US2625562A - N-ketoalkyl-p-aminobenzoates - Google Patents

Description

i atented Jan. 13, 195 3 2,625,562 N-KETOALKYL-p-AMINOBENZOATES.

David I. Weisblat, Barney J. Magerlein, and

Stanley T. Rolfson, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich a corporation of Michigan No Drawing. Application July 31, 1948,

Serial No. 41,889

15. Claims. (Cl. 260-470) This invention relates to N-(ketopropyD-paminobenzoate compounds, particularly to such compounds wherein the ketopropyl group is a 2-ketopropyl group having a substituent on the third carbon atom thereof, and to a method use- *ful in their preparation.

" The N-(2-ketopropyl) -p-aminobenzoate compounds of the invention have the generic formula I a-onzooOnt-p000 Nncnomongoommn' wherein R is from the group consisting of hydrogen and the alkyl radicals, n is from the group consisting of zero and the positive integers 1 to 7, inclusive, Z is from the group consisting of hydrogen and the arylsulfonyl radicals and R is from the group consisting of a halogen and the hydroxy, alkoxy, aryloxy, aralkoxy and acyloxy radicals. The term halogen as used herein is limited to chlorine, bromine and iodine.

In the naming of compounds of the invention and of other compounds mentioned herein when both a glutamic acid residue and a p-aminobenzoic acid residue are included in the molecule, the nitrogen atom of the glutamic acid residue is, for convenience, herein referred to by the symbol N and the nitrogen atom of the p-aminoben zoic acid residue is referred to by the symbol N. In the structural formulae given herein and in the appended claims aromatic nuclei are represented by one or more simple hexagons. As indicated by the generic formula given, compounds containing more than oneglutamic acid or ester residue contemplatedby the invention are those wherein only the gamma-carboxyl groups are involved in the peptide linkages.

The N-(2-ketopropyl)-p-aminobenzoate compounds are useful as intermediates in the preparation of certain compounds referred to broadly in the art as folio acids. Thus, as described and claimed in a concurrently filed co-pending application, Serial No. 41,882, now U. S. Patent No. 2,558,711, diethyl N'-(N-(3-hydroxy-2-ketopropyl) p toluenesulfonyl p aminobenzoyl) glutamate, which can be prepared by the method of the present invention, can be condensed with 2,4,5-triamino-6-hydroxypyrimidine to form diethyl N (N-( (Z-amino--hydroxy-G-pteridyl) methyl) -p toluenesulfonyl p aminobenzoyl) glutamate. The latter compound, upon treatment with hydrogen bromide in an aliphatic acid medium, and in the presence of a bromine ac- 'ceptor to prevent bromination of the benzene nucleus of the aminobenzoic acid residue, according to the method described and claimed in a concurrently filed co-pending application, Serial No. 41,883, now U. S. Patent No. 2,562,222, and after subsequent hydrolysis of the ester groups, is converted to N'- (N- (2-amino-4-hydroxy-6-pteridyl) -methyl -p-aminobenzoyl) -glutamic a c i d (pteroylglutamic acid) generally recognized, when the glutamic acid residue has the same configuration as 1(-'..') -glutamic acid, as being identical with the "L. casez' factor or vitamin Bo from liver. When N (N-(3-hydroxy -2-ketopropyl) -p-aminobenzoyl) -glutamic acid is condensed with 2,4,5- triamino-6-hydroxypyrimidine, pteroylglutamic acid is formed directly without the necessity of splitting a sulfonyl radical from the product with hydrogen bromide or of hydrolyzing ester groups. In similar fashion, other N-(2-ketopropy1) -paminobenzoate compounds of the inventioncan be condensed with 2,4,5-triamino-6-hydroxypyrimidine to form th corresponding 2-amino-4- hydroxy-fi-pteridyl compounds of the folic acid type in the manner just described.

It should be mentioned that certain of the N-(2-ketopropyl) p aminobenzoate compounds wherein R of the formula given is an acyloxy group having a plurality of carbon atoms, e. g. certain of the N-(3-acy1oxy-2-hydroxypropyl)-paminobenzoate compounds, often do not condense as smoothly with 2,4,5-triamino-6-hydroxypyrimidine as does the formoxy and the non-acyloxy N (2-ketopropyl)-p-aminobenzoate compounds described herein and for this reason they can with advantage be hydrolyzed to the corresponding hydroxy compounds, 1. e. to the N-(3-hydroxy-2- ketopropyl) p aminobenzoate compounds, and the latter then condensed with 2,4,5-triamino-6- hydroxypyrimidine in the manner mentioned when such condensation product is desired.

COOR

mCHgCHOHCH2TCO(NH( 011201120 o'),.o R

reaction mixture.

C O O R hologram-SEC O CHz-N-C CO(NHAHCHECHZOOLDR' III N-(3-halo-2-ketopropyl):p-aminobenzoate compound i alkali C O O B. HO-CHzC O CHz-NC C O (NHHCHzCHzC O),.O R Q N- (3-l1ydroxy-2-ketopropyl) -p-amlnobenzoate Icompoun'd [alkanol O O O R ac 1ox -ornooom-N- o o NricHomo H2 0), 0 R

N-(3-acyloxy-2-ketopropyl)-p-aminobenzoate compound Certain of the new N-(2-ketopropyl) -p-'aminobenzoate compounds of the invention, 1. e. the N- (3-R -2-ketopropyl) -p-aminobenzoate compounds having the formula (II) in the accompanying diagram wherein R and n have the values given previously and R' is from the group consisting of chlorine, bromine and iodine and thealkoxy, aryloxy, aralkoxy "and acyloxy radicals, can be'prepared by oxidizing an N-(3-R""-2- hydroxypropyl) p aminobenzoate compound having the formula (I) with 'chromic acid. The N- (3-R "-2-ketopropy1) -p-aminobenzoate ompound (II) is formed readily and in high yield and can be isolated without difficulty from the The reaction isgenerally carried out by subjecting the N-(3-R"'-2-hydroxypropyl) ep aminobenzoate compound to the action of chromic anhydride in an inert solvent. A mixture of an alkali metal dichromate and a mineral acid, such as sulfuric acid, jean often be used in the place of chromic anhydride, if desired. Although glacial acetic acid is'the'preierred solvent,

"other suitable solvents can be used, such as acetone'and propionic or valeric acids. A small proportion, e.'g.'irom 5 to per cent or less, of water can often be included in the mixture, ii desired. A solution of the N-(3+R"-2-hydroxypropyl) -paminobenzoate compound (I) and of chromic anhydride in acetic acid can be prepared and allowed to stand'ior several hours at from about 0 to about 30C., or somewhat higher, or the N-(3-R"%2-hydroxypropyl) p amino-benzoate compound can be added gradually to a solution or chromic anhydride in acetic acid. Reaction usually occurssmoothly at ordinary room temperatures, or somewhat below, but the mixture can, in certain instances, be warmed gently, if desired.

