Table Of ContentCOMLIITOEE IK CELARQE OP CANDIDACY;
Professor Charles Neal Jordan
Chairman end Adviser
Professor Edward Adel'bert Doisy
Doctor John Simon Kasper
Assistant Professor Philip Aaron Katzman
Professor Leonard Francis Yntema
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THE PREPARATION OP ALKAMINE ESTERS
OF ORTHO-ALKOXY BENZOATES.
by
Lawrence John Schroeder, B. S. in Chem.
D issertatio n Presented to the Faculty
of the Graduate School of St. Louis
U niversity in P a rtia l F ulfillm ent of
the Requirements for the Degree of
Doctor of Philosophy.
A. D. 1942.
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ACKNOWLEDGEMENT.
The author wishes to express his
sincere appreciation to
Doctor Charles N. Jordan
ior his cooperation and assistance
in th is work.
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TABLE OP CONTENTS.
PART I.
Page.
Introduction ........................................................................ 2
A. Oxy and GarboxyD erivatives of Benzol ................... 6
1. Hydroxy and Alkoxy Benzol D erivatives. 6
2. S alic y lic Acid and Related Compounds.. 8
ty
B. H istory of Local Anesthesia 12
C. The R elation of Chemical C onstitution to
Local A n e sth e sia .......................................................... 17
D. Local Anesthesia and the Alkamine Benzoates. 26
E. Cyclic Oxy D erivatives in Local A nesthesia.. 30
1. Cyclic Hydroxy D erivatives................. 30
2. Cyclic Alkoxy D eriv ativ es.................. 33
a. A liphatic alkoxy d e riv a tiv e s .... 35
b. Aromatic alkoxy d e riv a tiv e s .....' 36
3. Cyclic A lkylthio A nesthetics....................... 43
PART II.
Experim ental................................. .............................................. 47
A. M aterials.................................................................................. 47
B. Preparation of Methyl o-Alkoxy B enzoates.... 55
C. Preparation of o-Alkoxy Benzoic Acids.............. 67
D. Preparation of o-Alkoxy Benzoyl C h lo rid es... 77
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TABEE OP CONTENTS (continued)
E. D ialkyl Amino Alkyl o-AlkoxyB enzoates . . . . . 82
I. Condensation of halo-alkyl o-alkoxy
benzoates w ith secondary amines.................. 87
I I . Preparation of alkamine o-alkoxy
benzoates from the o-alkoxy benzoyl
chlorides and the dialkylamino alcohols 90
P. A nalytical Methods............................................................... 107
Summary and Conclusions................................................................. 110
Eibliography............................................................................................. 113
V ita A u cto ris. ................................................ 122
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TABLE OF CONTENTS (continued)
Table I , Alkyl H alides............................................................ . . 49
Table I I , Amino A lcohols............................................. 52
Table I I I , Methyl o-Alkoxy Benzoates................................ 65
Table IV, Ortho-Alkoxy Benzoic Acids............................... 75
Table V, Ortho-Alkoxy Benzoyl Chlorides.......................... 80
Table VI, Alkamine o-Methoxy Benzoate Hydro
ch lo rid es......................................................................... 95
Table V II, Alkamine o-Ethoxy Benzoate Hydro
chlorides. ..................................................................... 98
Table V III, Alkamine o-Propoxy Benzoate Hydro
c h lo rid e s ................................................................. 101
Table IX, Alkamine o-Butoxy Benzoate Hydro
ch lo rid es.......................................................................... 104
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PART I.
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s
"The practice of chemical therapy is an
e n tire ly d iffe re n t thing: i t existed long
before the existence of any chemist or
any physician; also the art of chemo
therapy of the future w ill develop not
from preconceptions; assumptions and
suppositions, not from wishes and d e sire s,
not from m asterly speeches and hand-works
of students, but from continuous obser
vations of the chemo-dynamical e ffe c ts ,
w ell conducted experiments in the lab
oratory of the b io lo g ist and keen obser
vation of the physician at the bedside.’1
Paracelsus.
- 1
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PART I*
INTRODUCTION.
Therapeutics, the treatm ent of d isease, is as
old as the human race its e lf . Man has always suffered
from disease and has always searched for remedies to
obtain r e lie f . The h isto ry of therapeutics 1 must,
th e re fo re, go back to ancient tim es. Prophylactic
1
measures were in s titu te d by the Egyptians and later...
by the Hebrews. H ippocrates, "The Father of Medicine",
ty p ifie d the Greek school of medical thought, c o n tri
buting much to our d ie te tic regimens and physical
therapy. D ioscorides, fiv e centuries l a t e r , described
such im portant drugs as opium, arsenic and aspidium.
As the Medieval period of medicine was reached,
empiricism continued to play an important ro le in
therapeutics. Great knowledge was acquired from keen
observation and experiment. The Arabians introduced
the f i r s t pharmacopeia in the eleventh century, de
scrib in g the use of mercury and opium. P aracelsus,
1. Solomon, "The T raffic in H ealth", p. 73 (1937).
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disclaim ing the importance of the older schools, f ir s t
formulated the ideas on the relatio n sh ip between
chemistry and medicine.
The early drugs were discovered purely em pirically.
These n atu rally occurring drugs, mainly derived from
organized stru c tu re s, were prim arily of vegetable origin.
Pharmacology was but a co llectio n of recip es, and was
hardly deserving the name of a science. The s c ie n tific
2
in v estig atio n of m edicinals began w ith the p u rific a
tion and iso la tio n of the individual components of crude
drugs and gave us some inform ation as to th e ir active
p rin cip les and molecular stru ctu re . In 1805, Serturner
studied the opium alkaloids and effected the iso la tio n
of morphine. In 1820, P e lle tie r in v estig ated Nux Vomica,
and found i t to contain strychnine and brucine. The
discovery of the active p rin cip le of the cinchona bark,
the alkaloid quinine, by P e lle tie r and Caventou in the
same year, must undoubtedly be considered as one of the
most important discoveries in the domain of pharmaceu
tic a l chemistry.
The iso la tio n of the active p rin cip les of drugs
2. P isch l and S chlossberger, "Handbook of Chemotherapy” ,
Vol. I , p. 201 (1933).
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