US2647915A - Nu-(2-keto-3-oximinoalkyl)-p-aminobenzoate compounds - Google Patents

Description

iatented Aug. 4, 1953 N- (z-xa-ro-a-ioxnvlmoatxn) i-Aimvd- BENZOATE COMPOUNDS David ILWeisblat' andBarney J Mage'rlein, Kalamazoo, Mich assignors to The Upjohn Company, Kalamazoo, Michigan Mich a corporation of NoDi-avving. "Appllcation February 16,1952, Serial No. 271,982

*8 Claim.

This invention relatesto N-(2 keto-S-'oximinoalkyD-p-amincbenzoate compounds and to a method-useful in "theirpreparati'on. application is a continuation-in-part of co-pending application Serial No. 180,502, filed August 19, 1950.

The N- (2-keto-3-oximinoalkyl) p-aminobenzoate Compounds Iwhich can be prepared by the 'meth'odof the invention have the generic formula HON ,oooR

N- (2-keto- 3-oximinoalkyl -p-aminobenzoate compound wherein R is a member of the :class consisting of hydrogen and the 'alkyl radicals, nis a member of the class consisting of zeroand-the positive integer 1 and Ris a member of-theclass consisting of hydrogen and the alkyl radicals. In the structural formulae given herein and ingthe appended claims aromatic vnuclei are represented by one or-mre simple hexagons.

Compounds having the 'genericiormula given are useful, as described and claimed in co-pendi-ng application-Serial No.;180,5 02, in thepreparation of certain compounds related to the-folic acids. Thus, the N-(2-keto-3-oximinoalkyl) paminobnzoate compounds can be reacted readily with 2,4,5-triamino-fi-hydroxypyrimidine to form certain -N-((2-amino--hydroxy-6-pteridyl) -methyl) p amino benzoate compounds which, uponhydrolysis of the ester groups and splitting of the p-toluenesulfonyl radical from the molecule with'hydrogen bromide and a bromine accepter, are converted readily to compounds identical with or 'very' similar to the folio acids isolated from natural sources. Inasmuch as the glutamic acid residues present in the latter compounds isolated from natural sources generally'have the 'l(+) configuration, compounds having the generic "Formula I in which the glutamic acid residue has the same configuration are ofsp'ecial value. V I

It is to be noted that when the 2-keto 3- oximinoalkyl radical of the N-(2ke to-3-oximinoalkyl) -p-amin'obenzoate Compound I contains more than three carbon atoms, i. e. "when R of the generic formula given is an allgylradicaL-the N-( (Z-amino--hydroriy -6 '-'pteridy1) -methyl) p-aminobenzoate compound formed-is an N (;(2- amino-4-hydroxy-7-all-:yl-6-pteridi 'l) -met-hyl) p aminobenzoate compound, there being an alkyl substituent in the 7 position of the -pterine nucleus. The alkyl substituted pteroic and folic acidswhich can beprep'ared fromthem appear to be of considerable interest from a physiological standpoint. The compounds of the invention are also useful inorganic syntheses because of the proximity in the molecule of the keto and oximino radicals.

Itis pointed out, ='also, that the method of the invention is" applicable to the preparation of compounds having the same formula as-the generic formula-given but with n having a value greater than 1, eg. a value of '2 to 7, inclusive. Such compounds containing a plurality of glutamic acid residues can have these residues connected by way ofthe gamma carboxyl groups ofthe glutamic acid residues to form the peptideulin'kage. It is pointed out, however, that the method is applicable to the preparation of compounds wherein the alpha 'carboxyl groups ."OI' some. of the alpha andsome of the gamma carboxyl groups are involved in the peptide linkage.

In the naming of compounds having the generic formula given, and'of other' com'pounds mentioned herein where .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'-aminobenzoic aeidfre's'idue is referred to by the's'ymbol N.