The reaction is usually substantially complete in from one to several hours and the N-(3-R"'-2- ketopropyl) -p-aminobenzoate compound can be recovered by diluting the reaction mixture with water and extracting the diluted mixture with ethyl acetate, etheror other suitable solvent. The extract is dried after washing with water or dilute aqueous sodium bicarbonate, depending upon whether it contains carboxy or carboxylic ester groupspand the ether or other solvent then distilled. The N-(3-R"'-ketopropyl) -p-aminobenozate compound is thus obtained as a solid residue which is usually sufficiently pure for further use but which can, if desired, be purified 'N (2-ketopropyl) -p-aminobenz0ate compounds having the formula (VI) 0 o o R I R -omCQom-NH-Ooomnonomomc o ,0 R

usually without isolating the arylsulfonyl-containing compound from the acetic acid reaction mixture, ifdesired. The reaction is carried out conveniently by mixing the arylsulfonyl compound, hydrogen bromide and a bromine acceptor,

such as phenol, catechol or naphthol, in an anhydrous aliphatic acid medium, usually at ordinary room temperature. Several molar proportions of hydrogen bromide are'usually employed. After standing for a sufficient length of time, usually from a few minutes to afew hours,-the mixture can be poured into ether or petroleum naphtha and th hydrobrornide of the free amine recovered by filtering. Other convenient and apparent ways of recovering the-amine or itshydrobromide can be employed.

Many of the N (3 R' 2 lzetopropyl) paminobenzoate compounds "and the free amines obtained as just described are crystalline or amorphous, white or yellowish solids, which can be purified by crystallizing from a suitable solvent. Other of the compounds are oily in nature. They form crystalline semi-carbazones and other normal ketone derivatives.

Certain of the N (3 2 ketopropyl) p-aminobenzoate compounds, i. e the N-(S-halo- 2 ketopropyl) p --aminobenzoate compounds (III), and particularly the N (3 acyloxy --2- -l :etopropyl) p aminobenzoate compounds (V) and also the corresponding free amines, can be sponding N- 3-hydroxy 2eketopropyl) -p-aminobenzoate compound (IV) is preferably carried out by treating the halogen-containing compound with approximately one chemically equivalent proportion of an aqueous or alcoholic alkali, such as aqueous barium carbonate, dilute aqueous or alcoholic sodium hydroxide, or aqueous or alcoholic potassium carbonate. The reaction is carried out conveniently by stirring a mixture of the reactants at ordinary room temperature for from one to several'hours. Soluble alkalies should be added to the mixture at approximately the rate at which they are consumed.

The conversion of an N-(3-acyloxy-2-ketopropyl).-p-aminobenzoate compound (V) to an N (3 hydroxy 2 ketopropyl) p aminobenzoate compound (IV) .isaccomplished conveniently byester interchange using an .alkanol, preferably vusing'the same alkanol from which any carboxylic ester radicals. in the molecule are derived. 'The reactionis carried out by heating, usually byrefluxing, a solution of the acyloxyketo compound in an excess, e. g. in from about 5 to about 20 molarproportions or more, of all sanol. The inclusion of an ester interchange ketopropyl)-p-aminobenzoate compound (IV) or free amine remains as a crystalline or syrupy residue which is usually sufiiciently pure for further use. Purification can be efiected using Girards reagent P. or T. to yield the keto compounds in solid form.

As indicated by the generic formula (VII), N- (2-ketopropyl) -p-aminobenzoate compounds containing more than one glutamic acid or ester residue contemplated by the invention are those wherein only the gamma-carboxyl groups are involved in the peptide linkages, such as the residues derived from N-(p-aminobenzoyl) -gammaglutamylglutamic acid, N'-(p-aminobenzoyl)- gamma-glutamyl-gamma-glutamylglutamic acid, and the like. Preferred compounds of the invention are those wherein n represents the integer 1, i. e. those containing one glutamic acid or ester residue, and the invention will be described with particular reference thereto.

Compounds similar to, or identical with, those of the folic acid group made by using compounds of the invention as intermediates, such as pteroylglutamic acid and pteroyl-gamma-glutamylgamma-glutamylglutamic acid, which are of greatest value as measured by their biological activity against Lactcbaczllus casei or Streptococcus fecalis R, are those wherein the glutamic acid residues possess the same configuration as l(i) -glutamic acid. However, the invention also contemplates compounds having the dextro configuration as well as racemic mixtures.

N- (2-ketopropyl) -p-aminobenzoate compounds wherein Z of the generic formula (VII) represents an arylsulfonyl radical are of particular value because of the protection afiorded the aromatic amino group by the arylsulfonic group. Compounds having the amino group thus protected are often not subject to decomposition and the formation of by-products when employed as a reactant, e. g. when condensed with 2,4,5- triamino-G-hydroxypyrimidine, to nearly the same extent as are compounds in which the aro matic amino group is unprotected. Following the carrying out of a reaction using an N-(Z-ketopropyD-p-aminobenzoate compound containing such an arylsulfonylamino group, the 'arylsulfonyl radical can be split readily from the molecule formed, as mentioned previously, by treating the compound with hydrogen bromide in an aliphatic acid medium and in the presence of a bromine acceptor.

Although the invention is described in the case of arylsulfonyl compounds with particular reference to p-toluenesulfonyl compounds, it is understood that the invention contemplates compounds and intermediates containing other arylsulfonyl radicals, such as the o-toluenesulfonyl, benzenesulfonyl, and naphthalenesulfonyl radicals as well as many others. Arylsulfonylradicals having substituents, such as chlorine, bromine, or a nitro group, on the aromatic nucleus can also be used provided only that the substituent is non-reactive under thereaction conditions. The preferred arylsulfonylradical is the p-toluenesulfonyl radicalbecause the com pounds formed are generally well defined 'crystalline solids and because it has been found that higher yields of amines are often formed when splitting a 'p-toluenesulfonylamino compound than when splitting certain other arylsulfonyl derivatives of the same amino compound. It should be mentioned, furthermore, that the method involved in the present invention can be carried out and the corresponding final compounds prepared using starting compounds wherein the arylsulfonyl group is replaced by an alkylsulfonyl, aralkylsulfonyl or cycloalkylsulfonyl group such as the methanesulfonyl, alphatoluenesulfonyl or cyclohexylsulfonyl radical respectively.

