K. L. SHRINER .WD
2x36
reduced niore easily than any reported type of organic compound. Reduction is effected a t room temperature, atmospheric pressure and in the absence of any catalyst The reaction is KK Hn --+ RE-I 3- KEI. The order of increasing ease of hydrogenolysis ( s i the phenyl derivatives is. Ca, Li, Na, K, Rb, C i This series follows essentially the series of rela-
+
JAMES
M. CROSS
Ird. Cio
tive reactivities as established by other reactants. The rates of hydrogenolysis appear to be unaffected by the presence of platinum and palladium ‘The rates of hydrogenolysis have been established for a series of RLi compounds having different K groups A?tr.s, I O I V A
KFCFIVI
u JULY 14, 1938
Urethans as Local Anesthetics. IV. Alkyl N-(p-Aminobenzy1)-carbamates BY R. L. SHRINEK AND JAMES M .CROSS
A study of the local anesthetic action of p aminopheriyl urethans (Formula I> showed that their anesthetic potency was high but that they were very irritating whether applied topically or intracutaneously. I t seemed possible that the irritation might be due to the p-phenylenediamine grouping present as a portion of the molecule since other derivatives of this compound have beeii found t o cause irritation.? In molecules of the type of alkyl N-(p-aminobenzyl)-carbamates (11) the urethaii grouping is separated from the benzene ring bv a methylene I HzNCaHtNHCOOR I1 H&GHaCHzPU”COOR 111 €I&;CsH~COOICH~ i,NR?
group and the p-phenylenediamine group is no longer present. The structure of urethans of type I1 is related to compounds of the novocaine type (111) in that each contains a p-aminophenyl radical attached to a carbon atom. Since the alkyl p-aminobenzoates are not especially irritating, i t was considered of interest to synthesize the urethans of type I1 in order to determine whether this structure would be non-irritating to the tissues but still retain the superiority in topical and injection anesthetic potency of the urpthans of type I over those of the p-aminobenzoates of type 111. The urethans were synthesized by means of the reactions summarized in Chart I. Although the find compounds are new, each of the individual steps in the above synthesis represents well-known reactions which were adapted to (11 Home, Cox and Shriner, Tars JOURNAL, 66, 3436 (1833) ( 2 ) Hanzlik, J.I n d . H y g , 4,386, 448 (19233: Erdmann and Rak im, Arch E x p l l Pnth Pharm , 53, 402 (1905)
HORTO
,
‘Id
NOz KOH
CHzNHCOOR
CH2NHCOOR
,
I
NO
t
NH? (11)
the present compounds with slight modifications which are given in the experimental part. Through the courtesy of the Lilly Research Laboratories the pharmacological action of ly0 aqueous solutions of the hydrochlorides of this series of urethans was determined. The data obtained are summarized in Table I The pharmacological data in Table I show that these urethans cause some local anesthesia when injected intracutaneously but that they are not especially active when applied topically. All of these urethans were irritating both to the skin and eyes and this fact probably accounts for the somewhat erratic results. These urethans are
Oct., 1938
ALKYLN-(@-AMINOBENZYL)-CARBAMATES AS LOCALANESTHETICS
2339
TABLE I rations using the above quantities and conditions gave PHARMACOLOGICAL ACTION OF ALKYL N-(#-AMINOBEN- an average yield of 10.6 g. (83.5%). The azide melted at 45' with decomposition. The azide decomposes upon ZYL)-CARBAMATE HYDROCHLORIDES standing and hence always was used within a few hours R O - IC 1 -N I -CH~~\-NH~ + c iafter it was prepared. Alkyl N-(pNitrobenzy1)-carbamates.-A solution of 10 Toxicity Anesthesia g. of the azide in 400 cc. of each of the anhydrous alcohols (mice) Skin Eyes was refluxed for three to four hours, a t the end of which (min.) (rnin.) mg./kg. time the evolution of nitrogen had ceased. The excess alcohol was removed by distillation and the residue chilled. 1000 30 None In most cases the urethan solidified and was recrystallized 340 25 None from ligroin. Four of the urethans were oils (see Table 11) 250 21 None which could not be crystallized satisfactorily and which de140 38 6 composed upon attempted distillation i n vacuo. The oils 125 11(?) 10 were washed with water and dried. The analyses of the 60 40 46 oils indicated that they were not quite pure but they were 30 None None sufficiently so for the next step. The data on the alkyl 50 None 36 175 100 90
10 45
None None 22
400 230 200 35 125
28 23 21 None 120
None None None None None
23
not as potent local anesthetics as the p-arninophenylurethans previously described.
