Table Of ContentSOME DERIVATIVES OF ALKANOLAMINE3
I . DIALKYLAMINO-AUfYL PHENCXYACETATES AND RELATED COMPOUNDS.
SYNTHESIS OT ALK&NOLAMINES AND DERIVATIVES FROM EPICHLOROHYDRIN.
m \
ri\/
Kaymond e* Boucher
Submitted to the Faculty of the Graduate School
In p a r tia l fu lfillm en t of the requirem ents
for the degree* Doctor of Philosophy* in
the Department of Chemistry,
Indiana un iv ersity
June 1950
ProQuest Number: 10296427
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ACKHQWLED0MEKT.
Tfcie author extends his sin cerest g ratitu d e
and. appreciation to Dr* EU E* Campaigne by whom
th is research was directed and followed w ith
utmost patience and frie n d lin e s s * The S te rlin g -
Winthrop Fellowship in Chemistry during 1949—50
was. a valuable aid in. the completion of th is
work:*
TABLE OF CONTENTS
FOREWORD----------------------------------------------------------------------------------------------- 1
FART I. ------- 2
INTRODUCTION - - - __ _ - 3
HISTORICAL ------------------- , - - 5
DISCUSSION ----------- 50
EXPERIMENTAL----------------------- 66
2~Hydroxy-l»3-dimethyLhenzene - - - - - - - - - - - - - 66
y-di-n-Propylam inopropanoL. - - - - - - - - - - - - - - 66
y -d i-n —But y1am i no p rop ano L - - - - - - - - - - - - - - - 67
2 6 -Dimet hy Lp he no xy acetic Acid - - - - - - - - - - - - 66
Piieny It hi o acetic Acid - - - - - - - - - - - - - - - - - 68
jo^Nitrophenoxyacetic Acid- - - - - - - - - - - - - - - 69
phenoxyacety1 Chloride - ------------------------------------------------------- 70
2 *6-Dimethylphenoxyacetyl Chloride - - - - - - - - - - ?p
F henylthioacetyl chloride - - - - - - - - - - - - - - - 71
£ —Nitrophenoxyacetyl Chloride - - - - - - - - - - - - - 72
/2 —Die t hy lam i no eth y l Benzoate Hydrochloride - - - - - - 73
/3 -Di e t hy lam i no ethyl Fhenoxy acetate Hydrochloride - - - 73
/^-Diethylam inoethy 1 2 *6-DimethyIphenoxyacetate Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 74
/^HDiethylam inoethyl Phenyl.thioacetate Hydrochloride - - 75
/3—Di met hy laminoet hy 1 £—N i t r ophenoxy ac et at e Hy dr o ~
chloride - - - - - - - - - - - - - - - - - - - - - - 76
/S-D lethylam inoethy1 £—N itrophenox„acetate Hydrochloride 7?
/3 -dl-nKButy laminoet h y l jo—N itr ophenoxy acetate Hydro
chloride - - - - - - - - - - - - - ----- _ _ _ _ _ _ _ 77
i i i
iv
ft -Et hy 1-/5-Pheny lam i no e th y l £-N itrophenoxyacetate
Hydrochloride - - - - - - - - - - - - - - - - - - - 78
—Morp ho lino eth y l £-N itr ophenoxy acetate Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 7 9
2f-di nx-Propylaminopropyl £-N itrophenoxyacetate Hydro—
chloride - - - - - - - - - - - - - - - - - - - - - - - 80
y-d i-o—Butylaminopropy1 £—Nitrophenoxyacetate Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 80
HCiethylaminoethy 1 £~Ami.nophenoxyacetate Hydrochloride 81
^ - d i - n —But ylarni no eth y l £-Aminophenoxyacetate. Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 82
y - d i—n—Pro py la mi nopropyl £—^n(iinophenoxy acetate Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 83
^ -d i-n —Butylaminopropyl £—Aminophenoxyacetate Hydra-
chloride - - - - - - - - - - - - - - - - - - - - - - 84
SUMMARY-------------------------------------------------------------------------------------- 86
REFERENCES ------------------------------------------------- 87
PART I I ------------ — ------------------------------------------------------------- 95
INTRODUCTION - - --------------------------------------------- 96
HISTORICAL ------------------------------------------------- 98
DISCUSSION --------------------------------------- n o
EXPERIMENTAL ---------------------------------------------------------- 137
l-( 2 f —Methy Iphenoxy }-o-chlor o—2—propano 1 - - - - - - - 137
1—(2 |l—Methy Iphenoxy r3—epoxypropane - - - - - - - - - 137
1-Diethylami no—2 >3-epoxy propane - - - - - - - - - - - - 139
1-C.2 f“*Methy Iphenoxy )“3-diethyl& m ino-2-propanol Method A 140
L~(2 Me thy Iphenoxy} -3 -diethy lamino-2 —propanol. Hydro
chloride - - - - - - - - - - - - - - - - - - - - - - 1 4 1
Method
Method C --------------------------------------------- 143
V
Method D - - ----------------------- -- - -- - 142
Method E - - - - - - - - - - - - - - - - - - - - 143
2—(2 r-MethyIphenoxy}-3-diethylam ina—1—propanol- - - - 144
2—C2r -Met hyIphe noxy)-3-di e t ny lamino— l.-propano 1 Hydro
chloride - - - - - - - - - - - - - - - - - - - - 14.4
1—CS^-dklethylphenoxy }“3“dimethyl.amino—2-propanol - - - 145
l-(2 1 “MethyIphenoxy )-3 “dimethy lam ino-2-propanol
Hydrochloride - - - - - - - - - - - - - - - - - - 1.4 6
1—(2 *“MethyIphenoxy }-U -piperidino-2-propanol - - - - - 146