Although benzoic acid ester or glutamic acid ester residues present in certain of the compounds of the invention can comprise an alkyl ester, such as the methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, amyl, lauryl, dodecyl and many other esters, the preferred ester is the ethyl ester due to matters of convenience and economy.

Although the invention is directed particularly, in case of esters of the glutamic acid residues, to alkyl esters, the process of the invention can also be carried out and corresponding compounds prepared using other esters, such as the phenyl, tolyl, xylyl, cyclohexyl, benzyl and many other aryl, aralkyl or cycloalkyl esters.

N (3 R"-2-hydroxypropyl) p-aminobenzoate compounds (I) which can be oxidized to the corresponding keto compounds by the method of the invention include compounds wherein, as mentioned previously, the symbol R" presents chlorine, bromine, iodine or the alkoxy, aryloxy, aralkoxy or acyloxy radicals. Alkoxy compounds which can be used include the methoxy, ethoxy, n-propoxy, iso-propoxy, amyloxy compounds and many others. Aryloxy compounds which can be used include the phenoxy, tolyloxy, naphthoxy compounds and many others. .Aralkoxy compounds which can be used include the phenylmethoxy, phenylethoxy, naphthlymethoxy, tolylethoxy compounds and many others. Cycloalkoxy compounds, such as the cyclohexoxy compounds, can also be used, if desired.

The N-(3 R 2 hydroxypropyD-p-aminobenzoate compounds which can be oxidized by the method of the invention can be prepared conveniently, as described and claimed in a concurrently filed co-pending application, Serial No. 41,884, by first reacting an epihalohydrin, i. e. epichlorohydrin, epibromohydrin or epiiodohydrin, with a p-aminobenzoate compound having the following formula (VIII) COOR' aryl-SOz :N- (3l1alo-2-hydroxypropyl)-p-aminobenzoate compound wherein Xrepresents chlorine, bromine oriodine.

7 The N (3-halo-2-hydroxypropyl)-p-aminoben@- zoate compound can then be treated with dilute alkali to remove hydrogen halide and form an N (2,3 epoxypropyD-p-aminobenzoate compound having the following formula (X) COOR aryl 02 N-(2,3epoxypropyl)-D-aminobenzoate compound The epoxy compound can then be-react'ed with ametal salt ofan alcohol or phenol or with a carboxylic acid to form an N-(3-alkoxy-2-hy droxypropyl)-p-aminobenzoate compound, an N (3 aryloxy-2-hydroxypropyl)p-aminobenzoate compound or an N-(3-acyloxy-2-hydroxypropyl) -p-aminoben'zoate compound, respectively. By using a metal salt-of an aralkanol an N-(3- aralkoxy 2 hydroxypropyl)-p-aminobenzoate compound is formed readily.

The paminobenzoate compounds (VIII) wherein n is an integer from the group 1 to '7, inclusive, can be obtained as described and claimed in a concurrently filed co-pending application, Serial No. 41,883. According to the method of the co-pending application, a paminobenzoate compound havin one glutamic acid residue in the molecule is prepared by reacting glutamic acid or an alkyl ester thereof with an arylsulfonyl-paminobenzoyl halide or with a p-nitrobenzoyl halide. The halides referred to in this connection are the chlorides and bromides. When a p-nitrobenzoyl halide is used an N'-(pnitrobenzoyl) -glutamic acid or ester is first obtained which, upon reduction, e. g. with hydrogen using platinum oxide as a catalylst, yields an N'- paminobenzoyl)-glutamic acid or ester. The

latter compound can be converted readily by means of an arylsulfonyl halide to an N-(arylsulfonyl-p-aminobenzoyl)-glutamic acid or ester. When an arylsulfonyl-p-aminobenzoyl halide is reacted with glutamic acid or its ester, an N-(aryl'sulionyl p aminobenzoyll-glutamic acid or ester is formed directly; Furthermore, N-(p-aminobenzoyl) -glutamic acid and the N'- (arylsulfonyl-p-aminobenzoyl)-glutamic acids can, if desired, be converted to the corresponding alkyl esters, e. g., by treatment with an alkanol and an esterification catalyst in known manner, or the esters can be hydrolyzed to the corresponding acids. In similar manner, other p-aminobenzoate compounds can be prepared having up to seven glutamic acid residues in the molecule by starting with the corresponding gammaglutamylglutamic acids or esters containing the requisite number of peptide linkages.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Eaample 1 .-Diethyl. N (p-nitrobenzoyl) -1 glutamate One houndred eleven grams of p-nitrobenzoyl chloride was added at about 0 C. over a period of about one hour to a solution of 95.8 grams of crud diethyl l(+) -glutamate hydrochloride and 80 milliliters of pyridine in 200 milliliters of benzone. The mixture was stirred for five hours, extracted first with dilute hydrochloric acid and then with aqueous sodium bicarbonate and the benzene removed under reduced pressure. The residue'icon'sisted ofllllgrams of a pasty; neutral fraction consisting largely of diethyl N'-(p-- nitro-benzoyl)-1-glutamate. After recrystallization from dilute ethanol, the ester melted at 93 to 95 C. It had a specific rotation of (a) =-18 in 95 per cent ethanol. The sodium bicarbonate extract upon acidification yielded 42 grams of p-nitrobenzoic acid.

Example 2.Diethyl N-(p-amz'nobenzoyl) -1- glutamate Crude diethyl N-(p-nitrobenzoyl) -1-glutamate prepared as in Example 1 was dissolved in ethanol and reduced with hydrogen under a pressureof about 40 pounds per square inch using platinum oxide as acatalyst. The mixture was then filtered to recover platinum and the ethanol evaporated under reduced pressure. There was thus obtained a 52 per cent yield of diethyl N-(paminobenzoyl) -l-glutamatemelting at to 138 C. Upon recrystallization from dilute ethanol, the ester melted at 140 to 141 C. and had a specific rotation (a) =-9.5 in 95 per cent ethanol.

