“PARA 'KLYl‘fl. METIWL PARAZOLONES
AND SOME BERNATWES

"L’EESES 371138 THE li’EGEEE W M. B.
Hamid Melvin Sell
1931

BA

 

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Para Xylyl Methyl Parazolones
and I

Some Derivatives

Para Xylyl Methyl Parazolones
and

Some Der int ive a

A Thesis

Suhmitted to the'Faoulty

of

Michigan.8tate College

In partial fulfillment of the re-
qpiremente for the degree ot'Maeter of

Science.

BY
Harold Melvin Sell

June 1951

1 ‘2»
~k T

"‘33 4- C
. _‘ "l

 

ACKNOWLEDGMENT

It is a pleasure that I welcome this
Opportunity to expreu my most grateful appreciat-
ion for the invaluable aid and friendly encourage-
ment given to me by Dr. R. C. Huston under whose

guidance this work was carried on.

103

«I

f“
V!
"n
We

II
III

'4

VII

II

III

VI

VII

TABLE OF CONTENTS

Review of Literature

Constitution of Pyrazole .................
Constitution of Pyrazolone ...............
The Pyrazole Blue Test ...................
Preparation of 5-Pyrazolone ..............
Preparation of 3-Pyrazolone ..............

Constitution and Preparation 0: Anti-

pyrinc eeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee

Preparation of Benzoyl Eaters ............

ExPerimental Part

Preparation of Tolyl Hydrazine and Para
Hydrazine eeoeoeeeeeeeeeeeeeeeeeeeeeee

Preparation of Ortho Tolyl Methyl Pyra-

zolone eeeeeeeeeeeeeeeeeeeeeeeeeeeeeee

Methylation of l-Ortho-Tolyl-fi-Methyl-S-
Pyrazolone ...........................

Preparation of Para xylyl S-Methyl-é-
PYI'aZOlone eeeeeeeeeeeeeeeeeeeeeeeeeee

Page

14
14
17

21
30

32

35

38

39

Methylation of Para xylyl Methyl Pyrazolone 42

Preparation of l-Para-Xylyl-S-Methyl-S-

PyraZOIOIlO ooeeeeeeeeoeoeeeeeeeeeeee... ‘3

Benzoyl Eaters or 5 and 5-Pyrazolona ...... 45

REVIEW OF THE LITERATURE

1. THE CONSTITUTIONHOF THE PYRAZOIE GROUP

The pyrazole compounds may be classed under the name
'Azoles which includes a five ”membered cyclic system containing
nitrogen.

In the pyrazole group we have those ccsspounds in 101101!
tin molecule contains a ring composed of two nitrogens and three

carbons arranged in the following manner (Ann. 279, 188; 293, 1;

see, 62) .
1N
ages
so 04

Pyrazole may be regarded as derived from pyrrcl by replace-
ment of a methine group adjacent to an NH group by nitrogen.
The Pyrazole stands in the same relation to pyrrcl as

pyridine does to bensem (Ann. 238, 138).

RE -.I:
‘ HO OH HO OH H OH N OH
or _ I . or
HG CH HG—CH HO CH 30— CH

pyrrcl pyrazole

 

 

 

 

 

 

The structure or the pyrazole ring has been proven by
many men of whom Knorr is the most outstanding.

The above rcmulae show that pyrrcl is closely related
to pyrazole, and for this reason the nomenclature is that
suggested by Knorr for the pyrrcl derivatives.

There is a dihydro pyrazole or pyrazoline am a tetra
hydrOpyrazole or pyrazolidine corresponding to the di and tetra

hydmpyrrols .
11%! NE NH
an ‘ one I 011. EN CH.
303 l I CH‘ HC CH8 H80 CHI:
pyrazole pyrazo line Pyrazoli dine

The position of a substituent group in pyrazol ring is
indicated by the numbers one to five. Numbering starts with
t1: nitrogen in the imino group and proceeds to the second
nitrogen atom as illustrated in the above formula.

In the investigation or pyrazole compounds, Knorr came
to the conclusion that the pyrazole molecule was symmetrical
and that the usual pyrazole formulae were in contradiction

with his results (Ann. 379, 188).

 

RE HE
N CH EQCH
RD E nc CH
Knorr and. Balbiano Buchner Bambe rger

There may exist i’cur isomers of the methyl pyrazole s.

NCHs NH 1m
,0“ W5 Om HOW.
HO OH 03.0 OH HO OCH. HC CE
1 methyl 3 methyl 4 methyl 5 methyl
pyrazole pyrazole pyrazole pyrazole
01’ these four the three and five have been proved idotical .
In 1893 the problem or the structure or pyrazole mtered
a new phase when Knorr and MacDonald discovered that 1 phmyl

3 methyl pyrazole and l phenyl 5 methyl pyrazoh or their amino

derivatives gave one and the same methyl pyrazole of boiling

point 204°C. (Ann. 1894, 279, 188). Therefore, it is not
possible to obtain the two methyl pyrazoles of the formulae.

N 003s
HO OH

 

Claisen and Roosen obtained two isomeric phasyl methyl
pyrazoles on condensing phenyl hydrazine with oxymethylsne
acetone. On the other hand Knorr and MacDonald failed to ob-
serve two isomeric phenyl methyl pyrazoles on condensing hydra-
zine hydrate with oxymethylene acetone. (Bar. 1891, 24, 1888;
Ann. 1894, 278, 261, 267).

N efis CeHs
I OH R OCH.
cH.c OH HO OH
m.p. svfic b.p. 254~255°C
b.p. ass-2559c sp.gr. 1.085 at 15°C
crystalline colorless liquid

From these results it appears that the positions tires
and five in pyrazole are equivalent to one another and tint
methyl pyrazole may be a mixture of two desmotropie forms
of the three methyl pyrazole and five methyl pyrazole in a
state of rapid and continuous interconversion; From the abae
results Knorr suggested the following formula for the three
and five methyl pyrazole (Ann. 2'79, 191).

OH

This conclusion was confirmed by the discovery that methyl
pyrazole could react either as a three methyl pyrazole or a five
methyl pyrazole.

Knorr assumed that one Ivarogen in the pyrazole is not
permanently attached to a given nitrogen but may alternate from
one nitrogen to the other with a readjustment of the double born

as show: below:

H
I
n N N NH
O
H En //////CH
H OH
I II

The first pyrazole derivative. was prepared by Knorr by the
reaction of benzoylacetosceticester on phenyl hydrazine: (Ann.238,
138; Ber. 18,311). c.H.
OsHsC.°CH(COCHs)COaCs:Hs + c.H.Nmf:H——-s N r

  
  
 

(NE

E
COHSC C0303H‘
yenzoyl acetc acetic phenyl Ester of diphmyl mettwl
ester hydrazine carboxylic acid

Later other methods were described by Knorr and other chomp
ists for synthesis of pyrazole compounds such as the follovdng.
l. Diphenylmethyl pyrazole was prepared by Fischer and

Bulow through the reaction of phenylhydrazine on benzoyl acetone

CsHsCOCHaCOCHs + CsHsNH.NHg ficsflsi-CH s CH3

N—NCBHS + 2H20
genzoyl acetone Phenyl 1,3,5 Diphecyl methyl
hydrazine pyrazole

2. Claisen obtained pyrazole by treating the acetal of
propargyl aldehydes with hydrazine (Ber. 36, 3666).
GREG-CHWCszh + HsN-NHg—e Hi—CH
rig/4;
NH

Acetal of prOpargyl Phenyl Phenyl pyrazole
aldehyde hydrazine

By treatment with phenyl hydrazine a phacyl derivative
was obtained:
CHEC-CH(OC2H§)2 + HgIIHNCaHsfifltlg—ffi
Ev
NCeHe

Acetal of propargyl Phenyl Phalyl pyrazole
aldehyde hydrazine

3. Balbiano prepared pyrazole by the treatment of
hydrazine hydrate upon epichlorhydrin (Ber. 23, 1103).
Hs-CH-CHzCl + NHe’Nflz—’ HW—CH
Q\b/' . HE £ + H20 + HCl
NH
4. Buchner obtained pyrazole derivatives by the inter-

action of unsaturated compounds on diazo acetic ester. (Ann.

