close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3040057

код для вставки
3,040,047
United States Patent 0 ” 1C6
Patented June 19, 1962
1
2
anti~fogging activity against sensitive materials used in
3,040,047
Z-(PYRAZOL-l-YD-PYRIMIDINE DERIVATIVES
Kenzo Sirakawa, Nishinomiya, Japan, assignor to Takeda
Pharmaceutical Industries, Ltd., Osaka, Japan
N0 Drawing. Filed Apr. 4, 1960, Ser. No. 19,448
8 Claims. (Cl. 260—256.4)
photographic industries. That is to say, the compounds
it this invention inhibit “fogging” appearing in the proc
ess for preparing or storing the sensitive materials.
To
make the compounds display their activities they may be
added to the raw materials or to the intermediate mate
rials or to the ?nal products, e.g. the compounds of this
invention may he added when a sensitive emulsion is to
This invention relates to Z-(pyrazol-l-yl)pyrimidine
derivatives which are usable in photographic industries as
be digested or when crystals of silver halide are to be pre
well as in the apeutic purposes. More particularly, the 10 pared or just before ?lm or paper is to be coated with a
compounds 01 this invention are representable by the
sensitive emulsion, or the like.
Formula I
An example of the use of the compounds of this in
vention as anti-foggant is shown in the following:
To a negative gelatino silver bromoiodide emulsion
15
(silver halide concentration: 0.25 gram-mole per kilo
gram) which was subjected to the second digestion are
added several kinds of compounds of this invention in
optional quantities, and a ?lm-base is coated with the
wherein each of (R)3 and (X)3 stands for a combination
of three monovalent substituents or of monovalent and 20 mixture and then dried.
The ?lm thus processed is stored in a vessel for 2 weeks, '
bivalent substituents. The respective components of
keeping the relative humidity at around 80%. Then the
(R)3 are combined at the 4-, 5- and 6-positions of the
?lm is developed for 10 minutes at 20° C. with a devel
pyrimidine nucleus and the respective components of
oper having the following components.
(X)3 are combined at the 3-, 4- and S-positions of the
pyrazole nucleus of the compound I. And, the mono 25
DEVELOPER
valent substituents of the compound I may be selected
Gramme
from hydrogen, halogen, cyano, hydroxyl, mercapto,
amino, alkyl and atomic groups derivable from them, for
instance. The bivalent‘ ,substituents may be selected, for
example, from trimethylene, tetramethylene and lactone 30
groups. But, the compounds representable by the For
mula I supra in which (R) 3 is a combination of only
hydrogen and alkyl groups have little photographic and
therapeutic activities, and therefore such compounds are
excluded from the scope of this invention.
N-methyl-p-aminophenol sulfate ____________ __
1.5
Hydroquinone
2.5
___________________________ __
Sodium sul?te ____________________________ __ 100.0
Sodium metaborate _______________________ __
2.0
Potassium bromide
0.5
_______________________ __
Water (enough to make the whole volume 1 litre).
The results (relative speed, gamma and fog) are shown
35 1n the following table.
Fresh test
Incubation for 2 weeks
at 40° 0.
Gramme
per tnole
Compounds
of silver
halide
Rela-
tive
speed
2 -
4 - Carbetho
- 5 -
niethylpyrimidxizie
henyl
p
Rela
Gamma
Fog
tive
speed
Gamma
Fog
yrazol - l - yl) - 5 - carbethoxy - 6 -
p
2-(4—Cyano-5-aminopyrazol~1-yl) 4-hydroxy-?-phenylpyrimidinec___ _
0. 4
95
0. 80
0. 07
90
0. 81
0. 3
90
O. 83
0. G6
85
0. 80
0. 14
O. 11
0. 3
95
0. 82
0. 07
90
0. 83
0. 13
0. 3
95
0. 83
O. 08
85
0. 2
O. 12
0.3
0. 03
0- 3
90
85
90
0. 81
0. 8O
0. 80
0.07
0. 05
0. 08
90
80
85
0. 81
0. 83
0. 82
0.13
0. 10
0. 0
100
0. 85
0. 07
85
0. 83
0. 30
2 - (4 - Carbethoxy - 5 - methylpyrazol - 1 - yl) - 4 - hydroxy - 5,6 -
trimethylenepyrimidinm.
2 - (4 - Oyano - 5 - aminopyrazol - 1 - yl) - 5 - carbethoxy - 6 - hydroxy-
py'rimid ‘no
,
2 — (3,5 - dimethylpyrazol - l - yl) - 4 - formylhydrazino - 5 - phenyl
pyrimidine
___
2-(3,5dimethylpyrazol-1-yl)-4-mercapto-6~phenylpyrimitline ______ __
2-(3,5-dimethylpyrazol-l—yl)-l—chloro—6-methylpyrimidinc ......... __
None (control).
And, in case the compounds of the Formula I have one
or more hydroxyl groups, they may form tautomeric
isomers, or keto forms. In such a case, they are, of
course, included in the scope of this invention. More
over, in case the compounds of the Formula I form acid
0. 14
In this experiment, “relative speed” is given in the cen
tuple value of the ratio of the speed of the control emul
sion to that of the sample emulsion, Where the speed is
estimated in 10/E (E is the light quantityv required to
produce a density of 0.10 above fog).
Moreover, the compounds of this invention have re
or metallic salts, etc., they also fall into the scope of
this invention.
marktble anti-tubercle activity in vivo as Well as in vitro.
More concretely, the substituents of the compounds of 00 Their minimum concentration for complete inhibition of
the Formula I may, for example, be:
the growth of Mycobacterium tuberculosis H37Rv strain
is about 0.5 to 10 rnicrogramme per millilitre or less on
Kirchner’s medium. The e?ectiveness of the compounds
of this invention bears comparison with that of strepto
65 mycin. And, the acute toxicity of the compounds of this
invention to rats is as low as LD50=5O0—l000 milligram
mes per kilogramme (intraperitoneally), which is vfar less
than that of isonicotinoyl hydrazine. Thus the compounds
of this invention can also he therapeutically usable for the
—COO-alkyl, —COO-alkali metal, —all<yl, —-alkenyl, 70 treatment of tubercule diseases of human beings by oral
—alkynyl, —aryl, —aralkyl, —alkylene—.
administration.
The compounds of this invention have remarkable
The compounds of this invention can be conveniently
4%
alcohol, or the solvent generally employed in the above
process, the products automatically separate out ‘from the
reaction system when such a solvent is employed. If the
synthesized by condensation between Z-hydrazinopyrirn
idine having a desired substituent or substituents at 4-,
5- and/or 6~positions as represented by the Formula II
compounds I do not separate completely, “water may be
added in a large portion to the reaction mixture or the sol
vent may be removed by distillation to secure the separa
tion.
