Bulletin on Malaria. 
Research . Page 
BOARD FOR THE COORDINATION.OF MALARIAL STUDIES 
2101 Constitution Avenue, 
Washington 25, D. C. 
1138 
Minutes of the Meeting of the 
CONFERENCE OF CMR CONTRACTORS 
ON THE SYNTHESIS OF AW^ARIAL DRUGS 
Chicago, Illinois 
19-20 July 1945 ' 
Dr. Marvel called the Conference to' order at 10:00 A.M. on 19 July 1945 at 
'the Blackstone Hotel, Chicago, Illinois. The following were present:' 
Dr. C. S. Marvel (Chairman) 
Dr.'.Roger Adams 
Dr.' Robert H. Baker 
' Dr.'F. W. Bergstrom 
Dr.' Kenneth C. Blanchard 
DtY E. L. Buhle " • 
Major B. A. Bull' 
Dr. Barbara Campbell 
Dr. Kenneth Campbell 
Dr. G. A. Carden, Jr. 
Dr. Robert B. Carlin 
Dr. Marvin Carmack 
Dr. John M. Chermerda 
Dr. Bert Christensen 
Dr. George H. Coleman 
Dr. A. C. Cope 
Dr. Lyman C. Craig 
Lt. L. D. Dibble 
Dr. Nathan L. Drake 
Dr. David P. Earle 
Dr. Robert C. Elderfield 
Dr. Louis F. Fieser 
Dr. H. E. French 
Dr. R. C. Fuson 
Dr. Marshall Gates 
Dr. W. J. Gensler 
Dr. Henry Gilman 
Dr. C. S. Hamilton 
Dr. Elden B. Hartshorn 
Dr. A. Baird Hastings 
Dr. C. R. Hauser 
Dr. Charles D. Hurd 
Dr. Thomas L. Jacobs. i 
Dr. Charles F. Jelinek 
Dr.' J. E. Kirby 
Dr. W. R. Kirner 
Dr. J. B. Koepfli-' ■ 
Dr.'W. M. Lauer 
Dr. Melson J. Leonard - 
Dr* Robert F. Loeb 
Dr. Robert E*. Lutz 
Dr. E. K.'Marshall, Jr. 
Maj or Matthew W. Miller 
Dr. Alexander M. Moore 
Dr. Erich Mosettig 
Dr. D. E. Pearson 
Dr. Charles C. Price 
Dr. Byron Riegel 
Dr. L. H. Schmidt 
Dr. R. S. Schreiber 
Dr. James A.Shannon 
Dr. Clarence S. Sherman 
Dr. Mary L. Sherrill 
Dr. D. W. Sherwood 
Dr. R. L. Shriner * 
Dr. Mark A. Stahmann 
Dr.- John V. Taggart 
Dr. b. Stanley Tarbell 
Dr. Cheves T. Walling 
Dr;'Frederick Y. Wiselogle 
) • , 
SUMMARY OF THE PHARMACOLOGICAL TESTING PROGRAM: Dr. E. K. Marshall, Jr. 
The chief problem confronting the pharmacologists has been. the..establishment 
of a suitable test for the evaluation of curative action.. Dr. Marshall reviewed 
the results of screening tests on the more important classes of drugs which have 
been developed to date. ■ ' . . . .. Bulletin on Jfelaria 
CONFIDENTIAL Research Page 
-With^he. ,4-aminoquinolines, of which about 155 have been tested and several 
found more" .effective than quinacrine as suppressives against vivax, avian screening 
has been effective and has shown good correlation with results in man. In general, 
experiments with two hosts and two parasites provide an adequate screen for activity 
against trophozoites. The most effective class of these drugs appears to be 4-amino- 
7-chloroquinolines with various side~chains; recently, however, there is some 
evidence to suggest that the 7 fluoro"compound may be superior to its chloro analog. 
In the quinoline methanols with Ainley-King (a-pipiridyl) and King-Work (diulkyl- 
aminomethyl) side chains, synthetic work has been fruitful in that, in the Ainley- 
King series, structural modifications of the original member of the series has 
resulted in 150 fold increase in the quinine equivalent accompanied by an only ten- 
fold increase in toxicity. In general, the King-Work series show even lower 
toxicities; but, since the examples prepared to-date have very low solubilities, 
their absorption in the body tends to be erratic and incomplete. 
An important goal in the antimalarial program is the development of an effect- 
ive curative agent. In avian screening tests several sulfanilamides are effective 
prophytactically, the best being $N 11,437, N' (5-chloro-2-pyrimidyl) metanilamide. 
It shows a quinine equivalent of Q - 16 to Q - 64 in different infections. It 
is causal prophylactic against lophurae in the turkey, gallinaceum in the chick, 
and cathemerium in the canary, but, rather strangely, shows no curative action. 
Unfortunately, it has no causal prophylactic action against either vivax or 
falciparum in man. The naphthoquinones have striking prophylactic activity in avian 
infections, but do not carry over in man. 
The most important goal of the program at present is the development of a 
drug which cures.- vivax in man. Right now, the best lead seems to be in the 8- 
aminoquinoline series, representatives of v/hich are curative in avian infections, 
and are now receiving clinical evaluation. 
TOXICITY OF THE 8-AMINOQUINOLINES: Dr. L. H. Schmidt 
Although, in lower animals, toxicity differences between members of this 
series are merely a matter of degree, in monkeys an important differentiation in 
kind occurs. 
Most 8-aminoquinolines in toxic doses produce hematological disorders- 
cyanosis, methemoglobinemia, etc...-which are reversible. However, those having 
a side-chain in which a secondary or tertiary amino group is separated from the 
aminoquinoline group by only two or three carbon atoms attack the central nervous 
system, producing profound anatomical lesions and resulting in irreversible 
neurological disturbances. Combination of data on avian screening and monkey 
toxicity has shown the most promising 8-aminoquinolines at present to be those in 
which the side-chain amino groups are separated by 5 - 6 carbon atoms. Dr. Schmidt's 
report has been reproduced as Malaria Report #469* 
SUMMARY OF THE CLINICAL TESTING PROGRAM: Dr. James A. Shannon 
The Clinical Testing Program was discussed by Dr. Shannon with particular 
emphasis on the changing objectives towards which the whole antimalarial program 
has been directed. At the outset of the work, the value of quinacrine as an anti- 
malarial was not appreciated, and emphasis was on the development of a quinine 
substitute. By 1943 there was recognition of the fact that quinacrine is superior 
1139 Bulletin on mlarie 
CONFIDENTIAL Research Page 
to quinine as a suppressive in vivax malaria, and an effective cure for falciparum 
malaria, at that time regarded as the greatest threat. At the same time, a large 
number of.miscellaneous compounds had,,been -put through screening, tests, with only 
a few classes showing antimalarial action. Accordingly (1943-44) it was decided 
to devote most of the effort of the program to these classes, in the hope that a 
drug showing enough action as a suppressive might turn out to be a curative for 
vivax as well. This hope met with disappointment when drugs such as SN 7618, 
which produces toxic reactions only.at blood-levels 25-50 times that required for 
suppressive action, failed to cure.vivax at near the maximum tolerated dose. ; 
Accordingly, this winter the program was shifted again towards finding drugs with. ■ 
a different mode of action from quinine and quinacripe. At present, the 8-amino- 
quinolines appear to offer the best lead, particularly when taken in ..combination 
with quinine. Thus,> .although experiments at present are incomplete, nine;patients 
with sporozoite induced vivax given 2 grams. :of quinine and ninety milligrams.. of 
plasmochin daily for 14 days (starting on the 5 th day of fever) have.given np 
relapses in 18 weeks. On the other hand, although it delays the primary attack, •, . 
plasmochin has been only partially effective as a prophylactic. 
Unfortunately, aside from toxicity studies which eliminate some compounds 
as too dangerous, there is no good, screening test for curative action. As. it takes 
about six patients and thirty days to evaluate a drug roughly, and thirty patients 
and ninety days to compare two similar drugs, selection•of,the most, promising . 
8-aminoquinoline ,will deplete clinical material for other purposes.. ... 
SUMMARY OF ACTIVE LEADS: Dr. F. Y. Wiselogle < , „• . ;'r 
A summary, of the vast amount of work done by the purvey Office in correlating 
and making .available the results, of screening tes ts on antimalariala was made by 
Dr. Wiselogle;in the form of a discussion of all the .'.classes of .compounds which 
have shown antimalarial action in screening tests. This discussion will be found, 
summarized in tabular form in Malaria Report #h93» 
SUMMARY OF EUROPEAN ANTIMALARIAL WORK: Dr. K. C. Blanchard' •• -- 
Dr. Blanchard reported on the'.information which.he gathered on his recqnt 
trip to Germany. Despite the evaluation of a large number of compounds,, the I.G., 
laboratories at Elberfeld developed no drugs superior to quinacrine and plasmochin. 
Dr. Blanchard discussed the'procedure.of drug preparation and evaluation at 
Elberfeld, and mentioned that both SN 7618 and SN 6911 were prepared, but that the 
former was early discarded as more toxic and no more effective than quinacrine. 
Further details of the report appear in Malaria Report #493, Section III. 
WORK OF DIVISION 9 OF NDRC: Dr. A. C. Cope 
A year ago, when the university contractors under Division 9 finished work on 
other projects, they were shifted to the preparation of intermediates for the anti- 
malarial program, and, recently, they have begun the preparation of some finished 
drugs as well. A summary of all intermediate compounds prepared by Division 9 
appears in Appendix !• 
Following Dr. Cope's report, Dr. Marvel, as chairman at the meeting, expressed 
the appreciation of everyone on the antimalarial program for the cooperative work 
of Division 9. Tho vast.amount of tedious oreoarative work they have done has en- 
1140 Bulletin on Malaria 
CONFIDENTIAL " Research Page 
abled the other contractors to turn out many more drugs than would otherwise have 
been possible. 
SUMMARIES BY REGIONAL DIRECTORS: 
Work on the 'West Coast has been mostly on the. quinoline methanols, with Eastern 
and Middle-western contractors concentrating on the aminoquinolines. The program 
now has three industrial contracts - duPont working on finished drugs and some 
special side-chains, Sharples using their specialized knowledge of amines hydrogenatic 
and their semi-wbrks equipment to prepare larger quantities of intermediates 
(particularly special side-chains), and National Aniline devoting its efforts to 
the large-scale synthesis at 4,7-dichloroquinoline and SN 7618. . Dr. Elderfield also 
reviewed the functions'of the Steering Committee of the Panel on Synthesis which 
assigns the preparation and- priority of specific drugs. 
GENERAL CONTRACT MATTERS: Dr. George A. Carden, Jr. 
Dr. Carden stated that all contracts were in process of being extended to.. 
31 December, 1945, and that, in all probability, synthetic work would, continue 
at the present scale until 1 July, 1946 pending unforeseen sudden termination of 
the war with Japan. As it is particularly important that we continue to obtain 
deferrment for trained personnel, he requested that all 42-A (Special Revised) forms, 
etc., for Mr. Bailey at the OSRD be sent through his. office to insure that they are 
handled promptly and that they receive suitable attention. Dr. Carden then thanked 
the contractors for the enthusiasm and cooperation they have shown despite.the 
sudden shifts on direction of the overall program which has inevitably led to 
abrupt changes in interest in specific compounds. The meeting then adjourned until 
the following morning. - . . . , , 
REPORTS ON SYNTHETIC WORK: 
The second day of the meeting was devoted to discussions of their programs by 
the different contractors. Detailed abstracts of these talks will be found in 
Appendix II< . • . 
The meeting then adjourned at 4:00 P. M., Friday,..July 20. 
1141 RESTRICTED 
July 3, I9U5 
A. C. Cope 
Antimalarial Intermediate Preparations Completed in Division 9, NDRC Division 9» NDR. 
July, I9UU - July 3, I9U5 
T 
Exhibit- 
No. 
Date 
assigned. 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
13 
8/7/44 
5 ke* 
^-Diethylamino- 
propylamine 
Homer Adkins 
and A.L.Wilds 
/ 
500 g. to J. E. Kirby 
500 g. to C. R. Hauser 
400 g. to N. L. Drake 
Balance to R. C. Elderfield 
Completed 
Shipped on 9/4/44 
Shipped on 9/9/44 
Shipped 416 g. 9/20/44 
Shipped 3825 g. 10/26/44 
14 
8/15/44 
200-300 g. 
Cis- ^-decalone 
it 
I. E. Eieser 
Completed 
Shipped 218 g. 9/23/44 
39 
10/2/44 
25 s. 
Spermine 
tt 
K. C. Blanchard 
Completed. 
Shipped 45.6 g. of spermine 
tetrahydrochloride 3/^/^5* 
40 
10/2/44 
25 g. 
Spermidine 
it 
K. C. Blanchard 
Completed. Shipped 12.5 £• 
of spermidine trihydro- 
chloride 1/13/45. 
46 
10/24/44 
100 g. 
2-(Diethylamino- 
methyl)-4- 
aminocy clo- 
hexanol 
n 
N. L. Drake 
Cancelled. ® £ 
co f- 
O F- 
p a 
4 c 
b4 d 
4? 
10/24/44 
4 kg. 
Di-n-nonylamine 
ti 
R. C. Elderfield 
• 0 
£ 
Completed. , 
Shipped 474 g. 11/25/44 ; .g 
Shipped 501 g. 11/29/44^ » 
Shipped 1395 g. 12/15/^ . 
Shipped 1642 g. 1/29/45 V 
Shipped 16/ g. 2/27/45 
Also shipped 550 g. of 
mono-n-nonylamine 2/27/454 
1142 No, 
Dp op 
assigned 
Amount 
Compound 
Contractor 
Preparing 
Compound 
RESTRICTED 
2> 
Shipped to 
Status 
70 
ll/27/UU 
50 g. 
2-Diethylamino- 
methyl-U- 
aminophenol 
hydrochloride 
Homer Adkins 
and A.L .Wilds 
L. H. Schmidt 
/ 
Completed. 
Shipped 81 g. I/I3/U5. 
92 
2/20/U5 
500 g. 
Hydrindene 
M 
E. R. Buchman 
Cancelled. 
10U 
3/5/H5 
1 kg. 
Methyliso- 
propylamine 
n 
R. C. Elderfield 
Completed. 
Shipped 505 g. on U/28/U5 
Shipped 600 g. on 5/IO/U5 
1143 
RESTRICTED No. 
Date 
assigned. 
Amount 
Compound 
Contractor 
preparing 
compound 
RESTRICTED 
3 
Shipped to 
Status 
16 
7/15/^ 
1.5 kg. 
Tetrahydro- 
phenanthrene 
9-aldehyde 
G. H. 
Coleman 
0.5 kg. to E. R. Buchman 
(first) 
Completed. 
Shipped 94 g. 10/9/44 
Shipped 234 g. 11/18/44 
(this amount will be 
enough for Dr.Buchman) 
1 kg. to L. F. Small 
Completed. 
Shipped 510 g. 12/7/44 
Shipped 270 g. 1/6/45 
Shipped 235 g. 2/26/45 
17 
7/15/"**+ 
1 kg* 
1-Diethylamino- 
3-aminobutane 
u 
R. C. Elderfield 
Completed. 
Shipped 1091 g.» final 
shipment on 9/2/44 
18 
8/9/44 
2 kg. 
|?-Di e t hyl am i n 0- 
ethylamine 
11 
1 kg. to J. E. Kirby 
1 kg. to R. C. Elderfield 
Completed. Final 
shipment on 9/22/44. 
Completed. Shipped 
1094 g.» final ship- 
ment on 10/24/44. 
19 
8/15/44 
1 kg. 
9-Acetyl 
phenanthrene 
it 
0.5 kg. to R.C.Elderfield 
0.5 kg. to Erich Mosettig 
Completed. Shipped 650 g. 
Completed. Final shipment 
on 11/1/44. 
20 
8/15/44 
500 g. 
9-Acetyl tetra- 
hydrophenanthrene 
« 
0.5 kg. to Erich Mosettig 
Completed. 
Shipped on 9/15/44 
20a 
9/28/44 
500 g. 
It 
n 
0.5 kg. to R. C.Elderfield 
Completed. 
Shipped on 10/24/44 
RESTRICTED 
1144 No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
RESTRICTED 
Status 
4 
20b 
9/29/44 
500 g. 
9-Acetyl tetra- 
hydrophenan- 
threne 
G. H. 
Coleman 
0.5 kg. to L. F. Small 
Completed. 
Shipped on 10/24/44. 
20c 
10/24/44 
5 
n 
ti 
R. C. Elderfield 
Completed. 
Shipped 1190 g. 11/28/44 
Shipped 2210 g. 12/5/U4 
Shipped 2115 g. 12/13/44 
Total of 5515 £• 
21 
8/29/44 
800 g. 
Rhenanthrene- 
9-aldehyde 
n 
300 g. to E. R. Buchman 
500 g. to E. Mosettig 
Completed. 
