HK1020570B

HK1020570B - Processes for preparing 3- (1-hydroxyphenyl-1-alkoximinomethyl)dioxazines

Info

Publication number: HK1020570B
Application number: HK99105542.4A
Authority: HK
Inventors: H‧盖尔; B‧加伦卡姆普; P‧格尔德斯; U‧海涅曼; B‧W‧克吕格尔; R‧兰茨施; T‧塞茨; U‧施特尔策
Original assignee: 拜尔公司
Priority date: 1996-05-30
Filing date: 1997-05-16
Publication date: 2002-05-17

Description

Process for preparing 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines

The present invention relates to novel processes and novel intermediates for the preparation of 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines and to processes for their preparation. These dioxazine derivatives are intermediates for the preparation of compounds having fungicidal properties (WO 95-04728).

It has been disclosed that certain 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines can be prepared starting from the corresponding hydroxyphenyl acetates (see WO 95-04728). Thus, for example, the dihydropyran ether (b) obtained in this way can be converted with tert-butylnitrile into 2- [2- (tetrahydropyran-2-yloxy) -phenyl]-methyl 2-hydroxyiminoacetate (c) which is alkylated with iodomethane to give 2- [2- (tetrahydropyran-2-yloxy) -phenyl]-methyl 2-methoxyiminoacetate (d) which is reacted with hydroxylamine to give 2- [2- (tetrahydropyran-2-yloxy) -phenyl]-2-methoxyimino-N-hydroxyacetamide (e) which is cyclized with dibromoethane to give 3- {1- [2- (tetrahydropyran-2-yloxy) -phenyl]-1-methoxyimino-methyl } -5, 6-dihydro-1, 2, 4-dioxazine (f), and finally removing the tetrahydropyran group with an acid catalyst to prepare (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) methanone O-methyloxime (1). This synthesis can be illustrated by the following flow chart:

one major disadvantage of this process is that it requires many steps, and the yield of some steps is low, which significantly affects the efficiency of the process.

It has now been found that 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines of the general formula (I) below, which is obtainable by one of the following processes a to c):wherein A represents an alkyl group, R¹、R²、R³And R⁴Are identical or different and each independently represent hydrogen, halogen, cyano or nitro, the corresponding optionally halogen-substituted alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl radical, and Z¹、Z²、Z³And Z⁴Are identical or different and each independently represent hydrogen, alkyl, haloalkyl or hydroxyalkyl, or Z¹And Z²Or Z¹And Z³Or Z³And Z⁴Together with the corresponding carbon atom to which they are attached, form an aliphatic ring, said process a) being an O-hydroxyethyl-O' -methylbenzofurandione dioxime of the following general formula (II), if appropriate in the presence of a diluent, and if appropriate in the presence of an acid or base, said general formula (II) being:a, R therein¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴In each case as defined above, the process b) is a reaction of hydroxybenzoyldioxazines of the general formula (III) with alkoxyamines of the general formula (IV) or acid addition complexes thereof, if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor, the general formula (III) beingWherein R is¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each as defined above, of the formula (IV)

A-O-NH₂(IV) wherein A is as previously defined and c) is a hydroxyphenyl-hydroxyiminomethyl dioxazine of the general formula (V)With an alkylating agent of the general formula (VI) below, if appropriate in the presence of a diluent and if appropriate in the presence of a base, said general formula (V) being:wherein R is¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each as defined above, said general formula (VI) being:

A-X (VI) wherein A is as previously defined, and

x represents a halogen, an alkylsulfonyloxy group, an alkoxysulfonyloxy group, or an arylsulfonyloxy group.

In the above definitions, saturated or unsaturated hydrocarbon chains, such as alkyl, and alkyl groups attached to heteroatoms, such as alkoxy or alkylthio, are in each case straight-chain or branched.

The process a-c) according to the invention is preferably used for the preparation of compounds of the general formula (1) in which A represents methyl, ethyl, n-or i-propyl,

R¹、R²、R³and R⁴Are identical or different and are each independently hydrogen, halogen, cyano or nitro, or are alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, each of which is optionally substituted by 1 to 5 halogen atoms and each has 1 to 6 carbon atoms,

Z¹、Z²、Z³and Z⁴Are identical or different and each independently represent hydrogen, alkyl or hydroxyalkyl having 1 to 4 carbon atoms, or haloalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, or

Z¹And Z²Or Z¹And Z³Or Z¹And Z⁴Together with the corresponding carbon atom to which they are attached, form an aliphatic ring having 5, 6 or 7 carbon atoms.

Particularly preferredIs prepared from a compound of the general formula (I) in which A represents methyl or ethyl R¹、R²、R³And R⁴Are identical or different and each independently represent hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-or i-propyl, n-, i-, s-or t-butyl, methoxy, ethoxy, n-or i-propoxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl, trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluorochloromethoxy, trifluoroethoxy, difluoromethylthio, difluorochloromethylthio, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl, and Z¹、Z²、Z³And Z⁴Are identical or different and each independently represent hydrogen, methyl, ethyl, n-or i-propyl, n-, i-, s-or t-butyl, hydroxymethyl, trifluoromethyl or trifluoroethyl, or Z¹And Z²Or Z¹And Z³Or Z¹And Z⁴Together with the corresponding carbon atom to which they are attached, form an aliphatic ring having 5, 6 or 7 carbon atoms.

The O-hydroxyethyl-O' -methylbenzofurandione dioximes required as starting materials in carrying out the process a) according to the invention are generally defined by the general formula (II). In the formula (II), A, R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, with A, R being the same as in the above-mentioned compounds of the formula (I) prepared according to the invention¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred.

The compounds of the general formula (II) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

O-hydroxyethyl-O' -methylbenzofurandione dioximes of the general formula (II) are obtained by one of the following processes d to g),

said process d) is of the formula (VII)O-hydroxyethyl-benzofurandione monoxime is reacted with an alkoxyamine of the general formula (IV) or an acid addition complex thereof, if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor, with the general formula (VII) beingWherein R is¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴As defined above, said process e) is a reaction of an O-alkylbenzofurandione dioxime of the formula (VIII), with an ethane derivative of the formula (IX), if appropriate in the presence of a diluent and if appropriate in the presence of a base, said compound of the formula (VIII) being

A, R therein¹、R²、R³And R⁴Each being as defined above, the formula (IX) being

Wherein

Y¹Represents halogen, alkylsulfonyloxy, arylsulfonyloxy or alkanoyloxy, and

g represents hydrogen, or

Y¹And G are connected to each other by a single bond, wherein

Y¹Represents oxygen and

g representsOr is or

Y¹And G together represent a single bond, and

Z¹、Z²、Z³and Z⁴Each of which is as defined above in the preceding paragraph,

said process f) is the reaction of O-hydroxyethylbenzofurandione dioximes of the general formula (X) with alkylating agents of the general formula (VI), if appropriate in the presence of a diluent and if appropriate in the presence of a baseThe general formula (X) is:

wherein

R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each of which is as defined above in the preceding paragraph,

said process m) is a reaction of O-oxyethyl-O' -methylbenzofurandione dioximes of the formula (XIII) with water or alcohols, if appropriate in the presence of a diluent and if appropriate in the presence of a base

Wherein

A、R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each of which is as defined above in the preceding paragraph,

e represents an acyl or ketal protecting group.

