Synthesis of some n-substituted alpha-amino-alpha-phenylacetic acid ester derivatives

SYNTHESIS OF SOME N-SUBSTITUTED

ALPHA-AMINO-ALPHA-PHENYLACETIC ACID

ESTER DERIVATIVES

By
MELVIN PHILIP FISHER

A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA
August, 1957

ACKNOWLEDGMENTS

The author would like to acknowledge the ala and encouragement

of Dr. W. M. Lauter, chairman of his supervisory committee, and

Dr. L, G. Gramling, Dr. C. B. Pollard, Dr. A. H. Gropp, and Dr. C. H.

Becker, the other regular members of tes committee. He would like also

to acknowledge the assistance of Dr. D. S. Anthony, wno has graciously

consented to serve as a substitute in the absence of a regular member.

The author wishes to thank the American Foundation for Pharma-

ceutical Education for its generous financial aid during 1955--1957.

The many suggestions and patience of the author's fallow graduate

students are sincerely appreciated.

And to his parents, for their immeasurable generosity and faith,

the author says, "Thanks."

TABLE OF CONTENTS

Page
ACKNOWLEDGMENTS . . . . 11

LIST OF TABLES . . . .

INTRODUCTION .

HISTORICAL REVIEW . . . 3

EXPERIMENTAL . . . . 7

PART I -- General . . . .. 7

PART II -- Preparation of -(-Phenyl-iK-bromoacetlc Acid
Esters . 8

PART III -- Preparation of Di-n-Propylaminopropylamine 12

Preparation of Di-n-Propylaminoproplonitrile 12

Reduction of Di-n-Propylaminopropionitrile .. 13

PART IV -- General . . . 15

Development of Method . . . 15

Processing the Reaction Mixture . . 19

Derivatives for Analytical Purposes . . 22

Experimental Set-Up . . . 23

Preparation of Ethyl *(-Phonyl-.K -(dimethylaminopropyl-
amino)-acetate . . . 23

Preparation of Ethyl 4-Phenyl-i-(tdlethylaminopropyl-
amino)-acetate . . . 25

ili

Preparation of Ethyl ,(-Phenyl-c -(di-n-propylamino-
propylamino)-acetate . . 26

Preparation of Ethyl O-Phenyl-e-(di-n-butylamino-
propylamino)-acetate . . 27

Preparation of Ethyl (-Phenyl- A-(morpholinopropyl-
amino)-acetate . . . 29

Preparation of ithyl E-Phenyl- .-(l-pyridyl)-acetate]
bromide . 30

Preparation of n-Propyl .t-Phenyl-. -(dlmethylamino-
propylamino)-acetate . . 31

Preparation of n-Propyl .A-Phenyl-4*-(diethylamino-
propylamino)-acetate . . 32

Preparation of n-wropyl A-Phenyl-e-(di-n-propylamlno-
propylamino)-acetate . . 33

Preparation of n-Propyl O-Phenyl-- -(di-n-butylamino-
propylamino)-acetate . . 35

Preparation of n-Propyl ea-Phenyl-o-(morphollnopropyl-
amino)-acetate . . . 36

Preparation of (n-Propyl .(-Phenyl- '-(l-pyridyl)-acetat
bromide . 37

Preparation of Isopropyl A-Phenyl-*(-(dimethylamino-
propylamino)-acetate . . 38

Preparation of Isopropyl *w-Phenyl-o4-(diethylamino-
propylamino)-acetate . . 39

Preparation of Isopropyl .-Phenyl- A-(di-a-propylamino-
propylamino)-acetate . . 40

Preparation of Isopropyl *(-Phenyl- c-(di-n-butylalino-
propylamino)-acetate . . 42

Preparation of Isopropyl wt-Phenyl- <-(morpholinopropyl-
aino)-acetate . . . 43

iv

Preparation of [Isopropyl ,-Phenyl---(l-pyridyl)-
acetate] bromide . . ... 44

Preparation of n-Butyl A-Phenyl-a-(dlmethylamlno-
propylamino)-acetate . . 46

Preparation of n-Butyl a.-Phenyl-"-(diethi laminopropyl-
amino)-acetate . . . 47

Preparation of n-Butyl A-Phenyl-- -(dl-r-propylamino-
propylamino)-acetate . . 48

Preparation of n-Butyl t-Phenyl-.-(dl-n-bitylamlno-
propylamino)-acetate . . 49

Preparation of n-Butyl *(-Phenyl-a -(morphollnoprouyl-
amino)-acetate . . . 50

Preparation of [n-Butyl o--Phenyl- --(1-pyrldvl)-
acetate] bromide . . . 51

Preparation of Isoamyl .-Phenyl- -(dlmethylamlno-
propylamino)-acetate . . 52

Preparation of Isoamyl ot-Phenyl-* -(dlethylamlnopropyl-
amino)-acetate . . . 53

Preparation of Isoamyl a(-Phenyl- -(dl-n-propylamino-
propylamino)-acetate . . 54

Preparation of Isoamyl A-Phenyl- -(.d-n-b.jtylamino-
propylamino)-acetate . . 55

Preparation of Isoamyl -A-Phenyl-v -(morphollnopropyl-
amino)-acetate . . . 56

Preparation of [isoamyl *(-Phenyl- m.-( l-p)rido )-
acetate] bromide . . . 57

SU AR . . 59

BIBLIOGRAPHY . 61

LIST OF TABLES

Table Page

1 4(-Phonyl-st-bromoacetic Acid Esters . 11

2 Summary of Products and Reaction Types . 20

INTRODUCTION

The ultimate aim of the pharmaceutical chemist is to be able to

design compounds to perform specific therapeutic functions. Unfor-

tunately, our present knowledge of the action of drugs on the body,

particularly at the cellular level, Is too meager to permit this.

Because of this, much of the work on synthetic drugs has followed the

pattern of modifying the therapeut ically active moiety of naturally

occurring substances. In this manner it has been possible in many

cases to improve the therapeutic index by increasing activity, decreas-

ing toxicity, or both.

It can be said with a great deal of certainty that gastro-

intestinal distress has been a major factor in stimulating the search

for synthetic drugs. Indeed, the literature is replete with papers

dealing with synthetic antispasmodic, many of which are enjoying wide

usage. However, the fact that so many have appeared on the market is

evidence of the shortcomings of each; we are still only In the foot-

hills of the mountain of success.

There have appeared nla the literature two compounds represent-

ing a marked departure from the classic synthetic approach in antispas-

modic chemistry. Whereas the majority of antispasmodics are anlnoalkyi

esters of various carboxylic acids, the isoamyl esters of -1-phenyl-4-

(dimethylaminoothylamino)-acetlc acid and the corresponding diethyl-

aminoethylamino- derivative have been reported to have significant

antispasmodic activity. In these It will no note that the amino

function is located in the acid portion of the eater and not In the

alcohol. This investigation has been undertaken to extend this approach

by synthesizing a series of A-phanyl- 4-(dlalkylaminopropylalmno)-

acetic acid esters.

HISTORICAL REVIEW

Although the origin of the use of Belladonna is lost in

antiquity. it was not until 1831 that atropine was isolated from the

root of Datura (1). This discovery, of course, fostered a great deal

of interest in many of the leading chemists of that time. Their work

was culminated by Ladenburg's successful synthesis In 1879 (2).

As we see from the formula, atropine is the ester of tropine

CH2---*CB-CH2
I I ?
N-CH3 CH-0-C-CH-

CH2- CH- CH2 CH20H

and tropic acid. Ladenburg, who synthesized atropine by esterifying

tropine with tropic acid, also prepared a number of similar esters with

different acids to form a group of compounds which he named "tropelnes."

Among these acids was mandelic acid, whose ester with troplne is called

homatropine. This compound has been a favorite of ophthalmologists for

years since it is a powerful sydriatic but is of shorter duration than

atropine (1).

Macht (1) became interested in the pharmacology of homatropine

through a study of mandelic acid. He had shown previously (3) that

benzaldehyde, a precursor in the synthesis of mandelle acid, exhibited

4

the antispasmodic properties of benzyl alcohol and certain Denzyl esters.

In addition, evidence was appearing in the literature which suggested

that homatropine had a different mode of action than atropine. Where

atropine exhibited neurotroptc activity, homatrorine appeared to be

musculotropic; where atropine slowed the pulse, homatroplre increased

the rate (1).

A comparative study was begun, then, to determine the relation-

ships of homatropine, its decomposition products, atropine, ind related

derivatives. From this work Macht concluded that mandelic acid, as

simple salts and esters, exhibits the characteristic effects of homatro-

pine on smooth muscle, and that this smooth muscle relaxation was due

to a direct action on the muscle cells. Contrast the action of atropine

which is mediated through blockade of the myoneural Junction of the para-

sympathetic nervous system (4). In addition, the action of atropine

resides in the intact ester, but in neither of its components alone or

in admixture.

Apparently this revelation caused little upheaval in anti-

spasmodic research, since most of the synthetic agents which have

appeared on the market have been aminoalkyl enters of cdrbox.,llc acids.

This probably can be attributed to elucidation of what is conslderea to

be the active molety (circled below) of the atropine molecule (5).