'\

 

(a) Action of
ester:
CHsOgC . C
onecec - c
.‘cetylmne

dicarboxylic
acid

acetylene dicarboxyli: acid on diazo acetic

-.N
. 3/ _. N W.
H COBCHO
CHICOBC COsCHe
Diazo pyrazole
acetic tricarboxylic
ester acid

(b) Action of diazo acetic acid on ethylene derivatives:

N’
coocmcn n - w / f°°m
+ \h//’ -—-—-—* w c-n:
COOCHsCH H COaCHs
CBeOOeC ECOaCHs
Fumaric ester Diazo acetic Pyrazoline tri carboxylic
ester acid

(c) Esters of saturated and umsaturated halqgen.substituted

acids react with diazo acetic ester to form pyrazoh compounds.

CgHIBrs ( COgCHg) + 30min ( COgCH‘)

 

V

Dibromo prOpionic Diazo acetic

ester

ester

CsHst (COBCHs ) s + ZCHsBr(COsCHe} + 21%

Dicarboxylic pyrazole Bromo acetic ester

ester

5. Knorr and.MacDonald.obtained pyrazole derivatives by the

condensation of oxymethylene acetone with.hydrazins hyirate (Ann.

279 , 190) Q

6. Bischler prepared derivatives of pyrazole by the action

of diazonium.sa1ts on substituted acetc acetic esters. (Bar. 1892,

25, 3143; 1893, as, 1881).

7. Stoermer and Martinsen obtained derivatives of pyrazole

 

by distillation of oxygen derivatives of pyrazolone with zinc
dust, penta sulphide or phosphorous tetra bromide (Ann. 1907,

 

352, 322).
Re C H . c
o>c.lis PsSs >N0efie
Phenyl methyl pyrazolone 1,3,5 dimethyl pyrazole

8. Certain hydrszones when heated with acid anhydrides

give derivatives of pyrazole:

cmc . H - RHOeEs CHs - ll
' : >30sHs
CHs + (amoeba ——» HO - c
CH. e GEsCOOH

Acete phenyl hydrazone Acetis anhydride 1,3,5 Phenyl Acetic
dimethyl pyrazole acid

9. Clai sen and Roosen prepared derivatives of pyrazoibs through
the condensation of the aldewde of acetc acetic ester with plenyl
hydrazine and acetone oxalic acid with phenyl hydrazim (Ber. 24,
1888). They also obtained pyrazole derivatives by the action of
phenyl hydrazine on orymethylene.

10. Pechsnm obtained pyrazole by the reaction cf aeetylem

on diazo methane:

 

. . R
OH + - '
III \6 n H
OH
BO 3
Acetylene Diazo methane Pyrazols

ll. Buchner obtained pyrazole by heating 3 : 4 : 5 pyrazole
triearboxylic acid (Ann. 273, 253).

I.

 

According to Knorr, the best means for the preparation
of pyrazole, is the prolonged heating of 3 : 5 pyrazole di-
carboxylic acid.

Knorr states that ldiketones, compounds of the formula
3' cc-cn 12" co - a"
to form pyrazole derivatives (Ann. 253, 139).

react wit h pr imary aromat ic hyd raz in s

In general, compounds containing two C0 groups or a
CO andCOOH group in the 8 position to one another or two
double linked carbon atoms adjacent to a 00011 or CO group
react with hydrazine to give pyrazole derivatives (shhmidt,
Organic Chemistry, P 56‘}.

Knorr has given a number of facts which illustrates the
aromatic character of pyrazole (Ber. 1895, 28, 714-716, Schmidt,
Organic Chemistry, P 567). '

l. Fuming sulphuric acid converts pyrazole into s sulphonic
acid (M.P. 330-335°C) which has reactiom similar to aromtic
sulphuric acids. ' -

2. In halogens derivatives, the halcgen is more firmly
held to pyrazole nucleus than in benzene derivatives.

3. Pyrazcle is nitrated with concentrated nitric acid, 4
nitro pyrazole being formed. The nitro compound may be reduced
to amino compounds.

4. Amino pyrazoles resemble the aromatic bases in its
behavior. It gives a color reaction with a solution of bleaching
powder.

5. Diazonium salts of pyrazole can be coupled with phat ole

to form azo dyes. These differ from aromatic azo dyes in the

stability of their salts. 0n boiling these solutions there
is no visible evolution of nitrogen; this occurs only on
prolonged heating at higher temperatures. Diazonium salts of
pyrazole, however, do not undergo the usual "diazo reaction“.
6. 5-hydroxy pyrazole or pyrazolone have a phenolic
character.
7. Towards oxidizing and reducing agents, pyrazole shows the
same remarkable stability as benzene.
8. Homologues of pyrazole resemble those of benzem in
being readily oxidized to the correspondirg carboxylic soils.
Pyrazon is a weak‘secondary base and it may be acetyhted,
benzolated and converted into derivatives of urethane and tree

(Ber. 1895, 28, 716).

11 Constitution of Pyrazolone
The pyrazolones or hate dehydrcpyrazclss are those pyrazole
derivatives which have been known for the longest time. These
compounds were discovered and investigated by Knorr. The pyra-
zolone compounds are divided into two classes: - 4 derivatives
or true ketones derived from ketonie acids and 3 and 5 derivat-

ives as derived from cyclic acid amides.

f NH
HI CE I am C I O
0.0 on H C 0’0 H C 033

3 pyrazolone 4 pyrazolone 5 pyrazolone

(Ann. 238, 145).

10

Pyrazolone bears the same relation to pyrazoline as

pyridine does to pyridone:

my "3;: 2162: 39::

Pyrazolone Pyrazo line Pyridone Pyr id. ine

I
HG

Knorr has determined the constitution of tie phenyl methyl
pyrazolone by the following reactions (Ann. 238, 148).

. 1. By distillation with zinc dust, a product is obtained
which is a weak base of composition clonlowz which in all its
properties and reactions resembles a pyrazole base. Its salts
are decomposed by water. Through the reduction with sodium ad
alcohol it is transformed into a base rich in hydroga, which
exhibits a reaction similar to a pyrazoline base in that it gives
an intense violet color upon the addition of an oxidizabls sub-
stance. These properties are identical with thus of l-phsnyl-
3-methyl pyrazole of the formula:-

NCsHe
H CH

CHsC CH

Through its formation, the origin of 1-phemyl methyl
pyrazolone from the pyrazole group is pror ed.

2. The methylene of aceto acetic ester is found unchanged.
It undergoes a number of reactions characteristic of this group.

3. The oxyg-i in phenyl methyl pyrazolone is entiriy
inactive in that it cannot be combined as an hydroxyl ar ketonic

ll

 

oxygen but only in the form of acid amides.

4. Phenyl methyl pyrazolone contains no more hydrogen
which could combine with nitrogen. It is indeed methylated
with methyl iodide attaching undoubtedly to the nitrogen
atom, giving the methylated base, antipyrine, in which tie
molecule of phenyl methyl pyrazolone undergoes a radical
change. The antipyrine no longer contains the methylene group
but a methine group. This phenomena led Knorr to a false
conception of the antipyrine molecule. 8

From the foregoing it is evident that the. had rogcns in
phenyl methyl pyrazolom distribute themselves as fella s: five
hydrogens are in the phenyl of the phenyl hydrazim, three
hydrogens on the methyl group and two hydrogens on tie methylene
of acetc acetic ester.

The post ble formulas for phenyl methyl pyrazolom may

be either of the following:
CeHs CeHs

 

w c-o 1! con.

 

 

 

 

CHsC - C31: 080 03s

The decision of the tvo: formula lies with the question
of the constitution of the phenyl hydrazine of acetc acetic
ester and the ketone and aldehyde derivatives of phenyl hydrazine

for which compounds there are two formula.