Shipped 150 g. 10/27/44 
Shipped 130 g. I/II/45 
Shipped 20 g. I/23/U5 
Shipped 110 g. 2/1/45 
Shipped 248 g. 2/23/45 
Shipped 164 g. 4/11/45 
55 
10/30/44 
2 kg. 
3-Chloro-5- 
nitrohenzoic 
acid 
n 
L. F. Small 
Completed. 
Shipped 50 g. 3/16/45 
Shipped 360 g. 5/25/^5 
Shipped 1441 g. 6/19/45 
56 
11/17/44 
500 g. 
4-Chloro-l-aceto- " 
naphthone 
T. L. Jacobs 
Completed* 
Shipped 200 g. 12/12/44 
Shipped 300 g. 1/10/45 
62 
11/17/44 
500 g. 
4-chloro-l- 
naphthaldehyde 
11 
E. R. Buchman 
Completed. 
Shipped 112 g. 1/24/45 
Shipped 260 g. 2/1/45 r 
Shipped 233 g. 2/8/45 f 
Shipped 12b g. 3/31/45 I 
bd 
RESTRICTED t 
1145 No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
RESTRICTED 
Shipped to 
Status 
81 
*3 
83a 
83b 
83c 
92 
103 
105 
1/2/U5 
1/2^5 
1/25^5 
2/14/45 
3/1U/U5 
2/8/45 
3/5/45 
3/5/^5 
1 kg. 
1.5 kg. 
1 kg. 
2 kg. 
5 kg. 
1 kg. 
3 kg. 
200 g. 
Ethyl cyclo- G. H. 
hexanone-2- Coleman 
carboxylate 
Nitrosomethyl " 
urea 
tt n 
H M 
n 11 
2-Cyclohexyl-U- M 
tert, butylphenol 
6-Methoxy quinoline " 
2-Chloro-U- " 
aninoanisole 
L. F. Small 
R. E. Lutz 
If 
II 
II 
F. Y. Wiselogle 
R. C. Elderfield 
L. F. Small 
Completed. 
Shipped 616 g. 2/2/45 
Shipped 575 g. 2/8/45 
Completed. 
Shipped 700 g. 1/12/U5 
Shipped 8U2 g. 1/20/45 
Shipped 1070 g. 2/5/U5 
Shipped 2 kg. 3/2/U5 
Shipped 2100 g. 3/16/45 
Shipped 3U86 g. 3/22/U5 
Completed 
Shipped 650 g. U/3/U5 
Shipped 350 g. U/U/U5 
Also shipped 5^0 g. to 
R. C. Elderfield U/2E/U5 
Completed. 
Shipped 3U3U g. on 5/2/^5 
Completed 
Shipped 50 g. on 4/17/45 
Shipped 150 g. on 5/5/U5. 
126 
5/10/45 
50 g. 
6-Aminohexanol-; 
L « 
B. E. Christensen 
Completed. . 
Shipped 71 £• on 5/31^0. 
W b 
CD C 
02 
0 F- 
CO CD 
1UO 
6/15/45 
100 g. 
U-Chloro-1- 
naphthoic acid 
n 
E. R. Buchman 
Completed. 
Shipped on 6/2/U5* 
RESTRICTED f 
6 b.< 
0 
pi 
•~d - 
s £ 
Q 55 
1146 No. 
Date 
assigned 
Amount 
RESTRICTED 
s. 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
26 
& 
26a 
7/15/44 
8/18/44 
14.1 kg. 
total 
Ethyl ethoxy- 
methylene- 
malonate 
R. C. 
Fuson 
1014 g. to M. Lauer 
1010 g. to B. Riegel 
506 g. to R. C. Elderfield 
1181 g. to C. C. Price 
1504 g. to C. S. Hamilton 
1010 g. to C. C. Trice 
14o6 g. -to C. C. Price 
4500 g. to C. C. Price 
Completed. 
More than 14.1 kg. 
was prepared 
27 
28 
7/28/44 
and 
8/15/44 
8/9/44 
10 kg. 
3 kg* 
4,7-Dichloro- 
quinoline 
Di-n-octylanine 
n 
fi 
412 g. to C. M. Suter Completed. 
100 g. to R. S. Shreiber A total of 10.5 kg. 
526 g. to C. C. Trice was prepared 
4,500 g. to N. L. Drake 
200 g. to F. W. Bergstrom 
4,385 g. to R. C. Elderfield 
26 g. to U.C.T.L. 
Completed. 
1 kg. to R. E. Lutz Shipped on 10/13/44 
2 kg. to R. C. Elderfield Shipped on 10/13/44 
^3 
10/13/44 
200 g. 
6-Chlorothio- 
naphthene 
it 
R. C. Elderfield 
Cancelled because of 
assignment of the 
final drug (no. 91). 
44 
10/13/44 
200 g. 
3-Hydroxy-6^ 
chlorothio- 
naphthene 
11 
R. C. Elderfield 
11 
50 
& 
50a 
10/24/44 
11/17/44 
200 g. 
100 g. 
2-Phenyl-4,7- 
dichloro- 
quinoline 
n 
175 ۥ to R. C. Elderfield 
100 g. to J. E. Kirby 
25 g. to C. C. Price 
Completed 2/7/45 
w 
co 
w 
CD 
P 
4 
O 
bd 
C 
0 
3 . 
1 
RESTRICTED 
Of 
1147 No. 
Date 
assigned 
Amount 
Contractor 
preparing 
Compound compound 
RESTI 
ilCTED ?. 
Shipped to 
Status 
52 
10/24/44 
50-100 g. 
3-Bromo- R. C. 
phenanthrene Fuson 
L. F. Small 
Completed. 
Shipped on 5/18/45. 
63 
11/17/44 
5 kg. 
Di-n-octylamine " 
1 kg. to R. E. Lutz 
4 kg. to R. C. Elderfield 
Completed. 
Shipped 1 kg. 
Shipped 3987 g. 
64 
11/17/44 
100 g. 
2-Fhenyl-4- n 
chloro-6- 
methoxyquinoline 
R. C. Elderfield 
Completed. 
Shipped 122.8 g. 
69 
11/23/44 
500 g. 
4-Amino-7- " 
ohloroquinoline 
Erich Mosettig 
Cbmpleted. Shipped 264 g. 
on 3/22/45. Requirement 
reduced to that amount. 
75 
12/8/44 
10 g. 
2-Phenyl-4-hydr©xy- n 
7-chloroquinoline 
R. C. Elderfield 
Completed and shipped. 
76 
12/8/44 
10 g. 
2-Phenyl-4-hydroxy- " 
6-me thoxyqui noline 
R. C. Elderfield 
Completed and shipped. 
77 
12/12/44 
5 kg. 
Di-n-hexylamine " 
1 kg. to Byron Riegel 
4 kg. to R. C. Elderfield 
Completed and shipped; 
partly supplied by Sharples. 
26 
12/29/44 
30 g. 
2-Amino-4-chloro- n 
benzoic acid 
C. C. Price 
Completed and delivered. 
88 
1/13/U5 
5 kg. 
3-Diethylamino- " 
propyl chloride 
500 g. to N. L. Drake Completed and all 
500 g. to R. C. Elderfield shipments made. 
500 g. to W. M. Lauer " w 
500 g. to C. C. Price n J| 
500 g. to Byron Riegel " 
500 g. to C. R. Hauser " 0 
500 g. to R. E. Lutz '' ^2® 
1500 g. to R. E. Elderfield •' 
RESTRICTED 
1148  
RESTRICTED 
8. 
- 
No. 
Date 
assigned 
Amount 
Contractor 
preparing 
C onp ound c omp ound 
Shipped to 
Status 
88a 
2/15/U5 
5 kg. 
3~Diethylamino- R. C. 
propyl chloride Fuson 
ai: 
L to R. C. Elderfield Shipped 4200 g. and 
974 g. of the hydro- 
chloride. 
89 
1/25/U5 
15-25 g. 
3-(l-Methyl-4- " 
diethylamino- 
■butylamino)-6- 
chlorothi onaphthene 
(SN 12,121) 
F. 
Y. Wiseiogle 
Cancelled 
91 
2/3/U5 
15-25 g. 
2-Methyl-3-(l-methyl- " 
4-die thylaminchutyl- 
aciino)-6-chlorothio- 
naphthene 
(SN 12,122) 
F. 
Y. Wiselogle 
Cancelled. 
97 
97a 
2/20/U5 
3/5A5 
100-125 g. 
500 g« 
4-Anino-7- " 
chloroquinoline 
n w 
R. L. Shriner 
200 g. to A. C. 
300 g. to R. C. 
Completed. 
Shipped 120 g. 3/22/45 
Completed. 
Cope Shipped on 3/22/45 
Elderfield Shipped on 3/22/45 
• 
106 
3/1^5 
750 g. 
(amount 
later 
reduced) 
N-Benzoyl " 
pipecolinic 
acid ethyl ester 
E. 
R. Buchman 
Completed. 
Shipped 211 g. 4/14/45 
106a 4/24/45 
100 g. 
11 it 
F. 
ft. Bergstrom 
Completed. Forwarded "by 
Dr. Buchman from amount 
supplied to him which 
was not needed. 
0 » 
• SS 
RESTRICTED 
W i-i 
CD n- 
1149 No. 
Date 
Assigned 
Amount 
Contractor 
preparing 
Compound compound 
RESTRICTED 
9. 
Shipped to 
Status 
116 
3/28^5 
15-25 g 
U-(U-diethylamino- R. C. 
1-methylhutyl- Fuson 
amino)-thiono [2,3-$ - 
pyridine (SN 12,78?) 
F. Y. Wiselogle 
Cancelled. 
119 
U/21/U5 
750 g. 
Ripecolinic acid " 
ethyl ester 
hydrochloride 
E. R. Buchman 
Completed. 
Shipped U00 g. on 5/7/^5 
Shipped 310 g. on 6/1/U5 
1150 
RESTRICTED No. 
RESTRICTED 1C. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
22 
8/1/44 
2 kg. 
m-anisidine 
Henry 
Gilman 
R. 
C. 
Elderfield 
Completed. 
Shipped 2781 g. 
22a 
10/10/44 
1 kg. 
it 
it 
C. 
R. 
Hauser 
Completed. Shipped 260 g. 
(Enough for Dr. Hauser) 
23 
8/1/44 
2 kg. 
Picolinic acid 
tt 
E. 
R. 
Buchman 
Completed. 
Shipped 1005 g- Requirement 
reduced to that amount. 
• 
23a 
& 
23b 
3/5/>+5 
U/U/U5 
2 kg. 
n 
it 
R. 
C. 
Fuson 
Completed. 
Shipped 511 g. 3/20/45 
Shipped 500 g. 4/16/45 
Shipped 500 g. 5/14/45 
Requirement reduced to 
that amount. 
24 
8/15/44 
3 kg* 
Ethylformyl 
phenylacetate 
11 
R. 
C. 
Elderfield 
Completed. 
Shipped 3010 g. 
25 
8/19/44 
300 g. 
2-Chloro-3- 
aminotoluene 
11 
C. 
R. 
Hauser 
Completed. 
Shined 300 g. 
41 
42 
9/25/44 
0 
a 
10/10/uug 
w 
5 kg. 
S a 
38 
Jib e' 
§2 
3-Di ethylam ino- 
2-hydroxy- 
propylamine 
1-diethylamin0- 
2,3-epoxypropane 
w 
H 
R. 
R. 
C. 
C. 
Elderfield 
Elderfield 
Completed. 
Shipped 116o g. 10/30/44 
Shipped 1090 g. 11/22/44 
Shipped 2228 g. 12/4/44 
Shipped 539 g- 12/28/44, w 
Q S 
CO 
Completed. Shipped J ® 
on IO/25/UU. 3 2 
b- 3 i 
1151 No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
RESTRICTED 
11.' 
Shipped to 
Status 
U7 
10/2U/UU 
100 g. 
8-Hydroxy 
cinchoninic acid 
Henry 
Gilman 
R. 
C. Elderfield 
Completed. Shipped &0 g* 
on 3/20/U5; balance 
cancelled. 
51 
1O/2U/4U 
200 g. 
6,7-Methylenedi oxy- 
2-phenylquinoline- 
U-carboxylic acid 
M 
J. 
B. Koepfli 
Completed. Shipped 125 g* 
plus an additional U7 g. 
2/1/U5. Dr. Koepfli 
states this amount will 
be sufficient. 
57 
11/17/UU 
500 g. 
Cinchoninic acid 
fl 
R. 
E. Lutr 
Completed. 
Shipped 327 g. I/5/U5. 
Shipped 190 g. 2/15/45. 
58 
11/17/UU 
200 g. 
2-chloro-6- 
nitroquinoline 
II 
R. 
C. Elderfield 
Completed. 
Shipped 197 g. 3/6A5* 
59 
11/17/W 
200 g. 
6-Nitr0-8-chloro- 
quinoline 
II 
R. 
C. Elderfield 
Completed. Shipped 
on 12/28/UU. 
65 
ll/23/W 
500 g. 
Ethyl- -bromo- 
crotonate 
II 
L. 
E. Fieser 
Completed. Shipped 
512 g. on 1/25/45. 
82 
1/2/U5 
500-750 g- 
2-Fhenyl-6-methoxy- 
cinchoninic acid 
n 
R. 
E. Lutz 
Completed. 
Shipped 3^0 g. I/16/U5 
Shipped U05 g. 2/16/U5 
82a 
1/5/U5 
500 g. 
n 
ti 
11 
Shipped 35O g. 2/27/45 a 
shipped 125 g. " 
20 
4 
Q 
tr 
RESTRICTED 
- s- (ilia to 
Bulletin oi 
1152  
RESTRICTED 12. 
No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
gU 
1/2/U5 
Optimum method for Henry- 
preparing 2-phenyl- Gilman 
6-methoxy-U-quinoline 
carbinols, i.e. 
chohch2n(cuh9)2 
CHjOf y ] 
Completed. 
Have developed procedures 
for the following preparations: 
(a) 6-methoxy-2-phenyl-U-carbethoxyquinoline• 
(b) 6-methoxy-2-phenyl-U-acetylquinoline. 
(c) ethyl 6-methoxy-2-phenylquinolyl-U-acetate. 
(d) The bromination of (c) to 6-methoxy-2-phenyl- 
U-(l-bromoacetyl)quinoline hydrobromide. 
* 
90 
1/30/U5 
2 kg. 
Isoaiqyl formate 
it 
Mary Sherrill 
Cancelled. 
93 
2/8/U5 
500 g. 
5,7-Di chloroi satin 
ft 
E. 
R. 
Buchman 
Completed. 
Shipped 313 g. 3/20/U5 
Shipped 192 g. U/17/U5 
gU 
2/15/U5 
500 g. 
Y-2-Pipe ri dyl 
propylchloride 
it 
y. 
W. 
Bergstrom 
Completed. 
Shipped 502 g. between 
3/19/45 and 3/31^5 • 
100 
3/5A5 
300 g. 
Quininic acid 
tt 
A. 
C. 
Cope 
Completed. 
Shipped 139 g. U/25/U5 
Shipped 165 g. 5/21/U5 
W tri 
CD £ 
CO £ 
CD W 
P CD 1 
y -f: 
0 g 
RESTRICTED 3 M 
1153 No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
RESTRICTED 1}. 
Status 
1 
7/11/UU 
15 1*. 
Ethyl oxalopropionate 
C. S. 
Hamilton 
2 kg. to C. R. Hauser 
Balance to R. C. Elderfield 
Completed. A total of 1U lb. 
was prepared and shipped. 
2 
7/11/^ 
1 kg. 
Quinoline-U-aldehyde 
11 
500 g 
500 g. 
. to L. F. Small 
. to E. R. Buchman 
Completed. 
Shipped I89 g. 10/1U/UU 
Shipped balance 11/1/UU 
Completed. 
Shipped 260 g. 11/1/UU, 
balance cancelled. 
3 
8/16/UU 
1 kg. 
U-Chioro-2-ni t ro- 
benzaldehyde 
n 
R. 
C. 
Elderfield 
/ 
Completed. 
Shipped 63 g. 12/2/UU, 
balance cancelled. 
5 
it 
w 
l-(U-Di ethylanino- 
1-nethylbutylanino) - 
benzo( f) quinoline. 
(Survey no.11,020) 
11 
1! 
Completed and shipped. 
6 
w 
H 
U-(U-diethylanino- 
1-methylbutylamino)- 
benzo(h) quinoline. 
(Survey no.11,021) 
n 
II 
Completed. Shipped 15*3 g* 
of diphosphate monohydrate 
on ^/9/U5. 
7 
8/29/uu 
15-25 g- 
6-Chloro-l-(U-diethyl- 
amin o-l-nethylbuty1- 
amino)-benzo(f)quinoline 
(SN 11,022) 
ii 
F. 
Y. 
