Oct., 1942
PHYSIOLOGICALLY ACTIVEPHENETHYLAMINES WITH TERTIARY HYDROXYL [CONTRIBUTION FROM
THE
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CHEMICAL LABORATORY OF NORTHWESTERN UNIVERSITY ]
Physiologically Active Phenethylamines Containing a Tertiary Hydroxyl BY C. M. SUTERAND ARTHURW. WESTON' It has been found that the introduction of an suitable Grignard reagent upon the aminoketone alkyl group into the beta position of phenethyl- hydrochlorides. This method of preparing byamines2 or a-methylphenethylamine~~ lowers the droxyamines has been used by other investigaJ ~ J * some of the compounds toxicity without appreciably affecting the physio- ~ o ~ s . ~ J J ~Although logical action. The extension of this study to contained two asymmetric carbon atoms only one include the effect of alkylating the carbon atom racemic modification was formed. This behavior tearing the hydroxyl in amines of the type also occurs in the reaction between amino ketones CeH&H(OH)CH(R)NHR (R is H or CH3) and aryl Grignard reagentP and has been attribseemed of interest. uted to the effect of the adjacent carbon atom Despite the great number of ephedrine deriva- bearing the amino group. tives that have been prepared, only one reference* The hydroxyamines were not isolated but were to the desired alkylephedrines, C~HE.C(OH) (R)- converted directly into their hydrochlorides and CH(CH3)NHCH3 (R is CHs or C2HE.), was found. purified by crystallization. The yields were very A report on the vasoconstricting action of these good. The reaction of t-butylmagnesium chloride compounds was also included. Similarly, only the upon a-methylaminopropiophenone gave a mixmethyl derivatives of norephedrine, CBHSC(OH)- ture of amines whose hydrochlorides could not be (CH3)CH(CH3)NHzl6and of its isomer CeH&- separated readily. Apparently both reduction (OH) (CHs)CH2NHCH3 (I)"' have been de- and addition had taken place.ls scribed. Of the other possible series of amines, The toxicities13 of the amine hydrochlorides C~HE.C(OH)RCH~NH~(II), the methyl,4*ag~lowere determined on white mice by the method ethyl,4p10butyl," and cyclohexyl" compounds outlined earlier." The results are listed in the have been prepared and some preliminary pharma- last three columns of Table I. For comparison cological data reported.4~" More recently the purposes 2-amino-1-phenyl-1-propanoland ephed2,5-dimethoxy derivatives of I and IF2have been rine are included. synthesized. Preliminary data obtained from investigating In the present investigation representatives of the effect of these compounds on rabbits, dogs three series of amines containing a tertiary and guinea pigs indicate that in general their hydroxyl in which the beta group is alkyl, alkenyl, pressor activity is similar to that of ephedrine and or cycloalkyl have been prepared and some pre- phenylpropanolamine although the effect may liminary data on their toxicity and other pharma- be more transient. Tachyphylaxis was noted in cological properties obtained.13 All these com- all tests with these compounds. In accordance pounds were synthesized by the reaction of a with the previous observations2J the presence of an alkyl group beta to the amino group greatly R"MgX CBHECOCH(R)NHR'.HClreduces the toxicity without apparently impairing then Hz0 the activity. CsHsC(OH)(R")CH (R)NHR' Three of the norephedrine derivatives, the n(1) Sharp and Dohme Research Associate, 1938-1940. butyl, n-hexyl, and cyclohexyl compounds, were (2) Weston, Ruddy and Suter, unpublished work. (3) Suter and Weston, THISJOURNAL, 64, 533 (1942). examined for surface anesthesia on the rabbit's (4) Levy and Sergent-Montsaratt, Paris MLdical, 21, 148 (1931). cornea.l8 Some anesthesia was produced by the (5) Mills and Grigor, J . Chem. Soc., 1568 (1934). (6) Tiffeneau, Ann. chim. $kys., 181 10, 145 (1907). n-butyl and cyclohexyl compounds in 3% solution (7) Fourneau, J. phorm. chim., [6] 20, 481 (1904). but this was accompanied by a marked irritation (8) Fourneau, ibid., [7] 9, 337 (1909). (9) Jacobs and Heidelberger, J . B i d . Chem., 21, 436 (1915). which was particularly pronounced in the n-butyl (10) Tiffeneau and Cahnrnann, Bull. SOC. chim.. [5] 9, 1876 (1935). (11) Kanao and Shinozuka, J . Pharm. SOC.Japan, SO, 1152 (1930); C. A . , 91, 1636 (1931). (12) Baltzly and Buck, THISJOURNAL, 69, 161 (1940). (13) We are grateful to Dr. Paul H. Mattis and Mr. Albert R. Latvin of Sharp and Dobme for permission to include a summary of their experiments on the toxicity and pressor activity of these compaunds.
(14) Tiffeneau, Oryekhov and Roger, Bull. soc. chim., [4] 40, 1757 (1931). (15) Tiffeneau, LCvy and Ditz, ibid., [51 2, 1848 (1935). (16) Kharasch and Weinhouse, J. Org. Chem., 1, 209 (1936). (17) Suter and Weston, TRISJOURNAL, 68, 602 (1941). (18) We are grateful to Mr. Harry Robinson of Sharp and Dohme for a report of these tests.
