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Publication numberUS3564016 A
Publication typeGrant
Publication dateFeb 16, 1971
Filing dateMar 7, 1968
Priority dateMar 7, 1968
Publication numberUS 3564016 A, US 3564016A, US-A-3564016, US3564016 A, US3564016A
InventorsMichael Finizio, Kew Gardens, Karl Schoen
Original AssigneeEndo Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Method of decarbonylation
US 3564016 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent O US. Cl. 260-313.1 14 Claims ABSTRACT OF THE DISCLOSURE Diand tri-substituted pyrroles may be prepared by decarbonylating of the corresponding monoand di-carboxylic acid esters and monoand di-ketones by warming the esters of ketones with phosphoric acid.

RELATED APPLICATIONS This application is a continuation-in-part of our copending application Ser. No. 468,633 filed June 30, 1965, now abandoned.

FIELD OF THE INVENTION A novel method of decarbonylation carboxylic acid esters and ketones of pyrroles.

DESCRIPTION OF THE PRIOR ART Heretofore it has been known to decarboxylate the carboxylic acid esters of diand tri-substituted pyrroles particularly C-substituted pyrroles. However these methods have been substantially unfeasible for commercial application. In the principal method known to the art, the esters are hydrolyzed and decarboxylated to the tri-substituted pyrroles of Formula A by heating with strong sulfuric acid (3 vols. conc. H SO +1 vol. H O) on a steam 40 bath until the evolution of CO and the alcohol, e.g., C H OH when R is C H is completed. In general, this step takes from one to one and one-half hours. (See Formulas I to V1 in column -3).

Since the tri-substituted pyrroles and even more so di-substituted pyrroles, are sensitive to oxygen and hot acids, it is customary to carry out the hydrolysis and decarboxylation in an atmosphere of nitrogen or other inert gas. However, even under the most careful working conditions, the yields of the tri-substituted pyrroles in most cases are unsatisfactory. In general, they are less than 50% of theory. The pyrrole is always accompanied by a large amount of resinous by-products (black or red tars) which, in many cases, form the main product of the reaction.

We have found that the formation of these tars is due to the oxidation of the substituted pyrroles which occurs, even in the absence of oxygen, by the oxidative action of the hot sulfuric acid used in the process. Indeed, in working up the reaction mixtures, we have always observed a strong odor of S0 which results from the oxidative action of the H 80 the latter being reduced in the process.

We have now made the surprising discovery that the formation of the tars can be completely suppressed by eliminating the sulfuric acid and using phosphoric acid (concentration of 60% to 100%) in place thereof. The phosphoric acid of commerce has proved to be an excellent replacement for the sulfuric acid. The phosphoric acid is not only devoid of oxidative action but has the added advantages that the decarboxylation of the esters of Formulae IX and XI occurs at much lower temperatures and at a much faster rate than decarboxylations effected with sulfuric acid. Thus, when using sulfuric acid, temperatures of l20 C. and time intervals of one to one and one-half hours are required for completion of the reaction. In contrast thereto, decarboxylations with 85% phosphoric acid usually occur at 65-80 C.; and in most instances, are completed in ten to fifteen minutes.

It was found by Treibs and Schmidt [Ann. 577, (1952)] that carboxylic acid esters of pyrroles may be readily decarboxylated by the sequential steps of saponifying the esters by heating with aqueous sodium hydroxide for several hours followed by acidification with acetic acid. It will be readily seen that the process of the present invention which can be carried out in one step in a shorter period of time constitutes a far more commercially viable process than that disclosed by Treibs.

Moreover, attempts were made to carry out the decarboxylation of the carboxylic acid esters by heating the esters under reflux with glacial acetic acid. It was found that such treatment caused no change in the ester whatsoever and the decarboxylation was not observed.

SUMMARY OF THE INVENTION In the process of the present invention, pyrroles of Formula A are obtained in a high state of purity and in yields of over 80% of pure product in most cases, by the phosphoric acid decarbonylation of the corresponding pyrrole carboxylic acid esters of pyrrolyl ketones.