' According to theinethod of the invention, as illustrated I in the accompanying reaction chart wherein n, R. and R have thevalues given previously, 7 l l- (2- keto-3 -oximinoalkyl) -paminobenzoate Compound I isprepa'r'e'd'readily'by reacting an *alkyl nitrite in either an *acid 'or an alkaline reaction medium, preferably in an acid medium, with an N-(Z-ketoalkyD-p-aminobenzoate compound havin'g'the Formula II.

o o o R cou h-2211011201120 o .o R

such as dioxane, diethyl ether, alcohol, tetrahydrofurane and the like. An organic liquid is preferably chosen in which the acid or alkaline catalyst is at least somewhat soluble. Ethereal solutions of hydrogen chloride and alcoholic solutions of alkali metal alcoholates have been used with satisfaction. Other acids and other alkaline substances can, however, be used, if desired.

Alkyl nitrites which can be used include n-butyl nitrite, tertiary-butyl nitrite, iso-octyl nitrite, ethyl nitrite and the like. Insofar as is known any alkyl nitrite can be employed. Substantially one mole, or somewhat more, of the alkyl nitrite is preferably used for each mole of ketoalkyl compound. The reaction mixture is generally allowed to stand at room temperature for from 6 to 12 hours, but higher temperatures can be employed, if desired, and the reaction time shortened accordingly.

When a volatile acid catalyst is used to promote the reaction of an alkyl nitrite with the ketoalkyl compound, the keto-oximincalkyl compound can be isolated conveniently by evaporating the volatile components of the mixture under reduced pressure. When the reaction is carried out in an alkaline medium, the keto-oximinoalkyl compound can be isolated readily by washing the reaction mixture with aqueous acid, subsequently drying the washed water-insoluble portion and evaporating under reduced pressure any volatile components which may be present. The N-(2- keto 3 oximinoalkyl) -p-aminobenzoate compound is thus generally recovered as a viscous yellow sirup which is sufiiciently pure for most purposes.

An N (2-ketoalkyl)-p-aminobenzoate Compound II useful as a starting material in the method of the present invention can be prepared, as described and claimed in co-pending application Serial No. 180,501, by first reacting a l,2 epoxyalkane (III) having the formula RCHCH2 o III 1,2epoxyalkane with an N-(arylsulfonyl) -p-aminobenzoate Compound IV having the formula C o R H-N oomnnomomoopoa and A0: 7 IV N- (arylsulfonyl) -p-aminobenzoate compound to form an N-(2-hydroxylalkyl)-p-aminobenzoate Compound V having the formula 0 o o R R-CHg-CHOH-CHg-N o 0 (NHr'JH CHzCHzCO),,OR'

My 0 2 V N- (2-hydroxyalkyl) -p aminobenzoate compound and subsequently oxidizing the hydroxyalkyl compound, e. g. with chromic anhydride in glacial acetic acid, 11., R and R having th values given previously. N (arylsulfonyl) -p-aminobenzoate Compound IV which can be employed with the production of the corresponding intermediate and final compounds of the process include the N- (arylsulfonyl)p-aminobenzoic acids, the N'-(N- (arylsulfonyl) -p-aminobenzoyl) -glutamic acids, and their alkyl esters.

Certain of the N-(arylsulfonyl) -p-aminobenzoate compounds are described and claimed in copending application Serial No. 41,888, filed July 31, 1948. They can be prepared readily as described therein by reacting an arylsulfonyl halide with p-aminobenzoic acid, N-(p-aminobenzoyl) glutamic acid, or with an alkyl ester thereof. N (arylsulfonyl)-p-aminobenzoate compounds which are esters can be hydrolyzed readily to free acids with alkalies and the free acids can be esterified in conventional manner.

Esters having the generic Formula II which can be used as starting compounds in the process of the invention with the production of the corresponding esters having the generic Formula I include the methyl, ethyl, n-propyl, iso-propyl, butyl, amyl, hexyl, nonyl and many other alkyl esters. As a matter of convenience, alkyl esters containing less than about 8 carbon atoms in the alkyl radical, preferably the ethyl esters, are used in the process, although insofar as is known any alkyl ester can be used.

Although starting compounds containing substantially any arylsulfonyl radical can be used in the process of the invention in the preparation of the corresponding final products (I), the preferred starting materials are those containing the p-toluenesulfonyl radical due to the ready availability of the p-toluenesulfonyl halides and to the generally crystalline nature of the p-toluenesulfonyl derivatives of compounds with which the present invention is concerned. Th invention,

however, is not limited to compounds containing the p-toluenesulfonyl radical, and compounds containing other arylsulfonyl radicals, such as the o toluenesulfonyl, naphthalenesulfonyl, methylnaphthalenesulfonyl and other arylsulfonyl radicals, can be used if desired. It should also be mentioned that compounds containing arylsulfonyl radicals having non-hydrocarbon substituents can be used in the process provided only that the substituent is non-reactive under the reaction conditions. Such non-reactive substituents include chlorine, bromine, and the methoxy, phenoxy, nitro and other radicals.

