Process for producing 2-(2-hydroxymethylphenyl)acetamide derivative and intermediate for the production thereof

A process for producing a compound of the formula (I): ##STR1## wherein R.sup.1 and R.sup.2 are the same or different and are hydrogen or alkyl, and R is hydrogen or alkyl, which comprises removing the protective group (P) of hydroxyl of a compound of the formula (II): ##STR2## wherein P is a protective group of hydroxyl, .about. indicates an E-isomer, Z-isomer or a mixture thereof, and the other symbols are as defined above; and an intermediate for the production of the compound of the formula (I).

This application is a 371 of PCT/JP95/02621 filed Dec. 21, 1995. 
FIELD OF THE INVENTION 
The present invention relates to a process for producing a 
2-(2-hydroxymethylphenyl)acetamide derivative, particularly a 
2-(2-hydroxymethylphenyl)-2-alkoxy(or hydroxy)iminoacetamide, which is an 
intermediate for the production of alkoxyiminoacetamide compounds useful 
as agricultural fungicides. The present invention also relates to an 
intermediate for the production of the 2-(2-hydroxymethylphenyl)acetamide 
derivative. 
BACKGROUND OF THE INVENTION 
A 2-(2-hydroxymethylphenyl)-2-alkoxy(or hydroxy)-iminoacetamide is an 
important intermediate for the production of alkoxyiminoacetamide 
derivatives useful as agricultural fungicides (see JP-A 3-246268, JP-A 
4-182461). The following processes for producing the intermediate are 
known: the process comprising reacting a 
2-(2-halomethylphenyl)-2-alkoxyiminoacetic acid ester with a metal 
acetate, followed by an amine (JP-A 3-246268), and the process comprising 
converting the halomethyl group of a 
2-(2-halomethylphenyl)-2-alkoxyiminoacetamide to a hydroxymethyl group 
(JP-A 5-097768). 
However, there is still room for improvement in these processes. 
The object of the present invention is to provide an industrially 
advantageous process for producing a 2-(2-hydroxymethylphenyl)-2-alkoxy(or 
hydroxy)iminoacetamide. 
Another object of the present invention is to provide an intermediate for 
the production of a 2-(2-hydroxymethylphenyl)-2-alkoxy(or 
hydroxy)iminoacetamide. 
DISCLOSURE OF THE INVENTION 
The present inventors have intensively researched to achieve the above 
objects. As a result, it has been found that a 
2-(2-hydroxymethylphenyl)-2-alkoxy(or hydroxy)iminoacetamide can be 
obtained by subjecting the corresponding compound in which the hydroxyl 
group of the hydroxymethyl group is protected to deprotection. Thus, the 
present invention has been accomplished. 
The present invention relates to a process for producing a compound of the 
formula (I): 
##STR3## 
wherein R.sup.1 and R.sup.2 are the same or different and are hydrogen or 
alkyl, and R is hydrogen or alkyl, which comprises removing the protective 
group (P) of hydroxyl of a compound of the formula (II): 
##STR4## 
wherein P is a protective group of hydroxyl, .about. indicates an 
E-isomer, Z-isomer or a mixture thereof, and the other symbols are as 
defined above. 
In a preferred aspect, the present invention relates to a process for 
producing a compound of the formula (I-2): 
##STR5## 
wherein R.sup.3 is alkyl and the other symbols are as defined above, which 
comprises removing a protective group (P) of hydroxyl of a compound of the 
formula (II-1): 
##STR6## 
wherein each symbol is as defined above, to obtain a compound of the 
formula (I-1): 
##STR7## 
wherein each symbol is as defined above, and then alkylating the compound 
of the formula (I-1). 
In the present invention, the compound of the formula (II) can be obtained 
by reacting a compound of the formula (IV): 
##STR8## 
wherein each symbol is as defined above, with a compound of the formula 
(III): 
EQU NH.sub.2 OR (III) 
wherein R is as defined above. 
The present invention also provides a compound of the formula (II'): 
##STR9## 
wherein R.sup.1 and R.sup.2 are the same or different and are hydrogen or 
alkyl, R is hydrogen or alkyl, P.sup.2 is aralkyl, trialkylsilyl, 
triaralkylsilyl, alkyldiarylsilyl, alkoxyalkyl, alkoxyalkoxyalkyl, 
alkylthioalkyl, tetrahydropyranyl, tetrahydrothiopyranyl, 
tetrahydrofuranyl, tetrahydrothiofuranyl or aralkyloxyalkyl, and .about. 
indicates an E-isomer, Z-isomer or a mixture thereof; and a compound of 
the formula (IV'): 
##STR10## 
wherein each symbol is as defined above (The compounds of the formulas 
(II') and (IV') are included in the above formulas (II) and (IV), 
respectively). 
The alkyl represented by R, R.sup.1, R.sup.2 and R.sup.3 in the above 
formulas includes, for example, alkyl having 1 to 8 carbon atoms, 
preferably 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isobutyl, 
sec-butyl, t-butyl, etc. In particular, methyl is preferred. 
The protective groups of hydroxyl represented by P and P.sup.2 include, for 
example, conventional protective groups of a hydroxyl group, such as 
ether-type protective groups, acetal-type protective groups, etc., 
described in T. W. Green, "Protective Groups in Organic Synthesis", p. 
1-113, John Willy & Sons (1981); C. B. Reese, "Protective Groups in 
Organic Chemistry", edited by J. F. McOmie, p. 95-143, Plenum Press 
(1973), etc. 
The ether-type protective groups include, for example, alkyl (e.g., 
C.sub.1-6 alkyl, preferably C.sub.1-4 alkyl, such as methyl, ethyl, 
propyl, t-butyl, etc.), alkenyl (e.g., C.sub.2-6 alkenyl, preferably 
C.sub.2-4 alkenyl, such as allyl, etc.), aralkyl (e.g., substituted or 
unsubstituted C.sub.6-10 aryl-C.sub.1-4 alkyl, such as benzyl, 
p-methoxybenzyl, triphenylmethyl, etc.), trialkylsilyl (e.g., 
tri(C.sub.1-6 alkyl)silyl such as triisopropylsilyl, t-butyldimethylsilyl, 
etc.), alkyldiarylsilyl (e.g., (C.sub.1-6 alkyl)di(C.sub.6-10 aryl)silyl 
such as t-butyldiphenylsilyl, etc.), triaralkylsilyl groups (e.g., 
tribenzylsilyl, etc.), etc. 
The acetal-type protective groups include, for example, alkoxyalkyl (e.g., 
C.sub.1-4 alkoxy-C.sub.1-4 alkyl such as methoxymethyl, 1-ethoxyethyl, 
1-methyl-1-methoxyethyl, etc.), alkoxyalkoxyalkyl (e.g., C.sub.1-4 
alkoxy-C.sub.1-4 alkoxy-C.sub.1-4 alkyl such as methoxyethoxymethyl, 
etc.), alkylthioalkyl (e.g., C.sub.1-4 alkylthio-C.sub.1-4 alkyl such as 
methylthiomethyl, etc.), tetrahydropyranyl (e.g., tetrahydropyran-2-yl, 
4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (e.g., 
tetrahydrothiopyran-2-yl, etc.), tetrahydrofuranyl (e.g., 
tetrahydrofuran-2-yl, etc.), tetrahydrothiofuranyl (e.g., 
tetrahydrothiofuran-2-yl, etc.), aralkyloxyalkyl (e.g., benzyloxymethyl, 
etc.), etc. 