I II
cm. 0 ° 5 " "
-CHsCOsCsfie CHs'\ - CHsCOsCsHe

Phenyl hydrazine of acetoaceticester

I II

Comm-n -'C(CH.). maxi/s - a
(Click

If these compounds possess fomula I, then I is tin
formla for pherwl methyl pyrazolone, and if these compouifls
have a structure as in II, than II is the formula for phenyl
methyl pyrazolone.

According to 3. Fischer, the ketones and aldehyde
derivatives of primary as well as the unsymmetrical ssmrdary
aromatic hydrazine under suitable conditions react very similar
to the formation of indol derivatives (Ann. 236, 116).

- '033 —->c -
CsHeH 1" t 0 one, CHs + We

‘CH.
CH. CHI
Aceto methyl phenyl Dimethyl indol
hydrazine

It is obvious that this reaction shcw s an analogy of atomic

linkage in both Classes of hydrazine derivatives.

CsHsN.CHsN . 0 (03s): CeHsNH-li - C (03.).
Methyl phenyl hydrazons of Phenyl hydrazons of acetom
acetone

Accordingly, the primary as well as the unsymmetrical
secondary hydrazine unite in the same manner with all ehyi es

and ketones at low temperatures while the symmetrical secoin ary

Y

hydrazine react with aldehydes (Ber. 19, 2239) at high temperat-

ll

 

urea and with ketones the reaction, in general, is more
difficult.

From this fact, it appears with great probability,
that the formula for the phenyl hydrazons of acetc acetic est-
er is that of formula I:

CsHsNH - N I: 0.03.
“CHaCOQCefli

From the above facts, Knorr cast aside the carbizim
structure for the pyrazolone and accepted the following

formula for'phenyl methyl pyrazolone:
NCsHe

w -c
“ cmc- CH.

 

Knorr states that l-phenyl-S-methyl-5-pyrazolone may
exist in three desmotropic forms. This is described by
Knorr as "double tautomerism" (Bar. 1895, 28, 706).

The 1-pheny1-3-methyl-5-pyrazolone itself has only
been obtained in the form of one substance of melting point
127°C. .

 

‘ NCsHs NCsHs NCsHe
In 10-0 Ema-o wl/l ]con
CHoC 0H. CHsC- CH 08.0 CH.
Methylene form Imine form Phenolic form

The imine structure is found in those compouxds known
as antipyrines.
The phenolic structure is found in those compounls

14

such as phenyl others, esters, and salts of phenyl methyl
pyrazolone.
The methylene structure is that type of compound whl ch

responds to pyrazole blue test.
III The Pyrazcle Blue Test

Knorr and Duden found that the oxidation of phenyl methyl
pyrazolone with ferric chloride or platinum chloride resulted
in the formation of pyrazole blue which.reprssents the indigo
of the pyrazole series. In a chloroform.solution, a deep blue
color results and in other solution violet needles of pyrazofe
blue are precipitated (heyer and Jacobson,‘vo1. II, 415; Ann.
see, 155; Ber. 25, 765).

Csfis efis

CHsO C 3 OCH.

 

 

Pyrazo 1e Blue

17' Preparation of 5-Pyrazolone

Phenyl methyl pyrazolone was prepared by Knorr in 1883
by condensing phenyl hydrazine with a Beta Ketonic ester.

To 125 gms. of phenyl hydrazine, 100 gms. of acetc acetic
ester were added and warmed cn.a water bath. The first reaction
consisted of the elimination of water with the formation of
phenyl hydrazons of acetc acetic ester.

CsEchH II 6-03.
-033C000235

This product was heated to a higher temperature which
resulted in a ring closure with the elimination of alcohol.

 

CeHINsH a 0-0m ClofiloNsO + CsHSOH

~032COOC 2115

The alcohol formed was distilled off,the condensation
product washed with ether, and the product dried in an oven
at 100°C. The product was recrystallized from.water or h>t
alcohol. The crystals melted at 127°C (Ber. 16, 2597; Ann.
238, 147).

Equations for the reaction of acetc acetic ester in the

 

keto form:
GeHeNHNHh + CHsCOCHsO:Ooc235 (-HeO) 4%

Phenyl Acsto acetic ester
hydrazine

CchNE NCeHe

N . ‘COOCaHs - CaHsOH———> N/ GO

CHhC ma. 08.0 CH.
Phenyl hydrazons of l-Phenyl-3-mettwl-5-
acetc acetic ester pyrazolone

Reactions of acetc acetic ester in the cnol form:

comma. + cmconcncoocga. (-H20) 4

 

Phenyl Aceto acetic ester
hydrazine

(3ch

    

 
  

.
'1
I

[COOCeHs '- CsHsOH—-—*HN
casc' GE Cflhc

Phenyl hydrazons l-phenyl-3-methyl-5-pyrazolone
of acetc acetic ester

 

io

Other methods for'the synthesis of pyrazolones.

1. Knorr and Dudcn found that unsaturated acid of the
acrylic acid series R.CH-CH-COOH react with hydrazines to
give derivatives of pyrazolone or pyrazolidone (Ber. 1892, 25,
761).

CHsCHuCH-COOH + Walk ——* 0-0 INK c HsO

 

 

 

 

 

 

Crotcnic acid ' phenyl hydrazine CB; 03.083
l-phenyl-3-methyl-5-pyra-
zolidcnc
NH /NCsHs
o.o[/\-nn + o —"——» 0-0 \“s
one CHCHe'* BC :CCHB
l-phenyl-3-methy1-5- l-pheny1-3-methyl-5-pyrazolone

pyrazolidone‘

2. Petrenk and Kretschenko have prepared dimethyl pyra-
zolone by the elimination of Go. from the acid fonned by the
condensation of phenyl hydrazine with.methy1 acetone dicarboxylic
acid ester.

3. Knorr and Klotz prepared diphenyl pyrazolone by con-
deqsiug phenyl hydrazine with ethyl benzoyl acetate (Ber. 20,
2545).

4. Knorr prepared ortho and.para tolyl methyl pyrazolone
through the condensation of[toly1 hydrazine with acetc acetic
ester. The melting point of the para compound was 137°C and
that of the ortho compound 183°C. (Ber. 1884,17, 550). Hushn
and Brigham,obtained in the preparation of O-tolyl methyl
pyrazolone (m.p. 183°C) an isomeric tolyl methyl pyrazolone

17

having a melting point of 169°C (Brigham's Thesis 1929).

5. Klauber prepared 1, 5, 4 xylyl methyl pyrazolone
by heating 1 part of the compound of the empirical formuh
ngflssfl.0. with one part of concentrated hydrochloric acid for
two hours at 145°C. ‘1‘ he hydrochloride was decomposed will
sodium acetate. The meta xylyl methyl pyrazolone was obtaired
as needles melting at 159°C (Monstsherte 12, 215).

Huston and Brigham prepared P-xylyl methyl pyrazolone
though the condensation of P-xylyl hydrazine with acetc acetic
ester. The P-xylyl methyl pyrazolone was crystallized from
alcohol and melted at 150-151°C (Brigham's Thesis).

Y Preparation of 5-Pyrazelone

Michaelis prepared l-pheny1-5-methyl-5-pyrazolone by
the action or 15 gms of acetyl phenyl hydrazine on 15 gms. or
acetc acetic ester to which 14. gas. or phoepho rous trichlcrfie
have been added gradually. The mixture was refluxed until no
generation or hydrogen chloride was evolved. The thick viscous
solution was dissolved in a 10% solution of hydrochloric acid.
The pyrazolone dissolved in the acid solution. The solution
was filtered, cooled and neutralized with ammonia hydroxide.

The pyrazolone was precipitated and the product dried on a
porous plate . (If the pyrazolone is dark colored it my be
decolorized by boiling in an alkaline solution or animal char-
coal). The yield was eight grams, due to the fact that di-
acetyl phenyl hydrazine was famed. The pyrazolone crystallizes
from alcohol as colorless crystals. (Ann. 558, 275).