Ana-1.: Calcd. for C16H2205N2: C, 59.6; H, 6.9; N, 8.7. Found: C, 59.6; H, 6.8; N, 9.0.

Example 3.Dzethyl N '-(p-toluenesuljo'nyl-paminobenzog/Z) -glutamatc Thirty and nine-tenths grams of p-toluenesulfonyl-p-aminobenzoyl chloride and 23.9 grams of diethyl1(+) -glutamate hydrochloride were dissolved in 300 millilitersof ethylene dichloride and the solution cooled to between 0 and 10 C. The cold solution was stirred vigorously and 22.3 grams of triethylamine in 72 milliliters of ethylene dichloride was added slowly over a period of about 20 minutes. The temperature of the mixture was held between 10 and 20 C. during the addition of the triethylamine and the mixture then allowed to stand at room temperature for one hour. The mixture was then washed successively with Water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate and finally with water. The colorless solution thus obtained was dried with anhydrous sodium sulfate and naphtha was added until the solution became opalescent. The mixture was then cooled to cause crystallization and filtered. The crystals, after drying, consisted of 36 grams of diethyl N-(ptoluenesulfonyl p aminobenzoyl) -l-glutamate meltin at 124 to 126 C.

Example 4.Diethyl N'-(p-toZuenesuZfonyZ-paminobenzoyl) -1 -glutamate A mixture of 407 grams of p-toluenesulfonyl-paminobenzoic acid and 3,450 milliliters of toluene was dried by distilling the mixture until 350 milliliters of distillate had been collected. A few drops of pyridine and 50 milliliters of thionyl chloride was then added to the dry toluene solution and the mixture stirred and refluxed for one-half hour. The solution was then cooled with agitation for two hours and the solid which precipitated was recovered by filtering and washing with toluene and then-with mixed hexanes and drying. There was thus obtained 387 grams ofp-toluenesulfonyl-p-aminobenzoyl chloride melting at 141 r0142" C.

A mixture of 48 grams of diethyl 1(-I) glutamate hydrochloride, 68 grams of p-toluenesulionyl-p-aminobenzoyl chloride, 19' grams of magnesium oxide, 250 milliliters of ethylene dichloride and 100 milliliters of water was stirred with coolingfor about e hours'. The mixture was filteredand the organic l'ayerwas separated from Example 5.--D2'ethyl N (N (3-chZoro-2-hydroxyprom Z) -p-toluenesulfonyl p aminobenaoyl) glutamate A mixture of 2.85 grams of diethyl N'-(ptoluenesulfonyl-p-'aminobenzoyl) -glutamate and 1.1 grams of epichlorohydrin was agitated at 135 C. Two drops of pyridine were added and agi-' tation at 135 C. was continued for five minutes. The excess epichlorohydrin was volatilized under reduced pressure. The residue which consisted of diethyl N'-(N- (3-chloro-2-hydroxypropyl) -ptoluenesulfonyl-p-aminobenzoyl) -glutamate was used in subsequent experiments without further purification.

Diethyl N (N (3-bromo-2-hydroxypropyl) -ptoluenesulfonyl-p aminobenzoyl) glutamate is prepared in similar fashion using epibromohydrin instead of epichlorohydrin.

Example 6.Ethyl N (3 -chloro 2 hydroxypropyl) -p-toluenesulfonyZ-p-aminobenzoate A mixture. of five grams of ethyl p-toluene.-, sulfonyl-p-aminobenzoate and 3.4 milliliters of epichlorohydrin was heatedat 135 C. and two drops of pyridine added. A vigorous action ensued and after five minutes the mixture was cooled, dissolved in 50 milliliters of ethanol and treated three times with'decolorizing carbon. The ethyl N-(3-chloro 2 hydroxypropyl) ptoluenesulfonyl p aminobenzoate which I remained upon volatilization of the ethanol and excess epichlorohydrin in vacuo was used in sub-- sequent reactions without further purification.

toluenesulfonyl-p-aminobenzoyl)-glutamate A mixture consisting of about 1.3 grams of diethyl N-(N-(3-chloro 2 hydroxypropyl) ptoluenesulfonyl-p-aminobenzoyl)-glutamate, 20 milliliters of methyl ethyl ketone, 0.17 gram of sodium bi-carbonate and 3 milliliters of water was refluxed for 410 minutes. The methyl ethyl ketone and water were then distilled in vacuo.

and the residue taken up in a mixture of ether and water containing a small proportion of alco'-" 1101. The ether layer was separated, washedwithcold dilute sulphuric acid and then with water and saturated sodium bicarbonate solution and finally twice with water and once with saturated sodium chloride solution. The washed solution was filtered through anhydrous sodium sulfate and the ether distilled in vacuo. The residue consisted of 0.98 gram of diethyl N'-(N(2,3-

epoxypropyl) -p toluenesulfonyl p aminoben Z yD-glutamate in the'form of a light brown 1' oil.- This is a yield cat-87.5 per cent of the theoretical amount.

The epoxypropyl compound obtained as just described and other epoxy compounds described in the examples were a$s l7 d $91 epoxy contentby the following procedure:

of absolute ethanol and 20 milliliters of a 0.1

to 0.15 normal standardized solution of hydrogen chloride in ether was added. After standing at room temperature for two hours, 30 to 10 milliliters of water was added to the mixture and the unreacted hydrogen chloride titrated with standardized alkali. The hydrogen chloride consumed was a measure of the amount of epoxy compound present. When analyzed in this manner, the crude epoxypropyl compound was shown to contain 49.4 per cent ofepoxy compound.

-When the above procedure was carried out using dilute ethanol instead of methyl ethyl ketone, there was obtained a per cent yield of product which upon assay for epoxy. content proved to be per cent-pure diethyl N-(N-(2,3- epoxypropyl) -p toluenesulfonyl p aminobenzoyD-glutamate.

When the procedure was carried out using anhydrous potassium carbonate and anhydrous methyl ethyl ketone there was obtained a 72 per cent yield of product which upon assay was found to contain 42.8 per cent of diethyl N'-(N-(2,3- epoxypropyl) -p toluenesulfonyl p aminobenzoyl) -glutamate.

