[CONTRIBUTION FROM
THE
LEDERLELABORATORIES D I V I s I o N , AMERICAN CYANAMID GO.]
AKr ANTIMALARIAL ALKALOID FROM HYDRANGEA. XV. SYNTHESIS OF 5-, 6-, 7-, AND 8-DERIVATIVES WITH TWO IDENTICAL SUBSTITUENTS B. R. BAKER, ROBERT E. SCHAUB, JOSEPH P. JOSEPH, FRANCIS J. McEVOY, AND
JAMES H. WILLIAMS
Received September 27, 1951
The study of the effect of benzene substituents on the antimalarial activity and chemotherapeutic index of the dl-form of the Hydrangea alkaloid has been continued (1). In this communication are described the syntheses of fourteen more derivatives of the dl-alkaloid. The method for the synthesis of the dl-alkaloid (2) was again employed by condensing l-carbethoxy-2-(y-bromoacetonyl)-3-methoxypiperidine with the appropriately substituted 4-quinazolone followed by two-stage hydrolysis of the blocking groups. -411 six possible dimethyl derivatives were synthesized. Four of the six possible dichloro derivatives were prepared; a fifth, the 5,7-dichloro, was replaced by the 5,7-dibromo in this series. The sixth isomer, 7,8-dichloro, was not synthesized since it was probable that it would be a poor antimalarial in view of the results obtained with other 7,8-disubstituted compounds. In addition, three tricyclic derivatives were synthesized, namely, 6,7-benzo, 6,7-tetramethylene, and 5 6-tetramethylene. The assay datal obtained with these compounds may be summarized roughly as follows : 1. Disubstitution in the 5,8- or 7,8-positions caused a great lowering of activity. 2. Disubstitution in the 5,7-, 6,7-, or 7,8-positions caused a lowering of the chemotherapeutic index and in some cases a decrease in activity. 3.5,6-Disubstitution gave an increase of about 30% in activity. The dimethyl derivative also had a doubled chemotherapeutic index, but the dichloro was unchanged in index.
I
I1
I11 0 II
1
The biological data are presented elsewhere by Dr. R. Hewitt and co-workers (3). 149
150
BAKER, SCHAUB, JOSEPH, MCEVOY, AND WILLIAMS
TABLE I ISOXITROSOACET.4NII.IDES
2 R 7
(,JNHCCH=NOH
-
R
GROCPS"
3, .l-Dible* 2,5-DiMe 2,4-DiMe 2,3-DiRIe 2,5-DiCl 3,5-DiBr 3,4- (CHz)4-'
BOIL PEBIOD
hin.)
YIELD,
2 5 8 3 15 15 12@
84 33.: 55d
%
M P.,
"c.
179-180d.b 151-153C 15&15gd 131-132' 166-168 197-200 147-150
Mc 22f llf S7f
LIT.
___ Y.P., "e.
148 (5) 165 (5) d
163 ( 5 ) 166 (8)
These compounds were prepared by the method employed for the parent isonitroso' acetanilide (6) with the exceptions noted. * Recrystallized from ethyl acetate-heptane' Anal. Calc'd for C10H12N~02:C, 62.6; H, 6.31; N, 14.6. Found: C, 62.5; H, 6.79; K, 14.7. c After recrystallization from toluene. After leaching oily impurities with toluene. ~-4naZ.Calc'd for ClpH12N202: C, 62.6; H, 6.31; N, 14.6. Found: C, 62.4; H, 6.45; N, 15.0. f Product isolated by solution of crude precipitate in 5% sodium hydroxide, filt,ration of by-products, and acidification. 0 At 75-80'. h For preparation of amine see ref. ( 7 ) . For preparation of amine see ref. (9).
TABLE I1
H M.P.,
COLOB
Red Orange Red Orange Orange Red Orange Orange-red Orange Orange Orange
25 75 46 91 57 60 99 68 88e 32 17
"C.
225-226 260-264 214-215 228-231 230-232 243-245d 239-241d 264-268d.d 254-2568 186190d. 176185d.