The O-hydroxyethyl-benzofurandione monooximes required as starting materials in carrying out process d) according to the invention are generally defined in the general formula (VII). In the general formula (VII), R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning.

The starting materials of the general formula (VII) have not been disclosed before and as novel compounds they also form the subject matter of the present invention.

O-hydroxyethyl-benzofurandione monoxime of the general formula (VII) is obtained by one of the following processes g-n),

said process g) is of the formula (X)I) With an ethane derivative of the general formula (IX), if appropriate in the presence of a diluent and if appropriate in the presence of a base, said compounds of the general formula (XI) being

Wherein R is¹、R²、R³、R⁴Each of which is as defined above in the preceding paragraph,

said process n) is an O-oxyethylbenzofurandione monoxime of the general formula (XIV), if appropriate in the presence of a diluent and if appropriate in the presence of an acid or base, with water or an alcoholE, R therein¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each as defined above.

The benzofurandione monooximes required as starting materials in carrying out process g) according to the invention are generally defined in the general formula (XI). In the general formula (XI), R¹、R²、R³And R⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³And R⁴Is the preferred or particularly preferred meaning.

The benzofurandione monooximes of the general formula (XI) are known and can be prepared by known methods (cf. Beilstein, E (II)17, 462; Mameli, G.56, 768; chem. Ber.35(1902), 1640-1646; Proc. Indian Acad. Sect. A (1976)83A (6), 238-242).

The O-oxyethylbenzofurandione monoximes required as starting materials in carrying out the process n) according to the invention are generally defined by the general formula (XIV). In the formula (XIV), R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning. E has the preferred or particularly preferred meaning, E in the compounds of the formula (XIII) described below and describing the invention being preferred or particularly preferred.

The starting materials of the general formula (XIV) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

O-oxyethyl-benzofurandione monoxime of the general formula (XIV) is obtained by the following process O),

said process o) is a reaction of a benzofurandione monooxime of the general formula (XI) with an ethanol derivative of the general formula (XV) if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor

E, Z therein¹、Z²、Z³And Z⁴Each of which is as defined above in the preceding paragraph,

Y²represents halogen, alkylsulfonyloxy, arylsulfonyloxy or alkanoyloxy.

The benzofurandione monooximes of the general formula (XI) required as starting materials in carrying out process o) according to the invention have already been described in connection with the description of process g) according to the invention.

The O-alkylbenzofurandione dioximes required as starting materials in carrying out the process e) according to the invention are generally defined by the general formula (VIII). In the general formula (VIII), R¹、R²、R³、R⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴Is the preferred or particularly preferred meaning.

The starting materials of the general formula (VIII) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

The O-hydroxyethyl-benzofurandione monoxime of the general formula (VIII) is obtained by the following process h) or p),

said process h) is a reaction of the benzofurandione monooxime of the formula (XI) with an alkoxyamine of the formula (IV), if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor,

said process p) reacting a benzofurandione dioxime of the following general formula (XII) with an alkylating agent of the general formula (VI), if appropriate in the presence of a diluent and if appropriate in the presence of a base, said general formula (XII) being:

wherein R is¹、R²、R³And R⁴Each as defined above.

The benzofurandione monooximes of the general formula (XI) required as starting materials in carrying out process h) according to the invention have already been described in connection with the description of process g) according to the invention.

The benzofurandione dioximes required as starting materials in carrying out process p) according to the invention are generally defined in the general formula (XII). In the general formula (XII), R¹、R²、R³、R⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴Is the preferred or particularly preferred meaning.

The benzofurandione dioximes (XII) of the general formula (XII) are known and can be prepared by known methods (see chem. be. 42(1909), 202).

The O-hydroxyethyl-benzofurandione dioximes required as starting materials in carrying out the process f) according to the invention are generally defined by the general formula (X). In the general formula (X), R¹、R²、R³、R⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴Is the preferred or particularly preferred meaning.

The starting materials of the general formula (X) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

The O-hydroxyethyl-benzofurandione dioximes of the general formula (X) are obtained by the following process i) or q),

said process i) being the reaction of an O-hydroxyethyl-benzofurandione monoxime of the general formula (VII), if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor, with hydroxylamine or an acid addition complex thereof,

said process q) reacting O-oxyethylbenzofurandione dioximes of the following general formula (XVI), with water or an alcohol, if appropriate in the presence of a diluent and if appropriate in the presence of an acid or a base, said general formula (XVI) being:

e, R therein¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Each as defined above.

The O-hydroxyethylbenzofurandione monooximes of the general formula (VII) required as starting materials in carrying out the process i) according to the invention have already been described in connection with the description of the process d) according to the invention.

The O-hydroxyethylbenzofurandione monoxime required as starting material in carrying out the process q) according to the invention is generally as defined in the general formula (XVI). In the general formula (XVI) R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning. E has the preferred or particularly preferred meaning, which is preferred or particularly preferred, as E in the compounds of the formula (XIII) which can be prepared according to the invention.

The starting materials of the general formula (XVI) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

The O-hydroxyethyl-benzofurandione dioximes of the general formula (XVI) are obtained by the following process r) or q),

said process r) is a reaction of O-hydroxyethyl-benzofurandione monoxime of the general formula (XIV) with hydroxylamine or an acid addition complex thereof, if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor.

The O-hydroxyethylbenzofurandione monooximes of the general formula (XIV) required as starting materials in carrying out the process r) according to the invention have already been described in connection with the description of the process n) according to the invention.

The O-hydroxyethyl-O' -methyl-benzofurandione dioximes of the general formula (XIII) required as starting materials in carrying out the process m) according to the invention are generally as defined in the general formula (III). A, R in the formula (XIII)¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as in the above-mentioned compounds of the formula (I) which can be prepared according to the invention, A, R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning. E represents an acyl group, preferably a formyl, acetyl or benzoyl group, or a ketal protecting group, preferably a 2-tetrahydropyranyl, 1-methoxy-1-ethyl, 1-ethoxy-1-ethyl, methoxymethyl or ethoxymethyl group.

Starting materials of the general formula (XIII) have not been disclosed before, and as novel compounds they also form part of the subject matter of the present invention.

O-hydroxyethyl-O' -methylbenzofurandione dioximes of the general formula (XIII) are obtained by one of the following processes s-u),

said process s) is a reaction of O-oxyethyl-O' -methylbenzofurandione dioximes of the general formula (XIV) with alkoxyamines of the general formula (IV) or their acid addition complexes, if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor,

said process t) is a reaction of O-oxyethyl-benzofurandione dioximes of the general formula (XVI) with alkyl reagents of the general formula (VI), if appropriate in the presence of a diluent and if appropriate in the presence of a base,

said process u) is a reaction of O-alkyl-benzofuran dioximes of the general formula (VIII) with ethanol derivatives of the general formula (XV), if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor.

