Synthesis of Diphenic Acid Derivatives

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PURDUE UNIVERSITY

THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER M Y SUPERVISION

BY

granoois Xavier Demers, Jr.

ENTITLKD

SYFDHESIS OP D I P H m c ACID DSRIVATIVBS

COMPLIES WITH THE UNIVERSITY REGULATIONS O N GRADUATION THESES

AND IS APPROVED BY M E AS FULFILLING THIS PART OF THE REQUIREMENTS

FOR THE DEGREE OF

Doctor of Philosophy

P r o f e s s o r m C h a r g e or TmgaTs

H

ead of

S c h o o i .o r D

epartment

A-u^st 8_____ lo

TO THE LIBRARIAN:-IS THIS THESIS ifrNOT TO BE REGARDED AS CONFmENTIAL.

kÂjt.—

yj

SOTÎHBSIS Of DIPHSKIC ACID DERIVATIVES

A

Thesis

SoUtted to the

faculty

of

Purdue University

hy

frsncois Xavier Demers, Jr.

In Partial fcdfil3Lment of the

Requirements for the Degree

of

Doctor of Philosophy

August, 19^9

ProQuest Number: 27712181

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is d e p e n d e n t upon the quality of the copy subm itted. In the unlikely e v e n t that the a u thor did not send a c o m p le te m anuscript and there are missing pages, these will be noted. Also, if m aterial had to be rem oved, a n o te will ind ica te the deletion.

uest ProQuest 27712181 Published by ProQuest LLO (2019). C opyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C o d e M icroform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346

To Dean Grlenn L» Jenkins, under whose direction this work was carried out, to Dr. John E. Christian for his assistance in the pre­ paration of the manuscript, my sincere appreciation.

I am deeply

grateful for the financial assistance received, in the form of a fellowship grant, from the American foundation for Pharmaceutical Education. fecial thanks are due to Anne E. Daaers, the writer's devoted wife, for her patience and encouragement throughout this work.

gîAELE Of oomims 1

A. Discussion and Purpose. B. Historical

....

1

..........................

2

0. Relationship of Structure to Activity...........

6

D. Dlphenic Acid......

9

METHODS OP SOTHBSIS................................ 1. Diphenic and Dlphenamio Acid Derivatives.

11

....

11

II. Diphenimide Derivatives. ....................

13

ARALYTICAE. METHODS.................................

17

EXPERimmi.......................................

IS

Part I. Diphenic Acid Derivatives................

IS

Erperiment ^ - The synthesis of ethyl 2-chlorofonnyl-S'-hiphenylcarhosylate (ethyl diphenoyl chloride).......

IS

Saroeriment 2 - The synthesis of etl^l (2-diethylemiDo)-ethyl diphenate hydrochloride..........

20

Experiment 2. - The synthesis of ethyl 2-dimethylaminoethyl diphenate l^drochloride...........

22

Experiment Jv - The synthesis of 2-dimethylaminoeth. yl hydrogen diphenate...........

2^

Experiment 5. - The synthesis of 2-dimethylaminoethyl hydrogen diphenate hydrochloride.........

2U

Experiment 6 - Synthesis of 2 - -dimethyl-Hphenylethylenediamino)-ethanol...............

25

Experiment 7 - Attempted synthesis of ethyl 2-(îJ*, E *-dimethyl-E-phenylethylenediamino)-ethyl diphen­ ate dihy^ochloride...........

29

Experiment S - Synthesis of 2-(E*,E‘-dimethyl-Ephenylethylenedlamino)-ethyl hydrogen diphenate . dihydrochloride.. .........................

29

EXPERIMENTAI, (Continued) Part II. Dlphenamio Acid Derivatives............... Emeriment ^ - Synthesis of ethyl ÏÏ,E-diethyl diphenamate......

30 30

Experiment 10 - Synthesis of ethyl E-(2-dimethylaminoethyl)-diphenenilate hydrochloride... ........ Eroeriment 11 - Attempted synthesis of E-(2-dimethyaminoethyl)-diphenanilic acid............ 32 Experiment 12 - Synthesis of E-(2-dimethylaminoethyl)-diphenanilic acid hydrochloride,.........

33

Experiment 13 - Synthesis of E-henzyl-E \ E 'dimethylethylenediamine......................

3^

Experiment l4 - ^mthesis of H-Benzyl-E-(2-dimethyl aminoethyl)-diphenamic acid Hydrochloride.....

37

Experiment IH - Synthesis of ethyl K-henzyl-E-(2dimethylaminoethyl)-diphenamate hydrochloride

39

Experiment l6 - Synthesis of E-(2-dimethylaminoethyl) -E-(2-pyTidyl)-diphenamic acid and dihydrochloride.. 39 Experiment 17 - Synthesis of ethyl E-(2-dimethylaminoethyl)-E-(2-pyridyl) dinhenamate dihydrochl­ oride..................................... Part III. Diphenimide Iterivatives................... Experiment 18 - Preparation of diphenimide.......

^ Ifl Ul

Experiment 19 - Attempted synthesis of lT-(2-diethylaminoethoxymethyl)-diphenimide........... Ul Experiment 20 - Synthesis of N-(2-chloroethyl)-Ephenyl-3Sf*,N*-dimethylethylenediamine dihydrochloride ^ Experiment 21 - Attempted synthesis of ¥,K-dimethylN '-phenyl-R'-(2-diphenimidoethyl)-ethylenediamine... ^ Experiment 22 - Synthesis of N,H-dimethyl-E'phenyldlethyletriamine............

U7

Experiment 23 - Attempted synthesis of H,E-dimethylN'-phenyl-E'-(2-diphenimidoethyl)-ethylenediamine... HS

EXPERIMENTAL (Coutlim ecL)

Page

Experiment 24 - Attea^ted synthesis of E-(2-dimethylaminoethyîT-diphenimide................

4$

Experiment 25 - Synthesis of E-(2-hydro]Qrethyl)diphenimide..............................

50

SUMMARY.............................................

52

TABLES AED CHARTS (List of).............................

53

HBLIOGRAPHY..............................

54

imODUCTIOE A,

Discussion and Purpose, following the discovery of the first antihisteminic agent, 929 F,

by Fourneau and Bovet (l) in 1933, there has appeared in the literature a plethora of oon^unds designed to alleviate the symptoms of allergic reactions, the generally accepted main causative agent of which is hista­ mine. A key to the literature of the antihistaminic drugs hes been provided by the exhaustive review of Haley (2). Of the hundreds of com­ pounds that have been made and screened for that purpose, more than a dozen have already found application in medicine. Furthermore, as potential antihistaminics continue to emerge from the research laboratory at a rapid pace, the list of therapeutically accepted products will probably show a proportionate growth.

However, this should not be cause for alarm —

as better drugs are found the less effective and l^st desirable ones will gradually fall into disuse and disappear from the market. Again, the lack of consistent response to a given antihistaminic drug by various patients being treated for the same synptoms, makes it desirable for the physician to have a number of drugs from which to choose.

To quote Feinberg (3):

•*The currently available histamine antagonists are not ideal. They do not work in all types of allergic manifestations, nor are they of help in all cases of any perticular syndrome,..."

It is known that the antihistamine

drags have meny undesirable side reactions, the most common of which is sedation. Other side effects are: dizziness, fall in blood pressure, excitation, and ^stro-intestinal disturbances. as follows on this point:

The H.E.S. (4) comments

All the antihistamine drugs produce undesirable side actions. The incidence and severity of these toxic actions and the dose required to produce them vary with the individual drug. Another pecularity of these compounds is that the individual person not only varies in his sensitivity to the toxic actions of the group as a whole but frequently varies in his response to particular drugs. Thus one may tolerate a drug having a high index of toxicity better than one with a lower index. Another disadvantage of the presently available antildstamics is that their action is of short duration. Thus it is obvious that the ideal anti­ histaminic, that is, a drug possessing more consistent action against histamine, being devoid of toxic side effects, and having a long lasting action, has yet to be found. The purpose of this investigation was to make available a number of diphenic acid derivatives for pharmacological evaluation as possible histamine antagonists or antispasmodics. S. Historical, Despite the possibility that other, as yet undiscovered, mechanisms may be involved in allergic conditions, the consensus is that histamine plays a predominant role in the majority of allergic reactions.

The evid­

ence leading to this conclusion has been studied by Dragstedt(5,6). The early attenç)ts to antagonize the effects of histamine, following the discovery of the role it plays in the.anaphylactic, asthmatic and allergic reactions, were not successful (7). The hopes rstsed by Best's discovery in 1929 (S) of a histamine destroying enzyme, histaminase, were not real­ ized — the destruction of histamine by this substance in vitro could not be reliably reproduced in man. Attempts to raise the tolerance to histamine by its injection were fruitless. The amino acids histidine, cysteine and arginine were found to exhibit histamine antagonism by Bdlbacher ^ al. in 1937 (9)» but they proved to be too feeble in action and too toxic for effective use. Fell et

(10) in 1943, advanced

the concept that tolerance to histamine might be obtained through the production of antibodies by histamine conjugates, which consisted of histamine coupled by an azo linkage to such proteins as casein and serum ^obulin.

"Hapamin", a histamine-azo.protein product, is considered to be

of little value. The successful synthetic approach to the problem of histamine antagon­ ism stemmed from Fourneau*s compound 929 F (I, Table I), which was the most promising of a series of phenolic etHers. The high toxicity of this com­ pound led Staub (11) to investi^te another of Fourneau's confounds 1571 F (11) which departed from the other type. This compound likewise proved too toxic for therapeutic use, but its importance rests on the fact that it is the prototype of the largest class of the antihistaminics — the ethylenediamine derivatives.

In 1942, Balpem (12) studied two com­

pounds produced by a different group of French workers. One of these, 2325 R.P. (Ill) differed from 1571 F. only by having a terminal dimethyl instead of a diethyl grouping, and showed but little advantage over the latter. The other compound studied by Halpern, 2339 R.P. (IV), was found to have a high order of activity and a moderate toxicity. Under the name of Antergem, it became the first antihistaminic conpound to be used in medicine.

Somewhat

later the same laboratories developed confound 2736 R.P. (V), known as Eeoantergan, which proved to be more effective and better tolerated then Antgergan. The first of the histamine antagonists to appear on the American scene was Benadryl (VI) (I3) which Is recognized as Diphenhydramine Hydrochloride in the E.N.R. It is of interest to note that VI is an alkyl-alkyl ether, while Fourneau'8 conq)Ound 929 is a mixed ether of the aryl-alkyl type. An ethylenediamine derivative was introduced almost concurrently with

Benadryl under the name of Pyrihenzamine (VII) (l4) which is described as Tripelennamine Hydrochloride in the N.H.R.

Two other antihistaminic

drugs described in the E.E.R. are; Methapyrilene %rdrochloride and Thonzylamine Hydrochloride*

TABLE 1 The Early Antihistaminics

FORMULA

10,

CE3-CH-CH-j •O-CHsCBA-E'

929 P

V * CH^

II

“2=5

1571 F %

III

2325 BP

IV

2339 RP Antergan

O

"

Or

CH, -CH2CH2-E( ^ CHj

^ OH,

2786 BP Eeoantergan

VI

Benadryl (Diphenhydramine)

0

\,

OR-O-CHgCHg-^X 5

VII

Pyrihenaamine (Tripelennemine)

0. Relationship of Structure to Activity. Antihistaminic drugs do not e:»rt their action by virtue of pharmaco­ logical responses diametrically opposed to those of histamine (15)* The mode of action which has been advanced for Benadryl by T/ells, ejb al. (l6) is the generally accepted mechanism of action of all the antihistamine drugs: It may be concluded as to the mechanism of this antagonism, that benadryl, by being absorbed onto the site of action of histamine may so disturb the histamine equilibrium that a given amount of histamine has much less opportunity to reach and combine with the site of action. Such an antagonism can be thought of as competitive. Feinberg (17) has expanded on this theme by including the concept of a structural similarity between histamine and its antagonists: ...Some confounds having a chemical structure similar to histamine are believed to unite with the same portions of the cell that would with histamine. ••• Ordinarily histamine would be absorbed by the sites of action in a receptive cell, producing physiologic histamine effects. #.en an antihistamine drug reaches the cell it is thought that because of structural similarity to histamine it rplaces histamine at the site of action.••• The ethylamine chain, which is present in histamine and in the majority of its antagonists, constitutes the basis of the structural similarity to which Feinberg makes allusion. With but few exceptions the antihistaminic drugs are derivatives of ethanolamine or ethylenediamine (IS). While this structural feature — the ethylamine moiety — is not a rigid reqoironent for antihistamine activity, as evidenced by Trimeton (l) and 3277 R.F. (ll), Q

ή3 -CHCH20H2ir(CH,)p

I

II

marked deviation from it as lengthening or branching of the chain, results in loss of activity. Thephorin (ill) represents

p

radical departure from

the coaamon pattern; and no explanation has "been offered for the activity of this anomalous compound.