The compounds of the present invention have the general Formula A wherein R and R may be hydrogen, lower alkyl, lower alkenyl, cycloalkyl having a maximum of 8 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, and benzyl; R and R have the same values as R and R and may additionally be linked together to form an alicyclic ring having a maximum of 8 carbon atoms provided that in the monocyclic system one or two members of the group R R R and R are hydrogen, and in the bicyclic system, one member of the group R and R is hydrogen.

The prefix lower alk. designates a straight or branched carbon chain of 1-6 carbon atoms.

In the general process of the present invention, a pyrrole nucleus having one or two carboxylic acid ester moieties, or keto-moieties substituted therein is heated with concentrated aqueous phosphoric acid. It is to be understood that they may be one or two carboxylic acid moieties or keto-moieties attached to the pyrrole ring itself provided that these moieties are not attached to adjacent carbon atoms. Thus, in the monocyclic system, the carboxylic acid ester, or keto-moieties if monosubstituted may be at positions 2, 3, 4, or in the ring, where bisubstituted may be at positions 2 and 4, 2 and 5 or 3 and 5, whereas in the bicyclic system, only monosubstitution at positions 2 or 3 is feasible.

PREFERRED EMBODIMENTS In the preferred modification of the present invention, the starting material utilized is a pyrrole of the following wherein n is 0, l, 2 or 3, R is OR, or R and R R R or R are lower alkyl, for example methyl, ethyl, propyl, butyl, pentyl, or hexyl; lower alkenyl such as vinyl, allyl, butenyl or hexenyl; cycloalkyl, for example, cyclopentyl, cyclohexyl, or cyclobutyl, phenyl, halophenyl, such as fluorophenyl, bromophenyl or chlorophenyl; lower alkoxyphenyl, such as methoxy-, ethoxy-, propoxy-, or pentoxy-, phenyl or benzyl. R is lower alkyl such as methyl, ethyl, propyl or butyl; phenyl; or benzyl.

The starting material is taken up in approximately ten times its weight of the phosphoric acid. It is preferred to use strong aqueous phosphoric acid of between 60 and 100% by weight, 85 commercial phosphoric acid being the most suitable. The mixture is heated if desired, in an inert atmosphere, preferably nitrogen at between 55 and 120 C. most suitably between 65 and 80 C. for from 5 to 30 minutes preferably for from between 10 to minutes. Where the starting material is a ketone rather than an ester reaction temperatures of between 130 and 145 C. are preferred. The reaction is quenched by pouring the reaction mixture onto ice and neutralizing the resultant aqueous suspension with a base, preferably aqueous ammonia. The decarbonylated pyrrole is then isolated suitably by extracting the aqueous suspension with a suitable water-immiscible organic solvent such as ether. The desired product is then isolated from the solvent in the usual manner.

PREPARATION OF STARTING MATERIALS A general two-step method for the synthesis of the tri-substituted pyrroles of Formula A consists in the reductive condensation of and a-OXiInlnO keetone (VII) with a fi-keto-ester (VIII) which results in the formation of ester (IX) in accordance with the following reaction A similar method of synthesis (which leads to di-substituted pyrroles) consists in the reductive condensation of an u-oximino-B-ketoester (X) with a fi-keto-ester (VIII) with the dicarboxylic acid (XI) ester in accordance with the following reaction scheme:

In the foregoing reaction schemes, R and R have the significance above defined, and R designates, conveniently, a suitable alkyl group, preferably lower alkyl, e.g., methyl, ethyl, propyl, etc., or a phenyl or benzyl group.

This method is also applicable to the formation of compounds of Formulae V and VI. Specific reference is made to the disclosure of tetrahydroindoles and cyclopentenopyrroles at Chem. Abs., vol. 29, col. 4356 and vol. 30, col. 8208 and Also, to the preparation of the corresponding cycloheptenopyrroles at vol. 54, col. 10898 STATEMENT OF UTILITY The compounds prepared by the process of the present invention may be converted to the corresponding pyrrol- S-ylketones which are useful as muscle relaxants and sedatives and which may themselves be converted into the corresponding 2-aminoethylpyrrol-3-ylketones which are valuable as tranquilizers and anti-depressants. The processes for converting the compounds produced by the present invention into these desirable compounds of pharmaeodynamic activity as well as methods of using them are disclosed in the application of Karl Schoen and Irwin J. Pachter Ser. No. 403,387, now US. Pat. No. 3,410,857, filed Oct. 12, 1964, and the continuation application thereof Ser. No. 682,670 filed Nov. 13, 1967, now abandoned.