Preferably, the protective groups are removable by acid treatment, 
particularly removable by acid treatment and stable under conditions for 
the synthesis of a Grignard reagent (e.g., the compound (VIII) described 
below) or basic conditions. Preferred examples of the protective groups 
include aralkyl (e.g., triphenylmethyl, etc.), trialkylsilyl (e.g., 
t-butyldimethylsilyl, triisopropylsilyl, etc.), triaralkylsilyl (e.g., 
tribenzylsilyl, etc.), alkoxyalkyl (e.g., methoxymethyl, 1-ethoxyethyl, 
1-methyl-1-methoxyethyl, etc.), tetrahydropyranyl (e.g., 
tetrahydropyran-2-yl, etc.), tetrahydrothiopyranyl (e.g., 
tetrahydrothiopyran-2-yl, etc.), tetrahydrofuranyl (e.g., 
tetrahydrofuran-2-yl, etc.), tetrahydrothiofuranyl (e.g., 
tetrahydrothiofuran-2-yl, etc.), etc. In particular, tetrahydropyran-2-yl, 
1-ethoxyethyl and tetrahydrofuran-2-yl are preferred. 
The compounds of the formulas (II) and (II-1) and (II-2) described below 
exist as E- or Z-isomers. These compounds include E- or Z-isomers and 
mixtures thereof unless otherwise indicated. In the above formulas, this 
is indicated by the wave line .about.. 
The compounds of the formulas (I), (I-1), (I-2) and (II-1) may be in salt 
forms. Examples of the salts include alkaline metal salts (e.g., sodium 
salts, potassium salts, lithium salts, etc.), etc. 
Preferred examples of the compound of the formula (I) include the compound 
of the formula (I) wherein R is a hydrogen atom or methyl, and R.sup.1 and 
R.sup.2 are a hydrogen atom; and the compound of the formula (I) wherein R 
is a hydrogen atom or methyl, and any one of R.sup.1 and R.sup.2 is a 
hydrogen atom and the other is methyl. 
Preferred embodiments of the process of the present invention are as 
follows. 
The desired compound of the formula (I) (hereinafter sometimes abbreviated 
to the compound (I); the other compounds are also abbreviated in the same 
manner) consists of the compound (I-1) wherein R is a hydrogen atom and 
the compound (1-2) wherein R is alkyl. The compound (I-1) can be prepared 
according to Scheme 1,and the compound (I-2) can be prepared according to 
Scheme 3 or 4. 
##STR11## 
wherein each symbol is as defined above. 
That is, the compound (I-1) can be obtained by removing the protective 
group (P) of hydroxyl of the compound (II-1). 
In this reaction, the protective group of hydroxyl is removed and the 
isomerization to the E-isomer proceeds at the same time. Therefore, a 
separate isomerization step to the E-isomer is not required, and the 
compound (I-1) can be obtained in high yield and purity. 
This reaction can be carried out by conventional deprotection methods of 
protected hydroxyl, for example, by those described in T. W. Green, 
"Protective Groups in Organic Synthesis", p. 1-113, John Willy & Sons 
(1981); C. B. Reese, "Protective Groups in Organic Chemistry", edited by 
J. F. McOmie, p. 95-143, Plenum Press (1973), etc. 
For example, when the protective group of hydroxyl is alkyl (e.g., t-butyl, 
etc.), alkenyl (e.g., allyl, etc.), aralkyl (e.g., triphenylmethyl, etc.), 
trialkylsilyl (e.g., t-butyldimethylsilyl, triisopropylsilyl, etc.), 
alkyldiarylsilyl (e.g., t-butyldiphenylsilyl, etc.), triaralkylsilyl 
(e.g., tribenzylsilyl, etc.), alkoxyalkyl (e.g., methoxymethyl, 
1-ethoxyethyl, 1-methyl-1-methoxyethyl, etc.), alkoxyalkoxyalkyl (e.g., 
methoxyethoxymethyl, etc.), alkylthioalkyl (e.g., methylthiomethyl, etc.), 
tetrahydropyranyl (e.g., tetrahydropyran-2-yl, 
4-methoxytetrahydropyran-4-yl, etc.), tetrahydrothiopyranyl (e.g., 
tetrahydrothiopyran-2-yl, etc.), tetrahydrofuranyl (e.g., 
tetrahydrofuran-2-yl, etc.), tetrahydrothiofuranyl (e.g., 
tetrahydrothiofuran-2-yl, etc.), or aralkyloxyalkyl (e.g., 
benzyloxymethyl, etc.), the deprotection can be carried out by treating 
the compound (II-1) with an acid. 
The acids that can generally be used include, for example, inorganic acids 
such as hydrohalogenic acids (e.g., hydrochloric acid, hydrobromic acid, 
hydroiodic acid, etc.), hydrogen halides (e.g., hydrogen chloride, 
hydrogen bromide, hydrogen iodide, etc.), boric acid, phosphoric acid, 
sulfuric acid, etc.; sulfonic acids (e.g., aliphatic sulfonic acids such 
as trifluoromethanesulfonic acid and aromatic sulfonic acids such as 
toluenesulfonic acid, etc.), carboxylic acids (e.g., acetic acid, 
trifluoroacetic acid, etc.), silica gel, Lewis acids e.g., aluminium 
halides (e.g., aluminium chloride, etc.), zinc chloride, titanium 
tetrachloride, etc.!. One or more appropriate acids can be selected from 
these acids. 
The amount of the acid to be used is a trace amount to 1 equivalent. 
Alternatively, carboxylic acids can be used as solvents. 
The solvents to be used include, for example, hydrocarbons (e.g., benzene, 
toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, 
1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), 
alcohols (e.g., methanol, ethanol, etc.), nitriles (e.g., acetonitrile, 
etc.), water, etc., and mixed solvent thereof. The reaction temperature is 
--80.degree. to 150.degree. C., preferably -10.degree. to 80.degree. C. 
The reaction time is 1 minute to 3 hours, preferably 5 minutes to 1 hour. 
When the protective group is substituted silyl, the protective group can 
also be removed under basic conditions (e.g., sodium 
hydroxide/water-containing ethanol, etc.) or in the presence of fluoride 
anion (e.g., n-Bu.sub.4 N.sup.+ F.sup.-, C.sub.5 H.sub.5 N.sup.+ HF.sup.-, 
etc.). 
Since the compound (I-1) thus obtained has a high E-isomer/Z-isomer ratio 
in which the preferred E-isomer predominates, it can be used in the next 
step as the reaction mixture or crude product, or if necessary, after 
purifying it by conventional methods (e.g., column chromatography, 
recrystallization, etc.). 
The compound (II-1) that can be used as the starting material of this 
reaction can preferably be prepared according to Scheme 2 below. 
##STR12## 
wherein each symbol is as defined above. 
That is, the compound (II-1) can be prepared by reacting the compound (IV) 
with hydroxylamine and/or its salt in an appropriate solvent. 
The amount of the hydroxylamine to be used is 1 to 4 equivalents, 
preferably 1 to 3 equivalents, based on the compound (IV). 
The hydroxylamine salts include, for example, salts with mineral acid such 
as hydrochloric acid, sulfuric acid, etc. When the hydroxylamine salts are 
used, the salts are neutralized with a base so as not to remove the 
protective group of hydroxyl. The bases that can be used include, for 
example, metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, 
etc.), metal carbonates (e.g., sodium carbonate, potassium carbonate, 
etc), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, etc.), 
amines (e.g., pyridine, etc.), etc. The amount of the base to be used is 1 
to 3 equivalents, preferably 1 to 2 equivalents, based on the 
hydroxylamine salt. 