TTiselogle 
Cancelled. 
® H 
CO f_i 
® f-> 
0 
29 
10/6/UU 
100 g. 
U-diethylanino- 
butylamine 
it 
N. 
L. 
Drake 
4 c+ „ 
Completed. Shipped & 
105 g. 12/26/W+. 
RESTRICTED 
1154 No. 
Date 
assigned 
Amount 
Compound 
✓ 
Contractor 
preparing 
compound 
RESTRICTED 
1K. 
Shipped 
to Status 
31 
10/10/U4 
15-25 g. 
8-(U-Diethylanino- 
1-nethylbutylanino)- 
benzo(g)quinoline 
(SN 11,016) 
C. S. 
Hamilton 
F. Y. Wiselogle 
Cancelled. 
U5 
10/2U/UU 
1 kg. 
5~nitro-8- 
chloroquinoline 
ti 
R. C. Elderfield 
Completed. Shipped 
500 g. 1/2/U5. 
Shipped 500 g. I/8/U5. 
5U 
lO/30/UU 
2 kg. 
2-brono~3-ni1 ro- 
benzoio acid 
n 
L. F. Snail 
Completed. 
Shipped 1 kg. 11/21/W 
Shipped 1 kg. 12/2/hU 
72 
12/9/UU 
500- 
1000 g. 
m-Nitroacetophenone 
ft 
C. C. Price 
Cancelled. 
110 
3/22/^ 
15-25 g- 
8- (3-Di e t hyl an in 0- 
propylanino)-6- 
ne thoxy-5-quinoline 
stibonic acid 
(SN 12,670) 
it 
F. Y. Wiselogle 
Cancelled. 
111 
3/22/U5 
g 
« 
M M » 
gg3 
&§3 
15-25 &• 
8-(j-die thylan ino- 
propylanino)-6- 
nethoxy-5-stiboso- 
quinoline 
(SN 12,669) 
11 
F. Y. Wiseiogle 
Cancelled. 
W td 
© £ 
08 1-1 
© l-J 
© © 
4 H- 
w s 
Km* 
O M. 
tr 3 
bi 
1 
0 
JO H f 
O M W 
K M O 
RESTRICTED " 
1155 No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
RESTRICTED 
Shipped to 
Status 
9 
7/26/UU 
500 g. 
Dibenzylamine 
C. D. Hurd 
C. R. Hauser 
Completed. 
Shipped on 8/ 8/UU. 
10 
8/1/UU 
500 g. 
Ethyl cinchoninate 
tt 
J. B. Koepfli 
Completed. Shipped 
**98 e. 9/25/UU. 
10a 
9/15/UU 
500 g. 
n n 
tt 
it 
Completed. 
Shipped 510 g. IO/I3/UU 
Shipped 40 g. 11/18/4U 
10b 
1 kg. 
n tt 
tt 
it 
Completed. 
-Shipped 500 g. on U/lO/U 
Balance cancelled. 
5. 
11 
8/9/UU 
2 kg. 
o-Nitr©benzaldehyde 
tt 
1.5 kg. to R.C.Elderfield Completed. Shipped 1268 g. 
Final shipment on 10/30/UU 
0.5 kg. to E. Mosettig Completed. 
Shipped on lO/30/UU. 
12 
C/9/UU 
2 kg. 
p-Chlorophenyl- 
acetic acid 
tt 
R. C. Elderfield 
Completed. Shipped 
2065 g. on 9/15/UU. 
32 
9/25/4U 
500 g. 
Ethyl 6-chlorc- 
cinchoninate 
ft 
K. M. Campbell 
Completed. Shipped 
on 11/13/UU. 
33 - 
10/6/UU 
50 g. 
9-Chloroacridine 
tt 
W. H. Holcomb 
Completed. Shipped 
on 11/10/UU 
CD 
tri 
£ 
3^ 
10/6/UU 
50 g. 
J,9~Dichloro- 
acridine 
tt 
W. H. Holcomb 
Completed. Shipped 
on 11/2U/UU. 
RESTRICTED 
CD 
0 
3 
o-' 
- 
CD 
1156 1157 
RESTRICTED 
16 
No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
35 
10/6/UU 
50 g. 
U-Methoxy-9- 
chioroacri dine 
C. D. Hurd 
W. H. Holcomb 
Completed. 
Shipped on 1 
1/2U/UU 
36 
10/6/UU 
50 ۥ 
5~Methy1-3,9- 
di chioroacri dine 
w 
W. H. Holcomb 
Completed. 
Shipped on 1 
1/2U/UU. 
37 
10/13/uu 
reinstated 
1/25/45 
50 g. 
N-(U-Hydroxyphenyl) • 
U-chl0ro-alpha- 
naphthylamine 
w 
R. C. Elderfield 
Cancelled. 
38 
10/13/44 
reinstated 
1/25/45 
50 g. 
N-(U-Hydroxyphenyl) - 
6-chloro-alpha- 
naphthylamine 
a 
R. C. Elderfield 
Cancelled. 
60 
11/17/uu 
500 g. 
6-Chloro-l- 
naphthaldehyde 
E. R. Buchman 
Completed. 
Shipped 58 g 
and 25.7 g. 
Requirement 
that amount 
;. on 6/U/U5 
on 6/1U/U5. 
reduced to 
73 
12/9/UU 
500 g. 
p-Ni t roace t ophen one 
t» 
C. C. Price 
Completed. 
Shipped lUO 
Requirement 
that amount 
g. on 2/8/45. 
reduced to 
• 
78 
12/12/UU; 
cancelled, 
reinstated 
3/5/45 
2 kg. 
m-Hydroxy- 
benzaldehyde 
tt 
H. E. French 
Completed. 
Shipped 288 
Requirement 
this amount 
g. on 6/30/45. 
reduced to 
• 
79 
12/12/44 
1 kg. 
Aminoacetal 
H 
H. E. French 
Cancelled. 
RESTRICTED  
RESTRICTED 
17. 
No. 
Date 
assigned 
Amount Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
80 
12/22/UU 
500 g. Homophthalic acid 
C. D. Hurd 
H. E. French 
Completed. 
Shipped 500 g. on 
3/29/U5. 
85 
1/2/U5 
500-750 g. Ethyl p-cyano- 
benzoate 
H 
R. C. Elderfield 
Cancelled. 
107 
3/5A5 
100-500 g. l,U-Dimethoxy- 
butyne-2 
ti 
D. S. Tarbell 
Completed. 
Shipped 250 g. on 
5/IO/U5. 
1158 
RESTRICTED  
RESTRICTED 
1S. 
No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Shipped to 
Status 
7U 
12/12/UU 
1 kg. 
5-amino 
isoquinoline 
R. L. Shriner 
R. L. Shriner 
Completed; 
prepared 1*5 
99 
2/26/U5 
50 e. 
l-Chloro-5- 
nitroisoquinoline 
tt 
M 
Completed. 
1159 
RESTRICTED No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Ship to 
priority 
Status 
15 
g/15/UU 
200-300 g. 
Trans- p - 
decaleno 
Homer Adkins 
and A.L.Wilds 
L. F. Fieser 
U 
No estimate of date 
for completion* 
67 
1O/23/UU 
500 g. 
ac.-tetralone 
n 
20 g. to Mary Sherrill 1 
U80 g. to L. F. Fieser 
(for first 100 g.) 1 
(for balance) 3 
Shipped 3/26/45 
Shipped 100 g. 3/26/U5 
Shipped 250 g. on 5/31/U5 
95 
2/15^5 
1 kg* 
Tetrahydro- 
anthracene 
it 
L. F. Small 
U 
In process. 
No estimate of date 
for completion. 
RESTRICTED 
July 3. I9U5 
A. C. Cope 
Division 9, NDRC 
Status as of July 3, 1^45 of Antimalarial Intermediate Preparations 
(Preparations completed before July 3 are listed separately) 
1160 
RESTRICTED  
• 
RESTRICTED 
3. 
No. 
Date 
assigned 
Amount 
Contractor 
preparing 
Coinpound compound 
Ship to 
Priority 
Status 
61 
250 g. 
2-Methoxy-6- G. H. 
chioro-9- Coleman 
acridine 
carboxylic acid 
ethyl ester 
E. R. Buchman 
3 
5 
for 75~^OC g* 
for balance 
No estimate of date 
for completion* 
66 
11/23/uu 
500 g. 
(/-Cyclopentyl- " 
valeric acid 
1. E. Eieser 
3 
No estimate of date 
for completion* 
13U 
5/22/U5 
500 g. 
Mono-tert.- " 
bvivlamine 
R. C. Elderfield 
2 
Shipped 15^ g. 
on 6/25/U5 
1161 
RESTRICTED No. 
Date 
assigned 
Amount 
Contractor 
preparing 
RESTRICTED 
Priority 
3. 
Status 
Compound compound 
Ship to 
63a 
6/6/45 
2 kg. 
di-n-octylamine R. C. Fuson 
R. 
C. 
Elderfield 
3 
No estimate of date 
for completion. 
6g 
11/23/44 
500 g. 
4-Anino-6- " 
methoxyquinoline 
Brich 
Mosettig 
3 
Have EMME on hand. 
No estimate of date 
for completion. 
96 
3/5/^ 
100-125 g. 
it n 
R. 
1. 
Shriner 
3 
tt 
101 
3/5/*»5 
200 g. 
4-Chloro-6-methoxy- n 
quinoline 
A. 
c. 
Cope 
2 
No estimate of date 
for completion. 
112 
4 
3/28/U5 
15-25 6. 
5~(4-di ethylam.no- " 
1-methylbutyl- 
anino) furo [3>2-f 1- 
quinoline (SN 12,786) 
F. 
Y. 
Wiselogle 
2 
No estimate of date 
for completion. 
113 
H 
n 
9-(4-diethylanino- " 
1-methylbutyl- 
anino) furo B,2-fJ- 
quinoline (SN 12,737) 
ti 
5 
n 
114 
It 
21 
H3 S3 m 
►H M 5 
n 
7-(4-diethylamino- " 
1-methylbutylamino)- 
5-methoxythia- 
naphthene (SN 12,782) 
h 
4 
11 
- * Id 
£ 
115 
s ® s 
w 9 
g«>w 
Eli 
Q W M 
n 
4-(4-diethylanino- M 
1 -met hylbutyl amino) - 
6-hj droxy-7-quinolyl 
methyl ketone, oxime 
(SN 12,785) 
tt 
5 
RESTRICTED 
Cl b-1 
II JO 
1162 No. 
Date 
assigned 
Amount 
Contractor 
preparing 
RESTRICTED 
4. 
Compound compound 
Ship to 
Priority 
Status 
117 
3/28/45 
15-25 g. 
5-(3-diethylamino- R. C. 
propylanino)-2- Fuson 
hydroxyace t ophenone, 
oxime (SN 12,784) 
F. Y. Wiselogle 
5 
1 
No estimate of date 
for completion. 
118 
1 
n 
o£-anino-8-(4-diethyl- " 
araino-l-methylbutyl- 
araino)-6-methoxylepidine 
(SN 12,788) 
4 
ti 
128 
5/10/45 
15-25 g- 
lO-(3-diethylanino- « 
propylamine)-7»9" 
dine thoxypyrido- 
£3»2-b^ quinoline 
(SN 12,948) 
F. Y. Wiselogle 
4 
No estimate of date 
for completion. 
129 
n 
n 
10-(3-diethylanino- « 
propylamine)pyrido- 
(3x210^ 
naphthyridine 
(SN 12,9^9) 
it 
4 
11 
130 
n 
w 
10-(3-diethylanino- « 
propylamine)-5- 
nethoxypyrido- 
£3»2-gj quinoline 
(SN 12,950) 
n 
5 
11 
w 
Q 
a 
to 
G 
I-1 
131 
'll 
« 
10-(3~diethylanino- " 
propylamino)pyrido- 
l3|2-g} quinoline 
(SN 12,951) 
it 
5 
RESTRICTED 
« 
'd 
a 
2$ 
CD 
1163  
Contractor 
RESTRICTED 
5. 
No. 
Date 
assigned 
Amount 
preparing 
Compound compound 
Ship to 
Priority 
Status 
132 
5/10/45 
15-25 g. 
5-(3-diethylamino- R. C. 
propylamino)-10- Fuson 
methoxypyrido- 
F. Y. Wiseiogle 
5 
No estimate of date 
for completion. 
quinoline 
(SB 12,952) 
- 
133 
n 
n 
5-(3"diethylamino- » 
p ropylamin 0)pyrido- 
(2»3-d quinoline 
(SB 12,953) 
tl 
5 
it 
135 
5/31A5 
15-25 g. 
7-Chloro-4,8-'bis « 
(4-diethylanino-l- 
nethylbutylanino)- 
5 * 6-dimethoxyquinoline 
F. Y. Wiseiogle 
4 
No estimate of date 
for completion. 
(SB 13,426) 
136 
tt 
11 
6,8-Dichloro-2- " 
(p-chlorophenyl) -c<- 
(dihexylaminomethyl) - 
3-methyl-4-quinoline- 
methanol (SN ) 
n 
- 
n 
137 
n 
tt 
7-Chloro-4-( 1-ethyl- '' 
4-piperidylamino) - 
quinoline (SN 13,425) 
it 
4 
H 
W td 
® C 
CO h-1 
138 
n 
it 
7-Chloro-U-(4-piperidyl- n 
amino)quinoline 
(SN 13,424) 
n 
4 
2 <D 
It 
13 
; 0 
139 
11 
« 
6,8-Dichloro-2-(p-chloro-" 
phenylJ-c<-(diethylanino- 
methyl)-3-methyl-4- 
quinolinemethanol (SN ) 
tt 
4 
RESTRICTED 
H 
H' 
1164 No. 
Date 
assigned 
Amount 
Contractor 
preparing 
RESTRICTED 
?riority 
6. 
Status 
Compound compound 
Ship to 
US 
10/2U/UU 
100 g. 
8-Mercapto Henry 
cinchoninic acid Gilman 
J. B. Koepfli 
U 
No estimate of date 
for completion. 
102 
3/5^5 
and 
3/22/45 
3 
5,6-dimethoxy- n 
8-nitroquinoline 
R. C. Elderfield 
2 
Shipped 23U g. 5/3O/U5 
Shipped 355 g. 6/1U/U5 
120 
U/16/U5 
15-25 g. 
^-(2-diethylamino- " 
e thyl)-6-me thoxy- 
2-phenyl-U- 
quinolinemethanol 
(SN 12,857) 
y. Y. Wiselogle 
3 
No estimate of date 
for completion. 
121 
U/16/U5 
15-25 g. 
c<-(3-di ethylamino- n 
propyl) -6-methczy- 
2-phenyl-U- 
quinolineraethanol 
(SN 12,858) 
E. Y. Wiselogle 
3 
No estimate of date 
for completion. 
122 
w 
11 
o<r(U-diethylanino- " 
butyl) -6-nethoxy- 
2-phenyl-U- 
quinolinenethanol 
(SN 12,859) 
E. Y. Wiselogle 
3 
n 
td w 
123 
II 
« 
alpha-(dibutylanino-" 
methyl)-2- J-2,5- 
dinethyl-l-pyrryl)- 
phenylf -6-methoxy- 
U-quinolinemethanol 
n 
5 
RESTRICTED 
K 
-0 1-* 
?0 CD 
4 c+- 
0 t-" 
a 
0 
3* ? 
1165  
- 
c 
RESTRICTED 
7* 
No. 
Date 
assigned. 
Amount 
Contractor 
preparing 
Compound compound 
Ship to 
Priority 
Status 
12U 
U/16/U5 
15-25 g. 
alpha-(dibutylaraino- Henry 
ne thyl)-6-me thoxy- GiIman 
2-(2-pyridyl)-U- 
qui nol i nem e than ol 
P. Y. Wiseiogle 
3 
No estimate of date 
for completion. 
127 
5/10/U5 
/ 
3 kg. 
U-Diethylanino-}- n 
hydroxybutyl an ine 
N. L. Drake 
2 
No estimate of date 
for completion. 
Shipped 1100 g. of 
^-hydroxy-Y - 
diethylaminobutyro* 
nitrile on 5/29/U5 
and 1200 g. on 6/7/U5. 
1166  
RESTRICTED 
8. 
No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
•onpound Ship to 
Priority 
Status 
4 
8/29/44 
15-25 g. 
4- (4-di e t hy lani no- 
1-me thylbutylamino) - 
benzo(g)quinoline. 
(SN 11,019) 
C. S. I*. Y. Wiselogle 
Hamilton 
4 
No estimate of date 
for completion 
8 
n 
n 
10-(4-diethylamino- 
1-methylbutylanino)- 
benzo(g)quinoline. 
(SEN 11,023) 
ft n 
4 
tt 
30 
10/10/44 
11 
8-( 4-diethylanino- 
1-me thylbutylamino) - 
^cnzot QxijLnoHno • 
(8N 11,015) 
h 11 
4 
Expect to complete 
by 7/1/U5. 