L r r . Y.P.,
"C
h
250 215 243 252
(5) (11) (12) (12)
252 (13) 275 (14) 189-190 (8) 189-190 (S)
4 Compounds prepared by 86% sulfuric acid ring closure (10) of the isonitrosoanilides of Table I unless otherwise indicated. * Recrystallized from 50% alcohol. Anal. Calc'd for C I ~ H D N OC,~ 68.6; : H, 5.18; N , 8.00. Found: C, 69.1; H, 5.57; N , 8.00. "Mixture of these two isatins obtained on cyclization of 3,4-dimethyl-~~-isonitrosoacetanilide. See experimental. e Recrystallized from methanol, crude m.p. 223-236". Anal. Calc'd for CsHsBrtl;02: C, 31.5; H, 0.98; S , 4.59. Found: C, 31.4; H, 1.18; N, 4.51.
151
AN ANTIMALARIAL ALKALOID FROM HYDRANGEA. X V
4. The most active compound obtained was the 6,7-dichloro with a quinine coefficient of 200, but an index of only 2. All of the required 4-quinazolones (V) (Table IV) were obtained by fusion of the proper anthranilic acid (IV) with formamide (4) except the 5,7-dimethyl where the anthranilamide was employed. Eleven of the thirteen anthranilic acids were prepared by alkaline peroxide oxidation of the corresponding isatins, 111, obtained from t,he available aromatic amines, I, via the isonitrosoacetanilides, TABLE I11
ANTHRANILIC ACIDS
-
R
GPOVPS~
5,6-DiMe 4,B-DiMec 3,6-DiMe 4,5-DiMe 3,5-DihrIe 3,4-DiMe 5,6-DiC1 3,6-DiC1 4,5-DiC1 3,B-DiCl 4,6-DiBr 5,6-(CHt)ci 4,5-(cHz)~-
ymw %
65b 91 58
81 65 69 59 59 99 39 73 62 86
x.P., "C. dec.
140-141 160-161 111-113 213-214 188-189 184-186 165-16ig 148-150
LIT. Y.P.,
'ec.dec.
b d
113 (10) e
187 (10) I
208
177 (15) 155 (15) 213-214 (15)
230-231d 170-171 114 171-173
135 (8) 183 (8)
h
a These compounds prepared by alkaline peroxide oxidation of the corresponding isatins (1) of Table I1 unless otherwise indicated. b M.p. 137-138' dec. Recrystallized from toluene. Anal. Calc'd for CoHltNOz:C, 65.5; H, 6.73; N, 8.48. Found: C, 65.2; H, 7.20; N , 8.17. The amide. See experiment. Recrystallized from xylene. Anal. Calc'd for C9HI1NO2: C, 65.5; H, 6.73; N, 8.48. Found: C, 65.1; H, 6.89; N, 8.38.1 Recrystallized from benzene. Anal. Calc'd for CoHl&On: C, 65.5; H, 6.73; N, 8.48. Found: C, 65.4; H, 6.59; N, 8.52. M.p. 173-174' after recrystallization from toluene. Recrystallized from dilute alcohol. Anal. Calc'd for C7H6Br2NO2: C, 28.5; H , 1.69; N , 4.75. Found: C, 29.1; H , 2.00; N, 5.11. i Oxidation allowed t o proceed one hour a t 60". @
11, by the Sandmeyer procedure (5). 3,5-Dichloroanthranilic acid and 3-amino2-naphthoic acid were known compounds prepared more simply by other means. Acknowledgement: The authors are grateful to Miss E. Sherman for extensive literature searches, to Mr. Louis Brancone and staff for the microanalyses, and to Messrs. Willard McEwen and John Poletto for large scale preparation of some of the intermediates. EXPERIMENTAL
&,6-(and 6,G)-Dimethylisatin. The crude isatin mixture obtained by cyclization of 55 3,4-dimethyl-a-isonitrosoacetanilidewith 292 cc. of 96% sulfuric acid and 29 cc. of
g. of
152
BAKER, SCHAUB, JOSEPH, MCEVOY, A N D WILLIAMS
water (10) was dissolved in 1200 cc. of water and 310 cc. of 107; sodium hydroxide. The solution was clarified with Xorit by filtration through Celite. The stirred solution was treated dropwise with 12 N hydrochloric acid until turbid, then 4-cc. portions of acid were added and a separate crop of solid collected after each addition. The first three portions of acid gave 12.6 g. of crude 4,5-dimethylisatin, m.p. between 205 and 214". The fourth portion gave no precipitate. The solution %-as then strongly acidified to give 23.3 g. of TABI..: I V
0
DISUBSTITUTED ~-&UINAZOLOSES
I R
GPOUPS'
ANALYSIS
42 70 70 57 59, 32i 62 73 92 84 83 89 43e 90