Example 8.Ethyl N-(2,3-epomypropyl) W0 enesuZfonyZ-p-aminobenzoate In a manner similar to thatdescribed .in Example 7, ethyl N-i3-chloro-2-hydroxypropyl) -ptoluenesulfonyl-p-aminobenzoate was treated,

with anhydrous potassium carbonate in an hydrous methyl ethyl ketone. refluxed two hours. From the mixture there was isolated a product containing 33 'per cent of ethyl N- (2,3-epoxypropyl) -p-toluenesulfonyl-p-aminoa benzoate. r

When the process was repeated using sodium bicarbonate and dilute ethanol instead of anhydrous potassium carbonate and anhydrous meth-,

yl ethyl ketone and the mixtures refiuxed'for thirty minutes, the crude product obtained contained 46.4 per cent of ethyl N '(2,3 -epoxypr'opyl) p-toluenesu1ionyl-p-aminobenzcate.

Example 9.Ethyl N-(S-benao Jy- Z-hydrOryprO- pyl) -p-toluenesulfonyl-p emium)enzoate A mixture of 1.88 grams of ethyl N- (2,3-epoxy propyl)-p-toluenesulfonyl-p-arninobenzoate and 0.61 gram of benzoic acid was heated at C.

and one drop of pyridine added to the agitatedmelt. Heating was continued for about two hours, the melt becoming so thick after aboutfifteen minutes that it could no longer bestirred.

Upon cooling, the melt hardened to a glass-like solid. The. reaction mixture was dissolved in 20 milliliters of n-butanol and the solution diluted with mixed hexanes until it became opalescent. The solution was allowed to'stand at room temperature for three days and the crystals which separated were recovered by filtering, washing with a butanol-hexane mixture and drying in vacuo over sulfuric acid.- There was'thus ob.- tained 1.56 grams of ethyl N-(3-benzoxy-2-hydroxypropyl) -p-toluenesulfonyl-p-a.minobenzoate which after crystallizing. twice .frornn-butanol...

melted at l33.5 to'135.5 C. J

AnaL: and. for czfiuz' bmsi (3.62.765 n, 5.47. Found: C', 62.38; H, 5.28. I if Example 10.-Ethyl N- (3-formoary-2hildroxy prom/l) -p-toZuenesuZfomuZ-p-aminobenzoatev A mixture consisting of 11.1 grams of ethyl N- One gram of the epoxy compound was dissolved in five milliliters The mixture was.

(2,3 epoxypropyl) p toluenesulfonyli-p-aminobenzoate, 1.57 grams of formic acid and three drops of pyridine washeated at about 100 C. with stirring for two hours. The reaction mixture which. contained "ethyl N- (3-formoxy-2-hydroxypropyl)-p-toluenesulfonyl-p-aminobenzoate was oxidized without isolation of the ester directly to the corresponding 2-ketopropyl compound.

Example 11. N 3-metho:cy-2-hydrozcypropyl) p-toluenesuZfonyZ-p-aminobenzoic acid A mixture of 1.1 grams of ethyl N-(2,3epoxypropyl) p toluenesulfonyl-p-aminobenzoate, 122 milliliters of methanol and 0.34 gram of sodium methoxide was allowe'dtostand at room temperature for three hours and then refluxed for one hour. The mixture was then cooled, diluted with water and extracted with .10 milliliters of ether. Acidification of the extracted aqueous solution with hydrochloric acid gave a precipitate which, after filtering and drying, consisted of 0.94 gram of N (3-methoxy-2-hydroxypropyl) -p-toluenesulfonyl-p-aminobenzoic acid melting at 152 to 158 C. After recrystallization from methanol, the product melted at 157 to 159 C. It had a neutral equivalent of 360 as compared with the calculated value of 379.

Example 12. Diethyl N '-(N-(3-pheno:cy-2-hydrorypropyl) p-toluenesulfonyl-p-aminobenzoyl -1 -glutamate A mixture of 14.3 grams of diethyl N-(p-'toluenesulfonyl -'p -aminobenzoyl)-1g1utamate, 4.5 grams of 1,2-epoxy-3-phenoxypropane and 3 drops of pyridine was heated at 140 C. for 30 minutes and then cooled. The viscous mass was dissolved in benzene and the solution'washed with dilute mineral acidand then with water and dried over'sodium'sulfate. Volatilization of the benzene in vacuo gave 19.7 grams of diethyl N'- (N- 3-phenoxy-2-hydroxypropyl) -p-toluenesulfonyl-p-aminobenzoyl) -1-glutamate as a 'viscous, yellow oil.

Example i3.--'--Diethyl N'--(N-(3-chZcro-2-ketopropyl) p toluenesulfonyl-p-aminobenzoyl) glutamate The oily diethyl N-(N-(3-chloro-2-hydroxypropyl) -p -toluenesulfonyl-p-aminobenzoyl) -glutamate prepared from 2.85 grams of diethyl N'- (p toluenesulfonyl-p-aminobenzoyl) glutamate and an excess of epichlorohydrin' was dissolved in milliliters of glacial acetic acid. A mixture of 0.8 gram of chromic anhydride, 18 milliliters of glacial acetic acid and .l'milliliter of water was added slowly with stirring and cooling. The mixture was allowed to stand atroom temperature for twelve hours and the acetic acid then volatilized under reduced pressure. Theresidue was taken up in a'mixture of water and ether and the layers separated. The ether layer was washed with water untilthe washings were no longer green and then treated with charcoal and dried over anhydrous magnesium sulfate. Upon distillation of the ether, there remained diethyl N- (N (3 chloro-Z-ketoprop'yl) -p-toluenesulfonylp-aminobenzoyl) -glutamate as a pale yellow viscous'oil.

Example 1 4.--Ethyl N (3-chZoro-2-ketopropyl) p-toluenesuZfonyZ-p-aminobeneoate The crude oily ethyl N-(3-chloro-2-hydroxypropyl) -p-toluenesulfony1-p-aminobenzoate prepared from grams of ethyl 'p-toluenesulfonylp-aminobenzoate and an excess of epichlorohydrin was dissolved in150milliliters of acetic acid and "a mixture. of.12 grams'ofisodium dichromate, 10 milliliters of sulfuric acid, 45 milliliters of water and 60 milliliters of acetic acid was added over a period of three hours while maintaining the mixture at 5 C. .After stirring for an additional three hours, the oxidation mixture was diluted with" water and extracted with ether. The ethereal extract was washed with sodium bicarbonate and the ether distilled. The residue of ethyl N-(3-chloro-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoate crystallized from dilute ethanol on prolonged standing. The crystallized product weighed 5.5 gramsand after two crystallizations from dilute ethanol, melted at 106 to 113 C.