The solvents that can be used include, for example, hydrocarbons (e.g., 
benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., 
chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, 
dioxane, etc.), alcohols (e.g., methanol, ethanol, n-propanol, 
isopropanol, etc.), water, etc., and mixed solvent thereof. 
The reaction temperature is 0.degree. to 150.degree. C., preferably 
20.degree. to 100.degree. C. The reaction time is normally about 15 
minutes to 24 hours. 
The compound (II-1) thus obtained can be used in the next step as the 
reaction mixture or the crude product, or after purifying it by 
conventional methods (e.g., column chromatography, recrystallization, 
etc.). 
The compound (I-2) can be prepared according to Scheme 3 below. 
##STR13## 
wherein each symbol is as defined above. 
That is, the compound (I-2) can be prepared by reacting the compound (I-1) 
with an alkylating agent in the presence of a base in an appropriate 
solvent to alkylate the compound (I-1). 
The alkylating agents include, for example, dialkyl sulfates (e.g., 
di(C.sub.1-6 alkyl) sulfates such as dimethyl sulfate, diethyl sulfate, 
etc.), alkyl halides (e.g., C.sub.1-6 alkyl halides such as methyl 
chloride, methyl bromide, methyl iodide, etc.), etc. The amount of the 
alkylating agent to be used is 1 to 10 mol, preferably 1 to 1.5 mol, per 
mol of the compound (I-1). 
The solvents include, for example, ketones (e.g., acetone, ethyl methyl 
ketone, etc.), ethers (e.g., tetrahydrofuran, dioxane, etc.), hydrocarbons 
(e.g., toluene, benzene, hexane, cyclohexane, etc.), halogenated 
hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), alcohols 
(e.g., methanol, ethanol, etc.), water, etc., and mixed solvent thereof. 
The bases include, for example, metal carbonates (e.g., sodium carbonate, 
potassium carbonate, etc.), metal hydroxides (e.g., sodium hydroxide, 
potassium hydroxide, lithium hydroxide, etc.), metal hydrides (e.g., 
sodium hydride, lithium hydride, etc.), etc. The amount of the base to be 
used is 1 to 10 mol, preferably 1 to 2 mol, per mol of the compound (I-1). 
If necessary, this reaction can be carried out in the presence of a 
phase-transfer catalyst. The phase-transfer catalysts include, for 
example, quaternary ammonium salts e.g., tetraalkylammonium halides 
(e.g., tetrabutylammonium chloride, tetrabutylammonium bromide, etc.), 
tetraalkylammonium hydrosulfates (e.g., tetrabutylammonium hydrosulfate, 
etc.), etc.!, amines (e.g., tris(3,6-dioxaheptyl)amine, etc.), etc. The 
amount of the phase-transfer catalyst to be used is 0.01 to 1 mol, 
preferably 0.01 to 0.2 mol, per mol of the compound (I-1). 
The reaction temperature is normally -20.degree. to 100.degree. C., 
preferably 0.degree. to 50.degree. C., and the reaction time is normally 1 
to 24 hours. 
The compound (I-2) thus obtained can be used in the next step as the 
reaction mixture or crude product, or after purifying it by conventional 
methods (e.g., column chromatography, recrystallization, etc.). 
Alternatively, the compound (I-2) can be prepared according to Scheme 4 
below. 
##STR14## 
wherein each symbol is as defined above. 
That is, the compound (I-2) can be prepared by removing the protective 
group (P) of hydroxyl of the compound (II-2). 
In this reaction, the protective group of hydroxyl group is removed and the 
isomerization to the E-isomer proceeds at the same time. Therefore, a 
separate isomerization step to the E-isomer is not required, and the 
compound (I-2) can be obtained in high yield and purity. 
This reaction can be carried out under the same reaction conditions as 
those of the reaction of Scheme 1. 
The compound (I-2) thus obtained can be used in the next step as the 
reaction mixture or crude product, or after purifying it by conventional 
methods (e.g., column chromatography, recrystallization, etc.). 
The compound (II-2) that can be used as the starting material of the 
reaction of Scheme 4 can preferably be prepared according to Scheme 5 
below. 
##STR15## 
wherein each symbol is as defined above. 
That is, the compound (II-2) can be prepared by reacting the compound (IV) 
with the compound (III-1) and/or its salts. The salts of the compound 
(III-1) include the same salts as those of the hydroxylamine of Scheme 2. 
This reaction can be carried out under the same reaction conditions as 
those of the reaction of Scheme 2. 
The compound (II-2) thus obtained can be used in the next step as the 
reaction mixture or crude product, or after purifying it by conventional 
methods (e.g., column chromatography, recrystallization, etc.). 
The compound (IV) that can be used as the starting material in Scheme 2 or 
5 can preferably be prepared according to Scheme 6 below. 
##STR16## 
wherein L is a halogen atom or alkoxy, and the other symbols are as 
defined above. 
That is, the compound (IV) can be prepared by reacting the compound (VI) 
with the compound (V). 
The halogen atoms represented by L include fluorine, chlorine, bromine and 
iodine. In particular, chlorine and bromine are preferred. 
The alkoxy represented by L includes alkoxy having 1 to 6 carbon atom, 
preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, etc. 
The compound (V) is added dropwise to the compound (VI) without diluting 
the compound (V) with a solvent, or after diluting it with an appropriate 
solvent. Alternatively, the gaseous compound (V) is introduced into the 
compound (VI). 
The amount of the compound (V) is 1 to 10 equivalents, preferably 1 to 5 
equivalents, based on the compound (VI). When the compound (VI) is an 
.alpha.-ketoacid halide, the amount of the compound (V) is preferably 2 to 
6 equivalents based on the compound (VI). 
When an isolated .alpha.-ketoacid ester is used as the compound (VI), it is 
diluted with an appropriate solvent. The solvents include, for example, 
hydrocarbons (e.g., benzene, toluene, xylene, etc.), halogenated 
hydrocarbons (e.g., dichloromethane, 1,2-dichloroethane, etc.), ethers 
(e.g., tetrahydrofuran, dioxane, etc.), alcohols (e.g., methanol, ethanol, 
etc.), water, etc., and mixed solvents thereof. 
The compound (V) is added dropwise or introduced at -75.degree. to 
50.degree. C., preferably -60.degree. to 30.degree. C., over 5 minutes to 
2 hours, preferably 15 minutes to 1 hour. Then, the reaction is carried 
out at -50.degree. to 100.degree. C., preferably -30.degree. to 60.degree. 
C., for 1 minute to 5 hours, preferably 10 minutes to 2 hours, to obtain 
the compound (IV). 
The compound (IV) thus obtained can be used in the next step as the 
reaction mixture or crude product, or after purifying it by conventional 
methods (e.g., column chromatography, recrystallization, etc.). 
The compound (VI) that can be used as the starting material in the reaction 
of Scheme 6 can preferably be prepared according to Scheme 7 below. 
##STR17## 
wherein X is a halogen atom, and the other symbols are as defined above. 
That is, the compound (VI) can be prepared by reacting the compound (VIII) 
with the compound (VII). 
The halogen atoms represented by X include fluorine, chlorine, bromine, and 
iodine. In particular, chlorine, bromine or iodine is preferred. 
