The Preparation of Substituted Amino-Dicarbamates

122 Pages·04.881 MB·English

by  Dunkel, Walter Lester

The undersigned, appointed by the Dean of the Graduate Faculty, have
examined a thesis entitled
THE PREPARATION OF SUBSTITUTED AMINO DICARBAMATES
presented by Walter L. Dunkel
a candidate for the degree of Doctor of Philosophy
and hereby certify that in their opinion it is worthy of acceptance.
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THE PREPARATION OF SUBSTITUTED AMINO DICARBAMATES
by
Walter L. Dunkel, A.B., A.M.
SUBMITTED IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
in the
Graduate School
of the
UNIVERSITY OF MISSOURI
1951
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TABLE OF CONTENTS
PAGE
I . STATEMENT OF THE PROBLEM.................................................... 1
I I . INTRODUCTION................................................................................. 2
I I I . DISCUSSION OF RESULTS...................................................................44
IV. EXPERIMENTAL
1. Preparation of Ethylene Dichlorocarbonate 5#
2. Preparation of Hydroquinone Dichloro­
carbonate........................................ . . . . . 5$
3* Preparation of jD-Aminodimethylaniline . $9
4. Preparation of N,N’-Di»(]3-dimethylamino-
phenyl)ethylene Dicarbamate. . . . . 60
5. Preparation of N,Nf-Di-(jo-dimethylamino-
phenyl)ethylene Dicarbamate Dihydro­
chloride ................................................................................ 60
6. Preparation of N,N-Dimethyl-o-nitroaniline 61
7. Reduction of N,N-Dimethyl-o-nitroaniline 61
S. Preparation of N,NT-Di-(o-dimethylamino-
phenyl)ethylene Dicarbamate Dihydro­
chloride ...........................................................62
9. Preparation of m-Nitrodimethylaniline • 63
10. Reduction of m-Nitrodimethylaniline • 64
11. Preparation of N,N’-Di-(m-dimethylamino-
phenyl) ethylene Dicarbamate.....................................64
12. Preparation of N,N’-Di-(m-dimethylamino-
636815
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PAGE
phenyl)ethylene Dicarbamate D ipicrate • 65
13. Preparation of N,NT-Di-(j>-diethyl-
aminophenyl)ethylene Dicarbamate . . 6$
14. Preparation of N,NT-Di-(jo-diethyl-
aminophenyl)ethylene Dicarbamate
D i p i c r a t e ................................................................. 67
15. Attempts to Prepare the Dihydrochloride
of N, N ’ -Di- (jo-diethylaminophenyl) -
ethylene Dicarbamate............................................ 67
16. Preparation of N,N’-Di-(j3-diethylamino-
phenyl)ethylene Dicarbamate D isulfate . 63
17. Preparation of £-Nitrobenzyldiethylamine 63
13• Reduction of jo-Nitrobenzyldiethylamine. 63
19• Condensation of £-Aminobenzyldiethyl-
amine and Diethyleneglycol Dichlorocar-
b o n a t e .................................................. 69
20. Preparation of N-Carboethoxy-N-butyl-
a n i l i n e ........................................................................ 70
21. Preparation of N,NT-D i-(N-butylamino-
phenyl)ethylene Dicarbamate . . . . 71
22. Preparation of Dimethylaminoacetonitrile 72
23. Preparation of Raney Nickel C atalyst . 72
24.. Reduction of D im ethylam inoacetonitrile. 73
25. Condensation of Ethylene Dichloro-
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PAGE
carbonate and the 129-130° Fraction
From the Previous Experiment . . . . 73
26. Condensation of Ethylene Dichloro-
carbonate and the 73-129° Fraction
From Experiment 24 . . . . . . 75
27. Preparation of Diethylaminoaceto-
n itr ile ................................................................. 75
2S. Reduction of D iethylam inoacetonitrile • 76
29. Condensation of Ethylene Dichloro-
carbonate and N,N-Dialkylamino-
ethylamines ................................................... 77
30. Preparation of N,NT-D i-(2-pyridyl)-
diethylene Dicarbamate ..................................... 77
31. Preparation of N,Nf-D i-(2-pyridyl)-
ethylene Dicarbamate Dihydrochloride • 73
32. Preparation of N,N, -Di-2-(6-methyl-
pyridyl)ethylene Dicarbamate
Dihydrochloride ..................................... 73
33* Preparation of N,Nl-Di-2-(3-m ethyl-
pyridyl)ethylene Dicarbamate
Dihydrochloride ................................................... 79
34# Preparation of N,Nf-D i-(2-benzothiazyl)-
ethylene Dicarbamate Dihydrochloride • SO
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PAGE
35* Preparation of N,N’-D i-(2 -th iazy l)-
ethylene Dicarbamate Dihydrochloride . • Si
36. Preparation of Benzimidazole • . . . 82
37. Preparation of N,N*-Di-(1-benzimida-
zolyl)tetram ethylene Dicarbamate
Dihydrochloride .........................................................82
38. Preparation of 2-Methylbenzimidazole . . 83
39* Preparation of N,NT-D i-l-(2-m ethyl-
benzimidazolyliethylene Dicarbamate . • 83
40. Preparation of 2-Methyl-5-methoxy-
b e n z im id a z o le ....................................................... 81+
