The method of obtaining derivatives of o-chloromethyloxirane acid

 

(57) Abstract:

The invention relates to a method for obtaining compounds of formula I, where X denotes the radical, inert under the conditions of the reaction; m is 0; R3denote hydrogen, CH3CH2F or CHF2Y denotes a group OR4N(R5)2or N(CH3)OCH3; R4and R5each independently of one another denotes hydrogen or C1-C8alkyl or (R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring, according to which (a) conduct the interaction of the compounds of formula II, where X and m have the above for formula I, values and R1and R2each independently of one another denote WITH1-C6alkyl, C1-C6alkenyl, C1-C6alkoxyalkyl or3-C6cycloalkyl or R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom, in an aprotic solvent with an organolithium compound of formula III, where R7denotes an organic anionic radical; b) conducting interaction akovali or different and represent a group OR4N(R6)2or N(CH3)OCH3; R4stands WITH1-C8alkyl; R6represents C1-C8alkyl; or R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring with obtaining the compounds of formula V; C) is connected in any order in 1) is subjected to occimiano 0-methylhydroxylamine or are occimiano hydroxylamine, and then methylated, formatierung or diftormetilirovaniya; 2) enter into interaction with the ether of Harborview acid. Also we propose a method for obtaining compounds of formula V in accordance with the above stages a) and b), the method of obtaining the compounds of formula I from compounds of formula V in accordance with the stages described above in 1) and 2), and the compound of formula V. the Technical result - the proposed methods make available new way of synthesis of microbicides number methoxybenzyloxy acid, and methods are easily accessible starting materials, a good yield of products in the individual stages and good feasibility of these stages. 4 C. and 13 C.p. f-crystals.

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Li-R7(III)

Y1-CO-CO-Y1IV,


m is 0-4;

R3denotes hydrogen, CH3CH2F or CHF2;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl, or

(R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring; and in this way

a) spend the interaction of the compounds of formula II

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where

X and m have the above for formula I value and

R1and R2each independently of one another denote WITH1-C6alkyl,

WITH1-C6alkenyl, C1-C6alkoxyalkyl or3-C6cycloalkyl, or

R1and R6together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom, in an aprotic solvent with an organolithium compound of formula III

Li-R7(III)

where R7denotes an organic anionic radical;

b) spend the interaction of the obtained lithium complex with the compound of the formula IV

Y1-CO-cups offers a group OR4N(R6)2or N(CH3)OCH3, imidazole or halogen;

R4stands WITH1-C8alkyl;

R6stands WITH11-C8alkyl; or

(R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

and then, if Y1denotes an imidazole or halogen, this group substituted by a group Y, where Y has the meanings indicated for formula I;

obtaining the compounds of formula V

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in this connection, in any order

B1) are occimiano O-methylhydroxylamine or are occimiano hydroxylamine, and then methylated, formatierung or diftormetilirovaniya;

B2) enter into interaction with the ether of Harborview acid.

The compounds of formula I are intermediates that are important for obtaining microbicides number of esters methoxybenzyloxy acid, as described, for example, in European patent application 254426 and international applications WO 95/18789 and WO 95/21153.

Unless otherwise noted, these terms have the following meanings:

The radical X may be any organic radical, with the condition is preferably m is 0.

Depending on the number of carbon atoms of alkyl group are remotemachine or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1-hexyl or 3-hexyl.

The term "alkenyl" means remotemachine or branched alkenyl, in particular allyl, methallyl, 1-methylvinyl or but-2-EN-1-yl. Preferred alkeneamine radicals, the chain containing 3-4 carbon atoms.

Halogen represents fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

Haloalkyl can contain identical or different halogen atoms, for example, vermeil, deformity, diperchlorate, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-triptorelin, 2-foretel, 2-chloroethyl, 2,2,2-trichloroethyl and 3,3,3-cryptochromes.

As alkoxygroup can be called, for example, methoxy, ethoxy, propyloxy, isopropoxy, h-Butylochka, isobutoxy-, second -, Butylochka - and tert-butylacrylate, preferably methoxy and ethoxypropan.

Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Of Organic Reactions, 26, page 1, and further, (1979) ª, and this is the last you can substitute in the ortho-position of the electrophile. However, in this reference as electrophiles derivatives of oxalic acid is not mentioned.

In addition, in the European patent 178826 pages 48-75 there is a General indication of what can be interaction phenyllithium compounds with esters of oxalic acid with obtaining esters phenylglyoxylic acid, but in the examples getting phenyllithium compounds substituted in ortho-position to the amino group, are not illustrated. Moreover, for the metallation using a mixture of utility with tert-piperonyl potassium.

It was found that the interaction of benzylamino formula II can be carried out with organolithium compound, and then with a derivative of oxalic acid of formula IV, receiving esters phenylglyoxylic acid of formula V.

In addition, it is known that tert-benzylamine can be converted into the corresponding benzylchloride with ether Harborview acid. For example, according to Indian Journal of Chemistry, volume 31B, page 626 (1992), the corresponding benzylchloride get interaction on-hydroxybenzylideneamino with ethyl ether of Harborview acid.

It was found that similar saintxi - or 1-ketoxime-2-oxoprop, moreover, this group is maintained, which is a surprising fact, considering the reactivity of such a functional group.

The method in accordance with the present invention makes available a new way of synthesis of microbicides number of esters methoxybenzyloxy acid of formula IX, as described, for example, in European patent 254426 and international applications WO 95/18789 and WO 95/21153, and this method of synthesis is easily accessible starting materials, a good yield of products in the individual stages and good technical feasibility of these individual reaction stages. This new method of synthesis is illustrated in reaction scheme 1 (see the end of the description).

A separate reaction stage is preferably carried out as follows.

The reaction stage a)

Reaction temperature: 0-120oC, preferably from 20oC to the boiling point of the solvent.

Organolithium compound of formula III is utility, second-utility, exility, diisopropylamide lithium (DAL), hexamethyldisilazide lithium or tetramethylpiperidine lithium (TMPL); especially preferred utility.

It is advisable to use the s substances, it is preferable to use the compounds of formula II, where m denotes 0, R1and R2denote C1-C6alkyl, or R1and R2together with the nitrogen atom form a piperidine.

The reaction stage b)

Reaction temperature: -50oC to the boiling point of the solvent, preferably from -20 to 30oC.

Use 0,9-4 mol.EQ. derivative of oxalic acid of formula IV from the amount of the compounds of formula II. This derivative of oxalic acid, especially an ether, can also be used as solvent.

Suitable solvents for the reaction stages a) and b) are simple ether, hydrocarbon or a mixture of primarily hexane, benzene, toluene, xylene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, dimethoxyethane, diethoxyethane and diethoxymethane. Both reaction stage preferably takes place in the same solvent mixture.

In the case when Y1the derivative of oxalic acid of the formula IV represents halogen or imidazole, spend the interaction of galodamadruga Glyoxylic acid or imidazolone derivative of formula V with HOR4or HN(R5)2under alkaline conditions to obtain the corresponding ester and the ω HN(R5)2or peresterilizovali alcohol, and in this case this ethyl ester is preferably converted into methyl or n-pentalogy ether.

As a derivative of oxalic acid, it is preferable to use an ether, especially ethyl ester.

After making the reaction stage b), the reaction mixture it is advisable to acidify to pH 7 or less, for example, an aqueous solution of acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or anhydrous acid, for example, carboxylic acid, such as propionic acid or acetic acid, or ammonium salt. Then the organic phase is thoroughly washed with water and the product of formula V is purified by distillation or crystallization. This product can also be cleaned by acid extraction of by-products. The reaction stage B1) or B2) can also be directly after the reaction stage b) without purification of the intermediate product V

The reaction stage B1)

Conduct or interaction of the compounds of formula V with O-methylhydroxylamine or its oxymorphine hydroxylamine or its salt, such as hydrochloride or sulfate, and then methylation, for example, methyliodide, m is the help ClCHF2in alkaline conditions.