Normally, a solution of the compound (VIII) is added dropwise to a solution 
of the compound (VII) in an appropriate solvent. The amount of the 
compound (VII) to be used is 1 to 4 equivalents, preferably 1 to 2 
equivalents, based on the compound (VIII). 
The addition is carried out at -100.degree. to 50.degree. C., preferably 
-70.degree. to 30.degree. C., over 5 minutes to 2 hours, preferably 15 
minutes to 1 hour. Then, the reaction is carried out at -100.degree. to 
50.degree. C., preferably -80.degree. to 30.degree. C., for 5 minutes to 2 
hours, preferably 15 minutes to 1 hour. 
The solvents include ethers such as THF, diethyl ether, dibutyl ether, 
etc., and hydrocarbons such as toluene. 
Examples of the compound (VII) include oxalyl halides such as oxalyl 
chloride, oxalyl bromide, etc., oxalic acid esters such as dimethyl 
oxalate, diethyl oxalate, etc., alkyloxalyl chlorides such as methyloxalyl 
chloride, ethyloxalyl chloride, etc. 
Alternatively, the compound (VII) which is not diluted or diluted with an 
appropriate solvent can be added dropwise to the compound (VIII) for the 
reaction. The solvent and the reaction conditions may be the same as those 
described above. 
When the compound (VI) thus obtained is an .alpha.-ketoacid halide, it can 
be used in the next step as the reaction mixture. When it is an 
.alpha.-ketoacid ester, it can be used in the next step as the reaction 
mixture or crude product, or after purifying it by conventional methods 
(e.g., column chromatography, recrystallization, etc.). 
Alternatively, when the compound (VI) is an .alpha.-ketoacid ester, the 
compound (VIII) in which the MgX is replaced with Li is used as the 
starting material and reacted with the compound (VII). 
The compound of the formula (VI'): 
##STR18## 
wherein each symbol is as defined above, included in the above compound 
(VI), is a novel compound and included in the present invention. 
L is preferably alkoxy. 
The compound (VIII) that can be used as the starting material of the 
reaction of Scheme 7 can preferably be prepared according to Scheme 8 
below. 
##STR19## 
wherein each symbol is as defined above. 
That is, the compound (VIII) can be prepared by reacting the compound (IX) 
with magnesium in an appropriate solvent. 
Normally, magnesium in an amount of 1 to 4 equivalents, preferably 1 to 2 
equivalents, based on the compound (IX) is reacted with the compound (IX). 
The solvents to be used include ethers such as dry THF, diethyl ether, 
dibutyl ether, etc. These solvents can be used alone or as mixtures with 
other solvents such as hydrocarbons (e.g., toluene, etc.), amines (e.g., 
triethylamine, etc.), etc. 
The reaction temperature is room temperature to 150.degree. C., preferably 
40.degree. to 100.degree. C. The reaction time is 10 minutes to 48 hours, 
preferably 30 minutes to 6 hours. 
If necessary, a small amount of iodine, dibromoethane, ethyl bromide, etc., 
is used as an activator of the reaction. The amount of the activator is 
0.001 to 0.4 equivalents, preferably 0.005 to 0.2 equivalents. 
The compound (VIII) in which the MgX is replaced with Li can be prepared by 
reacting the compound (IX) with metal lithium or an alkyllithium (e.g., 
n-butyllithium, etc.). 
The compound (VIII) thus obtained can be used in the next step as the 
reaction mixture or crude product. 
The compound (IX) that can be used as the starting material of the reaction 
of Scheme 8 can preferably be prepared according to Scheme 9. 
##STR20## 
wherein each symbol is as defined above. 
That is, the compound (IX) can be prepared by protecting the hydroxyl of 
the commercially available compound (X) with an appropriate protective 
group. 
The hydroxyl can be protected by conventional protection methods of 
hydroxyl, for example, by those described in T. W. Green, "Protective 
Groups in Organic Synthesis", p. 1-113, John Willy & Sons (1981); C. B. 
Reese, "Protective Groups in Organic Chemistry", edited by J. F. McOmie, 
p. 95-143, Plenum Press (1973). 
For example, the compound (IX) protected with tetrahydropyranyl, 
tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 
1-ethoxyethyl or 1-methyl-1-methoxyethyl can be prepared by reacting the 
corresponding olefins with the compound (X) in the presence of an acid 
catalyst in an appropriate solvent or in the absence of a solvent. 
The corresponding olefins are 3,4-dihydro-2H-pyran, 2,3-dihydro-4H-thiin, 
dihydrofuran, dihydrothiofuran, ethyl vinyl ether and 2-methoxypropene, 
respectively. These compounds are commercially available or can be 
prepared by known methods. 
The amount of the olefin to be used is 1 to 3 equivalents, preferably 1 to 
2 equivalents, based on the compound (X). 
The acid catalysts include, for example, hydrogen chloride, phosphorus 
oxychloride, p-toluenesulfonic acid, p-toluenesulfonic acid pyridine salt, 
montmorillonite, bistrimethyl sulfate, acetic acid, pyridinium polyvinyl 
p-toluenesulfonate, trifluoroacetic acid, boron trifluoride etherate 
(BF.sub.3.OEt.sub.2), acidic ion exchange resins, etc. 
When the solvent is used, a non-alcoholic solvent can be used. Examples of 
the solvents include hydrocarbons (e.g., benzene, toluene, xylene, etc.), 
halogenated hydrocarbons (e.g., chloroform, dichloromethane, etc.), ethers 
(e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), esters (e.g., ethyl 
acetate, etc.), N,N-dimethylformamide, etc., and mixture thereof. 
The reaction temperature is -30.degree. to 100.degree. C., preferably 
0.degree. to 60.degree. C. 
The reaction time is normally about 15 minutes to 24 hours. 
The silyl ether compound (IX) can be obtained by reacting the compound (X) 
with an appropriate silylating agent. In general, chlorosilane is used as 
the silylating agent, and reacted with the compound (X) in the presence of 
a base in an appropriate solvent. 
The chlorosilane is commercially available or can be prepared by known 
methods. 
The amount of the chlorosilane to be used is 1 to 5 equivalents, preferably 
1 to 2 equivalents, based on the compound (X). The bases to be used 
include organic bases (e.g., N,N-dimethylaniline, pyridine, triethylamine, 
imidazole, etc.), metal carbonates (e.g., sodium carbonate, potassium 
carbonate, etc.), metal hydrides (e.g., sodium hydride, potassium hydride, 
etc.), metal bicarbonates (e.g., sodium bicarbonate, potassium 
bicarbonate, etc.), etc. The amount of the base to be used is 1 equivalent 
or more, preferably 1 to 2 equivalents. 
The solvents to be used include hydrocarbons (e.g., hexane, benzene, 
toluene, xylene, etc.), halogenated hydrocarbons (e.g., chloroform, 
dichloromethane, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, 
dioxane, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), 
nitrites (e.g., acetonitrile, etc.), N,N-dimethylformamide, 
dimethylsulfoxide, etc., and mixed solvent thereof. 
The reaction temperature is -20.degree. to 100.degree. C., preferably 
0.degree. to 60.degree. C. 
The reaction time is 5 minutes to 30 hours, preferably 30 minutes to 15 
hours. 
The compound (IX) protected with methoxymethyl or triphenylmethyl and the 
above compound (IX) protected with tetrahydrofuranyl or 1-ethoxyethyl can 
be obtained by reacting the corresponding halides with the compound (X) in 
the presence of a base. 
