Note: Descriptions are shown in the official language in which they were submitted.
CA 02278179 1999-07-16
WO 98/31672 PCT/US98I00592
- 1 -
MST80D OF PRODUCING N,N'-DIAZOLE COMPO1?NDs
DESCRIPTION OP' THE INVBNTrrna
. The present invention relates to a method of producing
N,N'-diazole compounds selected from the group consisting
of~
N,N'-carbonyldiazole, N,N-carbonothioicdiazole, and N,N'-
thionyldiazole compounds. More particularly, the present
invention relates to a method of preparing such N,N'-diazole
compounds by reacting a 1-unsubstituted 1H-azole compound
with
a dihalide compound, e.g., phosgene, in the presence of
an
inert solvent and an organic base, e.g., a tertiary amine.
In
accordanc-rP with an embodiment of the method of the present
invention, the molar ratio of the 1-unsubstituted 1H-azole
to
the dihalide compound need not exceed 2:1. N,N'-diazole
IS compounds prepared in accordance with the present invention
have been found to have acceptable color.
N,N'-diazole compounds, such as N,N'-carbonyldiazole,
N,N'-carbonothioicdiazole and N,N'-thionyldiazole compounds,
are useful as reagents for introducing carbonyl,
carbonothioic, thionyl or azole groups into other compounds
without formation of a hydrohalide acid co-product. They
are
more convenient to handle and easier to measure than dihalide
compounds, such as phosgene. They are useful in reactions
involving dehydration, ester formation and isocyanate
formation, and as enzyme and protein binding agents. Further,
these diazole compounds are also useful as intermediates
for
synthesizing medicines and agricultural chemicals. For
example, U.S. Patent No. 4,237,709 describes the use of
N,N'-
carbonyldiazole compounds in the preparation of antibiotics
and peptides.
It is known that N,N'-carbonyldiazole, N,N'-
carbonothioicdiazole and N,N'-thionyldiazole compounds can
CA 02278179 1999-07-16
_ WO 98/31672 PCT/US98/00592
- 2 -
each typically be produced by a method involving the reaction
of a 1-unsubstituted 1H-azole compound and a dihalide compound
such as, respectively phosgene, carbonothioic dichloride and
thionyl chloride, each in a molar ratio of 4:1. See for
example, W. Forest, Newer M_rhods of p pa ari~o nr~~
~j,strv, Volume V, Academic Press, New York (1968) pages 61
- 108. For example, in the case of N,N'-carbonyldiazole
compounds, and more specifically N,N'-carbonyldiimidazole,
such a prior art method may be represented by the following
general scheme I.
General Scheme I
O Solvent
4 x N~NH
C1 C1
O
N~N"N~N HN~NH C1
+ 2x
In the above general scheme I, twice as many moles of the 1-
unsubstituted iH-azole compound are used relative to the
number of moles of the desired N,N'-carbonyldiazole compound
produced. An excess of the 1-unsubstituted 1H-azole compound
is required to form a salt with the co-product hydrochloric
acid generated in the reaction. Further, in general scheme I
the N,N'-carbonyldiazole compound and 1-unsubstituted iH-azole
hydrochloride salt compound precipitate together out of
solution at the same time, thus requiring the separation of
two intimately mixed solids. Such a separation can hP a
multi-step process requiring extra time and materials.
The method represented by general scheme I can be
expensive in that: (a) only half of the 1-unsubstituted 1H-
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WO 98131672 pCT/US981~00592
- 3 -
azole compound present at the beginning of the reaction is
used to form the desired N,N~-carbonyldiazole; and (b) the
se aration of the
p precipitated N,N~-carbonyldiazole compound
from the precipitated 1-unsubstituted 1H-azole hydrohalide
salt is typically a multi-step process requiring additional
time and materials. General scheme I is applicative also to
the production of N,N~-carbonothioicdiimidiazole and N,N~-
thionyldimidiazole compounds if the appropriate dihalide
compound, e.g., carbonothioic dichloride or thionyl chloride,
is substituted respectively for phosgene.
United States Patents 3,991,071, 4,080,462 and 4,154,945
disclose a method of preparing carbonylbisimidazole which
includes reacting, in an inert solvent, phosgene and 1H-
imidazole in the presence of an acid-binding agent. The acid-
IS binding agent is described as being a tertiary amine such as
triethylamine, pyridine or excess imidazole. Preferred levels
of the acid-binding agent and molar ratios of the acid-binding
agent to the iH-imidazole are not disclosed in United States
Patents 3,991,071, 4,080,462 or 4,154,945.
United States Patent 5,552,554 discloses a process of
preparing a carbonylating agent, such as N,N~-
carbonyldiimidazole or N,N'-carbonyldi(1,2,4-triazole), in-
situ by reacting, in the presence of a hydroxyl functional
ester and an inert solvent, phosgene and one of 1H-imidazole
or iH-1,2,4-triazole and an organic base selected from the
group consisting of trialkylamine, pyridine, picoline or other
substituted pyridine. Preferred molar ratios of the organic
base to the iH-imidazole or 1H-1,2,4,-triazole are not
disclosed in Ur~ited States Patent 5,552,554. Examples 2, 5
and 11 in columns 7, 8 and 10 respectively of United States
Patent 5,552,554 describe in-situ preparations of N,N~-
diazoles wherein the molar ratio of the organic base to 1H-
CA 02278179 1999-07-16
~a
" . ,~
eee en-
a
. .. .> ~ s n ~
- 4 -
azole compound is in each case greater than 1:1 when the molar
ratio of 1-unsubstituted 1H-azole compound to phosgene is less
than 2:1.
It has been observed that discolored, e.g., brown, N,N'-
diazole compounds can result from the reaction, in an inert
solvent, of a 1-unsubstituted 1H-azole compound, e.g., 1H-
imidazole, and an excess of a dihalide compound, e.g.,
phosgene, in the presence of an excess of an organic base such
as a tertiary amine. The discoloration has been observed to
occur in particular when the molar ratio of the organic base
to the 1-unsubstituted 1H-azole compound is greater than 1:1
while at the same time the molar ratio of the 1-unsubstituted
1H-azole compound to the dihalide compound is less than 2:1.
It would be desirable to have a method of producing N,N'-
diazole compounds having a minimum of discoloration, such as
N,N'-carbonyldiazole, N,N'-carbonothioicdiazole and N,N'-
thionyldiazole compounds, that is more efficient in terms of
the utilization of starting materials, and the process of
isolating the desired product.
It has now been discovered that N,N'-diazole compounds,
such as N,N'-carbonyldiazole compounds, can be produced by
reacting a 1-unsubstituted 1H-azole compound and a dihalide
compound, e.g., phosgene, in a molar ratio that need not
exceed 2:1. It has further been discovered that that N,N'-
carbonyldiazole compounds produced in accordance with the
present invention have a minimum of discoloration.
In accordance with the present invention, there is
provided an improved method of producing N,N'-diazole compound
selected from the group consisting of N,N'-carbonyldiazole,
N,N'-carbonothioicdiazole, and N,N'-thionyldiazole compounds,
comprising reacting in an inert solvent and in the presence of
a tertiary amine selected from the group consisting of
AMEiV~0E0 SHEET
-_i f. ..
REPLACEMENT PAGE
CA 02278179 1999-07-16
- 5 -
tri(alkyl)amines, wherein each alkyl group contains up to 12
carbon atoms, excluding alkyl groups containing 1 or 2 carbon
atoms, and tribenzylamine, a 1-unsubstituted 1H-azole compound
represented by the following general formula I:
I
Xl
X ;~ \N-H
~C=X3
R2
wherein X1, XZ and X3 are independently CR1 or nitrogen provided
that at least one of X1, X2 and X3 is nitrogen, R1 and Rz are
independently hydrogen, halogen such as chlorine and bromine,
C1 - C6 alkyl, phenyl, C1 - Cs alkyl substituted phenyl, halogen
substituted phenyl, C1 - C6 alkyl and halogen substituted
phenyl, or when X3 is CR1, R1 and R2 may together may form a
fused ring having 4 to 6 carbon atoms inclusive of the two
carbon atoms in the 1-unsubstituted 1H-azole ring through
which R1 and Rz are connected; with a dihalide compound
selected from a member of the group consisting of:
Z 0
i
Y-C Y and Y-S-Y
wherein Z is oxygen or sulfur, and Y is independently
fluorine, chlorine or bromine, preferably chlorine.
The molar ratio of the 1-unsubstituted 1H-azole compound
to the dihalide compound can vary from 1.7:1 to 2.3:1,
preferably from 1.8:1 to 2:1, and more preferably from 1.9:1
to 2:1. The tertiary amine is soluble in the inert solvent,
has a basicity greater than that of the 1-unsubstituted 1H-
azole compound, and forms a hydrohalide salt that is soluble
in the inert solvent. The molar ratio of the tertiary amine
to the 1-unsubstituted 1H-azole compound is 1:1 when the molar
AMEPiDED SHEET
- REPLACEMENT PAGE
CA 02278179 1999-07-16
,~~ ,. ( ,
. . . .. , ,
r,
,. . ..". ., , ~a ..'
- 6 -
ratio of the 1-unsubstituted 1H-azola compound to the dihalide
compound is less than 2:1.
DETAILED DESCRIPTION OF THE INVENTION
The 1-unsubstituted 1H-azole compounds useful in the
method of the present invention contain only one secondary
amino group which is located in the 1-position of the azole
ring, as described in general formula I above. With reference
to R1 and RZ of general formula I above, by substituted phenyl
is meant C1 - C6 alkyl substituted phenyl, halogen, e.g.,
chlorine and bromine, substituted phenyl or C1 - C6 alkyl and
halogen substituted phenyl. The substituents R1 and RZ are
chosen such that they do not preclude the desired reaction at
the 1-position.
1-unsubstituted 1H-azole compounds described with
reference to general formula I, wherein Xz is nitrogen, and X1
and X3 are each CR'', are commonly referred to as 1-
unsubstituted 1H-imidazoles, or 1H-imidazoles. Examples of
1H-imidazoles useful in the method of the present invention
include, but are not limited to: 1H-imidazole; 1H-4-
methylimidazole; 1H-5-methylimidazole; 1H-4-ethyl-5-
methylimidazole; 1H-2,4-dimethylimidazole; 1H-2-
phenylimidazole; 1H-4-phenylimidazole; 1H-5-phenylimidazole;
1H-2,4,5-triphenylimidazole; 1H-2-methyl-4,5-
diphenylimidazole; 1H-4-bromoimidazole; 1H-5-bromoimidazole;
1H-4-bromo-5-methylimidazole; 1H-4-methyl-5-bromoimidazole;
1H-4-bromo-5-phenylimidazole; 1H-4-phenyl-5-bromoimidazole;
1H-2,4-dibromo-5-methylimidazole; 1H-2,5-dibromo-4-
methylimidazole; and 1H-benzimidazole.
~ME~ED ~E~
REPLACEMENT PAGE -
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wo ~isri rcT~rs9s~oos9i
1-unsubstituted iH-azole compounds described with
reference to general formula I, wherein X1 is nitrogen, and XZ
and X' are CR1 are commonly referred to as 1-unsubstituted 1H-
pyrazoles or 1H-pyrazoles. Examples of iH-pyrazoles useful in
the method of the present invention include, but are not
limited to: 1H-pyrazole; 3,5-dimethyl-1H-pyrozole; and 1H-
indazole.
1-unsubstituted iH-azole compounds described with
reference to general formula I, wherein Xl and XZ are both
nitrogen and X3 is CR1 are commonly referred to as 1-
unsubstituted 1H-1,2,3-triazoles, or iH-1,2,3-triazoles.
Examples of 1H-1,2,3-triazoles useful in the method of the
present invention include, but are not limited to, 1H-1,2,3-
triazole and 1H-1,2,3-benzotriazole.
1-unsubstituted iH-azole compounds described with
reference to general formula I, wherein X2 and X3 are both
nitrogen, and Xl is CR1 are commonly referred to as 1-
unsubstituted 1H-1,2,4-triazoles, or 1H-1,2,4-triazoles.
Examples of 1H-1,2,4-triazoles useful in the method of the
present invention include, but are not limited to, 1H-1,2,4-
triazole and 1H-5-methyl-1,2,4-triazole.
Azole compounds described with reference to general
formula I, wherein Xl, XZ and X3 are each nitrogen are commonly
referred to as tetrazoles. Such tetrazoles can be represented
by two tautomeric forms, 1H-tetrazole and 2H-tetrazole.
Conversion between the two tautomeric forms is thought to
occur through a proton shift. While general formula I is
representative of tetrazoles having the 2H-tetrazole
tautomeric form, it is also meant to be representative of
tetrazoles having the more prevalent 1H-tetrazole tautomeric
form. Examples of tetrazoles useful in the method of the
present invention include, but are not limited to, 1H-
CA 02278179 1999-07-16
p. Y~ ~ f !i i
~ _ v 1 ~~
.. . ~.~ f,. ~ r ~~~ AO
-
tetrazole, 1H-5-methyl-tetrazole, and
1H-5-phenyl-tetrazole.
Preferred 1-unsubstituted 1H-azole compounds useful in
the method of the present invention include: 1H-imidazole; 1H-
benzimidazole; 1H-pyrazole; 1H-indazole; 1H-1,2,3-triazole;
1H-1,2,3-benzotriazole; and 1H-1,2,4-triazole. A particularly
preferred 1-unsubstituted 1H-azole compound is 1H-imidazole.
A single 1-unsubstituted 1H-azole compound or a mixture of
such compounds may be used as desired. The use of a single 1-
unsubstituted 1H-azole compound is preferred.
In the method of the present invention a 1-unsubstituted
1H-azole compound is reacted with a dihalide compound, as
described above, to form N,N~-carbonyldiazole, N,N-
carbonothioicdiazole, or N,N'-thionyldiazole compounds. The
molar ratio of the 1-unsubstituted 1H-azole compound to the
dihalide compound may range from 1.7:1 to 2.3:1, preferably
from 1.8:1 to 2:1 and more preferably from 1.9:1 to 2:1.
Since the desired products of the method of present invention
are N,N'-carbonyldiazole, N,N'-carbonothioicdiazole, and N,N'-
thionyldiazole compounds, the molar ratio of the 1-
unsubstituted 1H-azole compound to the dihalide compound is
preferably 2:1. However, it is understood by those skilled in
the art that in large scale practice, i.e., at the commercial
production level, an excess of the dihalide compound, e.g.,
phosgene, may be used. An excess of the dihalide compound)
e.g., phosgene, which can be as high as 20% molar excess, is
often present because of the difficulty in accurately
measuring such dihalide compounds, which are typically in the
gas phase under the reaction conditions employed.
The method of the present invention is conducted in the
presence of an inert solvent as the reaction medium, which is
preferably a solvent for the reactants. By inert, it is meant
A~AE~E~ ~''EET
REPLACEMENT PAGE
i
Y-C Y and Y-S-Y
wherein Z is ox
CA 02278179 1999-07-16
v , . . 1 1 A ' , O ,., ~ , ,
.1~ yA'a1 .1'.
_ g _
a solvent which will not interfere or otherwise preclude the
reaction between the 1-unsubstituted 1H-azole and dihalide
compound. Classes of inert solvents useful in the practice of
the present invention include, but are not limited to,
alkanes, aromatic solvents, halogenated solvents, ethers,
dioxanes, esters, amides and ureas. Halogenated and aromatic
solvents are the preferred classes of inert solvents. More
specific examples of inert solvents which may be used include:
alkanes such as, hexane, heptane and octane; aromatic
solvents, such as toluene, benzene, cumene, mesitylene,
propylbenzene, anisole and xylene; halogenate~i solvents, such
as methylene chloride, chlorobenzene, and 1,2-dichloroethane;
ethers such as, tetrahydrofuran, diethyl ether and 1,2-
dimethoxyethane; dioxanes such as 1,4-dioxane; esters such
as, methyl acetate and ethyl acetate; amides such as, N,N-
dimethylformamide and N-methyl-1,2-pyrrolidine; and ureas
such as 1,3-dimethyl-2-imidaxolidinone. Preferred inert
solvents are the organic solvents methylene chloride and
toluene. A particularly preferred inert solvent is toluene.
In the method of the present invention, the inert solvent is
present in an amount sufficient to solubilize the reactants.
The method of the present invention is conducted also in
the presence of a tertiary amine which has a basicity greater
than that of the 1-unsubstituted 1H-azole compound. The
reaction between'the 1-unsubstituted 1H-azole compound and the
dihalide compound results in the formation of a hydrohalide
acid co-product, e.g., hydrochloric acid in the case of
phosgene. By having a basicity greater than that of the 1-
unsubstituted 1H-azole compound, is meant that the formation
of the hydrohalide salt of the tertiary amine is at least
thermodynamically favored, and preferably also kinetically
favored, over the formation of the 1-unsubstituted 1H-azole
_'~ ~; ~;P~lc.~iiDEv7 ~~LT
:hYt ~~ a
REPLACEMENT PAGE
CA 02278179 1999-07-16
.. . ~ _ .
. : . . . ,. :.
..... .. ...
- 10 -
hydrohalide salt. Hydrohalide salt formation which occurs
predominantly between the tertiary amine and the hydrohalide
acid, allows the 1-unsubstituted 1H-azole compound to be free
to react with the dihalide compound.
Any tertiary amine, or mixture of tertiary amines, which:
has a basicity greater than that of the 1-unsubstituted 1H-
azole compound; will not form a covalent bond with the
dihalide compound; and together with its hydrohalide salt is
soluble in the inert solvent of the reaction mixture, may be
used in the practice of the present invention.
In the practice of the present invention, the molar ratio
of the tertiary amine to the 1-unsubstituted 1H-azole compound
is 1:1, provided the molar ratio of the 1-unsubstituted 1H-
azole compound to the dihalide compound is less than 2:1.
When the molar ratio of the 1-unsubstituted 1H-azole compound
to the dihalide compound is less than 2:1, it is necessary
that the ratio of the tertiary amine to the 1-unsubstituted
1H-azole compound not exceed 1:1, so that formation of a
discolored N,N'-diazole compound is minimized. Without
meaning to be bound by any theory, it is believed that when
for example producing N,N'-carbonyldiimidazole in the presence
of an excess of phosgene, the excess phosgene reacts with the
N,N'-carbonyldiimidazole to form an imidazole carbamoyl
chloride which in the presence of excess tertiary amine, e.g.,
tri(n-butyl)amine, forms as yet uncharacterized dark colored
species.
The presence of the tertiary amine in a molar ratio of
1:1 with the 1-unsubstituted 1H-azole compound, also allows
for the use of only that amount of 1-unsubstituted 1H-azole
compound that is desired to be incorporated through covalent
bond formation into the N,N'-diazole compound product. For
example, in producing N,N'-carbonyldiimidazole by the method
A~~E;~uc~ Si~l~ET
REPLACEMENT PAGE
CA 02278179 1999-07-16
a
.o w a w a f
v v v . s ~~~~ ..
~ a . r ~
.n~ ~~ ~~~ ~~ ~~
- 11 -
of the present invention, the ratio of 1H-imidazole to the
dihalide compound, e.g., phosgene, need not exceed 2:1.
Further, in the practice of the present invention when
the molar ratio of the 1-unsubstituted 1H-azole compound to
the dihalide compound is equal to 2:1, the molar ratio of the
tertiary amine to the 1-unsubstituted 1H-azole compound may be
1:1 or greater. Since the method of the present invention
does not require the presence of an excess of the tertiary
amine, it is preferable under these circumstances that the
molar ratio of the tertiary amine to the 1-unsubstituted 1H-
azole compound be 1:1.
Still further, in the practice of the present invention
when the molar ratio of the 1-unsubstituted 1H-azole compound
to the dihalide compound is greater than 2:1, the molar ratio
of the tertiary amine to the 1-unsubstituted 1H-azole compound
may be 1:1 or greater, or the molar ratio of the tertiary
amine to the dihalide compound may be 2:1 or greater. Since
the method of the present invention does not require the
presence of an excess of the tertiary amine, it is preferable
under these circumstances that the molar ratio of the tertiary
amine to the dihalide compound be 2:1.
In the practice of the present invention, the tertiary
amine and its hydrohalide salt are both soluble in the inert
solvent of the reaction mixture. This allows for the facile
separation of a N,N'-diazole compound that is substantially
free of the hydrohalide salt of the tertiary amine. For
example, N,N'-carbonyldiimidazole produced according to the
method of the present invention may be isolated from the
reaction mixture as a precipitate which is substantially free
of the hydrohalide salt of the tertiary amine. Although a
small amount of the hydrohalide salt of the tertiary amine may
be present in the precipitated N,N'-diazole compound, it is
AME~E~ BEET
~~;~ F r
REPLACEMENT PAGE
CA 02278179 1999-07-16
,. ,. . . "
_ : ..
_,~ " _
' - r ~ s .. , a ..
_ v
- 12 -
understood by those skilled in the art that the purity of the
N,N'-diazole product may be further increased by washing with
additional solvent followed by drying.
Examples of tertiary amines useful in the practice of the
method of the present invention include: tri(aryl)amines,
e.g., wherein each aryl group contains from 6 to 9 carbon
atoms, such as triphenylamine and tribenzylamine;
tri(alkyl)amines, such as, tri(n-propyl)amine,
tri(isopropyl)amine, tri(n-butyl)amine, tripen~ylamine,
trihexylamine, trioctylamine, tridecylamine and
tridodecylamine. Other useful tertiary amines include 1-
methylpyrrolidine, 1-methylpyrrole and 1-methylpiperidine.
The tri(alkyl)amines wherein each alkyl group contains from 1
to 12, e.g., 1 to 6, carbon atoms are preferred, with tri(n-
butyl)amine being particularly preferred.
The 1-unsubstituted 1H-diazole and dihalide compounds may
be charged to the reactor in any order. They may be
introduced concurrently or sequentially. The addition may be
continuous or intermittent. In a preferred embodiment of the
present invention, an appropriate amount of dihalide compound
is slowly introduced into a suitable reaction vessel
containing appropriate amounts of inert solvent, 1-
unsubstituted 1H-diazole compound and tertiary amine.
The temperature at which the reaction of the method of
the present invention is conducted may vary considerably, but
ordinarily is at a temperature at which the solvent is liquid,
and is in the range of from 15°C to 150°C. A temperature of
from 50°C to 80°C is preferred, particularly when the inert
solvent used is toluene.
AME~Ep SHEET
- REPLACEMENT PAGE -
CA 02278179 1999-07-16
wo msn rc~rrt~s9s~oos9z
- 13 -
The pressure at which the reaction of the method of the
present invention is conducted is also subject to wide
variation. Atmospheric and slightly superatmospheric
pressures are generally employed since the reaction is in the
liquid phase, although greater or lesser pressures may be
used. Preferably the pressure at which the reaction is
conducted is atmospheric pressure.
The present invention is more particularly described in
the following examples, which are intended to be illustrative
only, since numerous modifications and variations therein will
be apparent to those skilled in the art. Unless otherwise
specified, all parts and percentages are by weight.
EXAMPLE 1
This example describes the preparation of N,N~-
carbonyldiimidazole by a method approximating that represented
in General Scheme I, using the following enumerated
ingredients.
Ingredients Amount in
grams ~ moles
Cha'~_"g~
toluene 605.5 i 6.6
1H-imidazole 102.2 ~ 1.5
phosgene 40.8 ~ 0.41
Charge 1 was added to a 1 liter four-necked flask fitted
with a motor-driven stir blade, a temperature probe and
heating mantle (both of which were connected to a temperature
feed-back control device), a phosgene and nitrogen inlet tube,
the outlet of which was set above the liquid surface within
the flask, and a cold condenser vented to a caustic scrubber.
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WO 98/31672 PCT/US98/00592
- 14 -
The contents of the flask were then heated to a temperature of
about 65°C under a nitrogen purge. With the nitrogen purge
turned off, Charge 2 was fed into the flask over a period of
20 to 30 minutes, during Which time an exotherm peak of 82°C
was observed. At the completion of the addition of Charge 2,
the contents of the flask were allowed to cool and degas under
a nitrogen purge. At the completion of the degassing phase,
the contents of the flask were heated to 80°C and filtered
under nitrogen through a heated 70 to 100 micron glass fritted
filter. The collected solids were washed two times each with
173 grams of toluene heated to a temperature of 80°C. The
filtrates were collected into a single vessel and allowed to
slowly cool to room temperature with stirring under a nitrogen
purge, during which time white crystals began precipitating
from the filtrate. The precipitate was collected under
nitrogen using a 70 to 100 micron glass fritted filter. The
collected precipitate was washed four times each with 99 grams
of hexane at room temperature to remove excess toluene. The
washed precipitate was then dried with slight heating under a
nitrogen sweep. In all, 28 grams of dried precipitate were
isolated. The percent yield and summary of process steps are
tabulated in Table 1. Analysis of the precipitate is detailed
in Table 2.
EXAMPLE 2
This example describes the preparation of N,N~-
carbonyldiimidazole using tri(n-butyl)amine as the organic
base, wherein the molar ratio of tri(n-butyl)amine to 1H-
imidazole is 1.1:1.0 while the molar ratio of 1H-imidazole to
phosgene is less than 2.0:1Ø
CA 02278179 1999-07-16
_ wo ~»n rcrivs~oosn
- is -
Ingredients Amount in
grams ~ moles
hgr$~
toluene 250 ~ 2.7
tri(n-butyl)amine 103.0 ~ 0.56
1H-imidazole 34.0 ( 0.50
phosgene 25.5 ~ 0.26
Charge 1 was added to a 1 liter four-necked flask fitted
with a motor-driven stir blade, a temperature probe and
heating mantle (both of which were connected to a temperature
feed-back control device), a phosgene and nitrogen inlet tube,
the outlet of which was set above the liquid surface within
the flask, and a cold condenser vented to a caustic scrubber.
The contents of the flask were heated to a temperature of
about 65°C to 70°C under a nitrogen purge. With the nitrogen
purge turned off, Charge 2 was fed into the flask over a
period of about 20 minutes, while maintaining the contents of
the flask at a temperature of 7o°C to 75°C. At the completion
of the addition of Charge 2, the contents of the flask were
slowly cooled with constant stirring to and held at room
temperature during which time a crystalline precipitate was
observed to form. A brown to dark brown colored crystalline
precipitate was separated from the contents of the flask under
nitrogen by filtration using a 70 to 100 micron glass fritted
filter. The collected brown colored precipitate was next
washed three times with 150 grams each of toluene followed by
' two additional washings with 200 grams each of hexane. The
washed precipitate, which was still brown to dark brown in
color, was dried under a nitrogen sweep. In all, 26.5 grams
ii
CA 02278179 1999-07-16
wo m6n rcr~rs9s~oos9z
- 16 -
of dried brown colored precipitate were isolated. The percent
yield and summary of process steps are tabulated in Table 1.
Analysis of the precipitate is detailed in Table 2.
EXAMPLE 3
N,N'-carbonyldiimidazole was prepared in accordance with
the method of the present invention using the following
enumerated ingredients.
Ingredients Amount in
grams ~ moles
har9~
toluene 173 ~ 1.9
tri(n-butyl)amine 92.7 ~ 0.50
iH-imidazole 34.1 ~ 0.50
phosgene 26.0 ~ 0.26
Charge 1 was added to a 500 ml four-necked flask fitted
with a motor driven stir blade, a temperature probe and
heating mantle (both of which were connected to a temperature
feed-back control device), a phosgene and nitrogen inlet tube
the outlet of which was set above the liquid surface within
the flask, and a cold condenser vented to a caustic scrubber.
The contents of the flask were heated to a temperature of
about 65°C to 70°C under a nitrogen purge. With the nitrogen
purge turned off, Charge 2 was fed into the flask over a
period of from 20 to 30 minutes, while maintaining the
contents of the flask at a temperature of 70°C to 75°C. At
the completion of the addition of Charge 2, the contents of
the flask were cooled with constant stirring to 20°C to 25°C
over a period of 1 to 1.5 hours, and then held at that
CA 02278179 1999-07-16
wo msrz rcr~s~s~s92
- 17 -
temperature for an additional 30 to 45 minutes. A white
crystalline precipitate was separated from the contents of the
flask under nitrogen by filtration using a 70 to 100 micron
glass fritted filter. The collected precipitate was next
washed with 346 grams, of toluene and then dried with slight
heating under a nitrogen sweep. In all, 32.5 grams of dried
precipitate was isolated. The percent yield and summary of
process steps are tabulated in Table 1. Analysis of the
precipitate is detailed in Table 2.
Results
Example Example Example
1 2 3
Test
% Yielda 42% 65% 76%
Number of filtrations.b 2 1 1
Grams of 1H-imidazole used
per gram of precipitate
collected.' 3.7 1.3 1.1
a The % Yield was determined using the following equation,
100x(actual grams of precipitate collected / theoretical grams
of product).
b The number of filtrations required from the completion of the
reaction within the flask to the isolation of the final
precipitated product.
' The amount of 1H-imidazole added to the reaction at the
beginning of the reaction over the grams of precipitate
' 35 collected.
The data of Table 1 shows that the method of the present
invention is more efficient than that of the prior art method
represented in General Scheme I, in ternls of producing N,N~-
i i
CA 02278179 1999-07-16
wo ~t6~ rcrrt»sroosn
- 18 -
carbonyldiimidazole. When. compared to the prior art method,
as represented by Example 1, the method of the present
invention, as represented by Example 3, produces a higher
yield of product while using less raw materials, i.e. 1H-
imidazole.
TABLE 2
Analysis of the Isolated Precipitated Product
of Examples 1, 2 and 3.
Results
Example Example Example
1 2 3
Test
Visual appearance White Brown White
% Weight
N,N'-Carbonyldiimidazoled 9B.7% N.D.1 100.7%
(by C02 evolution analysis)
% Weight
N,N'-Carbonyldiimidazolee N.D. N.D. 99.5%
(by G.C. analysis)
% Weight Tri(n-butyl)aminee N.A.Z N.D. 0.08%
(by G.C. analysis)
% Weight Toluenee N.D. N.D. 0.06%
(by G.C. analysis)
% Weight Ionic Chloridef 0.44% N.D. 0.07%
(by AgN03 titration)
N.D. _ Not Determined.
2N. A. = Not Applicable.
d This analysis is based on the reaction: one mole of N,N'-
carbonyldiimidazole + one mole of HZO, in the presence of a
protic acid, will produce two moles of 1H-imidazole and one
mole of COZ .
CA 02278179 1999-07-16
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- 19 -
G.C. (Gas Chromatography. The percent weight of N,N'-
carbonyldiimidazole, tri(n-butyl)amine and toluene present in
the isolated precipitated product of Examples 1 and 2 were
determined here using standard gas chromatographic methods. A
Hewlett Packard 5890E gas chromatograph fitted with a column
having the following specifications, HP-5 30 M x 0.32 mm i.d.
with 0.25 micron film, was used.
The % Weight Ionic Chloride was determined by dissolving a
known amount of the isolated precipitated product in water
acidified with nitric acid, followed by potentiometric
titration of the chloride ion (anion) with AgN03 using a silver
billet electrode to detect the end point. This method is not
specific as to the source of the chloride ion.
The data of Table 2 shows that the method of the present
invention, as represented by Example 3, results in the
production of N,N'-carbonyldiimidazole having a white color
which is essentially equivalent to that of the prior art
method represented by Example 1. The data of Table 2 also
shows the criticality of maintaining the molar ratio of the
tertiary amine to 1H-imidazole at 1:1 when the molar ratio of
1H-imidazole to phosgene is less than 2:1, in comparing
Examples 2 and 3.
Y kMEVOED SHEET
.~~.F r
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