The O-oxyethylbenzofurandione monooximes of the general formula (XIV) required as starting materials in carrying out the process s) according to the invention have already been described in connection with the description of the process n) according to the invention.

The O-oxyethylbenzofurandione dioximes of the general formula (XVI) required as starting materials for carrying out the process t) according to the invention have already been described in connection with the description of the process q) according to the invention.

The O-alkyl-benzofurandione dioximes of the general formula (VIII) required as starting materials for carrying out process u) according to the invention have already been described in connection with the description of process e) according to the invention.

The O-hydroxybenzoyldioxazines of the general formula (III) required as starting materials in the practice of process b) according to the invention are generally as defined in the general formula (III). In the general formula (III), R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning.

The starting materials of the general formula (III) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

The hydroxybenzoyldioxazines of the general formula (III) are obtained by process k) as follows,

said process k) is an O-hydroxyethyl-benzofurandione monoxime of the general formula (VII) if appropriate in the presence of a diluent and if appropriate in the presence of an acid or a base.

The O-hydroxyethyl-benzofurandione monooximes of the general formula (VII) required as starting materials in carrying out the process k) according to the invention have already been described in connection with the description of the process d) according to the invention.

Hydroxyphenyl-hydroxyiminomethyl-dioxazines as starting materials required for carrying out the process c) according to the invention are generally defined by the general formula (V). In the general formula (V), R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as R in the compounds of the formula (I) which can be prepared according to the invention as described above¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning.

The starting materials of the general formula (V) have not been disclosed before and as novel compounds they also form part of the subject matter of the present invention.

Hydroxyphenyl-hydroxyiminomethyl-dioxazines of the general formula (V) are obtained by process l) as follows,

said process l) is a reaction of hydroxybenzoyl dioxazines of the general formula (III) with hydroxylamine or an acid addition complex thereof, if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor,

said process v) is a rearrangement of O-hydroxyethyl-benzofurandione dioximes of the general formula (X), if appropriate in a diluent and if appropriate in the presence of an acid or a base.

The hydroxybenzoyldioxazines of the general formula (III) required as starting materials for carrying out process l) according to the invention have already been described in connection with process b) according to the invention.

The O-hydroxyethylbenzofurandione dioximes of the general formula (X) required as starting materials for carrying out the process v) according to the invention have already been described in connection with the description of the process f) according to the invention.

The alkoxyamines required as starting materials in carrying out the processes b), d), h) and s) according to the invention are defined in a general manner in the general formula (IV). In the general formula (IV), the preferred or particularly preferred meanings of A have already been mentioned as preferred or particularly preferred A in the description of the invention for preparing the compounds of the formula (I). Preferred acid addition complexes of the alkoxyamines of the general formula (IV) are the hydrochlorides, sulfates and hydrogensulfates thereof.

Alkoxyamines of the general formula (IV) and their acid addition complexes are known chemical reagents for synthesis.

The alkylating agents required as starting materials in carrying out the processes c), f), p) and t) according to the invention are defined in a general manner in the general formula (VI). In the general formula (VI), the preferred or particularly preferred meanings of A have already been mentioned as preferred or particularly preferred A in the description of the compounds of the general formula (I) which can be prepared according to the invention. X represents halogen, preferably chlorine, bromine or iodine, alkylsulfonyloxy, preferably methylsulfonyloxy, alkoxysulfonyloxy, preferably methoxysulfonyloxy, or arylsulfonyloxy, preferably 4-tolylsulfonyloxy.

The alkylating agents of the general formula (VI) are known chemical reagents for synthesis.

The ethane derivatives required as starting materials in carrying out the processes e) and g) according to the invention are defined in a general manner in the general formula (IX). In the general formula (IX), Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as Z in the compounds of the formula (I) which can be prepared according to the invention as described above¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning. Y is¹Represents halogen, preferably chlorine, bromine or iodine, alkylsulfonyloxy, preferably methylsulfonyloxy, arylsulfonyloxy, preferably 4-tolylsulfonyloxy, or alkanoyloxy, preferably acetoxy. G represents hydrogen or is bound to Y by a single bond¹Connection, Y¹Is oxygen and G is carbonyl, or G and Y¹Together represent a single bond.

Ethane derivatives of general formula (IX) are known chemical reagents for synthesis.

Hydroxylamine, or the acid addition complexes thereof, preferably the hydrochloride, sulfate and bisulfate salts thereof, are further required as starting materials in carrying out processes i), l) and r) and are known chemical reagents for the synthesis.

The ethane derivatives which are further required as starting materials in carrying out the processes o) and u) according to the invention are defined in a general manner in the general formula (XV). In the general formula (XV), Z¹、Z²、Z³And Z⁴Preferred or particularly preferred meanings, having the same meanings as Z in the compounds of the formula (I) which can be prepared according to the invention as described above¹、Z²、Z³And Z⁴Is the preferred or particularly preferred meaning. E preferably or particularly preferably has the meaning which is preferred or particularly preferred when describing compounds of the formula (XIII). Y is²Represents halogen, preferably chlorine, bromine or iodine, alkylsulfonyloxy, preferably methylsulfonyloxy, arylsulfonyloxy, preferably 4-tolylsulfonyloxy, or alkanoyloxy, preferably acetoxy.

Ethanol derivatives of the general formula (XV) are known and can be prepared by known methods (see, for example, Newkome, George R; Marston, Charles R., J. org. chem. Ber., 7<1874>, 70).

If the processes a), k) and v) according to the invention are carried out in the presence of acids, suitable diluents are all inert organic solvents. These solvents preferably include aliphatic, cycloaliphatic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, dioxane, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; esters, such as methyl acetate or ethyl acetate, or sulfones, such as sulfolane, and mixtures of said diluents. Particularly preferred diluents are ethers, such as diethyl ether, 1, 2-diethoxyethane or anisole; and aromatic hydrocarbons such as benzene, toluene or xylene.

If the processes a), k) and v) according to the invention are carried out in the presence of a base, suitable diluents are water and all organic solvents. These solvents preferably include aliphatic, cycloaliphatic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n-or isobutyronitrile or benzonitrile; amides, such as N, N-dimethylformamide, N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate; sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof with water. Preferred diluents are water, alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof with water; particularly preferred diluents in this case are water or alcohols, such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, and mixtures thereof with water.

Suitable solvents for carrying out the processes b), d), h), i), l), r) and s) according to the invention are all inert organic solvents. These solvents preferably include aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; amides such as N, N-dimethylformamide, N-dimethylacetamide, N-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; organic acids such as acetic acid; esters, such as methyl acetate or ethyl acetate; sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, mixtures thereof with water or pure water. Particularly preferred diluents are amides such as N, N-dimethylformamide, N-dimethylacetamide, N-formylaniline, N-methylpyrrolidone or hexamethylphosphoric triamide; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, acids such as acetic acid, compounds thereof with water or pure water. Another particularly preferred is a two-phase mixture, such as water/toluene.

Suitable solvents in carrying out the processes c), e), f), g), o), p), t) and u) according to the invention are all inert organic solvents. These solvents preferably include aliphatic, cycloaliphatic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles such as acetonitrile, propionitrile, n-or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N-dimethylacetamide, N-methyl-N-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate; sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, mixtures thereof with water or pure water. Particularly preferred diluents are ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n-or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N-dimethylacetamide, N-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether. Another particularly preferred is a two-phase mixture, such as water/toluene.