CHl2- CH

-CH | N-CH3

CH2 CH

5

It logically followed that research was aimed at variation of this basic

structure. As examples are depicted the following compounds:

1 /CS2 s C2H5s
C-CH-O-CH2-CH2-W C-O-CH2-C-CH2-N
C2R5 C2H5

Trasentine Bentyl

C\25 C H3

0 CH-C-0-CH2-CH2-N-CH3 Bre ( -CH-C-O-CH2-C-CH2-N
I I- I 2"1
b C215 CH20H CH3

Banthine Syntropan

On the basis of Macht's observations, Brock (6) reported an

investigation of an extended series of mandelic acid esters. This led

his to a subsequent investigation of the isosterically related

4-phenyl-'-aminoacetic acid esters, which indeed also showed pro-

nounced spasmolytic activity. Extending tnts *ork, he condensed isoamyl

A-phenyl-A-aminoacetate with both dimethylaminoethyl chloride and

diethylaminoethyl chloride, the latter appearing on the market in Europe

under the trade name of "Avacan." Although this compound Is apparently

being promoted quite extensively, a recent pharmacological report (4)

indicates that its action is only temporary and variable.

A discussion of the relationships of structural changes and

pharmacological activity of antispasmodics can be found in many texts

and journals (8, 9, 10, 11). It has been purposely omitted from this

6

review since a restatement of previously published observations cannot

possibly resolve any of the controversies created. In addition, It has

been demonstrated repeatedly that the effects of structural changes in

one class of compounds can seldom, if at all, OD transposed onto

another. Inasmuch as this investigation has produced compounds which

deviate markedly from those which have undergone extensive treatment,

and since there is not adequate information concerning similar com-

pounds, any conjecture as to their mode of action, variation in activity.

and the like, would be altogether unrealistic before an adequate

pharmacological study has been completed.

EXPERIMENTAL

PART I

General

The amines used in this work, except for di-n-propylamlnopropyl-

amine, were graciously supplied by Carbide and Carbon Chemicals Company

and American Cyanamid Company. The phenylacetic acid was purchased in

part from the Amend Chemical Company (C.P.) and from Fisher Chemical

Company (Reagent). All other chemicals used were of reagent grade or

better, or were standard laboratory supplies.

Analyses were performed by the Weller and Strauss Microanalyti-

cal Laboratory, Oxford, England, and by Schwarzkopf Microanalytical

Laboratory, Woodside, New York. Melting points of derivatives are

uncorrected, and all temperatures are in centigrade.

The EXPERIMENTAL has been divided into three parts for discus-

sion purposes, the first two being preparation of intermediates and the

third, preparation of the final products.

As is customary, the compounds prepared have been listed in onder

of increasing molecular weight in each series. However, since their

actual preparation did not follow this homologous pattern in every case,

the preparations in each PART have been prefaced by a discussion of

methods and results in order to insure better continuity of presentation.

7

PART II

Preparation of A-Phenyl-A-bromoacetic Acid Esters

For the preparation of the proposed series of compounds, even

on a laboratory scale, Brock's (6) original method of condensing the

A-amino acid with alkyl chlorides was unsuitable due to the difficulty

in preparing the amino acid in sufficient quantity. Since quite a

large number of appropriately substituted propylenedlamlnes were avail-

able, it was felt that the reaction could be carried out by means of

the "-bromo- -phenylacetic acid esters. Floss (12) has prepared a

number of these using the classic Hell-Volhard-ZeJinsky metnod of red

phosphorous and bromine. This, too, was unsuitable due to the poor

yields reported.

It has been shown (13) that the critical intermediate In the

Hell-Volhard-Zelinsky reaction is the acid chloride. Schwenck and

Papa (14) have made A-bromo esters by treating the acid with thionyl

chloride to form the acid chloride and avoid the une of phosphorous

altogether. Their recommendation was to use an excess of tnionyl

chloride which would serve as the reaction medlun. for the subsequent

bromination. The excess thionyl chloride can be removed by vacuum

distillation prior to the addition of the alcohol.

The reaction was carried out ir a three-necked, round-bottom

9

500 ml. flask, fitted with thermometer, reflux condenser, pressure-

equalizing addition funnel, glass-covered magnetic stirrer, and electric

heating mantle. The condenser was equipped wlth a gas trap consisting

of a funnel inverted over a concentrated KOH solution. The sater ror

the condenser was circulated through a copper funnel immersed in an lee

bath to help minimize loss of bromine.

The thionyl chloride was added directly to the phenylacetic

acid with stirring, solution of the acid causlni, tre temperature ?n

drop to about 100. This mixture was heated to rerlus and kept ht until

evolution of ICl appeared to stop. This usually tool' about three hours

from the time of addition. At this point the temperature rnnRed from

105 1100, and the reaction mixture had darkened ronsiderablv. Bromine

was added dropwise, the time of addition varyinc from one and one-half

hours to four and one-half hours depending on the ability of the con-

denser to prevent loss of bromine vapor. The mixture was heated until

no more bromine vapors were present. This took from one to three hours,

the temperature at the end being about 1200.

Attempts to remove any excess thionyl chloride met with failure.

From all appearances, it seemed that most of It had boiled off during

the course of the reaction. Samples of the reaction mixtures, *hen

withdrawn, did not react vigorously with water as does tnlonyl chloride.

To insure complete removal, however, a substantial excess of each

alcohol was used during the esterification step.

The alcohol was added dropwise at such a rate as to keep the

10

reaction mixture gently refluxing. When completely added, the refluxing

was allowed to continue until evolution of gas ceased. The coined

time for this phase was approximately two to two and one-half hours.

The reaction mixture was allowed to cool to room temperature and poured

into a separatory funnel along with some water. The eaters were heavier

than water, but when ether was added and the mixture shaken, the, were

taken up in the ether layer. The ether solution was washed with sodium

bicarbonate solution, with water until neutral, and dried over sodium

sulfate for 24 48 hours. The ether solution, which was usually a very

dark reddish-brown, was filtered and the ether evaporated, The residue

was distilled under vacuum through a Claisen head.

Table 1 lists the various esters, their boiling points, and

yields. The very poor yield of the isoamyl 6rter cannot be explained.

When first prepared the distillate became contaminated due to bumping In

the still pot. An attempt to remove the undesirable coloring matter Dy

redistilling the ester was unsuccessful. The product would not distill;

it merely became darker. The preparation of this ester was repeated

three more times, each of which failed. Thus it beceoe necessary to

use the impure ester in the synthesis of lthe Isoamyl series.

It is advisable to handle all of these esters in the hood and

with adequate ventilation. The lower members, notably the ethyl and

propyl esters, are extremely lachrymose and Irritating.

TABLE 1

*(-PHNYL-- BR&IOAMCETIC ACID ESTERS

-C-O-R
\ Br

R Pressure, sm. B.P.0 Color viela, .

Ethyl 3 122-127 brownish- 60
yellow

Propyl 8 141-149 yellow 59

Isopropyl 2 110-126 yellow 54

Butyl 11 140-160 brownish- 33
yellow

Isoaayl 5 130-150 brown 15

PART III

Preparation of Di-n-Propylaminopropylaamine

Whitemore and co-workers (15) have published a general method

for the preparation of basically substituted aliphatic nitrilea and

their catalytic reduction to amines, in which they obtained the amine

in question in 49% yield. Amundsen and Nelson (16) report a general

method for the reduction of nitriles to primary amines using lithium

aluminum hydride, from which they obtained yields of better than 80%

with both aliphatic and aromatic nitriles. Also, by this method, the

products are not contaminated with secondary amine by-productq. Inas-

much as the hydride reduction can be carried out much more simply than

the catalytic reduction,and the yields are better, it was decided to

determine the applicability of the hydride to the reduction of a

basically substituted nitrile.

Preparation of di-n-propylaminoproplonitrile. --

C3117 C387
N- + CH2=CH-Cs N N-CH-CH2-C-N
C397/ C37H/

In a three-necked 200 al. round-bottom flask with reflux condenser,

thermometer, addition funnel, magnetic stirrer, ana electric heating

mantle, 68.5 al. (0.5 soles) of dipropylamine and 100 al. of

12

13

acrylonitrile (1.3 soles, practical grade) were mixed and heated to 800

for 48 hours. This mixture was allowed to stir at room temperature for

three days. The excess acrylonitrile %as removed under reduced pres-

sure on a steam bath to give 72 Gm. (93.7%) of a reddish-brown liquid

whose picrate melted at 109 1100 (literature, 1110).

Reduction of di-n-propylaminopropionitrile. --

C3y117 (1) LiA1H4 C3H7
,N-C12CN2-CSN z N-CB2-CH2-CH2-NH2
C3E~ (2) B20 C387

In a three-necked flask with mechanical stirrer, reflux condenser mltb

drying tube, and addition funnel, 19 CO. (0.5 moles) of lithium aluminum

hydride lumps was suspended in about 60 ml. of sodium-drled ether. This

was stirred for about five hours at ice bath temperature tn obtain a

fine suspension. Seventy-two Ga. (0.47 moles) of nitrile was addea

dropwise with vigorous stirring and continued cooling over a period of

two hours. Stirring was continued for 30 more minutes. Twenty al. of

water, 15 ml. of 20% NaOH solution, and 70 ml. of water were added very

slowly in succession with vigorous stirring and continued cooling; this

hydrolysis took approximately four hours. The etner solution was fil-

tered from the white, granular residue, the residue was washed with

ether, and the combined ether solutions were allowed to evaporate In the

hood. The residue was a brownish-yellow liquid weldhing 66 Ga. (89.3I),

whose picrate melted at 179.5 1810 (literature, 181).

