Synthesis of haloformimine compounds

Details Synthesis of haloformimine compounds Synthesis of haloformimine compounds

1999-05-25

2001-03-27

Nazario-Gonzalez, Porfirio (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S254000, C564S256000, C564S258000, C564S259000, C564S268000

Reexamination Certificate

active

06207863

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a method for preparing haloformimine compounds. In particular, the present invention relates to an improved process for halogenation of formimine compounds.
Haloformimine compounds are a commercially important class of organic compounds. Haloformimines are useful as intermediates in the synthesis of a wide variety of organic compounds, such as microbicides, agricultural pesticides and pharmaceutical agents, such as antitumor agents. Certain haloformimines are also known as industrial bactericides.
Haloformimine compounds are typically prepared by reacting a carbonyl compound, such as glyoxylic acid, with an iminating agent, such as hydroxylamine, to form a formimine, followed by the addition of a base to the reaction mixture prior to reacting the formimine with a halogenating agent. For example, U.S. Pat. No. 4,879,314 (Hsu) discloses methods of preparing dihalooformaldoximes that require the addition of sodium bicarbonate to glyoxylic acid oxime before the halogenation step. The yield of dibromoformaldoxime by this method is only 46%. There is no discussion of maintaining the reaction at a specific pH during the halogenation step.
Such methods of preparing haloformimines typically result in low yields and the presence of significant levels of by-products. Much cost and effort must then be spent to purify the resulting haloformimine compound.
There is therefore a continuing need for a method of preparing haloformimine compounds that provides high yields and produces very low amounts of by-products.
SUMMARY OF THE INVENTION
The present invention is directed to the surprising discovery that maintaining a pH between 2 and 5 during the halogenation of formimines greatly increases the yields of haloformimines and greatly decreases the rate of by-product formation.
The present invention is directed to a process for preparing haloformimine compounds of the formula
wherein: X, X
1
═halo; Y═halo, CO
2
R
1
, CX
1
(═NR), C(O)NR
10
R
11
; R═OR
2
, NR
3
R
4
, N═CR
5
R
6
; R
2
═H, C(O)R
7
, (C
1
-C
18
)alkyl, substituted (C
1
-C
18
)alkyl, (C
7
-C
10
)aralkyl, substituted (C
7
-C
10
)aralkyl, phenyl, substituted phenyl; R
3
and R
4
are independently selected from: (C
1
-C
8
)alkyl, substituted (C
1
-C
18
)alkyl, (C
7
-C
10
)aralkyl, substituted (C
7
-C
10
)aralkyl, phenyl, substituted phenyl; R
5
and R
6
are independently selected from: H, halo, CO
2
R
1
, (C
1
-C
18
)alkyl, substituted (C
1
-C
18
)alkyl, (C
7
-C
10
)aralkyl, substituted (C
7
-C
10
)aralkyl, phenyl, substituted phenyl; R
7
═(C
1
-C
18
)alkyl, substituted (C
1
-C
18
)alkyl, (C
7
-C
10
)aralkyl, substituted (C
7
-C
10
)aralkyl, phenyl, substituted phenyl, NR
8
R
9
; and R
1
, R
8
, R
9
, R
10
and R
11
are independently selected from: H, (C
1
-C
18
)alkyl, substituted (C
1
-C
18
)alkyl, (C
7
-C
10
)aralkyl, substituted (C
7
-C
10
)aralkyl, phenyl, substituted phenyl; wherein the process comprises combining a formimine compound with a solvent and sufficient base to provide a mixture having a pH in the range of 2 to 5, followed by reacting said formimine mixture with a halogenating agent to produce a haloformimine compound, while maintaining the pH of the mixture in the range of 2 to 5.
The present invention is also directed to haloformimine compounds prepared according to the process described above.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the following terms shall have the following meanings, unless the context clearly indicates otherwise.
“Alkyl” refers to straight chain, branched or cyclic carbon chain, or any combination thereof “Halo” and “halogen” refer to fluorine, chlorine, bromine and iodine. “Substituted phenyl” means one or more of the hydrogens on the aromatic ring are replaced by another substituent, such as cyano, hydroxy, (C
1
-C
4
)alkyl, nitro, mercapto, (C