Suitable diluents in carrying out the process m), n) and q) according to the invention are water and all organic solvents. These solvents include ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; ketones such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n-or isobutyronitrile or benzonitrile; amides such as N, N-dimethylformamide, N-dimethylacetamide, N-methyl-N-formanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate; sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane; alcohols such as methanol, ethanol, n-or isopropanol, n-, iso-, sec-or tert-butanol, ethylene glycol, propane-1, 2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, mixtures thereof with water or pure water.

The processes a), k) and v) according to the invention are, if appropriate, carried out in the presence of acids or bases. Suitable acids include all inorganic or organic protic and Lewis acids, and all polymeric acids. These acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, boron trifluoride (in the etherate form), boron tribromide, aluminum trichloride, zinc halide, iron (III) chloride, antimony pentachloride, acidic ion exchangers, acid clays, and acidic silica gels. Hydrochloric acid or hydrobromic acid is preferred. Suitable bases include conventional inorganic or organic bases. These bases preferably include alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxylates, acetates, carbonates or bicarbonates, such as sodium hydride, sodium amine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate, or tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopyridine, Diazabicyclooctane (DABCO), Diazabicyclononene (DBN) or Diazabicycloundecene (DBU). Particularly preferred bases are sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, and tertiary amines such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopyridine, Diazabicyclooctane (DABCO), Diazabicyclononene (DBN) or Diazabicycloundecene (DBU).

The processes b), d), h), i), l), r) and s) according to the invention are, if appropriate, carried out in the presence of acid acceptors. These acid acceptors include all common inorganic or organic bases. They preferably include alkaline earth metal or alkali metal hydroxides, alkoxylates, acetates, carbonates or bicarbonates, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium bicarbonate, sodium bicarbonate or ammonium carbonate, and tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopyridine, Diazabicyclooctane (DABCO), Diazabicyclononene (DBN) and Diazabicycloundecene (DBU).

The processes c), e), f), g), o), p), t) and u) according to the invention are, if appropriate, carried out in the presence of suitable acid acceptors. These acid acceptors include all common inorganic or organic bases. They preferably include alkaline earth metal or alkali metal hydrides, hydroxides, amides, alkoxides, carbonates or bicarbonates, such as sodium hydride, sodium aminate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate or sodium bicarbonate, and tertiary amines, such as trimethylamine, triethylamine, tributylamine, N-dimethylaniline, N-dimethylbenzylamine, pyridine, N-methylpiperidine, N-methylmorpholine, N-dimethylaminopyridine, Diazabicyclooctane (DABCO), Diazabicyclononene (DBN) and Diazabicycloundecene (DBU).

In carrying out the processes a), k) and v) according to the invention, the reaction temperatures can be varied within a relatively wide range, the reaction generally being carried out at temperatures of from-20 ℃ to 100 ℃ and preferably from-10 ℃ to 80 ℃.

In carrying out the process b), d), h), i), l), r) and s) according to the invention, the reaction temperature can be varied within a relatively wide range. The reaction is generally carried out at a temperature of from 0 ℃ to 200 ℃, preferably from 20 ℃ to 150 ℃.

In carrying out the process c), e), f), g), o), p), t) and u) according to the invention, the reaction temperature can be varied within a relatively wide range. The reaction is generally carried out at a temperature of-20 ℃ to 100 ℃, preferably 0 ℃ to 80 ℃.

The processes a) to v) according to the invention are generally carried out at atmospheric pressure. However, it is also possible to carry out under elevated or reduced pressure (generally from 0.1bar to 10 bar).

In a preferred process variant (A), the benzofurandione monoxime of the formula (XI) is first converted into the O-hydroxyethyl-benzofurandione monoxime of the formula (VII) by reaction with an ethane derivative of the formula (IX), as described in process variant g). Without further purification, it is then reacted with alkoxyamines of the general formula (IV) or their acid addition complexes, if appropriate in a buffer system such as sodium acetate/acetic acid as described in process d) to give O-hydroxyethyl-O' -methylbenzofurandione dioximes of the general formula (II) which are treated by process a) without further purification with acids or bases to give the desired 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines.

In a further preferred process variant (B), the benzofurandione monoxime of the formula (XI) is first converted into the O-hydroxyethyl-benzofurandione monoxime of the formula (VII) by reaction with an ethane derivative of the formula (IX), as described in process g). After acid or alkali treatment, the hydroxybenzoyl dioxazine with the general formula (III) is prepared, and then the hydroxybenzoyl dioxazine is reacted with alkoxyamine with the general formula (IV) or acid addition complex thereof to obtain the required 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazine with the general formula (I).

In a third process variant (C), the benzofurandione monooxime of the formula (XI) is first converted into the O-alkyl-benzofurandione dioxime of the formula (VIII) by reaction with an alkoxyamine of the formula (IV) or an acid addition complex thereof. Then reacting it with an ethane derivative of the general formula (IX) to give O-hydroxyethyl-O' -methylbenzofurandione dioxime of the general formula (II), treating this with an acid or a base to give the desired 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazine of the general formula (I).

Surprisingly, the process of the present invention, especially when combined, results in high yields of high purity product. Chem. be.1902, 1640 discloses that benzofurandione monoximes of general formula (XI) are cleaved by treatment with an acid or a base to give salicylic acid derivatives or hydroxyphenyl glyoxylic acid derivatives. It was therefore not foreseen that 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines could be prepared in a reaction comprising only three steps without any significant side reactions.

The process of the present invention has many advantages. For example, large quantities of 3- (1-hydroxyphenyl-1-alkoxyiminomethyl) dioxazines can be prepared in high yield and purity. A further advantage is that the desired benzofurandione monoxime (Beilstein, E (II)17, 462; Mameli, G.56, 768) as starting material can be obtained in a simple manner even in major amounts.

Method and preparation examples:

example 1

Method (A)

Step 1

Compound (VII-1)Method g)

11.8g (0.0725mol) of benzofuran-2, 3-dione-2-oxime (XI-1) (Stoermer, Kahlert, B.35, 1644) were dissolved in 75ml of dimethylformamide. Under cooling, 3g (0.075mol) of 60% strength sodium hydride (mineral oil suspension) are added in small portions and stirring is continued at a temperature of 25 ℃ for about 1 hour until gas formation ceases. The mixture is then cooled to 0 ℃ and 9.3g (0.0744mol) of 2-bromoethanol are added dropwise at this temperature and stirring is continued at 25 ℃ for a further 24 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The residue was recrystallized from a mixture of 150ml of toluene and 100ml of cyclohexane. 11.5g (64% of theory) of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) -oxime ] (VII-1) are obtained (content 83.5% by HPLC analysis). The sample recrystallized from toluene had a melting point of 110-111 ℃.