A note of caution must be entered here with regard to the

14

hydrolysis. With inefficient stirring a cake forms where the water

contacts the reaction mixture. On the first attempt at this reduction

the reaction got completely out of control when this cake was broken up

and dispersed into the reaction mixture. Most of the reaction mixture

was forced out of the flask and, of course, ruined. In the experiment

described in the preceding paragraph, also, the reaction started to get

out of hand again but was brought under control, before too much was

lost, by cooling and stopping the addition of the water.

PART IV

General

Inasmuch as the purpose for this work was to produce a series

of compounds for pharmacological testing, the question of yield assumed

a secondary importance in the determination of the method for production.

Once it wqa established that the proposed synthesis actually) did work,

it was decided to concentrate on makin~i enough of each compound for

testing purposes rather than concentrating on individual compounds. If

any does show particular promise, then the optimum conditions for Its

preparation can be determined later. In attacking the problem in this

way, the possibility exists that a satisfactory general method can be

developed during the course of the Investigation. This, then, can be

applied to subsequent products and also cdn be used to remake prior

compounds where more sl desired.

Development of Method

The general reaction can be represeotea by tie following

equation.

H-C-O-R + H-N-CH2-CH2-CR2-N
Br R,

F \_CH_-O-R R
H-N-CN2-CH2-CB2-N + llBr
RI

Since in all cases both starting materials were liquids, the logical

approach was to mix the two and observe the results. This proved

unsatisfactory due to the great amount of heat liberated. It was decided

to attenuate the heat of reaction by means of a solvent. A is seen

above, the by-product of the reaction is HBr, and pyridlne was selected

as the first choice of solvent by virtue of Its basicity and the fact

that both starting materials were soluole in It. By removing the HBr as

it is formed, the base should help to proo.ote the reaction. Indeed,

enough of compound I was isolated from a reaction mixture to be identi-

fied. However, it was shortly discovered that the pyridine itself *as

reacting with the 0'-bromo ester. This led unexpectedly to compounds

VI, XI, XVIlI, XXIV, and XXX, but eliminated pyridine as a general

reaction medium. The real significance of this was the isolation of the

desired compound, albeit in very lil.tted amount; this proved that the

reaction could be made to work.

Another direction was to select solvent In wrich Untn starting

materials are soluble, but in which tre desired product is Insoluble.

Since both the proposed compound ana the amine have basic nitrogens,

17

there would no doubt be a competition between them for the HBr. It was

felt, though, that if the reaction proceeded in a normal substitution

mechanism, the desired base might preferentially accept the HBr due to

its proximity at the site of the reaction.

H H H R H H

-C- + N- -) C--. -C- HBr

Br H Br B

Ether and benzene were selected as likely reaction media since

the esters and amines are soluble, and a hydrobromide would probably be

insoluble. By using equimolar amounts of each starting material and

slowly adding the amine to the ester, there should not be any excess

amine present.

An ether solution of amine was added to a cooled ether solution

of ester, and a significant amount of white precipitate was obtained.

A picrate salt was made from this precipitate to determine its identity.

Through some misfortune the derivative gave an erroneous melting point

and was not recognized as the amine hydrobromide until after ar analysis

had been performed. On the basis of the first evidence, though, a

series of amines was tried using the same general method with both

benzene and ether. From these the precipitates or oils which came out

were identified as amine hydrobromides. When it was realized what had

actually happened, the residues that had been obtained from tte

18

supernatant liquids were examined and Oielded the lesireo products. In

other words, the HBr was being picked up by unreacted amine, leaving The

free base in solution. This established that in using this method It

becomes necessary to have an excess of ai.ine in order to utilize all

the -(-bromo ester. This also accounts for the rather poor yields for a

number of compounds prepared by this method. In addition, some of the

residues had stood around for quite awhile before being processed and

probably had undergone some decompos.tlon. In soLe cases were the

starting materials had not all been used up, It was possible to repeat

the procedure and thereby improve the yields.

Since it was noted that uoth hidrobromlae and hydrochloride

salts of the amines were hygroscopic, tne etrer aid benzerne were dried

over sodium prior to using. This was an attempt to avoid gummy products

and also to lessen the possibility of tne hydronron-lae remaining In

solution. In most cases this was probibl> unnecessary since the majority

of the hydrobromides which came out were either ill-defined or oils

anyway.

In general ether proved to no far superior to oenzene .Is a reac-

tion solvent.

About midway In this investigation a patent (17) appeared in

which the two compounds mentioned on page 5 were made, utilizing the

0(-bromo ester as had been done in tris laboratory. The actual method

consisted of adding the ester Cropwise with stirring to tre amine which

19

had been cooled to 5 and at such a rate that the temperature did not

go above 100. Stirring is continued for some hours. and the mixture

left to stand for 12 hours at room temperature. A recommendation given

in the patent was the use of excess amine as the HBr acceptor although

the claims for excellent yields use equimolar quantities of ester and

amine. This method was tried and proved quite satisfactory when stir-

ring was continued for longer periods of time than recommended. Since

the mechanics of this operation lent themselves quite readily to setting

up multiple reactions and eliminated the ether hazards, it was decided

to use this method for the remaining compounds. Table 2 summarizes the

results.

Processing the Reaction Mixture

Processing the products except for the case of the ryrldinium

bromides became a function of the water-solubility of the starting

amines. Where the amine is completely soluble in water, the whole

reaction mixture, including the residue, was treated with WK1. This

insures that if there is any product hydrobromide in the precipitate or

residue, it will not be lost. Washing the aqueous mixture with ether

removes any unreacted ester. Making the aqueous solution alkaline

liberates the base and excess amine. The base is then taken up in ether

prior to being dried. Any amine that is extracted along with the base

can very easily be washed from the ether with water.

Since quite a bit of heat is liberated when the reaction mixture

TABLE 2

SUMMARY OF PRODUCTS AND REACTION TYPES

Actual Aaine, in Reaction
Compound Yield, (G. Yield, % ratio to time. Solvent
ester hour

I
II
III
IV
VI
VII

VII

x1
XII
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIXV

XXIx

XXIIx*
XXIII

XXV
XXVI
XXVII
XXVIII
XXIX
XXX*

1.27
1.57
6.53
5.95
1.98
4.81
2.28
7.72
4.56
7.37
9.05
11.87
68.64
10.11
4.70
13.39
9.85
9.06
1.72
3.63
4.10
2.67
5.37

1.17
1.40
1.59
2.01
1.58

8.92
9.92
73.4
63.4
12.0
55.4
16,4
50.5
54.6
81.5
56.5
70.5
5P.2
80.6
6P.7
90.4
75.2
65.9
24.2
46.7
48.5
58.2
66.2

20.6
22. 0
23.6
27.7
24.4

2
1
2
2
1
12
1
2
2
2
1
0.25
2
2
2
2
2
15
1

2
1.43
2
12.7
2
2
2
1 5
2
16.5

36
13
30
30
12
1.'B
48
20
32
32
18
3-1/2
22
48
30
48
31
12
23
40
30
30
25
20
30
30
48
30
29
32

benzene
benzene
none
none
ether
pyridlne
ether
ether
none
none
none
pyridine
ether
ether
none
none
none
pyrldine
none
none
none
none
none
pyridine
none
none
none
none
none
pyridine

*Have not yet crystallized.

21

is originally extracted with ICW and when the Cl ls later neutralized

with ammonium hydroxide, these operations must be performed very care-

fully, preferably with dropwise addition of reagents. This will help to

prevent hydrolysis of the eater in the presence of so much mater.

Di-n-propylaminopropylamine and di-n-butylamir.opropylamine

presented a different set of circumstances since they are only slightly

water-soluble. However, two avenues of attack were provided from the

nature of the reaction mixture. Using the no-solvent method, the result-

ing mixture in most instances was a solution, but in some It consisted

of two layers. Examination of the lower, discolored layers confirmed

the presence of amine hydrobromide. This layer can be mechanically

separated or washed out with water. The latter method seemed more

efficient.

Where the reaction mixture was a single solution, washing *lth

water became the only method for removing the amine hydrobromide. The

possibility exists that if any product hydrobromide is present, it will

be removed along with the amine. However, in no cases was more than

the theoretical excess of amine obtained.

The products using pyridine as the amine had to be handled dif-

ferently. The ethyl and propyl esters, when first prepared, precapi-

tated nicely from the pyridine without much discoloration. The Iso-

propyl, butyl, and isoamyl esters yielded products that were soluble;

in addition, the reaction mixtures were very dark. When ether was

22

added, dark oils separated from all three. Chilling and stirring

effected crystallization of the isopropyl c amponna, out the other t.o

have simply defied crystallization. It is Interesting to note that a

second batch of compound VI was prepared several sonthi after the

original experiment, using pyridine frnr.r the same bottle. This time,

instead of precipitating, the solution became dark, and the product

came out as an oil upon the addition o' e'her. Stirring ana chilling

made it crystallize. Perhaps there is a slgnlficance attached to the

age of the pyridine, and the water which might have been absorbed over

the course of time.

Derivatives for Analytical Purposes

Except for the pyridinlum compounds, all products aere analyzed

as dipicrates. It would have been desirable to prepare derivatives

suitable for administration, but preliminary attempts to make the hydro-

chloride, succinate, maleate, tartrate, camphorate, and salicylste salts

were unsuccessful. Therefore, these %ere not pursued extensively.

