Sept., 1943
ANTISPASMODICS : SUBSTITUTED p-XENYLHYDROXYACETIC ACIDSAND ESTERS
was immunologically distinct from other antigens present in castor beans was shown by the SchultzDale uterine strip method. Positive passive transfer reactions were pro-
[CONTRIBUTION FROM
THE
1725
duced with 1 X lo-'" g. of CB-1A. Positive cutaneous tests, on castor bean hypersensitive subjects, were obtained with C3-1A diluted 1:lo6. WASHINGTON, D.
c.
RECEIVED APRIL23, 1943
COLLEGE OF PHARMACY, UNIVERSITY O F MICHIGAN ]
Antispasmodics. V BY F. F. BLICKEAND NATHANIEL GRLER'J The two principal naturally-occurring anti- aminoethyl, 7-diethylaminopropyl or y-piperispasmodics are atropine and papaverine; the dinopropyl. former is a basic ester, the latter a cyclic amine. P-Xenylacetic acid was obtained by the series In the search for synthetic antispasmodics the of reactions outlined below structures of these two ClCOCOOCzHd + AlC13 H,O compounds have served C~H&HS > ~-CaHsC6H4COCOOC& +CsH6CsH4COCOOH I I1 as patterns for the preparation of a wide HzO 2H variety of basic esters C*HdCsH~CH(OH)COOC*H6 --f CsHaCaH4CH(OH)C0OH +C6H6C8H4CH2COOH 111 IV V and aminesa At the present time three antispasmodics of We were able to increase the reported yield of the ester type are on the market: Syntropan (the ethyl p-xenylglyoxylate (I) by a modification of primary phosphate of ,8,P-dimethyl-y-diethyl- R ~ u s s e t ' s procedure. ~ Hydrolysis of the ester aminopropyl tropate), Trasentin (the hydro- yielded p-xenylglyoxylic acid (11), while catalytic chloride of P-diethylaminoethyl diphenylacetate) reduction converted it into ethyl p-xenylhydroxyand Demerol (Dolantin, the hydrochloride of acetate (111). The latter was hydrolyzed to pethyl 1-methyl-4-phenylpiperidine-4-carboxyl-xenylhydroxyacetic acid (IV), and this acid was ate).6 reduced with red phosphorus and iodine t o pSince Trasentin is not only an effective anti- xenylacetic acid (V). spasmodic but is relatively easy to synthesize, the The substituted p-xenylacetic acids, C&,C&preparation and pharmacological study of esters, CH(R)COOH, were obtained according t o method similar in structure to this substance, offers an A7 or 3.* inviting field. The esters were prepared by two procedures: In this paper (Table 111) are described hydro- (C) the required acid, dissolved in isopropyl alchlorides of basic-alkyl esters of the general type cohol, was heated with a molecular equivalent g-C&,C6H4CH(R)COOR' : R = hydrogen, phenyl amount of the basic alkyl chlorideg; (D) the cyclohexyl, methyl, ethyl or propyl; R' = j3- necessary acid chloride was allowed to react with diethylaminoethyl, 0-piperidinoethyl, P-dibutyl- two molecular equivalents of the basic alcohol in (1) This paper represents part of a dissertation submitted t o the benzene solution whereupon a part of the basic Horace H. Rackham School of Graduate Studies by Nathaniel Grier in partial fulfillment of the requirements for the degree of Doctor of alcohol precipitated as the hydrochloride, and Philosophy in the University of Michigan. the desired ester base remained in solution. (2) Frederick Stearns and Company Fellow. (3) Cheney and Bywater (THISJOURNAL, 64, 970 (1942)) have Our products were examined pharmacologically described a number of morpholinoalkyl esters which were tested for by Dr. C. W. Geiter and Dr. A. N. Lands of antispasmodic activity by Rowe (J. A m . P h a m . Assoc., 81, 57 (1942)). A number of references to theliterature of this subject are Frederick Stearns and Company. A detailed act o be found in the article by Cheney and Bywater. Recently Burt-