18

Equations showing the reactions involved:

9° + CBHBNHNHCOCHa + P015 ————>

Acetoacetic ester Acetyl phenyl Phosphorous
hydrazine trichloride

93,

90 + ca,coc1 + P012(oc.s.)
CHB

CONHNHCBH.

Phenyl hydrazide or acetoaceticester

 

Cefialfl CeHaNH NCBH,
HN COCHa EN 00033 EN CCHa
A; ———-7
OC CH2 00 CH O CH
Keto form Enol form 1- Phenyl 5 methyl

5 pyrazolone

According to Michaelis the 5 and 5 pyrazolone may
be prepared by this method but the 5 pyrazolone is more
abundant than the five. In the action of free phenyl
hydrazine with acetoaceticester the NE, of the phenyl
hydrazine can.react directly with.the ketonic oxygen or the
ester but in case of an acylated hydrazine the reactivity
is less. Therefore the remaining group £30635 rearranges

with the OH of the enolized esters (Ann. 558, 275).

Equations showing the reactions involved:

§Hs
00

93a
COOCefig

Acetoaceticester
(Keto form)

935
C03

éccc.H5

Acetoaceticester
(Enol form)

CHaCfl——_—I N053.
Hq\ NHOCCH.

03000335

19

 

 

CHaC N
+ C H OH
HBN 2+5H20
HN0535 ’ HBO NCGH5
C=O
Phenyl 5 pyrazolone
hydrazine
CH O NO H
HFCBHB 8 6 6
$00035 :
NHOCCHa

 

 

H HQ\b
=0003H5
CH30”--]NC.H.
' O‘HacOCHa 8 H20 '————+
H0

5 Pyrazolone

other methods for the synthesis or the 5 pyrazolone.

1. Knorr and Duden prepared a 5 pyrazolone through the

condensation of phenyl hydrazine with cinnwmyl acid(Ber.25, 759)

c,n.cnacacoos

Cinnamyl acid

c,a.cazCHCONHNHc,H,

Cinnamyl hydrazide

CBHQCHQGHNHNHCQHQ

Cinnamyl hydrazide

 

+ H.NHNC.H. e

Phenyl hydrazine

 

+ H30
NH
" 0,3,0 N .
+ 2 H
as 0:0

1, 5 Diphenyl 5 pyrazolone

20

2. Bischler prepared pyrazolone derivatives by the action
or diazonium.sa1ts on substituted acetoaceticester(Ber.25, 5145;
26, 1881). He treated diazonium.chloride with phenyl acetoacetic

ester.

CgflgflzNCI ‘I' 033509033 + H80 __)
COCK; 0000335

Diazonium Phenyl acetoacetic

benzol chloride ester ‘

CefiaCQQHa + H01 + ca.coon

C¢H5NHNCOOCgH5

The hydrazons splits off water and a pyrazolone derivative

results.

Cefisco CE“ I 061150 2 CH
I " H30 -—__) ‘

CBH5NHNCOOCgH. ceHe

\ = 6000,33,

5. Michaelis and Behrens prepared ortho and para tolyl methyl
5 pyrazolone through the condensation of the corresponding
acetyl tolyl hydrazine with.acetoacetic ester and phosphorous
trichloride. The pyrazolones were recrystallized trom.a1cohol,
the para compound melting at 196°C and the orthe compound

at 169°C.(Ann. 558, 511).

4. The para xylyl methyl 5 pyrazolone was prepared by

Huston and Brigham.through the condensation of para xylyl
acetyl hydrazide with acetoaceticester and phosphorous
trichloride. The compound was recrystallized from alcohol.
m.p. ISO-181°C. (Brighams Thesis)

21

VI Constitution and Preparation of Antipyrine

Antipyrine is the methylated base which is obtained in
the form of its hydroiodide when phenyl methyl pyrazolone is
heated to 100°C together with methyl alcohol and methyl iodfie.
By treatment with sodium hydroxide antipyrine results. (Knorr,
Ann. 238, 202; Ber. 17, 550, 2037).

 

 

03H. . NCsHe
CH. /
B 0-0 + CHaI + CHsOH—v'” I;N 0-0
I . . H
CBC 033 03.0 CH
thyl methyl pyrazolone Hydroiod ide of Pyrazolone

Cefis eHe
cs. \
§:s=Lc-o + NaOH——* and 0-0
cmc a cmc sea

Antipyrine
(Knorr)
Dbl). 113°C

 

 

 

Knorr has given the following points which he considers
important for the constitution of antipyrine (Ann. 258, 205).

l. Antipyrine has without doubt a metm‘l group attached
to the second~nitrogen atom. This has been proven by the
synthesis of antipyrine from symmetrical methyl phenyl hydrazine
and the splitting off of this base from nitroso antipyrine. by
the action of alkali. The fact that aniline and methyl aniline
are split off from antipyrine-with zinc dust as well as the
reaction of metallic sodium in a boiling alcoholic solution

affords proof of the above structure.

22

2. Antipyrine, no longer, contains the methylene group as
in phenyl methyl pyrazolone, but has a methine group in place.
Nitrous and nitric acid produce nitroso and nitro antipyrim‘
of basic character. Benzaldehyde condenses with two molecules
of antipyrine according to the follaing equation:

scnnlzngo + 0,360 ——- 0293231992 + 0.3.011 + 23.0

The reaction of bromine with antipyrim results in 0
addition product, onslanzosr. which loses hydrobromie acid
wlmn treated with cold water and forms a mono-substituted
product, ClonnlleBr. All those derivatives of phalyl methyl
pyrazolone in which one hydrogul of the methylene group has
been replaced permit the 1: operation of antipyrine.

5. Antipyrine as a derivative of phenyl methyl pyrazolore
must retain the pyrazole nucleus.

4. The preparation of antipyrine through the con! ensation
of symetrical methyl phenyl hydrazine with acetc acetic ester
throws considerable light on the constitution of antipyrine in
that antipyrine contains a methine group (Ann. 258, 2(5 ,206; Ber.

17, 2037) ’3 cm.
- \ *' -0
6 GB. + CHsCOCBaC_OCRH‘——a CH. 00 + CaHsOH + H20
' 03.0 on
Methyl pharyl Aceto acetic ester Antipyrine
hydrazine

5. The action of sodium and alcohol on antipyrine ruptures
the ring with the formation of the anilide of Beta methyl crot-

onic acid.

23

 

CEO} ': NCsHs
e ‘ a

CH C I CH - CO '

0H.c - 03—00
Antipyrine Anilide of.Beta methyl orotonic
acid
The action of heat and phenyl hydrazine on nitroso
antipyrine causes the ring to be broken.in the 2 and 5 posit-

 

ion.
Gila? IfCeHs CHsNH—fi'mefis
CHaC . (.3 - 00 03s.? -‘fiOEI 0-0
H II 0 NaHGeHo
Nitroso antipyrine thyl hydrazoneoni‘so nitroso aceto

acetic methyl phenyl hydrazide

The above two reactions give rise to the amide type and
lad support to the above formulafor antipyrine containim
the group - N - GO - (Ann. 528, '78).

Michaelis has critized Knorr's formuh and has pro-
posed the phenol betaine formula for antipyrine (Ann. 520,
‘5; 551, 197)

  

 

-3-CHs

Michaelis gives the following points for the establish-
ment of the above formula (Ann. 520, ‘6).

1. The formation of antipyrine through tin methylation
of l-phenyl-5-methyl-5-pyrazolone is explained the simplest

way by the assunmtion of 2 : 5 pyrazole formula,sime the above

. \
U ‘_
,0

I.

24

named pyrazolone reacts quite often in the hydroxyl form.

 

/NCeH§ NC 6H5
N A COB _ + CHsI . —= CHsN I 003
CHsC H CH3 0

0n the other hand the formation of antipyrine from
symmetrical methyl phenyl hydrazine and acetc acetic ester
is explained by the assampt ion of the isopyrazolone formuh

in which aceto acetic ester reacts in the enol form.

 

 

CH: B—I'i-CHs (His
9 9
con + N-CsHa ——————~.Q.. N - CHe
9! I '9
OH H CIH + H20 + CszOH
9
COOCaHs CO NCeHs
Aceto acetic ester Phenyl Antipyrine
hydrazine?

