EP1131282A1

EP1131282A1 - Method for producing alkenyl-substituted bis(oximether) derivatives

Info

Publication number: EP1131282A1
Application number: EP99958032A
Authority: EP
Inventors: Wassilios Grammenos; Hubert Sauter; Andreas Gypser; Herbert Bayer; Norbert Götz; Roland Götz
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1998-11-20
Filing date: 1999-11-12
Publication date: 2001-09-12
Also published as: CN1326436A; JP2002530365A; US6417388B1; HUP0104376A2; HUP0104376A3; AU1553000A; WO2000031023A1; BR9915423A

Abstract

The invention relates to a method for producing alkenyl-substituted bis(oximether) derivatives of formula (I), wherein the substituents have the following meanings: R<1> represents unsubstituted C1-C4-alkyl or methyl substituted by C2-C4-alkenyl, C2-C4-alkinyl or phenyl; R<2>, R<4> represent, independently of each other, hydrogen or methyl; R<3>, R<5> represent, independently of each other, hydrogen or C1-C4-alkyl, trifluoromethyl or phenyl and X represents -C(=CHCH3)-COOCH3; -C(=CHOCH3)-COOCH3; -C(=NOCH3)-COOCH3; -C(=NOCH3)-CONHCH3 or -N(OCH3)-COOCH3.

Description

Process for the preparation of alkenyl-substituted bis (oxime ether) derivatives

description

The present invention relates to a process for the preparation of alkenyl-substituted bis (oxime ether) derivatives of the formula I,

in which the substituents have the following meaning:

R ¹ is unsubstituted Cι-C ₄ alkyl or by C ₂ -C ₄ alkenyl, C ₂ -C ₄ -alkynyl or phenyl-substituted methyl;

R ² , R ⁴ independently of one another are hydrogen or methyl;

R ³ , R ^{5 are} independently hydrogen or -CC ₄ alkyl, trifluoromethyl or phenyl and

X -C (= CHCH ₃ ) -COOCH ₃ , -C (= CHOCH ₃ ) -COOCH ₃ , -C (= NOCH ₃ ) -COOCH _{3 (} -C (= NOCH ₃ ) -CONHCH ₃ or -N (OCH ₃ ) -COOCH ₃ .

Alkenyl-substituted bis (oxime ether) derivatives of the formula I are described in the literature as interesting crop protection agents [cf. WO-A 95/21153, WO-A 95/21154, WO-A 96/16030 and WO-A 97/03057].

If the production processes described in these documents are used specifically for the construction of the alkenyl-substituted bis (oxime ether) derivatives of the formula I, the following difficulties emerge.

The synthesis route shown in Scheme 1, in which component A of the side chain and component B containing the pharmacophore are built up separately and only joined at the end, fails due to the poor accessibility of component A. For example, A is due to the route shown in Scheme A. the high ring closure tendency of the precursors is not accessible (cf. Tetrahedron Let. (1981) 2557).

Scheme 1:

A

WO-A 95/21153 WO-A 95/21154 WO-A 97/03057 WO-A 96/16030

Scheme A:

Furthermore, a successive construction of the side chain starting from building block B would be conceivable, but with the disadvantage that numerous synthesis steps would have to be carried out one after the other. Such a process can only be expected to produce a moderate overall yield and is also extremely lengthy.

The aim of the present invention was accordingly to provide an economical process which provides alkenyl-substituted bis (oxime ether) derivatives of the formula I in good yield starting from easily accessible starting materials.

Accordingly, the process mentioned at the outset was found, which is characterized in that an alkenylalkyl derivative of the formula II, in which the substituents R ¹ to R ⁵ and X have the abovementioned meaning, is rearranged with a base and / or an isomerization catalyst.

Compounds of the formula II are advantageously, as shown in scheme 2, accessible from a bis (oxime) monoether of the formula IV and a benzyl derivative of the formula III.

Scheme 2:

IV III II

For compounds I with an oxime ether amide pharmacophore, the synthesis strategy shown in Scheme 3 for the preparation of precursor IIb has proven to be particularly advantageous.

Scheme 3

IV purple Ha

Ilb The alkylation of compound IV with compound lilac gives the oxime ether ester Ha, which can be converted into the corresponding amide IIb. In the last step, the double bond is isomerized and the oxime ether amides of the formula I are obtained.