Anal: Calcd'for CiHzoOsNSCl: C, 55.7; 4.9; C1, 8.7. Found: 0, 56.0; H, 4.9; Cl, 6.1.

Example 15.--N-(3-chZ0ro-2-Icetopropyl) -p-toluenesuZfonyL-p-aminobenzoic acid A solution of one gram 'of-N-(3-chlorc-2-hydroxypropyl)-p-toluenesulfony1 -paminobenzoic acid in five'milliliters of acetic acid was added to a solution of'0.35 gram of chromic anhydride in a mixture of 10 milliliters of acetic acid and 0.2milliliter of water. The mixture was allowed to stand at room temperature overnight and the acetic acid then distilled in vacuo. The residue was taken up in ethyl acetate and the ethyl acetate solution washed with water and sodium bicarbonate and the ethyl acetate then distilled in vacuo. Crystallization of the residue from dilute ethanol gave 0.54 gram of crystalline N (3'- chloro-2-ketopropyl)-p-toluenesulfonylp-aminobenzoio acid melting at 154 to 158 C.

Example 16.-Ethyl N-(.i-beneoary-ZJaetopropyl) -p-toZuenesuZfonyZ-p-aminobenzoate A mixture of 1.8 grams of chromic anhydride, 5 milliliters of water and '50 milliliters of acetic acid was added at 18' C. over a period of one hour to asolution of ethyl N-(3-benzoxy-2- hydroxypropyl) p toluenesulfonyl p aminobenzoatein .250 milliliters of glacial acetic acid. The mixture was allowed to stand at room temperature for 24 hours and the acetic acid distilled in vacuo. The residue was taken up in a mixture of ethyl acetate and water and the layers separated. The ethyl acetate layer was washed with water to remove chromium salts and then with dilute aqueous sodium bicarbonate to remove acetic acid. The ethyl acetate was then distilled in vacuo and the residue Was crystallized from iso-propanol. There was thus obtained 4.74 grams of crystalline ethyl N-(3- benzoxy-2-ketopropyD-p toluenesulfonyl p aminobenzoate melting at 59 to 72 C. After repeated crystallization from iso-propanol, the product melted at 70 to 73 C. The semi-carbazone decomposed at to C. when heated slowly.

Anal: Calcd. for CzsHzsO'rNsi C, 63.0; H, 5.1. Found: C, 63.1; H, 5.2.

prom Z) p toluenesulfonyl p aminobenformoxy .2 -lhydroxypropyl) p toluenesul-i fonyl-paminobenzoyl) -g1utamate, 50 milliliters of acetic acid and 2.1 grams of chromic anhydride was heated for two hours at 24 to 30 C. The reaction mixture was then diluted with 500 milliliters of waterand extracted twice with.

benzene. The combined benezene extracts were washed three times with water and then dried over anhydrous magnesium sulfate. The mixture was filtered to remove magnesium sulfate and the benezene distilled in vacuo. There was thus obtained 6.8 grams of a, light yellow, oily residue of diethyl N'-(N-(3-formoxy-2-ketopropyl) p toluenesulfonyl p aminobenzoyD- glutamate.

Example 18.Ethyl N-(3'-formo:cy-2-lcetopropyl) p tolaenesalfonyl p aminobeneoate A mixture of 4.4 grams of chromic anhydride, 200 milliliters of acetic acid and the ethyl N (3 formoxy 2 hydroxypropyl) p toluenesulfonyl-p-aminobenzoate prepared from formic acid and 11.1 grams of ethyl N-(Z, 3- epoxypropyl) p toluenesulfonyl p aminobenzoate was stirred for one hour during which time the temperature rose to 30 C. The acetic acid was then distilled in vacuo and the residue triturated with ether. The mixture was centrifuged and the precipitate washed twice with ether. The combined ethereal solution and washings were washed successively with water, sodium bicarbonate solution and water and then dried with anhydrous magnesium sulfate. Evaporation of the ether left a residue of 7.91 grams of ethyl N-(3-formoxy-2-ketopropyl)-ptoluenesulfonyl-p-aminobenzoate as an oil having an index of refraction N :1.546.

Example 19.-Dz'ethyl N'-(N-(3-acetoa:y-2-Icetoglutamate A mixture was prepared consisting of 8.85 grams of diethyl N'-(N-(3-acetoxy-2-hydroxypropyl) p toluenesulfonyl p aminobenzoyD-glutamate having an index of refraction N :1.5396, 50 milliliters of glacial acetic acid and milliliters of propionic acid. The mixture was cooled to 0 C. and a solution of 1.65 grams of chromic anhydride in a mixture of 1.5 milliliters of water and 30 milliliters of glacial acetic acid was added slowly with stirring. The mixture was allowed to stand at about 5 C. for twelve hours and the solvent then distilled under reduced pressure. The residue was treated with a mixture of water and ether and the layers sep-- arated. The ether layer was washed twice with saturated sodium chloride solution then with saturated sodium bicarbonate solution and again with saturated sodium chloride solution. The washed ethereal solution was then dried with anhydrous magnesium sulfate and the ether distilled. There was thus obtained-6.1 grams of yellowish oily diethyl N'-(N- (3-acetoxy2-ketopropyl) -p toluenesulfonyl p 'aminobenzoyl) -glutamate.

Example 20.-N (S-methoay-Z-ketopropyl)-ptoluenesaljonyZ-p-aminobenzoic acid A solution of 0.33 gram of chromic anhydride in 0.5 milliliter of water and 3 milliliters of acetic acid was added to a solution of 0.95 gram of N-- (3 methoxy 2 hydroxypropyl) p toluenesulfonyl-p-aminobenzoic acid in milliliters of acetic acid. The mixture was allowed to stand overnight at room temperature and the acetic acid then distilled in vacuo. There was thus obtained a green syrup from which N-(3-methoxy- 2 ketopropyl) p toluenesulfonyl p aminobenzoic acid was isolated. I

:14 Example 21.-Diethyl N (N (3-phenoay-2 -ketoprom l) -p-aminobenzoyl) -1 -glatamate A solution of 6.2 grams of chromic oxide in 25 milliliters of water was added over a period of ten minutes and at a temperature of about 3 C. to a solution of diethyl N -(N-(3-phenoxy-2-hy droxypropyl) -p-amin'obenzoyl) -1-glutamate in a mixture of 215 milliliters of acetic acid and 60 milliliters of propionic acid. The mixture was allowed to stand at about 3 C. for twenty hours and then poured into water and the aqueous mixture extracted with benzene. The layers were separated and the benzene layer was washed several times with water and dried over anhydrous sodium sulfate. Benzene was distilled from the dried solution in vacuo after which there remained 17.5 grams of diethyl N'-(N-(3-phenoxy- 2 ketopropyl) -p-aminobenzoyl) -1-glutamate as a brown resinous oil having an index of refraction N =1.545.