The substituent or substituents of the compounds I
thus obtained can, if desired, be converted into other sub
wherein (R)3 stands for a combination of atoms and/or
stituent or substituents in the per se known manner or
atomic groups similar to (R)3 in the desired compound I
supra, and an ethylene derivative representable by the
Formula III
manners. For example, a carboxyl group can be con
verted into its ester or amide or alkali or alkaline earth
metal salt, an alkoxycarbonyl group can be hydrolyzed
A
into a carboxyl group by the use of an alkali or acid, a
/
X
15 hydroxyl group can be converted into halogen atom by
Y
the action of e.g. phosphorous oxyhalide, halogen atom
into thiouronium salt by thiourea, thiouronium salt into
mercapto group by hydrolysis, halogen atom into a sub
stituted amino group by the reaction with secondary or
(III)
wherein R’ stands for hydrogen or an alkyl group, X and
Y stand for an atom or'atomic group similar to the com
ponents of (X)3 in the Formula I supra, and A stands for
an acyl, carbalkoxyl or cyano group. In the’?rst step of
this condensation, the hydrazine group of II is con
primary amines.
,
The compounds I may be puri?ed by recrystallization
from eg water, alcohols, benzene or ligroin. Or, the
densed with the OR’ of III eliminating water or alcohol
puri?cation may be effected by distillation under reduced
to form an intermediate representable by the Formula
pressure, in case the compounds I have considerably low
IV or its isomer V
25 boiling point.
Most of the puri?ed compounds I are colourless or pale
coloured crystals, and some of the puri?ed compounds I
occur as liquid.
And, the detailed description on each
compound is given in the examples described later.
The following examples set forth presently-preferred
representative embodiments of the invention. In these
examples, parts and percents are given by weight unless
otherwise speci?ed. The relationship between parts by
Weight and parts by volume is the same vas that between
35 grammes and millilitres. And, the temperatures are all
uncorrected. All of the products were con?rmed by ele
mentary analysis on carbon-, hydrogen-and nitrogen-con
Then, in the second step, further condensation occurs
tents, etc.
between the imino group (marked with asterisk) of~IV or
Example '1
V and the group A to form the compound I. The inter 40
To
300
parts
by
volume
of water are added 5 parts of 2
mediate'IV or V can rarely be taken out, but the forma
hydrazino-4-amino-5-cyanopyrimidine and 7 parts of ethyl
tion'of the intermediate can not ‘always be perceptible
ethoxymethylenecyanoacetate. After boiling for 30 min
during the course of the reaction. In this reaction, in case
utes, the mixture is cooled. The separated 2-(4-carbeth
A is an acyl group, the substituent at the 5-position of the
. pyrazole nucleus of the compound I becomes hydrocarbon , oxy-S-amino-pyrazol-4-yl)-4-arnino-5 - cyanopyrimidine is
collected. Recrystallation of the product from diluted
radical; e.g. a methyl group is formed from an acetyl
acetic acid gives 5 parts of colourless needles, decomposing
group, 'a propyl group from a butyryl group, a phenyl
at 284° C.
group from a benzoyl group, a tolyl group'from a toluoyl
One of the starting materials of this example, 2-hy
group. In case A is a formyl group, it is, of course, con
drazino-4-amino-S-cyanopyrimidine, was synthesized by
verted into hydrogen atom. And, in case A is a carb
the reaction between 2-methylmercapto-4-amino-5-cyano
alkoxy group, the substituent at the 5-position of pyrazol'e
pyrimidine and hydrazine hydrate. This material is a
nucleus becomes a hydroxyl group, and a cyano group
novel compound.
changes into an amino group.
Example 2
In the compound III, if R’ is hydrogen atom, the com
pound can become a‘keto-form compound, since it has a '
hydroxyl group adjacent double bond. And, the reaction
‘of this invention may proceed when the compound II-I
becomes either of keto or enol form.
A
r
3-hydrazino-4-amino-S-cyanopyrimidine and 4.2 parts of
ethyl a-acety-l-?-ethoxyacrylate. The mixture is boiled for
5 minutes, whereupon 2-(4-carbethoxy-5~methylpyrazol
l-yl)-4-amino-S-cyanopyrimidine is produced. After be
60 ing recrystallized from diluted acetic acid, the product
occurs as colourless needles which color and sinter from
about 230° C. and change into a dark red liquid at a
‘ The reaction may be conducted in the presence or ab
sence of a solvent such as water, an aliphatic lower al
cohol, e.g. methyl, ethyl or butyl alcohol, dioxane, ben
zene, toluene, ligroin and their mixtures. The reaction is,
in general, effected at a mild condition.
To 300 parts by volume of Water are added 3 parts of
In most cases,
the reaction proceeds smoothly at around the boiling point
of the solvent employed, which is generally around 100°
C. Of course, the reaction may be carried out without
using any solvent, if desired. In such a case too, the reac—
tion conditions are not necessarily so drastic. The reac
tion generally requires rather short time, e.g. ranging
temperature over 248° C. The yield is 4.6 parts.
Example 3
Three parts of 2-hydrazino-4-amino-S-cyanoPyrimidine
is heated together with 100 parts by volume of 50%
(volume) ethyl alcohol. To the mixture is added 5.2
parts of ethyl a-benzoyl-?-ethoxyacrylate, and boiled for
15 minutes. After adding 100 parts by volume of water, the
hot mixture ‘is cooled to separate 2-(4-carbethoxy-5-phen
ylpyrazol-l-yl)-4-amino-S - cyanopyrimidine. Recrystal
lizations of the product ?rst from diluted ethyl alcohol,
then from ethylene chloride give 6 parts of colourless
from several minutes to one hour.
As most of the compounds I are hardly soluble in water, 75 needless, M.P. 20l~202° C.
3,040,047
5
ii
Example 4
A mixture composed of 0.7 part of 2-hydrazin0-4-arnino
S-cyanopyrimidine, 0.7 part of ethoxymethylenemalononi
bethoxypyrimidine as colourless ?ne crystals, M.P. 2'63
265 ° C.
Example 11
trile and 30 parts by volume of water is boiled for one
To 50 parts by volume of alcohol are added 3 parts of
Ch 2-hydrazino-4-hydroxy-5-carbethoxypyrimidine and
hour. After being cooled, the product separated is recrys
tallized from 70% formic acid to give 0.6 part of 2-(4
1.6
parts of acetylacetone. After boiling for one hour, the
cyano-S-arninopyrazol-l-yl)-4-amino-5 - cyanaopyrimidine
mixture is concentrated under reduced pressure. To the
residue 20 parts by volume of Water is added to separate
as colourless ?ne crystals, M.P.>360° C.
a product. Recrystallization from diluted ethyl alcohol
Example 5
10 of the product gives 3.2 parts of 2-(3,5-dimethylpyrazol
To a mixture of 6 parts of 2-hydrazino-4-amino-5
parts of 2-(3,5-dimethylpyrazol-1-yl)-4-amiuo-5 - cyano
l-yl)-4-hydroxy-5-carbethoxypyrimidine as colourless
prisms, M.P. 169-171° C.