247-248d .b 288-291d .d 255-256d. 8 248-249d .b 244-2459 252-254' 271-272' 297-2989 287-2880 337-338d .E 29b296g 273-274k 214-2208 238-2398
__ H
C
5,6-DiMe 5,7-DiMec 5,8-DiMe 6,7-DiMe 6,8-DiMe 7,8-DiMe 5,6-DiC1 5,8-DiC1 6,7-DiC1 6,8-DiCl 5,7-DiBr 6,7-Benzoi 5,6-(CH2)4-I 677-(CHz),-
Found
__-
68.8 68.8 68.8 68.8 68.8 68.8 44.7 44.7 44.7 44.7 31.6 73.5 72 .O 72 .O
N
5.80 16.1 5.80 16.1 5.80 16.1 5.80 16.1 5.80 16.1 5.80 16.1 1.87 13.1 1.87 13.1 1.87 13.1 1.87 13.1
C
69.2 68.6 68.0 69.0 69.0 68.8 44.5 44.7 45.1 44.7 32.4 72.6 71.7 72.1
H
__
6.20 5.71 6.14 6.08 5.75 5.96 2.43 2.16 2.36 2.12 1.52 4.46 5.98 6.23
N
16.2 16.4 16.3 16.3 16.3 16.1 13.1 13.5 13.5 13 .O 9.26 14.1
14.3 14.0
These compounds prepared by fusion of the proper anthranilic acid with formamide as described for 8-chloro-4-quinazolone (1) unless otherwise indicated. b Recrystallized from Methyl Cellosolve-water. c By fusion of the anthranilamide a t 180" for 75 minutes. d Recrystallized from absolute alcohol. Recrystallized from methanol. Crude product leached with methanol. 0 Recrystallized from Methyl Cellosolve. b Recrystallized from toluene. Crude product leached with toluene. From the filtrate was isolated 20% of 2,3dimethylformanilide, m.p. 101-102". A n a l . Calc'd for COHIINO: C , 72.5; H, 7.44; Ti,9.40. Found: C, 72.2; H, 7.42; N, 10.1. 3 For starting amino acid see ref. (19). Recrystallized from xylene. I Fusion run at temperature of 110" for hour prior to usual conditions. 1
+
crude 5,6-dimethylisatin, m.p. 208-209'. -4 mixture of the two isatins melted a t 150-175". See Table I1 for further details. It is probable that acetic acid acidification would effectively separate these two isatins (8). This procedure has been found effective in all the cases tried. 4,6-Dichloroisatin. A mixture of 21.5 g . of 4-chloroisatin (16), 440 cc. of acetic acid, 20 cc. of sulfuryl chloride, and a crystal of iodine was stirred in a bath a t 50" for four hours. The cooled mixture deposited 5.6 g . of a product, m.p. 245-247". Concentration of the fil-
153
AN ANTIMALARIAL ALKALOID FROM HYDRANGEh. XV
trate in vacuo gave an additional 9.7 g. (total 60%), m.p. 231-233'. Recrystallization of a sample of the first crop from acetic acid afforded deep red crystals, m.p. 243-245". ,4naZ. Calc'd for CsH,Cl,N02: C, 44.6; H, 1.41; N , 6.50. Found: C, 44.4; H, 1.78; N , 6.47. This compound could be either 4,5-dichloroisatin or 4,7-dichloroisatin. These would yield 5,6-dichloroanthranilic acid, m.p. 177" (15), or 3,6-dichloroanthranilic acid, m.p. 155" (15), respectively. The anthranilic acid obtained melted a t 174" showing the chlorine had entered the 5-position. Similarly, the action of sulfuryl chloride on 6-chloroisatin (16) at 50" for seven hours gave 22 g. (68%) of orange-red crystals, m.p. 264-268" (14), of 5,6-dichloroisatin. TABLE V
ANALYSIS
R
Y.P..
GPOVPS"
"c.
45 21 53
46 52 b
I
Calc'd I
C
H
N -__
63.6 52.6 52.6 65.9 65.3
6.99 5.04 5.04 6.17 7.03
10.1 9.20 9.20 9.60 9.53
-I -140-141 63.6 6.99 10.1 147-148 129 130 167-168 116-117
Found C
63.7 7.21 63.5 7.02 52.3 52.9 65.5 65.4
10.2 10.4
1 These compounds were obtained by condensationof l-carbethoxy-2-(~-bromoacetonyl)3-methoxypiperidine with the appropriate x-R-4-quinazolone in the presence of sodium methoxide as described for 4-quinazolone (3). Where necessary an equal volume of Methyl Cellosolve was added t o dissolve the quinazolone in the 1 N methanolic sodium methoxide. The 4-quinazolones of Table IV which did not give crystalline condensation products were hydrolyzed directly t o the compounds listed in Table VI. * A sample of this material crystallized after several months. The crude oil was hydrolyzed (Table VI).