Step 2

Compound (II-1)Method d)

11.5g of crude benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) -oxime ] (VII-1) and 5.15g (0.0616mol) of O-methylhydroxylamine hydrochloride were dissolved in 60ml of dimethylformamide and stirred at 80 ℃ for 30 minutes. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated off under reduced pressure. 14.1g of an oil are obtained which contains 40.5% of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) -oxime ]3- (O-methyl-oxime) (II-1) and 14% (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime.

Step 3

Compound (1)Method a)

14.1g of the oil containing compounds (II-1) and (1) from step 2 of process A are dissolved at 0 ℃ in 200ml of diethyl ether which has previously been saturated with hydrogen chloride gas. The mixture was stirred for 30 minutes without further cooling and then poured into a sodium bicarbonate solution cooled to 0 ℃. The organic phase was separated off and the aqueous phase was extracted repeatedly with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue is stirred with tert-butyl methyl ether, whereupon the product crystallizes. 5.4g (28% of theory, based on benzofuran-2, 3-dione 2-oxime) (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime crystals (88.8% content by HPLC) are obtained

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝4.10(3H)；4.19/4.20/4.21/4.22(2H)；4.47/4.48/4.49/4.50(2H)；6.26(1H)；6.95-7.0(2H)；7.21/7.23(1H)；7.31-7.36(2H)ppm。

Example 2

Method B

Step 1

Compound (VII-1)

This step has been described as method g) in step 1 of method variant (a).

Step 2

Compound (III-1):method k)

The dry hydrogen chloride was passed into a mixture of 19g (0.0917mol) of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) -oxime ] (VII-1) and 439ml of diethyl ether at 20 ℃ whereupon the mixture warmed to 35 ℃. After 7 hours, the mixture was decanted from undissolved material and the solvent was evaporated off under reduced pressure. The residue was poured into ethyl acetate, washed with 50ml of water and then with 20ml of saturated aqueous sodium bicarbonate solution. The organic phase is separated off and dried over sodium sulfate, and the solvent is then distilled off under reduced pressure. 17g of crude product are obtained. The product was chromatographed on silica gel using dichloromethane as the eluting solvent. 10g (yield 51.9% of theory, based on compound (VII-1)) of (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone (III-1) are obtained, which is 98.7% pure by HPLC analysis.

¹H NMR Spectrum (CDCl)₃，TMS)：δ＝4.28/4.29/4.30/4.31(2H)；4.55/4.56/4.57/4.58(2H)；6.90/6.92/6.93/6.95/6.99/7.02(2H)；7.50/7.51/7.53/7.54/7.55/7.56(1H)；8.27/8.29/8.30(1H)；11.52(1H)ppm.

Step 3

Compound (1)

Method b)

4.4g (0.021mol) (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone (III-1) and 1.87g (0.022mol) O-methylhydroxylamine hydrochloride in 22ml dimethylformamide are heated to 100 ℃ for 2 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure. 5.7g of crude (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime were obtained comprising 17.5% of the E isomer and 38% of the Z isomer (analyzed by HPLC). The crude product was purified by chromatography on silica gel using a petroleum ether/tert-butyl methyl ether (1: 1) mixture as eluting solvent. 1.55 gZ- (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime was obtained with a purity of 91.5% (HPLC) ═ 28.27% of theory.

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝4.08(3H)；4.30/4.32/4.33(2H)；4.53/4.54/4.55(2H)；6.89/6.92/6.94/6.98/7.01(2H)；7.28/7.31/7.33/7.34/7.35/7.37(2H)；10.11(1H)ppm。

At the same time, 0.9g E- (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime was obtained with a purity of 93.7% (HPLC) ═ 16.8% of theory.

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝4.09(3H)；4.18/4.19/4.20/4.21(2H)；4.47/4.48/4.50(2H)；6.28(1H∶OH)；6.94/6.95/6.97(2H)；7.20-7.36(2H)ppm。

Example 3

Method C

Step 1

Compound (VIII-1)

Method h)

3.26g (0.02mol) of benzofuran-2, 3-dione 2-oxime (XI-I) and 3.36g (0.04mol) of O-methylhydroxylamine hydrochloride in 20ml of dimethylformamide are stirred at 20 ℃ for 20 minutes and then at 80 ℃ for 45 minutes. The reaction mixture was poured into a mixture of aqueous sodium bicarbonate and ethyl acetate. The organic phase is separated off and dried over sodium sulfate and the solvent is then distilled off under reduced pressure. The residue was extracted with diethyl ether to give 1.4g of benzofuran-2, 3-dione-3 (O-methyloxime) -2-oxime (VIII-1) containing 70.7% of stereoisomer A and 8.5% of stereoisomer B (analyzed by HPLC).

¹H NMR Spectrum (CDCl)₃(TMS): δ 4.09(3H, isomer B); 4.11(3H, isomer A); 7.21/7.35 (1H); 7.51-7.65(1H, isomers A and 2H, isomer B); 8.02/8.04/8.05(1H, isomer A); 11.35(1H, isomer A); 11.74(1H, isomer B) ppm.

Step 2

Compound (II-1)

Method e)

4.49g (0.023mol) of benzofuran-2, 3-dione 3- (O-methyloxime) 2-oxime (VIII-1) are dissolved in 25ml of dimethylformamide. 1g (0.025mol) of 60% strength sodium hydride are added to the solution, and the solution is stirred at room temperature for 1 hour. 3.1g (0.0248mol) of 2-bromoethanol are added and the mixture is stirred at 25 ℃ for 12 hours. After addition of 0.5g of sodium methoxide and 1.22g of 2-bromoethane, the mixture was stirred at room temperature for 2 hours, then 0.5g of sodium methoxide and 1.22g of 2-bromoethanol were added, and the mixture was stirred at room temperature for a further 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate, and the organic phase was washed 3 times with 20ml of a 2N aqueous sodium hydroxide solution. The solvent was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel eluting with diethyl ether/petroleum ether (1: 1). The eluate was evaporated under reduced pressure to give 2.26g (39.6% of theory) of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) -oxime ]3- (O-methyloxime) (II-I) which, by HPLC analysis, contained 84.29% of stereoisomer A and 12.58% of stereoisomer B.

¹H NMR Spectrum (CDCl)₃(TMS): δ — 3.95-4.03 (2H); 4.20(3H, isomer B); 4.21(3H, isoform A); 4.37-4.40 (2H); 7.14-7.21 (2H); 7.40-7.49 (1H); 7.63/7.64/7.66(1H, isomer B)) (ii) a 8.04/8.06/8.07(1H, isomer B).

