Aminoalcohol and aminoketone derivatives of thymol

97 Pages·04.46 MB·English

by  Koehler, James O

UNIVERSITY OF CINCINNATI
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I hereby recommend that the thesis prepared under my
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entitled A
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be accepted as fulfilling this part of the requirements for the
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degree of
Approved by:
FORM 668— G. S. & T. C.— S00— 5-48
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, AMI NQALC OHOL AMD AMINOKETOUE
DERIVATIVES OF THYMOL
A dissertation submitted to the
Graduate School of Arts and Sciences
of the University of Cincinnati
in partial fulfillment of the.
requirements for the degree of
DOCTOR OF PHILOSOPHY
1951
by
James 0. Koehler
B.Sc. in Chem. University of AKron 194?
M.Sc. in Chem. University of Cincinnati 1949
AUu Z o !.351
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TABLE OF CONTENTS
Page
Acknowledgment........................................... v
Part- I — Introduction................................. 1
aI
^ A. Pharmacological Properties of Thymol.......... 1
B. Local Anesthetics ....................... 5
1. General History.......... 5
,/i 2. Esters of Benzoic Acid and Its Derivatives . .
6
^ a. Primary Amino Esters ...................
6
*
0 b. Secondary Amino Esters ................... 7
<?
c. Tertiary Amino Esters ................... 9
3. Ketones............ 12
C. Analgesics ............................. 14
1. Aralkyl&mine s ..................................14
a. Sympathomimetic Amines .............15
b.. Alkanol&mines ....................... 21
Part II — Procedure and Discussion.................... 24
Part III — Experimental Details......... 32
A. T-hymyl Acetate....................................32
B. T-hymyl Propionate............ 32
G. 4-Acetylthymol................. 32
D. 4-Propionylthymol.................................. 33
E. 4-Acetylthymyl Methyl Ether........................33
i
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F. 4-Acetylthymyl Ethyl Ether ........... 34
G. 4-Acetyltbymyl Benzyl Ether................... 34
H. 4-Propionylthymyl Benzyl Ether ............. 35
I. 4-(3-Piperidinopropionyl)-thymol
Hydrochloride............................... 35
J. 1-Methoxy-4~(3-piperidinopropionyl)-thymol
Hydrochloride.................... . . 36
K. 1-Ethoxy-4-(3-piperidinopropionyl)-thymol
Hydrochloride ................................. 36
L. 1-Benzyloxy-4-(3-piperidinopropionyl)-thymol
Hydrochloride . . . . . . . . ................. 37
M. 4-(3-Piperidinopropionyl)-thymol ............. 37
N. 4-Piperidinomethylthymol Hydrochloride . . . . 37
0. l-Benzyloxy~4-(2-methyl-3-piperidino-
propionyl)-thymol Hydrochloride ............... 38
P. dl-l-Methoxy-4-(l-hydroxy-3-piperidino-
propyl)-thymol Hydrochloride ................. 39
Q. dl-4- (1-hydr oxy-3-piper idinopr opyl) -thymol
Hydrochloride................................. 40
R. dl-l-Me t hoxy-4- (1-bydroxy-l-ethyl-3-
piperidinopropyl)-thymol Hydrochloride . . . . 41
S. /~l-Methoxy-4-(l~hydroxy-3-piperidinopropyl) -
thymol Hydrochloride.............. 42
Part I¥ — Suggestions for Future Thesis Problems . . . 45
ii
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Part ¥ — Summary ................. 47
Part- ¥1 — Appendix - Review of the Chemistry of Thymol. 50
I. Occurrence.............. 50
II. Production.......... 50
A. From Natural Sources ................. 50
B. From Synthetic Sources....................... 50
1. m-Cresol.................. 50
2. p-Cymene....................................51
III. Properties........................................ 52
A. Physical......................................52
1. Structural Formula......................... 52
2. Synonyms....................................55
3. Empirical Formula......................... 53
4. Molecular Weight.............................53
5. Rydroxyl Number ..................... 53
. C o l o r ......................................53
6
7. Freezing Point..............................53
. Boiling point ....................... 53
8
9. Dielectric Constant ................ . 53
10. Surface Pressure ................ 53
11. ¥apor Pressure..............................53
B. Chemical Properties............................54
1. Alkali Solubility.......... 54
2. Etherific&tion................ 54
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S. Esterific&tion . . ......................... 57
4. Acylation......................... 59
5. Bydrogenation...................... 60
. Sulfur Derivatives ....................... 61
6
a. Sulfur Chlorides................ 61
5. Sulfonic Acids . . . . . ............
68
7. Nitrogen Derivatives ..................... 64
a. Nitration . ......................... 64
b. Amination . .............. 65
c. Nitroso Compounds.....................
66
d« Azo Compounds . . . . . . . . . . . .
66
e. Urethans................................67
. Quinones.................................
8 68
IV. Pharmacological Properties ..................... 71
A. Anthelmintics.................................. 71
B. Punglcidal Properties ....................... 74
C. Bactericidal Properties ..................... 74
Bart VII — Bibliography....................... 78
iv
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ACOOWLEDGMENT
The'author wishes to express his deepest
gratitude to Dr. I. R. MacGregor under whose guidance
this work was undertaken.
V
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Part I
INTRODUCTION
A. Pharmacological Properties of Thymol' *
Thymol, 1.1, a naturally occurring aromatic
compound isolated from the volatile oil of thyme and
other plants, has received some attention in medicinal
chemistry since it is a natural phenol and hence shows
some bacteriocidal properties. It has been employed for
cu(cd3)z
ch3
i.l
many years as an anthelmintic and duodenal disinfectant.
In particular it has been used to combat ascarides and
hookworms. In dilute solution it has a pleasant taste
and leaves a sensation of cleanliness in the mouth. The
low toxicity (about £5 per cent that of phenol) of such
dilute solutions and the bacteriocidal properties lend
themselves naturally to the use of thymol as an antiseptic
in mouth washes. Although its phenol coefficient is about
28, it is reported to be relatively ineffective in large
amounts of organic matter.
Certain very definite fungicidal properties are
demonstrated by thymol. It has been proven active against
Epidermophyton, Tricophyton and Microspores. A one per cent
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