2-Nitro-4,6-dimethylbenzonitrile. T o a stirred mixture of 25 g. of pulverized 5-nitro-4amino-1,3-dimethylbenzene(Eastman) and 70 cc. of 6 N hydrochloric acid cooled in an ice-salt bath was added a t 0-5" solid sodium nitrite in portions until the amine dissolved (18.2 g . ) . The excess nitrous acid was destroyed with urea. The diazonium solution was added in portions t o a stirred solution of 35.6 g. of sodium cyanide and 34.5 g. of nickel chloride hydrate in 230 cc. of water warmed on the steam-bath. Nitrogen was evolved and a solid separated during the 45-minute addition. The orange-red product was collected and washed with water; yield, 20.7 g. (79%), m.p. 125-128". The patent literature (17) records m.p. 126", but affords no experimental details. %-Nitro-4,6-dimethylbenzamide. A mixture of 18.7 g. of 2-nitro-4,6-dimethylbenzonitrile and 50 cc. of Soyo(by volume) sulfuric acid was heated on the steam-bath under a condenser for five hours, then poured into excess ice. The dark solid was collected and the filtrate extracted several times with ethyl acetate. The solid was dissolved in the combined ex-
154
BAKER, SCHAUB, JOSEPH, MCEVOY, AND WILLIAMS
tracts. The filtered solution was concentrated in oacuo until the product began to separate; yield, 10.7 g. (52%), m.p. 169-171". The patent literature (17) claims that 80% sulfuric acid hydrolysis of the nitrile affords the acid, m.p. 180". That this compound is in reality the amide is shown by reduction and analysis of the amino amide which follows. 4,6-Dimethylanthranilamide.A warm solution of 12.9 g. of 2-nitro-4,6-dimethylbenzamide in 100 cc. of Methyl Cellosolve was stirred with 4 g. of Norit for 15 minutes. The filtered solution was shaken with hydrogen at 2-3 atm. in the presence of l g. of 10% palladiumTABLE V I
ANALYSIS
YIELD?
%
5,6-DiMe 5,7-DiMe 5,S-DiXle 6,7-DiMe 6,8-DiMe 7,S-DiMe 5,B-DiCI 5,8-DiC1 6,7-DiC1 6,8-DiC1 5,7-DiBr 6,7-Benzo 5,6-(CHz) 46,7-(CH2)4-
9.0 8.6 10 15 14 16 12 9.4 16 15 15 17 8.0
12
__ C
Calc'd N -
53.7
205
223-224 235 214
hemi none none di
51.5 53.7 51.5 54.8 53.7 43.7 43.7 44.6 44.6 35.7 56.3 52.7 55.9
-
4.72 4.59 4.59 4.57 5.81 6.90 6.65
1
I 1
1
1 ~
51.8 53.6 51.8 54.2 54.1 43.4
6.48 6.48 6.98 6.61 6.55 4.58
9.00 9.19 7.38 9.39 8.80 9.31
45.3 4.49 34.9 3.76 56.0 6.09 52.9 6.62 56.3 6.80
9.91 10.1 9.58 10.1 f 10.2 9.93 9.06 9.22 9.25 7.90 9.13 9.16 9.60
-
.These compounds were prepared b y 6 N hydrochloric acid hydrolysis of the compounds of Table V as described for 3-[~-keto-~-(3-methoxy-2-piperidyl)propyll-4-quinazolone dihydrochloride (2). * Based on original x-R-4-quinazolone of Table IV. charcoal catalyst until reduction was complete (20 minutes). The solution, filtered from catalyst, waa evaporated in vacuo;yield, 9.8 g. (91%), m.p. 155-159". Recrystallization of a sample from chloroform-heptane gave nearly white crystals, m.p. 160-161". -4naZ. Calc'd for CsHlJVzO: C , 65.8; H , 7.37; N , 17.1. Found: C, 65.9; H, 7.52; N, 17.1. J,6-Dichloroanthranilicacid. To a stirred solution of 20 g. of anthranilic acid in 500 c c . of acetic acid a t 40" was added 25 cc. of sulfuryl chloride over a period of 15 minutes with occasional cooling to maintain 40". After being stirred two hours more, the mixture was filtered. The wet solid was leached with 15% hydrochloric acid on the steam-bath; yield, 11.6 g. (39%) of gray solid, m.p. 230-231"; lit. m.p. 224226" (18).