‘3

III 06^ Another correlation is that loss of potency results if the terminal R atom is not a tertiary amine; hut it may he contained in a ring system, e.g., 2-morpholinoethyl benzyhydryl ether. Scholz (19) concluded that of the ethylenediamine compounds those having the generalized formula (17) are the most active antihistaminics. Aralkyl

>K-CHp-0H5,-!Sr Aryl^

^

IV In this fornula the aryl group may be phenyl, 2-,3-,or 4-pyridyl, picolyls, pyzmidyl, thiazolyl and so forth.

Inthe aralkyl group, the alkyl chain

should be a methylene group, whereas, the aryl part may be phenyl, parasubstituted phenyl, furyl,thienyl and others. The compounds prepared in this work differ from the typical anti­ histamine structures in thatthey are alkamine esters and amides. The following formulas show thatthe ester derivatives are releated to the ethanolamine-ether type of antihistamine conpounds, while the amides resemble the ethyl enediamine type:

Typical Antihistaminic Structures

Diphenic Acid Derivatives

a,

î-0-C^.0H2-îr(CH^)2

cr'

g-0-0H20H^(0H3)2 0 Bster

Ether type

At

Cm or 102% C-N-CH20H2-E(CH3)2 0 At

^002

^

Ar

Amide

Ethylenediamine type

Thus it is seen "ihat the net difference between the conventional antiliistaminic structures and the compounds prepared in this work is that, in the latter, a carbonyl group is interposed between the ozygen and the carbon linkage in the case of the esters, and between the nitrogen and an aryl group in the case of the amides. Precedence for a,nithistaminic activity in esters is furnished by the diethylaminoethyl esters of fluorene-9-, 9-sa.nthene and 9,10-dihydroanthracene carboaylic acids which were reported by Burtner and Gusic

(21,21). Lehmann and Shoefel (22,23) found the last of these to be the most potent of the three.

It showed marked antihistamine effect both in

vitro and An vivo. However, the antihistaminic action of these com%)Ounds is overshadowed by their superior anti spasmodic activity.

During the

course of this work, antihistaminic activity was reported (2^) for a series of amino-esters of substituted alicyclic carboxylic acids, and several of these possessed a higher magnitude of antihistaminic activity

than the conç>onnds of Bortner and Cusic.

Some of the more potent compounds

of this series (V) h^x a striking similarity in struct'ure to a few of the componnds (VI) in this work, e. g.;

^

G0gCB:ÿB^(CE^)2 VI

At the onset of this work no conçponnd of the amide type haying antihistaminic activity was known to the authors. However, in view of the close structural relationship of amides to esters, examples of which were shown to possess antihistaminic activity, it seemed reasonable to anti­ cipate that appropriate representatives of the amide class of componnds ought to ezblhit antihistamine properties. This view was subsequently substantiated by the appearance (25) of two amide compounds, 2S13 E.P. and SÜ

(VIII), whose activities, however, are of a conparatively low

order. CH20HgN(0a^)2

Sr

-s 0 2813 BP VII D. Diphenic. Acid.

.0 I

I SÜ 186 VIII

2,2*-Biphenyldicarboxylic acid, or diphenic acid, has not been found in nature as such. It does, however, exist in plants in the form of ellagic acid (26) which occurs free and as a constituent of certain tannins. Ellagic acid is the dilactone of ^^,^*,5,5%^,^'-hexahydroxydiphenio acid.

10

nttig 8uad Ostermayer (27) first obtained diphenic acid in 1873 by heating j^enathrene quinone with chromic acid solution. Thus diphenic acid, or a substituted diphenic acid, is frequently obtained in the degradatlve oxidation of such natural products as retene, colchicine and sinomenine, which contain the phenanthrene skeleton. The preparative method for diphenic acid described in Organic Syntheses (28) is based on the procedure of Vorl^der and Meyer (29) in which diazotized anthranilic acid is reduced ly means of an ammoniacal cuprous solution. A large number of 6,6'-substituted diphenic acids have been made in conjunction with studies on optical isomerism of the restricted rotation type (30). In 1925, Roberts and Johnson (3I) prepared diethylaminoethyl diphenate and diethylaminoethyl imido ester of diphenanilide, and reported local anesthetic activity for their hydrochlorides. More recently (19H1), Case and Koft (32) prepared diethylaminoethyl-5,5'-diaminodiphenate hydro­ chloride, the marked anesthetic activity of which was offset by its hi^ toxicity (33)* Ho other reference to pharmacological activity for diphenic acid derivatives has been found in the literature.

11

Methods of Synthesis I. Diphenic and Diphenamic Acid Derivatives. The suhstituted aminoesters and amides of diphenic acid prepared in this investigation are of two general types:

(a) those in which a car­

boxyl grot^ is retained; (b) those which do not have a functional carboxyl grotgp.

COOOg^

-CHgCHgNCCH,), E » -CH2CH2N(Cg]^72 -02Ei;E-02%;E(OE^)2

n [-M-E. E< a .CH2CH2N(CH3)2 E** = phenyl» benzyl» 2-pypidyl The generalized scheme for the synthesis of these compounds is depicted in Chart No. 1, in which I is diphenic acid. Series (A) simply involved the reaction of diphenic anhydride in an indifferent solvent, (a) with the appropriate alcohols to give acid-esters (III); (b) with the properly substituted ethylenediamines to give E-disubstituted diphenamic acids (IT). %mthesis of the (B) series was achieved by reacting diphenic acid monoethyl ester-mono acid chloride (VI) (a) with the substituted alcohols to give mixed esters of diphenic acid (Til): (b) with the secondary amines to give ethyl diphenamates (Till). The monoethyl mono acid chloride of diphenic acid (Tl) - properly named ethyl 2-chloroformyl-2*biphenylcarboxylate but, for the sake of brevity, will be referred to here­ after as ethyl diphenoyl chloride — was prepared by reacting diphenic anhydride (ll) with ethanol to give the half ester, ethyl hydrogen diphenate (T), which in turn was converted into (Tl) by the action of thionyl chloride. Another procedure %%ployed in the preparation of the mixed ester

12 coopounds consisted of reacting potassiina etliyl diphenate with a 2* diahylaminoethyl chloride in an absolute ethemol medium.

OHAKP go. 1

-COgSt 0 -moE ^

-OOgH

OOgE

V 1 SOClg

j^OOgH

^^COgH

r

•COgSt

"0001

'^COgR

VI

^COgSt

KgCOj

^^GOgEt

Gl-O^GEg-EE^^) (StOH)

^

(a) B = CHjjCg^

COgSt

CGgOHgGHgHRg

13 Two of the three alcohols employed in these syntheses, the dimeth^rland diethyl-aminoethanols, were obtained from commercial courses.

The

third, 2-(lT‘,uidimetbyl-H-phenyleth5rlenediaraino)-ethrnol, vres prepared by reacting 2-dimethylaminoethyl bromide hydrobromide with 2-anllinoethanol. The tri-substituted ethylenediamines were prepared by reacting 2-dimethylaminoethyl bromide hydrobromide with ee.ch of the following primary amines:

aniline, benzylsmine, and 2-eminopyridine.

In the following

generalized reaction Ar represent phenyl, benzyl, end 2-pyridyl: [(CH3)^CH2CH2B^ ^

+ Ar-îîHg

>(CH3)gîïCH20H2fH

H

Ar

The phenyl and the 2-pyridyl compounds ha.ve been previously described in the literature, but the benzyl derivative has been synthesized by a method just recently published (3^) which differs from the method reported in tliis paper, IX.

Diphenimide derivatives. It was thought tbp.t certain 1Î-substituted derivatives of diphenimide

mi^t have antihistaminic activity or other interesting pharmacologic properties.

Accordingly, attempts were ma.de to prepare a few represen­

tatives of this class. The first synthesis attempted in this series was that of aminoethoxymethyl)-diphenimide (7).

2-diethyl-

Efforts to obtain the requisite

intermediate, H-hydroxymethyldiphenimide (ll), for the synthesis of (V) by scheme A (Chart No. 2) were unsuccessful.

As an alternative, scheme B

was then devised, but the product obtained did not analyze correctly and consequently work on compound Y was abandoned.

ih

CHART NO. 2

COHHg

HCHO CO '>N-CHpBr CO

CO ^H-CHgOH

00

00

III

Ha/aylene (C2%)2HC2Hi|0H

Scheme A

HCHO (Ogl^)^-CgB^OH " ^ (Cg^ )2H-C2HI1.-O-CH2OI IV (a) III

Scheme B

:H-CB2-O-Og^H(CgHç)2

V(a)

Brackets Indicate hypothetical compound, (a) indicates uncharacterized compounds.

15

Both methods (Schemes A and B, Chart No. 3) attençted for the synthesis of N,N-dimethyl-N'-phenyl-N'-(2-dlphenimidoethy^l)-ethylene­ diamine (V) were unsuccessfnl.

In Scheme A, ÎI,N-dimethyl-N'-phenyl-

N'-(2-chloroethyl)-ethylenediamine (II), which was obtained as the dihydrochloride from the corresponding alcohol (l) by the action of thionyl chloride, was reacted with potassium diphenimide.

The reaction

did not take the ezqpected course; however, the product isolated analyzed correctly for (ill), a piperazinium compound fomed by intramolecular condensation of the chloro-base (ll). The condensation of diphenic anhydride with N,N-dimethyl-îî*-phenyl-diethylenetriamine (IV) Scheme B, which was obtained by a Gabriel synthesis, gave a reaction mixture from which we were unable to isolate (V). An unsuccessful attempt was ms.de to prepare IT-(2-dimethylaminoethyl)diphenimide by reacting 2-dimethylaminoethyl chloride with potassium diphenimide. The product isolated, which did not analyze correctly, was not identified. The only diphenimide derivative synthesized was N-(2-hydroxyethyl)-diphenimide, which ^ s obtained by the action of ethylene chlorohydrin on potassium diphenimide.

16

Chaxt ITo._l

i T V

CO MÎ.

•00

CO

Cgl%—IT(CH^)2 «6=5

IIBLCgHi^HCCHj)^

\=5

HgO

H0-Cg%-H-Cg%Jî(CH3)2 «6=5

1

Hd

SgN—02%^"^—C2%^— CE3)g %%

IT

80C1, Cl-C2%-^-Cg%^CCH3) 2

II

Scheme B

^ 0 0

^U-C2H4-B-Cg%-N(CH3)2 CO

II

Scheme A

i

1=5 T (Hot isolated)

OH, ^JH, I %

I® ^

0(%

III

17

ATJLYTiaAI. IfflTHOrS Melting Points Unless stated otherwise, the melting points reported in this work are nncorrected.

The melting points were determined hy the capillary

method using a modified Thiele tuhe ecpiipped with ?n air driven stirrer, Eefractive Indices The refractive indices reported in this work were determined with an Ahhe refractometer using a white electric hulh as the light source. Chlorine Petenainations The method of Blicke end Zienty (36) was used for all the chlorine determinations reported here with the exception of the.t for ethyl diphenoyl chloride.

The procedure enployed for the latter follows.

The acid chloride was "boiled with dilute alkali, the solution was acidified, made up to 100 cc and cooled to 0° to crystallize the diphenic acid.