The method according to the invention is explained in more detail below.

The isomerization can be carried out in the presence of a base and / or an isomerization catalyst.

Suitable bases are metal hydrides such as sodium hydride or in particular alkali metal alcoholates such as potassium tert. -butanolate and preferably sodium or potassium methylate.

The base is generally used in a molar ratio of 1 to 4, preferably 1 to 2, with respect to the starting compound II.

An isomerization catalyst can also be used as an additive or as an alternative to the base.

Particularly suitable isomerization catalyst is metallic palladium or also salts of palladium such as palladium (II) chloride or palladium (II) acetate.

The isomerization catalyst is usually used in a concentration of 0.1 to 5 mol%.

Examples of solvents which can be used are aliphatic or aromatic hydrocarbons such as toluene, xylene, heptane, aliphatic or cyclic ethers such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane or, in particular, polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide or dirne-thylaceta id .

The reaction temperature is generally 20 to 120 ° C and preferably 20 to 40 ° C. In the case of the palladium-catalyzed reaction, higher temperatures of 20 to 160 ° C and preferably 80 to 140 ° C are used.

Starting materials for the isomerization reaction are compounds of the formula II, which, as shown in Scheme 2a, are preferably based on route A) starting from a bis (oxime) monoether of formula IV and a benzyl derivative of formula III or on route B) O 00/31023 can be prepared from an oxime ether of formula V and a hydroxylamine of formula VI.

Scheme 2a:

V VI

Reaction A) is a nucleophilic substitution that can be carried out under the usual reaction conditions. The benzyl compounds III are compounds in which X has the meaning given in claim 1 and L ^{1 is} a leaving group such as halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy and in particular chlorine or bromine. The substituents R ¹ to R ^{5 of} the bis (oxime) monoethers of the formula IV are as defined in claim 1.

The reaction is conveniently carried out in an inert solvent such as an ether, e.g. Tetrahydrofuran or dioxane or a polar aprotic solvent, e.g. Acetone, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide, dimethylacetamide.

Sodium or potassium carbonate, sodium hydride, sodium methylate or a tertiary amine is generally used as the base.

The reaction temperature is usually -20 to 80 ° C.

The reaction can also be carried out in a two-phase system (eg dichloromethane / water) with the aid of a suitable phase transfer catalyst. The reaction mixtures can be worked up, for example, by extractive means.

The benzyl compounds of formula III are from EP-A 348766; EP-A 363818 or EP-A 624155 known.

An advantageous way of producing the starting materials IV and V is set out in Scheme 4.

Scheme 4:

b) f at

O

Stage a):

Stage a) is carried out analogously to the procedure described in US Pat. No. 4,707,484.

Alcohols such as methanol and, in particular, water can be used as solvents. Under certain circumstances, it can be helpful to add solubilizers such as surfactants or ethylene glycol.

Suitable bases are in particular sodium and potassium hydroxide, which are generally used in equimolar amounts or in an up to 10-fold molar excess based on the acetoacetic ester B. Nitrite is understood to mean, for example, an alkali metal nitrite, in particular sodium nitrite, which is generally used in equimolar amounts or in an excess of up to 30 mol%, based on the acetoacetic ester B.

The reaction temperature should generally not exceed 40 ° C, otherwise undesirable side reactions occur. It is therefore preferred to work in water at -20 to 40 ° C., in particular at 0 to 15 ° C.

The reaction mixture usually clears up after a period of 10 to 48 hours. Now a pH of 0 to 5 and preferably 1 to 3 is set with an acid such as hydrochloric acid or sulfuric acid.

The processing takes place according to common methods, for example by extraction. For cleaning, the oxime can be converted into the corresponding salt with bases, for example, and then precipitated again with acid.

The acetoacetic ester B used for the reaction can be prepared as described in Tetrahedron 4633 (1985) (see Scheme 5).