2. The behavior of antipyrine with alkyl iodides at. a
moderate temperature is explained on the simplest basis by the
assumption of 2 : 5 pyrazole formula. The antipyrine acts
in the same manner with alkyl iodides as the inner salts
of phenol ammonium bases (phenol betaines) in that iodim
attaches to the second nitrogen atom and the alkyl group to
the carbonyl.

NCsHe CsHBCH‘ NCeHs
0- C33 CH3 I CHsOG fl—C‘Hsom "Zen.
CH: HG

Ant ipyrine Ant ipyr ine l-phenyl-5 -ns thyl-
pseudo 5-pyraz ole
me thio dide

 

25

The pseudo methiodide formed is identical to tie
methiodide of 1-phenyl-5-methy1-5-methoxy pyrazole. Phenol
betaines unite with methyl iodide in a similar manner in
the presence of caustic potash. The resulting quarternary
iodides are identical with those obtained from the dimethyl

amino “12010..

CH; 00
magi) 03.1 c H"/0 03.1 / H’
N (CBS): 3 \ CsH‘\
‘_ N(CHa)sI N(CHs)s
O-trimethyl amonium 0-dimethy1
phenoxide anieole

5. The proof which Knorr has advanced is that phenol
betaine of Greiss reactsdifferently than antipyrine. This
does not contradict the 2 : 5 pyrazole formula, since both
compounds are constituted differently as clos e observations

show: 11
NC e35

n c/Ko/ 0H. N/\o\ c
a cLéLN CH. Wm
H

The four membered ring of the 2 : 5 pyrazole forum!
is only similar to phenol betaine since it contains no; two
carbon atoms, but only one. However, the oxygm forms a
five manbered ring as a result of which there must be a

difference in the behavior from a single betaim ring.

”v

4. The formation of chloro methylates from phenyl
methyl pyrazolone by the interaction of phosphorous oxy-

chloride on antipyrine gives good support for. the 2 5

pyrazole formula. In this case,one must assume a com-
plicated rearrangement of the isopyrazolone formula. (Ber.
32, 2400).

5. T1. 2-metho chloride of l-pheny1-5 methyl-5-
chloro pyrazole formed by the action at phosph: rcus oxy-
chloride on antipyrine, yields antipyrim when treated
with caustic soda. With sodium hydrosulphide, thiopyrine

is formed; with ammonia and amines, imino pyrines are foams d:

0.35 CsHs Cam
0 W011. c©ncm c N011.
HCI\O CHs HC__.ICCHs HC, 8 CCHs
Antipyrine Imine pyrine Thio pyrine

6. The constitution of thio pyrine and selanopyrin
with the atomic groupings c - S and C . So does not curre-
pond to the properties of these compounds.

Through the oxidation of a compound with three atoms
of oxygm, one can only obtain one acid of the following
structure:

NOeI'Is
CHsN CHSOeOH

03.0L on
but the actual fonnul-a produced by experiments has the empirical

 

he;

2'7

fomula of cunlzwzsos. 811011 a compound must ale: have

acid preperties since it would correspond to dimethyl
sulfanilic acid which produces salts. The above oxidation
is entirely different and corresponds to trimethyl sulfanilic

6.34:;

(CHs)e
The selenium has only a slight inclination to unite
with carbon through a double bond while the selanopyrin
forms quite readily and almost quantitatively. The selenium

acid.

urea, CSe(NHa)g of Yerneuil, which contains a bound selenilm
atom, will break down through oxidation with the elimination

of selenium. Selene pyrin trioxide will change into selanopyrin
dichloride quite smoothly without rupture of the molecule when
treated with concentrated hydrochloric acid.

In 1896, Knorr made a detailed comp risen of antipyrine
with O-trimethyl ammonium phenoxide, which revealed tin fact
that, apart from the addition of alkyl iodide, these csmpourds
were quite different in their behavior.

O-Trimethyl amonium Phenoxide Lntipyrine
O-trimethyl ammonium phcn- Antipyrine remains un-
oxide rearranges through dry decomposed whm boiled
distillation into 0-dimetlw1 in vacuum

amino anisole :

/0 /°°H‘
0 —"CH4
' ‘N'wm. ° \N(CHs)s

O-trimethyl ammonium phen- Antipyrine may not
oxide is easily hydrolyzed. be converted into tie
on exposure to the air; it phenol ammonium base.

absorbs a molecule of water and
regenerates the phenol

ammonium base.

O-trimethyl ammonium phen- Antipyrine may be pre-
oxide cannot be precipitated ' cipitated with alkali
with alkali from an aqueous 1101- in a strong aqueous
ution on account of the phenolic solution.

character of the ammonium

base.

The pseudo methyl iodide of Greiss phenol betaine
is stable when boiled with sodium twdroxide and when sub-
Jeeted to dry distillation regenerates dimethyl amino anti-
pyrine, whereas the pseudo methyl iodide of antipyrine aho
regenerates antipyrine by distillation under tin influeme
of sodium hydroxide. From the abate facts Knorr rejected

the phenol betaim formula for antipyrine (Ann. 528, 78).

Properties of antipyrine
1. Antipyrine decomposes by distillation at atmospheric
pressure.
2. Antipyrine is very soluble in water, alcohol,
chlorofom, hot toluene and difficultly soluble in cold toluene,
ether and ligroin. It crystallizes from water in large crystals

29

having a melting point of 115°C.

5. Antipyrine is a strong acidic base, precipitated
by alkali and forms salts with acids.

Knorr also prepared antipyrine by the methylation of
l-phenyl-B-methyl-5-ethoxy pyrazolone. The methylated pro-
duct was treated with sulphurous acid and supersaturated with
sodium hydroxide. The antipyrine was extracted with ether
and recrystallized. (Ber. 28, 712).

The ortho and para 5-t01yl antipyrine were prepared by
Knorr by heating the corresponding 5-pyrazolone with methyl
alcohol and methyl iodide at 100°C. The ortho compound
melted at 96-9700 aid the para compound at 157°C (Ber.17,550).

Klauber prepared 1, 5, (antipyrine by the heating of
a compound having the empirical formula, 033%04, with
methyl alcohol and methyl iodide at 150°C. The product was
crystallised from ligroin. T he crystals came down from
ligroin in needles, melting at 115°C (Monatshefte 12, 217),

The T 5 a antipyrine was prepared by Michaelis by methy-
lat ion of phenyl 5-methyl-5-pyrazolone with methyl alcohol and
methyl iodide. The 5-antipyrine melted at 115°C. (Ann.558,284|.

The ortho and para 5-tolyl antipyrine were also prepared
by Michaelis by heating the corresponding 5-pyrazolones wifi
methyl iodide and metm‘l alcohol in a closed tube. The methy-
lated product was dissolved in water and the: antipyrim lib-
erated by the treatment. with sodium hydroxide. The product
was extracted with chloroform, dried with Cacos and recry-

UV

stallised from ligroin. The para tolyl antipyrine had a
melting point of 98-10000 and the ortho tolyl antipyrim
had a melting point of 97°C. (Ann. 558, 517).

VII Preparation of the Benzoyl Esters
Nef prepared the benzoyl ester of phenyl methyl pyra-
zolone by Schotten Bauman reaction. The pyrazolone was
shaken with an excess of benzoyl chloride in an alkali sel-
ution. The product was recrystallized from alcohol and

melted at 75°C. (Ann. 266, 125)

 

 

 

 

 

CeHs - , no.2. ‘
EN \0-0 + CsHsCOCJ. CsHsCON(\lc-O 3 H01
CHsC=CH CHaC- CH
Phenyl methyl pyrazolone l-Phenyl-2-benzoyl-5-methyl
5-pyrazolone

Nef assumes that the pyrazolone reacts in the imire
form and that the benzoyl residue attaches to tie nitrcg-
atom. He assumes that the addition of benzoyl chloride to
antipyrine takes place in a different sense than tte addition
of alkyl iodides to antipyrine.