After filtering, an aliquot of the filtrate was taken and the

chlorine was determined hy the Volhaxd titrimetric method as descri"bed

(37) in the U.S.P. assay for sodinm chloride. Mtrogen Determinations The nitrogen determinations were carried out according to the Kjeldahl method of a semi-micro scale, using selenized granules as a catalyst. picrate of

The modification of lülek and Sobotka, (38) was used for the *-dimethyl-U-phenyldiethylenetriamine.

18

Part I. Dipheaic Acid Derivatives Bxperiinent 1

The synthesis of ethyl 2-chloroformyl.2'-blphenylcarboxylate (ethyl diphenoyl chloride). A. Preparation of dij^enic acid.

The method descrihed in Organic Syntheses (33) was followed with one modification. In the precipitation of the acid following reduction» the addition procedure was reversed; i.e., the hot diphenate solution was added to the hydrochloric acid (üTote 1). The product thus obtained varied from a light tan to a li^t brown color and melted at 226.228^ (Note 2). Yields ranging between 86 and 89*3^ were obtained. ms. 1

This modification avoided "the formation of small lumps of copper compounds" (35)^ Not# 2

The melting point given for the purified product is 225-228® (33). After preliminary runs, the purification step, which was found not to materially improve the color of the product, was omitted. Linstead and Doering (39) reported the melting point of a highly purified product to be 232-233®. % have observed the following melting points for a sample purified by vaouom sublimation: capillary tube, 230-231®; micro m.p. K 228°. B. Preparation of diphenic anhydride. The procedure of Roberts and Johnson (40) was used with the exertion that, instead of recrystallizing the product from glacial acetic acid, it was washed repeatedly with alcohol-free ether (Note 1) until the odor of acetic acid was hardly perceptible. A melting point of 222-22^0 was

19

consistently obtained (Note 2).

So.tg1 Alcohol-free ether is necessary to prevent ester formation.

It is

prepared by shpiclng tJ.S.P. ether with calcium chloride and allowing to stand two days. Note 2 Roberts and Johnson reported a melting point of 217®, while Under­ wood and Eochmann (Hi) reported 222-22H®. C. Preparation of ethyl hydrogen diphenate. The method employed was that of Underwood and Eochmann (42). D. Synthesis of ethyl di]^enOyl chloride. To SH g (0.31 mole) of ethyl hydrogen diphenate dissolved in 225 cc of dry benzene was added 33-3 co (O.H mole) of thionyl chloride and the mixture was refluxed for eight hours on a steam bath. The solvent was removed by distillation followed ty application of suction by means of a water pomp. Then three successive 10 cc portions of benzene were added and stripped off under reduced pressure to effect cocplete removal of thionyl chloride. The residual oil, distilled through a Claisen head with the aid of an oil pump, gave 86 g of a faintly yellow oil boiling at 195® (6.5 mm.) (Note 1). The yield was 95-8^ of the theoretical. Note 1 In a subsequent preparation, the product collected at 185-188° (3.5 mm.), was observed to deposit crystals in the receiver; upon cooling in ice water it solidified to a crystalline mass which melted at Hy®.

Calculated for Oi^%^G10^; Pound: Cl, 12.13*

Cl, 12.27;

20

Experiment £ The synthesis of ethyl (2-diethylamino)-ethyl diphenate hydrochloride. I. Procedure A. One-tenth mole (11.7 g) of 2-dietl^lBmino-ethanol was added to 0.1 mole (28.8 g) of ethyl diphenoyl chloride dissolved in 80 cc of benzene and the mixture was heated under reflux for one hour. The daik, s«nisolid li^drochloride, which remained after removal of the solvent, was dissolved in 100 cc of water and the solution was made alkaline with 6 K sodium hydroxide solution. The oily base which separated was taken up in ether and the ether solution was dried ovemi^t with anhydrous potass­ ium carbonate. Upon passage of hydrogen chloride into the ethereal solution, the hydrochloride was obtained as a viscous oil which resisted all efforts to convert it into a solid product. II. Procedure B. 1. Pr^mration of 2-chloroethyldiethylammonium chloride. The following procedure was based on that described by Slotta and Behnisch (43). A solution of 1 mole (117 g) of 2-diethylaminoethanol in 300 cc of dry benzene was cooled to 0°, and treated with I.3 moles (155 g) of thionyl chloride dissolved in 95 cc of dry benzene. The addition was made from a dropping funnel over a period of two hours and with mechanical stirring. The mixture was refluxed for about six hours on a steam bath, and then the solvent and excess thionyl chloride were removed under reduced pressure. The dark residue was dissolved in 95^ ethanol, the solution was boiled with charcoal for about a half hour, and then filtered hot. Large crystals separated on cooling. The product was collected on a Buchner funnel and dried.

21

2. Preparation of 2-d.iethylaminoethyl chloride. The procedure followed was adapted from that given for the preparation of the corresponding propyl compound by Gilman and Shirley (^4). The portion boiling at 51-52® (l6 mm.) was collected. Comments: This compound rapidly undergoes self-condensâtion forming a piperazinium compound at room temperature. Hence, it is important that it be used immediately following distillation.

It can be stored for short

periods in an ice box. 3* Preparation of potassium ethyl diphenate. To a solution of 2% g (O.l mole) of ethyl hydrogen diphenate in 100 cc of absolute ethanol was added 6.9 g (O.O5 mole) of anhydrous potassium carbonate and the mixture was refluxed over a steam bath until con%)lete solution of the carbonate was effected. For the subsequent reaction, the salt was not isolated, but the alcoholic solution was used as such. This conpound has not been reported in the literature. Comments: In a subsequent preparation, evaporation of the solvent left a hard, transparent glass having thermoplastic properties. A tightly stoppered alcoholic solution of the ester-salt, upon standing for several months, deposited a mass of large, colorless crystals. 4.

Synthesis of etl^l (2-diethylamino)-etl^l diphenate hydrochloride.

To a solution of 30.8 g (0.1 mole) of potassium ethyl diphenate in 120 cc of absolute ethanol was added 13-5 S (O.l) mole of 2-dietlylaminoethyl chloride and the mixture was refluxed on a steam bath for three hours. The solid, potassium chloride, wa,s filtered off end the filtrate wa.s evaporated by drawing a fine current of air, dried through a calcium

22

chloride tube, over the solution maintained at 50-60 • xtemovsl. of the alcohol caused the separation of more potassium chloride, which was re­ moved by dissolving the ester in ether and filtering. After removal of the ether, the residual ester-be.se we.s distilled under vacuum (Mercury pump). A yield of 20.5 g (55*^0 of a thick, yellowish oil, boiling at 205-210® (ca. 0.5 mm.) was obtained. About three-fourths of the distilled base was dissolved in absolute ether and, upon passing dry hydrogen chloride into the solution, the hydrochloride separated as a gummy semi-solid. The ether layer was decanted and the product was rubbed repeatedly with fresh portions of ether. After unsuccessful attempts to crystallize the product from a number of solvents, it was finally obtained as a solid by dissolving it in ethyl acetate-ether mixture, adding sufficient ligroin to produce a permanent turbidity and allowing the mixture to stand. The product so obtained melted at S5-S6® and was extremely îygroscopic. Analysis: Calculated for GggBggClNO]^: N, 3.^;

Cl, S.73.

Found: N, 3*64; Cl, 8.90. lîxperiment X The synthesis of ethyl 2-dimethyleminoethyl diphenate hydrochloride, I. Procedure A. One-tenth mole of 2-dimethylaminoethyl alcohol was added to 0.1 mole (2S.S g) of ethyl diphenoyl chloride previously mixed with SO cc of benzene and the mixture was refluxed on a steam bpth for three hours. After removing the solvent, the residue was dissolved in 120 cc of water, the solution was boiled with charcoal and filtered.

Sufficient 6 H sodium

hydroxide solution was added to the filtrate to precipitate the base. The oily base was washed several times with water, end then it wes taken up in

23

ether, and the ethereal solution was dried with anhydrous sodium sulfate overnight* Upon passing dry hydrogen chloride into the ether solution, the hydrochloride was obtained as a semi-solid.

This was washed several

times with anhydrous ether, and then dissolved in hot ethyl acetate. To this solution ether was added until a persistent cloudiness was produced. %on standing, the hydrochloride separated as rhite granules. After drying over phosphorous pentoxide, the product weighed 28 g (76*3^) end melted

0 at 109-111 • Recrystallization from absolute ethanol failed to raise the melting point. II.

Procedure B. 1.

Pr^ration of 2-dimethylaminoethyl chloride hydrochloride.

The method described below was based on that of Slotta and Behnisch (43). To 133*5 S (l'5 moles) of 2-dimethyleminoethanol dissolved in 450 cc of dry benzene and cooled to 0°, was added dropwise over a two and onehalf hour period with mechanical stirring, 2l4 g (1.8 moles) of thionyl chloride dissolved in an equa,l volume of dry benzene. After refluxing for six hours, the solvent and excess thionyl chloride were removed by means of a water pump. The dark residue was dissolved in 475 cc ethanol, 20 g charcoal was added end the mixture was boiled for 15 minutes under reflux then filtered. The crystalline product was collected on a Buchner funnel and washed with 40 cc of a 3%1 ether-ethanol mixture, end finally with ether. Two additional crops of crystals were obtained from the mother liquor, which were washed with acetone.

Total yield: 205*5 S (71*3;^)*

2. Preparation of 2-dimethylaminoethyl chloride. The procedure ençjloyed was that of Giluian and Shirley (^").

3* S’oithesis of ethyl 2-diraethylaminoethyl diphenate hydrochloride. Five g (0.046 mole) of 2-dimethj’-laminoethyl clfLoride was added to

24 l4.4 g of potassium ethyl diphenate dissolved in 65 cc of absolute ethanol, pud the mixture was refluxed three and one-half hours on a steam bath.

The potassium chloride was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in absolute ether, the solu­ tion filtered, and the ether solution was treated with dry hydrogen chloride. The gummy hydrochloride so obtained was treated as in procedure A.

Calculated for CgQHgi^OlNOlj.: N, 3.7O; 01, 9.30. Found; N, 3*37; 01, 9*23*

Experiment The synthesis of 2-dimethylaminoethyl hydrogen diphenate. A solution of 13*3 g (O.I5 mole) of 2-dimethylaminoethyl alcohol in 50 cc of benzene was added to 33*6 g (0.I5) mole) of diphenic anhydride and the mixture was refluxed on a steam bath until complete solution of the anhydride was effected.

The product, which had crystallized upon cooling,

was collected on a Buchner funnel and washed with a small araount of benzene, and then with isopropanol. Eecrystallization from isoproponal gave 33*2 g (70.8^) of a li^t, white powder which melted at 168-169®,

Aaalysis: Calculated for

N, 4.47,

Found: N, 4.26. Experiment 5.

The synthesis of 2-dimethylaminoethyl hydrogen diphenate hydrochlorjd e. An alcoholic solution of hydrogen chloride was added to 15.I g (0.04s mole) of 2-dimethyleminoethyl hydrogen diphenate dissolved in a minimum amount of absolute ethanol, until the solution was acid to litmus. The

25 solution was filtered and allowed to stand overnight. The crystalline product was collected on a Buchner funnel, washed with a little absolute ethanol, dried in a vacuum desiccator for about 12 hours, and finally in an over at 100® for 30 minutes. The product was obtained as a white powder which weighed l6.2 g and melted at 191-193®* Eecrystallization from absolute alcohol gave 14 g (83*4^) of the compound melting at 197-198®.

'Calculated for C^gHgQClNOj^: .H, 4.00. Found: N, 4.02. Experiment 6 Synthesis of 2.(N',N'-dimethyl-N-phenylethylenediamino)-ethanol. I. A. Préparation of N,N-dimethyl-N*-phenylethylenediamine. The methods used were those of Huttrer, et Solmssen (46); the latter gave higher yields.