Scheme 5:

B

The alkenylalkyls of the formula A, where R ² to R ^{5 have} the meaning given in claim 1 and L ^{1 represents} halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy, are known or can be synthesized by processes known from the literature (Z. Org. Khim. (1997) 486; Bull. Chem. Soc. Jpn. (1980) 2586; J. Am. Chem. Soc. (1984) 2211; J. Am. Chem. Soc. (1960) 1886; DE-A 19 556 66 ; DE-A 33 173 56; EP-A 271212; Tetrahedron Let. (1986) 6027; Tetrahedron Let. (1994) 1371 and 2679; J. Fluorine Chem. (1997) 67; Helv. Chim. Acta (1951) 1514 ; Organomet. Chem. (1985) 395). Level b):

The alkylation is usually carried out in the presence of an inert organic solvent. Among others, aliphatic or aromatic hydrocarbons such as toluene, xylene, heptane or cyclohexane, aliphatic or cyclic ethers such as 1, 2-dimethoxyethane, tetrahydrofuran or dioxane can be used. Polar aprotic solvents are preferably used: ketones such as acetone, nitriles such as acetonitrile, amides such as dimethylformamide, dirthylacetamide or N-methylpyrrolidone or ureas such as tetramethylurea.

A halide, preferably a chloride or bromide, a sulfate, preferably dimethyl sulfate, a sulfonate, preferably a methanesulfonate (mesylate) or a toluenesulfonate (tosylate) is usually used as the alkylating agent.

The amount of base or alkylating agent, based on the compound V, is preferably between one to two times the equimolar amount.

As a rule, in the presence of an inorganic base such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium hydrogen carbonate or an alkali alcoholate such as sodium methoxide or potassium tert. -butanolate worked.

The reaction temperature is generally between 0 ° C and 50 ° C ^- preferably between 0 ° C and 40 ^oC and especially at room temperature.

The processing can take place, for example, by an extractive route.

To remove residual amounts of alkylating agent, it may be advantageous to wash the reaction mixture with, for example, ammoniacal solution.

Step c): Hydroxylamine is used either in the form of an acid addition salt or as a free base, the latter being able to be released from the salt by adding a strong base.

The acid addition salts of hydroxylamine are preferably used. All common acids are suitable for the production of the acid addition salts. The following are just a few examples: Carboxylic acids such as acetic or propionic acid, dicarboxylic acids such as oxalic or succinic acid, mineral acids such as phosphoric or carbonic acid and especially hydrochloric acid or sulfuric acid.

If the acid addition salts of hydroxylamine are used, it is generally advantageous to add a base in order to bind the acid released during the reaction. In many cases a pH of 3 to 7 and in particular 4 to 6 has proven to be advantageous for the oximation. Outside of these pH ranges, side reactions such as ring closure reactions can occur.

As a rule, 1 to 2.5 molar equivalents of a base are added. Pyridines, trialkylamines, sodium hydroxide, sodium acetate and sodium methylate are particularly suitable as bases. When using sodium acetate, glacial acetic acid is usually added.

Conversely, of course, the hydroxylamine can also be used as the free base and one of the acids mentioned can be used to adjust the above-mentioned pH range.

Examples of solvents which can be used are those described in the previous step. In addition, carboxylic acids such as acetic acid or water / pyridine mixtures are also suitable. Alcohols such as methanol, ethanol, n-propanol or i-propanol and mixtures of these with water and / or pyridine are particularly suitable.

The reaction temperature is usually -20 to 50 ° C and preferably 0 to 40 ° C and in particular 20 to 25 ° C.

The reaction mixture is preferably worked up, as described in the previous step, by means of extractive methods. To remove the base completely, it may be helpful to wash the crude product beforehand with a dilute aqueous acid and then with water.

Path B) listed in Scheme 2a can be analogous to that in J. Chem. Soc, Chem. Commun. 1986, p.903 perform the procedure described. The preparation of the oxime ether V is described above; The hydroxylamines of the formula VI are known from EP-A 244786 or can be prepared in ways known from the literature. The above formulas were presented in the "transoid, transoid" notation. In the solid state and in particular in

The solution lies in the connections - as with connections I in

Scheme B illustrates - at least partially in the "transoid, cisoid" form or in the "transoid, cisoid" form

Balance.