53 
8/29/44 
n 
5~(4-di e thy lani n0- 
1-methyl butylamino)- 
benzo(f) quinoline. 
(SN 11,024) 
it ti 
4 
Expect to complete 
by 7/1^5- 
108 
3/22A5 
11 
8-( J-diethylaminopropyl- " H 
amino) -6-methoxy-5- 
quinolinearsonic acid 
(SN 12,668) 
5 
No estimate of date 
for completion. 
109 
3/22A5 
11 
5-arsenoso-8-(3-di ethyl- 11 n 
aminopropylamino)-6-. ' 
nethoxyquinoline 
(SN 12,667) 
5 
No estimate of date 
for completion. 
TO b 
CD £ 
fZ> H 
® f- 
£0 Ct 
c- 
0 V 
125 
5/10/U5 
50 g. 
be t a-hy droxy-be t a * - 
aninoethyl ether 
" B. E. Christensen 
3 
No estimate of date 
for completion. 
■< S 
# 5 
RESTRICTED 
§ i 
1167  
1 
RESTRICTED 
9. 
No. 
Date 
assigned 
Amount 
Compound 
Contractor 
preparing 
compound 
Ship to 
Priority 
Status 
71 
12/9/UU 
500 g. 
o-nitroacetophenone 
C. D. 
Hurd 
C. C. Price 
2 
Shipped 16U g. 
on 3/29/U5 
71a 
5/IO/U5 
200 g. 
tt 
tt 
T. L. Jacobs 
3 
-- 
-- 
50 ۥ 
6-Chloro-l- 
naphthylamine 
tt 
N. L. Drake 
No estimate of date 
for completion. 
- 
15-25 g. 
Several benzopyryliun 
salts; specific com- 
pounds to be listed 
later. 
a " 
P. Y. Wiselogle 
No estimate of date 
for completion. 
1168 1169 
"Exhibit. TZ 
CONFERENCE OF CMR CONTRACTORS ON THE SYNTHESIS 
OF ANTIMALARIAL DRUGS 
Chicago, Illinois 
July 19-20, 1945 
Abstracts of Material to be Discussed 1170 
CONTENTS 
Author Subject f Page 
T.L> Jacobs 2-'Substituted-a'-piperidyl-4-quinolinemethanols. 1 
F»We Bergstrom Synthesis of piperidyl alkyl side chains. 4 
J.Be Koepfli Chinese drugs. 5 
C,C, Price Miscellaneous quinolines. 5 
H«R. Snyder 
N.J. Leonard Cinnolines 8 
Miscellaneous heterocyclic compounds. 8 
E.B. Hartshfrn Quinolines with the atabrine side chain as 
the only substituent 11 
D.S. Tarbell Pyridoxine analogs. 12 
B, Riegel Miscellaneous quinolines, 15 
R.H. Baker 
R.L, Shriner Substituted amidines. 20 
J.H, Billman 
H.E. French 8-Aminoquinoline intermediates. 22 
K.N. Campbell Miscellaneous quinolines and other compounds. 22 
B. Riegel Chlorination and sulfonation of quinoline. 29 
R.E. Lutz a-Alkylaminomethyl-4-quinolinemethanols 32 
L.F. Fieser Naphthoquinone antimalariaIs. 34 
W.M. Lauer 8-Aminoquinolines. 36 
R.T. Arnold 
C.S< Hamilton Benzoquinoline derivatives. 38 
M.L, Sherrill Q^inazoline derivatives. 41 
J.E. Kirby and Novel side chains. 46 
associates 
R»C. Elderfield 8-Aminoquinclines. 50 
L.C. Craig Homogeneity of 8-aminoquinolines. 58 
L.H. Schmidt Toxicity of 8-aminoquinolines> 59 
N.L. Drake 8~Aminoquinolines. 60 1171 
2-SUB STITUTED a-PIP^RIDYL-4-QUINOLINafETHANOLS ' TTj 
T. L. Jacobs 
The discovery that the quinine degradation product obtained by the 
in yitrjg action of rabbit liver on quinine was a carbostyryl analog of 
quinine suggested the importance of the 2-position in related quinoline 
antimalarials and led to the preparation of 2-phenyl-a-piperidyl-4-quinoline- 
methanol, a compound much more active than a-piperidyl-4-quinolinancth anol 
(Koepfli's report, January meeting). As indicated in January, this lead has 
been followed by varying the group in the 2-position in the hope of finding 
more active and less toxic antimalarials. Table I summarizes the variations 
achieved so far. The introduction of chlorine or bromine in the para position 
of the blocking 2-phenyl group leads to a marked increase in activity, but 
otter substituents on the benzene ring appearto decrease its effectiveness. 
The low activity of the 2-o-chlorophenyl compound is striking. Various 
alkyl and amino groups are less effective than phenyl while hydroxyl destroys 
activity as anticipated. 
All of the compounds were prepared by the Ainley and King method 
as modified by Buchman and Sargent. When the blocking group was a substi- 
tuted phenyl the yields were usually as shown below, Q = 2-substituted 
quinoline attached in the 4-rosition: 
NaNH? \ 
QCC2Et ♦ EtO2C(CH2)5NHCO0 / QCOCH(CH2)^NHCO0 \ 
20-40% \ CO2Et / 
H2S0, V Br in HBr 
> QC0(CH_)cNHo - -> QCOCHBr(CH-). NH • (1 or 2HBr) 
Z 5 80-95% 24 
/ \ / 30-60% 
Na.CO 11 Pt, H 1 
-\ QCO / QCHOH X 
\ A/ / W 
Up to 50% of the cinchoninic acid usually could be recovered in the first 
step so that overall yields were 10-40%. The yields were about the same 
when the blocking groups were alkyl radicals, but in these cases the 
sodium derivative of ethyl benzamide caproate was prepared with sodamide 
and the cinchtninate then added. 
Attempts have been made to prepare compounds with groups containing 
0, N and S on the 2-position. 2-Di alkylamino cinchoninates were readily 
obtained from 2-chloroci nchoninic acid and could be converted to final 
product in the usual yields with no special difficulty. Ethyl 2-ethoxycin- 
choninate was converted to 2-hydroxy-a-pipericfy'l-4~quinolinemeth anol, 
hydrolysis of the ethoxy occurring during sulfuric acid treatment. 
Conditions for retaining the ethoxyl were not found and ethylation of the 1172 
** * % 
final product was unsuccessful. Ethyl 2-hydroxsrcinchoninate could not be 
condensed successfully with ethyl -benzami do caproate due to the insolubility 
of the sodium derivative. A 2-phenoxy or 2-phenylsulfide group was hydrolyzed 
during the reaction. Many attempts were made to condense ethyl 2-amino- 
cinchoninate with ethyl -benzami docapro ate, but the only product was 2- 
aminocinchoninic acid which was produced from a polymeric amide, the primary 
product in the condensation. 
These difficulties of the Ainley-King synthesis in the presence of 
alkoxyl, thiophenyl and amino groups have led us to the corresponding compounds 
with King-Work side chains. 2-Ethoxy-a-( dibutyl .aminomet hyl) -4- quinolinemeth anol 
was prepared without difficulty through the oxide and the syntheses of the 
2-amino and 2-thiophenyl compounds are going smoothly. It was necessary to 
protect the amino group by acetylation. 
Other attempts to block the 2-posit ion are underway. Larger groups 
such as a.- or p-naphthyl or biphenyl interfere with the condensation, possibly 
due to insolubility and the final product with a 3-pyridyl group in the 2- 
position was difficult to purify -and gave salts which darkened on standing. 
The Ainley-King synthesis appeared to proceed satisfactorily with the diethyl 
ester of bis-2,2'-cinchoninic acid but the final product could not be purified. 
It seems possible that a cinroline analog which has a nitrogen instead of a 
carbon in the 2-posit5 on will not be subject to the same degradation as the 
quinoline and might be otherwise similar. The syntheses of such compounds 
with both King-Work and Ainley-King side chains are underway. A highly 
satisfactory synthesis of 4-carbethoxycinnoline has been devised. 
Table I 
The Effect of Varying the 2-Substituent 
in a-Piperidyl-4-quinolinemeth anols 
SN 
A 
Quinine Equivalents 
Prepared 
at 
D~1 
Q-4 
1-D 
2549 
0.08 
0.3 
1 
CT 
8538 
Phenyl 
3 
0.3 
1.6 
CT 
10000 
p-Chlorophenyl 
16 
2 
10 
UC 
11454 
m-Chlorophenyl 
SC Table I continued 
1173 
SN 
A 
Quinine 
D-l 
Equivalents 
Q-4 1-D 
Prepared 
11455 
o-Chlorophenyl 
0.6 
0.4 
■- sc 
■MS i* 
13521 
2,4-Di chloro phenyl 
SC 
13486 
2, 5-Dichlorophenyl 
sc 
11456 
3,4-Di chlorophenyl 
10 
sc 
12600 
p-B romphen yl 
8 
1.4* 
5* 
uc 
11449 
p-Tolyl 
1 
0.2 
2.5* 
sc 
13147 
2,5-Xylyl 
uc 
11451 
p-Meth oxy phenyl 
2 
1 * 
4 
sc 
11452 
p-Diethyl aminophenyl 
1 
1* 
sc 
10748 
iso Propyl 
0.3i 
0.3 
CT 
10749 
Cyd ohexyl 
Methyl^ 
0,15 
0.3 
CT 
10956 
1 
0.1 
1.6 
CT 
10528 
Phenethyl 
0.3i 
0.3 
CT 
11444 
Styryl 
1 
0.6 
CT 1-U Q 3 
12663 
3-Pyridyl 
UC 
12089 
Hydroxyl 
0.06i 
UC A-l Q 0.036 
10001 
Piperidino 
0.5 
0.2 
4* 
UC 
10002 
Morpholino 
1 
0.5 
1.5 
UC 
13087 
Dibutylamino 
1.5 
0.8 
10* 
UC 
* B-4 
instead of Q-4 or 1-B 
instead of 1-D, 
4 In 
this case the nucleus was 6-meth oxy quinoline 
ins tead 
of quinoline. 1174 
THE SYNTHESIS OF PIPERIDYL ALKYL SIDE CHAINS 
F. W. Bergstrom 
These side chains were prepared for condensation with 6-methoxy-8- 
aminoquinoline and with 5,6-dimethoxy-8-aminoquinoline to form plasmoquin 
analogues of the type 
Two general methods of preparation were used. 
From 2-picolyl lithium and acetaldehyde, formaldehyde or propylene oxide 
the corresponding hydroxy alkylpyridines can be made in 50 percent yields. 
Where n is 3,5 or 6, the condensations with 2-picolyl potassium have 
been carried out in 80 percent yields, but this drops to percent when n 
is 2. 
The condensations with 6-methoxy-8-aminoquinoline and with 5,6- 
dimsthoxy-S-aminoquinoline were carried out by heating with .an equivalent 
of the side chain halide for 20 to 25 hours at 120-130°. The free bases 
were purified by distillation at 0.1 mm. at taupe natures from 190-220°. 1175 
Limitations of the method:- 
When x in the first formula is 2 or 6, .the yield of condensation 
product is 65 percent of the theoretical, but if x is 3 or the yield 
drops to about 30 percent, because of an intramolecular condensation with 
the formation of a new ring. If the halogen is secondary, the yield falls 
to about 10 percent. For the condensations with 5,6-di methoxy-8-ami no- 
quinoline, the yields are half of those obtained with 6-metlio^r-8-amino- 
quinoline. 
INVESTIGATION OF CERTAIN CHINESE DRUGS 
J. B. Koepfli 
An outline is present of the present status of some Chinese drugs, 
reputed to have antimal.ari.nl activity. 
The botanical identity of the various samples under investigation is 
discussed. Chunine and Ch'ang Shan are in all probability the leaves and 
roots respectively of Dichroa febrifuga, but this has not been determined 
with certainty, nor have most of the samples under investigation been 
identified botanically at the time of collection. 
The active principle of Chunine is non-nitrogenous and crude fractions 
have been obtained with quinine coefficients of approximately 8 in avian 
malaria. ■ 
Ch'ang Shan contains basic substances, one of which has been isolated 
as a picrate, m. p. 209-12°. Fractions of Ch hang Shan have been obtained 
with quinine coefficients of 8 in avian malaria. It is not known whether 
activity is due to basic substances or non-basic substances, or both. 
QUINOLINES 
C, C. Price, H. R. Snyder 
N. J. Leona.rd 
Endo ch in or 3-n-Heptyl-4-hydroxy-7-methoxy-2-methylquinoline. SN-13,421 1176 
7-Cyano-4-(4- di ethyl anino-l-methylbutyl amino)quinoline. SN-11,515 
4 - (6-Ami noh exy 1 am ino) -3 - ami nomc th yl-7- ch lo ro qui nol ine. 
7-Chloro-4-(4-di ethylamino-1 -meth ylbutylamino)-8- fluoro quinoline* SN-12, 267. 1177 
7-Chloro-4-(4- di e th ylami no-l-methylbu tylami no)-8-qui noline th i ol. SN-12,27 0 
10-(4-Diethylamino-l-methylbutylamino)-benzo [h] quinoline 
6,6'-Sulfonylbis 4-(4-cftethylamino-l~mei,hylbutylamino)quinoline. SN-12,278 
4-(2-Dibutylam inovi nyl)-2-phenylqui noline. 1178 
Cinnolines 
4-(4-~Diethylamino-l-niethylbutylamino)cinnoline, SN-11,202 
6"Brom©-4- (4-die thylamino-l-methylbutylamino) cinnolf pe. 
Other Hetcrocylic Compounds 
5 -Amino-3 - aminometh yl- 2- (4- di e thy Ima ino-l-me thylbuty 1 am i no) -6~hief*hyl-4- 
pyri dinemethan ol» SN-12, 259 1179 
2- (m-Aminob enzene su 1 fo nam i do) -5-ch loro -b en zimida zole. 
2-Amin o-5~ (4-diethylamino-l-methylbutylami nomethyl )-4-methylpyridmidine. 
SN-12,283 
7-Chloro-10-(4-diethyl ami no-1-methylbutyl am ino)pyri do[3,2-b]q uinoline. 
SN-12,279 1180 
^Amino-B-chloro*^ (4-<«thyl^ino-l~m<?thylbutyl^ 
Approaches to this typo of <d@»ohMn (in addition to th^t dosoHbod by 
R. C. Eld@rfio.ld). 1181 
QUINOLINES WITH THE ATABRTNE SIDE CHAIN AS THE ONLY 
SUBSTITUENT 
E. B, Hartshorn 
Four drugs have been prepared by Bucherer reactions of 1-diethyl- 
amino-4.-aminopentane sulfite and 5,6,7, and 8-quinolinols, respectively, 
in concentrated aqueous solution. 
Of these four isomeric N substituted aminoquinolines, the 8 isomer had 
been prepared by Tschelintsev and Dubinnin, J. Gen. Chern. USSR 10, 1395, 
in 1940. It is plasmochin without the methoxyl group in the 6 position. 
The procedure developed by the above Russians has been followed 
closely in these syntheses. Generally, 0.2 mole of sulfur dioxide was 
absorbed in a solution of 0.28 mole of l-diethylamino-4-aminopentane in 
100 ml. of water and then, .after addition of 0.1 mole of the appropriate 
quinolinol, the mixture was refluxed, under a pressure greater than 
atmospheric by 10 cm. of mercury, for thirty or more hours. The distilled 
products areyellow or orange, viscous oils which darken in air., 
No. 
Compound 
Boiling Range 
* 
Di pic 
Giv en 
IP 
: rate 
Found 
Yield 
Coupling 
Reacti on 
Hours 
Heated 
1 
2X Quinoline 
157-159 0.2mm. 
159-160 
164,-5-166.5 
57$ 
13 
2 
5X Quinoline 
cav 194 0.2 
-'- 
171.-7-173.3 
corr. 
29 
72 
3 
6X Quinoline 
174-176.5 0.2 
- 
--- 
37 
44 
4 
7X Quinoline 
173-175 0.15 
- 
169.0-169.8 
co rr. 
50 
40 
5 
8X Quinoline 
153-154.5 0.2 
150 
148-150 
54 
40 
6 
8Z Quinoline 
i 
142-143.5 0.2 
i 
178.6-180.0 
corr. 
41 
87 1182 
Kt 
The syntheses of these four products, Nos. 2,3,4,5, depended 
upon the availability of the corresponding quinolinols. 8-Quinolinol is 
an industrial product; the 6 .and 7 isomers were obtained by Skraup reactions 
on 4 and 3-anisidines, respectively, followed by ever cleavage; and 5 was 
obtained by nitration of quinoline, reduction of the separated 5-nitro quinoline 
and a reverse Buch er er to give 5-quinolinol. 