The corresponding halides are halomethyl methyl ethers, triphenylmethyl 
halides, 2-halotetrahydrofurans and 1-haloethylethers, respectively. These 
compound are commercially available or can be prepared by known methods. 
As the halides, chlorides or bromides can be used. 
The amount of the halide to be used, the kinds of bases and solvents, and 
the reaction conditions, etc., are the same as those of the reaction 
between the above chlorosilane and the compound (X). 
The above compound (IX) protected with methoxymethyl can also be obtained 
by reacting the compound (X) with dimethoxymethane in the presence of an 
appropriate catalyst (e.g., phosphorus pentaoxide, etc.). 
The solvents to be used and the reaction conditions are the same as those 
of the above reaction between the olefin and the compound (X). 
The compound (IX) thus obtained can be used in the next step as the crude 
product or after purifying it by conventional methods (e.g., column 
chromatography, recrystallization, etc.). 
The compound of the formula (IX'): 
##STR21## 
wherein X is a halogen atom, P.sup.1 is aralkyl, triaralkylsilyl, 
alkoxyalkyl, alkoxyalkoxyalkyl, alkylthioalkyl, tetrahydropyranyl, 
tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or 
aralkyloxyalkyl, included in the above compound (IX), is a novel compound 
and included in the present invention. Examples of each group represented 
by P.sup.1 are the same as those represented by P. 
The compound (I-2) obtained in the reactions of Schemes 3 and 4 can 
conveniently be converted to the alkoxyiminoacetamide compound (XI) that 
has potent fungicidal activity and is useful as an agricultural fungicide, 
for example, according to Scheme 10 below (JP-A 3-246268, JP-A 4-182461). 
Thus, the compound (I-2) is important as an intermediate for the 
production. 
##STR22## 
wherein A is optionally substituted phenyl or an optionally substituted 
heterocyclic group, X' is as defined as X, and the other symbols are as 
defined above. 
That is, the compound (I-2) is reacted with the compound (XII) according to 
JP-A 3-246268 or JP-A 4-182461 to obtain the compound (XI). 
The phenyl represented by A includes substituted or unsubstitued phenyl. 
The heterocyclic groups represented by A include, for example, 
heterocyclic groups containing at least one ring-constituting heteroatom 
selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, 
oxazolyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, 
quinolyl, etc. When these groups are substituted, preferred examples of 
the substituent include methyl, trifluoromethyl, trichloromethyl, 
fluorine, chlorine, methoxy, etc.

EXAMPLES 
The following examples and reference examples further illustrate the 
present invention in detail, but are not to be construed to limit the 
scope of the invention. 
Example 1 
Preparation of 1-bromo-2-(1-ethoxyethyl)oxymethyl-benzene 
Pyridinium p-toluenesulfonate (0.50 g, 0.002 mol) was added to a mixed 
solution of 2-bromobenzyl alcohol (18.70 g, 0.1 mol), dichloromethane (150 
ml) and ethyl vinyl ether (14.42 g, 0.2 mol) under ice-cooling, and the 
mixture was stirred at room temperature for 3 hours. After completion of 
the reaction, a half-saturated aqueous solution (300 ml) of sodium 
bicarbonate was added, and the mixture was extracted with dichloromethane 
(100 ml) twice. The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure to obtain 
1-bromo-2-(1-ethoxyethyl)oxymethyl-benzene (25.44 g, Yield: 98.2%) as a 
colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.22(3H,t,J=7.3), 1.41 (3H,t,J=5.5), 
3.49-3.77(2H,m), 4.59(1H,d,J=12.8), 4.70 (1H,d,J=12.8), 4.87(1H,q,J=5.5), 
7.11-7.55(4H,m). 
Example 2 
Preparation of 1-bromo-2-(2-tetrahydropyranyloxy-methyl)benzene 
Pyridinium p-toluenesulfonate (0.30 g, 0.0012 mol) was added to a solution 
of 2-bromobenzyl alcohol (25 g, 0.134 mol) in dichloromethane (100 ml), 
and the mixture was stirred at room temperature. To this mixture was added 
3,4-dihydro-2H-pyrane (16.86 g, 0.20 mol). After the resulting mixture was 
stirred at room temperature for 2 hours, a saturated aqueous solution (200 
ml) of sodium bicarbonate was added. The mixture was extracted with 
dichloromethane (200 ml). After the mixture was dried over anhydrous 
magnesium sulfate, the solvent was evaporated to obtain the desired 
compound 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (36.00 g, Yield: 
99.3%) as an oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.45-1.80(6H,m), 3.45-3.55(1H,m), 
3.80-3.90(1H,m), 4.52(1H,d,J=15.0), 4.80(1H,m), 4.90(1H,d,J=15.0), 
7.16(1H,t,J=7.3), 7.31(1H,t,J=7.3), 7.51(1H,d,J=7.3), 7.54(1H,d,J=7.3). 
Example 3 
Preparation of ethyl 2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-oxoacetate 
A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (3.11 g, 
0.012 mol) and dry THF (10 ml) was added dropwise at 50.degree. to 
60.degree. C. over 25 minutes to a solution prepared by adding dry THF (2 
ml) and ethyl bromide (0.2 ml) to magnesium (0.44 g, 0.018 mol) in a 
stream of nitrogen. After completion of the addition, the mixture was 
stirred at 50.degree. to 60.degree. C. for 1 hour and cooled to room 
temperature. After cooling, the mixture was added dropwise to a mixed 
solution of ethyl oxalate (2.63 g, 0.018 mol) and dry THF (30 ml) at below 
-50.degree. C. over 15 minutes. Then, the mixture was stirred at 
-50.degree. to -60.degree. C. for 1 hour. After completion of the 
reaction, water (200 ml) was added, and the mixture was extracted with 
ether (200 ml). The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure. The resulting residue was purified by 
silica gel chromatography (ethyl acetate/n-hexane) to obtain ethyl 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-oxoacetate (2.30 g, Yield: 68.4%) 
as a colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.19(3H,t,J=7.3), 1.36 (3H,d,J=5.5), 
1.41(3H,t,J=7.3), 3.47-3.68(2H,m), 4.42 (2H,q,J=7.3), 4.78-5.01(3H,m), 
7.32-7.71(4H,m). 
Example 4 
Preparation of ethyl 
2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetate 
Magnesium (2.67 g, 0.11 mol) and bromoethane (0.2 ml) were added to a mixed 
solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (27.11 g, 0.10 
mol) and THF (50 ml) under an atmosphere of nitrogen gas. The mixture was 
stirred at room temperature for 1 hour to prepare a Grignard reagent. The 
Grignard reagent was added dropwise to a mixed solution of diethyl oxalate 
(29.23 g, 0.20 mol) and THF (100 ml) cooled to -78.degree. C. The mixture 
was stirred at -78.degree. C. for 1 hour, water (150 ml) was added, and 
the mixture was extracted with ether (200 ml). The extract was dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure. The 
resulting residue was purified by silica gel chromatography (ethyl 
acetate/n-hexane) to obtain ethyl 
2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetate (22.60 g, Yield: 
77.3%) as a colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.38(3H,t,J=7.0), 1.40-1.85(6H,m), 
3.50-3.60(1H,m), 3.80-3.90(1H,m), 4.32-4.40(2H,m), 4.69(1H,m), 
4.85(1H,d,J=14.6), 5.09(1H,d,J=14.6), 7.43(1H,t,J=7.3), 7.58-7.70(3H,m). 