PREPARATION 1 5 -butyl-2,4-dimethyl pyrrole A mixture of 600 ml. of concentrated sulfuric acid and 200 ml. of water was heated on a steam bath in a nitrogen atmosphere; and 100 g. of ethyl 5-butyl-2,4-dimethylpyrrole-3-carboxylate added rapidly thereto with stirring. Heating was continued until the carbon dioxide formation ceased, which took about fifty minutes. The mixture was cooled, poured on ice, neutralized with sodium bicarbonate and the black oily residue taken up in ether. The ether solution was dried, the solvent removed and the residue distilled. The 5-butyl-2,4-dimethylpyrrole distilled at 105l14 C./17l9 mm. Yield: 30 g. (48% of theory).

PREPARATION 2 Diethyl 2,4-dimethylpyrrole-3,S-dicarboxylate 12 g. was refluxed in 100 ml. acetic acid for one hour, the solution poured on ice, the solid which separated filtered, washed with water and dried. There was recovered 11.5 g. of unchanged starting material, M.P. 134.

The following are examples in accordance with the method of this invention. The temperatures are centigrade.

EXAMPLE 1 5-butyl-2,4-dimethylpyrrole Ethyl S-butyl-2,4-dimethylpyrrol-3-carboxylate, 100 g., and 800 ml. of phosphoric acid were stirred and heated in a nitrogen atmosphere. Decarboxylation commenced at 65 and became quite vigorous at 75 Heating was continued for ten minutes at when the evolution of gas stopped. The mixture was cooled to room temperature, poured on 2 kg. of ice and neutralized with equal parts of ice and ammonia water. The 5-butyl-2,4- dimethylpyrrole separated as an almost colorless oil. It was taken up in ether, dried over magnesium sulfate, the solvent removed and the residue fractionated in vacuo; 11 mm 105407"; yield, 53 g. (82% of theory).

In accordance with the above procedure but starting with ethyl 5-butyl-3,4-dimethylpyrrole-2-carboxylate, and ethyl 4 methyl-3-cyclopentyl-5-propylpyrrole-Z-carboxylate, there is obtained 5-butyl-3,4-dimethylpyrrole and 4 methyl-3-cyclopentyl-5-propyl pyrrole.

EXAMPLE 2 -propyl-2,4-dimethylpyrrole Ethyl 5-propyl-2,4-dimethylpyrrole-3-carboxylate, '150 g., was decarboxylated in accordance with Preparation 1. 50 g. of the pyrrole, b mm 90 was obtained (51% of theory).

When the reaction was carried out in accordance with the method described in Example 1, 93 g. of the starting ester gave a yield of 55 g. of the pyrrole (90% of theory).

EXAMPLE 3 S-ethyl-2,4-dimethylpyrrole Ethyl 5-ethyl-2,4-dimethylpyrrole-3-carboxylate, 100 g. and 800 ml. of 85% phosphoric acid were heated and stirred under nitrogen at 65-80". Decarboxylation was completed in ten minutes. On working up the reaction mixture there was obtained 50 g. of 5-ethyl-2,4-dimethylpyrrole (80% of theory) 12 mm 91-92.

EXAMPLE 4 4-butyl 2,5-dimethylpyrrole This tri-substituted pyrrole was prepared in accordance with the method of Example 1 from ethyl 4-butyl-2,5-dimethyl-pyrrole-3-carboxylate. Decarboxylation began at 77 and was completed in ten minutes at 82. From 190 g. of the starting ester, a yield of 100 g. of the pyrrole (78% of theory) was obtained. b 103".

EXAMPLE 5 4-propyl-2,S-dimethylpyrrole This tri-substituted pyrrole was prepared in accordance with the method described in Example 1 from ethyl 4- propyl-2,5-dimethylpyrrole 3 carboxylate. Decarboxylation began at 81 and was completed at 84. From 125 g. of the starting ester, a yield of 66 g. of the tri-substituted pyrrole (82% of theory) was obtained.