These drugs, Nos. 2,3,4,5, should be formed by the interaction 
of l-diethylamino-4-brom opentan e hydrobromide and the appropriate amino- 
quinolines but difficulty was experienced with this reaction and Bucherer 
reactions were used instead. 
Compound No. 1 was not produced when a Bucherer reaction was 
attempted, as above, using 2-quinolinol. Howev r, bv the interaction 
of 2-chloro quinoline and l-diethylamino-4-ami nopentane at 150 degrees, 
and then at 175 degrees, the reaction proceeded satisfactorily and 
produced the desired product. This product did not seem to darken in air. 
Related Products 
Compound No. 6 in the table has a different side chain. It was 
formed by a Bucherer reaction between 8-quinolinol and 3-di ethyl amino-1- 
aminopropane sulfite in a procedure identical with that used in the other 
cases except that less solvent water was used. 
It is expected that a number of similar substances will be pre- 
pared with various side chains, of the same general type, in the 8 
position in quinoline in an attsn.pt to find the one that is most effective 
in this type of drug. 
In the work here reported it was the aim to secure final products 
as rapidly as possible without stopping to investigate and refine procedures. 
Yields higher than those shown in the table should be possible of attainment. 
Thus, No. 6 has been prepared in a much larger batch to give a 55% yield. 
Incidentally, yields were based on the tot al amount of quinolinol in the 
reaction mixtures, no correction being made for the quinolinols reclaimed 
from the reversible Bucherer reactions. 
SYNTHESIS OF PYRIDOXINE ANALOGS 
D, S. Tarbell 
Tlie synthesis of pyridoxine, analogs for testing as antimalarials 
was suggested by work of Seel er (Proc. Soc. Exptl. Biol. Med., 57, 113 
(1944)), who found that large doses of pyridoxine counteracted the effect 
of atabrine or quinine on P. lophurae in ducks. This might mean that 
pyridoxine was 
Pyri doxine 1183 
necessary for growth of the para sites, and hence that its action might 
be antagonized by a compound differing from it slightly in structure* 
The following analogs of pyridoxine are being prepared* 
2~Methyl-4"hydro^-5» 6-pyrimid ine- 
dimcthanol 
One method being investigated is the following: 
The condensation with CH^O is suggested by the cbservation 
that 4-methyluracil condenses with formaldehyde to fom the 5-methylol 
derivative (Kircher, Ann., 3^5, 293 (1911)). Another method of making 
the pyrimidine w uld be by c 'ndensation of EtOCH^COCH (CI^OEt^COOR 
with acetamidine; the former might be made by condensing EtOCH^COCHgCOOR 
with (EtO)^CH, followed by reduction of the ethoxymethylene group, or by a 
Reformatsky reaction. 
(cf. Mezamichi., C. A,., 20, 2679 (1926))< 1184 
Model experiments on CH^CH(NH2)COOH have yielded Zi-methyl^-meCR^xyt^iazole, 
analyzed as the picrate. Another method of effecting the ring closure would 
be to treat C^OC^CHCOOR with HCSSH (Todd et al, J. Chern. Soc., 1936, 1557; 
i 
^2 
1937, 362), forming the thioformyl derivative, which should then close. 
2-H ydre xy -4, 5 -t h i a z ol e di me th an ol. 
The following synthesis is under way: 
Some time has been spent on the attempted synthesis of 
through the 
diazonium compound, but so far no product has been obtained. 
Other projected syntheses were too long to look practical. 1185 
PRIORITY 1 
Byron Riegel, R. H, Baker 
d 'nd 1 - SN 7618 Resolution of dl-7-chloro-4-(4-diethyl amino-1-methyl- 
butylamino) quinoline. 
Salts of the following acids arc now being tried: 
d-Bromocamnhorsulfonic acid 
d-Camphorsulfonic acid 
dl-Lactic acid 
dl-Malic acid 
dl-Handelic acid 
d-Tartaric acid 
Up to the present time no satisfactory salt has been found although different 
ratios of the acids to the drug and different solvent have been used. 
PRIORITY 2 
SN-12,008 8-(3-Diethylaminopropylanino)~4(l)-quinolone 
Additional quantities of this drug have been made in an attempt to 
find a crystalline salt. 
SN-12,450 8-(3-Diethylaminopropylamino)-6-methoxy-4-quinolinol 
Catalytic reduction of the nitro group gives a very unstable amine which 
cannot be isolated. An alcohol solution of the amine rapidly goes to tar and 
cannot be coupled with a side chain. We propose the following substitution: 1186 
SN-13,528 6-Meth oxy-[6-(l-piperazyl)hexylamino]quinoline 
The hexamethylene chlorohydrin and the N-benzylpiperazine has 
been made. 
SN-13 >529 8-[6-(4-Sthyl~l-piperazyl)hexj^lamino]-6-meth oxyquinoline 1187 
The N-carbethoxypiperazine has been prepared. 
PRIORITY 3 
SN-11,213 3-Chloro-8-(4-diethylamino-l-methylbutylamino)quinoline 
This compound was cancelled, 21 June 1945, and two new ones sub- 
stituted for it which differ only in their side chains, i.e. , di ethyl am ino- 
hexylamino and diethylaminoethylamino. Two different methods for the prepara- 
tion of the nucleus, 3-chloro-8-aminoquinoline, have been investigated without 
success. We are now trying to decide on a third approach, 
PRIORITY 4 
SN-12,013 8-(3-Diethylaminopropyl ami no)-4- (methylmercapto )quinoline 
Cancelled, 21 June 1945, and two new side chains substituted. We have 
shipped to the Survey Office 16 g. of 4 -benzylmer capto-8-(3-di ethyl ami nopropyl - 
amino)quinoline in place of the 4-methylmercapto compound. The nucleus for the 
two new compounds is being prepared as follows: 1188 
The last two compounds have been prepared but not confirmed by 
analysis. 
SN-12, Oil 4-Acetylmercapto-8-(3-diethylaminopropylami no) quinoline 
Again it has been suggested that the two new side chains be sub- 
stituted here but we wish to cancel this assignment. 
SN-12.0.14 8-(3~Diethylamimopropyl?mino)-6-'(methylmercapto )quinoline 
Cancelled, 21 June 1945, and the two new side chains substituted. 
This series of reactions has caused us trouble. The nitroquinoline sulfonic 
acid is difficult to prepare. 
SN-12; 012 6~Acetylmercapto-8-(3-di ethylaminopropylamino)quinoline 
Again it has been suggested that the two new side chains be substi- 
tused :or the di ethyl ami nopropyl amino side chain. However, we wish to cancel 
tils assignment. 
SN-11 z 215 4~ (4-Diethylamino-l-methylbutylamino)-8-qui nolinethiol 1189 
We are now attempting to attach the Nov al amino side chain to the disulfide. 
PRIORITY 5 
SN-8773 4- (4-Diethvlami no-1-methvlbu tv lami no )-6-dime th vlamino auinoline 
^bnut 10 g, of the 4-ch loro-6-di methyl ami no quinoline has been made. 
SN-12 ■, CIO 7-Ohloro-4-(4~ di ethylami no-1-methylbutyl amino )-6-qui no line thiol 
Ws hope to remove the benzyl group in this way. 1190 
SUBSTITUTED AMIDINES 
R. L, Shriner and J. H, Billman 
The synthesis of a series of Substituted Amidines (l) was under- 
taken because they represent a simplification of Substituted 4-Amino- 
quinolines II. 
They are being made by the following general equations 
The foilova ng specific amidines have been prep a red 1191 
The following are in progress:- 1192 
SYNTHESIS OF INTERMEDIATES LEADING TO SUBSTITUTED 8-AMINO- 
QUINOLINES 
H. E. French 
Name:- 4-Methyl-8-nitroqui noline, by nitration of lepidine 
2-Methyl-S-nitroquinoline, by nitration of quinaldine 
3-Methyl-8-nitroqui noline 
chromic anhyd. 
o-Nitro toluene - o-nitrobenzaldehyde 
acet, anhyd, 
o-ami nobenzaldehyde 
The synthesis fails at this point, 
COMPOUNDS IN PROGRESS 
K. N. Campbell 
1, Name: 8-(sec-butylaminohexylamino)-6-me th oxyquinoline. SN-13,378. 
Priority, 1. 
Synthesis: 
NH2OH.HC1 H2 Raney Ni 
CHoCO-CHnCHo- X CHnC-CHoCHo X CHqCH-CH?CHq 
"Na2C03 7 " 60°, 60 lbs, 5 
NOH NH2 
cone HC1 sec. Butylamine 
CH20H(CH2LCH20H CH20H(CH2L CH2C1 5 -> 
toluene 150 , 50 lbs. 12 hrs. 
95 
W HBr 
CH20H(CH9).CH9NHBu CH9Br-(CH9). CH^NHBu.HBr 
reflux Z 4 
6-MeO-8~NH2 quinoline 
abs. ale, reflux 1193 
2. Name:- 8- (is obutylami nohexylamino )-6-methoxy quinoline. SN-13,379» 
Priority, 1*.. 
Synthesis; 
H2 Raney Ni, 
(ch3)2chcho -(ch3)2chch»noh ----- A (ch5)2chch2nh2 
5^b8'-. 
cone HC1 iso butylamine x 
CH20H(CH2),CH20H -- -> CHpOH (CH?). CH-Cl - i 
4 toluene' 150 r 50 lbs. 12 hrs* 
48% HBr 
CHo0H(CHo).CHoNHBu - > CHoBr(CHo).CH-NHBu.HBr 
2 242 reflux7 2 242 
6-Me0-8-NH2 quinoline 
abs. ale. reflux 
3». ' Name;- 8-(n-butylaminohexylamino)-6-methoxy quinoline. SN-13,380. 
Priority, 2, 
Synthesis; 
cone HC1 n-BuNH? x 
ch2oh(ch2), ch2oh ---A- ch2oh(ch2)/ch2ci $ ) 
toluene ' 150 , 50 lbs, 12 hrs> 
48% HBr 
CH20H(CH2), CH^Bu CH2Br(CH2\ CH2NHBuwHBr 
reflux 4 
6-MeO-S-NH quinoline 
Abs. alcohol,, reflux 
48 hours* 1194 
4. Name:- 8-£6-tert-butyLskminohe^i amino )-6-methoxy quinoline. SN-13,377. 
Priority^ * ^l***^^a*^^ 
Synthesis: 
cone HC1 tert-BuNH 
ch2oh(ch2)^ch2oh' -y ch2oh(ch2)^ch2ci 
toluene z 150 , 50 lbs. 
cone HBr 
CH20H(CH2)^CH2NHBu CH2Br(CH2), CH2NHBu.HBr 
reflux * 
6*MeO-8-NH quinoline 
Alcohol, reflux. 
Only the first step of this synthesis has been carried out to date, 
5. Name: 6-tert-butyl-a-(dihexylaminomethyl)*4-quinoline methanol, 
SN-not assigned. Priority, 5. 
Synthesis: 
This synthesis has been carried to the tert-butyl aniline stage. 6. Name:- 7~Chloro-a-(dihexylaminomethyl)-2-quinoline methanol. 
SN-11,196. Priority, 4. | | 3/f 
1195 
This synthesis has been carried to the bromo ketone stage, and a trial 
reduction to the bromohydrin has been made. 
7. Name: - 8- (4-diethylamine-l-methyl butylamino )-6-methoxyquinolinol, 
ester with acetic acid. SN-13,381. Priority, 1. 
Synthesis: 1196 
The last step in this synthesis has not been carried out yet, 
8. Name? N-Cholesteryl-N',N'-diethyl-1,4-pentandi ami ne. SN-12,125. 
Priority, 5. 
To date only a small amount of the desired product has been obtained; 
the major reaction appears to be loss of HX from the cholesteryl halide. NEW COMPOUNDS: 
1197 
** 
1. Name:- 6,8-Di ch loro-a-[ ( 4-die th yl am ino-lnnethyl butyl )ethylami no- 
methyl]-2-phenyl-4-qu. incline methanol. SN-not assigned yet. 
Priority, 5. 1198 
2, Name:- 6,8-Dichloro-a-(4-diethylamino~l-methylbutylamino)-2- 
phenyl lepidine. SN-not assigned. Priority, 5.. 
If the Rosenmund reduction fails, one of the two following methods 
may be tried: 1199 
THE CHLORINATION AND SULFONATION OF QUINOLINES 
Byron Riegel 
Chlorination 
1, Direct Halogenation. - Quinoline may be readily chlorinated^ 
in the 3-position by the use of sulfur dichloride (SClq). It may also 
be b nominated2 in the 3-position by heating with a mixture of bromine 
and sulfur. 3-Bromo-4-quinolinol is obtained in a 95^ yield by the 
bromination of 4-quinolinol. 
An intermediate we desired was 3-chioro-8-nitroquinoline. The 
halogenation of 8-nitro quinoline is difficult, and gives only small 
amounts of what apparently is the 5-chloro or bromo derivative. Nitra- 
tion of 3-ch loro quinoline gives 3-chloro-5-nitroqui noline. However, 
the nitration of chloro quinoline gives the 8-nitro derivative. 
o 
2. Meisenheimer Reaction. - This method^ for the preparation of 
mixtures of 2- and 4-ch loro qui.no lines is illustrated as follows. 
The isomeric 2- and 4-chloro quinolines can be separated by differences 
in basicity. 3-Chloro quinoline could not be converted into 2,3- and 
3,4-dichloro quinoline. An amine oxide could not be formed with 8- 
quinoline sulfonic acid. 1200 
3. Replacement of the 4-Hydroxyl Group by Chlorine» - An almost 
quantitative yield of 4-chloroquinoline is obtained from 4-quinolinol 
by treatment with phosphorus oxychloride. Substitution in either ring 
usually lowers the yield on this exchange. The following 4-chioroouinolines 
have been prepared by this method. 
1-Chloro quinoline 
3 • -Bro mo-4- ch 1 oro qui no 1 ine 
, 7-Dich loho qui noline 
4-Chloro-6-m>.t hoxyqui noline 
4-Chloro -6-phenoxyqui no line 
4-Chloro~6~-dimet hylaninoqui noline 
4 -Ch 1 oro - 7-ph en oxy qui noline 
4-Chloro -8-ni troqui noline 
Li} 7-Dichloro-6-bon2ylthi oquinoline 
We have not been able to replace the hydroxyl group with chlorine in 
6,7-dimethoxy~4-qui nolinol. 
4. Indirect Methods for Obtaining Halogen Substituted Quinolines- - 
The b enzene ri.ng of quinoline cannot be halogenated directly unless it 
contains other groups. The best method for preparing 5,6,7 or B-chlorc- 
quinoline is by the Skraup reaction on the appropriate chloroaniline. 
The chanical reduction of nitro qui nolines in the presence of the 
chloride ion often gives chlorine substituted products , such as: 
Sulfonation 
1? The Sulfonation of Quinoline and its Derivatives, - Quinoline 
is much more difficult to su) fonate than naphthalene. The isomers formed 
and the ratio of these isomers are effected by the concentration of the 
oleum and the temperature of the reaction. Only the benzene ring is 
sulfonated. 1201 
It is very difficult to chloro sulfonate quinoline or its derivatives. 
4,7-Dichloro--8--mtrequinoline could not be sulfonated. 
2. In-d.i re ct M ethy ds. - 6-Qui nolinesulfonic acid can be prepared 
by the Skraup reaction7 on svlfanilic acid. Another indirect method may 
be outlined as follows: 
The acto.ut ed sulfonation of SN-7618 gave the following. 1202 
References 
1. A. Edinger and H. Lubberger, J. prakt. Chem., 162, 340 (1396); 
Ber., 29, 2456 (1896). 
2, A. Edinger, J. prakt. Chem., 162, 355 (1896). 
3. J. Meisenheimer, Ber., 59, 1848 (1926). 
4. R. P. Dikshoom, Rec. trav, chim., 48, 147 (1929). 
5. Preparation by G. E. McCasland and D. S. Tarbell. 
6. K. Cybulsky, E. Sucharda, C, Troszkiewiczowna and W. Turska, 
Roczniki Chemiji, 14, 1172 (1934). 
7. A. Kneuppel, Ber., 29, 703 (1896). 
ALPHA-ALKYL AMI N0METHYL-4-QBI NOLINE METH INOLS 
R. E. Lutz 
To date 55 of these have been synthesized and submitted for test, 
and a number are still in the RIP or lower categories. 
The method of synthesis employed involves the following steps: 
(1) (2) (3) (4) 
Q-COOH Q-C0C1 Q-C0CH2N2 Q-COCH^r -Q-CH0HCH2Br 
(5) 
Q-CH0HCH2NR2 (overall yields from 25 - 3 5^) 
The step (2) uses CH2N2 which now is prepared in CH2C12 with 50& 
KOH from 185 g. dry weight batches of nitrosomethylurea. A stainless 
steel anchor type stirrer is used. The reaction with the acid chloride 
goes well except for the 5-chloro types where more drastic conditions seem 
to be required because of steric hindrance. The acid chloride, free or as 
its hydrochloride, was added slowly to the CH2N2in CHCl? with stirring con- 
tinued over night; the diazoketone usually crystallized,'- sometimes thorough 
cooling being required; it was not usually recrystallized but was washed 
with a suitable solvent. 