Example 22.--Diethyl N -(N-(3-metho.ry-2-ketopropyl) -p-tolaenesalfonyl p aminobeneoyl) glutamate A solution of 0.536 gram of chromic oxide in about 5 milliliters of water was added slowly at 20 C. and with stirring to a solution of 2 grams of diethyl N '-(N (3-methoxy-2-hydroxypropyl) p-toluenesultonyl-p-aminobenzoyl) -1-glutamate in 19 milliliters of glacial acetic acid. The mixture was allowed to stand for three and one-half hours and was then poured into water and extracted with benzene. The benzene layer was washed thoroughly with water and the benzene vaporized in vacuo. There was thus obtained a residue consisting of 1.3 grams of diethyl N -(N- (3-meth-oxy-2-ketopropyl) -p-toluenesulfonyl-paminobenzoyl)-1-g1utamate having an index of refraction N =L544O and melting at 82 to 84 C.

Example 23.-Diethyl N (N- (S-methoay-Z-lcetopropyl) -p-tolaenesalfonyl-p-aminobeneoyl) -1- glutamate A mixture was prepared consisting of 70 milliliters of acetic acid, 20 milliliters of propionic acid and 4.95 grams of diethyl N-(N-(3-methoxy-2- hydroxypropyl) -p-toluenesulfonyl-p-aminoben- ZoyD-I-gIutam-ate. The mixture was cooled at 3 C. and a solution of 1.17 grams of chromic anhydride in 10 milliliters of water Was added. The mixture was allowed to stand at'about 3 C. for seventeen hours then poured into a mixture of 200 milliliters of water and milliliters of benzene. After thorough agitation, the benzene layer was separated and washed with dilute aqueous sodium bicarbonate. Evaporation ofthe benzene from the washed benzene layer left a residue consisting-of 4.1 grams of syrupy diethyl N (N-(3-methoxy-2 ketopropyl) -p-toluenesulfonyl-p-aminobenzoyl)-1-g1utamate; Recrystallization of the syrup from dilute ethanol gave a crystalline product melting at 82 to 84 C.

Example 24.Ethyl N-(3-hydroxy-2-ketopropyl) -10-tolaenesuljonyl-p-amino beneoate One gram of ethyl N-(3-chloro-2-ketopropyl) p-toluenesulfonyl-p-aminobenzoate was dissolved in 20 milliliters of acetone-and the solution diluted with 10 millilitersof. water. One-half gram of barium carbonate was thenadded and the mixture stirred overnight at room temper ature and then refluxed for two hours. The mixture was then filtered, partially concentrated-refiltered and then concentrated. The thick liquid A solution was prepared consisting of 0.3 gram of ethyl N-(3-chloro-2-ketopropyl) p--toluenesulionyl-p-aminobenzoate, 15 milliliters of acetone and 3 milliliters of water and 7.5 milliliters of 0.1 normal sodium hydroxide solution was added with gentle agitation at room temperature over a period of one hour. The solution was then diluted with water and filtered. There was thus obtained 0.1 gram of solid ethyl N-(3-hydroxy-2- hetopropyl) -p-toluenesulfonyl-p-aminobenzoate which decomposed over a wide range on heating.

The compound was subsequently condensed with 2,4,5-triamino-6-hydroxypyrimidine to form the toluene sulionyl derivative of the ethyl ester of pteroic acid.

Example 26.-N- (3-hydroxy-2 -ketopropyz) -p-tcZ- ucnesuZfonyZ-p-aminobeneoic acid Eleven milliliters of 0.1 normal sodium hydroxide solution was added at room temperature over a period of one hour to an agitated solution or" 0.2 gram of N-(3-chloro-2-ketopropyl)-ptoluenesulfonyl-p-aminobenzoic acid in 10 rnilli liters of acetone and 8 milliliters of water. The rate of addition was adjusted so that the pl-l of the solution was at all times less than 8.5. Ace tone was then distilled in vacuo from the mixture and the residue extracted with ether. Upon drying the ethereal solution and volatilizing the ether, there was obtained a non-crystalline residue of N-(3hydroxy-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoic acid which was used in l a subsequent reaction without further purification.

In similar manner, N-(N- (3chloro-2-lsetopropyl) p toluenesulfony1 p aminobenzoyl) glutamic acid is hydrolyzed to N' (N-(B-hydroxy- 2-ketopropyl) p toluenesulfonyl-p-aminobenaoyl) -glutamic acid.

Emmple 27 .-Eth'yl N- (3 -hydroxy-2-kctoprc-pggl) p-toZuenesuZfonyZ-p-aminobeneootc A mixture consisting of 3.67 grams of ethyl N- droxide solution and refluxed for fifteen minutes. Uponcooling, the alkaline solution was titrated with 0.5 normal sulfuric acid solution and it was found that 16.72 milliliters of 0.5 normal sodium hydroxide had been consumed during the refiuxing. This corresponds to the presence in the original distillate of 93 per cent of the theoretical amount of ethyl rormate formed by ester interchange between the ethanol and the N-(3-formoxy 2-ketopropyll -p-toluenesulfcnyl p aminobenzoate. The process was repeated and an additional 2.8 per cent of ethyl for-mate accounted for in the second distillate bringing the total yield of ethyl formate to 95.8 per cent of the theoretical amount.

The residue from .the ethanol ethyl formats The distillate was mixed with 30 milliliters of 0.5 normal sodium hy- 16 distillation was concentrated in vacuo' to remove most of the alcohol and the residue taken up in ether. The ethereal solution was washed twice with water than with suiicient aqueous sodium bicarbonate to remove the p-toluenesulfonic acid and finally with water and dried. Distillation of the ether left an oily residue consisting of 3.4 grams of ethyl N-(3-hydroxy 2-ketopropyl) p-toluenesulfonyl-p-aminobenzoate having an .index of refraction N :1.550.