 

 

 

 

 

 

983. 0.250091 963‘
CHle 3 ('20 e CsHICOCl CH ”r N J00
s
CHeC SH 01133 OH

on the other hand Knorr believes that the addition of benzoyl
chloride and alkyl iodides to antipyrine takes place in tin sane

51

 

 

 

 

 

 

 

 

 

 

 

96H5 I CsHe
9 c
CHsK I 00 CH3! N COCaHS
+ 02351 ———>
CHsC CH CHsC CH
CeHs
I I
CHsN I 30 CHsN‘ N ~ COOCCsHs
+ CeH5COCl ———+ I H
CHsC SH CHsC *CH

 

 

 

 

No definite decision has been made, whether the benzoyl resfiue
is attached to the nitrogen or oxygen.atos. (Ann. 295,47).

Mi chae lis prepared 1-pheny1-5-methy1-5-benzoyl-5-pyrazolone
by shaking equal amounts of‘phenyl methyl 5-pyrazolone with
benzoyl chloride in an alkali solution. (Benetton-Bauman react-
ion). (Ann. see, 278).

The 1-pheny1-54methyl-5-benzoyl-5-pyrazolone was recry-
stallized frm alcohol and melted at 64-6590.

Ortho and para tolyl 5-methyl-5-benzoyl-5-pyrazolone were
prepared in the same manner. The correspondiig 5-pyrazolones
were shaken with benzoyl chloride in. an alkaline solution and
recrystallized from alcohol. The ortho compound melted at 72°C

and the para compound melted at 47°C. (Ann. 558,515).

32

EXI—‘ER IME NTAL PART

I Preparation of Tolyl Hydrazine and xylyl Hydrazine

Huston.and Brigham found that the usual methods for the
preparation of’hydrazine could not be used with very good re-
sults in the preparation of O-tolyl and P-xylyl hydrazine,
since there was much tar formed when sodium.nitrite and acid
were used for diazotizingz

They found that by using ethyl nitrite instead as the
diazotizing agent that better results could be obtained.
The method was similar to that used in preparation of cyml
hydrazine by Demonbreun.and Kramer (Menatshefte 11, 285; 12,
211). The ethyl nitrite was prepared according to tie mettnd of
Feldman (Jour. of the Am.Pharmaceutical.Assn. 12, 589).

A.mixture of 250 gms. of sodium nitrite and 100 gms. of
alcohol were placed in a flask fitted with a dropping funnel
and a condenser. The receiver was packed in ice in order to
condense the ethyl nitrite which has a boiling point of 17°C.
.1 solution of 200 gms of concentrated sulphuric acii , 1500 cc.
of water and 100 gms. of ethyl alcohol was slowly dropped into
the nitrite mixture. The ethyl nitrite was produced immediately
and condensed in.the ice cooled receiver. The yield was from.
89 - 92% of the theoretical.

o-tolyl hydrazine was prepared by diazotizing O-toluidine
with hydrochloric acid and ethyl nitrite ani reduction with
stannous chloride. 1228 cc. of concentrated hydm chlorie act
was added .to 100 gas. of O-toluidine in a large healer in a
freezing2mixture. 80 gms. of ethyl nitrite in 80 cc. of alcohol

were placed in a dropping funnel packed in ice.

55

The ethyl nitrite was added to the O-toluidine hydro-

chloride solution as fast as possible without the temperature

of the reaction mixture rising above -lO°C. The rapid addition
of ethyl nitrite reduces the tendency for the fornmtion of tb

amino azo compound. A mechanical stirrer was used to eliminate
local over heating of the reaction mixture. A solution of 592
gms. of stannous chloride in 540 cc. of concentrated hydmchlcr ic
acid was tlmn slowly added to the diazonium compound, keying
the reaction mixture below -5°C. The hydrazine hydrochloride
was obtained as light yellow crystals, which were filtered, dried,
and decomposed.by caustic potash (500 gms. per 500 cm). This
liberated the free base which was extracted with ether and dried
over anhydrous sodium sulfate. The ether was distilled (ff and
hydrazine purified by fractional distillation, tie greater part
of the hydrazine coming over between 110-125°C at 4 mm. pressure.
The yield was 64 gms. which is 56% of the theoretical. O-tolyl
hydrazine has a melting point of 61-620 and a boiling poizn
range of 95-1150 under 5 mm. pressure. It is very umtable de-
composing to tar on being exposed to light or air.

The reaction may be shown by the following equations:

NH NHeHCl

OCHe /\ 03s
4- H01" k/J

O-Toluidine O-Toluidine hydro chloride

34

NHzHCl N - NCl
OH; + CaHsONO -———> O CH. 4- H30 + (3211503
Ethyl nitrite O-toluidine diazonium chloride
ll - N01

NHNH;
OH. + 2H3 ($11012 + H01) —e O CH.

O-Tolyl hydrazine hydrochloride

NBNHaHCl /
GB; + KOH — H; CH. + KCl + H30

 

O-Tolyl hydrazine

The P-xylyl hydrazine was prep! red from P-xylidim by
using half quantities of the reagents in tin above method.
The hydrazine was purified by fractional distillation, the
product coming over at 120°C at 4 mm. pressure. A yield of
58 gms. was obtained which is 68% of the theoretical. P-
xylyl hydrazine has a melting point of 76-77°C ani decomposes
when exposed to light or air.

The reactions are shown by the following equations:

NH: 1:11.301

CHe + HCl ————> CEe
Ha HaC

P-xylidine P-xvlidine hvdrnnhlnrifia

35

NHeHCl N201
/\‘CH, + 023501!) ——t CH; + 1120 + CgHSOH
HsJ\Y/ ‘ He
Ethyl nitrite P-xylyl hydrazine
hydrochloride
N001
NENHsHCl
OH. + 2H2(SnClsHCI) —-—>
3.0 ' on.
use I/,

P-Iylyl hydrazine hydrochloride

NHNHeHCJ. NHNH;

CH:
OH. + KOH 4: + KC]. 4» H20

HsO He

 

P-xylyl hydrazine

11 Preparation of O-Tolyl Methyl Pyrazolone

l-O-Tolyl-3-methyl-5-pyrazolone was prepared by the
method used by Knorr in the preparation of l-phenyl-S-metmrl
5-pyrazolone (Ber. 16,2597; Ann. 238, 147).

To 64 gms. of O-tolyl hydrazine was added 68.6 gms. of
acetc acetic ester. This was refluxed for two hours at 1000C,
then for eight hours at 160-17006. A resinous nnss was ob-
tained which solidified on cooling. This was treated with
its own volume of acetone and allowed to crystallize in the

ice box. A cake of yellow crystals forned which were recry-

36

stal-lized from alcohol and washed with ether. The yield
was 26.5 gms. which is 50% of the theoretical based onihe
hydrazine used. The product melted at 183°C an! was t1!
same compound as that obtained by Knorr thrmgh the con-
densation of O-tolyl hydrazine with.aceto acetic ester.
An.attenpt was made to obtain the isomeric l-O-tolyl 3-
methyl-s-pyrazolone of melting point 169°C along with

the l-O-tolYl 5-methyl-5-pyrazolone of melting point 163°.
The above two isomeric 5-pyrazolones were obtained by Huston
and Brigham.(Brighamfls Thesis 1929) as a mixture through
the condensation of O-tolyl hydrazine with acetc acetic
ester. Nine condensations were made with the production
of only cne-tolyl-S~methyl-5-pyrazclone of melting point
18390.

The o-tolyl methyl pyrazolone cm.p. 183°C) is soluble
in hot alcohol, chloroform and benzene, slightly soluble
in ether and insoluble in water and petrolic ether.