Although R in the Formulae I and II given represents hydrogen or any alkyl radical, the preferred compounds are those wherein R is hydrogen and the invention has been described with particular reference thereto. Among the compounds that can be used in the process, if desired, are those wherein R is the methyl, ethyl, npropyl, iso-propyl, n-butyl, tertiary-butyl, octyl or any other alkyl radical.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is, therefore, to be limited only by the scope of the appended claims.

Example 1.Diethyl N'-(N-(p-toluenesulfonyl) p-aminobenzoyl) -glutamate Thirty and nine-tenths grams of p-toluenesulfonyl p amino benzoyl chloride and 23.9 grams of diethyl l(+)-glutamate hydrochloride were dissolved in 300 milliliters of 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-cgzvlgn less. solution thus obtained was dried withanhydrous sodium sulfate and naphtha was added, untilv 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'-(-N-(-petoluenesulfonyllip:aminobenzoyl) -l-glutamate melting at 12,49 to, 126 -10.

Example 2. Dieth'JZ N-(N(2-hyd'romypropyl)- N (p toluenesulfonyl) -p aminobenzogl)'- glutamate A mixture of 6.38 grams of propylene oxide, 47.? grams of diethyl N'(N-(p-toluenesulfonyl) p-aminobenzoyl)-glutamate and 10 drops of an hydrous pyridine was heated under pressure at, 130 C. for 2 hours. The reaction'mixture was then cooled to room temperature, 400 milliliters of benzene were added and the resulting benzene solution was washed with 50 milliliters of water and 5.0- milliliters of dilute hydrochloric acid and then dried. Removal of the solvent under re-, duced pressure gave a non-crystalline solid resitoluene-sulfonyl) -p-aminobenzoyl) -glutamate.

In a similar manner, and using 1,2-epoxy-nbutane or 1,2-epoxy-4-methyl-n-pentane in place of 1,2-epoxypropane, there are formed diethyl N (N (2 hydroxy n butyl) N (ptoluenesulfonyl) p aminobenzoyl) glutamate sulfonyl)-p-aminobenzoyl)-glutamate leads, in

analogous manner, to the tormation of ethyl N (2 hydroxypropyl) N (benzenesulfonyl) p aminobenzoate or triethyl N (N (2 hydroxypropyl) N (p chlorobenzenesulfonyl) p aminobenzoyl) glutamyl glutamate, respectively. These esters, upon hydrolysis with dilute alcoholic sodium hydroxide, are converted to N (2 hydroxypropyl) N (benz'enesulfonyl) p aminobenzoic acid and N e (N (12-.

hydroxypropyl) N (p chlorobenzenesul fonyl) p aminobenzoyl) glutamyl glutamic' acid, respectively. The free acids mentioned, upon esterification with an alkanol or with other alkyl ester-forming agents, are converted to the corresponding alkyl esters.

Example 3.Diethyl N (N 2- ketopropyD- N (p toluenesulfonyl) -p aminobenzoyD- glutamate The crude diethyl N-(N-(2-hydroxypropyl)- N (p toluenesulfonyl) p aminobenzoyD- glutamate obtained in Example 2 was dissolved in 400 milliliters of benzene and the solution was added with vigorous stirring to a solution consisting of 52.6 grams of potassium dichromate, 230 milliliters of water, 38 milliliters of acetic acid and 69 milliliters of sulfuric acid. The mixture was stirred vigorously at to C. for about 2 /2 hours, cooled and the benzene and aqueous layers separated. The aqueous layer was extracted twice with loo-milliliter portions of benzene and then discarded, the benzene extracts being added to the benzene layer from the reaction mixture. The combined benzene solutions were washed three times with ZED-milliliter por- 6 ion o W er. once w th 0D m l iiiters of; sat--- urat aqu ou o ium bicarbenate solemn wic w 250 li por o 01 e' e: and; Once h. 0 m ili er o saturated a ueous odi m. chloride solution- The wash d benzenesolution was. then dried nd h solven i t lled; under reduced p sure. The r sidue solvedin hot isopropanoland the solution r rystallizeat room. temp ra u e The was filtered and the crystals dried. There were us ned 34 .5 grams of: crude diethyl NV (N (,2 kfitopropyl) N. (p. toluen pyl) glutamate w ljch iqn n. r a ino, ,8 melted at'88" to 130 C. Recrystallization oi, the crude ketone raised its melting point to 99 to C.