Step (3) usually involved adding 485© HBr to the solid partly purified 
diazoketone suspended in absolute ether, and gave the bromoketone hydrobromide 
except where this is prevented by an 8-chloro (but the 8-mcthyl does not 
prevent salt formation). The bromoketone is usually somewhat sensitive and 
requires some care in purification (which is usually advisable). Long 
heating alone or in solvents should be avoided. 
The aluminum isopropylate reduction (Step 4) utilized the free 
bromoketone or its salt. Most of the 2-phenyl types reduced with moderate 
ease in good yields, but those without the 2-phenyl usually reduced with 
great speed, the reaction going too far if the reaction time was much over 
10 min. Surprisingly the reduction of one of the 2-phenyl types (the 2-(3,4~ 
dichloro phenyl) compound) proceeded with extraordinary rapidity rand has 
not yet been stopped, successfully at the bromohydrin stage. And we have 
not yet succeeded in controlling the reduction of the parent bromoketone or 
the 6-methoxy compound. 1203 
The 5-chloro-2-phenyl bromo keto ne, pr esumably because of steric 
hindrance, does not undergo reduction by aluminum isopropylate. Stannous 
chloride reduces out the bromine, giving the 4-acetyl-qui.noline which however, 
is not reduced further by aluminum isopropylate. 
In this connection a striking catalytic or solvent effect on the 
aluminum isopropylate reduction has just been noticed. 5,8-Dichloro-2- 
phenyl-4-bromoacetyl-quinoline is not reduced under the usual conditions 
in iso propanol but is when dioxane is present in considerable concentration. 
(This method has not yet been applied to other cases). 
Step (5), the condensation, g? es well inmost cases. The tempera- 
ture has been lowered to 60 - 90u and the time is 10 - 24 hours. Some cases, 
i.e. , the 2-phenyl compound, gave intractable products unless the milder 
extreme of these conditions was followed. 
The final products are now usually 'worked up by titrating (preci- 
pitating) out the unused amine as hydrochloride by standard ether-HCl, and 
continuing, often only through the monohydrochloride of the product. 
A mimeographed list of the derivatives prepared will be distributed 
at the meeting with the latest test results. The following facts are note- 
worthy in the 2-phenyl series: 
Representative a-dialkylaminomethyl-2-phenyl-4-quinoline-methands 
have been made with the following nuclear substituents: p-chloro, 7-chloro-, 
7,p-dichloro-, 7-chloro-p-methoxy-, 7-chloro-8-methyl-, 7,p-dichlcro-8- 
methyl-, 8-chloro-, 8,p-di ch loro-, 6,8-dichloro-, 6,8,p-t ri chloro-, 6-methoxy-, 
6-methoxy-p-chloro-, 7-methyl-, 7-methyl-p-chloro-, 8-methyl-, 8-methyl-p- 
chlor 8-phenyl-, 8-phenyl-p-chloro (in the 2-phenyl). In the RIP 
stage are the following: p-diethylamino-, 5-chloro-, 5,S-dichloro-, 6,7- 
dichloro-, 2-(3,4-dichloro)-, 6-chloro-, 6-methoxy-7-chloro-, 6-methoxy-8- 
chloro-, 6,8-dimethyl-, 6,8-dimethyl-p-chloro-; also the following without 
the 2-phenyl: 5-chloro-, and 7-chloro-3-methyl-; and the a-dioctylamino- 
methyl-5-isoquinoline methanol from the acid furnished by Dr. French. 
The choice of the dialkyl groups for the dialkylamino has not always 
been ideal, partly because synthesis has ranged too far ahead of testing. 
Some of the important testing data are summarized as follows: 
In the parent 2-phenyl series the diethyl, dibutyl and di amyl 
compounds showed 04 and DI = 0.1-0.5* but the dioctyl compound showed 
B4=3 and DI=2. 
In the 7-chloro-2-phenyl series the dibutyl compound showed Dl-4, 
the diamyl and dihexyl Dl=8, the dioctyl Dl=2 and the didecyl Dl-O.li, 
The secondary ariine, the monooctyl, showed Dl-4 which is identical with the 
activity of the tertiary amine of the same molecular weight, the dibutyl. 
In the 6-methoxy-2-phenyl series the peak activity maybe? at the 
di octyl. The diethyl showed Dl=0.25, the dibutyl, dianyl and dihexyl Dl-1 
and the dioctyl Dl-2. Here also the monooctyl gave Dl=l, identical with the 
result for the dibutyl. A p-chlorine in the 2-phenyl raised the activity 
of the dioctyl from DI-2 to 4. 1204 
In the B-chloro^-phenyl series the dihexyl gave B4=2 and Dl-4, 
but the dioctyl had half these activities. A p-chlorine in the 2-phenyl 
showed for the dihexyl, B4=3^5 and DIM but the di.octyl showed B4-O.7 and 
DIsOjS; and the di. decyl was inactive. The 6,8- di ch loro-2-phenyl diethyl 
compound showed D1-4+, the dihexyl 64*7 and DIM, but the dioctyl gave 
D1«O*25. The 6>8-dichloro-2-p-chlorophenyl di hexyl compound showed DI =4* 
but for the dioctyl Dl=0.5i. 
The 7-methyl- and 8-methyl-2-phenyl di octyl derivatives showed 
Dl=2 but the 2,8-diphenyl anolog gave Dl=0.25. 
Reports to date indicate that these types have uniformyl and con- 
siderably lower toxicities than the Ainley-King types and average a little 
less than the toxicity of quinine. It should be pointed out that theAinley- 
King types so far involve a fixed secondary amino group. Here however the 
dialkylamino group can be adjusted to fit the molecular weight and nuclear 
substitution. The 6-methoxy appears to go best with the di octylamino group 
whereas with nuclear chlorines the lower molecular weight dialkylami.no 
groups sean to give the best results. 
NAPHTHOQUINONE ANTIMALARIALS 
L. E, Fjeser 
Particular interest at the moment is centered in various stereo- 
isomeric substances of the following foimulas 
These are prepared by the alkylation of hydroxynaphthoquinone with the peroxide 
of an acid derived from a naphthyl butyric acid by hydrogenation. The product 
derived from nickel hydrogenation, an obvious mixture of various steric 
forms, is coded as SN-8557 and is now under clinical tests. A still more 
promising mat eri. al is another mixture, SN-12320, obtained by hydrogenation 
in the presence of platinum. Several concordant assays indicate that the 
Pt-mixture is about twice as potent against P, Lophurae as the Ni-mixture, 
and one comparison by Schmidt points to a very much lower toxicity for mice 
(ED.__c for quinine bisulfate-17.3 mg. ) 
7? 
££95 c 
Relative toxicity 
SN-8557 
8.6 mg* 
1 
SN-12320 
4.3 mg. 
e J-/H- 
The Pt-mixture SN-12320 has been separated into two apparently homo- 
geneous dl-forms, m.p. 130° (80%) and 120° (20%); the more abundant isomer 
has been identified by synthesis from cis-p-decalone as a cis isomer (probably 
cis-syn). Results of assays of these isomers, and of tests of the inhibition 
of the respiration of parasitized red blood cells, will be resorted. In 
anticipation of a requirement for clinical tests of SN-12320, work is in 
progress to develop methods of hydrogenation and purification that will 1205 
afford a mixture as rich as possible in whichever dl-form proves to be the 
more promising. 
Other new hydroxynophthoquinones that seem of special interest are 
as follows: 
EDO d ♦ 2.3 (one assay) 
70 
(The stereochemistry is being investigated) 
ED^c = 23 
(This compound might be very resistant 
to degradation.) 
EDnrc - 6.6 
70 
(The Pt-mixture is being synthesized) 
ED^c = 13.9 
(This substance might be resistant 
to degradation.) 
We are now maintaining a colony of ducks with P. Lophurae .and have 
perfected the technique of testing for drug activity by Wendell's in vitro 
method based on the antirespiratory activity against parasitized r.b.c, 
All of the compounds that appear promising by virtue of hi ph activity 
against avion infections or expected resistance to metabolic deactivation 
are being processed as follows: 
(a) Determination of toxicity: 
Chronic in mice, diet (Krayer). 
Intravenous in dog (Seligman). 
(b) Administration (if judged safe) to human subjects, 
observation of blood levels and symptoms (Seligman). 
(c) Determination of residual drug activity of plasma 
extracts by the in vitro Warburg method. 
(d) Attempted characterization of metabolites found in 
plasma and urine. 1206 
W, M, Lauer, R, T, Arnold 
A. l-Diethylamino-3-(5,6-dimethoxy-8-quinolylamino)-2-propanol, SN-12,516 
Sample (5.0 g. ) supplied to Dr. Elderfield. An additional amount 
(4.0 g.) is now available and the preparation is being repeated with some 
modifications which it is hoped will facilitate the removal of unchanged 
5»6-dimethoxy-8-aminoquinoline. 
B. 8-(3-Diethylamino-l-methyl propylamino)*6-methoxy quinoline, SN-13, 526 
The side chain has been prepared and we have recently received some 
6-ni ethoxy-8- ami no quinoline from Dr. Elder field. We plan to begin experiment 
on the attachment of the side chain within a few days. 
C, 8-(3"Diethylamino-l-methylpropylammno)~5> 6-dimethoxy quinoline. SN-13,527 
This compound is being distilled today. If the analysis of the 
material is satisfactory, a ten gram sample will be available within a 
few days. 1207 
Dt 5-Meth oxy ~6-pheno}y-8-aminoquinoline. 
It is planned to prepare this intermediate and hold it until we re- 
ceive further instructions concerning the nature of the side chain which 
is to be attached. Two methods of preparation of the intermediate are 
being investigated. They are 
So far we have not succeeded in replacing the methoxyl with a 
phenoxyl in the 1st step. 
The first step in this series has been carried out satisfactorily. 
E. 4,6~Dimethoxy-8-•(2,-diethylaminoethyl amLno)--a»ii noline. 1208 
The Price-Roberts EMME method has been successfully carried out and 
the acid has been isolated. No attempts have as yet been made to 
decarboxylate this compound. 
F. l-Diethylamino-3-(6-methoxy-8-quinolylamino)-2-propanol. 
The epihydrin is available, but no condensations hava been attempted 
as yet. 
The following additional compounds are on our list, but no work has 
been done on their preparation. 
1. 8-(l-n-propylaminopropylamino)-6-methoxy quinoline. 
2. 8-(l-isopropylamino propylamino)-6-methoxy quinoline. 
3. 8-(1-n-propylamino propylamino)-5,6-di.metho^ quinoline. 
4. 8-(l-isopropylamino propylamino )-5,6-dim?thoxy quinoline. 
5. 3, 6-dimeth oxy-8- (2 ' -diethylami noe thyl a nd.no) -quinoline. 
6. 3,6-dlmeth oxy-8-(6'-di ethylaminohexylamino )-qvi noline. 
7. A-, 6-dime th oxy-8-(6 '-diethylaminohexylamino)-quinolii|e. 
BENZOQUINOLINE DERIVATIVE'S 
C, _S. Hamilton 
Benzo(f)quinoline 
Benzo(g)quinoline 
B en z o (h) q vi no 1 in e 1209 
The preparation of the following benzo quinoline d^iy.atives has been 
completed or is under way: 
1-(1-methyl-4-die t hyl ami n obu tylamino)benzo(f) qui nol i ne 
4- (l-methyl-4-di ethyl ami nobuty lami no )ben zo(h) qui noline 
5-(di al kylami noalkylamino)b enzo(f)qui noline 
8- (di al kylami noal kylami no )b enz o( f) quinoline 
4- (1-methyl-4-die thyl ami no )benzo (g)quinoline 
10- (di. al kyl ami noal kylami no )b en z o( g) qui no 1 inc 
1-(1-Methyl-4-di ethylaminobuty lamino)benzo(f)quinoline was prepared 
from 3-naphthylamine as the starting material.. The synthesis involved anil 
formation with ethoxymethylenemalonic ester, cyclization as discussed at the 
January meeting by Price in connection with 4,7-di chloro qui noline, hydrolysis, 
decarboxylation, chlorination, and finally reaction with Novaldiamine. 
I II 
C10H7NH2 ♦ C2H5OCH=C(CO2C2H5)2 -C1OH7N=CHCH(CO2C2H5)2 , 
-OH III IV V 
(C13H7N) -J s (C13HgN)OH (1) > 
-CO2C2H3 Na™ ' 
VI VII 
(C13HgN)Cl (C3jHgN)NHCH(CH2)3N(C2H5)2 y Phosphate 
The overall yield of the free base was 38%. 
With certain variations the same set of procedures was used to synthe- 
size 4-(1-methyl-4-diethylami nobuty 1 ami.no) ben z o( h) quinolihe. The overall 
yield of free base was 31%. 
The preparation of 5-aminobenzo(f)quinoline, necessary for the synthe- 
sis of dial kylami no al. kylami nobenzo (f)qui noline s, was carried out as indicated: 
-OH (2) -NH2 (2) 
cioh6 co H(3) ~co H (c13h8n)C02h (5) ---> 
-bU2ri\.J/ -0U2n ) oULjJ-o 
(Ci3HgN(CO2CH^ hydrqzide --azide acetamino der. 
(C13HgN)NH2 (5) 
In the synthesis of 8-ami no ben zo (f) qui noline, 8-bromo and 8*-sulfo- 
benzo(f)quinoline were prepared by Skraup reactions on suitable starting 
materials but the substituent in each case could not be replaced by the 
amino group. The Skraup reaction failed when applied to l,6-dinitro-2- 
naphthylamine and l-bromo-6-m tro-2-naphthylamine. Finally the S-rmino 
derivative was pi^pared as follows: 1210 
Ac£O 
HOAc HNCL HOH 
cioH7NH2 (2) - 7s 
HC1 
(Ci3HgN)N°2 (8) -> (C13H8N)NH2 (8) 
An attempt is being made to synthesize 4-ch lorobenzo(g) quinoline, an 
intermediate in the preparation of 4- (l-methyl-4-di ethylamino buty lamino )- 
benzo(g)quinoline, from tetrahydro naphthalene, 
I II ME IV 
M12 -> ciohiin°2 -* W2 31111 -> 
C10^11^°2 (ct) 
-OH V -OH -CO, VII 
(Ci3h11N) -(c13h11N) --> (c13h12n)oh -> 
-co2c2h5 -CO^ VI 
-2H 
(q^ci ---2^ (c13h8n)ci 
This series of reactions is being studied with the hope that in the 
cyclization reaction a ben zo(g) quinoline will be preferentially formed or 
at least in equal amounts with the benzo (f )qui noline. The dehydrogenation 
reaction (VIII), the reaction vhich will answer the question, has not 
been accomplished as yet. It is proposed to attempt the dehydrogenation 
with bromine. 
For the synthesis of derivatives of 10-ami nobenzo(g)quinoline the 
ammonolysis of 10-chlorobenzo (g) quinoline is now being studied. The 10- 
chloro derivative was prepared by the following series of reactions: 
Ac 0 -Cl (1) 
-ClnH„NH9 - --C^H^NHAc (2) >8,^, (0,^)0! (10) 
10 7 2 AcOH^ 10 7 Z 10 6-NHAc (2) Z 13 8 
In contrast to a report in the literature no benzo (f )qui noline has 
been isolated from the Skraup reaction on l-nitro-2-naphthylamine. It 
may be advisable, therefore, to investigate the reaction with the view 
of obtaining 10-nitrobenzo(g)qui noline which could then be reduced to 
the amino compound. 1211 
QUIN AZOLINE DERIVATIVES 
Mary L. Sherrill 
This report is concerned with the preparation of quinazolone and 
quinazoline intermediates for coupling with 4-di(±hylamino-l-methyl-6- 
butyl amine and with 3-di. ethyl aminopropanol. 
A. 4- (4 ' -di et hylamino-1 ' -me th ylbutyl am ino )-quinaz oli ne. (SN-11 * 53 4) 
Test D-l Q 0.12 
Q-4 Q 0.2 
B. 4- (4 ' -diethylamino-1 ' -meth vlbuty lami no)-2-phenylquinazo line. 
(SN-11,534) 1212 
C. 4-(4 '-di ethyl amino-1 ' -methyl butylamino )-6-meth oxyquinazoline. 
(SN-12,253) 
A number of approaches to the synthesis of 6-methoxy-4~ 
quinazolone have been tried, two of which have been moderately successful. 