The general method employed for the preparation of the p1crates

consisted of mixing a few drops of the base with a few drops of etnanol.

To this was added an excess of a saturated solution of picric acid in

ethanol; it was necessary to provide enough nicric acid for both basic

nitrogen. The pirates usually came out as oils. These aere crystal-

llzed by heating to dissolve and allowing to cool siowly. It was

usually necessary to decant the supernatant liquid, redissolve several

23

times, and chill in various ways (sometimes for prolonged periods)

before the compounds crystallized. The difficulties probably stem from

the fact that the product is a mixture of both optically active forms of

the compound.

Experimental Set-Up

The reactions using solvents were run in three-necked, round-

bottom flasks fitted with mechanical stirrer, thermometer, and pressure-

equalizing addition funnel.

The no-solvent reactions were run in 50 ml. beakers fitted with

mechanical stirrer, thermometer, and addition funnel.

Cooling was provided by a bath of crushed ice and water.

Preparation of ethyl a-phenyl- 0 -(dlmethylain lropropylanino)-acetate. --

H-C-f-C 2H
HC-C2R5 /CH3 (1)
H-N-CH2-CH-.-CB2-N
CH3

Thirteen and one tenth Gm. (0.054 moles) of ethyl o(-phenyl-e -bromo-

acetate in 20 ml. of dry benzene was added dropwise with stirring to

11.0 Gm. (0.108 moles) of dimethylaminopropylamine in 60 ml. of dry,

benzene. After about 15 minutes the temperature rose about six degrees

but returned to room temperature with continued stirring. About one

hour after the start of addition the reaction mixture started to cloud,

and In another half-hour a considerable layer had formed. After

24

stirring overnight, the oily layer crystallized but appeared quite gummy.

In order to insure completeness of reaction, the mixture was allowed to

stir for an additional 24 hours. The benzene was filtered from tfe

solid material, which could not be weighed due to its hygroscopicity and

difficulty in handling. This residue was identified as dimethylamino-

propylamine hydrobromide by means of its picrate.

The benzene was extracted with dilute HC1, the aqueous phase

made alkaline with ammonium hydroxide, and the layer which formed taken

up in ether. The ether was washed with water until neutral and was

dried over sodium sulfate. A considerable amount of water was required

for this operation, indicating incomplete reaction. Filtration and

evaporation of the ether gave 1.27 Ga. (8.92% of theoretical) of a

yellow liquid. This compound did not seem to want to form salts readily

with tartaric, succinic, maleic, or camphoric acids. An oxalate was

finally prepared but was quite difficult to crystallize and was unsuit-

able for analytical purposes. The dipicrate was prepared and melted at

194 1960 with decomposition.

Analyses: calculated for C27H30oNgO1 (dipicrate)

calc. found

Carbon 44.88% 45.00%
Hydrogen 4.18% 3.93%
Nitrogen 15.5 S 14.4 S

25

Preparation of ethyl o.-phenyl-d,-(deth-ylamlnopropylamino)-acetate. --

--CIH-C-C2115
H_- y I C2H5 ( I)
i-N-CH2-CH-CH22-N
C2A1

Seven and two tenths (n. (0.054 moles) of diethylaminopropylamine in

10 ml. of dry benzene was added dropwise with stirring to 13.1 Os.

(0.054 moles) of ethyl K-phenyl-v.-bromoacetate In 20 ml. of dry

benzene. The temperature rose quite rapidly to 420, and the mixture

began to cloud. Addition was slowed to keep the temperature from rising

too fast. In about one-half hour a crust of reddi:oi-bronr had formed on

the bottom of the flask, and the reaction mixture was cloudy. Stirring

was continued overnight to give a reddish, gummy precipitate which

finally settled out as an oil weighing approximately 13 (k. This was

thought to be the hydrobromide of the product and was dissolved In water

and extracted with ether to remove unreacted starting material. The

aqueous solution was made alkaline with ammonium hydroxide, extracted

with chloroform, washed with water until neutral, and dried over sodium

sulfate. Filtration and evaporation of the chloroform gave 1.57 Ch,.

(9.92% of theoretical) of a yellow-brown liquid. Apparently the oil

was a mixture of product hydrobromide and amine hydrobromide. Attempts

to make the hydrochloride from a chloroform solution failed, the product

was gummy and ill-defined. An oxalate was prepared out was unsuitable

26

for analytical purposes. The dipicrate was made and melted at 191 1820

with decomposition.

Analyses: calculated for C29H35N8OI6 (alpicrate)

calc. found

Carbon 46.33% 46.44%
Hydrogen 4.69% 4.41%
Nitrogen 14.9 % 14.9 %

Preparation of ethyl *4-phenyl- -(di-n-propylaminopropylamino)-acetate.--

H-C-O-C2H5 3

H-N-CH2-CH2-CH2-N (III)

Eight and fifty-four hundredths On. (0.054 moles) of di-n-propylamino-

propylamine was cooled to 5, and 6.56 Gm. (0.027 moles) of ethyl

(4-phenyl---bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 30 hours after the

addition had been completed. The onl noticeable change during this

period was the gradual development of a reddish coloration. Where,

allowed to settle, the reaction mixture consisted of two layers, the

upper being yellow and the lower, red. The whole reaction mixture was

taken up in ether and water in a separatory funnel. Assuming the red

layer to be dl-n-propylaminopropylamine hydrooromide, it should appear

in the aqueous phase; it did. Making the aqueous phase alkaline,

extracting with ether, and boiling off the ether on a steam bata gave

27

1.89 0(. of a yellow liquid which was identified as the amine Dy Its

picrate. The theoretical excess was 4.27 Gm., but some was apparently

lost during evaporation of the ether since the vapors caused moist red

litmus to turn blue.

The original ether layer was extracted with dilute ICl, the

aqueous layer made alkaline with ammonium hydroxide, the layer which

formed taken up in ether, and the ether washed with water until neutral

and dried over sodium sulfate. Filtration and evaporation of the ether

gave 6.54 an. (75.4% of theoretical) of a brownish-yellow oil. As this

is being written, the picrate has not yet crystallized; therefore,

neither melting point nor analytical data are available. By analogy

with the remaining compounds for which these values are reported, It is

felt that this synthesis has been successful.

Preparation of etnyl .-phenyl-- -(al-n-Dutllamlnopropylamino)-

acetate. -

--J-O-C2%

H-N-CH2" "C2"-C NC49

Ten and one tenth Oe. (0.054 moles) of di-n-butylaminopropylamine was

cooled to 5O, and 6.56 Qo. (0.027 moles) of ethyl e-phenyl-~ -bromo-

acetate was added dropwise with stirring, keeping the temperature below

10. Stirring was continued for 30 hours after addition had been

28

completed. The reaction mixture was a clear yellow solution. This was

rinsed into a separatory funnel with ether and water. The aqueous layer

was alkalinized with ammonium hydroxide, extracted with ether, and the

ether boiled off on the steam bath to give 2.87 (k. of a light yellow

liquid. This was identified as dl-n-butylaminopropylamlne by Its plc-

rate. The theoretical excess was 5.03 M&., but there was loss on

evaporation of ether as Indicatea by tre vapors turning moist red

litmus blue.

The original ether solution was extracted with dilute ICl,made

alkaline with ammonium hydroxide, the layer wrtch separated taken up in

ether, and the ether washed aith water and dried over sodium sulfate.

It must be noted that even after repeated washings there were traces of

alkalinity; this also could account for some of the original amine since

it has only limited water-solubillty. Filtration and evaporation of

the ether gave 5.95 Ot. (63.4% of theoretical) of a yellow liquid whose

dipicrate melted at 130.5 132.50 with decomposition.

Analyses: calculated for C33B42N8016 (dipicrate)

calc. found

Carbon 49.11% 49.28%
Hydrogen 5.25% 5.27%
Nitrogen 13.9 % 13.5 %

29

Preparation of ethyl A-phenyl-o(-(morpholinopropylamino)-acetate. --

H-N-Ca2-CH2-CH2-N

Thirteen and one tenth Gm. (0.054 moles) of ethyl a-phenyl-o-bromo-

acetate was dissolved in 20 al. of dry ether and cooled to S. Seven

and seventy-eight hundredths GQ. (0.054 moles) of morphollnopropylamine

was added dropwise with stirring. Almost immediately a white precipi-

tate began to form, but this disappeared as addition progressed. This

was assumed to be morpholinopropylamine hydrobromade which perhaps

formed from any free HBr in the ester. As addition continued, however,

a white precipitate formed again, without any significant rise in

temperature. Eventually the whole reaction mixture practically solldi-

fied. Additional ether was added to loosen up the mass, and the precipi-

tate was filtered from the ether. After standing for about an hour on

the filter, most of the precipitate had liquefied and passed through.

The filter was washed with ether and water, the aqueous phase being

washed with additional ether and then made alkaline. There was no evi-

dence of a precipitate or insoluble oil, signifying that the precipitate

was probably morpholinopropylamine hydrobromide; the free amine enjoys

complete mislcibility with water. This was confirmed by repeating the

procedure and making a picrate from the white precipitate.