Experimental Methyl pNitropheny1acetate.-Forty grams of p-nitrophenylacetic acid, prepared by the hydrolysis of p-nitrophenylacet~nitrile,~ was dissolved in 120 g. of absolute methanol and dry hydrogen chloride passed into the solution for two hours. The solution was refluxed for two hours and the excess methanol removed by distillation. The residue was extracted with warm ligroin and the resulting solution cooled in a n ice-bath. The ester separated in the form of colorless needles which melted at 54O. The yield was 83.5%. This procedure is a modification of the one used by Curtius," who obtained a 42% yield. p-Nitrophenylacethydrazide.-A mixture of 34 g. of the ester with 50 g. of 42% hydrazine hydrate solution was heated on a steam-bath for thirty minutes. At first a red coloration developed which gradually disappeared and the mixture solidified to a hard yellow cake. The product was washed with water and recrystallized from absolute ethanol. Thirty-three grams (97%) of needles was obtained melting at 167' which agreed with the value given by C~rtius.~ @-Nitr0phenylacetazide.-Twelve grams of the hydrazide was dissolved in two liters of warm water and 8 cc. of concentrated hydrochloric acid added. This solution was cooled t o 20' and 5 g. of sodium nitrite sifted in with vigorous mechanical stirring. The insoluble azide floated on the surface and was separated by filtration. Nine prepa(3) Robertson, "Organic Syntheses," Coli. Vol. I , John Wiley and Sons, Inc., New York, N.Y.,1932, p. 398. (4) Curtius, J . prokt. Chem., 197, 521 (1813).
TABLE I1 ALKYLN-(#-NITROBENZOYL)-CARBAMATES Alkyl Yield, M.p., ' C . Mol. N Analyses, % group % (torr.) formula Calcd. Found Methyl 68 104-105 CeHlo04Nz 13.33 13.53 Ethyl 63 115-116 C1~H1204N2 Ref. 4 n-Propyl CIIHI~OPNZ11.76 11.95 97 89-90 Isopropyl 76 107- 108 CllH1404Nz 11.76 11.75 n-Butyl 66 62-63 CizHi604Nz 11.11 11.06 Isobutyl 70 59-60 CizHieOiNz 11.11 10.94 2-Butyl 61 62-63 CizHieOiNz 11.11 11.24 n-Amyl 52 49-50 CiaHi804Nz 10.52 10.77 Isoamyl 70 Oil C13H1804N~ 10.52 10.03 2-Pentyl 70 50-51 ClsHla04N~ 10.52 10.49 3-Pentyi 55 50-51 C1~Hl~O4Nz10.52 10.72 2-Methyl1-butyl 70 Oil C l s H l ~ O ~ N10.52 ~ 10.10 +Hexyl 61 Oil C14Hz0O4N~10.00 10.92 n-Heptyl 63 Oil CISHZZO~NZ9.52 9.29 1-Octyl 63 48-50 CieH2404Nz 9.09 9.00 2-0ctyl 56 64-65 CisHzrOaNz 9 09 8.94 TABLE 111 ALKYLN-(~-AMINOBENZYL)-CARBAMATE HYDROCHLORIDES
Alkyl
group
Decomposition temp.,"
OC.
Mol. formula
C1 Analys.cs, % Calcd. Eound
Methyl 177-178 CgH130zNzCl 16.39 16.50 Ethyl 160-161 CioHisOzNaCl 15.41 15.05 n-Propyl 153-155 CiiHirOzNzCl 14.51 14.90 Isopropyl 177-178 Cl1H1,O2N2C1 14.51 14.60 n-Butyl 156-158 CizHisOzNzCl 13.84 13.84 Isobutyl 160- 162 CizHisOzNzCl 13.84 13.76 2-Butyl 153-154 CizHisOzNzCl 13.84 14.05 n-Amyl 152-154 CisHziOzNzCl 13.03 12.84 Isoamyl 157-159 CisHziOzNzCl 13.03 13.20 2-Pentyl 140-146 CiaHziOzNzCl 13.03 13.70 3-Pentyl 149-150 CisHz102NzCl 13.03 13.15 2-Methyl-lbutyl 152-153 CiaH210zNzCl 13.03 13.30 n-Hexyl 157-158 C14HzsOzNzCl 12.37 12.33 n-Heptyl 157-158 Ci~Hz~OZNzCl11.81 12.01 1-Octyl 159-161 CisHnOzNzCI 11.29 11.39 2-Octyl 147-148 Ci$HZ,OzNzCl 11.29 11.47 I n all cases these salts darkened 5 to 10' below the decomposition temperature.
23 .Io
'TORSTEN H;~SSEI,STROM AND JOHN D. MCPHERSON
N-(~-nitrobenzyI)-carbari~ates are suinniarized in Table 11. Alkyl N-(pAminobenzy1)-carbamates. - A solution of 5 g of the alkyl ru'-(P-nitrohenzyl)-carbarn~tein 100 cc. o f ahsolute ethanol ww shnkw -filth 1 ) ii' g of pia1 Inuiii o\i& platitiuiii black a n d hydrngeii at. :iatiti. prrssure. 'rile reductions were complete in three to ten niinirtes. T h y platinum was renrovrd by filtration a i ~ ihe l filtrate sarurated with dry hyrlrogen chloride. A n erlnal volume of absolute ether was addcd to facilitate the separation of t h e hydrochloride. Thr livctrochloride salts w m rriiioved bp iiltratioii. The yields varied from 5 0 to %l%, most of the loss being due 10 the difliculiies in causing complete separation of the hydrochlorides. Evaporation of the ald i o l - e t h e r mother liquor gave colored impure products which could not be obtained in a colorless condition by rccrystallization. T h e k i t a are summarized in Table 111.
