Oct. 20, 1954
THIOL ESTERS
OF 4-AMINO-2-HYDROXYBENZOICA C I D
The infrared spectrum has absorption maxima that are attributable to hindered carbonyl, 1,2,4-trisubstituted phenyl and t-butyl groups and to the fluorine atom. Action of t-Butylmagnesium Chloride on Duryl p-Fluorophenyl Ketone.I2-The procedure was similar to that just
51-31
described. The crude product weighed 2.45 g. (84% yield) and, after crystallization from ethanol, melted a t 126127". A mixed melting point with an authentic sample of p-t-butylphenyl duryl ketone (V) was not depressed.
URBANA,ILLINOIS
[CONTRIBUTION FROM THE STERLING-WINTHROP
RESEARCH INSTITUTE]
Derivatives of 4-Amino-2-hydroxybenzoic Acid. 111. Thiol Esters BY R. 0. CLINTON, U. J. SALVADOR A N D S. C. LASKOWSKI RECEIVED MAY8, 1954 Dialkylaminoalkyl ester derivatives of 4-amino- and 4-alkylamino-2-alkoxythiolbenzoicacids have been prepared for testing as local anesthetics. Among these thiol esters have been found compounds far surpassing in activity any local anesthetics hitherto known.
In previous communications1r2from these labora- latter compounds, ;.e., through condensation of a tories there have been described several series of dialkylaminoalkanethiol with a 4-alkylamino-2dialkylaminoalkyl-4-amino- and 4-alkylamino-2- alkoxybenzoyl chloride hydrochloride, gave poor hydroxybenzoates and the corresponding 2-alkoxy- yields, and purification of the products was very and 2-benzyloxybenzoates, prepared in a search for difficult. The thiol ester derivatives of 4-amino-2-hydroxymore active local anesthetics. Prior investigations3 have shown that basic benzoic acid are listed in Tables 1-111. In order to determine whether the unexpectedly esters derived from thiolbenzoic acids are frequently more active as local anesthetics than the high local anesthetic activity found with the corresponding oxygen analogs (e.g., 2-diethyl- dialkylaminoalkyl 2-alkoxy-4-aminothiolbenzoates aminoethyl 4-aminothiolbenzoate (Thiocaine) vs. was anomalous, or could be ascribed to other alk2-diethylaminoethyl 4-aminobenzoate (procaine) 4), oxy aminothiolbenzoates, we also prepared several although this increase in activity is usually accom- position isomers of this type. In these isomers the panied by a proportionate increase in toxicity and a alkoxy group *occupied the 2-, 3- or 4-position and more than proportionate increase in i r r i t a n ~ y . ~the amino group occupied the 3-, 4- or 5-position; However, when we extended previous series'J included was the example given by Harris and to include the corresponding thiol esters, a sur- Braker.? All of these compounds proved to be prisingly large increase in local anesthetic activity much less active and much more irritating than the was noted and, further, this increase in activity was corresponding 2-alkoxy-4-amino analogs. The not accompanied by a proportionate increase in properties of these compounds are listed in Table irritancyS6 IV. Experimental9 A single position isomer of the compounds presently described has appeared in the literature. Dialkylaminoalkyl2-Alkoxy-4-nitrothiolbenzoates .