Example 12
To va mixture composed of 80 parts by volume of water
and 10 parts by volume of alcohol are added 3 parts of
pyrimidine, as colourless plates which decompose at 262°
C.
2-hydrazino-4-methyl-5-carbethoxypyrimidine and 3 parts
of ethyl a-acetyl-B-ethoxyacrylate. The mixture is boiled
Example 6
for 1-5 minutes to separate 2-(4-carbethoxy-5-methylpyra
zol-l-yl)~4-methyl-5-carbethoxypyrimidine whose recrys
tallization from ligroin gives 4.3 parts of colourless
cyanopyn'midine and 6 parts of acetylacetone is added 150
parts by volume of water. After boiling the mixture for
15 minutes, the separated product, is ?ltered. Recrystal
lization of -the product from 70% acetic acid gives 6
To a hot solution of 3 parts of 2~hydrazino-4-amino-5
carbethoxypyrimidine in 50 parts by volume of 50%
(volume) ethyl alcohol is added 2.7 parts of ethyl ethoxy
methylenecyanoacetate. The mixture is boiled for 10 min_
needles, M.P. 82-83 ‘‘ C.
2-hydrazino-4-methyl-5-carbethoxypyrimidine, one of
the starting materials, was obtained through a reaction
utes, whereupon 2-(4-carbethoxy-S-aminopyrazol-1-yl)-4
amino-S-carbethoxypyrimidine is produced. Recrystalliza
25
tion from diluted acetic acid of the product gives 3.4 parts
of colourless crystals which decompose at 245-247° C.
2-nitroamino-4-methyl-5-carbethoxypyrimidine
Example 13
2-hydrazino-4-amino-S-carbethoxypyrimidine employed
in this example was obtained by reacting 2-nitroamino-4
30
amino-S-carbethoxypyrimidine with hydrazine hydrate ‘
To a solution of 2 parts of 2-hydrazino-4-methyl-S-car
bethoxypyrimidine in 30 parts by volume of ethyl alcohol
is added 2.6 parts of ethyl a-benzoyl-B-ethoxyacrylate.
The mixture is boiled for 15 minutes and water is added to
(Journal of the Pharmaceutical Society of Japan, vol. 79
(1959), pp. 1174-1182).
Example 7
Three parts of 2-hydrazino-4-amino-5-carbe1;hoxypyrimi_
separate 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4-methyl
S-carbethoxypyrimidine.
The product occurs as colour
less plates, M.P. 90—91.5° C., after recrystallization from
dine is dissolved in 50 parts by volume of 50% (volume)
ethyl alcohol, then 1.7 parts of acetylacetone is further
added. The mixture is boiled for 20 minutes to give 2
(3,5-dimethyl-pyrazol-1-yl) -4-amino-5 - carbethcxypyrimi
between
and hydrazine hydrate ‘as shown in Journal of the Pharma
ceutical Society of Japan, vol. 79 (1959), pp. 1477-1482.
a mixture of ligroin and benzene. The yield is 3.8 parts.
40
dine. Recrystallization of the product from monoethyl
ether of ethyleneglycol gives 3.4 parts of colourless ?ne
needles, M.P. 220-221° C.
Example 14
A mixture composed of 3 parts of Z-hydrazino-4
methyl-S-carbethoxypyrimidine, 2 parts of ethoxymethyl
enemalononitrile and 80 parts by volume of water is boiled
for 15 minutes to give 2-(4-cyano-S-aminopyrazol-l-yl)
4-methyl-S-carbethoxypyrimidine. The product is recrys
tallized from diluted ethyl alcohol to give 3.2 parts of
Example 8
In diluted ethyl alcohol are boiled for 5 minutes 3 parts
_ colourless plates, M.P. 218-220” C.
of 2~hydrazino-4-hydroxy-5-carbethoxypyrimidine and 3
parts of ethyl ethoxymethylcneacetoacetate to give 2-(4
Example 15
A mixture composed of 3 parts of 2-hydrazino-4
carbethoxy - 5 - methylpyrazol - l - yl) - 4 - hydroxy -5 -
carbethoxypyrirnidine. Recrystmlization of the product
from diluted ethyl alcohol gives colourless scales, M.P.
50
methyI-SV-carbethoxypyrimidine, 1.8 parts of acetylacetone
and 80 parts by volume of water is boiled for a while.
207-209° C. The yield is 3.3 parts.
2-hydrazino-4-hydroxy-S-carbethoxypyrimidine, one of
the starting materials, was obtained by reacting Z-nitro
After cooling the mixture, the separated 2-(3,5-dimethyl
pyrazol-l-yl)-4-methyl-5-carbethoxypyrimidine is col
lected. The product is recrystallized from diluted ethyl
amino-4-hydroxy-5-carbethoxypyrimidine with hydrazine
hydrate, see e.g. Journal of the Pharmaceutical Society
of Japan, vol. 79 (1959), pp. 1477-1482.
alcohol to give 4 parts of colourless needles containing
2 moles of water of crystallization. The crystals sinter
from about 70° C. and melt at about 84° C.
Example 9
Example 16
To a mixture of 90 parts by volume of an aqueous
To a hot solution of 7 parts of 2-hydrazino-4-hydroxy (it)
solution of potassium hydroxide (l-normal) and 30 parts
S-carbethoxypyrimidine in 150 parts by volume of water
is added 6 parts of ethyl ethoxymethylenecyanoacetate,
by Volume of ethyl alcohol is added 8 parts of 2-(3,5
and the mixture is boiled for 2 minutes to produce 2-(4
dimethylpyrazol - 1 - yl) - 4 - hydroxy - 5 - carbethoxy
carbethoxy-S-aminopyrazol-1-yl)-4~hydroxy-5 - carbeth
pyrimidine. After being boiled for 30 minutes, the mix
oxypyrimidine. Recrystallization of the product from
diluted acetic acid gives 6 parts of colourless crystals, M.P.
226-227 ° C.
Example 10
A mixture composed of 3.3 parts of 2-hydrazino~4
hydroxy-S-carbethoxypyrimidine, 2.2 parts of ethoxymeth
ylenemalononitrile and 50 parts by volume of water is
boiled for a while. The separated product is recrystal
lized from diluted acetic acid to give 2.4 parts of 2-(4
cyano - 5
-aminopyrazol - 1 - yl) - 4 - hydroxy - 5 - car
' ture is concentrated under reduced pressure to obtain the
potassium salt of 2-(3,S-dimethylpyrazol-l-yl)-4-hydroxy
S-carboxypyrimidine as colourless needles, M.P. >300° C.
A hot aqueous solution of the product is acidi?ed with
hydrochloric acid to separate 2-(3,5-dimethylpyrazol-1
70 yl)-4-hydroxy-5-carboxypyrimidine, as colourless needles,
M.P. 255° C. (decomposition). The yield is 2.3 parts.