Evaporation of the ether washings from the reaction mixture gave

30

a reddish-brown oil with a lachrymose odor. Several weeks later this

residue was taken up in dilute CI, washed with ether, the aqueous solu-

tion made alkaline with ammonium hydroxide, the layer which formed taken

up in ether, and the ether washed neutral with water and dried over

sodium sulfate. Filtration and evaporation of the ether gave 1.98 as.

(12.0% of theoretical) of a yellow liquid whose dipicrate melted at

187 1890 with decomposition.

Analyses: calculated for C29H32Ng017 (dipicrate)

calc. found

Carbon 45.55% 45.23%
Hydrogen 4.22% 4.38%
Nitrogen 14.7 S 14.8 %

Preparation of ethyl A-phenyl-'t -(l-pyridyl)-acetatea bromide. --

\ O-C-C-C2H5 j r r
I, (VI)

Six and fifty-six hundredths (B. (0.027 moles) of ethyl A-phenyl-ok-

bromoacetate was mixed with 25 al. of pyridine. In about ten minutes

the mixture became hot and practically solidified. The white precipi-

tate was filtered from the excess pyridine. The product weighed 4.81 ON.

(55.4% of theoretical). Purification was accomplished by dissolving In

ethanol, precipitating with ether, and refrigerating. The melting point

is 150 with decomposition.

Analyses: calculated for C.15H1NO2Br

calc. found

Carbon 55.91% 56.27%
Hydrogen 5.05% 4.79%
Nitrogen 4.35% 4.17%

Preparation of n-propyl e.-phenyl- .-(dimethylaminopropylamino)-

acetate. --

/ -7 -C-O-C37 CH3
I / 3 (VII)
H-N-CH2-C2-CH2-N\ CH3
Cs3

Twelve and eighty-five hundredths (]. (0.05 moles) of n-propyl

--phenyl-A -bromoacetate was dissolved in 150 ml. of dry ether and

cooled to 100. Five and one tenth Gm. (0.05 moles) of dixethylamino-

propylamine was added dropwise with stirring. The first few drops

caused cloudiness which was attributed to free HBr in the eater. After

stirring for twelve hours, there was a considerable precipitate, but

stirring was continued for an additional 36 hours before filtering the

ether. The precipitate was gummy and weighed about 5 (1m. after

desiccation. Identification through the picrate showed it to be

dimethylaminopropylamine hydrobromide.

Evaporation of the ether gave 9.9 Om. of a yellow oil. This was

taken up in dilute IC1, washed with ether, the aqueous phase made

alkaline with ammonium hydroxide, the layer which formed taken up In

32

ether, and the ether washed Alth water until neutral and dried over

sodium sulfate. Filtration and evaporation of the ether gave 2.28 Gn.

(18.4% of theoretical) of a yellow liquid whose diplcrate melted at

186 1680 with decomposition.

Analyses: calculated for C28H32N a01 (dipicrate)

cale. found

Carbon 45.65% 46.17%
Hydrogen 4.38% 4.57%
Nitrogen 15.2 % 15.1 %

Preparation of n-propyl ok-phenyl-cA-(diethylamlnopropylamlno)-

acetate. -

H-C-0-C3H7
C2 H5 (VIll)
H-N-CH2-CI2-CH2-N
C295

Thirteen Gm. (0.1 moles) of diethylaminopropylamine was dissolved in

90 ml. of dry ether and cooled to 100. Twelve and eighty-five

hundredths Gm. (0.05 moles) or r-propyl et-phenyl-m.-bromoacetate was

dissolved in 30 ml. of dry ether and added dropwise with stirring.

There was no significant rise in temperature during the addition. Anout

three and one-half hours later the reaction mixture started to cloud,

and eventually a layer formed on the bottom of the flask. As stirring

continued the layer slowly discolored, oecomini reddish-brown. After

20 hours the supernatant ether was decanted and made alkaline with

ammonium hydroxide. The oil which separated was taken up in ether, the

ether washed neutral with water and dried over sodium sulfate. Filtra-

tion and evaporation of the ether gave 7.72 Gi. (50.5% of theoretical)

of a yellow liquid whose dipicrate melted at 171 1720 with decompo-

sition.

The residue mentioned above was water-eoluble, and nothing

separated when its aqueous solution was made alkaline. Since the free

amine is water-soluble, this was accepted as evidence for the residue

being amine hydrobromide without further testing.

Analyses: calculated for C 3036NgO01 (dipicrate)

calc. found

Carbon 47.121 46.70%
Hydrogen 4.741 4.R11
Nitrogen 14.7 % 14.7 %

Preparation of n-propyl d<-phenyl-SA-(di-a-propylaminopropylamlno)-

acetate. --

0
(/ \) CH-C-0-C07
\- 37 C3H7 (IX)
H-N-CR2-CR2-CH2-N
C3H7

Seven and nine tenths On. (0.05 moles) of dl-n-propylaminopropylamlne

was cooled to 5, and 6.42 Ga. (0.025 moles) of n-propyl -.-phenyl-9,-

bromoacetate was added dropwise with stirrinG, keeping the temperature

34

below 100. Stirring was allowed to continue for 32 hours after addition

had been completed. The resulting mixture consisted of two layers, the

top, yellow, and the bottom, reddish-brown. These were separated,

although not too cleanly, and each treated in the following manner.

They were taken up in dilute 1C1, washed with ether, the aqueous solu-

tion made alkaline with ammonium hydroxide, the layer which formed taken

up in ether, and the ether washed with water and dried over sodium

sulfate.

The ether solution (1) containing the upper layer of the reaction

mixture was washed neutral, but the ether solution (2) containing the

lower part was not. Although the picrate made from the residue after

evaporation of ether solution (2) did not crystallize and provide posi-

tive Identification, this layer was assumed to be di-n-propylamino-

propylamine hydrobromide. The fact that the washings were slightly

alkaline can be attributed to the alight water-solubilltv of the amine.

Filtration and evaporation of ether solution (1) gave 4.56 an.

(54.0% of theoretical) of a yellow liquid whose diplcrate melted at

153 1540 with decomposition.

Analyses: calculated for C32H40NOI6 (dipicrate)

calc. found

Carbon 48.48% 48.480
Hydrogen 5.09% 4.80%
Nitrogen 14.1 % 13.9 7

35

Preparation of n-propyvl -phoenyl-O'-(di-n-butylaminopropylamino)-

acetate. -

1, ,c

R-N-CHg-CH2-CH2-N

Nine and three tenths On. (0.05 moles) of di-n-butylaninopropylamine

was cooled to 50, and 6.42 GO. (0.025 moles) of n-propyl A-phenyl-'.-

bromoacetate was added dropwise with stirring, keeping the temperature

below 10o. Stirring was continued for 32 hours after the addition had

been completed. The result was a dark yellow solution to which ether

and water were added in a separatory funnel. The aqueous solution was

made alkaline and extracted with ether. Evaporation ot the ether gave

3.00 OG. (theoretical excess, 4.65 On.) of a yellow oil which was identi-

fied as di-n-butylaminopropylamine by its picrate. Soe loss of this

amine can be accounted for during evaporation of its ether solution.

The original ether layer was extracted with dilute MC1, the

aqueous layer made alkaline with ammonium hydroxide, the layer which

formed taken up in ether, and the ether washed with water and dried over

sodium sulfate. There was a trace of alkalinity which remained after

repeated washings which also can account for some of the excess arine.

Filtration and evaporation of the ether gave 7.37 cam. (81.5% of

theoretical) of a yellow oil whose dipicrate melted at 136 1380 with

decomposition.

Analyses: calculated for C34H44N0O16 (dipicrate)

cale. found

Carbon 49.75% 49.70%
Hydrogen 5.40% 4.95%
Nitrogen 13.7 % 13.1 %

Preparation of n-propyl m-phhenyl-c.-(morphollnopropylamlno)-acetate. --

N--CH2-CH2-CB2-N 0

Seven and twenty-one hundredths Oa. (0.05 moles) of morphollnopropyl-

amine was cooled to 5, and 12.85 Ga. (0,05 moles) of n-prop1l

at-pheanyl-,-bromoacetate was added dropwise with stirring, keeping the

temperature below 10. Stirring was continued for 18 hours after the

addition had been completed. The resulting brownish-yellow solution

was acidified with dilute ICI, washed with ether, the aqueous solution

made alkaline with ammonium hydroxide, the layer that formed taken up

in ether, and the ether solution washed until neutral with water and

dried over sodium sulfate. Filtration and evaporation of the ether

solution gave 9.05 (s. (56.5% of theoretical) or a yellow liquid whose

diptcrate melted at 166 1690 with decomposition.

37

Analyses: calculated for C3D034NSOI6 (dipicrate)

ealc. found

Carbon 46.27% 45.68H
Hydrogen 4.40% 4.08%
Nitrogen 14.4 S 14.2 %

Preparation of [n-propyl aI-phenyl-e(-(1-pyridyl)-acetate| bromide. -

e-C-O-C3B7

Twelve and eighty-five hundredths On. (0.05 moles) of n-propyl

ek-phenyl-ak-bromoacetate was cooled to 5, and 25 ml. of pyrldine was

added dropwise with stirring. About 30 minutes after the start of the

addition a white precipitate had formed. Stirring was continued for

three hours. The precipitate, which had assumed a brownish color, was

filtered and washed with pyridine; this removed the color. The precipi-

tate weighed 11.87 On. (70.5% of theoretical) after desiccation under

water pump vacuum. It was purified for analytical purposes by dissolv-

ing in ethanol, precipitating with other, and refrigeratin: to effect

crystallization. The melting point was 152.5 1530 with decomposition,

although purification seemed to lower the melting point rather than

raise it. After the first purification the melting point was 160 1610.