1
-C
4
)alkylthio, halo and (C
1
-C
4
)alkoxy. “Substituted alkyl” means one or more of the hydrogens on the carbon chain are replaced by another substituent, such as cyano, hydroxy, (C
1
-C
4
)alkyl, nitro, mercapto, (C
1
-C
4
)alkylthio, halo, carbonyl and (C
1
-C
4
)alkoxy. “Substituted aralkyl” means one or more hydrogens on the aromatic ring or alkyl chain are replaced by another substituent, such as cyano, hydroxy, (C
1
-C
4
)alkyl, nitro, mercapto, (C
1
-C
4
)alkylthio, halo, carbonyl and (C
1
-C
4
)alkoxy.
“Iminating agent” refers to any compound that reacts with an aldehyde to form an amine. “Aldehyde” refers to aldehydes and aldehyde derivatives, such as acetals and hemiacetals. “Halogenating agent” refers to any material that reacts with a formimine to produce a haloformimine.
All amounts are percent by weight (“% wt”), unless otherwise noted. All ranges are inclusive. As used throughout the specification, the following abbreviations are applied: g=gram; C=Centigrade; mL=milliliter; m.p.=melting point; and mol=mole.
The process of the present invention may be used to prepare the haloformimine compounds of formula (I). It is preferred that at least one of X and Y is bromine or chlorine. It is more preferred that the haloformimines are those wherein R═OR
2
. When any of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are alkyl or substituted alkyl, it is preferred that they are (C
1
-C
8
)alkyl or substituted (C
1
-C
8
)alkyl. When R is N═CR
5
R
6
, it is preferred that at least one of R
5
and R
6
is bromine or chlorine.
Suitable haloformimine compounds that can be prepared by the process of the present invention include, but are not limited to: bromochloroformaldoxime; dibromoformaldoxime; dichloroformaldoxime; 2-chloro-2-hydroxyimino acetic acid; 2-chloro-2-hydroxyimino methyl acetate; 2-chloro-2-(acetoxyimino) ethyl acetate; 2-bromo-2-hydroxyimino ethyl acetate; 2-chloro-2-(acetoxyimino) methyl acetate; 2-chloro-2-(benzoyloxyimino) methyl acetate; 2-chloro-2-(N-methylcarbamoyloxyimino) methyl acetate; 2-chloro-2-hydroxyimino benzyl acetate; 2-bromo-2-hydroxyimino benzyl acetate; 2-chloro-2-hydroxyimino phenyl acetate; 2-bromo-2-hydroxyimino phenyl acetate; 2-chloro-2-hydroxyimino octyl acetate; and 2-bromo-2-hydroxyimino octyl acetate.
The formimine compounds useful in the present invention are any that are capable of reacting with a halogenating agent to give the haloformimine compounds of formula (I). In general, the formimine compounds useful in the present invention are those of formula (II)
wherein X
3
and X
4
are independently selected from halogen and hydrogen; Y
2
═H, CO
2
R
1
, CX
4
(═NR), C(O)NR
10
R
11
; R, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, and R
11
are as defined above; provided that at least one of X
3
and X
4
is hydrogen. Preferred formimines are those wherein R═OR
2
.
The formimine compounds useful in the present invention can be prepared by methods well-known in the art. Such methods include the reaction of aldehydes or other carbonyl containing compounds with an iminating agent, such as hydrazine; a substituted hydrazine, such as phenylhydrazine, dimethylhydrazine, and t-butylhydrazine; hydroxylamine; a substituted hydroxylamine, such as methyl hydroxylamine and ethyl hydroxylamine; and hydrazones, such as phenylhydrazone. Monohaloformimines can also be used as formimine compounds in the present invention to prepare dihaloformimines. Such monohaloformimines can be prepared by the process of the present invention or other known methods. For example, Kozikowski et al.,
Journal of Organic Chemistry,
vol. 48, pp 366-372 (1983), discloses methods of preparing monohaloformimine compounds, herein incorporated by reference to the extent it teaches how to prepare such compounds.
In the process of the present invention, a sufficient amount of a base is combined with a formimine compound and a solvent to provide a mixture having a pH in the range of 2 to 5. It is preferred that the pH of the mixture is 2.5 to 4.5, and more preferably in the range of 3.0 to 4.0. Any base that does not react with the formimin

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