155
A N ANTIMALARIAL ALKALOID FROM HYDRANGEA. XV
ANALYSIS
YIELD,
%
M.P.,
"c.
dec .
EYDBATE
Calc'd
Found
- - __ - - C
H
N
C
H
N
___
6.57 9.80 50.0 6.21 10.1 9.95 6.57 9.80 49.9 6.65 6.43 10.0 51.4 6.47 9.66 6.63 9.59 49.2 6.70 9.68 6.43 10 .o 51.5 6.61 10.0 6.43 10.0 51.4 6.26 9.67 4.50 9.12 41.4 3.99 9.58 4.44 9.31 43 .O 4.65 9.31 4.50 9.12 40.5 4.06 9.45 44.2 4.05 3.84 4 .OS 7.38 33.6 3 .E3 7.75 5.76 9.30 52.9 5.68 9.52 6.60 9.23 52.5 6.86 9.06 6.60 9.23 53.0 6.69 9.32 TO - - - -- Prepared by 48% hydrobromic acid hydrolysis of the compounds of Table V I as described for dl-alkaloid (2). 5,6-DiMe 5,7-DiMe 5,S-DiMe 6,7-DiMe 6,8-DiMe 7,S-DilMe 5,6-DiC1 5,S-DiCl 6,7-DiC1 6,S-DiCl 5,'I-DiBr 6 , 7-Benzo 5,6-(CH2)46,7-(CH?)0-
66 33 56 77 71 73 66 66 61 54 52 64 61
229 193 218 189 222 223 231 213 234 240 222 202 207 201
sesqui sesqui mono di mono mono mono hemi mono none di sesqui sesqui sesqui
50.3 50.3 51.4 49.3 51.4 51.4 41.6 42.6 41.6 43.4 33.8 53.1 52.7 52.7
0
SUMMARY
The syntheses of fourteen derivatives of the dl-form of the Hydrangea alkaloid containing two identical substituents on the benzene ring are described, all of which are active antimalarials. ]'EARL
RIVER,N. Y . REFERENCES
(1) BAKER,SCHAUB, JOSEPH, MCEVOY, AND WILLIAMS, J. Org. Chem., 17, Paper XIV of this series. (2) BAKER,SCHAUB, MCEVOY, AND WILLIAMS,J. Org. Chem., 17, Paper X I 1 of this series. (3) HEWITT,GILL,WALLACE, AVD WILLIAMS, A m . J. Trop. Med., in press. (4) NIEMENTOWSKI, J. prakt. Chem., [2] 61,564 (1895). (5) SAVDMEYER, Helv. Chim. Acta, 2 , 234 (1919). (6) MARVEL AND HIERS, Org. Syntheses, Colt. Vol. I, 327 (1941). (7) (a) ZAUGG,J. A m . Chem. SOC.,67, 1861 (1945); (b) ADAMS LVD NOLLER, J. A m . Chem. SOC.,46, 1892 (1924). (8) YON B R A U ~Ann., ', 461, 1 (1927). (9) JESELY A N D CHUDOZILOV, Rec. trav. chim., 44, 352 (1925).
156 (10) (11) (12) (13) (14) (15) (16) (17) (18) (19)
BAKER, SCHAUB, JOSEPH, MCEVOY, AND WILLIAMS
MAYER,SCHAFER, AND ROSEXBACA, Arch. Pharm., 267, 571 (1929). KRANZLEIN,Ber., 70, 1776 (1937). German Patent 514,595; Chem. Abstr., 26, 2157 (1931). GEIGY,German Patent 320,647; Chem. Zentr., IV, 223 (1920). RAPPORT, SENEAR,MEAD,AND KOEPFLI,J . Am. Chem. Soc., 68,2697 (1946). VILLEGER,Ber., 43, 3529 (1909). SENEAR,SARGENT, MEAD,AXD KOEPFLI,J . Am. Chem. Soc., 68, 2695 (1946). KALLEAND Co., German Patent 239,092. A X D MITTOX,J . Am. Chem. Soc., 69, 3142 (1947). ATKINSON ALLENILVD BELL,Org. Syntheses, 22, 19 (1942).