The reaction stage B2)

For replacement of an amino chlorine is preferable to use ethyl ether of Harborview acid.

This reaction can be carried out in an anhydrous aprotic solvent or without solvent; the solvent can also be used ether of Harborview acid. Preferred solvents are hydrocarbons, halogenated hydrocarbons, esters, ethers, ketones, NITRILES and the ether Harborview acid, primarily benzene, toluene, xylene, chlorobenzene, nitrobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane, trichloroethane and ethyl ether of Harborview acid, the preferred acid ethyl ester, tert-butyl methyl ether, methyl isobutyl ketone and acetonitrile. The preferred reaction temperature is from 0oC to the boiling point of the solvent, primarily 20-120oC.

In some cases, this reaction should be carried out in the presence of a base, which is used for example in amounts of 1-50 mol.% in terms of the compound of formula V. Preferred bases are the bicarbonates, or carbonates of the alkali metal is excess, and unreacted portion can be selected; it should be used in the amount of 100 to 200 mol.% the amount of compounds of formula V.

You can choose any alcohol residue of the ester of Harborview acid, provided that he did not enter into any unwanted reactions; it is advisable to contain not more than 8 carbon atoms, preferably optionally halogenated C1-C4alkilany ether, optionally halogenated C1-C4alkenilovyh ether, unsubstituted or substituted benzyl or phenyl ether, are particularly preferred ethyl ether of Harborview acid.

R1and R2preferably denote C1-C6alkyl, or R1and R2together with the nitrogen atom form a piperidine, piperazine, hexahydroazepin or tetrahydroisoquinoline primarily piperidine.

When using amine containing two amino groups, such as piperazine, the reaction can be used both amino groups, i.e., in other words, in this case, only half molar equivalent of the amine.

Acceptable reasons are, for example, hydroxides, hydrides, amides, alkanoate, carbonates, dialkylamino and N-alkylated, saturated or unsaturated cyclooctylamine, basic heterocyclic compounds, ammonium hydroxide, and carbocyclic amines. As examples hydroxide, hydride, amide, methanolate and sodium carbonate, tert-butanolate and potassium carbonate, diisopropylamide lithium bis(trimethylsilyl)amide, potassium, calcium hydride, triethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N, N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N, N-dimethylamino)pyridine, N-methylmorpholine, hydroxide designed and 1,8-diazabicyclo[5.4.0]undec-5-ene (DBU).

The reaction stage d)

The interaction of the compounds of formula I with the compound of the formula HOR, where R denotes an organic radical, is carried out in alkaline conditions in a solvent in accordance with known methods. When Y represents the group OR4obtained compound of the formula IX, optionally subjected to a transesterification or amidation in accordance with known methods. In a particularly preferred embodiment, in the reaction stage d) conduct the interaction of the compounds of formula I, where m denotes 0, R3denotes methyl and Y denotes methoxy or ethoxypropan, with the compound of the formula A1 or A2

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During interesterification WITH2-C8Akilov methyl ether.

Such reactions can also be carried out using interphase catalyst in an organic solvent, such as methylene chloride or toluene, in the presence of aqueous base, e.g. sodium hydroxide solution, and in the presence of such a phase transfer catalyst such as tetrabutylammonium bisulfate.

Typical reaction conditions are presented in the examples.

The invention relates also to a method for obtaining compounds of formula V

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where X denotes a radical which is inert at the reaction;

m is 0-4;

R1and R2each independently of one another denote C1-C6alkyl,

WITH1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl, or

R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom,

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl, or

(R5)2together with the nitrogen atom, in an aprotic solvent spend the interaction of the compounds of formula II

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where X, m, R1and R2have the meanings specified for formula V, with an organolithium compound of formula III

Li-R7(III)

where R7denotes an organic anionic radical;

b) spend the interaction of the obtained lithium complex with the compound of the formula IV

Y1-CO-CO-Y1(IV)

where each of the substituents Y1that may be the same or different, represents a group OR4N(R6)2or N(CH3)OCH3, imidazole or halogen;

R4stands WITH1-C8alkyl;

R6stands WITH1-C8alkyl or

(R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

and then, if Y1denotes an imidazole or halogen, this group substituted by a group Y, where Y has the meanings indicated for the formula I

obtaining the compounds of formula V.