Example 5 
Preparation of 
2-2-{(1-ethoxyethyl)oxymethyl}-phenyl!-N-methyl-2-oxoacetamide 
A 40% methylamine-methanol solution (1.63 g, 0.021 mol) was added to a 
mixed solution of ethyl 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-oxoacetate (1.96 g, 0.007 mol) 
and THF (7 ml) under ice-cooling. The mixture was stirred at room 
temperature for 1 hour. After completion of the reaction, water (100 ml) 
was added, and the mixture was extracted with dichloromethane (80 ml) 
twice. The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure. The resulting residue was purified by 
silica gel chromatography (ethyl acetate/n-hexane) to obtain 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (1.35 g, 
Yield: 72.7%) as a colorless oil. .sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 
1.17(3H,t,J=7.3), 1.29(3H,d,J=4.9), 2.96(3H,d,J=5.5), 3.41-3.63(2H,m), 
4.70-4.92(3H,m), 7.04(1H,brs), 7.33-7.84(4H,m). 
Example 6 
Preparation of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide 
A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (7.77 g, 0.03 
mol) and dry THF (27 ml) was added dropwise at 50.degree. to 60.degree. C. 
over 30 minutes to a solution prepared by adding dry THF (3 ml) and ethyl 
bromide (0.2 ml) to magnesium (1.09 g, 0.045 mol) in a stream of nitrogen. 
After completion of the addition, the mixture was stirred at 50.degree. to 
60.degree. C. for 1 hour and cooled to room temperature. After cooling, 
the mixture was added dropwise to a mixed solution of ethyl oxalate (6.58 
g, 0.045 mol) and dry THF (50 ml) at below -60.degree. C. over 15 minutes. 
Then, the mixture was stirred at -60.degree. to -70.degree. C. for 1 hour. 
A 40% methylamine-methanol solution (11.65 g, 0.15 mol) was added to the 
reaction mixture, and the temperature of the mixture was raised from 
-50.degree. C. to room temperature over 1 hour. After completion of the 
reaction, water (500 ml) was added, and the mixture was extracted with 
ether (300 ml), followed by dichloromethane (300 ml). The extract was 
combined, dried over anhydrous magnesium sulfate and concentrated under 
reduced pressure. The resulting residue was purified by silica gel 
chromatography (ethyl acetate/n-hexane) to obtain 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (3.83 g, 
Yield: 48.1%) as a colorless oil. 
Example 7 
Preparation of 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide 
A 40% methylamine-methanol solution (2.65 g, 0.0341 mol) was added to a 
mixed solution of ethyl 
2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetate (2.00 g, 0.0068 
mol) and methanol (20 ml). The mixture was stirred at room temperature for 
2 hours. After completion of the reaction, the mixture was concentrated 
under reduced pressure. The resulting residue was purified by silica gel 
chromatography (ethyl acetate/n-hexane) to obtain 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide (1.30 
g, Yield: 69.0%) as a colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.49-1.80(6H,m), 2.96(3H,d,J=4.9), 
3.47-3.52(1H,m), 3.77-3.86(1H,m), 4.62(1H,t,J=3.1), 4.76(1H,d,J=13.4), 
4.98(1H,d,J=13.4), 7.06(1H,brs), 7.34-7.80(4H,m). 
Example 8 
Preparation of 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide 
A mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (2.71 
g, 0.01 mol) and dry THF (8 ml) was added dropwise at 50.degree. to 
60.degree. C. over 20 minutes to a solution prepared by adding dry THF (2 
ml) and ethyl bromide (0.1 ml) to magnesium (0.36 g, 0.015 mol) in a 
stream of nitrogen. After completion of the addition, the mixture was 
stirred at 50.degree. to 60.degree. C. for 1 hour and cooled to room 
temperature. After cooling, the mixture was added dropwise to a mixed 
solution of oxalyl chloride (1.90 g, 0.015 mol) and dry THF (30 ml) at 
below -50.degree. C. over 15 minutes. Then, the mixture was stirred at 
-60.degree. to -70.degree. C. for 40 minutes. A 40% methylamine-methanol 
solution (4.66 g, 0.06 mol) was added to the reaction mixture, and the 
mixture was stirred at -20.degree. to -10.degree. C. for 30 minutes. After 
completion of the reaction, water (150 ml) was added, and the mixture was 
extracted with ether (150 ml). The extract was washed with saturated 
brine, dried over anhydrous magnesium sulfate and concentrated under 
reduced pressure. The resulting residue was purified by silica gel 
chromatography (ethyl acetate/n-hexane) to obtain 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide(1.18 g, 
Yield: 42.5%) as a colorless oil. 
Example 9 
Preparation of 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide 
A mixed solution of 1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene (2.71 
g, 0.01 mol) and dry THF (8 ml) was added dropwise at 50.degree. to 
60.degree. C. over 20 minutes to a solution prepared by adding dry THF (2 
ml) and ethyl bromide (0.1 ml) to magnesium (0.36 g, 0.015 mol) in a 
stream of nitrogen. After completion of the addition, the mixture was 
stirred at 50.degree. to 60.degree. C. for 1 hour and cooled to room 
temperature. After cooling, the mixture was added dropwise to a mixed 
solution of ethyl oxalate (2.19 g, 0.015 mol) and dry THF (20 ml) at below 
-60.degree. C. over 10 minutes. Then, the mixture was stirred at 
-60.degree. to -70.degree. C. for 1 hour. A 40% methylamine-methanol 
solution (3.88 g, 0.05 mol) was added to the reaction mixture, and the 
temperature of the mixture was raised from -50.degree. C. to room 
temperature over 1 hour. After completion of the reaction, water (200 ml) 
was added, and the mixture was extracted with ether (200 ml). The extract 
was washed with saturated brine, dried over anhydrous magnesium sulfate 
and concentrated under reduced pressure. The resulting residue was 
purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide (1.21 
g, Yield: 43.6%) as a colorless oil. 
Example 10 
Preparation of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-hydroxyimino-N-methylacetamide 
Methanol (4 ml) and 50% aqueous hydroxylamine solution (0.4 g, 0.006 mol) 
were added to 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (0.53 g, 
0.002 mol). The mixture was stirred under reflux for 5 hours. After 
completion of the reaction, water (100 ml) was added, and the mixture was 
extracted with dichloromethane (50 ml) twice. The extract was dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure. The 
resulting residue was purified by silica gel chromatography (ethyl 
acetate/n-hexane) to obtain 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-hydroxyimino-N-methylacetamide 
(Isomer A: 0.21 g (Yield: 37.5%), colorless oil; Isomer B: 0.14 g (Yield: 
25.0%), colorless crystals). 
Isomer A: 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.67(3H,t,J=7.3), 1.30(3H,d, J=5.5), 
2.82(3H,d,J=5.5), 3.42-3.63(2H,m), 4.54(1H,d,J=11.6), 4.66(1H,d,J=11.6), 
4.73(1H,q,J=5.5), 6.00(1H,brs), 7.30-7.49(4H,m). 
Isomer B: mp 85.degree.-87.degree. C. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.16(3H,t,J=7.3), 1.28(3H,d, J=4.9), 
2.90(3H,d,J=4.9), 3.44-3.61(2H,m), 4.44(1H,d,J=12.8), 4.58(1H,d,J=12.8), 
4.71(1H,q,J=5.5), 6.72(1H,brs), 7.18-7.51(4H,m), 8.30(1H,brs). 