Example 17
To a mixture of 30 parts by volume of sodium hydrox
75 ide solution (1 N) and 10 parts by volume of ethyl
a i 040,047
7
8
obtain the sodium salt of 2-(4-carboxy-5-aminopyrazol-1-'
alcohol is added 2.6 parts of 2-(4,5-dimethylpyrazol-1-yl)
4-methyl-S-carbethoxypyrimidine. The mixture is boiled
yl)-4-methyl-6-hydroxypyrimidine (M.P. >300° C., col
ourless ?ne crystals). An aqueous solution of the product
is acidi?ed with hydrochloric acid to obtain 2-(4-carboxy
for 10 minutes, then is concentrated to separate the so
dium salt of 2-(4,5-dimethylpyrazol~l-yl)-4-methyl-5-car
S-aminopyrazol-l-yl) -4-methyl-6-hydroxypyrimidine. This
boxypyrimidine as colourless ?ne crystals, M.P. >300° C.
product occurs as colourless ?ne needles, M.P. 217° C.,
A hot aqueous solution of the sodium salt is acidi?ed with
after recrystallization from diluted acetic acid. The yield
hydrochloric acid to obtain 2-(4,5-dimethylpyrazol-l-yl)
is 5.6 parts.
4-rnethyl-5-carboxypyrimidine. Recrystallization of the
Example 24
product from diluted ethyl alcohol gives 1.8 parts of
10
colourless needles, M.P. 282° C. (decomposition).
A mixture composed of 6 parts of 2-hydrazino-4
methyl-6-hydroxypyrimidine, 5 parts ‘of acetylacetone and
Example 18
100 parts by volume of water is boiled for 10 minutes to
separate a product. Recrystallization of the product from
To a mixture of 14 parts of 2-hydrazino-4-methyl-6
diluted ethyl alcohol gives 7.1 parts of 2~(3,5-dimethyll
hydroxypyrimidine and 18 parts of ethyl ethoxymethyl
enecyanoacetate is added 200 parts by volume of water. 15 pyrazol-l-yl) -4-me-thyl-6=hydroxypyrimidine, as colourless
crystals, M.P. l35—l37° C.
The mixture is boiled for 15 minutes, then allowed to
stand for cooling. Crystals separated are recrystallized
Example 25
from diluted ethyl alcohol to give 22 parts of 2-(4-car
To 100 parts by volume of Water are added 6 parts each
bethoxy - 5 - aminopyrazol - l - yl) - 4 - methyl - 6 ~ hy
of Z-hydrazino-4-phenyl-6-hydroxypyrimidine and ethyl
droxypyrimidine, as colourless needles, M.P. 199.5
200.5° C.
ethoxymethylenecyanoacetate. The mixture is boiled for
10 minutes to produce 2-(4-carbethoxy-S-aminopyrazol
One of the starting materials, 2-hydrazino-5-methyl-6
hydrazinopyrimidine, was obtained by reacting 2-nitro
amino‘4-hydroxypyrimidine with hydrazine hydrate in a
l-yl)-4-phenyl-6-hydroxypyrimidine. Recrystallization of
ceutical Society of Japan, vol. 79 (1959), pp. 1477—1482.
the product from acetic acid gives 8 parts of colourless
scales, M.P. 236-238° C.
One of the starting materials, 2-hydrazino-4-phenyl-6
Example 19
hydroxypyrimidine, is obtained by reacting 2-nitroamino
4-phenyl-6-hydroxypyrimidine with hydrazine hydrate as
similar manner as described in Journal of the Pharma
described in Journal of the Pharmaceutical Society of
To a hot solution of 3 :5 parts of 2-hydrazino-4-methyl
6-hydroxypyrimidine in 90 parts by volume of water is 30 Japan, vol. 79 (1959),pp. 14774482.
added 3.9 parts of ethyl a-acetyl?-ethoxyacrylate. The
Example 26
mixture is boiled for ?ve minutes. When the mixture is
cooled, =2-(4-carbethoxy-5-methylpyrazol-l-yl)-4-methyl
To a hot solution of 2 parts of 2-hydrazino-4-phenyl-6
6-‘1ydroxypyrimidine'is separated. The product is recrys
hydroxypyrimidine in 60 parts by volume of 50% (vol
talized from diluted ethyl alcohol to give 5.5 parts of 35 ume) alochol is added 2.1 parts of ethyl a-acetyLB-ethoxy
acrylate. The mixture is boiled for 10 minutes, then 40
parts by volume of Water is added thereto. After cooling,
the separated crystals are collected. Recrystallization of
colourless needles, M.P. 156.5—158° C.
Example 20
the crystals from diluted ethyl alcohol gives 3 parts of
To a hot solution ‘of 2.1 parts of 2-hydrazino-4-methyl
?-hydroxypyrimidine in 60 parts by volume of 50% (vol
ume) of ethyl alcohol is added 3.8 parts of ethyl oc-bel'l
zoyl-?-ethoxyacrylate. After boiling the mixture for 15
2 - (4 - carbethoxy _ 5 - methylpyrazol-l-yl) - 4 - phenyl
6-hydroxypyrimidine as colourless needles, M.P. 197—
199° C.
2 - (4 - carbethoxy - 5 - phenylpyrazol - 1 - yl) - 4 -methyl
To a hot solution of 3.2 parts of 2-hydrazino-4-phenyl
6-hydroxypyrimidine. The product is recrystallized from
é-hydroxypyrimidine in 100v parts by volume of 50%
(volume) ethyl alcohol is added 4.1 parts of ethyl a-ben
zoyl-?-ethoxyacrylate. The mixture is boiled for 15‘ min
a mixture of ligroin and benzene to obtain 3.9 parts of
colourless needles, M.P. 153-155 ° C.
utes, whereupon 2-(4-carbethoxy-S-phenylpyrazol-l-yl)-4~
Example 21
phenyl-6-hydroxypyrimidine is produced. After recrys
To 100 parts by volume of water are added 7 parts of
tallization from benzene the product melts at 196-198" C.
The yield is 5 parts.
Example 28
2-hydrazino-4-methyl-6-hydroxypyrimidine and 8 parts of
ethoxymethylenemalononitrile. The mixture is boiled for
10 minutes. After cooling the mixture, the product sepa
rated is collected. The product is recrystallized from di
luted ethyl alcohol to give 8 parts of 2-(4-cyano-5-amino
pyrazol-l-yl)-4-niethyl-6-hydroxypyrirnidine, as colourless
long plates, M.P. 260—26l° C.
Example 22
To a hot solution of 1.4 parts of 2-hydrazino-4-methyl
6-hydroxypyrimidine in 30 parts by volume of water is
added a mixture of 1.3 parts of v2-formylcyclohexanone
.
Example 27
minutes, 60 parts by volume of water is added to separate
To 100 parts by volume of Water are added 6 parts of
Z-hydrazino~4~phenyl-6-hydroxypyrimidine and 4 parts of
ethoxymethylenemalononitrile. The mixture is ‘boiled for
10 minutes to separate 2-(4-cyano-5-aminopyrazol-1-y1)
4-phenyl-6~hydroxypyrimidine. The product is recrystal
60
lized from acetic acid to give 7 parts of colourless needles,
M.P. 273—275° C.