-All of Harris and Braker7 have prepared 2-diethylamino- the nitrothiolbenzoates were prepared by a standard procedure, involving a definite ratio of components. An exethyl 3-amino-4-butoxythioIbenzoate, but no phar- ample follows. macological data on this compound have been To a stirred mixture of 26.7 g. (0.10 mole) of 2-hexyloxy-4published. nitrobenzoic acid, 9.5 g. (0.12 mole) of pure, dry pyridine The dialkylaminoalkyl 2-alkoxy-4-nitrothiol- and 300 ml. of drv benzene was added. droDwise. a solution 9.5 g. (0.08 mole) of pure thionyl chloiide in 50 ml. of benzoates were readily synthesized from the parent of dry benzene during a period of ten minutes. The hetero2-alkoxy-4-nitrobenzoic acids2 and dialkylamino- geneous mixture was stirred and refluxed for ten minutes, alkylthiols8 by a modification of the procedure cooled to 40°, and there was added slowly with stirring a used for the preparation of the corresponding oxy- solution of 8.0 g. (0.06 mole) of 2-diethylaminoethanethiol in 50 ml. of dry benzene. After stirring for ten minutes a t gen analogs2 Reduction to the 4-amino deriva- 50°, the mixture was cooled, water was added and the tives and subsequent reductive alkylation to the aqueous layer was made strongly alkaline by the addition 4-alkylamino derivatives offered no difficulties. of solid potassium carbonate. The benzene layer was The alternative path used for the preparation of the separated and washed with water, dilute sodium bicarbon(1) R. 0. Clinton, S . C. Laskowski, U. J. Salvador and Mary Wilson, THIS JOURNAL, 75, 3674 (19rj1). (2) R. 0. Clinton, S . C. Laskowski, U. J. Salvador and Mary Wilson, ibid., 74, 592 (1952). (3) R. 0. Clinton, U. J. Salvador and S. C. Laskowski, ibid., 71, 3366 (1919); N. F. Albertson and R. 0. Clinton, ibid., 67, 1222 (1945). (4) L. S. Fosdick and H. L. Hansen, J . Pharmacol.. SO, 323 (1934); Y. K. Nolle, Farm. i . Faumacol. (U.S.S.R.), No. 2. 1 (1937) [C. A . 54, 3820 (1940)l. (5) Inter al., Thiocaine is more than seven times as irritating as procaine by the Standard Trypan Blue test (unpublished observations of Dr. F. P. Luduena). (6) Preliminary pharmacological results: F. P. Luduena, R. 0. Clinton and S. C. Laskowski, Science, 118, 138 (1953). (7) S. E. Harris and W. Braker, U. S. Patent 2,342,142 (1944). ( 8 ) Cf. rei. 3 and references cited therein.
ate solution, and again with water. After drying over Drierite the benzene solution was decolorized by means of Darco G-60 and concentrated to dryness in zmcuo. The residual oil was diluted with toluene and again concentrated in vucuo to remove traces of pyridine. There was thus obtained crude 2-diethylaminoethyl 2-hexyloxy-4-nitrothiolbenzoate as a pale yellow oil. The yields varied from 8090%. The derivatives were prepared by the usual methods. Dialkylaminoalkyl 2 -Alkoxy - 4 - aminothio1benzoates.These compounds were prepared by the iron-hydrochloric acid reduction of the nitrothiol esters by the general method
(9) All melting points are corrected. They were determined in a modified Hershberg apparatus, using total-immersion N.B.S. calibrated thermometers. The sample was immersed 15O below the melting point, 3 O rise per minute. The analyses were done by Mr. M. E. Auerbach, Mr. K. D. Fleischer. and their staffs.
R. 0. CLINTON, U. J. SALVADOR AND S. C. LASKOWSKI
5122
Vol. 76
TABLE I h-02
DIALKYLAMINOALKYL 2-ALKOXY-4-NITROTHIOLBENZOATES
OOR
ZOS(CH~)~NR/~
Hydrochloride 1%
R
R'z
M.P., 'C.
Formula
146.4-147.9 157.0-158.0 109.0-110.6 200.0-201.1 117.2-118.8 185.0-185.8 185.9-187.7
CicHziCINtOiS Ci6HuClNtOiS CinHaClNeOiS Ci6HnC1NzOkS CiaHzaClNzOiS CisHzaClNzOiS CnHaClNeOiS
196.6-198.0 210.0-211.5 171.7-173.3 179.3-180.5 170.0-171.0 165.0-165.9 193.4-194.6 129.6-131.2 115.4-116.6 124.4-128.2 151.9-153.0
Analyses, ?Z Sulfur Nitrogen Calcd. Found Calcd. Found T y p P d
d
8.84
8.80
8.56
8.89
8.24
8.38
CizHz1ClNz0iS 7.95 CiaHeiClNzOiS 7 . 9 3 CiiHzrClNzOiS CiaHziClNzOkS 7.95
8. IO
B P F
8.15
P
CigHzsClNzOiS CieHaoClNzOiS CoHziClNzOiS CiaHzeClNzOiS CieHaiClNzOiS CisHzaClh'zOrS Ci9HaiClNoOiS
7.68 3.24' 8.36 7.94 7.36 8.52 8.48'
7.69 3.35c 8.20 7.91 7.635 8.50
8.46.