Example 11 
Preparation of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-methoxyimino-N-methylacetamide 
Methoxyamine hydrochloride (0.50 g, 0.006 mol) was dissolved in methanol (6 
ml), and a 28% sodium methoxide-methanol solution (1.45 g, 0.0075 mol) was 
added to the solution to obtain a suspension. A mixed solution of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (0.80 g, 
0.003 mol) and methanol (3 ml) was added to the suspension, and the 
mixture was stirred under reflux for 1 hour. After completion of the 
reaction, half-saturated brine (150 ml) was added, and the mixture was 
extracted with dichloromethane (100 ml) twice. The extract was dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure. The 
resulting residue was purified by silica gel chromatography (ethyl 
acetate/n-hexane) to obtain an E/Z mixture of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-methoxyimino-N-methylacetamide 
(0.82 g, Yield: 92.8%) as a colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.18(1.20)(3H,t,J=7.3), 
1.28(1.33)(3H,d,J=5.5), 2.87(2.91)(3H,d,J=4.9), 3.41-6.64(2H,m), 
3.95(4.00)(3H,s), 4.36-4.83(3H,m), 6.76(7.01) (1H,brs), 7.14-7.49(4H,m). 
Example 12 
Preparation of 
2-methoxyimino-N-methyl-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamid 
e 
Methoxyamine hydrochloride (0.33 g, 0.004 mol) was dissolved in methanol (4 
ml), and pyridine (0.47 g, 0.006 mol) was added to the solution. To the 
mixture was added a mixed solution of 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide (0.55 
g, 0.002 mol) and methanol (2 ml). The mixture was stirred under reflux 
for 2 hours. After completion of the reaction, half-saturated brine (100 
ml) was added, and the mixture was extracted with dichloromethane (80 ml) 
twice. The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure. The resulting residue was purified by 
silica gel chromatography (ethyl acetate/n-hexane) to obtain an E/Z 
mixture of 
2-methoxyimino-N-methyl-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamid 
e (0.37 g, Yield: 60.4%) as a colorless oil. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.43-1.90(6H,m), 2.87(2.91) 
(3H,d,J=4.9), 3.44-3.60(1H,m), 3.78-3.91(1H,m), 3.94(4.01) (3H,s), 
4.36-4.94(3H,m), 6.75(7.00)(1H,brs), 7.15-7.48(4H,m). 
Example 13 
Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide 
Hydroxylamine hydrochloride (0.28 g, 0.004 mol) was dissolved in methanol 
(4 ml), and a 28% sodium methoxide-methanol solution (0.96 g, 0.005 mol) 
was added to obtain a suspension. A mixed solution of 
2-{2-(1-ethoxyethyl)oxymethyl!phenyl}-N-methyl-2-oxoacetamide (0.53 g, 
0.002 mol) and methanol (2 ml) were added to the suspension. The mixture 
was stirred under reflux for 2 hours. After completion of the reaction, 
half-saturated brine (150 ml) was added, and the mixture was extracted 
with dichloromethane (100 ml) twice. The extract was dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure to obtain a 
crude product of 
2-2-(1-ethoxyethyl)oxymethyl!phenyl-2-hydroxyimino-N-methylacetamide. 
Methanol (4 ml) and pyridinium p-toluenesulfonate (0.05 g, 0.0002 mol) 
were added to the crude product thus obtained, and the mixture was stirred 
under reflux for 30 minutes. After completion of the reaction, the mixture 
was concentrated, and acetone (4 ml) was added to the residue. Then, 
potassium carbonate (0.41 g, 0.003 mol) and dimethyl sulfate (0.30 g, 
0.0024 mol) were added under ice-cooling, and the mixture was stirred at 
room temperature overnight. After completion of the reaction, the 
insoluble materials were filtered off, and the filtrate was concentrated 
under reduced pressure. The residue was purified by silica gel 
chromatography (ethyl acetate/n-hexane) to obtain 
2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.24 g, Yield: 
54.0%, E 100%) as a colorless oil. A part of it was recrystallized from 
ethyl acetate/n-hexane to obtain crystals (mp 107.degree.-108.degree. C.). 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 2.95(3H,d,J=4.9), 3.13(1H,t,J=6.1), 
3.96(1H,s), 4.40(2H,d,J=6.1), 6.95(1H,brs), 7.11-7.55(4H,m). 
Example 14 
Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide 
Methanol (4 ml) and pyridinium p-toluenesulfonate (0.04 g, 0.00017 mol) 
were added to an E/Z mixture of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-2-methoxyimino-N-methylacetamide 
(0.50 g, 0.0017 mol), and the mixture was stirred under reflux for 2 
hours. After completion of the reaction, half-saturated brine (100 ml) was 
added, and the mixture was extracted with dichloromethane (50 ml) twice. 
The extract was dried over anhydrous magnesium sulfate and concentrated 
under reduced pressure. The resulting residue was purified by silica gel 
chromatography (ethyl acetate/n-hexane) to obtain 
2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.34 g, Yield: 
90.0%, E/Z=96/4) as a colorless oil. 
Example 15 
Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide 
Methanol (2 ml) and a 36% aqueous hydrochloric acid solution (0.01 g, 
0.0001 mol) were added to an E/Z mixture of 
2-methoxyimino-N-methyl-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamid 
e (0.31 g, 0.001 mol), and the mixture was stirred at room temperature for 
30 minutes. After completion of the reaction, half-saturated brine (80 ml) 
was added, and the mixture was extracted with dichloromethane (50 ml) 
twice. The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure. The resulting residue was purified by 
silica gel chromatography (ethyl acetate/n-hexane) to obtain 
2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.21 g, Yield: 
94.6%, E/Z=97/3) as colorless crystals. 
Example 16 
Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide 
Methoxyamine hydrochloride (0.22 g, 0.0026 mol) was dissolved in methanol 
(2 ml), and a 28% sodium methoxide-methanol solution (0.58 g, 0.003 mol) 
was added to the solution to obtain a suspension. A mixed solution of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (0.53 g, 
0.002 mol) and methanol (2 ml) was added to the suspension. The mixture 
was stirred under reflux for 3 hours, and then cooled to room temperature. 
After cooling, p-toluenesulfonic acid monohydrate (0.19 g, 0.001 mol) was 
added, and the mixture was stirred at room temperature for 1 hour. After 
completion of the reaction, half-saturated brine (80 ml) was added, and 
the mixture was extracted with dichloromethane (50 ml) twice. The extract 
was dried over anhydrous magnesium sulfate and concentrated under reduced 
pressure. The resulting residue was purified by silica gel chromatography 
(ethyl acetate/n-hexane) to obtain 
2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.37 g, Yield: 
83.2%, E/Z=97/3) as colorless crystals. 
Example 17 
Preparation of 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide 
Pyridinium p-toluenesulfonate (6.70 g, 0.027 mol) and 3,4-dihydro-2H-pyran 
(97.6 ml, 1.067 mol) were added to a solution of 2-bromobenzylalcohol 
(100.9 g, 0.539 mol) in dichloromethane (500 ml), and the mixture was 
stirred at room temperature for 70 hours. After completion of the 
reaction, the mixture was washed with water (200 ml) twice. The organic 
layer was dried over anhydrous magnesium sulfate and concentrated under 
reduced pressure to obtain an oil (152.11 g). 