Step 3

Compound (1)

Method a)

2g of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) -oxime ]3- (O-methyloxime) (II-I) prepared by process e) (96.88% by HPLC, 0.0082mol) are dissolved at 0 ℃ in 50ml of diethyl ether which has previously been saturated with hydrogen chloride gas. The mixture was stirred for 30 minutes without further cooling, then the solvent was distilled off under reduced pressure, and the residue was poured into diethyl ether again. Some of the product crystallized out and was filtered off. The mother liquor was concentrated under reduced pressure and the residue was dissolved in 25ml of diethyl ether saturated with hydrogen chloride gas at 0 ℃. The solution was stirred for 30 minutes without further cooling, then the solvent was distilled off under reduced pressure, and the residue was treated again with diethyl ether. A further portion of the product crystallizes out and is likewise filtered off. The total amount of 1.37g (69% of theory) of (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime crystals (I) were obtained (97.59% content by HPLC analysis)

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝4.09(3H)：4.18/4.19/4.20/4.21(2H)；4.47/4.48/4.50(2H)；6.94/6.95/6.97(2H)；7.20-7.36(2H)ppm

Example 4

Method (D)

Step 1

Compound (XIV-1)

Method o)

1.63g (0.01mol) of benzofuran-2, 3-dione 2-oxime (XI-1) and 1.14g (0.0108mol) of sodium carbonate in 5ml of N-methyl-dipyrrolidone are stirred at 20 ℃ for 20 minutes. After addition of 1.7g (0.0102mol) of 2-bromoethyl acetate, stirring is continued for 2 hours at 70 ℃ the mixture is poured into 30ml of water and the product is filtered off, 1.57g (63% of theory) of ethyl 2- (3-oxo-3H-benzofuran-2-ylideneaminooxy) -acetate (XIV-1) are obtained after drying.

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝2.11(3H)；4.43/4.44/4.45/4.46/4.47(2H)；4.52/4.54/4.55/4.57(2H)；7.28/7.30/7.33(2H)；7.72/7.74/7.76/7.78/7.80(2H)ppm.

Step 2

Compound (XIII-1)

Method s)

10g (0.04mol) of ethyl 2- (3-oxo-3H-benzofuran-2-ylideneaminooxy) -acetate (XIV-1) and 4.18g (0.05mol) of O-methylhydroxylamine hydrochloride were dissolved in 40ml of N-methyl-2-pyrrolidone and stirred at 80 ℃ for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure, giving 10.6g of crude product which, after purification by chromatography on silica gel with tert-butyl methyl ether/petroleum ether (1: 1) as eluting solvent, gives 6.9g (59.1% of theory) of ethyl 2- (3-methoxyimino-3H-benzofuran-2-ylideneaminooxy) -acetate (XIII-1) which, by HPLC analysis, contains 82.15% of isomer A and 13.38% of isomer B.

¹H NMR Spectrum (CDCl)₃(TMS): δ 2.10 (3H); 4.21(3H, isomer B); 4.22(3H, isomer A); 4.41-4.48 (4H); 7.15/7.17/7.20 (2H); 7.44-7.50 (1H); 7.63-7.66(1H, isomer B); 8.05-8.09(1H, isomer A) ppm.

Step 3

Compound (II-1)

Method m)

2g (0.00718mol) of ethyl 2- (3-methoxyimino-3H-benzofuran-2-ylideneaminooxy) -acetate (XIII-1) in 8ml of dimethylformamide are treated at 20 ℃ with 7.2ml (0.0144mol) of 2N aqueous sodium hydroxide solution and stirred at 20 ℃ for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure, giving 1.7g (67.6% of theory) of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) oxime ]3- (O-methyloxime) (II-1) which, by HPLC analysis, contains 56.8% of stereoisomer A and 10.7% of stereoisomer B.

GC/MS analysis of the data (substances were silylated with N-methyl-N-trimethylsilyl trifluoroacetamide before analysis):

stereoisomer a:

retention index of 2062

M⁺＝209，308，293，249，233，192，176，145，132，89，73，45，26。

Stereoisomer B:

retention index of 2000

M⁺＝309，308，293，249，218，192，176，145，132，90，73，74。

And 4, step 4:

compound (1)

This step has been described as method a) in step 3 of method variant (a) and in step 3 of method variant (C).

Other embodiments of the methods

Example 5

Compound (1):

method c)

1.2g (0.0054mol) of Z- (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanoxime (V-1) in 5ml of dimethylformamide are initially stirred at 20 ℃ for 30 minutes together with 0.66g (0.0062mol) of sodium carbonate. 0.83g (0.00658mol) of dimethyl sulfate are then added and stirring is continued for 16 hours at 20 ℃. The reaction mixture was adjusted to slightly acidic pH with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 0.8g (50.35% of theory) of Z- (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone O-methyl-oxime (1) are obtained in a purity of 80.3% (HPLC).

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝4.08(3H)；4.30/4.32/4.33(2H)；4.53/4.54/4.55(2H)；6.89/6.92/6.94/6.98/7.01(2H)；7.28/7.31/7.33/7.34/7.35/7.37(2H)；10.11(1H)ppm.

Example 6

Compound (II-1):

method e)

3.19g (0.0166mol) of benzofuran-2, 3-dione 3- (O-methyloxime) 2-oxime (VIII-1) (mixture of the two isomers, A: B ═ 13: 86) are suspended in 20ml of methanol and treated dropwise with 8.3g of 2mol sodium methoxide solution at 20 ℃. After the mixture became homogeneous, methanol was distilled off under reduced pressure, and the crystal residue was dried in a desiccator for 12 hours. 3.55g of the sodium salt of benzofuran 2, 3-dione 3- (O-methyloxime) 2-oxime (VIII-1) are obtained. The salt was suspended in 16ml of N-methyl-2-pyrrolidone at 20 ℃ and 2.1g (0.0168mol) of 2-bromoethanol were added. The mixture was stirred at 20 ℃ for 48 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate, and the organic phase was washed 3 times with 20ml of a 2N aqueous sodium hydroxide solution. The solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel with diethyl ether/petroleum ether (1: 1). The eluate was evaporated under reduced pressure to give 2.91g (73.8% of theory) of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) -oxime ]3- (O-methyloxime) (II-I) which, by HPLC analysis, consisted of 88.6% of stereoisomer B, 7.7% of stereoisomer A and 3.2% of stereoisomer C.

¹H NMR Spectrum (CDCl)₃(TMS): δ — 3.43(1H, broad); 4.0-4.03 (2H); 4.20 (3H); 4.38-4.41 (2H); 7.14-7.21 (2H); 7.40/7.42/7.43/7.445 (1H); 7.63/7.67/7.66(1H) ppm.

Example 7

Compound (II-1):

method f)

0.44g (0.002mol) of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) oxime ] 3-oxime (X-1) in 5ml of dimethylformamide are stirred at 20 ℃ for 20 minutes with 0.08g (0.002mol) of 60% strength sodium hydride. After no more gas formation, 0.28g (0.002mol) of methyl iodide were added and the mixture was stirred at 20 ℃ for 16 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure to give 0.5g (35% of theory) of crude product. The crude product was analyzed by HPLC for 23% stereoisomer A and 10.1% stereoisomer B of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) oxime ]3- (O-methyloxime) (II-1).

retention index ═ 2053 (isomer a)

M⁺＝309，308，293，249，233，192，176，145，132，89，73，45，26。

Retention index 1997 (isomer B)

M⁺＝309，308，293，249，218，192，176，145，132，90，73，45。

In addition, the crude product contained 20.5% (HPLC) of N- [2- (2-hydroxyethoxyimino) -benzofuran-3-ylidene ] -N-methylamine N-oxide.