Scheme B: possible spellings of the compounds I

transoid, transoid "" transoid, cisoid "

Manufacturing examples

Production of intermediate IV and V

example 1

Preparation of 5-methyl-hex-5-en-2, 3-dione-3-oxime

200 g of 2-acetyl-4-methyl-pent-4-enoic acid methyl ester (preparation: see Tetrahedron (1985) 4633) in 2000 ml of aqueous 10% potassium hydroxide solution were mixed with 85 g of sodium nitrite at 10 ° C. and 18 Stirred at 23 ° C for hours. 1000 ml of 10% strength sulfuric acid were then added dropwise with ice cooling in such a way that the internal temperature remained below 10 ° C. Thereafter, stirring was continued at 10 ° C. until the CO ₂ evolution had ended. Working up was carried out with methyl tert. -butyl ether extracted, the combined organic phases were extracted with 3 N sodium hydroxide solution and the alkaline phases were brought to pH 1 with 20% sulfuric acid. The mixture was then extracted with methylene chloride, dried over sodium sulfate and the solvent removed in vacuo. 142 g of the title compound remained as a yellow oil, which crystallized on standing.

ⁱ H NMR (CDC1 ₃ , ppm) δ = 4.8 (1H); 4.6 (1H); 3.3 (2H); 2.4 (3H) 1.8 (3H). 11

Preparation of the mono (oxime ether) V

Example 2

Preparation of 5-methyl-hex-5-en-2,3-dione-3- (O-methyloxime)

141 g of 5-methyl-hex-5-en-2, 3-dione-3-oxime from Example 1 were dissolved in 750 ml of acetone, and 165.6 g of potassium carbonate were added. 145 g of dimethyl sulfate in 100 ml of acetone were then added dropwise and the mixture was subsequently stirred at 23 ° C. for 4 hours. The solvent was then removed in vacuo, the residue in methyl tert. -butyl ether / water added and the aqueous phase several times with methyl tert. -butyl ether extracted. The combined organic phases were washed with 15% ammonia solution and water, dried over sodium sulfate and the solvent removed in vacuo. 141 g of the title compound remained as a yellow oil.

^! H-NMR (CDC1 ₃ , ppm): δ = 4.77 (1H); 4.57 (1H); 4.0 (3H); 3.2 (2H).

Example 3 Preparation of 5-methyl-hex-5-en-2,3-dione-3- (O-ethyloxime)

285.7 g of 5-methyl-hex-5-en-2, 3-dione 3-oxime from Example 1 were dissolved in 750 ml of acetone, and 335.8 g of potassium carbonate were added. Then 362 g of diethyl sulfate in 300 ml of acetone were added dropwise and the mixture was subsequently stirred at 23 ° C. for 2 hours. The solvent was then removed in vacuo, the residue in methyl tert. -butyl ether / water added and the aqueous phase again with methyl tert. -butyl ether extracted. The combined organic phases were washed with 15% ammonia solution and water, dried over sodium sulfate and the solvent removed in vacuo. 355.4 g of the title compound remained as a yellow oil.

^! H-NMR (CDCI ₃ , ppm): δ = 4.8 (1H); 4.6 (1H); 4.3 (2H); 3.2 (2H); 2.4 (3H); 1.7 (3H); 1.3 (3H).

Preparation of the bis (oxime) monoether IV

Example 4

Preparation of 5-methyl-hex-5-en-2,3-dione-3- (O-methyloxime) -2-oxime

283.4 g of 5-methyl-hex-5-ene-2, 3-dione-3- (O-methyloxime) in 800 ml of methanol were added dropwise to the solution of 140.6 g of hydroxylammonium chloride in 400 ml of water and 216.7 g of pyridine, and the mixture was stirred for 3 hours at 23 ° C. The solvent was then removed in vacuo and the residue was added to ice water. A pH of 1 was then set with 20% sulfuric acid, which aspirated product sucked off, in methyl tert. -butyl ether added and washed with water. The organic phase was then dried over sodium sulfate and the solvent was removed in vacuo. There remained 266 g of the title compound as a colorless solid.

ⁱ H-NMR (CDC1 ₃ , ppm): δ = 9.3 (1H); 4.8 (1H); 4.6 (1H); 4.0 (3H); 3.3 (2H).

Example 5

Preparation of 5-methyl-hex-5-en-2,3-dione-3- (O-ethyloxime) -2-oxime

211.3 g of hydroxylammonium chloride in 400 ml of water and 240 g of pyridine were reacted analogously to Example 4 with 342.4 g of 5-methyl-hex-5-en-2,3-dione-3- (O-ethyloxime) in 800 ml of methanol. 305 g of the title compound were obtained as a yellowish solid.