A mixed solution of the crude 
1-bromo-2-(2-tetrahydropyranyloxymethyl)benzene thus obtained and dry THF 
(100 ml) was added dropwise in a stream of nitrogen at 50.degree. to 
55.degree. C. over 45 minutes to a solution prepared by adding dry THF (50 
ml) and ethyl bromide (1 ml) to magnesium (16.8 g, 0.70 mol). After 
completion of the addition, dry THF (200 ml) was added. The mixture was 
stirred at 55.degree. C. for 30 minutes and cooled to room temperature. 
After cooling, the mixture was added dropwise to a mixed solution of ethyl 
oxalate (118.6 g, 0.80 mol) and dry THF (400 ml) at -65.degree. to 
-70.degree. C. over 1 hour, and the resulting mixture was stirred at 
-78.degree. C. for 1 hour. Water (300 ml) and a saturated aqueous solution 
(80 ml) of ammonium chloride were added, and the mixture was stirred. 
Then, the organic layer and the aqueous layer were separated from each 
other, and the aqueous layer was extracted with ether (500 ml). The 
organic layer was combined, washed with saturated brine, dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure to 
obtain an oil (214.7 g). 
A 40% methylamine-methanol solution (167.4 g, 2.156 mol) was added to a 
mixed solution of the crude ethyl 
.alpha.-oxo-2-(2-tetrahydropyranyloxymethyl)phenylacetate thus obtained 
and methanol (100 ml), and the mixture was stirred at room temperature for 
40 minutes. After completion of the reaction, the mixture was concentrated 
under reduced pressure. Benzene (300 ml) was added to the resulting 
residue to filter off the insoluble materials, and the filtrate was 
concentrated under reduced pressure. The resulting residue was purified by 
silica gel chromatography (ethyl acetate/n-hexane) to obtain 
N-methyl-2-oxo-2-2-(2-tetrahydropyranyloxymethyl)phenyl!acetamide (114.8 
g, Yield: 76.8%) as an oil. 
Example 18 
Preparation of 
2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide A mixed 
solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (25.92 g, 0.1 mol) 
and dry THF (90 ml) was added dropwise at 50.degree. to 55.degree. C. over 
40 minutes to a solution prepared by adding dry THF (10 ml) and ethyl 
bromide (0.2 ml) to magnesium (3.65 g, 0.15 mol) in a stream of nitrogen. 
After completion of the addition, the mixture was stirred at 50.degree. to 
55.degree. C. for 1 hour and cooled to room temperature. After cooling, 
the mixture was added dropwise to a mixed solution of ethyl oxalate (21.92 
g, 0.15 mol) and dry THF (100 ml) at -70.degree. to -65.degree. C. over 1 
hour. Then, the mixture was stirred at -75.degree. to -70.degree. C. for 1 
hour. After completion of the reaction, water (200 ml) and a saturated 
aqueous solution (100 ml) of ammonium chloride were slowly added, and the 
mixture was extracted with ether (300 ml). The extract was dried over 
anhydrous magnesium sulfate and concentrated under reduced pressure. The 
resulting residue was dissolved in methanol (100 ml), and an aqueous 40% 
methylamine (23.30 g, 0.3 mol) solution was added under ice-cooling. The 
mixture was stirred at room temperature for 2 hours. After completion of 
the reaction, water (300 ml) was added, a part of the methanol was 
evaporated under reduced pressure, and the residue was extracted with 
ethyl acetate (300 ml). The extract was washed with saturated brine (300 
ml), dried over anhydrous magnesium sulfate and concentrated under reduced 
pressure. The resulting residue was purified by silica gel chromatography 
(ethyl acetate/n-hexane) to obtain 
2-2-{(1-ethoxyethyl)-oxymethyl}phenyl!-N-methyl-2-oxoacetamide (19.11 g, 
Yield: 72.0%) as a colorless oil. 
Example 19 
Preparation of 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide 
Methoxyamine hydrochloride (7.52 g, 0.09 mol) was dissolved in methanol (60 
ml), and a 28% sodium methoxide-methanol solution (19.68 g, 0.102 mol) was 
added to the solution under ice-cooling to obtain a suspension. A solution 
of 2-2-{(1-ethoxyethyl)oxymethyl}phenyl!-N-methyl-2-oxoacetamide (15.92 
g, 0.06 mol) in methanol (60 ml) was added to the suspension. The mixture 
was stirred under reflux for 2 hours. After completion of the reaction, 
about half of the methanol was evaporated under reduced pressure, water 
(400 ml) was added, and the mixture was extracted with dichloromethane 
(200 ml) twice. The extract was dried over anhydrous magnesium sulfate and 
concentrated under reduced pressure. The resulting residue was dissolved 
in methanol (30 ml), a 36% aqueous hydrochloric acid solution (0.61 g, 
0.006 mol) was added under ice-cooling, and the mixture was stirred for 
0.5 hours. After completion of the reaction, water (370 ml) and saturated 
sodium bicarbonate (30 ml) were added, and the mixture was extracted with 
dichloromethane (200 ml) twice. The extract was dried over anhydrous 
magnesium sulfate and concentrated under reduced pressure to obtain crude 
2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (12.98 g, 
Yield: 97.3%, E/Z=96/4) as colorless crystals. 
Reference Example 1 
Synthesis of 
(E)-2-2-(5-chloro-3-trifluoromethylpyridin-2-yloxymethyl)phenyl!-2-methox 
yimino-N-methylacetamide 
2-(2-Hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (300 mg) was 
dissolved in THF (5 ml). 40% sodium hydride (65 mg) was added, and the 
mixture was stirred for 10 minutes. 2,5-Dichloro-3-trifluoromethylpyridine 
(350 mg) was added, and the mixture was stirred at room temperature for 12 
hours. The mixture was neutralized with 1N-hydrochloric acid and extracted 
with ethyl acetate. The resulting organic layer was dried over MgSO.sub.4, 
and the solvent was evaporated under reduced pressure. The resulting 
residue was purified by column chromatography on silica gel to obtain the 
title compound (398 mg, Yield: 74%). 
m.p. 105-106.degree. C. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 2.94(3H,d,J=5.1 Hz), 3.96 (3H,s), 
5.23(2H,s), 6.82(1H,brs), 7.21(1H,dd,J=7.3,1.7 Hz), 7.36(1H,td,J=7.3,1.7 
Hz), 7.42(1H,td,J=7.3,1.7 Hz), 7.58(1H, dd,J=7.3,1.7 Hz), 
7.81(1H,dd,J=2.4,0.7 Hz), 8.16(1H,dd,J=2.4,0.7 Hz). 
The present invention provides an economically and industrially 
advantageous process for producing a 2-(2-hydroxymethylphenyl)-2-alkoxy(or 
hydroxy)iminoacetamide derivative which is useful as an intermediate for 
the production of alkoxyiminoacetamide compounds useful as agricultural 
fungicides, as well as an intermediate used in the process. 
The alkoxyiminoacetamide compound useful as agricultural fungicides can be 
obtained from the compound (I) in a few steps. Since its E-isomer has more 
potent fungicidal activity than its Z-isomer, it is preferred to obtain 
the compound (I) as the E-isomer. In the process of the present invention, 
the protective group of hydroxyl is removed and isomerization to the 
E-isomer proceeds at the same time. Therefore this process can provide the 
E-isomer of the compound (I) in a few steps and in high yield and purity 
without any separate isomerization step to the E-isomer. This process is 
thus highly useful for industrial production.