38

after the second it was 136 1570, and after the third it was 152.5 -

1830 with browning starting at about 1500.

Analyses: calculated for C16H18NO0Br

calc. found

Carbon 57.15% 57.49%
Hydrogen 5.40% 3.28%
Nitrogen 4.17% 4.07%

Preparation of Isopropyl -'-phenyl- .-(dimethylaminopropylamino)-

acetate. --

// \ B-C-< 7
\ -/ / C13 (XIII)
B-N-CR2-CH2-CH2-_N CH3

light and thirty-six hundredths Go. (0.082 moles) of dimethylamlno-

propylamlne was dissolved in 90 ml. of dry ether and cooled to 150. Ten

and fifty-three hundredths Oa. (0.041 moles) of isopropyl ok-phenyl-m.-

bromoacetate was dissolved in 30 ml. of dry ether and added dropwise

with stirring. In about 30 minutes a precipitate started to form on the

stirrer. Stirring was continued for 22 hours, and the ether decanted

from the white precipitate. The ether was extracted with dilute 'l,

the aqueous phase made alkaline with ammonium hydroxide, the layer which

formed taken up in ether, and the ether solution washed with water until

neutral and dried over sodium sulfate. Filtration and evaporation of

the ether gave 6.64 Ga. (58.2% of theoretical) of a yellow liquid

39

whose dipicrate melted at 188 1900 with decomposition.

The white precipitate was dissolved In water, and the aqueous

solution made alkaline. Since no layer formed, and the free amine is

water-soluble, this was accepted as evidence for the residue being the

amine hydrobromide.

Analyses: calculated for C28,32N8016 (dipicrate)

calc. found

Carbon 45.65% 45.14%
Hydrogen 4.38% 4.37%
Nitrogen 15.2 % 15.2 %

Preparation of lsopropyl o-phenyl-w -(diethylaminopropylamino)-

acetate. -

I-- /C295 (XIV)
-[-CR2-CH2-CH2-N\C

Ten and seven tenth on. (0.082 moles) of diethylaminopropylamine was

dissolved in 90 ml. of dry ether and cooled to 150. Ten and fifty-three

hundredths Ga. (0.041 moles) of isopropyl *a-phenyl-A-bromoacetate was

dissolved in 30 ml. of dry ether and added dropwise with stirring.

Stirring was continued for 48 hours after addition had been completed.

There was a reddish oil on the bottom of the reaction vessel. The whole

reaction mixture, including this oil, was taken up in water and addi-

tional ether. The ether layer was extracted with dilute 11l, combined

40

with the original aqueous phase, the combined aqueous portions made

alkaline with ammonium hydroxide, the layer which formed taken up in

ether, and the ether washed neutral with water and dried over sodium

sulfate. Filtration and evaporation of the ether gave 10.11 Ga. (80.06

of theoretical) of a yellow liquid whose dipicrate melted at 189.5 -

170.50 with decomposition.

Analyses calculated for C30o36N8OIg (diplcrate)

calc. found

Carbon 47.12% 46.79%
Hydrogen 4.74% 4.86%
Nitrogen 14.7 % 14.8 %

Preparation of saopropyl --phenyl--*-(di-n-propylaulnopropylamino)-

acetate. --

0 C /C397 (XV)
H-M-CH2-C2-CH2 C3

Six and forty-eight hundredths Gn. (0.041 moles) of di-n-propylamino-

propylamine was cooled to 5, and 5.26 (Ik. (0.0205 males) of isopropyl

c-phenyl-~.-bromoacetate was added dropwiae with stirring, keeping the

temperature below 100. Stirring was continued for 30 hours after the

addition had been completed. The resulting reaction mixture conelited

of two layers, the top, yellow, and the bottom, red. These were

separated, and each was treated in the following manner. They were

taken up in dilute H01, washed with ether, the aqueous solution made

alkaline with ammonium hydroxide, the layer which formed taken up with

ether, and the ether washed with water and dried over sodium sulfate.

The ether solution (1) containing the upper layer of the

reaction mixture was washed neutral, but the ether solution (2) contain-

ing the lower part was not. Although the picrate made from the residue

after evaporation of ether solution (2) did not crystallize and provide

positive identification, this layer was assumed to be dl-n-propylamlno-

propylamine hydrobromide. The fact that the washings were slightly

alkaline can be attributed to the slight water-solubillty of this amine.

Filtration and evaporation of ether solution (1) gave 4.70 (Ch.

(68.7% of theoretical) of a yellow liquid whose dipicrate melted at

158 1590 with decomposition.

Analyses: calculated for C32H40NNOI6 (dipicrate)

cale. found

Carbon 48.48% 48.88%
Hydrogen 5.09% 5.04%
Nitrogen 14.1 S 13.9 .

Preparation of Isopropyl 9-phsnyl-S-(di-n-butylauinopropylamino)-

acetate. --

--CB-C-O-C3H7
-- C4n (XVI)
H-N-CH 2-C H2-CH2-
C489

Fifteen and twenty-five hundredths Gm. (0.082 moles) of di-n-butylnmino-

propylamine wan cooled to 5, and 10.53 (]. (0.041 moles) of lsopropyl

o<-pheayl-vk-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 48 hours after addi-

tion had been completed. The result was an orange, viscous solution

which clouded when ether was added. This cloudy mixture was washed

with water, the water made alkaline, extracted with ether, and the ether

evaporated to i-ve 4.95 Gm. of a yellow liquid which was Identified as

dl-n-butylaminopropylamlne by its pirate. The theoretical excess was

7.62 Oa., but some was lost during evaporation of the ether since it

was noted that the vapors turned moist red litmus paper blue.

The original ether solution was extracted with dilute lCI, the

aqueous layer made alkaline with ammonium hydroxide, the layer which

formed taken up In ether, and the ether solution washed neutral with

water and dried over sodium sulfate. Evaporation of the ether gave

13.39 On. (90.4% of theoretical) of a yellow liquid whose diplcrate

melted at 147 1490 with decomposition.

43

Analysesi calculated for C34H44N016, (dipicrate)

Colo. found

Carbon 49.75% 49.72%
Hydrogen 5.40% 5.41%
Nitrogen 13.6 % 12.9 %

Preparation of Itopropyl '-p.henyl-o'-(morpholinopropylamino)-

acetate. -

0 R 4 (XVII)

Eleven and eight tenths 0G. (0.082 moles) of morpholinopropylamine was

cooled to 50, 'and 10.53 Oa. (0.041 moles) of isopropyl e.-phenyl-Kt-

bromoacetate was added dropwise with stirring, keeping the temperature

below 100. Stirring was continued for 31 hours after addition had been

completed. At the Ice-bath temperature the reaction mixture had

solidified, but when the ice melted, the mixture became soft and gummy.

This was taken up in dilute Wit, washed with ether, the aqueous layer

made alkaline with ammonium hydroxide, the layer which formed taken up

in ether, and the ether solution washed neutral with water and dried

over sodium sulfate.

Filtration and evaporation of the ether gave 9.B5 G. (75.2% of

theoretical) of a light yellow liquid whose dipicrate melted at

171 1730 with decomposition when heating was commenced near room

temperature. When put in at 150 the sample melts almost immediately.

Also, when heating is started at room temperature, there are signs of

softening around the edges for a prolonged period. Since there is an

asymmetric carbon, the possibility exists that during the slow heating

the compound is being resolved into one of its optically active isomers.

Analyses: calculated for C3034N017 (dipicrate)

ca found

Carbon 46.27% 45.201
Hydrogen 4.401 4.41%
Nitrogen 14.4 S 14.4 S

Preparation of Esopropyl o%-phenyl-c-(l-pyridyl)-acetate] bromide. --

S- Br (XVIII)

Fifty al. of pyridine was cooled to 5, and 10.53 Gn. (0.041 moles) of

isopropyl e(-phenyl-o(-bromoacetate was added dropwise with stirring.

No sign of reaction was noted during the addition, and even after the

ice had melted, except for darkening. The mixture was allowed to stir

all night In the event that the reaction was just slow. At the end of

this time the only apparent change was increased darkening. Since the

45

ethyl and propyl esters of this type were insoluble in ether, ether was

added to this reaction mixture as a precipitant. It clouded, and a

brown oil settled out. Chilling and stirring caused this oil to

crystallize. The precipitate seemed hygroscopic when handled. It was

dissolved in ethanol and reprecipitated with ether as a purification

step, but again it came out as a brown oil. This oil was chilled again

and washed repeatedly with ether, crystallizing eventually. The

precipitate weighed 9.06 Ga. (65.9% of theoretical) after desiccation.

SIIpc it was extremely difficult to recrystallize this compound, a small

sample was repeatedly washed with more ether for analytical purposes.

This melted at 126 1320 with decomposition after desiccation.

Although the analysis of this compound deviates considerably

from the calculated values, this can be attributed to inability to

obtain an analytically pure sample. By analogy with compounds VI and

XII it is felt that the synthesis has been successful.