The invention relates also to a method for obtaining compounds of formula I

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where X denotes a radical which is inert in respect of reactions;

m is 0-4;

R3denotes hydrogen, CH3CH2F or CHF2;

Y denotes g each represent hydrogen or C1-C8alkyl, or

(R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

moreover, in this method, the compound of formula V

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where X, m and Y have the meanings stated for formula I, and

R1and R2each independently of one another denote C1-C6alkyl, C1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl or

R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom,

in any order

B1) are occimiano O-methylhydroxylamine or are occimiano hydroxylamine, and then methylated, formatierung or diftormetilirovaniya;

B2) enter into interaction with the ether of Harborview acid.

The invention relates also to novel compounds of formulas V and VII

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where X denotes a radical which is inert in respect of reactions;

m is 0-4;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independent nitrogen, with which they are linked, form a 5 - or 6-membered unsubstituted or substituted ring;

R1and R2each independently of one another denote WITH1-C6alkyl,

WITH1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl, or

R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom.

Preferred compounds in which

m denotes 0;

Y denotes a group OR4;

R4stands WITH1-C8alkyl, especially ethyl;

R1and R2each independently of one another denote WITH1-C6alkyl, especially methyl, or

R1and R2together with the nitrogen atom form a piperidine.

Particularly preferred compounds of the formula Vb and VIIb

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The invention relates also to compounds of the formula I

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where X denotes a radical which is inert in respect of reactions;

m is 0-4;

R3denotes hydrogen, CH3CH2F or CHF2;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;1-C8alkyl, or

(R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

preferably to compounds in which the

m denotes 0;

R3denotes CH3;

Y denotes a group OR4;

R4stands WITH2-C4alkyl, especially ethyl.

In addition, the invention relates to new compounds of the formula

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Examples of making

Abbreviations: CT denotes room temperature; THF refers to tetrahydrofuran; h means hours, min means minutes.

Example 1: Methyl ester of o-(N,N-dimethylaminomethyl)phenylglyoxylic acid Va

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Example 1.1

A solution of n-utility in hexane (15%; 107,6 g; 0,25 mol) at RT add for 20 min in a solution of N-benzyldimethylamine IIa (24,1 g; 0,175 mol) in 60 ml of diethyl ether and the mixture was kept at the temperature of reflux distilled at approximately the 50oC for 3 hours Then this mixture at -50oC add to 50.1 g (at 0.42 mole) of diethyloxalate in 160 ml of THF and heated to CT, type of 20.3 g (of 0.21 mole) of methylchloroform, the mixture is stirred at RT for 1.5 h and concentrated by evaporation in a vacuum. To the residue dhtem get to 38.1 g of the product (the content of the basic substance: 80%; yield: 79%).

Example 1.2

A solution of n-utility in toluene (20%; 82.3 g; of 0.26 mol) is added over a period of 10-15 min in a solution and 24.1 g of N-benzyldimethylamine (0,175 mol) in 60 ml of tert-butyl methyl ether. The mixture is maintained at 55-60oC for 3 h, cooled to CT and at -50oC added to a solution of 50.1 g (at 0.42 mole) of diethyloxalate in 138, 7mm g of toluene. The reaction mixture is heated to CT and stirred for 13 h at approximately 25oC add a 20.3 g (of 0.21 mole) of methylchloroform, the mixture is stirred at RT for 1 h and concentrated by evaporation in a vacuum. To the residue was added 100 ml of methylene chloride and 100 ml of water and separate the organic phase. In this way gain of 26.6 g of the product (basic substance content: 87%; yield: 69%).