Example 29
To a mixture of 70 parts by volume of an aqueous solu
and 5 parts of ethyl alcohol. The mixture is boiled for
15 minutes to separate 2-(4,S-tetramethylenepyrazol-l-yl)
tion of sodium hydroxide (1 N) and 70 parts by volume
of ethyl alcohol is added 8 parts of 2-(4-carbethoxy-5
4-methyl-6-hydroxypyrimidine. The product is recrystal
methylpyrazol-l-yl) - 4 - phenyl - 6 - hydroxypyrimidine.
lized from diluted acetic acid to give 1 part ‘of colourless
long plates, M.P. l78—18l° C.
Example 23
Sevenparts of 2-(4-carbethoxy-S-aminopyrazol-l-yl)
4-rnethyl-6-hydroxypyrimidine is boiled for 30 minutes
with a mixture of 80 parts by volume of an aqueous solu
After ‘being boiled for 30 minutes, the mixture is concen
trated to obtain the sodium salt of 2-(4-carboxy-5-methyl
pyrazol-l-yl)-4-phenyl-6-hydroxypyrimidine, as colourless
70 ?ne crystals, M.P. >300° C. An aqueous solution of this
product is acidi?ed with hydrochloric acid to separate
2-(4-carboxy-S-methylpyrazol-l-yl)-4-phenyl-6 _ hydroxy
pyrimidine. Recrystallization of the product from ethyl
ene glycol monoet'nyl ether gives 4.4 parts of colourless
tion of sodium hydroxide (1 N) and 80 parts by volume of
ethyl alcohol. The reaction mixture is concentrated to 75 ?ne crystals, M.P. 325° C. (decomposition).
3,040,047
9
10
Example 30
To 70 parts by volume of 30% (volume) ethyl alcohol
ethyl alcohol to give 11 parts of 2-(4-carbethoxy-5-amino
pyrazol-l-yl)-4,5-trimethylene - 6 - hydroxypyrimidine as
are added 6 parts of 2-hydrazino-4-phenyl-6-hydroxy
colourless needles, M.P. 183.5—185.5° C.
pyrimidine and 4 parts of acetylacetone. The mixture is
boiled for 30 minutes, and is cooled. The separated sub
stance is recrystallized from diluted ethyl alcohol to give
ylene-G-hydroxypyrimidine, was synthesized from 2-nitro
One of the starting materials, 2-hydrazino-4,5-trimeth
amino-4,5-trimethylene-6~hydroxypyrimidine and hydra
zine hydrate (Journal of the Pharmaceutical Society of
Japan, vol. 79 (1959), pp. 1477-1482).
Example 36
8 parts of 2-(3,5-dimethylpyrazol-1-yl)-4 - phenyl - 6 - hy
droxypyrimidine, as colourless needles, M.P. 150-151° C.
Example 31
10
To a hot solution of 16.6 parts of 2-‘1ydrazino-4,5-tri
(a) A mixture composed of 10.1 parts of Z-hydrazino
methylene-6-hydroxypyrimidine in 500 parts by volume of
4-phenyl-6-hydroxypyrimidine, 8.1 parts of benzoylace
water is added 20.5 parts of ethyl a-acetyl-?-ethoxyacry
tone and 200 parts by volume of 50% (volume) alcohol
late. The mixture is boiled for a While to produce 2-(4
is boiled for 30 minutes. To the mixture is added water,
whereupon (4-phenyl-6-hydroxypyrimidine-2-yl) - hydra 15 canbethoxy-S-methylpyrazol-l-yl) - 4,5 - trimethylene - 6
hydroxypyrimidine. Recrystallization of the product
zone of benzoylacetone is produced. From diluted mono
from diluted ethyl alcohol gives 22.2 parts of colourless
ethyl ether of ethyleneglycol, the product is recrystallized
scales, M.P. 175° C.
to give 14.2 parts of colourless needles, M.P. 184-186° C.
Example 3 7
Four parts of this product is heated in a bath of 200 to
205° C. to obtain 2-(3-methyl-5-phenylpyrazol-1-y1)-4 20
To a boiling solution of 3 parts of 2-hydrazino-4,5-tri
phenyl - 6 -hydroxypyrimidine. Recrystallization of the
methylene-6-hydroxypyrimidine in 100 parts by volume
product from alcohol gives colourless plates which melt
of Water is added a solution of 4.7 parts of ethyl ethoxy
at 178-180° C.
methylenebenzoylacetate in 20 parts by volume of ethyl
(b) A mixture composed of 20.2 parts of Z-hydrazino
alcohol. The mixture is boiled for 20 minutes. After
4-phenyl-6-hydroxypyrimidine and 19.4 parts of benzoyl
cooling, the separated 2-(4-carbethoxy-S-phenylpyrazol-l~
yl)-4,5-trimethylene-6-hydroxypyrimidine is recrystallized
acetone is heated at about 140 to 150° C. for 5 minutes,
then at about 200 to 210° C. for 15 minutes. The prod
from diluted ethyl alcohol to give 3.6 parts of colourless
prisms, M.P. 173-174“ C.
Example 38
pyrazol-l-yl)~4-phenyl-6-hydroxypyrimidine. This prod 30
uct is recrystallized from ethylene chloride, then from
ethyl alcohol to give 25 parts of 2-(3-methyl-5-phenyl
. A mixture com-posed of 7 parts of 2-hydrazino-4,5-tri
uct occurs as colourless plates, M.P. 178-180° C.
methylene-6-hydroxypyrimidine, 7 parts of ethoxymethyl
Example 32
Five parts of 2-hydrazino-4-phenyl-6-hydroxypyrimidine
enemalononitrile and 100 parts by volume of Water is
boiled for 10 minutes, and is cooled. The separated
is admixed with 4 parts of ethyl acetoacetate, and the mix
ture is heated at about 140-150° C. for 5' minutes, further
at about 205-210° C. for 5 minutes to produce 2-(3-meth
crystals are recrystallized from normal butanol to obtain
6 parts of 2-(4-cyano-5-aminopyrazol-l-yl)-4,5-trimethyl
yl-S-hydroxypyrazol-l-yl)-4 - phenyl - 6 - hydroxypyrim—
ene-6-hydroxypyrimidine, as colourless needles, M.P.
277° C.
idine. When recrystallized from acetic acid, the product
Example 39
is obtained as colourless scales decomposing at 271° C. 40
The yield is 3.9 parts.