¹ H NMR (CDCI ₃ , ppm): δ = 9.4 (1H); 4.8 (1H); 4.6 (1H); 4.2 (2H); 3.3 (2H); 2.1 (3H); 1.8 (3H); 1.3 (3H).

Compounds of formula II

Example 6

Preparation of 2-methoxyimino-2- [2- (2-methoxyimino-l, 4-dimethylpent-4-enylideneaminooxymethyl) phenyl] -N-methylacetamide

To 133.2 g of 5-methyl-hex-5-en-2, 3-dione-3- (O-methyl-oxime) -2-oxime (Example 4) in 150 ml of DMF were added 141 g of a 30% strength methanolic see sodium methylate solution and stirred 30 min. at 23 ° C. 246 g of (2-bromomethyl-phenyl) methoxyiminoacetic acid methyl ester (preparation: see EP-A 254426) in 400 ml of DMF were then added dropwise (temperature rise to 50 ° C.) and the mixture was stirred at 23 ° C. for one hour . 607 g of 40% strength aqueous methylamine solution were then added dropwise, the mixture was stirred at 23 ° C. for 1 hour and the reaction solution was poured onto ice water / n-pentane. The mixture was then stirred for an hour, the product was suction filtered, washed with water and a little n-pentane and dried in vacuo. Yield: 216 g of the title compound. iH-NMR (CDCI ₃ , ppm): δ = 6. 7 (1H); 5. 05 (2H); 4th 7 (1H); 4th 5 (1H); 4th 0 (3H); 3rd 95 (3H); 3rd 3 (2H).

Example 7 5 Preparation of 3-methoxy-2- [2- (2-methoxyimino-l, 4-dimethylpent-4-enylideneaminooxymethyl) phenyl] acrylic acid methyl ester

112.2 g of a 30% strength methanolic sodium methylate were added to 11.5 g of 5-methyl-hex-5-en-2,3-dione-3- (O-methyloxime) -2-oxime 15 from Example 4 in 55 ml of DMF Solution and stirred 30 min. at 23 ° C. 21.3 g of methyl 2- (2-bromomethylphenyl) -3-methoxy-acrylic acid (preparation: see EP-A 178826) in 400 ml of DMF were then added dropwise (temperature rise to 35 ° C.), and one was allowed to Stir at 20 23 ° C and added the reaction solution to ice water / n-pentane. The mixture was then stirred for an hour, the product was filtered off with suction, washed with water and a little n-pentane and dried in vacuo. Yield: 16.7 g of the title compound as a yellowish solid. 25 ⁱ H-NMR (CDCI ₃ , ppm): δ = 5.1 (2H); 4.7 (1H); 4.5 (1H); 3.9 (3H); 3.8 (3H); 3.7 (3H); 3.3 (2H).

Example 8 30 Preparation of 2- [2- (2-ethoxyimino-l, 4-dimethyl-pent-4-enylidene-aminooxymethyl) phenyl] -2-methoxyimino-N-methylacetamide

97.8 g of a 30% strength methanolic sodium methylate were added to 100 g of 5-methyl-hex-5-en-2,3-dione-3- (O-ethyl-oxime) -2-oxime from 40 Example 5 in 150 ml of DMF Solution and stirred 30 min. at 23 ° C. 171 g of (2-bromomethyl-phenyl) methoxyiminoacetic acid methyl ester (preparation: see EP-A 254426) in 400 ml of DMF were then added dropwise (temperature rise to 50 ° C.) and the mixture was stirred for an hour at 23 ° C. . Then 421 g of 40% strength aqueous methylamine solution were added dropwise, the mixture was stirred at 23 ° C. for 1 hour and the reaction solution was poured onto ice water / n-pentane. Then there was an hour - Stirred, the product filtered off, washed with water and a little n-pentane and dried in vacuo. Yield: 196 g of the title compound.

5 ⁱ H-NMR (CDC1 ₃ , ppm): δ = 1.25 (3H); 1.7 (3H); 2.0 (3H); 2.85 (3H); 3.3 (2H); 4.0 (3H); 4.2 (2H).