7.10
3.56' I 3.74c 7.24
6.UG
8.10
6.79 3.58'
6.66 3 . 80C
n
3.345 7.43 3.3P
M . p . , OC.
d
d
3.71' I 3.71' 7.43
Derivative Analyses, mo Sitrogen b h-itrogeii Calcd. Found Calcd. Found
n
3.40' 7 49 3.29'
B P P
P B P F P P P P P P
60.1- 61.2 118.2-119.2 131.4-132.2 65.6- 67.7 134.2-135.0 138.4-141.4 141.0-182.9 110.6-112.2 56.3- 5 7 . 2 128.9-129.6 164.5-165.2 135.9-137.2 103.4-104.4 115.8-116.6 96.4- 97.4 150.0-155.9 117.4-120.4
8.27P 2.40 2.46
8.1GP 3.43 2.49
2.40
2.40
h
2.35 2.39 7.0P 2.35 k
4.13 9.83 9.83 3.97 9.63
4.10 9.80 10.02 3.95 9.97
9.40 9.00 3.83 9.40
0..57 9.86 3.79 9.47
9.19 9.60 9.37 9,lB 9.84 9.16
9.2i 9.61
h
2.33 2.58 7.42p 2.34 k
2.29 2.40
2.28 2.38
2.29
2.26
9.13
9.14 9.71 9.3G
a B = base; F = flavianate; P = picrate. Amino nitrogen, by titration with perchloric acid i n glacial acetic acid solution. S i t r o nitrogen, by titration with titanous chloride. Calcd.: C, 48.24; H , 6.07. Found: C, 48.22; H , 6.11. e 1-Piperidyl. f Calcd.: C1, 9.45. Found: C1, 9.10. n-Propyl. * Calcd.: S, 9.41. Found: S,9.37. i 2-Methyl-lpiperidyl. j %-Butyl. k Calcd.: S, 9.22. Found: S, 9.26. &Butyl. n-Amyl. n Calcd.: C1, 8.75. Found: CI, 8.83. %-Hexyl. P Total nitrogen. q 1-Dimethylaminopropyl-2. For the thiol used, rf. R. R . Renshaw, et nl., THIS JOURSAL, 60, 1765 (1938). l,l-Dimethyl-2-diethylaminoethyl.For the thiol used cf, H.R. Snyder, et nl., &id., 69, 2672 (1947). a Chlorine analyses. Q
TABLE I1
DIALKYLAMINOALKYL 4-AMINO-2-ALKOXYTHIOLBESZOBTES
Salt
n
R
2 3
CHa CHa CHB CHa CzHa C3H7'" C3H7'" CaHP CaH7" C4Hgr C4H8 CIH~' CiHo' CiHg" CaHii" CeH2 CiHo' CiH7'
s i
3 3 9 2 3 2 2 9
3 '2
2 2
2 y I
R't
Typea
(CZH5)Z (CzHs)z (CzHa)z CsHioj (CzHa)a (CzHs!r CsHia' C5Hioi CeHiz' (CzHs)% CLHiaj C;Hmi CeHiP (C2Hs)a (CzHa)z (C2Ha)z (CH3)Z (CzHa),
Phd Ph Ph Ph
€1 Ph H DH DH H H H H H H H H H
M.P., "C. 188.2-190.0 208.0-208.9 198.1-199.1 202.5-203.4 175.0-176.3 150.4-151.8 189.2-190.9 170.4-172.0k P
135.0-155.5 172.3-173.9 135.0-157.0 191.2-192.3 163.0-164.2 150.2-151.2 110.2-111.6 122.9-126.8 lfi8.1-170.3
Formula
Analyses,
Nitrogen Ca1cd.c FoundC Calcd. Found Typeb
CiiHzaNz0~PS e CIIHZINZO~PS24.85 25.02 CiaH,9Nz06PS 24.00 24.29 CisHnN,OaPS 24.12 24.20 CiaHnrClNzOeS 10.22 10.40 CieHzsNaOaI'S 24.00 23.98 Ci7H~iCINzOzS 9 . 8 7 9.72 Ci~HaoClzN~0zS 7.838 7.770 CizH~oC1zNzOzS 17.32 17.61 C I I H Z ~ C ~ N ~ O 9.82 ZS 9.55 9 38 CiaHzsCINzOzS 9.50 CipHaiClNzOzS 9.10 9.35 9.02 CioHsiClNzOzS 9.16 9.82 9.61 CiiHzsClNz01S 9.66 CISH~ICIN~OZS 9.45 Ci9HaaCINsOzS 9.11 9.28 CieHnClN10zS 1 0 . 2 2 9.94 8.248 8.468 CioHaaCINzOzS
Derivative Analyses,
70
7.36 8.1ZQ 7.858 7.88' 8.07 6.85 8.930 0.84 0.84 7.76 7.51
7.35 8.24" 7.85g 7.94O 7.83 6.72 9.05" 6.61 7.11 7.03 7.38
7.24 7.70 7.47 7.20 8.07 7.20
7.28 7.66 7.45 7.02 7.95 7.17
'
f
M.p., "C.