EXAMPLE 6 2-benzyl-4,S-dimethylpyrrole This tri-substituted pyrrole was prepared in accordance with the method of Example 1 from methyl 2-benzyl-4,5- dimethylpyrrole-3-carboxylate (M.P. l151l5.5). Since the solid ester was insoluble in the phosphoric acid, the mixture had to be heated to 110-115 whereupon the ester melted and decarboxylation proceeded rapidly. After working up the reaction mixture, a solid material was obtained which after repeated crystallations from 75% ethanol had a melting point of 51-51.5. From 22.6 g. of the starting ester, a yield of 17 g. (99% of theory) was obtained.

EXAMPLE 7 5-propyl-2,4-dimethylpyrrole Ethyl S-propyl-2,4-dimethylpyrrole-3-carboxylate 100 g. was suspended in 800 ml. of 60% phosphoric acid and heated with stirring in a nitrogen atmosphere. The ester liquefied at 103 and at the same time was decarboxylated. Heating was continued at 103-108 for 30 minutes when the evolution of carbon dioxide ceased. The solution was poured on ice, neutralized with ice cold ammonia water, the soil which separated taken up in ether, dried, and after evaporation of the solvent the residue distilled in vacuo; 55 g. of 5-propyl-2,4-dimethylpyrrole. b mm, 85-88 was obtained (84% of theory).

EXAMPLE 8 2,4-dimethyl-S-phenylpyrrole To a mixture of 85.8 g. of 1-oximino-1-pheny1-2-propanone and 68.9 g. ethyl acetoacetate in 400 ml. acetic acid was added 85 g. zinc dust in small portions with stirring. The mixture became hot and the temperature rose to 70. After addition of the zinc, the mixture was refluxed for 45 minutes, then poured on 2 kg. ice. The

6 solid which separated was filtered, washed with water; dried and extracted with cyclohexane. After evaporating the solvent, 93 g. ethyl 2,4-dimethyl-5-phenylpyrro1e-3- carboxylate M.P. 119 'was obtained.

The ester 4.5 g. was heated with 50 ml. of phosphoric acid with stirring. At about 115 the ester melted and decarboxylated within a few minutes. The mixture was quenched in 200 g. ice. A solid separated which was filtered, washed with water, dried and crystallized from hexane. 2,4-dimethyl-S-phenylpyrrole M.P. 74 was obtained; yield 3.2 g.=% of theory.

EXAMPLE 9 2,4-dimethylpyrrole The preparation of this pyrrole by decarboxylation of diethyl 2,4-dimethylpyrrole-3,5-dicarboxylate with hot sulfuric acid is described in the book: Die Chemie des Pyrrols, by H. Fischer and H. Orth (Leipzig 1934) vol. I, page 42. Using 200 g. of the ester they obtained 27 g. 2,4-dimethylpyrrole, a yield of 32% of theory.

Running the decarboxylation with phosphoric acid we have heated 195 g. ester with 1 liter 85 phosphoric acid with stirring in a nitrogen atmosphere. Decarboxylation began slowly at 80 but due to the high melting point of the ester the reaction proceeded rapidly only at -115 and was finished in 30 minutes. After pouring the solution on 3 kg. ice, neutralization with strong ammonia, ether extraction of the pyrrole, drying the ether solution with M SO and evaporation of the solvent, the 2,4-dimethylpyrrole was distilled in vacuo B.'P. 12 mm 50. 51.3 g. was obtained, a yield of 66% of theory.

EXAMPLE l0 3-methyl-4,5,6,7-tetrahydroindole Ethyl 3-methyl-4,5,6,7-tetrahydroindole 2 carboxylate (100 grams) and 800 ml. of 85% phosphoric acid is heated and stirred under nitrogen at 65 to 80 C. Decarboxylation is completed in 15 minutes. The mixture is cooled and poured onto 2 kg. of ice, neutralized with concentrated aqueous ammonia, the aqueous mixture extracted with ether, the ether dried over magnesium sulfate, filtered evaporated to yield 3methyl-4,5,6,7-tetrahydroindole.