To a hot solution of 1.6 parts of 2-hydrazino-4,5-tri
methylene-6-hydroxypyrimidine in 50 parts by volume of
Example 33
20% (volume) ethyl alcohol is added a mixture of 1.3
parts of 2-formylcycl0hexanone and 5 parts by volume of
G-hydroxypyrirnidine in 150 parts by volume of Water is 45 ethyl alcohol. After boiling the mixture for a while, the
separated 2-(4,5-teuamethylenepyrazol-l-yl)-4,5-trlmeth
added 2.2 parts of acetylacetone. After the mixture is
ylene - 6 - hydroxypyrimidine is collected. Recrystalliza
boiled for a while, the separated product is recrystallized
tion of the product from diluted ethyl alcohol gives 1.7
from diluted acetic acid to give 3.1 parts of 2-(3,5-di
parts of needle-like crystals, M.P. l70-173° C.
methylpyrazol-1-yl)-4-amino - 6 - hydroxypyrimidine, as
colourless plates, M.P. 266—268° C.
50
Example 40
To a hot solution of 2.8 parts of 2-hydrazino-4-amino
2-hydrazino-4-amino-G-hydroxypyrimidine employed in
To 50 parts by volume of water are added 8 parts of 2
this example is obtained by the reaction between hydra
zine hydrate and 2-nitroamino~4-amino-6-hydroxypyrim
idine synthesized by the condensation of nitroguanidine
and ethyl cyanoacetate.
This material is a novel com
hydrazino-4,5-t1imethylene - 6 - hydroxypyrirnidine and 5
55
pound.
idine, as colourless prisms, M.P. 195-1960 C.
To a solution of 3 parts of 2-(3-methyl-5-phenylpy
Example 41
60
volume of chloroform is added 4 parts of bromine at room
crystallized from diluted ethyl alcohol, then from toluene
to obtain 3.5 parts of 2-(3-methyl-4-bromo-5-phenylpy
phenylpyrazol-l-yl)-4,5-trimethylene - 6 - hydroxypyrim
idine Which is recrystallizable from a mixture of benzene
and ligroin to obtain 5.5 parts of colourless plates, M.P.
154-15 6° C.
razol-l-yl)-4-phenyl - 5 - bromo - 6 - hydroxypyrimidine as
colourless prisms, M.P. 229-231° C.
A mixture composed of 7 parts of 2-hydrazino-4,5~tri
methylene-6-hydroxypyrimidine, 8 parts of ethyl ethoxy
methylenecyanoacetate and 100 parts by volume of Water
is boiled for 10 minutes. After cooling the mixture, the
To a hot solution of 5 parts of 2-hydrazino-4,5-trimeth
ylene-6-hydroxypyrimidine in 100 parts by volume of 50%
(volume) ethyl alcohol is added 5 parts of benzoylacetone.
The mixture is boiled for 20 minutes, and 100 parts by
volume of Water is added to separate 2-(3—methyl-5
temperature. After being left standing overnight, the
mixture is concentrated. To the residue, water is added
and the matter separated is ?ltered. The product is re
Example 35
lized from diluted ethyl alcohol to give 9 parts of 2-(3,5—
dimethylpyrazol-l-yl)-4,5-trimethylene-6 - hydroxypyrim
Example 34
razol-l-yl)-4-phenyl-6-hydroxypyrimidine in 40 parts by
parts of acetylacetone. The mixture is boiled for 5 min
utes and cooled. The product is ?ltered and recrystal
70
Example 42
To 100 parts by volume of water are added 9 parts each
of Z-hydrazino -4,5-tetramethylene-6 - hydroxypyrimidine
and ethyl ethoxymethylenecyanoacetate. The mixture is
boiled for 15 minutes to produce 2-(4-carbethoxy-5-ami
separated substance is recrystallized from 90% (volume) 75 nopyrazol-l-yl) -4,5-tetramethylene-6- hydroxypyrimidine.
3,040,041’
12
1l
Example 49
In 200 parts by volume of 50% (t1olume) ethyl alcohol,
9 parts of 2-hydrazino-4,5~tetramethylene-G-hydroxypy
Recrystallization of the product from diluted ethyl alcohol
gives 12 parts of colourless needles, M.P. 169—171° C.
One of the starting materials, 2-hydrazino-4,5-tetra
methylene-6-hydroxypyrimidine, was synthesized from 2
rirnidine is reacted with 8.1 parts of benzoylacetone for 1
nitroamino-4,5 - tetramethylene-6-hydroxypyrimidine and
hydrazine hydrate (Journal of the Pharmaceutical Society
of Japan, vol. 79 (\1959), pp. 14774482).
Example 43
To a hot solution of ‘6 parts of 2-hydrazino-4,5-tetra
methylene-6-hydroxypyrimidine in 200 parts by volume
hour under boiling. The crystals obtained through evap
oration of the reaction mixture under reduced pressure
are recrystallized from ethylene chloride to obtain 8.8
parts I of 2- ( 3-methyl-5-phenylpyrazol- 1 -yl ) -4,5 -tetrameth
ylene-6-hydroxypyrimidine. The product occurs as col
10 ourless needles, M.P. 197—1'99° C.
Example 50
of Water is added 6.5 parts of ethyl a-acetyl-?-ethoxyacry
late. The mixture is boiled for 110 minutes, whereupon
A mixture or" 84 parts of 2-(3,5-dimethylpyrazol-1-yl)
4-methyl-6-hydroxypyrimidine and 191) parts of phospho
2-(4-carbethoxy - S-rnethylpyrazol-l-yl) - 4,5-tetramethyl
ene-G-hydroxypyrimidine is produced. The product oc
rus oxychloride is boiled for 2 hours. Under reduced
pressure, the mixture is concentrated. The residue is
poured into ice-water. After a while, the solution is neu
tralized with an aqueous ammonia to produce 2-(3,5
curs as colourless needles, M.P. 164—166° C., after re
crystallization from diluted ethyl alcohol. The yield is
7.2 parts.
Example 44
dimethylpyrazol-1-yl)-4 - rnethyl-o-chloropyrimidine.
An
alcoholic solution of the product is ?ltered, then Water is
To a hot solution of 3 parts of 2-hydrazino-4,5-tetra
added thereto, whereupon 50 parts of colourless needles,
M.P. 57° C. is obtained. The yield is 50 parts.
Example 51
A mixture of 83 parts of 2-(3,5-dirnethylpyrazol-1~yl)
4-phenyl-6-hydroxypyrimidine and 260 parts of phospho
methylene-6-hydroxypyrimidine in 80 parts by volume of
50% (volume) of ethyl alcohol is added 4.2 parts of ethyl
a-benzoyl-B-ethoxyacrylate. The mixture is boiled for 15
minutes. After addition of 80 parts by volume of water,
the mixture is allowed to stand to separate crystals. The
product is recrystallized from a mixture of benzene and
rus oxychloride is boiled for 2 hours. The mixture is con
ligroin to obtain ‘4.2 parts of 2-(4-carbethoxy-5-phenyl
centrated under reduced pressure, then the residue is
pyrazol-l-yl)-4,5-tetrarnethylene-6-hydroxypyrimidine, as
‘poured into ice-water. After agitating, the solution is
colourless needles, M.P. ISO-152° C.