41. Condensation of 2-Methyl-5-methoxy-
benzimidazole and Ethylene Dichloro-
c a rb o n a te ......................................................................85
42. Preparation of 3-Nitro-4-aminoanisole . 86
43 • Preparation of 3 )4_Di aini rioani sol e 86
44• Attempt to Prepare 5-Methoxy-
benzimidazole .......................................................... 87
1+5• Preparation of N-Carboethoxy-5, 5-
dieth y lb arb itu ric Acid ..................................... 87
46. Preparation of N,N'-Dicarboethoxy-
5, 5-diethylbarbituric Acid ............................. 88
47. Attempt to Condense Sodium B arbital
and Ethylene Dichlorocarbonate . . . . S9
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PAGE
45 • Preparation of Potassium 5,5-
D iethylbarbiturate ............................................ . 90
49. Condensation of Potassium 5,5-Di-
ethylbarbiturate and Ethylene
Dichlorocarbonate ............................................ . 90
50. Preparation of Potassium Phthalimide • . 90
51. Preparation of N-Carboethoxyphthalimide . 91
52. Preparation of N,N’-D i-(phthalim ido)-
tetramethylene Dicarbamate . . . . . 92
53. Attempt to Condense Ethylene Dichloro­
carbonate and ^-Dimethylaminoethyl
£-n-Butylaminobenzoate (Tetracaine) . 92
54. Preparation of Ethyl £-aminobenzoate . . 94
55. Preparation of Ethyl £-n-Butylamino-
benzoate .................................................................
56. Attempt to Condense Ethyl ja-n-Butyl-
aminobenzoate and Ethylene Dichloro­
carbonate .................................................................
57. Preparation of N,N'-Di-(2,3-dimethyl-
phenyl)ethylene Dicarbamate . . . . . 96
55. Attempt to Prepare N,NT-Di-(3-amino-
quinolyl)ethylene Dicarbamate . . . . 96
59. Preparation of N,Nf-D i-2-(5-diethyl-
am inotolyl)ethylene Dicarbamate . . . 97
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PAGE
60. Preparation of Benzamidine Hydro­
chloride ................................................................. 93
61. Preparation of NjN’-Di-lbenzimido)-
tetramethylene Dicarbamate . . . . 99
62. Preparation of N,NT-Di-(benzimido)-
ethylene Dicarbamate ..................................... 100
63.- Preparation of Acetamidine
Hydrochloride ................................................... 100
64. Preparation of N,NT-D i-(acetim ido)-
ethylene Dicarbamate ..................................... 101
65. Preparation of £-A nisonitrile • . . 102
66. Preparation of £-anisamidine • . . 104
67. Preparation of N,N’-Di-jo-anisamido-
ethylene Dicarbamate ..................................... 105
V. SUMMARY............................................................................106
VI. ACKNOWLEDGEMENT..............................................................10$
VII. BIBLIOGRAPHY.....................................................................109
V III. V I T A ...................................................................................114
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I . STATEMENT OF THE PROBLEM
The purpose of th is investigation was to study the
reactions of alip h atic dichlorocarbonates with alip h atic,
aromatic and heterocyclic amino compounds to obtain diure-
thans. Since the diurethans of certain heterocyclic amines
are related to amidines, the la tte r type compounds were in­
cluded also in the study.
I t was hoped th at the substituted diurethans might
have desirable physiological prop erties.
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I I . INTRODUCTION
Part I .
The re a l introduction of local anesthesia, as pointed
out by H irschfelder (3&), into the practice of medicine and
surgery dates from 1S&k* I t was in th is year th at Karl
Kohler and Sigmund Freud, two young Vienna physicians, made
a systematic investigation of various alkaloids in the hope
of finding a su b stitu te for morphine. In the course of
th is study, Kohler accidentally dropped a l i t t l e cocaine
solution into the eye of one of his colleagues and noted
the anesthesia which resulted . He then demonstrated th at
conjunctional and corneal anesthesia re su lt from the appli­
cation of cocaine to the eyes of guinea pigs, rab b its, and
dogs and then applied the drug c lin ic a lly in ophthalmologi-
cal surgery. Kohler reported his re su lts to the Opthalmo-
logical Congress at Heidelberg in September, l£S4 and i t s
application to surgery rapidly became general.
Next in importance to K o h lers introduction of co­
caine must rank the demonstration by Einhorn in 1$99 that
esters of aminobenzoic acid have local anesthetic proper­
tie s when brought into contact with nerves or nerve endings
and th at th e ir water soluble basic derivatives are effec­
tu a l su b stitu tes fo r cocaine. His synthesis of procaine
(novocaine) as a much less toxic local anesthetic in 1905
may tru ly be said to have introduced the modern era in lo-
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