(45) and Leonard and

The requisite 2-brom)ethyl-

dimethylemnondum bromide was prepared by the method of Cortese (47). B. Attempted synthesis of 2-(N ',N '-dimethyl-N-phenylethylenediamino)ethanol. A mixture of 0.2 mole (32.8 g) of N ',N*-dimethyl.N-phenylethylenediemine and 0.3 mole (24 g) of ethylene chlorohydrin was heated in an oil bath under 0 reflux. Hïhen the temperature reached about 130 , the reaction becpme vigorous and the flask was removed from the bath until the reaction had sub­ sided, and then heating was continued for 15 minutes.

The reaction mixture

was made alkaline with 6 N sodium hydroxide solution and extracted with benzene. The solvent was removed, the residue was combined with the material obtained from previous runs, and distilled through a Claisen head under a 4 mm. pressure.

Three fractions were collected;

(1) 105-l40®, 9*5 SÎ

(2) 140-165®, 24.1 g; (3) 165-180°, 4.9 g. The second fraction was taken

26

as the product. The third fraction, upon standing several hours, deposited fine white crystals which melted at l66.5-l67*5®* This solid was not identified, nomments%

The product obtained by this method, as shown by its wide boiling range, could not have been pure. II. Attempted synthesis of 2-(N',N’-.dimethyl-N-phenylethylenedismino).

ethenol using lithium amide and 2-chloroethyl acetate. N,N-Dimethyl-N*-phenylethylenediamlne, Ul g (0.25 mole) was mixed with 4o cc of toluene and heated on a steambath to about 90®. Then 6 g (0.25 mole) of lithium amide was added and the heating was continued under reflux until the evolution of ammonia had ceased (about one hour). To the mixture ws.s added 30*6 g of 2-chloroethyl acetate and the mixture was heated under reflux with mechanical stirring for four hours. After the mixture had cooled and the toluene layer was decanted, a hard residue remained. This was dissolved in ca. 125 cc of water with the aid of heat (steam bath) and the solution was extracted with two 25 comportions of toluene. Five g of anhydrous sodium carbonate were added and the solution was extracted with 100, then 50 cc of ether. The toluene and ether extracts were combined and dried %rith anhydrous potassium carbonate, and after removal of the solvents, the residual oil was distilled under vacuum. A 2&i yield (17.5 s) of crude 2-(N’,N*-dlmethyl-l'T-phen5''lethylenediamino)-ethyl acetete, boiling at 128-l60° (4 mm) was obtained. The quantity of ester obtained was considered insufficient to hydrolyze to the alcohol. III. A. Preparation of 2-anilinoethanol. Sixty-seven g of p-toluenesulfonanilide, prepared according to the general directions of Shriner and Puson (48), was dissolved by heating on

27

a steam bath with 110 cc of 10^ sodium hydroxide solution, and then 2k g {0.3 mole) of ethylene chlorohydrin was added, tsithin a few minutes the solution became milky and an oil separated to the bottom of the flask. The mixture was heated for 13 minutes longer on the steam bath end then allowed to cool. The aqueous layer was decanted and the oily layer of N-(2-hydroxyethyl)-p-toluenesulfonanilide was washed with ca. JO cc of water. IB^drolysis of the substituted anilide was effected by boiling it under reflux with 800 cc of 23,^ hydrochloric until practically all of the oil had gone into solution (about ei^t and one-half hours). After cool­ ing, the solution was made alkaline with 20^ sodium hydroxide solution and extracted with four

cc portions of ether. The ether extract was dried

ovemi^t with Drierite, and then the solvent was removed. The residue, upon distillation, ^ve I6.3 g of 2-anilinoethanol boiling at 157-l60° (13 mm.). Heilbron (49) gives the boiling point as I67® (17 mm.). Despite the loss of some material due to bunqoing during the hydrolysis, a 43.5^ yield was obtained. Upon repetition of the preparation, using larger quantities, a 55*5^ yield was obtained. Comments:

The preparation of 2-anilinoethanol by the above method has not been found in the literature.

Subsequent to this preparation, this conpound was

prepared by the method of Khoir (50), which consisted of heating equivalent quantities of aniline and etlylene chlorohydrin for one hour at 110®. B. Synthesis of 2-(N^,N'-dimethyl-N-phenylethlenediamino-ethanol. 2-Bromoethyldimethylammonium bromide, 2J0 g (1.16 moles), was dissolved in 625 cc of 99*5^ ethanol w^th the aid of heat, 159 g (I.I6 moles) of 2-anilinoethanol was added followed by I60 g of anhydrous potassium

2g

carbonate, added in approximately five equal portions. The mixture was heated under reflux with mechanical stirring for seven and one-half hours. After filtering, the solid was washed with 100 cc of ethanol, and the alcoholic filtrate was evaporated under reduced pressure. The residue was dissolved in ca. 300 cc of water, 46 g of sodium hydroxide was added, and the mixture was extracted with I50 cc of benzene. The water phase was extracted with two $0 cc portions of benzene, the benzene solutions were combined, washed with 30 cc of water and dried over anhydrous potassium carbonate overnight. After removal of the solvent, the residue gave l43.% g (60.35^) of product boiling at 141-149® (4 mm.). Index of refraction: n ^ 1.5603, n iF 1.5579. 3,3-Dinitrobenzoate: To a small amount of the amine-alcohol was added an approximately equivalent amount of 3»5-dinitrobenzoyl chloride and the mixture was stirred until reaction had ceased.

The product was washed

with 3^ sodium carbonate solution, then with water, and finally, it was dissolved in boiling ethanol. The white acicular crystals which separated, melted at 139-160®. Dihydrochloride: To 2.6 g of the amine-alcohol dissolved in 25 cc of ether, was added 10^ alcoholic hydrogen chloride solution until the solution became acid to litmus. The ether was decanted from the oil which separated, and the oil was washed twice with ether. Upon rubbing the oil with fresh ether, it crystallized. Eecrystallization from isopropanol gave white crystals melting at 103-106®. Analysis:

Calculated for C^^gHggClgNgO: N, 9*96 Found; N, 10.13

29

Experiment % Atteoçted synthesis of ethyl 2-(N'#NLiimethyl-N-phenylethylenediamino)-ethyl diphenate dihydrochloride* A solution of ethyl diphenoyl chloride, 23 g (0.08 mole) in 20 cc of chloroform was added to 16.8 g (0.08 mole) of 2-(N% N '-dimethyl-Nphenylethylenediamino)-ethanol dissolved in 30 cc of chloroform. After the reaction mixture had cooled, sufficient alcoholic hydrogen chloride solution was added to make the solution acid to litmus. Dry ether was then added until a permanent turbidity was obtained, the flask was stoppered, and the solution was allowed to stand several days to crystallize. During this period the solution gradually developed a strawberry-red color which was tranmnitted to the crystals that were formed. The product was collected on a Buchner funnel washed with an alcohol-ether mixture, and dried in a vacuum desiccator. This crude product weighed 10 g end melted at 113-118®. Becrystallization from an absolute ethanol-ether mixture gave 3*2 g (12.2^) of a white miorocrystalline powder which melted at 121123®. Comments; After a week or so, the product, which had been stored in a tightly stoppered container, gradually developed a purplish-rose color. No explanation can be advanced for this color formation. Analysis:

Calculated for 02gH34Cl2N20^; N, 5*25 Found: N, 6.18. Experiment £ %mthesis of 2-(N*,N*-dimethyl-N-phenylethylenediamino)-ethyl hydrogen diphenate dihydrochloride.

30

One-tenth mole (22.4 g) of diphenic anhydride wee added to a solution of 0*1 mole (21 g) of 2-N',N‘-dimethyl-N-phenylethylenediamino)-ethanol in 6o cc of dry benzene and the mixture was heated under reflux for a half hour. The solution was acidified with alcoholic hydrogen chloride, and then poured into 200 cc of ether to precipitate the hydrochloride. The supernatant liquid was discarded, and the gomizy solid which remained was ground to a powder under ca. 200 cc of ether. After decanting the ether, the product was heated to 60-63® (Note 1) for 10 minutes with 100 cc of 99^ ethanol, and then collected on a Buchner funnel. After drying over calcium chloride in a dessicator for twenty-four hours, a yield of 18 g (33.6^) of a white powder which melted at 182-186®, was obtained. m s k

In a previous experiment, the product, at this point, was dissolved by boiling with about 400 cc of 99^ ethanol. The solution turned to a deep purple color upon standing and the product failed to crystallize.

Calculated for G26N30CI2N2O4; N, 5*54; Cl, 14.03. Pound: N, 3*3S; 01, 14.24. Part II. Diphenamic Acid Derivatives tesEteâài %mthesis of ethyl N,N-diethyl diphenamate. To a solution of ethyl diphenoyl chloride, 28.8 g (0.1 mole), in 50 cc of benzene was added 1*3 ë (0.1 mole) of diethylamine mixed with 7*9 g (0.1 mole) of pyridine. The addition wa-s made in 2-3 cc portions with shaking. Heat was evolved, the reaction mixture became yellowish-red.

31

and crystals of pyridine hydrochloride separated out. The mixture was allowed to cool, then filtered. The filtrate (benzene solution) wa,s washed with 4o cc of 3 N hydrochloric acid solution to remove any unreacted base, and after washing with water, it was dried over anhydrous potassium carbonate for fifteen hours. The benzene solution was filtered, boiled with charcoal for 10 minutes and again filtered,

(This treatment did not

appreciably improve the color). The solvent was removed with the aid of a water-pomp, the viscous brown oil which remained was dissolved in 50 cc of a 3:2 ether-petroleum ether mixture, and the solution was allowed to stand to crystallize. The crude product, after washing with etherpetroleum ether mixture (1:1), weighed 13 g. Eecrystallization from a 3:2 mixture of the same solvents gave 10.3 g (31*7^) of white, large crystals, melting at %2-74®. WL y#" ; Calculated for C20%3^^'

N, 4.30,

Pound: N, 4.09. Experiment 10 Synthesis of ethyl N-(2-dimethylaminoethyl)-diphenanilate hydrochloride. A solution of N,N-dlmethyl_N'-phenylethylenediamine, 19 g (0.115 mole), in 30 cc of diy chloroform was treated with a solution of ethyl diphenoyl chloride, 33*1 g (0.115 mole), in 30 oc of dry chloroform. The addition was made in smell portions with shaking and occasional cooling in icewater, and then the solution was allowed to stand at room temperature for one hour. Dry ether (about 110 cc) was then added until a small persis­ tent precipitate was formed, and the mixture was left in an ice-bath over night. The bulky white product was collected on a Buchner funnel, washed with 4o cc of ether and then dried in a dessicator under vacuum. The

32

product was dissolved in 100 cc of isopropanol with the aid of heat, and after the solution had cooled to about 35®» 100 cc of ether was added and the solution was set in a cool place to crystallize.

In order

to facilitate transfer of the bulky solid, 100 cc of a 1:1 isopropanolether mixture was added, then the product on the Buchner funnel was washed with 50 cc of the solvent mixture, and finally with 50 cc of dry ether. The compound was dried under vacuum in a desiccator for about six hours, and then in the oven at 100® for one hour. The product thus obtained was a white, bulky, granular powder, which weighed 43.2 g (82.9^) and melted at 136.5-138®. Eecrystallization from ethanol gave m.p. of 139-141 . Analysis; Calculated for Og^HggClNgO^î N, 6.18. Pound: N, 6.01. Experiment 11 Attmpted synthesis of N-(2-dimethylaminoethyl)-diphenanllic acid. One-tenth mole (22.4 g) of diphenic anhydride was added to a solution of N-(2-dimethylaminoethyl).^iline, 0.1 mole (l6.4 g), in 90 cc of benzene, and the mixture was heated on a stem bath until all of the an­ hydride had gone into solution (about one and a quarter hours). Partial crystallization had taken place after the solution had stood overnight. After decanting the supernatant liquid, it was found impossible to dis­ lodge the hard mass from the flask. The material was dissolved in 70 cc of benzene with the aid of heat. The benzene solutions were combined and treated with an excess of ether to precipitate the product — it separated as gummy semi-solid. Attempts to obtain the conq)Ound in a powdery state by ether precipitation from chloroform and isopropanol solutions, likewise gave rubbery masses.