In accordance with the above procedure, but starting with ethyl 3-methyl-4,5-cyclopenteno-pyrrole-2-carboxylate, ethyl 2-methyl-4,5-cyclopentenopyrrole-3 carboxylate and ethyl 2-methyl-4,5-cyclohepteno-pyrrole-3-carboxylate in place of ethyl 3-methyl-4,5,6,7-tetrahydroindol-2 carboxylate, there is obtained the corresponding 3-methyl- 4,S-cyclopenteno-pyrrole, Z-methyl 4,5 cyclopentenopyrrole and 2-methyl-4,S-cyclohepteno-pyrrole.

EXAMPLE l1 2,3,5-trimethylpyrrole 2,4,5-trimethylpyrrol-3-yl methyl ketone (62 g.) was dissolved with stirring in 600 mml. of 85% H PO and heated in a nitrogen atmosphere to 140 for 30 minutes. After cooling to 60 the solution was poured onto ice, neutralized with aqueous ammonia and the pyrrole extracted with four portions of 200 ml. ether. The combined ether solutions were dried over magnesium sulfate, the solvent evaporated, the residue distilled in vacuo yield 34 g. 2,3,5-trimethylpyrrole (76% of theory) B.P. 74-76.

EXAMPLE 12 3-butyl-2,5-dimethylpyrrole 4-butyl-2,5-dimethylpyrrole-3-yl methyl ketone 62 g.) was heated in 600 ml. 85% H PO for 30 minutes to under nitrogen and worked up as described in the preceding example. There was obtained 40 g. 3-butyl-2,5- dimethylpyrrole (83% of theory) B.P. 102-106.

It will be understood that the foregoing description of the invention and examples set forth, are merely illustrative of the principles thereof. Accordingly, the appended claims are to be construed as defining the invention within the full spirit and scope thereof.

We claim:

1. A method of preparing a C-substituted pyrrole of the following Formula A R4R3 til. H

wherein R R R and R may each be hydrogen, lower alkyl having from 1 to 6 carbon atoms, lower alkenyl having from 2 to 6 carbon atoms, cycloalkyl having from 4 to 8 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl having from 1 to 6 carbon atoms, and benzyl, and R and R may additionally be linked together to form an alicyclic ring having from 5 to 7 carbon atoms, provided that when Formula A is monocyclic, one or two members of the Group R R R and R are hydrogen, and when Formula A is bicyclic R or R is hydrogen,

which comprises heating a carbonyl compound of the following Formula B with phosphoric acid:

- Rall i I N R2 H Formula A Formula B wherein R R R and R may each be selected from the same groups from which R R R and R are selected, and in which one or two non-adjacent moieties selected from the group consisting of R R R and R are i C-R wherein R is R or OR in which R is alkyl having from 1 to 4 carbon atoms, phenyl or benzyl; neutralizing the reaction mixture; and isolating the pyrrole of the foregoing Formula A therefrom.

2. Method of claim 1, wherein the phosphoric acid has a concentration of to 3. Method of claim 1, wherein the carbonyl compound is ethyl 5-butyl-2,4-dimethylpyrrol-3-carboxylate.

4. Method of claim 1, wherein the carbonyl compound is ethyl S-ethyl-2,4-dimethylpyrrole-3-carboxylate.

5. Method of claim 1, wherein the carbonyl compound is ethyl 4-butyl-2,5-dimethylpyrrole-3-carboxylate.

6. Method of claim 1, wherein the carbonyl compound is methyl 2-benzyl-4,5-dimethylpyrrole-3-carboxylate.

7. Method of claim 1, wherein the carbonyl compound is propyl S-propyl-2,4-dimethylpyrrole-3-carboxylate.

8. Method of claim 1, wherein the carbonyl compound is ethyl 2,4-dimethyl-5-phenylpyrrole-3-carboxylate.

9. Method of claim 1, wherein the carbonyl compound is diethyl 2,4-dimethylpyrrole-3,S-dicarboxylate.

10, Method of claim 1, wherein the carbonyl compound is methyl 2,4,5-trimethylpyrrol-3-yl ketone.