Analyses: calculated for CI6HN1M0r

calc. found

Carbon 57.15% 54.57%
Hydrogen 5.40% 5.23%
Nitrogen 4.17% 3.48%

Preparation of n-butyl '-pnenyl-',-(dimethylalmnopropylamino)-

acetate. -

/ -M-C 2-CHB-CH9-l\.

Two and forty-eight hundredths Ga. (0.0243 moles) of dinethylamino-

propylamine was cooled to 5o, and 6.59 Ga. (0.0243 moles) of n-butyl

0(-phenyl-e(-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 23 hours after the

addition had been completed. It was noted that the stirrer had

apparently splashed out same of the reaction mixture during the night.

The result was a viscous, yellow solution. This was taken up In dilute

EC1, washed with ether, the aqueous solution made alkaline with ammonium

hydroxide, the layer which separated taken up in ether, and the ether

layer washed with water until neutral and dried over sodium sulfate.

Filtration and evaporation of the ether gave 1.72 Ga. (24.2% of

theoretical) of a light yellow liquid whose dipicrate melted at 187.5 -

1890 with decomposition.

Analyses: calculated for C2ggH34Ng01 (dipicrate)

cal,. found

Carbon 46.40% 46.87%
Hydrogen 4.56% 4.58%
Nitrogen 14.9 % 14.7 1

47

Preparation of n-butyl o(-phenyl---(diethylaminopropylamilno)-

acetate. --

O -C9-C-O-C4 /C2115 ()

H-N-CH H2-CH-N C2-N

Three and sixteen hundredths Ga. (0.0243 moles) of diethylaminopropyl-

amine was cooled to 5O, and 6.59 Ow. (0.0243 moles) of n-butyl

o(-phenyl-<-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 40 hours after the

addition had been completed. The resulting mixture consisted of two

layers, the top, yellow, and the bottom, brown. The whole mixture was

taken up in dilute CIl and ether. The aqueous layer was made alkaline,

the layer which formed taken up in ether, and the ether washed neutral

with water and dried over sodium sulfate. Filtration and evaporation

of the ether gave 3.63 On. (46.7% of theoretical) of a yellow liquid

whose dipicrate melted at 179.5 1810 with decomposition.

Analyses; calculated for C31H38N8016 (diplcrate)

calc. found

Carbon 47.81% 48.17%
Hydrogen 4.92% 5.07%
Nitrogen 14.4 % 14.2 %

48

Preparation of n-butyl o(-phenyl-e<-(di-n-propylaminopropylamino)-

acetate. -

\ H-C-OC /Hg

-N-CH24-CH2-CH-N \C
C3'7

Seven and sixty-eight hundredths Go. (0.0486 moles) of di-a-propylamino-

propylamine was cooled to 5, and 6.59 G1. (0.0243 moles) of n-butyl

A*-phenyl-ot-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 30 hours after the

addition had been completed. The result was a reddlsh-brown solution.

When ether was added, there was an initial clouding; however, the whole

reaction mixture did dissolve. When the beaker was rinsed with more

ether, it clouded again, suggesting a hydrobromide which was being

solubilized by the other components in the mixture. Water was added,

which removed the red color from the ether, leaving It yellow. The ether

was extracted with dilute I1, the aqueous phase made alkaline with

ammonium hydroxide, the layer which formed taken up In ether, and the

ether solution washed with water until neutral and dried over sodium

sulfate. A considerably greater amount of washing was required than

with the completely water-miscible amines. Filtration and evaporation

of the ether gave 4.10 Ga. (48.5% of theoretical) of a yellow-brown

liquid whose dipicrate melted at 146.5 1480 with decomposition.

49

The aqueous solution which resulted from washing the reaction

mixture was alkalinized and became cloudy, Indicating the presence of

the slightly water-soluble di-n-propylaminopropylamlne.

Analysest calculated for C33H42NO16

calc. found

Carbon 49.131 50.360
Hydrogen 5.24% 5. 60
Nitrogen 13.9 % 13.7 %

Preparation. of n-butyl -phernyl-.(-(di-n-butylaminoprop lamlno)-

acetate. --

C49H (MXIl)
H-N-CH2-CH2-CH2-N'

Three and twenty-six hundredths Ga. (0.0175 moles) of di-n-but lamlno-

propylamine was cooled to 5, and 3.30 GI.. (0.0122 moles) of n-butyl

e(-phenyl-oa-broaoacetate was added dropwlse with stirring, keeping the

temperature below 100. Stirring was continued for 30 hours after addi-

tion had been completed. The result was an orange solution. This was

dissolved in ether aqd washed with water to remove the hydrobromildes.

This aqueous solution was made alkaline and extracted with ether.

Evaporation of the ether on the steam bath gave 1.08 Om. (theoretical,

1.00 OG.) of an oily liquid which was Identified as dl-n-butylamino-

propylamine by its picerate.

s0

The original ether solution was extracted with dilute HCI, the

aqueous phase made alkaline with amonlum hyaroxide, the layer which

formed taken up in ether, and the ether washed neutral with water and

dried over sodium sulfate. Filtration and evaporation of the ether

gave 2.87 Ga. (58.21 of theoretical) of a yellow liquid whose diplcrate

melted at 132 1330 with decomposition.

Analyses: calculated for C35H46? 8016 (diplcrate)

cal. found

Carbon 50.35% 50.85%
Hydrogen 5.SSY 6.11%
Nitrogen 13.4 % 13.3 %

Preparation of n-butyl -(-phanyl-rn-(morpholinopropylamino)-acetate. --

\/ /--C--C (XXI1B

B-N-CH2-CH2-CH-N\ 0

Seven On. (0.0486 moles) of morpholinopropylamine was cooled to 50o, and

6.59 Ga. (0.0243 moles) of n-butyl at-phenyl-K-bromoacetate was added

dropwise with stirring, keeping the temperature below 100. Stirring

was continued for 25 hours after addition had been completed. The

resulting mixture consisted of two layers, the top, yellow, and the

bottom, brownish-yellow. The whole mixture was taken up in dilute I.l,

washed with ether, the aqueous phase made alkaline with ammonium

hydroxide, the layer which formed taken up in ether, and the ether

washed with water until neutral and dried over sodium sulfate. Filtra-

tion and evaporation of the ether gave 5.37 Ga. (66.2% of theoretical)

of a yellow liquid whose dipicrate melted at 181 1830 with decomposi-

tion.

Analyses: calculated for C31H36N8017 (dipicrate)

calc. ond

Carbon 46.97% 46.77%
Hydrogen 4.58% 5.01%
Nitrogen 14.1 % 14.5 1

Preparation ot n-butyl -.-phenyl-aB-(L-pyridyl)-acetatej bromide. --

l4-C-0-C4Ha
-- Br (XXIV)

Twenty-five ml. of pyridine was cooled to 5, and 6.59 (b. (0.0243 moles)

of n-butyl c<-phenyl-t-bromoacetate was added dropwise with stirring.

The solution became quite dark, but there was no sign of a precipitate.

Ether was added as a precipitant for the bromide, and a dark brown layer

settled out. Chilling did not make the oil crystallize. The oil was

washed with additional other, dissolved in acetone and reprecipitated

with ether. The solvent was removed and the product desiccated.

Finally it was dissolved in dry methanol, again precipitated with ether,

and placed in the deepfreeze. After three weeks in the deepfreeze there

was no sign of crystallization.

Preparation of isoamyl ,-phenyl--.-(dimethylsminopropylamlno)-

acetate -

1H-C-0-C5H11
-O | ,C3 (X1V)
H-N-CH2-CH2-CH2-N
CH3

Three and seventy-nine hundredths Ga. (0.0372 moles) of dimethylamino-

propylamine was cooled to 5, and 5.30 n. (0.0186 moles) of isoamyl

d-phenyl-ek-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 30 hours after addi-

tion had been completed. The resulting mixture consisted of two layers

which were taken up together in WC1, the aqueous solution washed with

ether, made alkaline with ammonium hydroxide, the layer which formed

taken up In ether, and the ether washed with water until neutral and

dried over sodium sulfate. Filtration and evaporation of the ether

gave 1.17 nt. (20.80% of theoretical) of a yellow liquid whose dipicrate

melted at 173.5 1760 with decomposition.

Analyses: calculated for C30H36N8016 (dipicrate)

calc. found

Carbon 47.12% 47.49%
Hydrogen 4.74% 4.35%
Nitrogen 14.6 S 14.0 %

Preparation of Isoamyl '--phenyl-=.-(diethylaminopropylamino)-

acetate. --

0
-CH-C-O-CSH11
C2H5 (XXVI)
H-N--CH2-H2-CH2-N
C2H5

Four and eighty-four hundredths (k. (0.0372 moles) of dietnylamino-

propylamine was cooled to o, and 5.30 Cm. (0.0186 moles) of laoamvl

--phenyl-e.-bromoacetate was added dropwise with stirring, keeping

the temperature below 100. Stirring was continued for 30 hours after

addition had been completed. The resulting reaction mixture consisted

of two layers wnich were taken up together in dilute E1, the aqueous

solution washed with ether, maae alkaline with ammonium hydroxide, the

layer which formed taken up in ether, and the ether washed with water

until neutral and dried over sodium sulfate. Filtration and evaporation

of the ether gave 1.40 (0I. (22.0% of theoretical) of a yellow liquid

whose dipicrate melted at 183 1850 sith decomposition.