F F F F
184.5-183.5 166.2-108.1h 171.3-172.Si 183.4-184.2k~1 178.0-177.0
F
158.0-1R3.0k
DF DF F DF
13O.0-140.Ok
DF DF DF DF DF
I'
..
Cilcd. 5.47l 10.50' 10.20°
10.30Q 10.O1°
410
Found 5,311 10.60Q 10.02Q 10.42' 10.048
5.80' 5.8iq
5 . T,?
195.0-1l)ij.O"
5.7?
.j
169.6-173.0' 1A7-174k 163-167k 182.9-189.2 183k
5.87'
(i.l4'7
179.0-181.0' 158.0k
w
5.71q na
5.71'I,hh
j.84q
,Ifi'l
w
5.sF.q Rn
5.81
Ph = phosphate, H = monohydrochloride, DH = dihydrochloride. b P = picrate, I; = flavianate, D F = diflavianate. The crystalline base had 111.p. 77.0Phosphoric acid analyses on phosphates; chlorine analyses on hydrochlorides. 78.0'. Calcd.: N, 9.92. Found: N, 9.75. 0 Calcd.: C, 44.19; H,6.58; S, 8.42. Found: C, 44.19; H, 6.44; S, 8.60. J 'Table I, ref. b. Sulfur analysis. A Shown t o be a monoflavianate hv the deternlination of primary aromatic amine through diazotization: Calcd.: Kmz, "29. Found: N N H ~2.32. , Cf.ref. h. Calcd.: NsH,, 2.24. Found: Nxrilr 2.34, i 1-Piperidvl. With decompositlon. I C j . ref. h. Calcd.: S N A 2.2ri. ~ , Found: Nxnz,--2.44. nb ?!-Propyl. 7' Calcd.: C, 50.93; H,5.06. Found: C, 51.18; H , 5.09. 2-ll.Ieth~-l-l-l,iperidyl. p Sintered a t lin-180", not tnelted a t 300". Table I, ref. c. n-Butyl. Calcd.: C, 51.68; €1, 5.26. Found: C, 51.41; H , 5.45. Calcd.: c, 58.97; H, 8.07. Found: C, 58.84; H, 8.10. " i-Butyl. "n-Amyl. w Calcd.: C, 47.19; H , 4.37. Found: C , 47.23; IT, 4.,58. n-Hexyl. See Ref. q , Table I. 2 See Ref. r , Table I. *a Cnlcd.: C, 46.04; H , 4.07; N, 8.95. Found: C, 46.20; TI, 4 1 6 : S , 8.74. Mi Cnlcd.: C, 47.74; H. 4.52. Found: C, 48.02: 11, 4.74. c
Q
0
THIOL ESTERSOF 4-AMINO-2-HYDROXYBENZOICACID
Oct. 20, 1954
5123
TABLE I11 NHR"
I
00.
DIALKYLAMINOALKYL 4-ALKYLAMINO-2-ALKOXYTHIOLBENZOATES
COS( CHI).PU'R'Z
Salt .n
R
R'n
R"
Type0
2
CHa CHI CHz CHI CHI CaHi
(CzHsIz (CrHa)i (CzHa!r C6Hioi (CZH6)Z (C2Hs)a
CaHii CaHiiOd OHs CkHs CrHs C4H8
DH DH B B B
2
3 3 4 2
DH
M.p., OC.
Sulfur
Formula
Analyses,
Calcl. Found
149.2-1.50.5 CieHs4ClrN,OaS 140.0-141.0 CieH34ClaNaOaS
7.57 7.25 CieH3nNzOaS 9.09 Oil Oil CaoHarNzOzS 8.79 CzoHuNaOzS 8.74 Oil 142.2-143.9 CrnHasClrNiO~S 7.29
7.44 7.29 8.91 8.73 8.56
7.16
Derivative
3'%
Calcd. e
16.08' 7.94P 7.6W 7.64' 16.13'
Found
Type6
Analyses, $& Calcd. Found
e
16.1Se 7.70' 7.94' 7.4gU 16.08'
P F F DF
*
P = picrate, F = flavianate, D F =I diflavianate. B = base, DH = dihydrochloride. Found: C, 53.82i H,.7.89. 5-Hydroxyamyl. Chlorine analysis. f See Table I, ref. c. decomposition. 1-Piperidyl. a
M.p., OC.
