Nov., 1945
ALKAMINEESTERSOF SUBSTITUTED p-XENYLGLYCOLIC ACIDS
[CONTRIBUTION FROM THE
1897
SCIENTIFIC LABORATORIES, FREDERICK STEARNS AND COMPANY DIVISIONOF STERLING DRUG, INC.]
Alkamine Esters of Substituted p-Xenylglycolic Acids' BY JOHNA. FAUST,R. F. FELDKAMP AND MAURICE L. MOORE A series of alkamine esters of substituted pxenylacetic acids has been prepared by Blicke and Grier'" and found to possess antispasmodic activity.laV2 Subsequent investigation of a series of alkamine esters of substituted a-thienylacetic acidsa has shown that, in general, the spasmolytic activity of the esters of hydroxyacetic acids (glycolates) is much greater than that of the esters of acetic acid^.^,^ Since the observed activity of some of the esters of alkyl-p-xenylacetic acids is relatively high, in comparison with known antispasmodic agents, the present work was concerned with the synthesis of a series of related esters of substituted p-xenylglycolic acids for pharmacological investigation. The necessary shstituted p-xenylglycolic acids have been prepared previously by the reaction of the appropriate Grignard reagent on p-xenylglyoxylic acid.la These acids were dissolved 'in isopropanol and heated with a molecular equivalent of the desired basic alkyl chloride for the
line quaternary salts The properties of these compounds are summarized in Table I. The P-diethylaminoethyl ester hydrochlorides of the propyl- and butyl-p-xenylglycolic acids were found to have nearly identical melting points and there was no depression in the melting point of a mixture of the two compounds. This was also true of the P-N-piperidinoethyl ester hydrochlorides of the same acids. In checking these results new acids were prepared and esterified with the appropriate basic alkyl chloride to yield new samples of the four esters. The properties of three of the new samples coincided with those of the first. However, the P-diethylaminoethyl ester hydrochloride of butyl-p-xenylglycolic acid had a much lower melting point than that of the initial material, although the analytical data on both were acceptable. The melting point of a mixture of the two was the same as that of the higher melting form and both yielded the same acid upon saponification.
TABLE I ALKAMINEESTERS OF SUBSTITUTED fi-XENYLGLYCOLIC ACIDS $-CBH,C~HICR'OHCOOR.HCI Antispasmodic activityb average max. e5ective dilution o,n.isolated rabbit Analyses, %"--jejunum Nitrogen Chlorine AcetylBarium Calcd. Found Calcd. Found choline chlorine *
NO.
1 2 3 4
5 6
7 8
9 10 11 12
R
R'
CHa CzHs CiH7 CiHo I I1 --CHZCHZCHIN(CZH~)~.CHa CiHa CaHi'J C~HDV
-CHzCH:N(CzHa):
- C H ~ C H ~ N C ~ HCH, ,~~ CzHs CaHi CiHa
Yield,
%
82 84
55 61 67 87' 62 31 57 92' 70 64 73
y. ;.,
7-
C.
Formula
160-161 157-158 r37-139 135-137 119-120 115-117 122-123 126-128 155-156 207-208 116-147 183-18-1 181-182
CziHzsOaNCl CzzHmOaNCF CzcHnOaNCl CirHaiOaNC1
3.78 3.68 3.37 3.28 3.36 CzzHaaOaNCI 3.57 3.55 CisH1z0aNCl 3 . 4 5 3.38 CzaHssOaNBr 2 . 0 3 -3.18 CmHssOaNBr 2 . 8 4 3.00 C ~ ~ H , ~ O3.59 ~ N C3.79 I CiaIiaoO~NCI C.rH3zOaNCI CzsHsiOaNCI
3.71 3.57 3.45 3.34
3 47 :3.3.? :1 24
3 62 3.37 3 24
0.39
Y.66
lMe
9.0r5
0.33 8.81
100-200T 100-200T 100-200T 100-200T 500T-1M 200-500T 200-300T
8.73 8 44 9 . 0G 8.74 16.70 16.23 9.m
8.78 8.48
X.21
8,63 8.31 9.03 8.74 1 G . 81 l G 39 9.46 8.60
R .43 8.22
200-500Td 100-200T 100-200T 100-200T 100-200T 200T
200-600T
200-LOOT SOOT-lbf 200-BOOT ~ O O T - ~ M 200-5001' 100-200T 100-200T 100-200T 100-200T 100--200T 100-200T
We are indebted t o Mary Jane Eastwood and Elizabeth B. M a c k for the analytical data on these compounds. The figures recorded represent preliminary results only but they are suificiently accurate to permit a relative comparison of 1:200,000-500,000. All the melting points reported are uncorrected. Crude the compounds. 1 : 1,000,000. NCnHlo = Piperiditlo. Compoutid no. 6 was recrystallized froin benzene, compound yields. 0 Methobroniides. 9 from methanol, compounds 11 and 12 from isopropanol, compounds 1 and 5 from a mixture of methanol and isopropyl ether, and all others from a mixture of isopropanol and isopropyl ether.