Analysees calculated for C32HgNg018, (dipicrate)

calc. found

Carbon 48.48% 49.50%
Hydrogen 5.09% 4.83%
Nitrogen 14.1 1 14.2 %

Preparation of lsoasyl A-phenyl-W-(di-n-propylaminopropylamino)-

acetate. -

c C I C37 (XXVII)
H-N-CH2-CH2-CH2-N'

Five and eighty-eight hundredths CB. (0.0372 moles) of dl-n-propylamino-

propylamlne was cooled to 5, and 5.30 (k. (0.0186 moles) of Isoamyl

'A-phenyl-O-bromoacetate was added dropwise with stirring, keeping the

temperature below 100. Stirring was continued for 48 hours after addi-

tion had been completed. The resulting solution was taken up in ether

and water and washed with more water to remove any hydrobroides. The

aqueous solution was made alkaline, but no layer formed. It was

extracted anyway with ether, and evaporation of the ether gave 1.75 on.

(theoretical excess, 2.94 ka.) of a yellow liquid which was identified

as di-n-propylaminopropylamine by its pirate.

The original ether layer was extracted with HC1. the aqueous

phase made alkaline with ammonium hydroxide, the layer which formed

taken up in ether, and the ether solution washed neutral with water and

dried over sodium sulfate. Filtration and evaporation of the ether

gave 1.59 Ch. (23.0% of theoretical) of a yellow liquid. Am this Ji

being written, the pirate has not yet crystallized; therefore, neither

melting point nor analytical data are available. By analogy with the

55

remaining compounds for which those values are reported, it is felt

that this synthesis has been successful.

Preparation of isoamyl 0.-phenyl-A-(di-n-butylaminopropylamino)-

acetate. -

-a-c-o'cll1
/4CA (XXVIII)
*--C2-CH2-CH2-NC C

Five and nineteen hundredths OG. (0.0279 moles) of di-n-butylamino-

propylamine was cooled to 5, and 5.30 Go. (0.0186 moles) of Isoamyl

<-phenyl-.(-bromoacetate was added dropwise with stirring, keeping

the temperature below 100. Stirring was continued for 30 hours after

addition had been completed. The result was an orange solution. This

was dissolved in ether and washed with water to remove any hydro-

bromides. The water was alkalinized and extracted with ether. Evapora-

tion of the ether on the steam bath gave 1.63 On. (theoretical, 1.71 (b.)

of an oily liquid which was Identified as di-n-butylamainopropylamine by

its picrate.

The original other layer was extracted with dilute WBl, the

aqueous layer made alkaline with ammonium hydroxide, the layer which

formed taken up in other, and the ether solution washed with water

until neutral and dried over sodium sulfate. Filtration and evaporation

of the ether gave 2.01 On. (27.7% of theoretical) of a yellow liquid

whose dipicrate melted at 162 1640 with decomposition when beating

was commenced near room temperature. When put in at about 1400, the

compound melts almost immediately. This it quite mimllar to compound

XVII which also melts at different temperatures depending where heat-

ing is started.

Analyses: calculated for C36R48gNgo0 (dipicrate)

calc. found

Carbon 50.941 50.78%
Hydrogen 5.701 5.85'
Nitrogen 13.2 5 13.3 %

Preparation of laoamyl -phenyl-w -(morpholinopropylamino)-acetate. --

{H-C-O-CSHI I
I (xXIz)
H-N-CH2-CH2-CH2-N 0

Five and thirty-five hundredths Om. (0.0372 moles) of morpholinopropyl-

amine was cooled to 5,and 5.30 On. (0.0186 moles) of imoamyl e-phenyl-

A-bromoacetate was added droplame with stirring, keeping the tempera-

ture below 100. Stirring was continued for 29 hours after addition had

been completed. The result was an orange solution. This eas taken up

in dilute IC1, washed with ether, the aqueous solution made alkaline

with ammonium hydroxide, the layer which formed taken up In ether, and

the ether solution washed with water until neutral and dried over sodium

57

sulfate. Filtration and evaporation of the ether gave 1.58 Om. (24.4%

of theoretical) of a yellow liquid whose dipicrate melted at 169 172

with decomposition.

Analyses: calculated for C32H8N8017 (dipicrate)

caic. found

Carbon 47.64% 48.11%
Hydrogen 4.75% 4.89%
Nitrogen 13.9 % 14.3 %

Preparation of isoamyl -Phoenyl--(l-pyridyl)-acetate1 bromide. -

Five and three tenths Ga. (0.0186 moles) of isoamyl ot-phenyl-A-bromo-

acetate was cooled to 5, and 25 ml. of pyridine was added with stirring.

Stirring was continued for 32 hours. The only apparent reaction was

darkening in color. Ether was added to precipitate the bromide, and a

dark oil separated. This was washed with ether a number of times but

remained gummy. It was dissolved in ethanol and reprecipitated with

ether, coming out again as a dark oil; this was refrigerated. After

about a week the oil had partially crystallized but was still gummy

after decantation of the ether. Desiccation did not help nor did

58

additional washing with ether and benzene. The oil was dissolved in

dry methanol and precipitated with ether. This was placed In the deep-

freeze and after three weeks is still only partially crystalline.

SUMMARY

Two series of N-substituted (.-amino-A-phenylacetic acid enters

have been synthesized as potential antispasmodics.

The first series can be represented by the following general

formula s

0
S-C-0-R

*-N-Cf2a-C2-CH2-RlI

R is ethyl, n-propyl, isopropyl, n-butyl, and isoamyl. Hi is dimethyl-

amino, diethylamino, di-n-propylamino, di-n-butylamlno, and morpholino.

These compounds have been analyzed as the dlpicrates, whose melting

points have been reported.

The second series can be represented by the following general

formula:

R is ethyl, n-propyl, Isopropyl, n-butyl, and Isoamyl. Melting points

59

for the ethyl, n-propyl, and isopropyl derivatives have been reported.

The n-butyl and isoaayl compounds have not crystallized.

Di-n-propylaminopropylezine has been synthesized by the lithium

aluminum hydride reduction of di-n-propylaalnoproplonltrile.

A pharmacological evaluation is In progress.

BIBLIOGRAPHY

1. Macht, D. I.. J. Am. Pharm. Assoc.. U, 882 (1922).

2. Ladenburg, A., Ber. deut. chem. Gee., 12. 941 (1879).

3. Macht, D. I., Proc. Soc. xptl. Biol. Mled., 1, 85 (1919).

4. Krantz, J. C., Jr., and Carr, C. J., "The Pharmacologic Principles
of Medical Practice," The Williams and Wilkins Company,
Baltimore, 1951, p. 633.

5. Wilson, C. 0., and Gisvold, 0., "Textbook of Organic Medicinal and
Pharmaceutical Chemistry." J. B. Lippincott Company, Philadelphia,
1954, p. 347.

S. Brock, N., Arch. exr. Pathol, Pharmnakol., 2~ 122 (1950).

7. Murano, T., and Yamano, K., Japan. J. Pharmacol.. Z 122 (1956).

8. Goodman, L. S., and Gilman, A., "The Pharmacological Basis of
Therapeutics," The MacMillan Company, New York, 1955, p. 541.

9. Drill, V. A., "Pharmacology in Medicine," McGraw-Hill Book Company.
Inc., New York, p. 27/1.

10. Stoll, H. C., Am. J. o 215, 577 (1948).

11. Lands, H. M., J. Pharm. Lxptl. Therap., 102, 219 (1951).

12. Klosa, J., Archly. Phar-., 285, 332 (1952).

13. Watson, H. B., Chem. Rev.. 7, 173 (1930).

14. Schwenk, E., and Papa, D., J. Am. Chem. Soc., 70, 3620 (1948).

15. Whitmore, F. C., a ibi. 725 (1944).

16. Amundsen, L. H., and Nelson, L. S., ibid., 73, 242 (1951).

17. Wander, A., British pat., 746,096 (1956).

61

BIOGRAPHICAL ITEMS

Melvin Philip Fisher was born In Syracuse, New York, on

February 16, 1933. He attended public school in Syracuse and was

graduated from Nottingham High School in June, 1950. He matriculated

in September, 1950, at the Albany College of Pharmaci and graduated In

June, 1954. He entered the Graduate School of the University of Florida

in September, 1954, and -as awarded the degree of Master of Science in

Pharmacy In January, 1956. He has pursued a course of study In pharma-

ceutical chemistry leading to the degree of Doctor of Philosophy.

The author Is a registered pharmacist in the states of New York,

Florida, and Vermont and is a member of the American Pharmaceutical

Association, the New York State pharmaceutical Association, the American

Cherlcal Soclet), Sigma XI, Rho Crl, Gamma Sigma Eplsilon, Phi Kappa Phi,

and Rho PI Phi.

This dissertation was prepared under the direction of the

chairman of the candidate's supervisory committee and has been approved

by all members of the committee. It was submitted to the Dean of the

College of Pharmacy and to the Graduate Council and was approved as

partial fulfillment of the requirements for the degree of Doctor of

Philosophy,

August 10, 1957

Dean, College of Pharmacy

Dean, Graduate School

SUPERVISORY CGOMITTBK:

//

Chairman

G/) f L
C i'V

3l 1252 08554 8062l
3 1262 08554 8062

	Title Page
	Acknowledgement
	Table of Contents
	List of Tables
	Introduction
	Historical review
	Experimental
	Summary
	Bibliography
	Biographical sketch
	Back Matter

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