Y
T T V
ner and Cusic (THIS JOURNAL, 66, 262 (1943)) published the syntheses of a number of basic esters of arylacetic acids which have been examined pharmacologically by Lehmann and Knoefel ( J Pharmucol.. 74, 217,274 (1942). (4) Trasentin-H is the hydrochloride of p-diethylaminoethyl cyclohexylphenylacetate. ( 5 ) Syntropan and Trasentin, like atropine, are esters in which the basic nitrogen is in the alcoholic radical of the ester, in Demeroi. however, the basic nitrogen is found in the acyl group
(6) Rousset, Bull. SOC. chim., [3]17, 809 (1897). (7) Grignard (Ann. chim. bkys., [7]37, 548 (1902))was the first t o study the action of aliphatic Grignard reagents on ethyl phenylglyoxylate. (8) McKenzie and Ritchie (Bcr., TO, 33 (1937)) showed that ethylphenylbydroxyacetic acid can be obtained in good yield from ethylmagnesium bromide and pheny€glyoxylic acid. ( 8 ) General method of Horenstein and Pghlicke, dbid., 71, 1654 (1938)
F. F. BLICKEAND NATHANIEL GRIER
17%
VOl. 65
which boiled at 205' (5 ni111.).'3 The estt.1
ltethod A
p-XenylglyoxylicAcid (In.-Thirty-nine grams of ethyl p-xenylglyoxylate, 500 cc 7HCl of a 10% sodium carbonate solution and Xethod 6' %lib1 gx 100 cc of alcohol were refluxed for three ~-C~HF,CQH~COCOOH C ~ H ~ C ~ (OMgX H I C (R)COOM KX hours. The sodium p-xenylglyoxylate, R = C2H5,C3HI or CnRy which separated when the solution was count will be published soon by them in another cooled, was iiltered and dissolved in 2 liters of hot water. journal. However, it may be stated here that The mixture was cooled, acidified with dilute hydrochloric acid and the xenylglyoxylic acid extracted with ether. The dll of our estersI0 produced relaxation of the un- extract was shaken with water, the ether layer separated, treated, isolated intestine. In general, esters of the solvent removed and the oily residue dried thoroughly alkyl-p-xenylacetic acid are more active than a t 100" under reduced pressure. The product solidified corresponding esters of p-xenylacetic acid ; the when cooled, and was recrystallized from carbon disulfide; most active esters are those of rnethvl-p-xenyl- yield 29 g. (84%)); ni. p. 105-107°.~5 When moistened with concd. sulfuric acid, the material turned deep red. acetic acid. Antrl. Calcd. for ~ , J 3 , & ~ : c, 74.33; W,4.42. I'oitrid: i.Z . l L 1 ; H , 4.36 Experimental Part Ethyl p-Xenylhydroxyacetate (111) and p-XenylhgdroxyEthyl p-Xenylglyoxylate (I).---One hundred and eighty- acetic Acid (IV).--.4 mixture of 25.4 g. of ethyl p-xenylglyoxylate, dissolved in 175 cc. of absolute alcohol, 0.85 g. two grams (1.18 moles) of biphenyl and 175 g. of ethyl of platinized charcoal (Norit-1 and (icc. of water, which oxalyl chloride" (1.28 moles) were dissolved in 750 cc. of dry carbon disulfide and the solution poured into a 3-liter, contained U.33 g. of palladiurii chloride,I6 was shaken for 3-necked, round-bottomed flask equipped with a mercury- eight hours in the presence of hydrogen under an initial sealed stirrer and a reflux condenser; a long calcium chlo- pressure of 3 atmospheres. Slightly more than the calcuride tube was attached to the latter. One neck of the flask lated amount of hydrogen was absorbed. Since some of the ethyl p-xenylhydroxyacetate precipitated, the mixivas connected with a 500-cc. Erlenmeyer flask by means of ture was filtered and the precipitate extracted with ethyl a piece of wide rubber tubing about 8 inches long. The Erlenmeyer flask was supported by a ring stand, neck acetate. The