R the naphthyl radical-the vinyl and l-propenyl radicals. 3. Beta-(l-naphthyl) beta'-furylisobutyric acid.
4. Alpha-(l-naphthyl methyl) delta-tetrahydrofuryl valeric acid.
5. Alpha-(l-naphthyl)-beta-furylpropionic acid.
6. Alpha (l-naphthyl)-beta-tetrahydrofurylpropionic acid.
7. Alpha (1 naphthyl)-delta-tetrahydrofuryl valeric acid.
8. Beta (1 naphthyl) beta'-tetrahydrofurylisobutyric acid.
9. Alpha-(l-naphthyl) delt-a-4-hexenoic acid.
10. Alpha-(l-naphthyl) delta-4-pentenoic acid.
11. Process for the production of a compound according to claim 1, which comprises hydrolysing under reflux, for at least 10 hours, an alpha-substituted nitrile of the formula K CHCN mom).
12. An ester of a compound according to claim-1 of the formula CHOOORa RKCHZM in which n, R and R have the same meanings as in claim 1 and R denotes a member of the group consisting of the alkyl containing at most five carbon atoms and dilower alkylaminoethyl radicals.
13. The methyl ester of the acid according to claim 3.
14. Diethylaminoethyl beta-(l-naphthyl) beta'-furylisobutyrate.
15. The methyl ester of the acid according to claim 4.
16. The methyl ester of the acid according to claim 5.
17. Diethyl-aminoet-hyl alpha-(l-naphthyl) bet'a-furylpropionate. i
18. The methyl ester of the acid according to claim 6.
19. Diethylaminoethyl alpha-'(l-naphthyl) beta-tetrahydrofurylpr-opionate.
20. D'iethylaminoethyl alpha-(l-naphthyl) delta-tetrahydrofurylvalerate.
21. The methyl ester of the acid according to claim 9.
22. Diethylaminoethyl alpha-'(1-naphthyl)delta-4-hexenoate.
23. Diet-hylaminoethyl alpha-(1-naphthyl)delta-4?pentenoate.
18 24. Neopentyl beta-(l-naphthyl)-beta'-fnrylisobutyrate. 25. Neopentyl alpha (1 naphthyl) beta-furylpropionate.
26. Neopentyl alpha-(1-naphthyl)-beta-tetrahydrofury1- propion-ate.
References Cited by the Examiner OTHER REFERENCES Mofiett et al., J. Am. Ph. A., Sci. Ed., vol. 42, 1953, pp. 720-721.
Sidgwick, Organic Chemistry of Nitrogen (1937), pages 312-13.
HENRY R. JILES, Acting Primary Examiner.
FRANK CACCIAPAGLIA, JR., ANNA P. FAGELSON,
Assistant Examiners.

Claims (2)

1. A COMPOUND OF THE FORMULA
12. AN ESTER OF A COMPOUND ACCORDING TO CLAIM 1 OF THE FORMULA
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US3334105A (en) * 1962-12-04 1967-08-01 Lipha Carboxylic acids substituted in the alpha-position by at least one aminoheterocyclic, and processes for the preparation thereof
US3445574A (en) * 1962-09-20 1969-05-20 Lipha Compositions and method for arresting spasms with the diethylaminoethyl ester of beta-(1-naphthyl)-beta'-tetrahydrofurylisobutyric acid
US3686307A (en) * 1969-02-07 1972-08-22 Standard Oil Co Conversion of nitriles to amides in the presence of alkaline catalysts
US3699151A (en) * 1967-08-14 1972-10-17 Bruno Cavalleri Pharmacologically active compounds
US3956323A (en) * 1972-01-03 1976-05-11 Hoffmann-La Roche Inc. Furan, benzofuran and tetrahydrofuran carboxylic acid esters
US4131615A (en) * 1976-08-06 1978-12-26 A. Wasserman S.P.A. Furan derivative for use as pharmaceutical product particularly for the treatment of rheumatic illnesses
US4224226A (en) * 1977-07-22 1980-09-23 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler Process for the production of N-substituted α-ketocarboxylic acid amides
US4652583A (en) * 1985-04-23 1987-03-24 Lipha, Lyonnaise Industrielle Pharmaceutique Use of naftidrofuryl to regenerate nerve fibers
US5329054A (en) * 1993-07-19 1994-07-12 Albemarle Corporation Decarboxylation process

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DE2003363A1 (en) 1969-01-30 1970-08-06 Ciba Geigy Process for dyeing and printing textiles with Kuepen- and reactive dyes

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US2834789A (en) * 1955-02-15 1958-05-13 Sadolin & Holmblad As Process of preparing lower lakyl 2, 3, 6-trihydroxybenzoate, and intermediates therefor
US2841594A (en) * 1958-07-01 Production of beta-furoic acids
US2843607A (en) * 1954-07-13 1958-07-15 Air Liquide Process of preparing esters
US2937117A (en) * 1953-06-19 1960-05-17 Chimie Atomistique Process for lowering high blood cholesterol levels
US3013023A (en) * 1959-02-27 1961-12-12 Ueno Ryuzo Process for the production of 5-nitrofuryl acrylic acid
US3057777A (en) * 1957-10-28 1962-10-09 Lilly Co Eli Method of reducing cholesterol level of the blood
US3060198A (en) * 1959-10-06 1962-10-23 Du Pont Tetracyanofuran

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US2841594A (en) * 1958-07-01 Production of beta-furoic acids
US2937117A (en) * 1953-06-19 1960-05-17 Chimie Atomistique Process for lowering high blood cholesterol levels
US2843607A (en) * 1954-07-13 1958-07-15 Air Liquide Process of preparing esters
US2834789A (en) * 1955-02-15 1958-05-13 Sadolin & Holmblad As Process of preparing lower lakyl 2, 3, 6-trihydroxybenzoate, and intermediates therefor
US3057777A (en) * 1957-10-28 1962-10-09 Lilly Co Eli Method of reducing cholesterol level of the blood
US3013023A (en) * 1959-02-27 1961-12-12 Ueno Ryuzo Process for the production of 5-nitrofuryl acrylic acid
US3060198A (en) * 1959-10-06 1962-10-23 Du Pont Tetracyanofuran

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3445574A (en) * 1962-09-20 1969-05-20 Lipha Compositions and method for arresting spasms with the diethylaminoethyl ester of beta-(1-naphthyl)-beta'-tetrahydrofurylisobutyric acid
US3334105A (en) * 1962-12-04 1967-08-01 Lipha Carboxylic acids substituted in the alpha-position by at least one aminoheterocyclic, and processes for the preparation thereof
US3699151A (en) * 1967-08-14 1972-10-17 Bruno Cavalleri Pharmacologically active compounds
US3686307A (en) * 1969-02-07 1972-08-22 Standard Oil Co Conversion of nitriles to amides in the presence of alkaline catalysts
US3956323A (en) * 1972-01-03 1976-05-11 Hoffmann-La Roche Inc. Furan, benzofuran and tetrahydrofuran carboxylic acid esters
US4131615A (en) * 1976-08-06 1978-12-26 A. Wasserman S.P.A. Furan derivative for use as pharmaceutical product particularly for the treatment of rheumatic illnesses
US4224226A (en) * 1977-07-22 1980-09-23 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler Process for the production of N-substituted α-ketocarboxylic acid amides
US4652583A (en) * 1985-04-23 1987-03-24 Lipha, Lyonnaise Industrielle Pharmaceutique Use of naftidrofuryl to regenerate nerve fibers
US5329054A (en) * 1993-07-19 1994-07-12 Albemarle Corporation Decarboxylation process

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