94.2- 96.0 153.9-155.oh 136.0-140.oh 160,5-161.6h
7.031 9.61e 9.44' 5.63f
7.271 9.64' 9.48' 5.65t
Calcd.: C, 53.89; H, 8.09. Nitrogen analysis. h With
TABLE IV 2-DIETHYLAMINOETHYLALKOXY-NITROAND ALKOXY-AMINOTHIOLBENZOATES COSCHEHzN( C Z H S ) ~ Hydrochloride
X"
Y
M.P., o c .
Formula
Analyses, % Nitrogen Chlorine Calcd. Found Calcd. Found
Typec
Derivative Analyses. yo Nitrogen M.p., 'C. Calcd. Found
3-OPr 4-NOp 130.0-131.2 CteHzsClNtOdS 3 . 71b 3. 71b 9.41 9.10 P 135.0-136.4 9 . 8 4 10.02 2-OBu 112.6-113.4 C~~H~~C~N 3.58b Z O ~3.60b S 9.07 9.05 P 68.4-70.6 9.60 9.56 2-OBu 5-NO2 169.0-170.5 C1,HziClNzOrS 3.5Sb 3.55b 9.07 9.23 P 110.5-111.9 9 . 6 0 9.44 P 128.6-129.6 9.60 9.64 4-OBu 3-NO2 139.6-141. 2d C ~ H Z ~ C I N P O3~. 5Sb S 3 . 52b 9.07 8.97 3-OPr 4-NHz 188.8-191.0 CleH~sC12NzOzS 7.30 7.13 18.50 18.30 DF 188.0-189.5" 5.96 5.83 2-OBu 3-"z 191.0-192.3 CI~HPOCIZNZOS 7.05 6.92 17.84 17.53 F 147.7-150.1 f h 2-OBu 5-ru"z 123.0-127.0 CnH~oCIzNzOzS 7.05 7.35 8.06' 7.87' 184.7-185.7 4-OBu 3-"z 115.2-115.8< Ci,H,oClpNzOL3 7.05 7.01 17.84 18.00 Cf.Table I, footnote c. P = picrate, F = flavianate, D F = diflavianate. a OPr = n-propoxy; OBu = n-butoxy. Harris and Braker, ref. 7, reported m.p. 100-105°. With decomposition. f Calcd.: C, 50.77; H, 5.37. Found: C, 51.05; H, 5.48. Sulfur analyses. Hemiflavianate. Calcd.: C, 48.28; H, 4.70; S, 10.07. Found: C, 47.90; H, 4.98; Reported (ref. 7) m.p. 123-125'. S, 9.97.
'
!J
previously outlined.2 The aminothiol esters were obtained in yields of 8 5 9 5 % . Dialkylaminoalkyl 2-Alkoxy-4-alkylaminothiolbenzoates. -The reductive alkylation of the aminothiol esters by means of an aldehyde, zinc dust and acetic acid' gave the bases in yields of 8@8 -5%. This procedure was found preferable to the direct preparation from a 2-alkoxy-4alkylaminobenzoyl chloride hydrochloride and a dialkylaminoalkanethiol. In certain cases (cf. Table 111) where a crystalline water-soluble derivative could not be prepared, the bases were purified by a method previously outlined.' Alkoxynitrobenzoic Acids.-The two new alkoxynitrobenzoic acids used in the present work were prepared by alkylation of the hydroxynitrobenzoic acids with butyl ben-
zenesulfonate as previously described,z followed by saponification of the oily intermediate esters with sodium hydroxide in dilute alcoholic solution. 2-Butoxy-3-nitrobenzoic acid: yellow needles from Skellysolve B, m.p. 52.5-54.0'. Anal. Calcd. for CllH18N06: C, 55.20; H , 5.49; N, 5.86. Found: C, 55.65; H , 5.18; N, 5.81. 2-Butoxy-5-nitrobenzoic acid: yellow prisms from ethanol, m.p. 117.4-118.9° Anal. Calcd. for C11H1aNOs: C, 55.20; H , 5.49; N, 5.86. Found: C, 55.43; H , 5.32; N, 5.92. RENSSELAER, NEW YORK
