Synthesis of 2-cyanoaziridine-1-carboxamide

Details Synthesis of 2-cyanoaziridine-1-carboxamide Synthesis of 2-cyanoaziridine-1-carboxamide

2001-11-26

2002-11-05

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06476236

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for producing an aziridine-1-carboxamide compound, and a process for producing a 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one compound from the aziridine-1-carboxamide compound.
BACKGROUND OF THE INVENTION
Aziridine-1-carboxamide compounds and derivatives thereof have a variety of therapeutical useful activities such as immunostimulant activities. See, for example, U.S. Pat. No. 4,376,731. In addition, aziridine-l-carboxamide compounds are useful intermediates for a wide variety of pharmaceutically active compounds including 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one and its derivatives. See, for example, U.S. Pat. No. 4,083,987. As these references show, 2-cyanoaziridine-1-carboxamide or its derivatives are particularly useful both as a pharmaceutical agents and as intermediates for other pharmaceutically useful compounds.
However, some of the conventional methods for producing 2-cyanoaziridine-1-carboxamide involve generation of a toxic reagent and/or potentially explosive reaction conditions. For example, a synthetic method for producing 2-cyanoaziridine-1-carboxamide as disclosed by Uwe Bicker in East German Patent 110,492 involves passing a hot toxic isocyanic acid into ether which is generated from pyrolysis of cyanuric acid. This is a dangerous procedure because high flammability of ether and generation of a highly toxic blistering agent isocyanic acid. Moreover, due to the dangerous conditions, a special apparatus is generally required for this process.
Therefore, there is a need for a safer alternative method for producing aziridine-1-carboxamide compounds.
SUMMARY OF THE INVENTION
One aspect of the present invention provides a process for producing an aziridine-1-carboxamide of the formula:
said process comprising:
(a) contacting an aziridine of the formula:
 with an isocyanate of the formula R
5
—N═C═O under conditions sufficient to produce an N-acylated aziridine of the formula:
 wherein
each of R
1
, R
2
and R
3
is independently hydrogen or C
1
-C
6
alkyl;
R
4
is cyano, carboxamide or carboxylic acid ester; and
R
5
is a moiety of the formula —C(═O)—R
6
, where R
6
is haloalkyl, and
(b) removing the R
5
group by contacting the N-acylated aziridine with a nucleophilic reagent under conditions sufficient to produce the aziridine-1-carboxamide of Formula I.
Another aspect of the present invention provides a process for producing a 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one of the formula:
from the aziridine-1-carboxamide of Formula I, where R
1
, R
2
and R
3
are those defined above.
DEFINITIONS
“Alkyl” refers to a linear fully-saturated hydrocarbon moiety having one to ten, preferably one to six, carbon atoms or a branched fully saturated hydrocarbon moiety having three to ten, preferably three to six, carbon atoms.
“Carboxamide” refers to a moiety of the formula —C(═O)NR
a
R
b
, where each of R
a
and R
b
is independently hydrogen, alkyl, cycloalkyl, aryl or aralkyl.
“Carboxylic acid ester” refers to a moiety of the formula —C(═O)OR
a
, where R
a
is alkyl, cycloalkyl, aryl or aralkyl.
“Haloalkyl” refers to an alkyl moiety, as defined above, in which one or more hydrogen atoms attached to the carbon backbone have been replaced with one or more halides, preferably chloride, bromide or fluoride. Exemplary haloalkyl groups include mono-, di- and trichloromethyl, mono-, di- and trifluoromethyl and the like.
When referring to a chemical reaction, the terms “treating”, “contacting” and “reacting” are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
As used herein, the terms “those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention provides a process for producing an aziridine-1-carboxamide of the formula:
where R
1
, R
2
, R
3
and R
4
are those defined above. The processes of the present invention comprise contacting an aziridine of the formula:
with an isocyanate of the formula R
5
—N═C═O under conditions sufficient to produce an N-acylated aziridine of the formula:
where R
1
, R
2
, R
3
, R
4
and R
5
are those defined herein.
The processes of the present invention also comprise removing the R
5
group by contacting the N-acylated aziridine of Formula III with a nucleophilic reagent under conditions sufficient to produce the aziridine-1-carboxamide of Formula I.
Preferably, R
5
is haloacetyl. More preferably R
5
is trichloroacetyl, dichloroacetyl, chloroacetyl, trifluoroactetyl or tribromoacetyl. More preferably, R
5
is trichloroacetyl.
Preferably, R
4
is cyano.
In one particular embodiment, R
1
, R
2
and R
3
are hydrogen.
The reaction between the aziridine-1-carboxamide of Formula II and the isocyanate can be conducted at a wide range of reaction temperature in an inert solvent, i.e., a solvent that is non-reactive to the starting materials. Conveniently, however, the reaction is conducted at room temperature or less. Typically, the reaction temperature range is from about −10° C. to about 5° C. Suitable reaction solvents include inert aprotic solvents such as aromatic solvents, e.g., toluene, xylenes, benzene, and the like; ethers, e.g., diethyl ether, tetrahydrofuran, and the like; and halogenated solvents, e.g., dichloromethane, chloroform, and the like.
The resulting N-acylated aziridine of Formula III can be purified prior to removing the R
5
group. Often, however, the N-acylated aziridine of Formula III can be used directly on the next step without further purification.
The R
5
group can be removed from the N-acylated aziridine of Formula III by reacting with a nucleophilic reagent to produce the aziridine-1-carboxamide of Formula I. The reaction is conveniently carried out in an anhydrous alcoholic solvent, such as methanol, ethanol, isopropanol and propanol. Suitable nucleophilic reagents include ammonia and amines. Typically, a mixture of ammonia in methanol is used to remove the R
5
group from the N-acylated aziridine of Formula III. Often, the reaction is conveniently conducted at about 0° C.
The processes of the present invention provide the aziridine-1-carboxamide of Formula I from the aziridine of Formula II in an overall yield of at least about 70%. Preferably, in an overall yield of at least about 75%, and more preferably at least about 80%.
One of the advantages of processes of the present invention includes eliminating a need for potentially flammable conditions because no pyrolysis of any starting material is needed. In addition, processes of the present invention avoid generating toxic isocyanic acid. Furthermore, starting materials for the present invention are commercially available or can be readily prepared without requiring any special apparatus.
When at least one of R
1
, R
2
, R
3
and R
4
is cyano, the aziridine-1-carboxamide of Formula I can be converted to a 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one. For example, 2-cyanoaziridine-1-carboxamide of the formula:
can be prepared using the processes described above. This 2-cyanoaziridine-1-carboxamide of Formula IV can be converted to a 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one of the formula:
by reacting with a base.
The 4-imino-1,3-diazabicyclo[3.1.0]-hexan-2-one of Formula V can exist in one or more tautomeric form as shown below:
Thus, the term “4-imino-1,3-diazabicyclo[3.1.0&rs

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