(b) Reference: Mason, J, Chern. Soc. 12?, 1197 (1925); 
Heilbron et al,, ibid, 127, 2172 (1925) 
Acknowledgement is made to the Heyden Chemical. Company 
for donating the m-hydroxybenzald ehyde and for transforming it into the 
aldehydophenyl carbonate: 1213 
In method (a) purification of 6-methojy-4-quinazolone and in method 
Cb) the isolation of 5-methoxyanthranilic acid need further study* 
D. 4-(3 f-Diethylaminopropoxy)-6-chloroquinazoline. SN-12,254. 
The purification of SN-12,254 needs further investigation,* the side 
chain is rather easily removed especially in the presence of traces of acid. 
The 4-ethoxy-6-chloroquin?zoline was obtained easily in 85 per cent yield 
and crystallized readily from 50 per cent ethanol (m.p. 104. 5-105 C. corr. )* 
Electrometric titrations of a number of the above compounds have been 
made (Dr. Lucy W. Pickett), From the results of these measurements the mole- 
cular weights and dissociation constants have been determined ?nd the thermo- 
dynamic values of the latter calculated (Speakman, J. Chern. Soc. , 1940, 
855). The titration curves were of three types, that of 4-quinazolone, 4- 
chloroquinazoline, 2-phenyl-4-quinazolone, 4-chloro-2-phenylquinazoline, and 
6-amino-4-quinazolone were "11 of one type, I, and showed no basic properties. 
Noval diamine and its homolog gave similar curves (type II) with one end- 
point, pH 6.15 (molar ratio of acid tobase of 2) indicating the second dis- 
sociation constant is net appreciably smaller than the first. The condensed 
product 4-(41-diethylnmino-l-mcthylbutylamino)-quin3zoline gave two different 
end-points , the first at pH 8,15 -and tho* second at pH 4.,3Ot corresponding 
to acid-base molar ratio of one and two respectively. Table I gives 
molecular weights calculated and Pv values 1214 
Mol. Wt. 
Substance (exp.) 
Table I 
Mol. Wt. 
(theor) 
Per cent 
Purity 
p p 
\ K2 
•'■approximate 
Noval di amine 160.8 
158 
92.28 
3.36 
4.60 
6-diethyl amino- / \ 
2-aminohexane 186.9' 
173 
92.12 
3.48 
4.42 
4- (41 - di e th y 1 am ino- 
1'-methylbutyl- 
amino)-quinazoline 287.3 
286.4 
99.76 
4.10 
>7.44 
(a) This compound had been standing several months with probable absorption 
os moisture, 
I. Frohardt, Kremer, and Williamson, Columbia University, 
A. 8-aminoquinazoline 
1. 3-nitroanthranilic acid 
phthalic anhydride -> nitro phthalic anhydride nit ro ph thalamic 
acid 3-nitroanthranilic (Chapman and Stevens. J. Chern. SOc. 
1925, 1791). 
2. 8-nitro-Zi.-qainazolone 180-190° 
3-nitroanthranilic acid + formamide 
2-3 hrs. 
3. 4-chloro-8-nitroquinazoline 
4. 8-aminoquinazoline 
First successful reduction of a 4-chloroqui nazoline to a quinazoline. 
(c. f. Dewar, J. Chern. Soc. 1944, 619) 
B. 6-metho3y-8-amino quinazoline 
Steps in synthesis 
1. 4-nitroso-meta-cresol by nitro sating met a-cresol 
2. 4-amino-meta-cresol by reduction ofnitroso compound with 
ammonium sulfide 
3. 4-acetamino-meta-cresol by reaction of acetic anhydride and 
sodium acetate on the amine 
4. 2-acetamino-5-methoxytoluene by action of dimethyl sulfate on the 1215 
4-ac et am ino-met acre so 1 
5. 2-acetamino-3-nitro-5-methoxytoluene by nitration of above material 
with nitric acid (1.5 density) 
6. 3-nitro-N-acetyl-5-methoxy anthranilic acid by oxidation of the 
meth oxy toluene with KMnO^ 
7o 3-nitro~5-methoxy anthranilic acid by hydrolysis of the acetyl compound 
8. 4-ehj oro-6-methoxy-8-nitroquinazoline has been prepared from the 
3-nitro-5-methoxyanth rani lie acid by Niementowski reaction 
fd lowed by PClc. No reductions have been run on this but 
good results expected as in reduction of 4-chloro-8-nitro- 
qdnazoline (A. 4.). 
11• From Bert E_,_ Christensen, Oregon State College 
Compounds Prepared and Submitted to Survey 
Supplier's 
Number 
Survey 
Number 
Name of Compound 
Results of Tests 
OSC 8 
11.641-4 
2,4-dimethyl-a-(2-dimethyl- 
aminoethyl)-7~quinazoline- 
me th .anol, dihyd ro ch Iori de 
B-4 Q 0,07 i 
(possibly active at 
higher doses,) 
G-5 Q 0,06 i 
OSC 15 
12,410 
4-methyl-2-qui naz ol ine 
carboxamide 
A-l Q 0,5 t, 
G-5 Q 0,5 t. 
Predicted Activity 
gall. Q 0.1 i< 
loph. Q 0.1 i. 
OSC 16 
12,496-4 
4- (1-piperidyl )cfuinazoline, 
mon ohyd ro ch 1 ori de 
B-4 Q 0,06 i. 
OSC 19 
13, 268 
2-(4~quinazo lylamino) e th an ol 
Submitted for 
testing. 
OSC 21 
13,265 
3- (4- qui nazo lyl.ami no )-l, 2- 
propanediol 
Submitted f or 
testing. 
OSC 22 
13,266 
2- (7-chloro-4-qninazolylamino) 
ethanol 
Submitted for 
testing. 
OSC 23 
13,267 
3 - (7 - ch 1 o ro -4- -qu in a zo ly 1 .amino) 
1,2~propanedi ol 
Submitted for 
te sting. 1216 
CLASSIFIED-RESTRICTED 
NOVEL SIDE CHAINS 
Dr, J. E. Kirby, Dr. R. S. Schreiber, Dr. L. 0. Behr, 
Dr. E. W. Bousquet, Dr. A. J. Hill, Jr., and Dr. C. W. Todd; 
OEMcmr-46?, Chemical Department, E. I. du Pont de Nemours 
and Company, Wilmington, Delaware. 
I. co-Cyanoalkylquinolines 
The introduction of co-cyanoalkyl radicals on the amino 
group of 6-methoxy-8~aminoquinoline will lead to compounds con- 
sidered key intermediates since the character of the side chain 
can be varied quite widely by conversion of the nitrile group 
into an ester, amide, amidine, amine, or a heterocycle, like 
pyrimidine. Particular interest is attached to those side chains 
which will contain basic substituents of an aliphatic type. 
(80% isolated as 
hydrochloride) 
II. S-Methylpseudothiourea Substituted Quinolines 
The introduction of an S-methylpseudothiourea radical 
on the amino group of 6-methoxy-8-aminoquinolIne will yield an 
intermediate capable of being condensed with amines, amides, 
sulfonamides, and guanidines to produce side chains of varying 
types and containing a multiplicity of basic nitrogen atoms. 
-1- CLASSIFIED-RESTRICTED 1217 
CLASSIFIED-RESTRICTED 
This same series of reactions can be applied to 7-chloro- 
4-aminoquinoline and to p-chloroaniline which is currently being 
used as a model compound to define the reaction conditions. 
-2- 
CLASSIFIED-RESTRICTED 1218 
CLASSIFIED-RESTRICTED 4 RFSTR 
III# Alicyclic Polyamines and Aminoalcohols 
A. The following alicyclic diamines and aminoalcohols are 
being prepared by catalytic reduction of the corresponding 
aromatic diamines and aminophenols* 
1. Diamines 
2. AminoalcohoIs 
B. The addition of acrylonitrile to piperazine followed by re- 
duction of the adduct affords a simple method for obtaining a 
tri- or tetramine containing an alicyclic ring. 
80% yield 75% yield 
-5- 
CLASSIFIED-RESTRICTED 1219 
CLASSIFIED-RESTRICTED 49. 
IV. New Aliphatic Amines 
A. (C2H5)2NCH2CH2NH2 + CH2=CHCN -X (C2H5)2NCH2CH2NHCH2CH2CN 
/ * 91% yield 
[ttl 
V/ 
() 2n( ch2 ) 2nh( CH2) jNH2 
84% yield 
B. CHjCH(CH2)5N(C2H5)2 + CH2=CHCN CII3CH(CH2)5N(C2H5)2 
kh2 nhch2ch2cn 
.1 77% yield 
M 
V 
h2n(ch2)3nh-ch(ch2)2N(c2h5)2 
CH5 
85% yield 
C. (CHj)2N(CH2)6NH2 + CH2=CHCN -4 (CHj)2N(CH2)6NHCH2CH2CN 
j 88% yield 
1 
(CH ) N(CH ),NH(CH ),NH 
D. CH2-CH-CH2 + HN(C2H5)s -> CH2CH-CH2N(C2H5)2 > 
Cl 0 Cl OH 
CE2-CH-CH2N(C2H5)2 ) H2NCH2CHCH2N(C2H5)2 
0 yield 0H 52.5% yield 
-4- 
CLASSIFIED-RESTRICTED 1220 
SHAMINQGUINOLINES 
Rt Ct El deb field 
Our work has for the nest part been devoted to the synthesis of various 
analogs of piasnoehin. For purposes of discussion this can be resolved into 
three categories: • 1) Synthesis of certain nuclear variations; (2) Synthesis 
of side-chain variations and (3) Attachment of the side chains synthesized 
t ova riou o n icj er„ 
I Synthesis ch nu:~hear variations: 
(a) Chloro-m^tho^y-S'-aminoquinoline: General method of Robinson 
and Tomlinson (J, Churn, Soc0 1934s 1524)J 
(b) 5 ,6-Dimethoxy-8-aminoquinoline: 1221 
An alternate synthesis developed by Dr, N. L. Drake proceeds as follows: 
and nr t h;e;? or vfa the Skraup reaction. 
x.•; 5 .Arano -B-di.'■ -diethylamino-l-methylbutylamino)-quinoline: 
(d) 5-Aminoplasm.ochin: Nitration of plasmochin followed by reduction 
(e) 5-Hydroxy-8-(3'-diethylaininoproiylanino)-quinoline. Reference: 
Gattermann, Ber., 27, 1927 (1891). 
(f) 5 -Hydroxy~6~nie thoxy-8- □ 'b ethylandn o pro pylarano) qui noline 
II or 
1„ > J:'eohylwrancpertralbrraride: Two synthesis have been used. 
HBr fcaOCHo 
(a) HO Br-(CH2)$Br 
(C9HJ9NH HBr 
Br-(CH2)5-OCH3 (C2H5)2N-(CH2)5-OCH3 (C2H5)2N-(CH2)5-Br 1222 
(b) <71 PBr5 
--Xthence as above. 
CO^T 
2. 7-Diethylsminoheptylbrcmide: 
Br 
AgOOC-(CH2)r7-COOAg -Br(CH2)?Br thence as above* 
/R1 
3* Side chains of the type CH3-CH-CH2-CH2"CH2-N^ 
* Rp 
Cl 
where Rp - R2 " ethyl; Rp = H and R2 - alkyl* 
(a) Noval chloride as tyrical of the reactions involved may be given 
0 CH 
" Al(OisoPr) ' 
CH3-C-(CH2)2C1 CH3-CH-(CH2)3-C1 
OH Cl 
R2NH ' SOC1 ' 
CH3-CH(CH2)3NEt2 CH5OH-(CH2)3-NEt2 
benzene 
The above reaction series has been carried out using a variety of 
primary and secondary amines* The yields are good, and, judging from 
preliminary information from Dr. Craig, the resulting halides are free 
from isomers. 
In the cases where a terminal secondary amine is present it is 
necessary to vary the general, procedure scmevhat as follows: 
OH OH 
' 1 mole Ac20 f /Et 
CH3-CH-(CH2)3-NHEt -> CH3-CH-(CH2)3-N 
pyridine \Ac 
0° 
Cl 
SOC12 ' zEt 
x CH -CH-(CH ) -N 
Z \Ac 
4. Cl-CH-CH2-CH2-NEt2: 
c2h5 
HC1 CpHcMgBr 
CH?- CH-CHO CH?C1-CH?-CHO ---- 
QH (C2H5)2NH 
cich2-ch2-ch j (c2h5 )2n-ch2-ch2-choh 
c2h5 c2h5 1223 
S0C1 
± (C2H5 )2N*iCH2-CH2-CHC1 
c2h5 
This amino chloride has been evaluated by Dr. Craig as containing 
less than 5% of isomeric chlorides. 
5. Cl-(CH2)3-O-(CH2)rN(C2H5)2 : 
Cl-(CH2^Br * NaO-(CH2)3-N(C2H5)2 
ci-(ch2)3-o-(ch2)3-n(c2h5)2 
6. Cl-tCH^-CH-g H5: 
hnc2h5 
ch3o-(ch2)^-ci * ch3ch2-cho -^ch3o-(ch2)3-ch-c2h5 
OH 
SOC1 C2H5NH HC1 
CH3O-(CH2)3-CH-C2H5 CH3O-(CH2)3-CH-C2H5 
Cl NHC^ 
C1-(CH2)3-CH-C2H5 
nhc2h5 
7. C1-(CH2)3-CH-(CH2)5CH3: 
C .A ',-<1^2 
CH3O(CH2}MgCl ♦ CH3CH2CH2CH2CN CH3O-(CH2)3-C-C^H9 
0 
reduction HBr 
CH3O-(CH2)3-CH-C^H9 Br(CH2)3-CH-C^H9 
of oxime T 1 
nh2 nh2 
8. C1-CH-CH 2-CH 2-CH~N(C 2H 5)2: 
ch3 ch3 
N(C2H5)2 
ci-ch2-ch-ch3 
ch3co-ch2-co2c2h5 -CH3-CO-CH-COOC2H5 
NaOC2H5 X ' 
ch2-ch-ch3 
N( C oHr ) O 1224 
Ketone Split 
x CH3-CO-CH2 
Z » Na*C?HcOH 
CH2-CH-CH3 
n(c2h5)2 
OH Cl 
' SOClp I 
CH3-CH-CH2-CH2-CH-N(C2H5)2 C-(CH2)2-CH-CH3 
CH^ CH3 ^^2H5^2 
9. BrCH2-CH-CH2-CH2-NHC2H5: In process. 
OH 
CH2=CH-CH^gBr ♦ HCHO CH2=CH-CH2-CH20H 
P Br^ ^2^5^2 
CH2=CH-CH2-CH2Br CH2=CH-CH2-CH2-NHEt 
Ac20 CH3C0-NHBr 
y CH2=CH-CH2-CH2-NEt -- 
X ' AcOH Z 
coch3 
CH2-CH-CH2-CH2-NEt - Coupled with nucleus 
r ' ' 7 at this point and then 
Br OAc COCH3 deacetylated. 
Synthesis has been carried up to coupling with the nucleus. 
10. Br-CH2-CHOH-CHOH-CH2-NHC2H5: In process. 
c2hsnh 
CH2=CH-CH-CTI2 CH2=CH-CH-CH2-NHEt 
Ac 0 0 ™ 
- CH^ZCH-CH-CH^NEt -thence as in the case of I above, 
OAC COCH3 
up to this stage. 
In the synthesis of all of the above side chains, difficulty has 
been encountered in the formation of isomeric halides. As this abstract 
is written it appears that this difficulty may be overcome by the use of 
thionyl chloride as a reagent for the replacement of hydroxyl by halogen. 
However, such conclusions must be made with reserve, pending receipt of 
more detailed data as to the homogeneity of the side-chains in question 
from Dr. Craig. 1225 
Ill - Attachment of side chains to nuclii: 
Numerous methods have been tried for the attachment of side chains 
to 8-aminoquinolines, but only those involving the halides have given any 
results. The direct reaction between the nucleus and ary stable flialkyl- 
ami noalky Ihal ide in absolute alcohol is the most satisfactory method for 
the preparation of the compounds. [Rohrmann and Shonle, J. Am. Chern. 
Soc., 66, 1640 (1944); 66, 1643 (1944)]. This procedure gives yields 
of from 60-75% for all dial kylamino alkylhalides except those which con- 
tain four or five carbons between the halogen and the amino group. 
Recommended Procedure 
Reflux a mixture of 0.1 mole of an 8-aminoquinoline and 0.11 moles 
of a dialkylaminoalkyIhal.ide in 60 cc. of absolute ethanol for 60 hours. 
Dilute the reaction mixture to 300 cc. and make strongly alkaline with 
NaOH. Extract with ether, dry the extract over MgSO , concentrate and 
distill at a pressure less than Q.5 mm. 