Ernample 28.Diethyl N (N (3hydr0my-2-Icetopropyl) -p-toZuene-suZjonyZ-p aminobenzoyl) glutamate A mixture of 2.6 grams of diethyl N'-(N(3- acetoxy-2-ketopropyl) p toluenesulfonyl p aminobenzoyl) -glutamate, 0.1 gram of p-toluenesulfonic acid and 40 milliliters of absolute ethanol was refluxed for three hours and then distilled slowly until 25 milliliters of distillate had been collected. An additional 40 milliliters of absolute ethanol was added and the mixture again refluxed for 2.25 hours. The mixture was then concentrated in vacuo and the syrupy residue taken up in ether and washed successively with 3 portions of water and one portion of saturated sodium chloride solution. The ethereal solution was then dried over anhydrous magnesium sulfate and the ether evaporated in vacuo. There was thus obtained 2 grams of viscous diethyl N-(N- (3-hydroxy 2 ketopropyl) p toluenesulfonyl-p-aminobenzoyl) -glutainate having a specific rotation at 25 C. in absolute ethanol or -1S.

Example 29.Ethyl N (3-chZoro-2-Icetopropyl) p-aminobeneoate-hydrobromide A mixture was prepared consisting of 0.5 gram of ethyl N-(3-chloro-2-ketopropyl) -N- (p-toluenesulfonyl)-p-aminobenzoate, 0.235 gram of phenol and 5 milliliters of a 25pm cent solution of hydrogen bromide in glacial acetic acid. The mixture was allowed to stand for 2 hours at room temperature and then poured into 40 milliliters of dry ether. The mixture was filtered and the crystalline residue washed with dry ether and then dried. There was thus obtained 0.0! gram of ethyl N -(3-chloro 2 ketopropyl) -paminobenzoate hydrobromide. This product, when condensed with 2,4,5-triamino-6-hydroxypyrimidine, yielded a product having a marked activity for Streptococcus fecalis R.

Example 30 Inamanner similar to that described in ample 29 the p-toluenesulionyl radical is split- 17 We claim: 1. The method which includes oxidizing a compound having the formula o o R ac 1oxy-cmononcm-Nooomncnomomoo)"011' ary1S O 2 wherein R is a member of the class consisting of hydrogen and the alkyl radicals, n is a member of the class consisting of zero and the positive integer 1 and wherein the acyloxy radical is the acyloxy radical of a carboxylic acid with chromic acid in an inert water-soluble solvent to form a compound having the formula COOR acyloxy oHZoo CH1 r iccomncncnomcmnos aryl-SO:

wherein R n have the values iven.

2. The method of claim 1 wherein the oxidation is carried out in acetic acid as a reaction medium.

3. The method which includes oxidizing an alkyl N-(3 acyloxy 2-hydroxypropyl) p-arylsulfonyl-p-aminobenzoate wherein the acyloxy radical is the acyloxy radical of a carboxylic acid with chromic acid in an inert water-soluble solvent to form an alkyl N-(3-acyloxy-2-keto- 'propyl) -p-arylsulfonyl-p-aminobenzoate.

4. The method which includes oxidizing ethyl N-( 3 benzoxy-Z hydroxypropyl) -p-t0luenesu1- fonyl-p-aminobenzoate with chromic acid in an inert water-soluble solvent at a. temperature between about 0 and about 30 centigrade to form ethyl N- (3-benzoxy-2-ketopropyl) -p-toluenesulfonyl-p-aminobenzoate.

5. The method which includes oxidizing ethyl N-( 3 formoxy-Z hydroxypropyl) -p-toluenesulfonyl-p-aminobenzoate with chromic acid in an inert water-soluble solvent at a temperature between about 0 and about 30 centigrade to form ethyl N-(3-formoxy-2-ketopropyl) -p-toluenesulfonyl-p-aminobenzoate.

6. The method which includes oxidizing a dialkyl N (N-3--acyloxy2-hydroxy-propyl) -p-arylsulfonyl-p-aminobenzoyl) glutamate wherein the acyloxy radical is the acyloxy radical of a corboxylic acid with chromic acid in an inert watersoluble solvent to form a dialkyl N'-(N-('3- acyloxy 2 ketopropyl) p arylsulfonyl p aminobenzoyl) -glutamate.

7. The method which includes oxidizing diethyl N'- (N- (3-formoxy-2-hydroxy-propyl) -p-toluenesulfonyl-p-aminobenzoyl)-glutamate with chromic acid in an inert water-soluble solvent at a temperature between about 0 and about 30 centigrade to form diethyl N-(N-(3-formoxy-2- ketopropyl) -p -toluenesulfonyl-p-aminobenzoyl) glutamate.

8. The method which includes oxidizing diethyl N (N- 3-acetoxy-2-hydroxypropyl) -p-toluenesulfonylp-aminobenzoyl)-g1utamate with chromic acid in an inert water-soluble solvent at a temperature between about 0 and about 30 centigrade to form diethyl N'-(N-(3-acetoxy-2- ketopropyl) -p-toluenesulfonyl-p-aminobenzoyl) glutamate.

9. A compound having the formula wherein R is a member of the class consisting of hydrogen and the alkyl radicals, n is a member of the class consisting of zero and the integer 1, Z is a member of the class consisting of hydrogen and the arylsulfonyl radicals and wherein the acyloxy radical is the acyloxy radical of a carboxylic acid.

10. Diethyl N (N-(3-acetoxy-2-ketopropyl) -ptoluenesulfonyl-p-aminobenzoyl) -glutamate.

ll. Alkyl N-(3-acyloxy-2-ketopropy1) p-arylsulfonyl-p-aminobenzoate wherein the acyloxy radical is the acyloxy radical of a carboxylic acid.

12. Ethyl N (3-benzoxy 2 ketopropyl) ptoluenesulfonyl-p-aminobenzoate.

13. Ethyl N-(3-formoXy-2-ketopropyl) -p-toluenesulfonyl-p-aminobenzoate.

14. Dialkyl N-(N-(B-acyloxy-Z-ketopropyl) -ptoluenesulfonyl p aminobenzoyl) glutamate wherein the acyloxy radical is the acyloxy radical of a carboxylic acid.

15. Diethyl N'- (N-( 3-formoxy-2-ketopropyl) p-toluenesulfonyl-p-aminobenzoyl) -glutamate.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN. STANLEY T. ROLFSO-N.

No references cited.

Claims (1)

1. THE METHOD WHICH INCLUDES OXIDIZING A COMPOUND HAVING THE FORMULA