1~(2 r-MethyIphenoxy )~3-piperidine—2-propanol Hydro-
chloride - - - - - - - - - - - - - - - - - - - - - 147
1—(2 r “Methy Iphenoxy )-3.“diethy lam ino-2-propyl acetate
Hydrochloride - - - - - - - - - - - - - - - - - - 147
2—{ 2.r —Met hy Ipheno xy} -3 -d i e t hy 1 a rn i no —1 -p r 00 y 1 acetate
Hydrochloride - - - - - - - - - - - - - - - - - - 149
1—(2 r—Methyiphenoxy)-3-dimethy lamino—2—propy 1 acetate
Hydrochloride - - - - - - - - - - - - - - - - - - 149
1* (. 2 r —Me t hy Ip he n o xy; -3 -p i p e r i d ino -2 -pr o py 1 acetate
Hydrochloride - - - - - - - - - - - - - - - - - - 150
l —( 3 *'-Methy lphenoxy) -3-d i et hy 1 amino-2 —pr opy 1 di pheny 1 -
acetate Hydrochloride - - - - - - - - - - - - - - 150
1—(2 r -Me t ny Ip he no xy} -5 -di e t ny lami no- 2—pro py 1
benzoate Hydrochloride - - - - - - - - - - - - - - 1 3 1
M- ( 2 * “Met hy Iphenoxy) -3 -diethy Iamino-2-proyy 1 py-nitro-
benzoate Hydrochloride - - - - - - - - - - - - - - 152
l - ( 3 f—Thiothieny1 )-3 -d ieth y lamino-2 —p ropanol - - - - 153
l-(3 r“Ih io th ien y l)-3 “d ie th y lam ino-2-proc; 1 acetate
Hydrochloride - - - - - - - - - - - - - - - - - - 153
vi
I - C 2 * -Me t hy 1 p he no xy ) -3 -d i e t hy I a m i n o -2 -c hi o r o p r o p ane
Hydrochloride - - - - - - - - - - - - - - - - - - 154
1“ (2 '—MethyIphenoxy}-3—diBethylam iao-2—chloropropane
Hydrochloride - - - - - - - - - - - - - - - - - - 155
1“(2 ‘—Llethy iphenoxy )-3 “benzylQxy“2-propanol — - - - - 155
Method A - - - - - - - - - - - - - - - - - - - - - i 55
Method B - - - - - - - - - - - - - - - - - - - - - 156
l-(2 * “Methy Iphenoxy }-2—benzj loxy-3-diet hy larninopro-
pane - - - - - - - - - - - - - - - - - - - - - - - 157
1“ (2 f“MethyIphenoxy) -2-benzy lo.xy-3-dimetny laminopropane 157
1*(2 * —liethy Iphenoxy }-3“di ethy lamino-2“ (3 r-theny Ioxy}“
propane Hydrochloride - - - - - - - - - - - - - - 453
1-C2 *-Methy Iphenoxy }“3~dimethylamino-2“ (3 ' “theny loxy
propane - - - - - - - - - - - - - - - - - - - - - 159
1“ (2 ^-Methy Iphenoxy )“3“dimetnylan]in0“2“ (3 *—thenyloxy )“
propane Hydrochloride - - - - - - - - - - - - - - 150
3 -Chloro“2“hydroxypropyl acetate - - - - - - - - - - p$Q
3—OhlorO“2“hydroxypropyl diphenylacetate - - - - - - - 161
3“PiperidinO “2“hydroxypropy1 diphenylacetate - - - - X6Z
SUMMARY--------------- 164
REFERENCES ------------------- - i65
1
FOREWORD
Tills th e sis has been divided into two p arts because *
during the course of the o rig in a l investigation,, other workers
in the fie ld reported that sim ilar compounds were p ra c tic a lly
devoid of activ ity * As a consequence no attem pt was made to
expand the work which had been completed and a new in v e sti
gation was undertaken* The la tte r problem has been of much
g reater in te re s t with regard to possible physiolo0ical
a c tiv ity of the products * and It. has been explored more
thoroughly*
r
DULm ^im -ALKXL FHENOXYACETATES
AND BELATED COMPOUNDS
INTBODU CTION
The cfa.oi.ce in the c lin ic for a lo cal an esth etic is not
based necessarily upon the potency of the compound, but upon
other fac to rs in most in stan ces. F irst of all* the drug
should have a minimum, of side re a c tio n s. Many of the com
pounds described as d esirab le are reported to produce irrita tio n *
which may be due to the free base or more frequently to the
acid ity of its salts* A second facto r is the s ta b ility of
the drug* Since i t is often necessary to s te r iliz e solutions
of the anesth etic without producing d e te rio ra tio n , the drug
must he su ffic ie n tly stab le for pharm aceutical preparation.
A th ird fa c to r, not as d ecisiv e, is the ease of chemical
m anufacture; for a l l other things being equal, the m ateriaL
which can be produced most economically w ill be p referred .
A survey of the lite ra tu r e fa ile d to show any basic
este rs of phenoxyacetic acids for possible use as lo cal
an esth etics; and since such a large and varied number of
acids had been used to prepare active compounds, i t seemed
lo g ic al to attempt the preparation of several of these e s te rs .
The fact th at the phenoxyacetic acids are highly active
compounds as plant hormones, and in higher concentrations
as weed k ille r s , enhanced the p o s s ib ilitie s of th e ir being
physiologically activ e in the body*
With th is in mind the synthesis of various dialkylam ino-
alky'l e ste rs of phenoxyacetic acid s— p rin c ip ally the p-amino-
phenoxyacetic acid e s te rs — was undertaken.
An attempt, was made to try to co rrelate anesth etic
a c tiv ity with arom aticity by running u ltra -v io le t absorption
sp ectra on a series of five or six related type compounds with