preparation of the esters, according to the geiieral method of Horenstein and Pahlicke.6 The hydrochloride salts of two of the esters could not be isolated in crystalline form. These were converted to methobromides and isolated as crystal(1) Prepared for the 1945 meeting-in-print of the Division of Medicinal Chemistry, A. C. S. (la) Blicke and Grier, THISJOURNAL, 66, 1725 (1943). (2) Lewis, Lands and Geiter, Federation Proc., 4, 29, 86 (1043). (3) Blicke and Tsao, THISJOURNAL, 66, 1645 (1944). (4) Lands and Nash, Proc. SOC.Expll. B i d . M c d . , 61, 55 (1944). (6) Horenstein and Pahlicke, B e . , 71, 1654 (1938).
We are indebted to Dr. A . M. Lands and Miss V. L. Nash, of the Phariiiacological Kesearch Laooratories, for a preliniinary report on the antispasmodic activity of these compounds as included in Table I. In general, the spasmolytic activity is about the same as for the corresponding esters in the p-xenylacetic acid series. The esters of methyl-p-xenylglycolic acid are the most active in the series, with P-diethylaminoethyl methyl-b-xenylglycolate having an activity against acetylcholine 011 the isolated rabbit
R. F. FELDKAMP AND MAURICE L. MOORE
1898
jejunum in a dilution of 1:1,000,000. It was surprising to note that the esters of glycolic acids were of the sanie order of activity as the esters of the corresponding acetic acids.
Experimental Basic Esters. (a) Hydrochlorides.-A homogeneous solution of equimolecular quantities of the glycolic acid and the basic alkyl chloride in an appropriate volume (50 ml. per 0.03 mole) of isopropanol was refluxed for fifteen hours. After filtration the solvent was removed by evaporation at room temperature with a current of air and the oily residue became crystalline, in most cases, after heing repeatedly rubbed with fresh portions of anhydrous ether. The product was recrystallized from a suitable solvent as indicated in the table. (b) Methobromidss.-Hydrochlorides which persisted as oils were converted to methobromides according to the procedure of Blicke and Maxwell.* A cold aqueous solution of the hydrochloride was made alkaline with loc/o aqueous sodium carbonate and the liberated basic ester extracted with ether. After washing with water, the extract
-
[CONTRIBUTIONFROM
THE
was dried over anhydrous magnesium sulfate. The magnesium sulfate was filtered off and the ether evaporated leaving an oil which was disso1.ved in ethanol. This solution, contained in a citrate bottle, was cooled in an ice-salt mixture and treated with four to six equivalents of methyl bromide. The bottle was stoppered and allowed to stand at room temperature for twenty-four, hours after which the product was worked up in the manner described for the hydrochlorides.
summary Twelve alkamine esters of substituted p-xenylglycolic acids were prepared by the reaction of a molecular equivalent of the appropriate acid and basic alkyl chloride. The properties of these compounds are described. The anomalous data on certain of these derivatives are discussed. All of the esters possess antispasmodic activity, although i t was surprising to find that they were of the same order of activity as the esters of the corresponding acetic acids. L)ETROIT,
(6) Blicke and Maxwell, THISJOURNAL, 64, 428 (1942).
Vol. 67
RECEIVED AUGUST20, 1945
MICH.
SCIENTIFIC LABORATORIES, FREDERICK STEARNS AND COMPANY DIVISIONOF STERLING DRUG, INC.]