c. 111. SUTER AND -4RTHUR w. WESTON
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VOl. ti4
TABLEI PROPERTIES OF AMINEHYDROCHLORIDES Yield,
%
Amine
CaHrC(0H)(Cd3dCHlNHz" CeHrC(0H) (c&H,-?~)clX&":* CaHrC(0H)(C€Ia)CH(NHdCHaC Ce&C!(OHJ (CIH~)CH(NHX)CHB Cb&C(OH) (OHrx)CH(NH,JCH3 CtHpC(0H) (CI&x-n)CH(NHx)CH3 CJtC(0H) (CsHusyclo)CH(NHz)CH3 CtHsC(0H) (CHdCH(NHCHdC1Ha' CsHrC(OH) ( C I S )CH(NHCHa) CHIP GKrC[OH) (CIH7-m)CH(NHCHi1CHn CiHC(0H)(CIHtn)CH(NHCHa) CHa GH+C(OH)(Ca€L)CH(NHCHdCHa' GHrCHOHCliMHtCHt CtHrCHOHCH(NHCHx)CH:
73
78 lj3
93 8.5 81 57 75 93
91 88 90
c1, %
M. p . , "C:.
Formula Calcd. 180 --I81 IXoxanP CioHieONCl 17.59 151 -152 Dioxane Ci~HmONC1 15.44 239 -239.jd Abs. alc. CiaHiiONCl 17.59 220..5-22Zd Acetone-alc. CitHliONCl 16.44 213 -216d
[email protected] CI~HISONCI14.55 193 -200d EtOAc-pet.ether c1&60NC1 13.05 261 -263'r' blc.-dioxane CirHuONCl 13.14 234 -238 'Abs. alc. CiiHieONCl 16.44 197.5-188.5' 9bs. a1c.-ether CirHSONCl 15.44 182.5-183.5d Chloroform CisHnONCI 14.55 149 -150 Acetone CitILiONCl 13.75 166.5-167.8 Abs. alc.--ether ClahONCI 14.67 (cor.!
SOlYQnt
Toxicity Poundh LDa LDno LDIN
17.66 15.49 17.69 16.47 14.53 12.94 13.11 16.44 15.44 14.25 13.75 14.88
'
400 200
600 200
200 300 200 900 400 200 200 300 100 200
630 900 310 601) 850 1100 350 450 315 4513 375 450 275 350 1100 1400 525 600 310 400 325 500 550 700 490 900 390 700
' Previously prepared by reduction of oxime, m. p. 183.5' (cor.) ref. 10; ref. 4, m. p. 184-186'. Ref. 11, m. p. 151Ref, 5, m. p. 244". Melted with decomposition. e This material forms a dihydrate which retained water of 152'. crystallization even after two hours at 100" and 40 mm. After drying at 140' for nine hours the solvent was lost but was regained when exposed to the air for a day. Anal. Calcd. for CuH,rONC1.2H*O: HzO, 11.78. Found: HtO, 12.46 Ref. 4, m. p. 192". Since the agreement between our m. p. values and those given in the Ref. 4, m. p. 245-248'. literature was not always entirely satisfactory, analyses for previously known compounds are included. The disagreement probably occurs because the "melting points" are decomposition temperatures and hence vary with the rate of heating. The allylmagnesium bromide was prepared according to the procedure of Gilman and McGlumphy, BuU. soc ckim., 43, 1322 (1928).
'
and n-hexyl compounds and was evident even in ITo solutions. Because of this undesirable effect only preliminary tests were made. Experimental Aminoketone Hydrochlorides.-The w-aminoacetophenone hydrochloride was prepared by hydrolysis of the product obtained from phenacyl bromide and hexamethylenetetramine.'* a-Aminopropiophenone hydrochloride was obtained by reduction of the corresponding isonitroso compoundz0 with stannous chloride*l while the N-methyl derivative was obtained by the action of methylamine upoil a-bromopropiophenone.2z Reaction of Aminoketone Hydrochlorides with Grignard Reagents.-The preparation of B-ethylnorephedrine is described as a typical example. A Grignard reagent was prepared from 5.3 g. (024 mole) of magnesium and a slight excess of ethyl bromide so that no unused magnesium remained. To the ether solution was added at 0" with stirring 10 g. (0.054 mole) of a-aminopropiophenone hydrochloride. Stirring was continued for several hours and the mixture was allowed to stand overnight.23 A two-layer (19) Slotta and Heller, B e y , bSB, 1037 (1930), Mannich and Hahn. ibrd., 44, 1548 (1911). (20) Hartung and Crossley, Org. Syn., 16, 44 (19363 (21) Behr-Bregawski, & Y , 80, 1521 (1897) (22) Hyde. Browning and Adams, THIS JOURNAL, 60, 2287 (1928) (23) This was unneeessary as there was little evidence of reaction after a few hours of stirring la the case of the higher alkyl Grr guards, however, it was sometimes necessary to reflux the mixture as iinreacted solid remained A f t e r t h e additlon
system formed. After hydrolysis with ice and dilute sulfuric acid the ether layer was removed and evaporated to dryness but left no residue. The aqueous layer was made alkaline, the amine extracted with ether, the ether layer dried over sodium sulfate and made acid with hydrogen chloride gas. The weight of air-dried material, m. p. 210212' (dec.), was 10.8 g. or 93% of the theoretical amount. Crystallization from an acetone-alcohol mixture gave 8.8 g., m. p. 219-221 ' (dec.). Further crystallization raised the m. p. only slightly to 220.5-222' (dec.). Essential data for this and other similar compounds are listed in Table I. All melting points are corrected. The yields given are for the crude products.
Summary 1. Twelve P-hydroxyphenethylamine derivatives in which the hydroxyl group is tertiary have been prepared by the action of aliphatic Grignard reagents upon aminoalkyl phenyl ketone hydrochlorides. Seven of the amines are new compounds. 2 . Toxicity data of these amines toward white mice indicate that they are less toxic than the corresponding hydroxy amines having no beta alkyl group. 3 . A preliminary report on other pharmacological properties of these compounds has been made. EVANSTON, ILLINOIS
RECEIVED APRIL11, 1942