The following equations represent the reactions which
take place in the preparation of the compound of me]. ting
point 185°C:

cameraman. + cmgcngcoocgm jflgOI fl,

 

 

O-tolyl O
hydrazine

011:0st11 cascamn

‘ n ’COOCefis _ c r N co

I I 811503 J

CHsC Ha 0330 CE:
O-tolyl hydrazone of l-O-tclyl-S-methyl-5-pyralclens
acetc acetic ester mtp. 183

(methylene fo rm)

57

The following equations represent the reactions

which take place in the preparation of the compound of

melting point 169°C.

on
/
enammmn. + cm-c-cn-coocefis (-ch) 4

O-tolyl hydrazine acetc acetic ester

CHsCsHeNH 11053.03.
HNl/ 000C235 -' 033503 ——> CO
GHsC ==|CH CHsC CH

0~tolyl hydrazine of aceto l-O-tclyl-‘é-methyl-5-
acetic ester pyrazolone

(imine form) m.p. 169°C.

Knorr assigned the methylene form to the pyrazo ions
which responds to the pyrazole blue test (Ann. 838, 155;
Ber. 25, 765) The 5-pyrazolcne melting at 183° responded
to the pyrazole blue test, while the 5-pyrazolone meltixg
at 169°C did not respond to this test and must therefore

be of the imine structure.

III Methylation of 1-0-Tolyl-B-Methyl-5~Pyrazclone

The l-0-toly1-5-methyl-5-pyrazolone (m.p. 185°C) was
methylated by the method used by Knorr (Ber. 17, 550).

10 gms. of the pyrazolone were heated in a seabed tube
(carius tube) with 10 gms. of methyl iodide and 10 gms. ct '
methyl alcohol eight to ten hours at 120°C. The methyl ahaohol
was distilled off under diminished pressure. The product was
dissolved in.water and the tolyl antipyrine liberated by the
addition of sodium hydroxide (37 gns. per 100 cc.) The cruie
product was crystallized from a mixture of chloroform.amd
high test gasoline. The tolyl antipyrine was then.recry-
stallized several times from high test gasoline. The crystahs
came down.as long needles which melted at 90-91°C. The yield
was 6.4 gms. which is 31% of the theoretical.

The reactions may be shown by the following equations:

 

 

 

 

NCsHLCHs NCeHLCHs
I//“\\
CO + CHsOH + 0331 —’ CHsH CO
‘1! H l
CHaC CH3 CHsC=====CH
O-tolyl-S-methyl-S-pyrazclone Hydroiodide of 5-pyrazolone
I CeHsCHs NCeHcCHs
CBsN 0-0 + NaOH Chl(\ 0-0
0330:» CH CHac_=é=‘cn
Hydroiodide of Tolyl antipyrine
5-pyrazolone m.p. 90-91°C

The tolyl antipyrin which was prepared by Knorr by the

above method had a melting point of 96-9700.

39

A nitrogen determination was run on the compound
melting at 90-91°C.
The data of the determination is g1! en below:

.1812 gm. of sample gave .0255 gms. of R

Calculated for Found
012314N2°
R 13 .86$ 14 .O’m

The l-o-tolyl-S-methyl-S-pyrazolone (m.p. 169°C) was
methylated. as in the above method. The tolyl antipyrine
was recrystallized several times from high test gasoline.
The crystals came down in long needles melting at 90-9100.

The methylation products of the two isom ric loo-tolyl-
6-methyl-5-pyrazolones have the same melting points (90-9100)
which indicates that 1-e-tolyl-3-methy1-5-pyrazolone (m.p.
183°C) and 1-o-to1y1-5-methyl-5-pyrazolonc (m.p. 16900) are

i somers .

IV Preparation of p-xylyl-S-methyl-5-pyrazolcne

l-p-xylyl-S-methyl-s-pyrazolone was prepared by the nethod
used by Knorr in the preparation of 1-phenyl-3-methyl-5-
pyrazolone (Ber. 16, 2597; Ann. 238, 147).

2'7 grams (1 mol.) of p-xylyl hydrazine were added to
26 gms. (1 mol.) of aceto- acetic ester in a flask connected
to a reflux condenser. The reaction mixture was heated on an
oil bath for eight hours at 150-16000. When the contents

of the fls sk cooled it solidified to a dark brown resinous
mass.

The resinous mass was treated with its own volume
of acetone and allowed to crystallize. The crude prodmt
was crystallized from a mixture of alcohol and high test
gasoline. ‘(The product was first dissolved in the laast
amount of alcohol and than gasoline was added. The mixt-
ure was boiled until a homogenous solution was obtained.

It was set aside and allowed to crystallize).

The xylyl methyl pyrazolone was recrystallis ed several
times from gasoline and separated as very fine needhs which
melted at lGdOC. The yield was 9 gms. which is 22% of the
theoretical.

Huston and Brigham.obtained a xylyl methyl pyrazolone
melting at 150-151°C by the above method (Brighamfls Thesis
1929). ‘

The pyrazole blue test was applied t1 the xylyl meUhyl
pyrazolone (msp. lcqfii a positive test was obtained which
indicated that the pyrazolone had a methylene structure. The
test was also applied to the xylyl methyl pyrazolone (mwp.
150-151°C) and a negative test was obtained which indicated
that the pyrazolone had the imine structure.

The following equat iors represent the reactions which

take place in the preparation of the compound melting at 164°C:

(CHs)sCsHsNHNHa + CHs c'BHscoocgns -.§so
p-xylyl hydrazine aceto acetic ester

41

(CH8)BCeH8 NCeH8(CHb)2
N COOCQHB - C2H50H———'N| lC'O

0330 CH: CHsC CH2
p-xylyl hydrazons of p-xylyl-S-methyl-S-
aceto acetic ester pyrazolone
(methylene form)
m.p. 164°C

The following equations represent the reactions
which take place in the preparation of the compound
melting at 150-151°C.

(CHs)gCeHaNHNHa + enac'eficoocens “H20

 

 

p-xylyl hydrazine aceto acetic ester
(CHs)gCeHsNHI I CsEbGGHb).
EN 00002115 - CsHEOH—eflN c-o’ ‘
9
01130 - CH CH3 CH
p-xylyl hydrozone of p-xylyl methyl pyrazolone
aceto acetic ester (imine form)

mop e 150’15100

A nitroga: determinat ion was run on the compound nslt ing

at 164°C.
The data of the determination is given below:

(a) .1540 gms. of sample gave .02164 gms. of'N

(b) .1598 " " ” ” .01947 " " '
Calculated for Found
C13H1‘N20

(a) 14.05%

(b) 15.0% 13.92%

42

The p-xylyl methyl pyrazolone (m.p. 164°C) is soluble

in alcohol, chlorofbrm and hot gasoline.

V Methylation of p-Xylyl Methyl Pyrazolone

The l-p-xyly1-5~methyl-5-pyrazolone was methylated
by the method used by Knorr in the preparation of tolyl
antipyrine (Ber. 17, 550)

Seven grams of 1-p-xyly1-5-methyl-5-pyrazolom (m.p.
164°C) were heated in a sealed tube with sevm grams of
mthyl iodide and sevei grams of methyl alcohol eight burs
at 130°C. The methyl alcohol was distilled off from the
methylated product under diminished pressure. The product
was dissolved in water and the xylyl antipyrine liberated by
the addition of sodium hydroxide (67 gms. per 100 cm). The
crude product was crystallized from a mixture of a]: ohol and
high test gasoline. The xylyl antipyrine was then recry-
stallixed several times from high test gasoline. The crystals
came down as small plates with a silver luster which melted
at 97.500. The yield was two grams which is 27% cf ts
thereticel. I

The p-xylyl antipyrine is soluble in alcohol, chloroform
and soluble in hot gasoline.

The reactions may be shown by the Ibllowing equat’ons:

 

CeHs(CEe)s I CeHs(CHs)s
C-O 4' CHsI + CHaOH CH8 N .0
II I H
CHsC He CH8 H

Iylyl methyl pyrazolone
m.p. 164°C Hydroiodide of 5-pyrazolone

 

NCsHe(CHs)2 NCBH8(CH3)2
033 -0 + NaOH
H
CHaC CH
Hydroiodide of p-xylyl antipyrine
5-pyrazolone m.p. 97 .500

A nitrogen determination was run on this compani.
The data of the determination is givm below:

(a) .1705 grams of the sample gave .02221 grams of N

(b) .1888 ” " " n a .02496 e w w
Calcuh ted far Founl
ciefiicnéo
(a) 13.02%
(b) 18.96% 13.22%

VI Preparation of 1-p-Xylyl-5-Methy1-5-Pyra2e lone

The l-p-xylyl-5-methyl-5-pyra2olone was prepared
according to the method given by Michaelis (Ann. 258,510).