It was finally obtained as a

33 yellowish white powder by dissolving it in boiling ethyl acetete end pouring the hot solution into an excess of ether (two to three times the volume of the ester).

The product was collected on a Buchner funnel washed with

ether and, after drying in a vacuum desiccator, it weighed 7.4 g.

117-120®

shrinkage at

it showed

and melted at an indefinite point between i20-l40®.

The compound ws.s kept in an oven at 100° for eighteen hours during which it lost 0.3 g

in weight, suffered considerable shrinkage and assumed the

appearance

of dried egg albumin. The crude material was dissolved in

sufficient 5^ sodium hydroxide solution to give an alkaline reaction to phenolphthalein. with

30^0 acetic

The solution was boiled with charcoal, filtered, acidified, acid solution, %nd then chilled.

as an oil.The aqueous layer m s in ca. 100

The product separated

decanted, the oily residue m s dissolved

cc of water with heat, end after filtering, the solution m s

allowed to stand overnight.

Again, an oil was obtained.

Atteinpts to cry­

stallize this material from various proportions of methanol and water were unsuccessful.

Picrate: To a hot aqieous solution of the oily diphenanilic acid derivative was added s. hot aqueous solution of picric acid and the mixture was allowed to crystallize overnight. The product was washed with water and recrystall­ ized from 95^ ethanol. Tine, yellow crystals were obtained which weighed 1.8 g. and melted sharply at 214-215°. Experiment 12 Synthesis of N-(2-dimeth^'^laminoethyl)-diphenanilic a d d hydrochloride. A mixture of di]^enic anhydride, 22.4 g (0.1 mole), H-(2-dimethylarainoethyl)-aniline, l6.4 g (0.1 mole) and 200 cc of ethyl a.cetate was heated until a clear solution was obtained.

The ethyl acetate solution was

treated with 40 cc (slight excess) of lO'fo alcoholic hydrogen chloride

solution snd ether was added in srnll portions with shsking until s per­ sistent precipitate of the hydrochloride bed formed.

The finely cry­

stalline, white product which wa.s obtained, was washed with ethyl acetate, then ether, and recrystallized from 99? ethanol several times. of

15.6 g (36.8^)

of white glistening crystals, which melted at

A yield

127-128°,

was obtained. Analysis: C5aloulated for O24H25CIN2O3; N, 6.59; Found:

N, 6.40;

01, 2.34

01, S.I3.

Experiment 13 Synthesis of N-benzyl-N',E '-dimethylethylenediamine. I. Procedure A, This method was based on a patent for the sminoalkylation of amines by Schulanann et gl. (51).

One mole (107 g) of benzylamine was added to

0.4 mole (93*2 g) of 2-dimethylaminoethyl bromide hydrobromide placed in

300 cc

flask to which was attached an air condenser.

A vigorous

reaction took place at once with considermble evolution of heat.

After the

initial reaction had subsided the flask was boated in an oil bath at l40-150° for five and one-half hours.

The tenterature was then raised

rapidly until a clear solution was obtained (ca. 180°).

The flask was

removed from the bath and allowed to cool, thereupon the solution cryst­ allized to a solid mass.

Tliis was dissolved in 110 cc of water,

60 g

of anhydrous potassium carbonate was added followed by sufficient water to dissolve the solid.

The resulting solution was extracted with four

100 cc portions of benzene.

After drying the benzene extract over

anhydrous potassium carbonate, the solvent was removed by distillation. The residual oil, distilled under reduced pressure through p Claise.i head,

35 gave 12.3 g of a nearly colorless oil collected at 120-14$° (16 mrn. ), This represents a 17*^ yield of crude product. The above reaction was repeated but the method of isolating the product wa,s modified as follows;

After the melt had solidified, 100 cc

of 99^ ethanol was added followed by 200 cc of an alcoholic solution containing $2 g (equivalent to 0,8 mole) of potassium hydroxide.

The

potassium bromide which precipitated was filtered off, and the alcoholic filtrate was distilled (during this step a violent bumping resulted in the loss of an estimated 18$ cc of the solution or about 4-0/^). Distill­ ation of the residual oil gave 15*5 g (21.Sfo) of product boiling at 120-14o° (16 mm.).

Assuming no loss had occurred the yield would have

amounted to 2$.8 g or 36.3/^ of crude product. II.

Procedure B. This method is an ©adaptation of that used by Leonard & Solmssen (4-6)

for the preparation of the corresponding phenyl compound.

To 175 g

(0.75 mole) of 2-dimethylaminoethyl bromide hydrobromide was added 375 cc of dry toluene and the mixture was heated until the distillate was free from water.

Then 159 g (1.5 moles) of anhydrous sodium carbouate was

added followed by I6O.5 g (1.5 moles) of benzylamine.

The mixture was re­

fluxed and stirred with a Hershberg stirrer for 7 hours.

The reaction

mixture was filtered, the solid residue was washed with 100 cc of toluene through the filter, and the toluene wa.s distilled off.

Distillation of the

residual oil gave 2b.6 g (19*92?) of crude product boiling at 120-l4o° (16 mm.). III.

Procedure C. To 53.5 g (0.5 mole) of benzylamine mixed with 100 cc of dry toluene

was added 23 g (l mole) of lithium amide suspended in 100 cc of toluene

36

and the mixture was heated on a steam hath, with occasional stirring, for three hours.

(The contents were protected from moisture by means of a

calcium chloride tube). After the reaction mixture had cooled to room tenq)erature, II6.5 g (0.5 mole) of 2-dimethylsminoethyl bromide hydrobromide was added (Note 1) followed by another 100 cc portion of toluene and the mixture was heated with refluxing and stirring for twelve hours. The cooled mixture was filtered and the toluene solution was dried with anhydrous sodium sulfate. The solid residue left in the reaction flask was dissolved in 250 cc of water, 40 g of anhydrous sodium carbonate was added, and the mixture was extracted with two 100 cc portions, then a 50 cc portion of ether. After drying the ether extract with anhydrous pot­ assium carbonate the solvent was removed by distillation. The toluene solution was added to the residue and this solvent was removed.

(The

flask was accidentally allowed to go dry — a dark viscous residue remained, and son» decomposition may have occurred). The viscous materiel was distilled under reduced pressure collecting 11 g (12.3?) (Note 2) at I26-I32® (15 mm.) M l 1 The reaction started when about two-thirds of the salt he.d been added. It was necessary to connect © coneenser to the flask and allow the initial reaction to subside before adding the remaining, portion. Note 2 Because of the overheating, no velid conclusion can be drawn as to the préparativè merid of this procedure from the yield obtained.

37 Physical Constants. The crude ©mine obtained by the above procedures was oo libined and redistilled.

The physical constants found ere coo^.red in table 2

with those recently reported in the literature. Table 2 Physical constants of N-Benzvl -N '.N *-dimethylethylenediamine ' Observed Gardner and Brit, Patent Constants Values Stevens (34) (32)____ Boiling Point

12o-132°/l4 mm.

ll$-117®/4 mm.

128-132/18 mm.

Density^^^ (d 20°)

0.9345

Index of Réfraction

oq

n

1*5093

n

27 d I.5052

Molar Refraction E(calc.) $6.936 E(exp.) 57*018

(a)

This value was determined with a pycknometer.

Dihydrochloride. This salt was prepared by adding alcoholic hydrogen chloride to the amine,

Eecrystallization from absolute ethanol gave white crystals which

melted at 205-207®.

(Gardner and Stevens (34) reported the same melting

point. Analysis; Calculated for O^iH^gOlgNg: Pound;

N, 11.15*

N. 10.94,

Experiment l4 Synthesis of N-Benzyl-N-(2-dimeth^-'laminoethyl)-diphenamic acid Hydrochloride. One-tenth mole (22.4 g) of diphenic anhydride was added to 0.1 mole

3S

(17.8 g) of H-beazyl-NSN'ydimethylethylenedisjjiine previously mixed with 70 cc of benzene, and the mixture was heated to effect complete reaction of the anhydride. After standing about twelve hours a hard crystalline mass was formed on the bottom and sides of the flask. The supernatant benzene solution was decanted, the solvent was evaporated, the residue was dissolved in a small amount of 99^ ethanol and 100 cc of ethyl acetate was added followed by sufficient 10^ alcoholic hydrogen chloride to make the solution acid to congo red paper. A white, bulhy precipitate was formed which was collected on a filter,Upon standing^

the filtrate

deposited 5*7 S 0^ crystals in the form of hemispherical masses. The hard, crystalline cake in the reaction flask was dissolved in 99^ ethanol with heat, about 200 cc of ethyl acetate was added, and then the solution was acidified as above. No crystallization occurred after the solution had stood overnight. The addition of ether caused the separation of a rubbery mass. This was redissolved with heat, and as the solution evaporated, a hard cake formed on the walls of the beaker and asemi-solid separated to the bottom. After pouring off the mother liquor, this residue irae rubbed with ether ^til it granulated. The product was transferred to a mortar and triturated with ether then collected on a filter end dried. In this way, a yield of 17*1 g melting at 154-160° was obtained — total yield, 22.S g (52^). A

solution of 11.2 g of the impure hydrochloride

in 30 cc of 99^ ethanolwas prepared with the

aid of heat and after it

had cooled, 30 cc of ether was added. Upon standing, 5*7 g (26/«) of white crystals, which melted at 172-174°, were obtained. Analysis; Calculated for C2^H2yClN20^; N, 0.38; 01, S.07. Found; N, 6.20; Cl, 7*96.

39

Experiment 13 Synthesis of ethyl N-benzyl-N-(2-dimethylaminoethyl)-diphenamate hydrochloride. To a solution of 28.8 g (0.1 mole) of ethyl diphenoyl chloride in

25 oc of dry benzene was added in smell portions and with shaking, I7.8 g (0.1 mole) of N-benzyl-N’,H*-diinethylethylen©diamin© dissolved in 35 cc of dry benzene. The reaction mixture was heated on a steambath for one hour. The solvent was evaporated and the residue was dissolved in isoproiKUiol. The compound failed to crystallize from this solvent and the solvent was evaporated. The viscous oil which remained, after standing in a desiccator for two weeks, partially crystallized. The product vb,b 0

placed in an oven at 100 for twenty-four hours to free it from iso­ propanol. A li^t brown glass was obtained which, upon boiling with ethyl acetate followed by cooling, gave 23 g (4-9.3^) of a white powder melting at 139-l40®. Eecrystallization from 93f^ ethanol and ether raised the melting point to 142-144-°. Analysis; Calculated for 02yE^iClN20^: N, 6.00; Ql, 7-59. Pound; ÏÏ, 6.07; Cl, 7*54. Experiment 16 Synthesis of N-(2-dimethylaminoethyl)-N-(2-pyridyl)-diphenamic acid and dihydrochloride. A.

solution of 16«5 g (0.1 mole) of 2-(2-dimethylaminoethyl)-

aminopyridine (45) in 100 cc of dry benzene was added to 22.4 g (O.l mole) of diphenic aniqrdride and the mixture was heated under reflux on a steam bath until all of the anhydride had gone into solution. The dihydrochloride was formed by blowing a stream of hydrogen chloride over

4o the surface of the solution with constant stirring,

(it was necessary to

interrupt the process at frequent intervals to rub the gcmmy precipitate until it granulated). (Note l). The precipitate was transferred to a Buchner funnel and washed with benzene. Â portion of the product, pre­ viously dried in a desiccator, was crystallized

from an alcohol-ether

mixture. The remainder

hot

(l6 g) was dissolved in

n-butyl alcohol

(43 cc) and ethyl acetate was added until a persistent precipitate was formed, and then the mixture was placed in an ice-box ovemi^t.

The

product separated as a fine, white powder. It wa-s collected and washed with a 1:1 ethyl acetate-ether mixture and dried in a desiccator under o vacuum, and finally, in an oven at 100 for one and one-half hours.A yield of IS.4 g (39*8$)

of a fine, white powder

was

obtained, which

melted at 213-214° after recrystallization from absolute ethanol. Note 1 The use of alcoholic hydrogen chloride would probably be a more expedient procedure.