30 neutralized with a diluted'aqueous ammonia to produce
2-(3,5-- dimethylpyrazol-d-yl)4-phenyl=6 - chloropyrimi
Example 45
dine. The product is recrystallized from diluted ethyl
To a mixture of 20 parts by volume of an aqueous solu
alcohol, then from ligroin to obtain 79 parts of colourless
tion of sodium hydroxide (1 N) and 20 parts by volume
prisms, M.P. 115-1 17° C.
of ethyl alcohol is added 2 parts of 2-(4-carbethoxy-5
Example 52
A mixture of 48‘parts of 2-(3,5-dimethylpyraz0l-1-yl)
4,5-trimethylenet6-hydroxyprimidine and 80 parts of
arriinopyrazol~l-yl)-4,5 - tetramethylene-6~hydroxypyrim
idine. After being boiled for 40 minutes, the mixture is
concentrated to a little quantity, whereupon the sodium
salt of 2-(4-cmboxy~5eaminopyrazol-l-yl)-4,5-tetrameth
phosphorus oxychloride is boiled for one hour. After the
ylene-6-hydroxypyrirnidine is obtained as colourless ?ne 40. concentration of the solution under reduced pressure, ice
crystals, M.P. >300“ C. A hot aqueous solution of the
pieces are added to the residue. The mixture is kept
product is acidi?ed With hydrochloric acid to separate
standing for a while to obtain .2-(3,5-dimethylpyrazol-l
2-(4-carboxy-5 - aminopyrazol-l-yl) - 4,5-tetramethylene
6-hydroxypyrimidine.
yl)-4,S-trimethylene-G-chloropyrimidine. The product is
Recrystallization of the product
recrystallized from a mixture of benzene and ligroin,
from diluted ethylene glycol monethyl ether gives 1 part ' whereupon 49.5 pants of colourless needles, M.P. 131~
of colourless needles, M.P. 248° C. (decomposition).
132° C., are obtained.
Example 46
Example 53
A mixture composed of 9 parts of 2-hydrazino-i4,5-tetra
‘A mixture of'85 parts of 2-(3,5-dimethylpyrazold-yl)
methylene-?-hydroxypyrimidine, 7 parts of ethoxymethyl 50 4,5-tetramethylene-6-hydroxypyrimidine and 160 parts of
enemalononitrile and 100 parts by volume of water is
boiled for 20 minutes to seperate 2-(4-cyano-5-amino<
phosphorus oxychloride is boiled for 2 hours, and the ex
cess of the phosphorus oxychloride is removed by distillla~
pyrazol-1-yl)-4,‘5 - tetrarnethylene-6 - hydroxypyrimidine.
tion under reduced pressure. Thewresidue is poured into
’ ‘Recrystallization of the product from normal butanol gives
ice-water. After a While, the mixture is extracted With
7.5 parts of colourless needles, M.P. 2615-2635 ° C.
55 benzene. The concentration of the benzene solution gives
Example 47
53 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-tetramethyl
' In 30 parts by volume of water 1.8 parts of Z-hydrazino
ene-S-chloropyrimidine, as colourless needles, M.P. 130
132° C.
4,5-tetramethylene-6-hydroxypyrimidine is heated, and a
Example 54
mixture of 1.3 parts of 2-formylcyclohexanone and 5 parts 60
by volume of ethyl alcohol is added. The mixture is
A mixture composed of 5 parts of 2~(3,5-dirnethylpy
boiled for. 15 minutes, and the separated crystals are re
razol-l-yl)~4,5-trimethylene-6-chloropyrirnidine, 1.8 parts
crystallized from diluted ethyl alcohol to give 2-(4,5-tetra
of thiourea and 40 parts by volume of ethyl alcohol is
methylenepyrazol - »1-yl)-4,5-tetrametl1ylene - 6-hydroxy
boiled for 1 hour. After cooling, the separated S-[2-(3,5
pyrimidine, as colourless prisms, M.P. 17l—l72° C. The 65 dimethylpyrazol - l-yl)-4,5-trimethylenepyrimidin - 6-yl1
yield is 1.3 parts.
thiouronium hydrochloride is collected. Recrystallization
of the product gives 1.6 parts of pale yellow needles which
Example 48
decompose at 207-208” C.
To 50 parts by volume of water are added 8 parts of
Z-hydrazino-4,5-tetramethylene-6~hydroxypyrimidine and 70
6 parts of acetylacetone. The mixture is boiled for 10
minutes to separate 2-(3,5-dirnethylpyrazol-1-yl)-4,5-tetra
methylene-‘6-hydroxypyrimidine. The product is recrystal
lized from a diluted ethyl alcohol to give 8.2 parts of
colourless needles, M.P. l63—165° C.
Example 55
To 50 parts by volume of ethyl alcohol are added 5
parts of 2-(3,S-dimethylpyrazol-l-yl)-4,5-tetramethylene
6-chloropyrimidine and 1.7 parts of thiourea. After boil
ing for 20 minutes, the mixture is allowed to stand to
75 cool. The separated crystals are recrystallized from acetic
3,040,047
13
14
acid to obtain S-[2-(3,5-dimethylpyrazol-l-yl)-4,5-tetra
4,5 - trimethylene - 6 - hydrazinopyrimidine, as colourless
methylenepyrirnidin - '6 - yl] - thiouronium hydrochloride
long plates, M.P. 185—187° C.
Example 62
which occurs as pale yellow needles, M.P. 205° C. (de
composition). The yield is 2.7 parts.
5
Example 56
To a hot solution of 25 parts of 2-(3,5-dimethyl
pyrazol-l-yl)-4,S-tetramethylene-6-chloropyrimidine in a
little quantity of ethyl alcohol is added 15 parts by vol
ume of 80% hydrazine hydrate. After boiling for 5
minutes, the mixture is cooled to separate 2-(3,5-di
To 50 parts by volume of ethyl alcohol are added 10
parts of 2-(3.5-dimethylpyrazol-l-yl)-4-methyl-6-chloro
pyrimidine and 4.2 parts of thiourea. The mixture is
boiled for 4 hours, then allowed to stand to separate pale 10 methylpyrazol-l-yl)-4,5-tetramethylene - 6 - hydrazine
pyrimidine. The product is recrystallized from diluted
yellow crystals ( showing M.P. 196—197° C. after recrystal
ethyl alcohol to give 20 parts of colourless needles, M.P.
lization from normal butanol). The product is boiled
182-183" C.
together with 60 parts by volume of an aqueous solution
Example 63
of potassium hydroxide (1 N), then is acidi?ed with acetic
acid to separate 2-(3,5-dimethylpyrazol-l-yl)44-methyl-6 15 A mixture of 5 parts of 2-(3,S-dimethylpyrazol-l-yl)
mercaptopyrimidine. Recrystallization of the product
from 90% acetic acid gives yellow needles, M.P. 174
175° C. The yield is 1.3 parts.