Alkamine Esters of Substituted 1-Naphthaleneglycolic Acids’ BY R. F. FELDKAMP AND MAURICE L. MOORE The substituted 1-naphthaleneglycolic acids In view of the observations noted in the preceding article of this series,la it was of interest to syn- were prepared according to the method already thesize a series of alkamine esters of substituted described by the reaction of the appropriate Gri1-naphthaleneglycolic acids for pharmacological gnard reagent on 1-naphthaleneglyoxylic acid. investigation in comparison with the previously Whereas a large excess (50%) of Grignard reagent prepared esters of substituted 1-naphthalene- was previously employed in this synthesis it was acetic acids,2several of which have been reported found that B small excess (10%) gave a granular to possess relatively high antispasmodic activity. solid complex and yields of 7848%. Two of A L K A M I N E ESl’tZKS CIV SIIHSCI LUI‘EU
No. 1 2 3 4 5 fi
7
s 9
10 11
I2
13 E
R’
CHa CsHs CaH7 C4Ho CHI CIHI CIHI C4Hu GHt, CHI CrHi CaH7 CbHs
TABLEI 1-NAPHTHALENEGLYCOLIC ACIDS, l-CloH,CR’OHCOOR.HCl
Yield,
5. P., C.
87 90 95 82 74 89
139-1 4 1 147-148 153-1 5 5 138-135 13.1-135 13R-140 153-154 123-125 183-165 148-149 164-166 143-145 128-130
%
83
77 93 74 50 81 89
-
Antispasmodic activityb av. mar. effective diln. on isolated rabbit jejunum Analyses, 7a AcetylBarium Nitrogen 8hloirine choline chloride Culcd. Found Calcd. Found NOTd 3 . 9 8 3 . 0 5 10.07 IO.25 2 M C 8 . 8 2 500T-1M 3.83 3.84 9.69 200-500T 9 . 5 5 500T-1M 250-500T 3 . ~ 9 3.83 9.33 3 . 5 8 9 . 0 0 500T-1M 250-500T 0.35 3.56 18.83 18.73 zoo-~OOT ioo-2001’ 3.30 3 . w 2.io-soo’r 9.33 250-500~ 3 . 7 8 9 . 3 3 3.69 9.00 ioo-zoo~ 9.00 2 5 0 - 5 0 0 ~ 3.56 3.52 2001‘ 8.69 8 . 5 8 100-200T 3.43 3.46 20O-.iOO‘1’ 3.27 3.24 8.29 8 . 3 3 5WT-lM 250-5001’, 18.92 3.32 3.31 18.69 500T-1M 100-200T, 9.38 3.71 3.63 9 . 3 8 200-M)OT 9.05 lOOT 3.57 3.77 8 . 8 5 100-200T, 3 . 4 5 3.62 8.74 100-200”. 8 . 3 2 100-200T
-
e -
Furmula CiaHmOiNCl CsHuO8NCI C1iHa0aNCl CnHazOaNCl CnHoOiNBr’ CriHlrOnNCl CaHuOiNCl CzaHuO8NCl CuHstOaNCI CnHnOiNBr‘ CnHuOiNCl CaHoOaNCl %HaOaNCI
We are indebted to Mary Jane Eastwood and Elizabeth B . Macks for the analytical data on these compounds.
* The figures recorded represent preliminary results only but they are sufficiently accurate to permit a relative comparison
of the compounds. 1:2,OOO,OOO. 1:5OO,ooO. a Methobromides. f “&€Il, Piperidino. Compounds 1, 2, 3, 4, 5 , 6 , 1 0 and 11 were recrystallized from isopropanol and isopropyl ether, compounds 7,8,9 and 12 from isopropanol and ethyl ether, and compound 13 from isopropanol. 5
(1) Prepared for t h e 1945 meeting-in-print of the Division Medicinal Chemistry, A. C.S . fla) See Tsns JOURXCAL,67, 1897 (1915). (2) Blicke and Pelilkamp. i b i d . . 66, 1087 (1944)
of
these acids have nut been reDorted and are noted in the Experimental Part. The desired esters were prtbpared by the method of Horensteiti and