Calculated for C23H25CI2N3OJ; N, 9*OS Found: N, 9.22. Experiment 17 Synthesis of ethyl N-(2-dimethylaminoethyl) -N-(2-pyridyl) diphenamate dihydrochloride. 2-(2-Bimethyaminoethyl)-aminopyridine, 16.5 g (O.l mole) was dissolved in 50 cc of dry benzene and added to a. solution of 28,8 g (0.1 mole) of ethyl diphenoyl chloride, previously mixed with 50 cc of dry benzene, and the mixture was refluxed for about one-half hour. The solution was

4l

filtered, 100 cc of benzene was added, and the solution was treated with hydrogen chloride to convert the monohydrochloride to the dihydrochloride. After decanting the solvent, the gummy product was reduced to a yellowi ^ powder by triturating with ether. This was leached with boiling ethyl acetate and the extract was kept in an ice-box overnight. Â yield 0

of 23.9 g (48.8$) of a white powder, melting at 116-120 , was obtained. Eecrystallization from ethyl acetate gave 17*9 g (36.5$) of conpound 0

meltii^ at 119-121 .

Calculated for Cg^Hg^ClgN^O^; N, 8.56. Found:

N, 8.58,

l^BXt III.

Diphenimide Derivatives

Experiment 18

Preparation of diphenimide. The diphenimide %iq)loyed in this work was prepared by the action of acetic anhydride on diphenamic acid (53) according to the procedure of Underwood end Clough (54). Experiment 19 Attempted synthesis of N-(2-diethylaminoethoxymethyl)-diphenimide. I. Attengpted synthesis of N-hydroxymethyldiphenimlde.. A.

The method of Buc (55) for the preparation of the corresponding

phthalimide conq>ound was followed. To 22.3 S (0.1 mole) of diphenimide was added 53*S cc of water and 8 cc (O.IO6 mole) of formaldehyde solution (U.S.P.) and the mixture was heated under reflux. According to 3uc, a clear solution resulted five minutes after the boiling point was reached. This was not the case with diphenimide — after boiling over a half-hour no sign of solution was evident.

42

B. Pucher and Johnson ($6) prepared H-hydroxymethylphthaliraide hy heating e. mixture of phthalimide and formaldehyde solution for four hours at 103-108°. This method was enroloyed. The reaction mixture from the above attençts was placed in an oil bath and heated for eight hours without any visible change. The mixture was filtered and a portion of the crystals was dried and found to melt at 219° (diphenimide). When the filtrate was evaporated to dryness on a steam bath, a gummy residue remained which proved to be a formaldehyde polymerization product. The above procedure was modified by the use of a solvent for diphenimide. To the recovered imide dioxan was added in small portions, while refluxing on a steam bath, until a clear solution w©.s obtained. This required about 75 cc of the solvent. Eight cc of formaldehyde solution was added and the mixture was heated in an oil bath maintained at 108-115° for approximately one and one-half hours. The solution was poured into a beaker, and after it had cooled, a white precipitate formed. This was collected, washed with water and sir-dried. Eecrystallization from ethanol ^ve 13*5 g of crystals which showed no depression of melt­ ing point when mixed with diphenimide. C. The procedure of Zief and ifeson (57) for the preparation of morpholinomethanol was tried.

To 11.1 g (0.0$ mole) of diphenimide was

added 5 cc of formaldehyde solution (375) end 27 cc of water.

The

mixture was cooled in an ice bath and 1.5 g of anhydrous potassium carbonate was added.

The mixture was shaken and allowed to stand in ice

for a half-hour (Note 1). No apparent change was observed.

The mixture

was heated on a steam bath for one and one-half hours, filtered, and the filtrate was evaporated. An ember resin remained which was assumed to be a formaldehyde polymer.

^3 M e 1 Zief and Iviason did not isolate their product, but used the aqueous solution as such,

in aqueous solution of I-hydrosyraethyldiphenimide

muld not have served our purpose, since the next step would have been the preparation of the corresponding bromo-conroound.

II. A. Preparation of 2-diethylaminoethyl chloromethyl ether hydrochloride. In a

125 cc

flask containing 29.2 g (0.25 mole) of 2-diethylamino-

ethanol was added 19 cc of U.S.P. formaldehyde solution. liberated upon mixing the liquids.

(Heat was

The flask was placed in ice and e

slow stream of hydrogen chloride m s bubbled into the solution.

The

tenperature rose rapidly to 55*, at which point the gas current was stopped until the tenperature dropped to 45*, then the gas flow was resumed for one hour.

The solution assumed a pink color and became viscous.

solution was evaporated under reduced pressure at 35-40^.

The

A white,

gummy solid weigliing 38*5 g m,s obtained. B.

Attenpted synthesis of H-(E.diethylcminoetho:c;/metb.yl)_ dipheniiaide.

A solution of

11.5 g

of the above product in 35 cc of absolute

ethanol was added to a solution containing 15 g of potassium diphenimide (Hote 1) in SO cc of absolute ethanol. immediately formed.

A fine, white -precipitate was

The mixture was heated on a steam bath for about

fifteen minutes end then filtered. ium chloride and diphenimide.

The precipitate proved to be potass­

The filtrate was evaporated under reduced

pressure, the viscous residue was poured into placed in a desiccator.

crystallizing dish and

After standing several deys, a. crystalline sub­

stance was noted to be imbedded in an amber, translucent gel having a bluish fluoresence (Note 2).

The product was transferred to a small

44 beaker, mixed with benzene and covered with filter paper.

After stand­

ing several weeks, the solvent had evaporated and a sirupy liquid con­ taining crystals remained.

The crystals were collected on a. filter end

washed with 20 cc of a 1:2 ethanol-we-ter mixture.

After drying, the

crystalline product weighed 2.5 g and melted at ol-S2®.

M â 1 Potassium diphenimide was prepared according to the method used by Wegerhoff (58) for the preparation of sodium diphenimide. Note 2 Upon heating a portion of this material with allceli, en amine odor was observed,

"hen the solution was acidified, e. vhite crystalline

precipitate formed on standing, which melted at lo6-13‘o®. A mixed melt­ ing point of this precipitate anc. diphenamic acid showed no depression.

Analysis: Calculated for ^21%4^^2^3*

7*35-

Found: N, 4.96. 3xoeriment 20 Synthesis of N-(2-chloroethyl)-N-phenyl-N',N'-dlmethyleth^/lenediamine

dihydrochloride. Dry hydrogen chloride was passed into 41,6 g (0.2 mole) of 2-(N',ir*dimethyl-N-phenylethylenediamino)-ethanol, dissolved in

175 cc

of dry

chloroform, until the theoretical quantity (7*2 g) was tahen up.

To

the ice-cold solution was added dropwise 26.2 g (0.22 mole) of thionyl chloride mixed with 30 cc of chloroform.

The addition wss m de over r

thirty minute period with mechanical stirring.

The mixture v/as allorec.

to warm to room temperature overnight, then the solvent v;as removed under reduced pressure.

Two 20 cc portions of benzene iere rdcec ;nc. stripped

45 off to remove excess thioi^l chloride, and the product was dried in s vacuum desiccator over solid sodium hydroxide for twenty-four hours. A portion to.s crystallized from acetone, but it ras foijnd that the product can be satisfactorily purified by merely washing ^dth hot acetone. A yield of 54.1 g (90.^^) of a white, crystalline powder, which melted at 115-119* (dec.) wrs obtained. Analysis: Calculated for

8.93.

Pound: N, S.98. abcoeriment 21 Attenç)ted synthesis of H,H-dimethyl-H'-phenyl-*'f‘-(2~diphenimidoethyl)-ethylenediamine. The following procedure for the liberation of the chloro-base is that of Tilford ^ gl. (59). To a solution of 25.2 g (0.084 mole) of N-(2-chloroethyl).-N-phenyl-N ',N *-dimethylethylenediamine dihydrochloride in 35 cc of water was added JO cc of toluene and the mi^rbure was cooled to 0-5®. A solution of 10,8 g of potassium hydroxide in 11 cc of water was then added dropwise with stirring over g ten-minute period. The tenqjerature was then lowered to -15® with dry ice and the toluene layer was decanted from the frozen aqueous layer. The la,tter was extracted with 40 cc of toluene and again separated by freezing. The combined toluene solution was dried over anhydrous megnesiuia sulfate. A solution of 5«3 S of potassium hydroxide in 5*3 cc of water was added to 100 cc of 99^ ethanol, and to this solution, \?as added 19 g (0.08 mole) of diphenimide. The solid mass produced was dissolved by hez^ting, and upon cooling, long needles of potassium diphenimide T,ere formed. After filtering and drying, the product weighed 11.7 g. The imioe salt was

46 covered with 65 cc of toluene end tl.e toluene solution of the clfLorohase was added ©11 at once (Note 1) end the mixture -ps heated under reflux for one and e quarter hours. The toluene was distilled and the hard residue was dissolved in about $0 cc of a 5^ potassium hydroxide solution, whereupon an amber oil separated.

The entire mixture was

extracted ulth 50 cc, then 25,cc of ether, the extracts were combined and dried over anhydrous sodium sulfate, followed by acidification with alcoholic hydrogen chloride. The product obtained was recrystallized from 99f^ ethanol a,nd a small amount of ether giving 3.5 S cf white crystals which melted at 229-231* (dec.). Note 1. An attempt was made to add the toluene solution dropwise to the cold imide solution, but the dropping funnel soon became clogged with a crystalline solid. Identity of the -product; If the product obtained was the desired imide derivative, acid hydrolysis should yield diphenic acid. One g of the subst©,nce was refluxed with 4 cc of concentrated hydrochloric acid for four hours in an oil bath maintained at l40-150®. Ho diphenic acid was foimed, and the original product was recovered as shown by melting point. It was then concluded that the product was not a diphenimide derivative, but rather, a piperazinium compound formed by the intramolecular conden­ sation of the chloro-ba.se;

7"

L

%

01 •„ /%

X*rT

.

OH? OH? T

GrFr

nhenyl;>ii>ers2inium chLoiic.e,

'ij

This view was confirmed by analysis. Analysis; Calculated for C^gHj^^ClîTgî N, 12.35; Gl, IF.$3* Found; H, 12.21; Cl, 15.4-0. Experiment 22 Synthesis of N,N-dimethyl-N'-phenyldieth^^-letriemine. The procedure followed was essentially that described in "Organic Syntheses" (60) for the preparation of N,N-dibutyltrimethylenediai.iine. In a 500 cc flask was placed 50.S g (0.2 mole) of H-(g-bromoethyl) phthalimide (6I) 120 cc of xylene and the mixture was heebed, collecting 12 cc of distillate, to expel moisture. After cooling, 65.6 g (0,4 mole) of H*H'-dimethjrl-N-phenylethylenediamine was added and the mixture was heated under reflux for nine end a half hours.

The hydrobromide of the

amine formed sn oily layer at the bottom of the flask wliich solidified upon cooling. The xylene solution wa,s decanted and the solvent was removed under reduced pressure. The oily residue, N*,JT*-dimethyl-Hphenyl-IT-(2-phthalimidoeth^^^l)-ethylenediamine, was l^rdrolysod by reflurdm with 15 cc of water and 100 cc of 12 IT hydrochloric acid for four end a half hours in an oil bath at l4O-150®. The phthallc acid, wMch had separated, we,s filtered and washed rith water, and the filtrate m s evaporated on a steam bath. A deep-red, sirup;?- residue remained which was treated with a solution of 50 g of potassium hydroxide in 50 cc of Valter and extracted with JO cc of benzene.

The benzene extrs,ct was

dried over solid potassium hydroxide, the solvent was removed under reduced pressure, and the residual oil was distilled through a Clrisen head. The bulk distilled between 138-l60^ (2 mm.). Eedistillation ^ve 11,2 g (27.2^) of a nearly colorless oil boiling at 147-154® (2

Us

25 20 Index of refraction; n ^ 1.5540, n d 1.55%. Tri-Ficrste; All attenqpts to prepare a crystalline hydrochloride were unsuccess­ ful. The hase was recovered from the gummy hydrochloride and treated with a saturated alcoholic picric acid solution. After several recry­ stallizations from 99/» ethanol, orange crystals were obtained which melted at 177-179*« The product, which was presumed to be the tripicrate, gave a low nitrogen analysis for which no ei^lenation can be offered. Analysis; Calculated for G3o^30%2^21*

IS. 78.