Qxi-dation in a, similar manner of diethyl. N'- (N 2 hydroxy n b utyl) N' (p toluene sulfony-l) -1' p aminobenzoyl) glutamate, di-.. ethyl N (N (2 hydrox-y 4 methyl n1 pentyl) N (ptoluenesulfonyl) p amino-- benzoyl) glutamate, N" (N ("2 hydroxynv bu-tyl) N'- (p toluenesul-fony-l) p amino. ben'zoyl) glutamic acid, N (2 hydro xy-.

' propyl) N' (benzenesulfonyl) p aminobenzoic acid, ethyl N (2 hydroxy-propyl) N- (benzenesulfonyl) p aminobenzoate, triethyl N (N (2 hydroxypropyl) -'N- --(p chlorobenzenesulfonyl) p aminobenzoyl) l glutamylu a ate and N N (2- ydr xy tqmfll- (p, chlorotol-uenesulfonyll p aminohenzoyl-lglutamyl glutamic acid gives diethyl Nf (N- (2 keto n butyl) N (p toluenesulfonyl) p aminobenzoyl) glutamate, diethyl (N- (2 keto 4 methyl n pentyl) N (p tol uenesulfonyl) p aminohenzoyl) glutamate, N (N (2 keto n butyl N (p etoluene sulfonyh p minobe zo s it ni cidv N k p b N b nze esul qnyl P aininobenzoic acid, ethyl N 2 ketopropyl)- -v N (benzenesulfonyl) p aminobenzoatei, tri-- ethyl N (N (2 ketopropyl N (p chlorobenzenesulfonyl) p aminobenzoyl) '7 lutarnyle glutamateand (N 2 kctopropyl) N'. (p chlorotoluenesulfonyl) p aminobenzoyl utamy g t i sp ctivel Example 4.-Diethyl N (N (z-kcto-wximinwqpyl) -N (p-toluenesulfonyl) p aminobenza yl) -glutamate I A mixture of 1.0 gram of diethyl N -(N- (g-lgetopropyl) 1N (p-toluenesu ronyn -alt n be zgyl) -glutaniate, 15 milliliters O anhydrous diethyl ether saturated with hydrogen chloride anddgti milliliter of n-butyl nitrite was stirred at room temperature for 2 2 hours and the volatilecomponents then volatilized under reduced pressure. There was thus obtained 1.05 grams of diethyl N"- (N -(2.-keto-.3-.oximinopropyl) ,N. (IJ-toluenee sulfonyl)-p-aminobenzoyl)glutamate, as a viscous yellow oil.

Other alkyl nitrites, such as ethyl nitrite, propyl nitrite and amyl nitrite when reacted with diethyl N-(N-(2-ketopropyl) -N-(p toluenesulfonyD-p-aminobenzoyl)-glutamate in the manner just described lead to the formation of the same diethyl N-(N-(2-keto-3-oximinopropyl) -N- (p-toluenesulfonyl) -p-aminobenzoyl) -glutamate.

In similar fashion other esters, such as diethyl N-(N (2-keto-n-butyl) -N- (p-toluenesulfonyl) p aminobenzoyl) glutamate, diethyl N-(N-(2- keto-4-methyl-n-pentyl) -N-(p-toluenesulfonyl) p-aminobenzoyl) -glutamate, ethyl N-(2-ketopropyl) -N- (benzenesulfonyl) -p-aminobenzoate and triethyl N-(N-(2-ketopropyl)-N (p chlorobenzenesulfonyl) p aminobenzoyl) -glutamylglutamate, are reacted with butyl nitrite to form diethyl N'-(N (2 --keto 3 oximino n butyl) N (p-toluenesulfonyl) -p-aminobenzoyl) glutamate, diethyl N-(N-(2-keto 3 oximino-lmethyl-n-pentyl) -N- (p-toluenesulfonyl) -p-aminobenzoyl) -glutamate, ethyl N-(2-keto-3-oximinopropyl) N (benzenesulfonyl) p-aminobenzoate and triethyl N'-(N-(2-keto-3-oximinopropyl) N-(p-chlorobenzenesulfonyl) -p-aminobenzoyl) -glutamyl-glutamate, respectively.