11. Method of claim 1, wherein the carbonyl compound is 4-butyl-2,5-dimethylpyrrol-3-yl methyl ketone.

12. The method of claim 1, wherein the decarbonylation is carried out at temperatures of from 55 to 145 C.

13. The method of claim 1, wherein the carbonyl compound of Formula A is an ester and in which the resulting decarboxylation is carried out at temperatures of from 55 to C.

14. The method of claim 1, wherein the carbonyl compound of Formula A is a ketone and in which the resulting decarbonylation is carried out at temperatures of from to C.

References Cited UNITED STATES PATENTS 3,428,648 2/1969 Umio et al 260-3131 ALEX MAZEL, Primary Examiner I. A. NARCAVAGE, Assistant Examiner US. Cl. X.R. 260319.1, 326.5

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, Dated l6.

Inventor(s) Karl sChOen t a1 It is certified that error appears in the above-identified paten and that said Letters Patent are hereby corrected as shown below: Column 1, line 29, "decarbonylation" should read decarbm 1 i Column 1, line 16, for "carbonyla'ting" rea carbonylation line 9, for "esters of ketones" read esters or ketones Colum line 50, for "they" read there Column 3, line 55 for "and" r an line 55, for "keetone" read ketone line 68, for the dicarboxylic acid (XI) ester" read which results in the formati the dloarboxylic acid ester (XI) Column line 1, after "schemes read R, Column 5, line 63, for "soil" read oil Colu line 45, for "cyclopenteno-pyrrole" read cyclopentenopyrrole 1 for "cyclohepteno-pyrrole" read cycloheptenopyrrole line 50, f "cyclopenteno-pyrrole" read cyclopentenopyrrole line 51, for "cyclohepteno-pyrrole" read cycloheptenopyrrole Signed and sealed this 7th day of September 1971 (SEAL) Attest:

EDWARD M.FLET 3 ROBERT GOTTSCHALK Attesting Officer Acting Commissioner of Pa

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US4318917 *May 14, 1981Mar 9, 1982E. I. Du Pont De Nemours And CompanyAntiinflammatory 2,3-diaryl-5-[2,2,2-trifluoro-1-(trifluoromethyl]ethyl-1H-pyrroles
US4335136 *Mar 4, 1981Jun 15, 1982E. I. Du Pont De Nemours And CompanyAnti-inflammatory 4,5-diaryl-α-(polyfluoroalkyl)-1H-pyrrole-2-methanamines
US4511576 *Aug 10, 1982Apr 16, 1985Pfizer Inc.Antidiabetic pyrrolecarboxylic acids
US6573293Feb 15, 2001Jun 3, 2003Sugen, Inc.Pyrrole substituted 2-indolinone protein kinase inhibitors
US6642232Oct 10, 2002Nov 4, 2003Sugen, Inc.3-[4-Substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2- indolinone derivatives as kinase inhibitors
US6653308Feb 15, 2002Nov 25, 2003Sugen, Inc.3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
US7125905Jan 4, 2005Oct 24, 2006Agouron Pharmaceuticals, Inc.Pyrrole substituted 2-indolinone protein kinase inhibitors
US7179910Sep 8, 2003Feb 20, 2007Agouron Pharmaceuticals, Inc.3-(4-amidopyrrol-2-ylmethlidene)-2-indolinone derivatives as protein kinase inhibitors
US7256189Aug 28, 2006Aug 14, 2007Sugen, Inc.3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone der derivatives as protein kinase inhibitors
US7572924Sep 6, 2006Aug 11, 2009Sugen, Inc.Pyrrole substituted 2-indolinone protein kinase inhibitors
US7582756Jul 18, 2007Sep 1, 2009Sugen, Inc.3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors
Classifications
U.S. Classification548/560, 548/540, 548/539, 548/516, 548/536, 548/564, 548/531
International ClassificationC07D209/08
Cooperative ClassificationC07D209/08
European ClassificationC07D209/08
Legal Events
DateCodeEventDescription
Nov 22, 1982ASAssignment
Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, 1007 MARKET S
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ENDO LABORATORIES, INC., A CORP. OF DEL.;REEL/FRAME:004063/0107
Effective date: 19821110