4-phenyl-6-hydrazinopyrimidine and 35 parts by volume
of 80% formic acid is boiled for 22 hours and then con
centrated. The residue is recrystallized from diluted
acetic acid to give 1.7 parts of 2-(3,5-dimethylpyrazol-1
20 yl)-4-phenyl-6-formylhydrazinopyrimidine which occurs
Example 57
A mixture composed of 10 parts of 2-(3,5-dimethyl
pyrazol-l-yl)~4-phenyl-6-chloropyrimidine, 3.2 parts of
thiourea and 50 parts by volume of ethyl alcohol is boiled
as colourless needles, M.P. 245-246" C.
Example 64
for 6 hours. The mixture is concentrated until its volume
becomes about a half, then a large quantity of Water is
In an autoclave, a mixture of 10 parts of .2-(3,5-di—
met'hylpyrazol-l-yl)-4-methyl-6-chloropy1imidine and 33
parts by volume of 33% aqueous solution of dimethyl
added. After being left standing for a while, the sep
arated product is collected. Recrystallization of the prod
uct from pyridine, then from normal butanol gives 2 parts
of 2-(3,5 - dimethylpyrazol - l-yl)-4-.phenyl-6 - mercapto
amine is heated for 1 hour at 98 to 102° C. After being
cooled, the mixture is extracted with ether. The ethereal
solution is concentrated to obtain 2-(3,5-dimethyl
pyrimidine, as yellow needles, M.P. 174-175 ° C.
pyrazol-l-yl)-4-methyl - 6 - dimethylaminopyrimidine.
The product is recrystallized from ligroin to give 7.2
Example 58
parts of needle-like crystals, M.P. 87-880 C.
To 18 parts by volume of an aqueous solution of po
tassium hydroxide (1 N) is added 1.5 parts of S-[2-(3,5
dimethylpyrazol-l-yl) - 4,5 - tetramethylenepyrimidin-6
35
Example 65
A mixture composed of 10 parts of 2-(3,5-dimethyl
pyrazol-l-yl)-4-methy1-6-chloropyrimidine, 6.1 parts of
yl]-thiouronium hydrochloride. After boiling for 1.5
diethanolamine and 6.2 parts by volume of anhydrous
hours, the mixture is acidi?ed with acetic acid to separate
2-(3,5-dimethylpyrazol-l-yl)-4,5-trimethylene - 6 - mer
potassium carbonate is heated ‘at about 180—190° C. for
captopyrimidine. Recrystallization of the product from
acetic acid gives 0.25 part of pale yellow needles which
ume of water is added to separate 2-(3,5-dimethyl
20 minutes. After cooling the mixture, 60 parts by vol
pyrazol-l-yl) - 4 - methyl-6-bis~(?-hydroxyethyl) -,amino
decompose at 217° C.
pyrimidine. The product is recrystallized from water to
give 4 parts of colourless needles, M.P. 75-77° C.
Example 59
Fifty parts by volume of aqueous potassium hydroxide
Example 66
solution (1 N) and 2.7 parts of S-[2-(3,5-dimethy1
A mixture composed of ‘10 parts of 2-(3,5-dimethyl
pyrazol-l-yl)-4,S-tetramethylenepyrimidin - 6 - y1]-thio
uronium hydrochloride are boiled ‘for 3 hours, then the
mixture is ?ltered. The ?ltrate is acidi?ed with acetic
acid. The crystals separated are recrystallized from _
acetic acid to give 1 part of 2-(3,5-dimethylpyrazol-1
yl)-4,5-tetramethylene-6-mercaptopyrimidine as pale yel
low needles, M.P. l99~200° C.
Example 60
To a mixture of 13 parts by volume of 80% hydrazine
hydrate and 20 parts by volume of ethyl alcohol is added
20 parts of 2-(3,5-dimethylpyrazol-1-yl)-4-phenyl-6
chloropyrimidine.
pyrazol-l-yl) -4-methyl-6-chloropyrimidine, 19.1 parts of
piperidine and 45 parts by volume of water is boiled for
1 hour. After cooling, the mixture is extracted with
ether, and from the ethereal layer, the solvent is removed.
The residue is distilled under reduced pressure to obtain
2-(3,5-dimethylpyrazol-1-yl)-4-methyl - 6 - piperidino
pyrimidine, B.P. 200-205” C. (0.3 millimeter Hg). The
yield is 7.4 parts.
55
Having thus disclosed the invention what is claimed is:
As soon as the mixture is heated, it
gives 2-(3,5-dimethylpyrazol-l-yl)-4-phenyl-6-hydrazino~
1. 2-(4-carbethoxy-5-aminopyrazol-l-yl) - 4 - methyl
6-hydroxypyrimidine.
2. 2-(4-carbethoxy-S-methylpyrazol-1-yl) - 4 - methyl
6-hydroxypyrimidine.
3. 2-(4-carbethoxy-S-phenylpyrazol-l-yl) - 4 - methyl
pyrimidine. Recrystallization of the product from nor
mal butyl alcohol gives 13 parts of colourless needles,
6-hydroxypyrimidine.
M.P. 206—207° C.
droxypyrimidine.
Example 61
5. 2-(4,5-tetramethylenepyrazol-l-yl) - 4 - methyl-6
To a mixture of 12 parts by volume of 80% hydrazine
hydrate and 12 parts by volume of ethyl alcohol is added
10 parts of 2-(3,5-dimethylpyrazol-1-yl)-4,5-trimethyl
ene-6-chloropyrimidine. After boiling the mixture for 30
minutes, 50 parts by volume of water is added.
4. 2-(4-cyano-5-aminopyrazol~l-yl) -4-methyl - 6 - hy
The
product separated is recrystallized from diluted ethyl al 70
cohol to give 7.8 parts of 2-(3,5-dimethylpyrazol-1-yl)
hydroxypyrimidine.
6. 2-(4-carboxy-5-aminopyrazol-l-yl) - 4 - methyl-6
hydroxypyrimidine.
7. 2-(3,5-dimethylpyrazol - 1 - yl) - 4 - methyl - 6 - hy
droxypyrimidine.
8. A sodium salt of the compound claimed in claim 6.
No references cited.
UNITED STATES PATENT OFFICE
‘CERTIFICATE OF CORRECTION
Patent No. 3,040,047
June 199 1962
Kenzo Sirakawa
i
* It is hereby certified that‘ error appeazce in the above numbered pat.
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 1, line 10, for "the apeutic" read -— therapeutic -—;
column 4, line 46, for "Recrystallation" read —— Recrystallization
——; line 56, for "3—hydrazino—" read —— 2-hydrazino- -—; column
5, line 7, for "-cyanoapyrimidine" read -—- -cyanopyrimidine ——;
column 7, line 29I for "3:5" read —- 3.5 —-; column 8‘ line 36u
for "alochol"
read
-— alcohol -—.
Signed and sealed this 20th day of November 1962.
(SEAL)
meat:
ERNEST W. SWIDER
“testing Officer
DAVID L. LADD
Commissioner of Patents
Документ
Категория
Без категории
Просмотров
0
Размер файла
1 168 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа