CA2278179A1 - Method of producing n,n'-diazole compounds - Google Patents
Method of producing n,n'-diazole compounds Download PDFInfo
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- CA2278179A1 CA2278179A1 CA002278179A CA2278179A CA2278179A1 CA 2278179 A1 CA2278179 A1 CA 2278179A1 CA 002278179 A CA002278179 A CA 002278179A CA 2278179 A CA2278179 A CA 2278179A CA 2278179 A1 CA2278179 A1 CA 2278179A1
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- unsubstituted
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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Abstract
Describes a method of producing N,N'-diazole compounds, e.g. N,N'carbonyldiimidazole, by reacting in an inert solvent, e.g., toluene, a 1unsubstituted 1H-azole compound, e.g., 1H-imidazole, and a dihalide compound, e.g., phosgene, in the presence of an organic base, e.g., a tertiary amine such as tri(n-butyl)amine. The molar ratio of the 1-unsubstituted 1H-azole compound to the dihalide compound may range from 1.7:1 to 2.3:1. The organic base: 1-unsubstituted 1H-azole compound molar ratio is 1:1 when the molar ratio of the 1-unsubstituted 1H-azole compound to the dihalide compound is less than 2:1. The organic base has a basicity greater than that of the 1unsubstituted 1H-azole compound, and along with its hydrohalide salt is soluble in the inert solvent.
Description
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 _ WO 98/31672 PCT/US98/00592 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
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-WO 98131672 pCT/US981~00592 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-~a " . ,~
eee en-a . .. .> ~ s n ~
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 _ WO 98/31672 PCT/US98/00592 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
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-WO 98131672 pCT/US981~00592 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-~a " . ,~
eee en-a . .. .> ~ s n ~
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
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
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 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:
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
,~~ ,. ( , . . . .. , , r, ,. . ..". ., , ~a ..' 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 -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-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 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
.. . ~ _ .
. : . . . ,. :.
..... .. ...
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
a .o w a w a f v v v . s ~~~~ ..
~ a . r ~
.n~ ~~ ~~~ ~~ ~~
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
,. ,. . . "
_ : ..
_,~ " _ ' - r ~ s .. , a ..
_ v 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 -wo msn rc~rrt~s9s~oos9z 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.
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.
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.
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
_ 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 wo m6n rcr~rs9s~oos9z 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.
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 wo msrz rcr~s~s~s92 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 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 wo ~t6~ rcrrt»sroosn 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.
Analysis of the Isolated Precipitated Product of Examples 1, 2 and 3.
Results Example Example Example 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 .
__.. t~
_ . . -:
( . ..~ s ,. ,~~' ' ~ ~ 1~~
v I 1 o. . '!~ 1~ _.
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 REPLACEMENT PAGE
I
Xl X ;~ \N-H
~C=X3 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:
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
,~~ ,. ( , . . . .. , , r, ,. . ..". ., , ~a ..' 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 -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-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 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
.. . ~ _ .
. : . . . ,. :.
..... .. ...
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
a .o w a w a f v v v . s ~~~~ ..
~ a . r ~
.n~ ~~ ~~~ ~~ ~~
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
,. ,. . . "
_ : ..
_,~ " _ ' - r ~ s .. , a ..
_ v 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 -wo msn rc~rrt~s9s~oos9z 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.
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.
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.
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
_ 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 wo m6n rcr~rs9s~oos9z 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.
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 wo msrz rcr~s~s~s92 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 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 wo ~t6~ rcrrt»sroosn 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.
Analysis of the Isolated Precipitated Product of Examples 1, 2 and 3.
Results Example Example Example 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 .
__.. t~
_ . . -:
( . ..~ s ,. ,~~' ' ~ ~ 1~~
v I 1 o. . '!~ 1~ _.
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 REPLACEMENT PAGE
Claims
We claim:
1. 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:
(a) 1-unsubstituted 1H-azole compound represented by the following general formula, wherein X1, X2 and X3 are independently CR1 or nitrogen provided that at least one of X1, X2 and X3 is nitrogen; R1 and R2 are independently hydrogen, halogen, phenyl, C1 - C6 alkyl substituted phenyl, halogen substituted phenyl, C1 - C6 alkyl and halogen substituted phenyl, or when X3 is CR1, R1 and R2 may together 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 R2 are connected; and (b) a dihalide compound selected from a member of the group consisting of wherein Z is oxygen or sulfur, and Y is independently fluorine, chlorine or bromine, the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound being from 1.7:1 to 2.3:1, in the presence of a tertiary amine selected from the group consisting of tri(alkyl)amines, wherein each alkyl group contains up to 12 carbon atoms, excluding alkyl groups containing 1 or 2 carbon atoms, and tribenzylamine, said tertiary amine being soluble in said inert solvent and having a basicity greater than that of said 1-unsubstituted 1H-azole compound, the molar ratio of said tertiary amine to said 1-unsubstituted 1H-azole compound being 1:1 when the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is less than 2:1, thereby producing said N,N'-diazole compound and a hydrohalide salt of said tertiary amine, said hydrohalide salt being soluble in said inert solvent.
2. The method of claim 1 wherein when X3 is CR1 and R1 and R2 together form a fused ring, said fused ring is a benzene ring.
3. The method of claim 1 wherein X1 and X3 are CR1 and X2 is nitrogen.
4. The method of claim 3 wherein R1 and R2 are each hydrogen.
5. The method of claim 1 wherein Y is chlorine or bromine.
6. The method of claim 5 wherein Y is chlorine.
7. The method of claim 6 wherein said dihalide compound is phosgene.
8. The method of claim 1 wherein the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.8:1 to 2:1.
9. The method of claim 8 wherein the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.9:1 to 2:1.
11. The method of claim 1 wherein said tertiary amine is selected from at least one of the group consisting of tri(n-propyl)amine, tri(isopropyl)amine and tri(n-butyl)amine.
12. The method of claim 11 wherein said tertiary amine is tri(n-butyl)amine.
13. The method of claim 1 wherein said inert solvent is selected from the group consisting of aromatic solvents and halogenated solvents.
14. The method of claim 13 wherein said inert solvent is an aromatic solvent.
15. The method of claim 14 wherein said inert solvent is toluene.
16. An improved method of producing N,N'-carbonyldiazole compounds, comprising reacting in an inert solvent:
(a) 1-unsubstituted 1H-azole compound represented by the following general formula, wherein X1, X2 and X3 are independently CR1 or nitrogen provided that at least one of X1, X2 and X3 is nitrogen; R1 and R2 are independently hydrogen, halogen, C1 - C6 alkyl, phenyl, C1 - C6 alkyl substituted phenyl, halogen substituted phenyl, C1 - C6 alkyl and halogen substituted phenyl, or when X3 is CR1, R1 and R2 may together 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 R2 are connected; and (b) a dihalide compound represented by the following general formula, wherein Y is independently fluorine, chlorine or bromine, the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound being from 1.7:1 to 2.3:1, in the presence of a tertiary amine selected from the group consisting of tri(alkyl)amines, wherein each alkyl group contains up to 12 carbon atoms, excluding alkyl groups containing 1 or 2 carbon atoms, and tribenzylamine, said tertiary amine being soluble in said inert solvent and having a basicity greater than that of said 1-unsubstituted 1H-azole compound, the molar ratio of said tertiary amine to said 1-unsubstituted 1H-azole compound being 1:1 when the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is less than 2:1, thereby producing said N,N'-carbonyldiazole compound and a hydrohalide salt of said tertiary amine, said hydrohalide salt being soluble in said inert solvent.
17. The method of claim 16 wherein when X3 is CR1 and R1 and R2 together form a fused ring, said fused ring is a benzene ring.
18. The method of claim 16 wherein X1 and X3 are CR1, X2 is nitrogen, Y is chlorine, and said inert solvent is selected from the group consisting of aromatic solvents and halogenated solvents.
19. The method of claim 18 wherein R1 and R2 are each hydrogen, said tertiary amine is tri(n-butyl)amine, said inert solvent is an aromatic solvent, and the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.8:1 to 2:1.
20. The method of claim 19 wherein said inert solvent is toluene, and the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.9:1 to 2:1.
1. 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:
(a) 1-unsubstituted 1H-azole compound represented by the following general formula, wherein X1, X2 and X3 are independently CR1 or nitrogen provided that at least one of X1, X2 and X3 is nitrogen; R1 and R2 are independently hydrogen, halogen, phenyl, C1 - C6 alkyl substituted phenyl, halogen substituted phenyl, C1 - C6 alkyl and halogen substituted phenyl, or when X3 is CR1, R1 and R2 may together 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 R2 are connected; and (b) a dihalide compound selected from a member of the group consisting of wherein Z is oxygen or sulfur, and Y is independently fluorine, chlorine or bromine, the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound being from 1.7:1 to 2.3:1, in the presence of a tertiary amine selected from the group consisting of tri(alkyl)amines, wherein each alkyl group contains up to 12 carbon atoms, excluding alkyl groups containing 1 or 2 carbon atoms, and tribenzylamine, said tertiary amine being soluble in said inert solvent and having a basicity greater than that of said 1-unsubstituted 1H-azole compound, the molar ratio of said tertiary amine to said 1-unsubstituted 1H-azole compound being 1:1 when the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is less than 2:1, thereby producing said N,N'-diazole compound and a hydrohalide salt of said tertiary amine, said hydrohalide salt being soluble in said inert solvent.
2. The method of claim 1 wherein when X3 is CR1 and R1 and R2 together form a fused ring, said fused ring is a benzene ring.
3. The method of claim 1 wherein X1 and X3 are CR1 and X2 is nitrogen.
4. The method of claim 3 wherein R1 and R2 are each hydrogen.
5. The method of claim 1 wherein Y is chlorine or bromine.
6. The method of claim 5 wherein Y is chlorine.
7. The method of claim 6 wherein said dihalide compound is phosgene.
8. The method of claim 1 wherein the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.8:1 to 2:1.
9. The method of claim 8 wherein the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.9:1 to 2:1.
11. The method of claim 1 wherein said tertiary amine is selected from at least one of the group consisting of tri(n-propyl)amine, tri(isopropyl)amine and tri(n-butyl)amine.
12. The method of claim 11 wherein said tertiary amine is tri(n-butyl)amine.
13. The method of claim 1 wherein said inert solvent is selected from the group consisting of aromatic solvents and halogenated solvents.
14. The method of claim 13 wherein said inert solvent is an aromatic solvent.
15. The method of claim 14 wherein said inert solvent is toluene.
16. An improved method of producing N,N'-carbonyldiazole compounds, comprising reacting in an inert solvent:
(a) 1-unsubstituted 1H-azole compound represented by the following general formula, wherein X1, X2 and X3 are independently CR1 or nitrogen provided that at least one of X1, X2 and X3 is nitrogen; R1 and R2 are independently hydrogen, halogen, C1 - C6 alkyl, phenyl, C1 - C6 alkyl substituted phenyl, halogen substituted phenyl, C1 - C6 alkyl and halogen substituted phenyl, or when X3 is CR1, R1 and R2 may together 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 R2 are connected; and (b) a dihalide compound represented by the following general formula, wherein Y is independently fluorine, chlorine or bromine, the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound being from 1.7:1 to 2.3:1, in the presence of a tertiary amine selected from the group consisting of tri(alkyl)amines, wherein each alkyl group contains up to 12 carbon atoms, excluding alkyl groups containing 1 or 2 carbon atoms, and tribenzylamine, said tertiary amine being soluble in said inert solvent and having a basicity greater than that of said 1-unsubstituted 1H-azole compound, the molar ratio of said tertiary amine to said 1-unsubstituted 1H-azole compound being 1:1 when the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is less than 2:1, thereby producing said N,N'-carbonyldiazole compound and a hydrohalide salt of said tertiary amine, said hydrohalide salt being soluble in said inert solvent.
17. The method of claim 16 wherein when X3 is CR1 and R1 and R2 together form a fused ring, said fused ring is a benzene ring.
18. The method of claim 16 wherein X1 and X3 are CR1, X2 is nitrogen, Y is chlorine, and said inert solvent is selected from the group consisting of aromatic solvents and halogenated solvents.
19. The method of claim 18 wherein R1 and R2 are each hydrogen, said tertiary amine is tri(n-butyl)amine, said inert solvent is an aromatic solvent, and the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.8:1 to 2:1.
20. The method of claim 19 wherein said inert solvent is toluene, and the molar ratio of said 1-unsubstituted 1H-azole compound to said dihalide compound is from 1.9:1 to 2:1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78562697A | 1997-01-17 | 1997-01-17 | |
| US08/785,626 | 1997-01-17 | ||
| PCT/US1998/000592 WO1998031672A1 (en) | 1997-01-17 | 1998-01-09 | Method of producing n,n'-diazole compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2278179A1 true CA2278179A1 (en) | 1998-07-23 |
Family
ID=25136102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002278179A Abandoned CA2278179A1 (en) | 1997-01-17 | 1998-01-09 | Method of producing n,n'-diazole compounds |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1019381A1 (en) |
| CN (1) | CN1109021C (en) |
| CA (1) | CA2278179A1 (en) |
| WO (1) | WO1998031672A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19830556A1 (en) | 1998-07-08 | 2000-01-13 | Basf Ag | Process for the preparation of carbonyldiimidazoles |
| DE19833913A1 (en) | 1998-07-28 | 2000-02-03 | Bayer Ag | Process for the preparation of N, N'-carbonyldiazoles |
| DE10035011A1 (en) | 2000-07-19 | 2002-01-31 | Bayer Ag | Pure N,N'-carbonyl-diazole preparation in high yield, by reacting azolide salt with phosgene in aromatic or ether solvent |
| US6455702B1 (en) * | 2001-05-16 | 2002-09-24 | Aims Fine Chemicals, Inc. | Process for the production of N,N-carbonyl diimidazole |
| DE10359797A1 (en) | 2003-12-19 | 2005-07-21 | Bayer Chemicals Ag | Process for the preparation of N, N'-carbonyldiazoles |
| CN102321026A (en) * | 2011-08-02 | 2012-01-18 | 海门瑞一医药科技有限公司 | The production technique of carbonyl dimidazoles |
| CN104496908A (en) * | 2014-12-24 | 2015-04-08 | 江苏康乐新材料科技有限公司 | Preparation method of carbonyl diimidazole |
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| GB1469772A (en) * | 1973-06-21 | 1977-04-06 | Boots Co Ltd | Fungicidal imidazole derivatives |
| US3997071A (en) * | 1975-08-14 | 1976-12-14 | Laserplane Corporation | Method and apparatus for indicating effective digging depth of a backhoe |
| ES2098901T3 (en) * | 1992-11-13 | 1997-05-01 | Du Pont | PROCEDURE FOR PREPARING 2,4-OXAZOLIDINDIONAS. |
-
1998
- 1998-01-09 CN CN98802686A patent/CN1109021C/en not_active Expired - Fee Related
- 1998-01-09 WO PCT/US1998/000592 patent/WO1998031672A1/en active Application Filing
- 1998-01-09 CA CA002278179A patent/CA2278179A1/en not_active Abandoned
- 1998-01-09 EP EP98901791A patent/EP1019381A1/en not_active Withdrawn
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| Publication number | Publication date |
|---|---|
| WO1998031672A1 (en) | 1998-07-23 |
| EP1019381A1 (en) | 2000-07-19 |
| CN1109021C (en) | 2003-05-21 |
| CN1248247A (en) | 2000-03-22 |
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