The acetyl xylyl hydrazide was prepered in the fillewing
way: To 55.5 grams (1 mol.) of p-xylyl hydrazim was added
17.6 grams (1 mol.) of glacial acetic acid and refluxed for
six hours. The contents of the fled: were then poured into
water and the entire mass evaporated to dryness on a ste-
bath. The brown crystalline residue was dried ‘onra pomus .
plate, washed with a small amount of ether, and again dried
on a porous plate. This was pure enough to be used in the

preparation of the 3-pyrazolone. The yield was fourteen

44

grams which is 50% of the theoretical. Better results were
obtained when the residue was recrystallized from water.

The reactions may be shom by the following equations:

 

NHNHg COCH.
' GB. + cmcoon e 4, on.
1..
C C
p-xylyl hydrazine p-acetyl xylyl hydrazi de

The l-p-xylyl-S-methy1-5-pyrazolone was prepared by
placing fourteen grams (1 mol.) of acetyl xylyl hydrazide
and ten grams (1 mol.) of aceto acetic ester in a flask fitted
with a reflux condenser with a delivery tube immersed in water
to collect the liberated hydrogen chloride gas. To this mixt-
ture twenty-seven grams (2 1/2 mol.) phosphorous trichloride was
gradually added through a reflux condenser. Then the flat
was heated, gradually at first and then to a temperature which
would cause.the reaction mixture to reflux, until no more
hydrogen chloride was evolved. The prepared pyrazolone was
dissolved in a 10% solution of hydrochloric acid. The solut-
ion was cooled, filtered, and neutralized with amonium
hydroxide, which caused the pyrazolone to be precipitated.

The pyrazolone was filtered off and crystallized from a
mixture of alcohol and high test gasoline. The crystals came
down as small cream colored crystals melting at 178-17900.

The yield was five grams which is 9.5% of the theoretical.

The 1-p-xYlyl-5-methyl-5-pyrazolone is soluble in hd:
alcohol and chloroform, s1 ightly soluble in cold alcohol
and nearly insoluble in water and petroleum ether.

The following equations represent the reactions:

(cm).c.n.wmw§coca. + CmC'gIHiCOOCRH‘ (-Hgo) _.
.

Acetyl p-xylyl hydrazide Aceto acetic ester

N-GeHs(CHe)s NCeHs(CHs)2
I EN/
HsCOCg CHs (-CHsCOOCsHs) ——-. can.
CanOOC H 0- CH
Acetyl xylyl hydrazone 1-p-xyly1-5-methy1-5
of aceto acetic ester pyrazolone

111.1) 9 178-17900

The above 5-pyrazolone was prepared by Huston md
Brigham (Brigham's Thesis 1929).
‘

“"' VII Benzoyl Esters of 5 and 5 Pyrazolones

The l:p-xy1y15-benzoyl-5-methyl-5-pyrazclone was prepared
by a method similar to that used by Michaelis (Ann. 558,515) .

A mixture of 4 grams 1-p-xy1y1-5-methyl-5-pyrazolone,
10 grams of pyridine and 4 grams of benzoyl fichloride was
shaken in a stoppered 50 cc. Erlenmeyer fled: and was allowed
to set over night.

The contents were poured into water and washed, first
with a dilute solution of sulphuric acid and them with a
dilute solution of sodium carbonate. The product was crystall-

ized several times from ligroin in an ice chest. The cry-

46

stale came down as small cream colored rhomboids meltixg
at 74°C. The yield was 2.5 grams which is 41% of the the-
oretical.

The equation for the reaction is shell: as follows:

 

Nefidcfiels NCsHs(CHs)s
Bl OCH. + , 04311500 Cl pyr id up: I OCH.
owl—Jon c.n.-cooc__
p-xylyl-S-methyl-5 benzoyl l-p-xylyl-5-benzoyl-5—
pyrazolone chloride me thyl-5-pyra2o lone
m.p . 74°C

The l-p-xylyl-5-hen2oy1-5-methyl-15-pyrazolone is soluble
in alcohol, chloroform, hot ligroin and hot gasoline.

The. above fo mule for l-p-xylyl-5-benzoyl-5methyl-5-
pyrazolcne is the one assumed by Knorr in which the bmmyl
radical is attached to carbonyl group.

A nitrogen determination was run on this compounl.

The data of the determination is given below:

(a) .2065 grams of the sample gave .01895 grams of N

(b) .2219 w n w fl n .02068 n w w
Calcuh ted for Found

019111311202
(3) 9 017%
(b) 9.15% 9 .52%

The p-l-xylyl-5-benzoyl-5~methy1-5-pyrazolone was prep-

47

are! to the method given above. A mixture of 4 grams of
1-p-xylyl-5-methy1-5—pyrazolone, 10 grams of pyridim and 4
grams of benzoyl chloride was shakened in stoppered 60 cc.
Erlemieyer flask and allowed to set over night. The con-
tents were poured into water and washed first with a dilute
solution of sulphuric acid and then with a dilute solution
of sodium carbonate. The product was crystallized from
high test gasoline.

The crystals came down as small white needles melting
at 11900. The yield is 4 grams which is 66% of the theoretical.

The equation for the reaction is shown as folloss:

 

N0.H.(CH.). NCeHs(CHs)s
R' \\00 + CeHsCOCl Pyridinge, N“ COOCCsHs
case CH: CHsC————CH
l-p-xylyl-5-methyl- 1-p-xylyl-5-benzoyl-5~methyl-
5-pyrazolone 5-pyrazolone
m.p. 1190

A nitrogen determination was run on this compound.
The data of the determination is given below:
(a) .1509 grams of the sample gave .01595 grams of R

(b) .2448 " " " " " .0226 w n -
Calcula ted for Found

C19313N2°2
(a) 9 .15% 9 .25%
(b) 9 .2596

The l-p-xylyl-5-benz oy1-5 omethyl-S-pyrazolone 1s a) 111) le

11: n1nnhn'l- nh'lnrn‘f'r‘hm anti hnt anon14nn

P-Xylyl Melhyl Pyrazolones

and Some Derivalivee

NHI NHzHCl N'l“CI
CH
3 HC' CH3 r2H50N0
lhfl H53
P'Xylldlne P-Xylidlne Hydrochlnrlde valyl Dimnnium Chloride
H H H SCl2+HCl
N-NCOCH3 N-NH, HN- NH ZHCI
CH3 CH3
HCH3COOH _ ‘
H,C H30
P‘Acelyl Xylyl Hydrazlde P-Xylyl Hydrazine P-Xylyl Diazonlum
m.p.l04-l06' m.p. 76-77° Hydrochloride
‘CH3COCHZCOOCZH5 l CH5C_0C7H_2COOC2HS
CH3 CH3
H5C H3C

N

HNOCCHg
o-C CH

P‘Xylyl Mclhyl 3-Pyrazolonc
"Lp.|78479.

l * C6H5COCI

CH3

H3c
N

06H5COOC CH

P-Xylyl S'Melhyl
3'Benzoyl 3'Pyrazolone
m.p. 74'

N

H,CC CH

N0 C-O

HJCCO CH,

P'Xylyl Melhyl S‘Btrazolonc P'Xylyl Melhyl S‘Pyrazolone

(Imlne Form)

(Melhylene Form)

m.p. (50-15!“ \ "LP. |e+°
95899//// I CH31+CH30H
//
CH3 CH3
H,C H30
N N

Nacooccws
H300 CH

P‘Xylyl 3'Melhyl
S'BenZOyl S'Pyrazolone
amp. “9’

H300 CH
P 'Xylyl Antlpyrlne

m. p. 9 5'

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