GC/MS analysis (silylated samples)

Retention index 2234

M⁺＝310，308，233，192，175，159，132，102，73，45，26

Example 8

Compound (X-1):

method i)

10.1g (0.05mol) of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) oxime ] (VII-1) in 50ml of N-methyl-2-pyrrolidone are stirred at 80 ℃ for 2 hours together with 3.5g of hydroxylamine hydrochloride. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel using tert-butyl methyl ether/petroleum ether (1: 1) as eluting solvent. The eluate is evaporated under reduced pressure to give 4.2g (29.6% of theory) of benzofuran-2, 3-dione 2- [ O- (2-hydroxyethyl) -oxime ] 3-oxime which consists of 62.4% of isomer A and 15.8% of isomer B (HPLC).

¹H NMR Spectrum (CDCl)₃(TMS): δ — 3.64-3.71 (2H); 4.10-4.26 (2H); 4.78-4.87 (1H); 7.2-7.3 (1H); 7.3-7.4 (1H); 7.5-7.7 (1H); 8.11-8.14 (1H); 12.82(1H isomer A); 12.91(1H isomer B) ppm.

Example 9

Compound (V-1):

method l)

4.14g (0.02mol) of (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone (III-1) in 20ml of dimethylformamide are stirred at 80 ℃ for 2 hours together with 2.1g (0.03mol) of hydroxylamine hydrochloride. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. 4.7g of a crude product consisting of 15% of the E isomer and 57.5% of the Z isomer (HPLC) are obtained. The crude product is purified by chromatography on silica gel using diethyl ether/petroleum ether (1: 1) as eluting solvent. 2.7g (60.8% of theory) of (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone oxime (V-1) are obtained, the content of which, by HPLC analysis, is 93.4%.

¹H NMR Spectrum (DMSO-d)₆/TMS)：δ＝4.19/4.20/4.21(2H)；4.45/4.46/4.47(2H)；6.89-6.92(2H)；7.22-7.32(1H)；7.33-7.40(1H)；10.30(1H)；12.16(1H)ppm.

Example 10

Compound (VII-1)

Method n)

2.07g (0.01mol) of benzofuran-2, 3-dione 2- { O- [2- (tetrahydrofuran-2-yloxy) -ethyl ] -oxime } (XIV-2) are dissolved in 12ml of methanol and stirred at room temperature with 100mg of acidic ion exchange resin for 16 hours. 40ml of methanol was added to the reaction mixture, which was then warmed until the crystals dissolved. The acidic ion exchange resin was filtered off, the filtrate was concentrated and the residue was recrystallized from 10ml of toluene. 1.69g (81.5% of theory) of crystals of benzofuran-2, 3-dione 2- [ O- [2- (hydroxyethyl) -oxime ] (VII-1) are obtained which have a melting point of 110-111 ℃.

¹H NMR Spectrum (CDCl)₃(TMS): δ ═ 2.33(1H, broad peak), 4.00-4.03 (2H); 4.47-4.50 (2H); 7.27-7.32 (2H); 7.70-7.78(2H) ppm.

Example 11

Compound (XIV-2)

Method o)

5g (0.03mol) of benzofuran-2, 3-dione 2 oxime (XI-1) are dissolved in 30ml of methanol and 15ml of a 2mol solution of sodium methoxide in methanol are added dropwise at 20 ℃. The solvent was distilled off under reduced pressure. The crystalline residue is dissolved in 30ml of N-methyl-2-pyrrolidone and treated with 6.27g (0.03mol) of 2- (2-bromoethoxy) -tetrahydrofuran at 20 ℃. The reaction was treated at 20 ℃ for 16 hours, poured into 100ml of water and the resulting mixture was extracted twice with 100ml of dichloromethane each time. The solvent was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel eluting with diethyl ether/dichloromethane/petroleum ether (1: 2). 5.55g (62.1% of theory) of benzofuran-2, 3-dione 2- [ { O- [2- (tetrahydropyran-2-yloxy) -ethyl ] -oxime } (XIV-2) are obtained.

¹H NMR Spectrum (CDCl)₃/TMS)：δ＝1.50-1.86(6H)；3.49-3.53(1H)；3.81-3.88(2H)；4.02-4.09(1H)；4.52-4.55(2H)；4.66-4.69(1H)；7.26-7.31(2H)；7.69-7.80(2H)ppm.

Example 12

Compound (VIII-1)

Method p)

11g (0.0617mol) of benzofuran-2, 3-dione dioxime in 50ml of dimethylformamide are added dropwise to a suspension of 2.4g (0.06mol) of 60% strength sodium hydride in 25ml of dimethylformamide and stirred at 20 ℃ for 1 hour. 7.55g (0.06mol) of dimethyl sulfate are then added dropwise and stirring is continued for 16 hours at 20 ℃. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel eluting with hexane/acetone (7: 3). The residue was stirred with diethyl ether to give 0.7g of benzofuran-2, 3-dione 3- (O-methyloxime) 2-oxime (VIII-1) as a mixture of stereoisomers consisting of 90.6% of isomer A and 9% of isomer B (HPLC).

Example 13

Compound (X-1):

method q)

5.28g (0.02mol) of ethyl 2- (3-hydroxyimino-3H-benzofuran-2-ylideneaminooxy) -acetate (XVI-I) in 20ml of dimethylformamide are stirred at 20 ℃ for 3 hours with 4.24g (0.048mol) of 45% strength sodium hydroxide solution. The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The crude product contained 23.4% of stereoisomer A and 4.1% of stereoisomer B of benzofuran-2, 3-dione 2[ O- (2-hydroxyethyl) oxime 3-oxime (X-1) according to HPLC analysis. After stirring the crude product with diethyl ether, 1.4g (28.5% of theory) of benzofuran-2, 3-dione 2- [ O- (2-hydroxy-ethyl) -oxime ] 3-oxime (X-1) crystals consisting of 84.7% of isomer A and 6% of isomer B are obtained.

¹H NMR Spectrum (DMSO-d)₆(TMS): δ — 3.64-3.71 (2H); 4.10-4.26 (2H); 4.78-4.87 (1H); 7.2-7.3 (1H); 7.3-7.4 (1H); 7.5-7.7 (1H); 8.11-8.14 (1H); 12.82(1H, stereoisomer A); 12.91(1H stereoisomer B) ppm.

Example 14

Compound (XVI-1)

Method r)

5g (0.02mol) of 2- (3-oxo-3H-benzofuran-2-ylideneaminooxy) -ethyl acetate (XIV-1) and 1.74g (0.025mol) of hydroxylamine hydrochloride are dissolved in 20ml of dimethylformamide and stirred at 100 ℃ for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on silica gel using a tert-butyl methyl ether/petroleum ether (1: 1) mixture as eluting solvent. 2.7g (38.5% of theory) of 2- (3-hydroxyimino-3H-benzofuran-2-ylidene) -ethyl acetate (XVI-1) are obtained, which consists of 64.23% of stereoisomer A and 14.9% of stereoisomer B (HPLC).