Example 5.--Diethyl N-(N-(2-keto3-oximin0- prom/l) -N-(p-toluenesul,fo'nyl) p aminobenzoul) -glutamate A mixture of 1.0 gram of diethyl N'-(N-(2- ketopropyl) -N-(p-toluenesulfony1) -p-aminobenzoyl) -glutarnate, 0.23 milliliter of n-butyl nitrite, 0.13 gram of sodium methoxide and milliliters of benzene was stirred at room temperature for hours under an atmosphere of nitrogen. The benzene solution was then extracted with an equal volume of dilute aqueous hydrochloric acid, then with an equal volume of water and dried. Upon volatilization of the solvent under reduced pressure there remained 990 mg. of diethyl N'- (N-(2-keto-3-oximinopropyl) -N-(p-toluenesulfonyl) -p-aminobenzoyl) glutamate as a viscous, yellow oily residue.

Example 6.N'-(N-(2-keto 3 oximinopropyl) N-(p-toluenesuljonyl) -p-amin0benzoyl) glutamic acid N(N-(2-keto 3 oximinopropyl) -N-(p-toluenesulfonyl)-p-aminobenzoyl) glutamic acid is prepared substantially as by the method of Example 4 by treating N-(N-(2-ketopropyl) -N-(ptoluenesulfonyl) -p-aminobenzoyl) -glutamic acid with n-butyl nitrite in ethereal hydrogen chloride. The product is recovered by volatilizing the low-boiling constitutents of the mixture under reduced pressure.

In similar fashion other acids such as N-(N- (Z-keto-n-butyl) -N- (p-toluenesulfonyl) -p aminobenzoyl) -glutamic acid, N-(Z-ketopropyl) N- (benzenesulfonyl) -p-aminobenzoic acid, and N'- (N-(2-ketopropyl) N (p-chlorobenzenesulfonyl) -p-aminobenzoyl) -glutamyl-glutamic acid are reacted with butyl nitrite to form N'-(N-(2-keto- 3 oxirnino-n-butyl) -N-(p-toluenesulfonyl) paminobenzoyD-glutamic acid, N-(Z-keto-B-oximinopropyl) -N-(benzenesulfonyl) -p aminoben- -zoic acid and N-(N-(2-keto-3-oximinopropyl)- N-(p chlorobenzenesulfonyl) -p-aminobenzoyl) glutamyl-glutamic acid, respectively.

We claim: 1. A compound having the formula rioN COOR R-(L-CO-GHz-N GO(NHCHCH|CHC0).OR'

aryl 01 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 R is a member of the class consisting of hydrogen and the alkyl radicals.

2. A compound as claimed in claim 1 where- In the arylsulfonyl radical is the p-toluenesulfonyl radical.

3. A compound having the formula HON c o O-alkyl HJ'.|!C0CH;-N C0NH( JHCH1CH:CO0-alkyl aryl Oz 4. A compound having the formula HON c o 0 -alkyl 5. Diethyl N (N (2-keto-3-oximinopropyl) N-(p-toluenesulfonyl-p-aminobenzoyl) glutamate.

6. The method which comprises reacting a 2- ketoalkyl compound having the formula COOR aryl O 2 wherein R is from the group consisting of hydrogen and the alkyl radicals, n is from the group consisting of zero and the positive integer 1 and R is from the group consisting of hydrogen and the alkyl radicals with an alkyl nitrite to form a 2-keto-3-oximinoalkyl compound having the formula HON 00 o R B( /COCHzN comm momcmoopo R aryl O:

ate.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN.

No references cited.

Claims (2)

1. A COMPOUND HAVING THE FORMULA

6. THE METHOD WHICH COMPRISES REACTING A 2KETOALKYL COMPOUND HAVING THE FORMULA