Preparation of organozinc halides from reactive halogen...

Details Preparation of organozinc halides from reactive halogen... Preparation of organozinc halides from reactive halogen...

2002-12-03

2003-08-05

Nazario-Gonzalez, Porfirio (Department: 1621)

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

Organic compounds

Heavy metal containing

C560S208000, C560S209000, C560S210000, C560S215000, C252S182110

Reexamination Certificate

active

06603034

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing organozinc halides (halogen-zinc compounds, Reformatsky reagents) from reactive halogen compounds and to their use in preparing keto, hydroxyl and amino compounds in carboxylic esters.
2. The Prior Art
The reaction of reactive halogen compounds, in particular of &agr;-halocarbonyl compounds, with electrophilic substrates, for example aldehydes, ketones, imines, nitriles, carboxylic anhydrides, carboxylic chlorides, lactones, orthoformates, formates, epoxides, azirines, aminals and nitrones, in the presence of zinc metal, is known as the Reformatsky reaction. This reaction produces important synthetic building blocks for preparing active pharmaceutical ingredients, scents and crop protecting agents.
The choice of the solvent and the activation of the zinc used or of the entire reaction mixture are of decisive importance for the achievement of good yields and high selectivities and therefore good product purities.
It is known that particularly useful solvents for the Reformatsky reaction include ethers such as diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and in particular tetrahydrofuran. In addition, further solvents which have proven useful include aromatic hydrocarbons or mixtures of the abovementioned ethers with aromatic hydrocarbons, the mixture of tetrahydrofuran with trimethyl borate, and the polar solvents acetonitrile, dimethylformamide, dimethyl-acetamide, dimethyl sulfoxide and hexamethyl-phosphoramide. A review on this subject is contained, for example, in A. Fürstner,
Synthesis
1989, pp. 571-590.
EP-A-562 343 discloses that the reaction of &agr;-bromocarboxylic esters with carbonyl compounds in the presence of zinc in the solvent methylene chloride proceeds with high yields.
The use of the solvents and solvent mixtures mentioned has the following disadvantages:
the water-miscible ethers 1,4-dioxane and tetrahydrofuran and also the water-miscible polar solvents acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoramide dissolve in the aqueous phase on aqueous workup to hydrolyze the zinc compounds and zinc salts formed.
Particularly when applied on the industrial scale, it is necessary, for economic reasons and to reduce the amounts of waste, and to recover the solvents used from the aqueous phase. This recovery may be done for example by extraction or distillation, which is, however, associated with considerable cost and inconvenience.
In addition, when the abovementioned water-miscible solvents are used in the hydrolysis of the reaction mixture, it is customarily necessary to use water-immiscible organic solvents such as ethyl acetate or methyl tert-butyl ether as cosolvents for better phase separation. These solvents have to be recovered and, before reuse, freed of impurities by distillation, which is likewise associated with high cost and inconvenience. When solvent mixtures are used for Reformatsky reactions, the recovery, separation and any purification of the individual solvents used generally entails even more considerable cost and inconvenience.
Furthermore, when diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and tetrahydrofuran are used as solvents for Reformatsky reactions, they tend to form explosive peroxides by autoxidation. This makes their use on the industrial scale dangerous, in particular on repeated use after recovery (danger of accumulation of the explosive components). Or it makes their use more difficult or possible only at great cost and inconvenience.
The use of methylene chloride as solvent, as disclosed by EP-A-562 343, or of other halogenated hydrocarbons as solvents is objectionable for environmental reasons. Accordingly it is to be avoided, on the industrial scale in particular. In addition, many of the abovementioned solvents are expensive which additionally compromises the economic viability of the reaction without recovery of the solvent used.
SU 472127 discloses the reaction of &agr;-bromoketones and zinc with nitrites in ethyl acetate as solvent for preparing &agr;-iminoketones. A mixture of bromoketone (reactive halogen compound) and nitrile (electrophilic substrate) is added to activated zinc, and the organozinc halide formed (Reformatsky reagent) reacts immediately with the substrate. For many substrates, the addition of a mixture of reactive halogen compound and electrophilic substrate described in SU 472127 is highly disadvantageous.
Certain substrates which have further functional groups, for example amino or epoxide functionalities, react as soon as they are combined with the reactive halogen compound (for example &agr;-haloester, &agr;-bromoketone). They form undesired by-products before the actual contact with the zinc takes place. For instance, those skilled in the art are familiar with the reaction of amines or epoxides with reactive halogen compounds, for example from X.-P. Gu, I. Ikeda, M. Okahara,
Bull. Chem. Soc. Jpn
., 1987, 60, pp. 397-398. The process described is accordingly unsuitable for such substrates.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a process which solves the problems known from the prior art.
The present invention provides a process for preparing organozinc halides in solvents, which comprises reacting a reactive halogen compound with zinc in one or more carboxylic esters.
In a preferred embodiment of the invention, the process according to the invention is used to prepare organozinc halides of the general formula (4)
HalZn—R
3
R
4
C—(X)
1
—Y  (4)
by reacting reactive halogen compounds of the general formula (2)
 Hal-R
3
R
4
C—(X)
1
—Y  (2)
with zinc, where
R
1
and R
2
are each hydrogen or an optionally halogen- or cyano-substituted C
1
-C
30
-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by —O—, —CO—, —COO—, —OCO—, or —OCOO—, —S— or —NR
x
— groups and in which one or more methine units may be replaced by —N═ or —P═ groups,
R
3
, R
4
, R
5
, R
6
and R
7
are each hydrogen, halogen or an optionally halogen-substituted or cyano-substituted C
1
-C
30
-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by —O—, —CO—, —COO—, —OCO—, or —OCOO—, —S— or —NR
x
— groups and in which one or more methine units may be replaced by —N═ or —P═ groups,
X is selected from
l is an integer having the value 0 or 1,
Y is CN, (C═O)—Z, (SO
2
)—Z, (P═O) (—Z)
2
, R
5
C═CR
6
R
7
, C≡C—R
5
or an aromatic radical in which one or more methine units in the ring may be replaced by —N═ or —P═ groups and which may carry the heteroatoms —O—, —S— or —NH— in the ring, where the aromatic ring is optionally halogen- or cyano-substituted or is substituted by C
1
-C
30
-hydrocarbon radicals in which one or more nonadjacent methylene units may be replaced by —O—, —CO—, —COO—, —OCO—, or —OCOO—, —S— or —NR
x
— groups,
Z is an optionally halogen-substituted C
1
-C
30
-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by —O—, —CO—, —COO—, —OCO—, —OCOO—, —S— or —NR
x
— groups and in which one or more methine units may be replaced by —N═ or —P═ groups, OH, OR
1
, OSi(R
3
)
3
, NHR
1
or NR
1
R
2
,
Hal is chlorine, bromine or iodine,
R
x
is hydrogen or an optionally halogen-substituted C
1
-C
30
-hydrocarbon radical in which one or more nonadjacent methylene units may be replaced by —O—, —CO—, —COO—, —OCO—, or —OCOO—, —S—, —NH— or —N—C
1
-C
20
-alkyl groups and in which one or more methine units may be replaced by —N═ or —P═ groups, and pairs of radicals selected from R
1
and R
2
, R
3
and R
4
, R
4
and R
5
, R
5
and R
6
, R
6
and R
7
, R
1
and R
3
, R
1
and Y, R
1
and Z, R
3
and Y, R
3
and Z, R
5
and Y, R
5
and Z, where Z may be a direct bond, may each be linked to each other.
The invention further provides the use for preparing keto, hydroxyl and amino compounds of organozinc halides obtained in a first step f

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