Found; N, 15.92. Experiment 23 Atten^ted synthesis of N,N.dimethyl-N'-phenyl-IT'-(2-diphenimldoeth;rl). ethylenediamine. The following procedure was based on "Method A" of Moore and Hapala (62) for the preparation of N-alhylamine derivatives of phthalimide. Diphenic anhydride, 9.4 g (0.42 mole) and S.7 g (O.oUig mole) of N,Ndimethyl-H '-phenyldiethylenetriemine were heated in an oil-bath at I6O-ISO® (Note 1) for one hour. After cooling a dark resinous material remained. After leaching with aqueous hydrochloric acid, a viscous residue (A) was left. The acid solution was treated with charcoal and filtered, the filtrate was made alkaline with sodiuca carbonate and the liberated be.se was extracted with chloroform. The extract \7as dried and the solvent was evaporated. The oily residue was treated with alcoholic hydrogen chloride solution, then with ether. Ho crystalline product was obtained after the solution had stood in an ice-box for

49

several days. The base was recovered in the usual manner, and an attenç>t was made to prepare an acid tartrate. A solution of 1.4 g of.tartaric acid (U.S.P.) in 30 oc of hot 99^ ethanol was added to 1.7 g of the base. The gummy semi-solid, which separated upon cooling, could not be cry­ stallized. Residue A. The acid insoluble material, when rubbed with ether became grenular. %on similar treatment with acetone, partial solution was effected. The acetone solution was evaporated and the residue was again rubbed with ether. This left a pale yellow amorphous solid which foamed in the capillary tube at 6S®. The material was dried in an oven at 60® for one hour, after which it melted at 94-105®. The identity of this substance was not ascertained. Note 1 0

The temperature of the oil bath reached over 200 for a few minutes. It is probable that decomposition of the amine took place. Experiment 24 Attempted synthesis of N-(P-dimethylaminoetlyl)-diphenimide. To 33*4 g (0.15 mole) of diphenimide was added 0.3 mole of potass­ ium hydroxide dissolved in SO cc of hot 'j9p ethanol. After the imide bed gone in solution, a solution of 26 g (O.I5 mole) of 2-dimethylaminoetlyl chloride liydi-ochloride in 1;.0 cc of absolute etbenol v.as added and the mixture was heated under reflux with stirring for one and one quarter hours. After cooling the solid (potassium chloride) ras filtered and the filtrate was evaporated. The clear, amber semi-solid which remained failed to yield e crystalline product from a number of solvents tried. It m s found that its solubility in water varied with the amount of water used, that is, it dissolved in a small amount of water, but upon the further addition of water it precipitated. Following this observation,

50 the r«mining s«ni-solid material was dissolved in a minimum ©mount of water and precipitation was induced by the gradual addition of water with constant stiridng. The precipitate thus obtained, ws,s collected on a filter and washed with water. After drying, it appeared as a finely crystalline white powder, which weighed 7*7 ê and melted at 9393*5*' Attempts to prepare a hydrochloride were unsuccessful. %drolysis of the product with alkali followed by acidification ^ve a white solid which was identified as diphenamic acid. Analysis showed that the product w©.s not the desired diphenimide derivative and the compound has not been identified. Analysis; Calculated for

N, 9.51.

Found: H, 5*27* Experiment 23 Synthesis of N-(2-hydroxyethyl)-diphenimide. To 7 g (0.026s mole) of potassium diphenimide dissolved in 30 cc of absolute ethanol was added 2.l6 g (0.0268 mole) of etlylene chlorohydrin and the solution was heated on e. steam bath for twenty minutes. The potassium chloride precipitate was filtered and washed with 5 cc of ethanol. The filtrate was evaporated to its original volume and allowed to cool. Tater was added in small portions until a permanent turbidity was produced. About 5 cc of the solution vms evaporated off and the solution was allowed to stand in a desiccator overni^t.

The crystals

formed were collected on a filter, washed with water and air dried. Colorless glistening crystals weighing 1.2 g and melting at 93® was obtained. Attempts to obtain another crop from the mother liquor were unsuccessful.

51 A n e ly s is ;

Calculated for Found; N, 5*09*

N, 5*23

52 SUMMARY 1. Derivatives of diphenic and diphenamic acids were prepared for pharmacologic evaluation as possible antiMstaminé and/or antispasmodics. 2. In the diphenic acid series, the monoethyl diphenabes of diethyland dimethyl-aminoethanols were prepared, as well as the hydrogen diphenates of these alcohols and of 2-(H',N'-dimethyl_N-phenylethylenediamino)-ethanol. 3. A series of N-(2-dimethylaminoethyl)-N-R diphenamic acids and ethyl diphenamates, in which R represents phenyl, benzyl and 2-pyridyl, were prepared. 4. In addition to the above, the following new confounds were prepared! ethyl 2-chloroformyl-2 *-biphenylcarboxylate, 2-(H',H*-dimethyl-Kphenylethylenediamino)-ethanol, N-(2-chloroethyl)-N-phenyl-N•,!?'dimethylethylenediamine dihydrochloride, 1,1-dimethyl-4-phenylpiperazinium chloride, ethyl N,N-diethyl diphenamate and N-(2-l%rdrozyethyl)diphenimide*

53

TlABIiES AND CHARTS TAble 1 The Early Antlhistaminlcs.........................

5

Table 2 Physical Constants of N-Benzyl-N%N'-dimethylethylenediamine. »................

37

Chart 1 .............................................

12

Chart 2

l4

Chart 3

l6

54

BIBLIOGRAPHY I.

Fourneau, E., and Bovet, D., Arch, intern, pharmacodynamie, ^ 178 (1933).

2*

Haley, T. J., J. Am. PhEücm. Assoc., 31» 383 (1948).

3.

Peihberg, S. M.,J. Am. Med. Assoc., 132. 713 (1946).

4.

New and Nonofficial Remedies, J. B. Lippincott Company, Phil­ adelphia, Pa., 1949, p. 22.

5. Dragstedt, 6.

C. A., J. Allergy, I6, 69 (1945).

Dragatedt, C. A., Quart. Bull., Northwestern Thiiv. Med.School, la, 303 (1945).

7. Feinherg, S. H.,J. Am. Med. Assoc., 122, 704-707 (1946). 8.

Best, 0. H.,J. Physiol., 6%, 256 (1929).

9.

Bdlhacher. S., Jucker, P., and Baur, H., 2. physiol, chem., 247. 63, (1937).

10. Fell, N., Rodney, G., and Marshall, D. 1., J, Inmmol. 4^, 237 (1943). II. Stauh, A. M., Ann. Inst. Pasteur 63. 400 (1939). 12. Balpem, B., N., j . de med. de Lyon, 22, 409 (1942); Arch, intern, pharmacodynamie, 339 (1942). 13. Rieveschl, G. Jr., U. S. Patent 2,421,714 (1947). 14. Mayer, R. L., Huttner, C. P., and Scholz, C. R., Science, 102. 93 (1945). 15. Pfeiffer, C. C., and Loew, B. R., "Annual Review of Physiology", Annual Reviews, Inc., and American Physiological Society, Stanford University P.O., Cel., 1947, vol. IX, p. 655. 16. Tells, J. A., Morris, H. C., Bull, E. B., and Dragstedt, C. A,, J. Pharmacol., 127 (1945). 17. Feinherg, S. M., J. Am. Pharm, Assoc., Pract. Pharm. Ed, 8, 547 (1947). 18. Haley, T. J., J. Am. Pharm. Assoc., 21» 384 (1948). 19. Scholz, C. R., Ahsts. First Nat. Med. Chem. Symposium of the Am. Chem. Soc., Ann Arbor, Mich., June (1948).

55 20. Burtuer, R. R., and Cosic, J. tf., J. Ara. Chem. Soc.,

262 (1943).

21. Ihid.. p. 1582. 22. lehraann. G., and Eaoefel, P. %., J. Pharmacol. j4, 274 (1942). 23.

îMâ., 80, 335 (1944).

24.

Tllford, C. E., Van Casq>hen, M. G., end Shelton,R. S., J. Am. Chem. Soc., 63., 2902 (1947).

25. Scholz, C. R., pp. cit.. pp. 10, 11. 26. Richter, G. H., "Textbook of Organic Ghendstry", 2ndéd., John Wiley and Sons, Inc., New York, N.Y., 1943, p. 506. 27. Pittig, E., and Ostermayer, Ann. I66, 3 % (1873). 28.

Atkinson, E. R., and Lawler, H. J., "Organic Syntheses", Coll. Vol. I, John Wiley and Sons, Inc., New York, N.Y. 1941,p. 222.

29. VorlAider and Meyer, P., Ann. 320. 122 (1902. 30. Oilman, H., "Organic Chemistry", 2nd ed,, John Wiley and Sons, Inc., York, N.Y., 1943, pp. 343-374. 31. Roberts, R. C., and Johnson, T. B., J. Am. Chem. Soc., 4%, 139^ (1925). 32. Case, H. P., and Koft, B., ibid.. 33. Fellows, E., J. Pharmacol.

508 (1941).

l46 (l94l).

34. Gardner, J. H., and Stevens, J. R., J. Am. Chem. Soc., Jl, ISSS (1949). 35. "Organic Syntheses", Coll. Vol. I, John Wiley and Sons, Inc. York, N.Y., 1941, p. 222. 36. Blicke, P. P., and Zienty, F. B., J. Am. Chem. Soc.,

77^ (1939).

37. "The PhamBCopoeia of the United States of America", Thirteenth Revision, Mack Printing Oong)any, Baston. Pa., 1947, p. 489. 38. Elek, A., and Sobotka, H., J. Am. Chem. Soc.,

50I (1946),

39. Linstead, R. P., and Doering, W. B., ibid, 64, 1998 (1942). 40. Roberts, R. C., and Johnson, T. E., ibid. 41. Underwood, H. W., and Kochmann, S. L., ibid.

1399 (1925). 5073 (1923).

42. Ibid.. 46, 2072 (1924). 43. Slotta, K. S., and Behnisch, E., Ber., |S, 758

(1935).

56

44. Gilman, H., and Shirley, D. A., J. Am. Chem. Soc., (1944).

889

45. ffiittrer, 0. P., Djerassi, 0., Beears, V?. L,, Mayer, E. L., and Scholz, C. R., Ihid. 68, 2001 (1946). 46.

Leonard, P., and Solmssen, U. V., ihid.70. 2064 (1948).

47. Cortese, P., "Organic Syntheses", Coll. Vol. II, John Wiley and Sons, Inc. New York, N.Y., 1943, p. 91. 48. Shriner, R. L., end Pason, R. C., "The Systematic Identification of Organic Conroonnds", 2nd ed., John Wiley and Sons, Inc. New York, N.Y., 1940, p. 4?. 49. Heilhron, I. M., "Dictionary of Organic Compounds", Vol. II, Oxford University Press, New York, N.Y. 1936, p. 264. 50. Khorr, L., Ber. 22, 2092 (1889). 51. Schnlemann, W., Schonhofer, P., and Wingler, 1,752,617 (April 1, 1930).

A.,

ÎT. S, Patent

52. Brit, patent 6o6,181 (Aug. 10, 1948); 0. A., 4^, 3472* (1949). 53. Underwood, H. ÏÏ., and Kochmaim, B. L., J, Am. Chem. Soc., 46 , 20J2 (1924). 54. Underwood, H. ?., and Clough, L, A., ihid.. 51. 583 (1929). 55. Buc, S. R.,

6i, 254 (1947).

56. Pucher, G. ?/., and Johnson, T. B., ihid.. 44, 820 (1922). 57. Zief, H., and Mason, J. P., J. Org, Chem., 58. Wegerhoff, P., Ann.,

3 (1943).

18 (1889).

59. Tilford, C. H., Shelton, R. S., and Van Cempen Jr., H.G., J. Am. Chem. Soc., JO, 4001 (1948). 60. "Organic Syntheses", 1944, p. 44.