The presence of extra hydroxyl groups on the side chain or of an 
ether linkage in the side chain as: does not 
inLerfere with this reaction. This method finds further application in 
the attachment of neutral side chains such as Y-phthalimidopropyl chloride, 
but a one mole excess of the nucleus must be used in order to keep the 
reaction medium basic. Otherwise, the reaction will stop when half com- 
plete due to the formation of the salt of the nucleus with the acid 
liberated in the reaction. Baldwin [J. Chern. Soc., 1929 2959] uses 
equimolar amounts of side chain and nucleus and in general gets lower 
yields, although in certain cases the reaction product is more basic than 
the unreacted nucleus and so the product holds the acid formed in the 
reaction allowing it to go to completion. Rohrmann and Shonle state that 
the side chain may be used either as the free base or as the tydro- 
halide, but it has been found that the yields are improved in most cases 
by the use of an extra mole of the nucleus, which may be easily recovered. 
Several compounds with secondary amino groups in the side chain have 
been prepared, and a very s atisfactory procedure has b een developed for 
them. The Rohrmann and Shonle procedure using the side chains as their 
salts, keeps the side chains in a stable form, but the yields, varying 
from 25-40%, were not satisfactory, An extra mole of nucleus wculd 
probably solve this difficulty also, but an even more satisfactory method 
involves the use of a 50% ale diol solution with the addition of sodium 
acetate to buffer the solution to the proper pH, so that the side chain 
is present as the unreactive salt, while the nucleus is present as the 
free base. Yields of from 50-60% have been obtained by the following 
Procedure. 
Reflux 0.1 mole of an 8-amino quinoline and 0.1 mole of an al kyl- 
amino alkylchloride hydrochloride in 50 cc. of 50% alcohol containing 0.2 
moles of sodium acetate for seventy-two hours. Dilute to 250 ml,, make 
strongly alkaline, extract with ether, dry and distill as usual. The 
use of sodium acetate rather than excess nucleus would probably give 
very satisfactory yields in the attacment of neutral side cha ins by the 
modified Rohrmann and Shonle procedure. 1226 
The above procedure is not satisfactory f^r side chains containing8^^^ 
four or five carbons between the halogen and the secondary amino group. All 
such compounds have been acetylated either by a selective acetylation of 
the amino alcohol followed by chlorination in pyridine, er by acetylation 
of the alkylaminoalkylbromide hydrobromides in acetic acid solution containing 
some sodium acetate with acetic anhydride. The resulting neutral side chains 
can then be attached by the procedure given previously. The reaction mixture 
is mast easily worked by simply adding two volumes of 20% NaOH, refluxing 
for two hours and then diluting further, extracting with ether and proceeding 
as usual. 
Compounds in which the side chain contains a primary amino group may be 
treated in the same manner as the secondary amines, ar mere conveniently in 
many cases, the phthalimide derivative may be prepared by the procedure of 
Baldwin, In this case, an extra mole of nucleus or sodium acetate should be 
added as for other neutral side chains. The choice between the above methods 
depends largely on the ease of preparation of the required intermediates. 
The most difficult side chains are those of the noval type attached 
through a secondary halogen and containing four carbons between the halogen 
and the tertiary amino group. In our experience, the only even partially 
satisfactory method for this type of condensation involves the use of carefully 
buffered* concentrated reaction mixtures with l«ng periods of heating. 
CommerSiitl noval bromide hydrobromide was attached to the nucleus giving 
plasmochin in 35-40% yield in a concentrated solution at a pH of 5,5-5.8, 
using a 2 mole excess of the side chain. The reaction mixture was buffered 
in this case with a very large excess of sodium acetate. This procedure gave 
yields in one experiment of 10% when noval chloride hydrochloride was used. 
The yield of 15% based on noval bromide consumed might be considered 
acceptable, but further improvement is obviously desirable. The following 
procedures represent the best ones currently available from our laboratory. 
Further work is in progress, 
Plasmochin from Commerical Noval Bromide Hydrobromide: 
A mixture of 0.1 mole of 6*methoxy^8-aminoquinoline, 0.15 moles of noval 
bromide hydrobromide, and 0.5 moles of sodium acetate is refluxed in 100 cc. 
of 50% alcohol for three days. An additional 0.1 mole of noval bromide hydro- 
bromide is added, and the mixture is refluxed for an additional three days. 
After the six day heating period is complete, the mixture is diluted to one 
liter, made strongly alkaline and extracted with ether and worked up as 
described below, The yield is 40% based on the nucleus used,. 15% based on the 
side chain used,, and 30% of the nucleus may be recovered by distillation. 
Pasmochin from N*val Chloride Hydrochloride: 
The use of noval chloride under these same conditions results in the 
formation of considerable amounts ef a high boiling amine, possibly n^val 
acetate. If excess nucleus is used as a buffer, the yields are ab^ut the 
same as those obtained with noval bromide. Heating to a higher temperature 
or use of a pH appreciably above tr bel$w 5.8 gives poorer yields than that 
obtained as follows,. 1227 
A mixture of one mole of 6-methoxy-8~aminoquinoline, 0,3 moles of noval 
chloride hydrochloride and 100 cc. of 50% alcohol is heated at reflux for 
five days. The mixture is worked up as below. The yield is 10% based on the 
side chain used and 70% of the nucleus used may be recovered, 
III. Purification and Preparation of Salts: 
* 
The purification of the drugs prepared by any of the above procedures is 
satisfactorily carried out by distillation of the material at less than 0.5 mm, 
and then redistillation under nitrogen. The path through which the vapor 
must pass should be as short as possible, and should be of wide bore. A small 
Claisen flask with a low wide bore side arm has proved quite satisfactory. 
Unreacted nucleus comes over first and is followed by the drug at a higher 
temperature. The redistilled base should be stored under nitrogen and 
converted as quickly as possible into a stable salt. 
Frequently it may be desirable to recover unreacted nucleus without 
distillation, since often other nuclei than the 6-methoxy-8~aminoquinoline 
are not stable on distillation. The concentrated solution from the reaction 
mixture when diluted to twice its volume and acidified with HC1 and then 
cooled, gives a crystalline precipitate of the nucleus hydrochloride which 
may be filtered off. The filtrate when treated with sodium acetate until 
slightly basic toward congo red may be extracted with ether to almost completely 
remove unreacted nucleus. It is often more convenient to remove all the 
nucleus by extraction from the buffered solution rather than to filter off 
part of it as the hydrochloride. The solution after extraction with three 
or four portions of ether is made strongly alkaline and worked up as usual. 
The most satisfactory procedure for the preparation of salts involves the 
addition of an anhydrous ether solution or an absolute alcohol solution 
of the acid to an anhydrous ether solution of the free base. Many of the salts 
prove to be quite hygroscopic and no generalities as to the best salt for a 
given group of compounds can be drawn. Aromatic acids are frequently 
unsuitable, as they do not form soluble salts readily, Hydriodic acid is the 
most satisfactory acid in that it usually forms non-hygroscopic salts, but 
it must be eliminated, since many of the salts are unstable to light and 
nearly all of them contain some free iodine after standing even in the dark. 
The most satisfactory salts have been chlorides, citrates, oxalates, tartrates 
and malates, although almost any other acid might be tried, Sulfate and 
phosphates have in all cases tried in our experience proved to be very 
hygroscopic. Dr. Drake has had success with phosphates, 
The salts of the 8-aminoquinolines when prepared from carefully distilled 
free base are usually analytically pure as formed. If not, one or at mast 
two recrystallizations from absolute alcohol or alcohol and ether is sufficient 
to render them pure. With certain hydrochlorides, 95% alcohol has been found 
to be the best recrystallizing solvent, but in general the salts should be 
handled only in anhydrous media. These salts occasionally and unpredictably 
form stable monohydrates on contact with the air. The number of moles of acid 
reacting with a mole of base may be one or two, but is not predictable. 1228 
HOMOGENEITY OF 8-ALINOQUINOLINES 
L, C. Craig 
It is well known that in the series of synthetic antimalarial drugs, 
comparatively small changes in structure aften give rise either to greatly 
enhanced activity or to the undesired toxic manifestation. For this reason 
it would appear important to be absolutely sure of the homogeneity of the 
preparations tested or at least to know the nature of the contaminating 
material. Combustion analyses and the conventional organic technique often 
fail to reveal a considerable percentage of a contaminating material 
especially when the formation of isomers is likely during synthesis. 
Accordingly an attempt has been made in this laboratory to investigate certain 
strategic preparations of the survey to ascertain the degree of absolute 
homogeneity in so far as present day available methods will allow. 
Two general methods have been used for this purpose wherever possible. 
One is the "solubility" method which depends on the phase rule and is 
applicable to stable crystalline preparations. The second is much newer 
method called the "counter-current distribution" method, which depends on 
the partition coefficient of the substance in two immissible liquid phases. 
The latter is a much more flexible method applicable to salts, free bases 
or the drug even after it has been incorporated into tablets. It has 
proven more sensitive than the first method where comparison has been 
possible, but theoretically is not as all inclusive in excluding possible 
inhomogeneity. 
The 4-aminoquinolines tested have all proven to be relatively satis- 
factory preparations, with not more than three percent total inhomogeneity. 
This has certainly not been the case with many of the 8-aminoquinolines 
studied. The various preparations of plasmochin studied have shown from 
10 to 30 percent of total inhomogeneity, depending on the particular 
preparation. In every case the main contaminant has been an isomeric 
substance which has been fractionated from the mixture and isolated as the 
citrate melting at 136-139°♦ It is probable that the cause of inhomogeneity 
does not lie in the nucleus, since a sample of 6-methoxy-8-aminoquinoline 
did not appear to have gross inhomogeneity. On the other hand, the amino 
bromide side chain is known to be quite impure. 
It would appear from not too complete data at hand at this time that 
the normal propyl side chain gives relatively satisfactory preparations. 
On the other hand, a sample of 3-chloro-diethylaminopentane which itself did 
not show gross inhomogeneity,, upon addition to 6-methoxy-8-aminoquineline 
yielded a preparation which contained approximately 20% of one substance and 
80% of another.. This would seem to indicate that isomerization was taking 
place during the addition reaction,- 
It would appear that the free bases themselves do not have very great 
stability, especially in daylight,. It would also appear that each compound 
is more or less of a special case in itself. The problem is made difficult 
by strong deviation from Beers law in the spectroscopic work and by the 
apparent tendency to associate in solution and thus cause large shifts of 
partition coefficient with concentration,. Nevertheless a considerable 
number of preparations are being investigated as rapidly as present 
facilities and the inherent nature of the technique will permit. 1229 
59. 
.THE toxicity OF THE 8-AMIN0QUIN0LINES 
L, H, Schmidt 
When the chemical synthetic program on the 8-aminoquinolines was 
set up, a study of the pharmacological characteristics of plasmochin 
(SN 971) and plasmocid (SN 3H5) was initiated in this laboratory, This 
study encompassed work on rats, dogs and monkeys and shewed that in all 
three species SN 3115 was distinctly more toxic than SN 971. In the rat 
and in the dog there appeared to be no qualitative difference in the 
reactions to SN 971 and SN 3115. In the monkey, however, the difference 
in qualitative reactions was literally astounding, SN 971 produced a 
profound depression of physical activity, severe cyanosis, anemia, 
leucopenia and neutropenia, SN 3115, on the other hand, produced severe 
central nervous system derangement, characterized by nystagmus, loss of 
pupillary reflexes, loss of equilibrium, inability to coordinate movements 
of the limbs, and in some instances spastic paralysis. These physiological 
derangements were associated with some of the most severe and specific 
brain lesions ever encountered in a reaction to a drug. 
The significance of the above findings became more readily apparent 
when toxicity studies on eleven other 8~aminoquinolines had been completed, 
As was the case with SN 971 and SN 3115, the toxicities of these drugs 
for the dog and rat were quantitatively different but qualitatively the 
same. In the monkey, however, there were both quantitative and qualitative 
differences in toxicity. Some drugs produced reactions essentially identical 
to those obtained with SN 961; others produced reactions like those obtained 
with SN 3115* There was a very suggestive relationship between type of 
toxicity and chemical structure. 
On the basis of the above findings, a program for screening the toxicity 
of the 8-aminoquinolines in the monkey was set up. In all, 45 derivatives 
have been examined with this technique in «ur laboratory. The results 
obtainedhave shown that insofar as reactions in the monkey are concerned, 
the drugs tested either produce reactions like those attributed to SN 971 
or SN 3115 or have an apparently specific effect on the heart. It seems 
fairly clear that these type reactions are associated with certain chemical 
groupings, The relationship of chemical structure to the various mani- 
festations of toxicity will be the principal item for discussion. 1230 
60. 
THE SYNTHESIS OF 8-AMIN0QUIN0LINE DERIVATIVES 
N. L. Drake 
A. Synthesis of Side Chains 
Eight methods of synthesis have been employed: 
1) Br(CH2)3Cl * 2R2NH >R2N(CH2)3C1 * R2NH2Br 
2) Br(CH2)6Br * CH^ONa ^CH3O(CH2)6Br + NaBr 
CH3O(CH2)6Br + aR^H ^CH3O(CH2)6NR2 + RNH2Br 
CH3O(CH2)6NR2-S2^[r2^^ + CH3Br + H20 
boil 
3) Br(CH2)$Br * C6H4(C0)2NK ^Br(CH2)5N(CO)2C6H4 + KBr 
4) ch2 - ch(ch2)8cooh J®^ch2^^ 
CH2Br(CH2)9C00H R2N(CH2)10C00H 
4 9 
R2N(CH2)10C00C4H9 > R2fJ(CH2)10CH20H -g-> 
[R2NH(CH2)nBr]+ Br" 
5) CH2 = CH(CH2)8CH2OCOCH3 ->CH2BrCH2(CH2)gCH20C0CH3 
CH2Br(CH2)lcpCOCH3 R2N(CH2)11OCOCH3 + R2NH2Br 
Br" 
> R2N(CH2)nBr 
6) CH3O(CH2)5Br > CH3O(CH2)^H2 
CHjO(CH2)5NH2 + (CH )2C0 -> CH3O(CH2)5NHCH(CH3)2 
> C(CH3)2CHNH2(CH2)jBr]+Br- 
boil 
7) Br(CH2)1QBr + NaOC6H1;L >Br(CH2)loOC6H11 + NaBr 
otherwise like method 2 1231 
61. 
3) SHoCOCHCO 5% < , 
3 / hc! > ch3go(ch2)3oh * C02 
ch2ch2 H20 If 
.E2^.^2 C?HtNHCH(CHq) (ch9)oh 
H9 + Ptz 2 5 y 2'3 
v (c2h5)2so4 
(C^^CHCCH^) ch2ch2ch2oh 
C.HcN SOC19 
> 5 > f £ 
( c2h p^CHC CH3) CH2CH2CH2C1 
The following side chains were prepared by the method indicated; 
Side chain Method 
(C„H,)„N(CH ) Cl 1 
z > z Z 3 
(C.HjJlCCHokCl 1 
(C8H17)^I(CH2)3C1 1 
C6H4(CO)2N(CH2)5Br 3 
[(CH3)2CHNH2(CH2)5Br]*Br 6 
[(CH3)2NH(CH2)6Br]+ BF 2 
[(C2H5)2NH(CH2)6Br]+ Br 2 
[(C,H9)2NH(CH2)6Br]+ Br 2 
[(C6Hi3)2NH(CH2)6Br]* BF 2 
[(CH3)2CHNH(CH3)(CH2)6Brr Br 2 
[(C2H5)2NH(CH2)10Br]+ BF 7 
[(C2H5)2NH(CH2)11Br]+ Br 4 
(C6Hi3)2N(CH2)iiBr 5 
B» Attachment of Side Chains 
1) Method described by Rohrman and Schonle, J. A» C. S. 1643 (1944). 
Condensation carried out by refluxing side chain, either as free base or 
as salt with nucleus in dry alcohol for 48 hours. In one case the 
phthalimido quinoline was hydrolyzed by acid to give the free amine. 1232 
62 * 
2) By heating 1 mole of nucleus with 0*5 m#le of side chains either 
as free bas^ or as salt, in presence of a small amiunt of water* (Me^hj^d 
given In memorandum of Huber to Suter.) 
3) One drug made by the following reactions: 1233 
CORRECTIONS TO BE MADE IN ABSTRACTS OF MATERIAL 
DISCUSSED AT CHICAGO CONTRACTORS' CONFERENCE 
Page Corrections 
4 Method B, third step: Heat 3 hours. 
5 Endochin, third step: n~Cyi I 
14 III, formula preceding cleavage should be: 
CH OCH -C N 
2 II li 
CHq0CH2'C C-OH 
31 Noval side chain on left formula. 
32 R.E. Lutz, after step (5): overall yields about 54%. 
37 All formulas: Replace 0C1 by phenoxy group. 
39 Delete the next to the last sentence. 
44 Table I, novaldiamine, % purity = 99%. 
46 Final product under I, B: Side chain (8 position) is 
i 
N~CH2CH2CN 
I 
COCH^ 
52 Last compound under (a) is: 
Cl 
CH3-CH-(CH2)3-NEt2