Compounds of the formula I (isomerization stage)

10 Example 9

Preparation of 2-methoxyimino-2- [2- (2-methoxyimino-l, 4-dimethylpent-3-enylideneaminooxymethyl) phenyl] -N-methylacetamide

20 34.7 g of solid sodium methylate in 250 ml of DMF were stirred for 3 hours at 23 ° C., then 120 g of amide from Example 6 in 250 ml of DMF were added dropwise (temperature increase to 30 ° C.). The mixture was then stirred at 23 ° C. for 12 hours and worked up as in Example 6. 108 g of the title compound were obtained as a colorless solid

25 substance obtained which, according to NMR, GC and HPLC analysis, contained about 10% of the starting compound (Example 6).

¹ H NMR (CDCI ₃ , ppm): δ = 6.7 (1H); 5.7 (1H); 5.0 (2H); 3.9 (3H) 2.9 (3H).

30

Example 10

Preparation of 3-methoxy-2- [2- (2-methoxyimino-l, 4-dimethylpent-3-enylideneaminooxymethyl) phenyl] acrylic acid methyl ester

40

4.9 g of solid sodium methylate were added to 16.7 g of methyl 3-methoxy-2- [2- (2-methoxyimino-l, 4-dimethyl-pent-4-enylideneaminooxymethyl) phenyl] acrylic acid from Example 7 and the mixture was stirred for 1 hour 23 ° C. Working up was carried out analogously to Example 6. After chromatographic purification over silica gel with cyclohexane / methyl tert.- WO 00/31023 -, -. PCT EP

15

'Butyl ether (9: 1) gave 7.1 g of the title compound as a colorless solid.

IR (cm- ¹ ): 1697, 1624, 1256, 1100, 860, 771 5 mp: 48-52 ° C.

Example 11

Preparation of 2- [2- (2-ethoxyimino-l, 4-dimethylpent-3-enylidene aminooxymethyl) phenyl] -2-methoxyimino-N-methylacetamide

48.4 g of solid sodium methyl t in 400 ml of DMF were stirred at 23 ° C. for 3 hours before 174 g of amide from Example 8 were added dropwise in 250 ml of DMF. The mixture was then stirred at 23 ° C. for 18 hours and worked up analogously to Example 6. 154 g of the title compound were obtained as a colorless solid which, according to NMR, GC and HPLC analysis, contained about 12% of the starting compound (Example 8).

5 ^! H-NMR (CDC1 ₃ , ppm): δ = 6.7 (1H); 5.7 (1H); 5.1 (2H); 4.2 (2H); 3.95 (3H).

0

5

0

5

Claims

claims

1. Process for the preparation of alkenyl-substituted bis (oxime ether) derivatives of the formula I,

in which the substituents have the following meaning:

R ^{1 is} unsubstituted Cα-C ₄ alkyl or methyl substituted by C ₂ -C alkenyl, C ₂ -C ₄ alkynyl or phenyl;

R ² , R ⁴ independently of one another are hydrogen or methyl;

X -C (= CHCH ₃ ) -COOCH ₃ , -C (= CHOCH ₃ ) -COOCH ₃ , -C (= NOCH ₃ ) -COOCH ₃ , -C (= NOCH ₃ ) -CONHCH ₃ or

-N (OCH ₃ ) -COOCH ₃ ,

characterized in that an alkenylalkyl derivative of the formula II,

in which the substituents R ¹ to R ⁵ and X have the abovementioned meaning, is rearranged with a base and / or an isomerization catalyst.

2. The method according to claim 1, characterized in that the

Alkenylalkyl derivative of the formula II by reacting a benzyl compound of the formula III,

in which the substituent X has the meaning given in claim 1 and L ^{1 represents} halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy, with a bisoxime monoether of the formula IV,

in which the substituents R ¹ to R ^{5 have} the meaning given in claim 1, is prepared in an inert organic solvent in the presence of a base.

3. The method according to claim 2, characterized in that the alkenylalkyl derivative of the formula Ilb,

in which the substituents R ¹ to R ⁵ and X have the meaning given in claim 1, by reacting a benzyl compound of the formula purple,

in which L ^{1 represents} halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy, with a bisoxime monoether IV as defined in claim 2 to give the alkenylalkyl derivative of the formula Ha,

and subsequent reaction of Ha with methylamine is obtained.