extract was added .to the alcoholic filtrate, down, and 173 g. (1.30 moles) of aluminum chloride, the solvents removed under diniinished pressure and the ,vhich had been placed in the flask, was added to the re- residue, ethyl p-senylhydroxyacetate, refluxed for t r o hours with 235 cc. of l(ly$ alcoholic potas::ium hydroxide. action mixture in portions. This waS effected with the aid of two pinch clamps which had been attached to the The mixture was poured into an equal volume of water, treated with Xorite and filtered. Upon acidification of rubber tubing a few centimeters aparl. The mixture was tlie filtrate with dilute hydrochloric acid, 22.0 g. (97%,j of heated until it began to boil, and lhe aluminum chloride ivas added at such a rate that the mixture continued to re- colorless p-xenylhydroxyacetic acid was obtained; in. p. 7 recrystallization from acetic acid. When flux without the aid of external heat. During this opera- ~ 0 1 - Z l ~ 0 1after moistened with concd. silfiiric acid, the acid became palc tion the mixture was stirred vigorously. A red cornplch precipitated12 and continued t o increase in amount until yellow-green in color. A n d . Calcd. ior C,413,zOs: C, T3.7t); H, .i.2ti. Found: the end of the reaction. Bfter complete addtioil o f t h v aluminum chloride, the mixture was stirred for tell 1iouI~. i,7 3 . 6 ; ; H, ;xi. The carbon disulfide solution and the precipitate were p-Xenylacetic Acid ( V j . -.A mixture of 15.5 g. of p treated separately with ice and then combined. The xenylhydroxyacetic acid, 1.4 g. of iodine, 3.2 g. of red greenish-yellow carbon disulfide layer was separated, phosphorus and 135 cc. of acetic acid was refluxed for washed thoroughly with water, dried and the solvent re- twelve hours, filtered and the p-senylacetic acid precipimoved on a steam-bath. When the residue was distilled iated by the addition of a small amount of water to the under reduced pressure there was obtained 15.5 g. of hi- filtrare. Aft.er recrys:allization from acetic acid, 10.1 g . phenyl and 188.0 g. (707,) of ethyl p-xenylglyoxylatc (70'2,)of product was obtained; ni. p. If11-1A2~.~*Thr. 2H
C ~ H ~ C B H ~K) CH COO I H
+-CsHqCcH,C (OH)(R)COOH
-__f
(IO) The hydrochloride of P-piperidinoethyl and of ;-piperidinepropyl phenyl-$-xenylacetate were not tested. (11) Adickes, Brunnert and Liicker, J . prukf. C h e n . , 130, 168 11931). We found thdt the use of stirring and a solvent were unoecessary, and that five times the quantity of acid chloride mentioned by Adickes and co-workers could be prepared at one time with no diminution in yield. (12) A general discusrion relative to the preparation of pure aryl. glyoxylic acids has been published by Bouveault (BuEI. SOC. chim., [a] 17, 363 (1897)). It might be advantageous to use a mixture of carbon disulfide and nitrobenzene. as he suggested, and thus prevent thr v i a-ipitation uf f hr cnmolr\
(13) Rousset (ref. ti) reported 232' (9 mm.) (14) Rousset (ref. 6) found 39'. r15) I t was stated by Rousset (ref. 6 ) that p-xenylglyoxylic acid. which he obtained by hydrolysis of the ethyl ester, decomposed at 170° after recrystallizing from benzene. Since he must have obtained the acid, we believe that the melting point was reported in tmxctly. (lti) The calalyst wab prepared according tu the directions of Zelinsky and Turowa-Pollak, Ber., 68, 1296 (1929). (17) Riebsomer, Stauffer, Glick and Lambert (TEE
[email protected], 64. PO81 (1942)) found 192'. (18) Lesser (German Patent 658,114; Chcm Zentx , 109, 1. 438'~ 11381) reported thr