¹H NMR Spectroscopy (CDCL)₃-d₆(TMS): δ ═ 2.11(3H, stereoisomer a); 2.12(3H, stereoisomer B); 4.43-4.46 (4H); 7.19-7.23 (2H); 7.46-7.52 (1H); 7.65-7.8(1H, stereoisomer B); 8.16/8.17/8.19(1H stereoisomer A); 8.9(1H) ppm.

Example 15

Compound (XIII-1)

Method s)

10g (0.04mol) of ethyl 2- (3-oxo-3H-benzofuran-2-ylideneaminooxy-acetate (XIV-1) and 4.18g (0.05mol) of O-methylhydroxylamine hydrochloride are dissolved in 40ml of N-methyl-2-pyrrolidone and stirred for 1 hour at 80 ℃ the reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 10.6g of crude ethyl 2- (3-methoxyimino-3H-benzofuran-2-ylidene) -acetate (XIII-1) which is purified by chromatography on silica gel using a tert-butyl methyl ether/petroleum ether (1: 1) mixture to give 6.9g (59.1% of theory) of ethyl 2- (3-methoxyimino-3H-benzene-carboxylate And furan-2-ylidene) -acetic acid ethyl ester (XIII-1), which contains 82.15% of stereoisomer A and 13.38% of stereoisomer B.

¹H NMR Spectrum (CDCl)₃(TMS): δ 2.10 (3H); 4.21(3H stereoisomer B); 4.22(3H, stereoisomer A); 4.41-4.48 (4H); 7.15/7.17/7.20 (2H); 7.44-7.50 (1H); 8.05-8.09(1H) ppm.

Example 16

Compound (XIII-1)

Method t)

0.26g (0.01mol) of ethyl 2- (3-hydroxyimino-3H-benzofuran-2-ylideneaminooxy) -acetate are dissolved in 2ml of dimethylformamide. At 20 ℃ 0.04g (0.001mol) of 60% strength sodium hydride are added and the mixture is stirred until no more gas is formed. Then, 0.05g (0.0005mol) of sodium carbonate and 0.13g (0.001mol) of dimethyl sulfate were added to the reaction mixture, and allowed to stand at 20 ℃ for 2 days. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure, giving 0.24g (42.5% of theory) of crude ethyl 2- (3-methoxyimino-3H-benzofuran-2-ylideneaminooxy) -acetate (XIII-I), which contains 33.9% of stereoisomer A and 15.4% of stereoisomer B by HPLC analysis.

GC/MS analysis data:

retention index ═ 2097 (stereoisomer a)

M⁺＝279，278，218，187，160，144，130，87，75，43，26。

Retention index 2036 (stereoisomer B)

M⁺＝279，278，218，187，160，144，130，87，63，43，26。

Example 17

Compound (XIII-1)

Method u)

1.92g (0.01mol) of benzofuran-2, 3-dione acetate 3- (O-methyloxime) 2-oxime (VIII-I) are dissolved in 10ml of dimethylformamide at 20 ℃. 0.4g (0.01mol) of 60% strength sodium hydride are added to the solution and the mixture is stirred for 1 hour at 20 ℃. 1.67g (0.01mol) of 2-bromoethyl acetate are then added and stirring is continued for 16 hours at 20 ℃. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give 2.3g (52.6% of theory) of ethyl 2- (3-methoxyimino-3H-benzofuran-2-ylideneaminoxy) -acetate (XIII-I), which consists of 51.17% of stereoisomer A and 12.49% of stereoisomer B (HPLC).

retention index ═ 2097 (stereoisomer a)

M⁺＝279，278，218，187，160，144，130，87，75，43，26。

Retention index 2035 (stereoisomer B)

M⁺＝279，278，218，187，160，144，130，87，75，43，26。

Example 18

Compound (V-1)

Method v)

1.11g (0.005mol) of benzofuran-2, 3-dione 2- [ O- (hydroxyethyl) -oxime ] 3-oxime (X-1) are dissolved at 0 ℃ in 10ml of diethyl ether which has previously been saturated with hydrogen chloride gas. The mixture was stirred for 3 hours without further cooling and then poured into a sodium bicarbonate solution cooled to 0 ℃. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, yielding 0.8g (29.9% of theory) of crude (5, 6-dihydro-1, 4, 2-dioxazin-3-yl) - (2-hydroxyphenyl) -methanone oxime (V-1) which consists of 19.7% of isomer E and 21.8% of isomer Z (HPLC).

retention index ═ 1980(E isomer)

M⁺＝368，351，307，292，250，235，203，176，147，117，100，73，45。

Retention index 2036(Z isomer)

M⁺＝360，351，306，292，250，235，203，176，147，117，100，73，45。

Claims

1. A process for the preparation of a compound of formula (I):

wherein

A represents a methyl group or an ethyl group,

R¹、R²、R³and R⁴Are identical or different and each independently represent hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, n-or i-propyl, n-, i-, s-or t-butyl, methoxy, ethoxy, n-or i-propyl, methylthio, ethylthioMethylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl, trifluoroethyl, difluoromethoxy, trifluoromethoxy, difluorochloromethoxy, trifluoroethoxy, difluoromethylthio, difluorochloromethylthio, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl and

Z¹、Z²、Z³and Z⁴Are identical or different and each independently represent hydrogen, methyl, ethyl, n-or i-propyl, n-, i-, s-or t-butyl, hydroxymethyl, trifluoromethyl or trifluoroethyl, or

Z¹And Z²Or Z¹And Z³Or Z³And Z⁴Together with the corresponding carbon atom to which they are attached form an aliphatic ring having five, six or seven carbon atoms,

the method comprises the following steps:

h) benzofurandione monooximes of the general formula (XI),

wherein R is¹、R²、R³And R⁴The definition of (A) is the same as that of (B),

with alkoxyamines of the general formula (IV),

A-O-NH₂ (IV)

wherein

A is as defined above for the above-mentioned compounds,

if appropriate in the presence of a diluent and if appropriate in the presence of an acid acceptor, to give a compound of the formula (VIII),

wherein

A、R¹、R²、R³And R⁴The definition of (1) is as above;

e) reaction of O-alkylbenzofurandione dioximes of the general formula (VIII) with ethane derivatives of the general formula (IX), if appropriate in the presence of a diluent and if appropriate in the presence of a base,

a, R in the general formula (VIII)¹、R²、R³And R⁴Each being as defined above, the formula (IX) being

Wherein

Y¹Represents halogen, alkylsulfonyloxy, arylsulfonyloxy or alkanoyloxy, and

g represents hydrogen, or

Y¹And G are connected to each other by a single bond, wherein

Y¹Represents oxygen and

g representsOr is or

Y¹And G together represent a single bond, and

to produce the compound of the general formula (II),

wherein

A、R¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴The definition of (1) is as above;

a) the compound of the general formula (II) is rearranged,

a, R in the general formula (II)¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴The definition of (A) is the same as that of (B),

if appropriate in the presence of a diluent, and if appropriate in the presence of an acid or base.

2. A compound of the general formula (II)

A, R therein¹、R²、R³、R⁴、Z¹、Z²、Z³And Z⁴Is as defined in claim 1.

3. Conversion of the general formula (VIII)Compound (I)

A, R therein¹、R²、R³And R⁴Is as defined in claim 1.