TTol.BO
Summary A series of alkyl N-(p-nitrohenzy1)-carbamates was prepared by the action of the alcohols from methyl to octyl on the azide of p-nitrophenylacetic acid, Catalytic reduction of these nitro cornpounds and subsequent treatment with hydrogel1 chloride produced the corresponding hydrochlorides O i alkyl x-(p-amitiobenzyl)-carbamates. Solutions of these hydrochlorides produced intracutaneous anesthesia but orlly a few caused surface anesthesia. X11 w r r quite irritating to the tisT :KBAP;A, ILLINOIS
IIECEIVRD J U L Y 15, 1
iCrlNTKIHUTION O F T H F G & A LABORATORIES, I N C , SAVANNAH, GEORGIA]
Reactions Involved in the Sulfonation of Heat Treated Abietic Acid
nl' 'rORSTE?:
4ND JOHN HASSELSTROIM
Recent work of Fieser arid Campbell' oii deliydroabietic acid together with the investigations of Fleck and Palkin2 arid Littman3 has produced evidence that a-pyroabietic acid heretofore regarded as an isomeric abietic acid is actually a mixture of dehydroabieiic acid and hydrogenated abietic acids produced t h r o q h the reactions of dehydrogenation and dispropc,rtioiiatioii of abietic acid. I n a previous commuilicatioll we reported that the sulfonation o f heat treated abietic acid yields a crystallme sulfonic acid and as a by-product a lactone belonging to the tetrahydroabietic acid series of compounds Mre have obtaiiied e v deiice that the sulfonic acid5 has the composition of CmH~s05S3H20 and hence may be established as a dehydroabietic acid sulfonate. This identity is established further by the preparation of the dimethyl ester, diethyl ester and diamide of this sulfonic acid Since the lactoiie is saponified only with difficulty arid easily regenerated,i it is apparently a ?-lactone formed from a 1 '*'"-dih? droabietic acid as a result of hydratior1 due to the sulfuric acid employed Heiicr i t is likely that the correspoiiditig h~dros?-tttrahydrctabietic acid has the hydroxyl in positioii 10. It i5 worthy o f note that the addition of two atoms of hydroI) Fieser and Campbell Tars TCK,RYAI 60, 154 \l!I'Al (2) Fleck and Palkin, r b r d , 6 0 , '321 (1978) (3) Littman, rbrd , 60, 1419 (1938) (4) Hassefstroni, Brcnnnn and McPherqon ibtd , 60, 67 (19.78) ' 6 ) (a) Hasselstrotn I' b Patent 3,131 032 (1938) (b) Hasiel,(ram lr S Patmt 2 121 OR3 (193s) I
n.M C P H E R S O N
gen to abietic acid by catalytic means produces an easily lactonized dihydroabietic acid.6 This lactone formation in the abietic acid series points to the fact that on saturation of one double bond of the original abietic acid, the remaining double bond moves to a positioii more favorable for hpdratioii and lactonization. The results obtained by us on the sulfonation of heat treated abietic acid do not agree with those previously recorded in the literature. On sulfonation of a-pyroabietic acid Fanica' obtained a crystalline monosulfonic acid for which the formula CzoHJ~OSS was designated. He also reports as a residue a non-crystalline sulfur containing material Our findings that the sulfonation of heat treated rosin yields a dehydroabietic acid sulfonate and a lactone belonging to the tetrahydroabietic series ( ~ compounds f are additional proof that the dehydrogenation arid disproportionation of abietic arid occur on lieat treatment.
Experimental Dehydroabietic Acid Sulfonate.-The sulfonic acid was pr epared froin partially refined pseudopimaric acid according to Hasselstr~m.~'It was recrystallized from water. glacial acetic acid and water, in. p. 223-224" (dec 1 It wa5 dried a1 100" under vacuum. A n d . Calcd. for C Z O H Z ~ O & . ~ H C,~ O 55.29; : H,7.&3. (6) iaj Ruzicka and Meyer, He&#. Chim. Acta, 6, 333 (1922); (h) Kuzicka, Waldman, Meier and Htisli, ibid.. 16, 139 (1933). ( 7 ) (a) Fanica, BUZZ.inst. pin., 44, 161 (1933); (h) ibid., 45, 181 (1333); ( c ) Greth, Z . a?rctw. Chzm., 47, 927 (1934).