John Wiley and Sons, Inc., New York, N.Y.,

61. Ibid.. Coll. Vol. I, John Wiley end Sons, Inc., New York, N.Y. 19m, p. 119. 62. Moore, M. B., and ±^pala, R. T., J. Am. Chem. Soc., (1946).

1657

SYNTHESIS OP DIPHENIC ACID DBRIVATIVB8

An Abstract of

A Thesis

Submitted, to the Paculty

of

Purdue University

by

Prancois Xavier Demers, Jr.

In Partial Fulfillment of the

Requirements for the Degree

of

Doctor of Philosophy

August, 1949

ABSTRACT Synthesis of Diphenic Acid Derivatives The purpose of this investigation was to meke available for pharma­ cologic evaluation, as possible antihlstaminics and/or antispasmodics, a munber of substituted aminoesters and amides of diphenic acid and of ethyl hydrogen diphenate. Precedence for antihistaminic activity in esters is furnished by the diethylaminoethyl esters of fluorene-9-, 9-xanthene and 9,10dihydroanthracene carboxylic acids reported by Burtner and Ousic (l). During the course of this work, antihistaminic activity was reported (2) for a series of substituted alicyclic carboxylic acids, and some of these showed a strlMng structural similarity to a few of the conpounds pre^mred in this work. At the onset of this investigetion, no anti­ histamine compounds having an amide structure was known to the authors. However, in view of the close structural relationship of amides to esters, it seemed logical to anticipate antihistaminic properties in appropriately substituted amides. This view was subsequently confirmed by the a^pes^aiice (3) of two amide compounds, 2813 BP and SU 186. In 1923, the hydrochlorides of diethylaminoethyl diphenate and diethylaminoethyl imido-ester of diphenanilide were reported (4) to possess local anesthetic action. More recently (1941), diethylaminoethyl. 3,3*-diaminodiphenate was prepared (5) and shown to have marked local anesthetic activity. The compounds reported in this paper are of two general types; (A) those in which a carboxyl group is retained; (B) those which do not have a functional carboxyl group. Synthesis of type A (Procedure A)

simply involved the reaction of diphenic anhydride with (l) the appropriate alcohols to give acid-esters; (2) the substituted ethylenediamines to give N-substituted diphenamic acids.

Synthesis of the

(B) series (Procedure B) was achieved by reacting ethyl diphenoyl chloride with (l) the substituted alcohols to give mixed esters; (2) the secondary amines to give ethyl diphenamates. The mixed esters were prepared (Procedure C) by another method which consisted of reacting potassium ethyl diphenate with a 2-dialkylaminoethyl chloride. These procedures are illustrated under experimental by specific examples, and the compounds thus prepared are listed in tables 1 and 2. In the course of this work, a diphenimide derivative was prepared, and in an attempt to prepare another, a piperazinium compound was obtained. EXPERIMTAL^ Ijhterials; Diphenic acid was prepared according to "Organic Syntheses" (6) with the modification that, in the precipitation of the product, the addition was reversed; i.e., the hot diphenate solution was added to the hydrochloric acid. This modification avoided the formation of "small lunq)s of copper compounds," (6), and gave a product melti%% at 226-228*. A m.p. of 232-233* Is reported (7) in the litera­ ture. The procedure of Roberts and Johnson (4) for the preparation of diphenic anhydride was followed with the exertion that, instead of recrystallizing the product from acetic acid, it was washed with alcohol, free ether. The product so obtained melted at 222-224®, a value reported in the literature (8), while (4) reported a m.p. of 217*.

1. Melting points are uncorrected.

Ethyl S-chlorofbnnyl-S^-hiphenylcerhoxylate (ethyl diphenoyl chloride): To S4 ®a. of ethyl hydrogen diphenate (9) dissolved in 225 cc. of dry benzene was added 33*3 cc. (.4 mole) of thionyl chloride and the mixture was refluxed for ei^t hours on a steam bath. The solvent was removed by distillation followed by aspiration. Then three successive 10 cc. portions of benzene were added and stripped off under reduced pressure to effect ranoval of the excess thionyl chloride. The residual oil, distilled throu^ a Claisen head with the aid of an oil pump, gave 8b Qm. of a faintly yellow oil boiling at 195* (6.5 mm.). The yield was 95*^ of the theoretical. In a subsequent preparation, the product collected at 1S5-1SS® (3*5 mm.) solidified upon cooling to a crystalline mass which melted at 4%*. Analysis: Calcd. for

Cl, 12.27.

Found: 01, 12.13. 2-(N ’,N *-dimethyl-N-phenylethylenediemino)-ethanol. 2-Bromoethyldimethylammonium bromide (10), SJO On. (I.I6 moles), was dissolved in 625 cc. of 99^ ethanol with the aid of heat, 159 Cta. (1.16 moles) of 2-anilinoethanol (11) was added, followed by I60 Cm. of anhydrous potassium carbonate, added in approximately five equal portions. The mixture was heated under reflux with mechanical stirring for seven and one-half hours. After filtering, the solid was washed with 100

CO.

of ethanol, end the alcoholic filtrate was evaporated

under reduced pressure. The residue was dissolved in ca. 300 cc. of water, 46 Cm. of sodium hydroxide was added, and the mixture was extracted with I50 cc. of benzene. The ws.ter phase was extracted with two 50 cc. portions of benzene, the benzene solutions were combined

and washed with 50 cc. of water, and dried over anhydrous potassium carbonate ovemi^t.

After removal of the solvent, the residue gave

145.7 Gfen. (60.3^) of a viscous, nearly colorless oil, boiling XUl-lltgO (Ij nm.), n “

at

1.5603, n p 1.5579.

Dihydrochloride: To a 2.6 Gm. of the amine-alcohol dissolved

in25cc.

of ether was added 10^ alcoholic lydrogen chloride until the solution became acid to litmus. The ether was decanted from the oil which separated, and crystallization was induced by rubbing the oil with fresh ether. Becrystallization from isopropanol gave white crystals melting at 105-106®. iSêlZSlâ* Calcd. for Found: N, 1015. N-Benzyl-N',N*-dimethylethylenediamine. P This compound has been prepared by a method just recently publish­

ed (l2) which differs from the one described here, and it has also been reported in a patent (13). The following procedure was based on a patent (l4) for the aminoalbylation of amines.

One mole (10J Gta.) of

benzylamine was added to 0.4 mole (93.2 Gta.) of 2-bromoethyldimethylammonium bromide placed in a 300 cc. flask to which was attached an air condenser. A vigorous reaction took place at once with considerable evolution of heat. After the initial reaction had subsided the flask was heated in an oil bath maintained at lMO-150® for five end one-helf hours. The teaiperature was then raised rapidly until a clear solution was obtained (ca. ISO®). Upon cooling, the solution crystallized to a solid mass. This was dissolved in 100 cc. of 99^ ethanol and, to this

2. The publication appeared while this manuscript was being prepared.

solution, m s added 52 ftn. (equivalent to 0.8 mole) of potassium . lydroxide dissolved in 200 oc. of ethanol. The potassium bromide which jflpecipitated was filtered, and the filtrate was evaporated under reduced pressure. The residual oil gave 15.5

(21.^)^'^ of crude

0

product boiling at 120-l40 (l6 mm.). Redistillation gave a nearly colorless oil boiling at 126-132® (14 mm.), d

0.9345, n

1.5093,

R (calcd) 56.936, R (exp.) 57.018. The following constants have been reported;

(I2)b.p. 115-117*/4 mm., n ^ I.5052; (13) b.p. 12S-132*/lS

nm. The dihydrochloride, recrystallized from absolute ethanol, melted at 205-207* which is the value reported in the literature (12). Analysis; Calcd. for OiiH2o^^2^2’

11.15*

Found: N, 10.94. N-(2-Ghloroethyl)-IT-phenyl-N' ,H*-dimethyletl^lenediemine dihydroch­ loride. Dry hydrogen chloride was passed into 4l,6 Gm. (0.2 mole) of 2(N*,N*-dimethyl-N-phenylethylenediamino)-ethanol, dissolved in 175 cc. of dry chloroform, until the theoretical quantity (7.2 &n. ) was taken tq>. To the ice-cold solution was added dropwise 26.2 Gm, (0.22 mole) of thionyl chloride mixed with 30 cc. of chloroform. The addition was made over a thirty minute period with mechanical stirring. The mixture was allowed to warm to room temperature overnight, then the solvent wa,s removed under reduced pressure. Two 20 cc. portions of benzene were added and stripped off to remove the excess thionyl chloride, and the

3. During the evaporation, an estimated I85 cc. of the solution was accidentally lost. Assuming no loss had occurred, the yield would have amounted to 36*3^ (crude product). 4, The amine was also obtained in a 19*9^» yield by a method (15) used for the preparation of the corresponding phenyl compound.

residue was dried under vacuum over sodium hydroxide for twenty-four hours* A portion was crystallized from acetone, hat it was found that the product can he satisfactorily purified hy merely washing with hot acetone. A yield of 54.1 Gta. (90.2^) of a white crystalline powder, which melted at 115-119* (dec.) was obtained. Atmlvslflt

Calcd. for -

N, 8.93*

Found: N, 8.98. 1,1-Dimethyl-4-phenylpiperazinium chloride. In an attendit to prepare N,N-dimethyl-N*-phenyl-N*-(2-diphenimidoethyl)ethylenediamine, the chloro-Mse, N-(2-chloroethyl)-ITphenyl-N* ,N*-dimethylethlenediamine, which was liberated from its dihydrochloride by the method of Tilford ^

(I6), was reacted with

potassium diphenimide (prepared by a method described (I7) for the sodium confound) in a toluene medium. A white crystalline product, which melted at 229-231* (dec.), was isolated. This substance, however, upon boiling for four hours with concentrated hydrochloric acid, failed to yield diphenic acid as would be expected from the hydrolysis of a düLphenimide derivative. Hence, it was concluded that the product wa.s a piperazinium compound which was formed by an intramolecular conden­ sation of the chloro-base.

Calcd. for Found: N, 12.21; Cl,

F, 12*35î 01. 15.63.

15.4o.

N-(2-hydroxyethyl)-diphenimide. To 7 Om. (0.0268 mole) of potassium diphenimide, dissolved in 50 cc. of absolute ethanol was added 2.16 Cm. (0.02&8 mole) of ethylene chloro-

hydrin, and the solution was heated on a steam hath for twenty minutes. The potassium chloride precipitate was filtered and washed with 5 cc, of ethanol. The filtrate was evaporated to the original volume and allowed to cool. Water was added In small portions until a permanent turbidity was produced, about 5 cc. of the solution was evaporated off and the solution was allowed to stand in a desiccator overni^t. The crystals which separated were collected and washed with water on a filter, and air-dried. Colorless glistening crystals, wei^ng 1.2 Cm. and melting at 93* were obtained.

Calcd. for C16H13NO3: N, 5.2) Found: N, 5.09. Procedure A. 2-dimethylaminoethyl hydrogen diphenate hydrochloride (IX, table 1). A solution of 13*3 (ha. (0.I5 mole) 2-dimethylamlnoethanol in 50 cc. of dry benzene was added to 33-6 Gm. (0.I5 mole) of diphenic anhydride end the mixture was refluxed on a steam bath until complete solution of the anhydride was effected. The product, which had cry­ stallized upon cooling, was collected on a Buchner funnel and washed with a small amount of benzene, and then with isopropanol. Crystall­ ization from isopropanol gave 33*2 Cm. (70.8^) of a li^t, white powder which melted at I68-I69*. The hydrochloride was prepared by adding an ethanolic solution of hydrogen chloride to 15*1 Cm. (0.04s mole) of the monoester dissolved in a minimum amount of absolute ethanol until the solution was acid to litmus. The crystalline product which formed overnight was washed with a little absolute ethanol, dried in a vacuum desiccator for about twelve hours, end finally in an oven at 100® for thirty minutes. The product was obtained as a white powder which weired 16.2 Gm. and melted at 191-193®- Hecrystallization from absolute

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