Example 1.3

A solution of n-utility in hexane (15%; 89,7 g; of 0.21 mole) is added over a period of 10-15 min in a solution and 24.1 g of N-benzyldimethylamine (to 0.17 mol) in 60 ml of diethyl ether. The mixture was kept at the temperature of reflux distilled approximately 55oC for 3 hours the mixture is cooled to CT and add the solution to 66.3 g (of 0.52 mole) pre-cooled to -20oC methylacetylene in 160 ml of diethyl ether. After stirring for 30 min at a temperature of from -10 to 0oC is in the range from -20 to - 10oC, add a solution of methanolate sodium in methanol (30%; 56,8 g; 0,31 mol). The mixture is heated to CT, add 200 ml of methylene chloride and the mixture is stirred over night. Salt is filtered off, the concentrate was dissolved in 200 ml of toluene and salt, which are filtered off and washed with 50 ml of toluene. In the form of filtrate obtain 23.1 g of product (basic substance content: 72%; yield: 43%).

Example 1.4

A solution of n-utility in hexane (15%; 52 g; 0.12 moles) is added over a period of 10-15 min in a solution of 13.8 g (of 0.10 mole) of N-benzyldimethylamine in 60 ml of diethyl ether. The resulting mixture was kept at the temperature of reflux distilled 40-45oC for about 3 h and then cooled to CT. Then this mixture at a temperature of from -20 to -10oC add in the cooked mixture of 31 g of triethylamine (0,30 mol) and 37.9 g of methylacetylene (0,30 mol) in 160 ml of diethyl ether. The resulting mixture is cooled to -20oC and add 32 g of methanol, and during this operation the temperature rises up to CT. The mixture is stirred at RT overnight, followed by filtration, washing twice with 100 ml diethyl ether and concentration by evaporation in vacuum. The residue is dissolved in 100 ml of methylene chloride and is their primary substance: 69%; yield: 51%).

Example 2: Ethyl ester of o-(N, N-dimethylaminomethyl)phenylglyoxylic acid Vb

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Example 2.1

A solution of n-utility in hexane (15%; 183,8 g; of 0.43 mole) is added over 15 min a solution to 48.3 g of N-benzyldimethylamine (0,35 mol) in 120 ml of methyl tert-butyl ether. This mixture is maintained at 50-55oC for 4 h, and then for 30 min add cooled to -20oC suspension 124 g (0,84 mole) of diethyloxalate in 320 ml of methyl tert-butyl ether. Next, this reaction mixture is heated to CT and type of 25.2 g (of 0.42 mol) of 100% acetic acid, and then a mixture of 100 g of powdered ice with 200 g of water. The phases are separated and the organic phase is washed with 100 ml of water and concentrated by evaporation in a vacuum. Thus obtain 78 g of the product (the content of the basic substance: 86,4%; yield: 82%).

Example 2.2

The technique is similar to that described in the previous example, except that instead of utility in hexane using utility in toluene (20%). Yield: 72 g (basic substance content: 84,8%; yield: 74%).

Example 2.3

A solution of n-utility in hexane (15%; 54,2 g; of 0.13 mol) is added over a period of 10-15 min in a solution of 13.8 g of N-benzyldimethylamine (0,10 mol) in 60 ml of diethyl ether and the mixture myderived added to pre-cooled to -20oC a solution of 42.2 g (0,30 mol) of acrocallosal in 160 ml of diethyl ether. The reaction mixture was stirred for 30 min at 30oC and then cooled to -20oC. At a temperature of from -20 to 0oC successively added 46 g of ethanol (1.0 mol) and of 36.4 g of triethylamine (0,35 mol). After that the reaction mixture is heated to CT and stirred for 1 h, the salt is filtered off and washed with 3 portions of 50 ml of diethyl ether. The combined filtrates are concentrated by evaporation in a vacuum. The residue is dissolved in 200 ml of methylene chloride and 50 ml of water and the organic phase is separated and concentrated by evaporation. This way obtain 19.3 g of product (basic substance content: 77%; yield: 63%).

Example 3: n-Pentalogy ether of o-(N,N-dimethylaminomethyl)phenylglyoxylic acid Vc

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Example 3.1

The technique is similar to that described in example 1.1, except that instead of dimethyloxalate use di-n-pentyloxide. Yield: 62%.

Example 3.2

A solution of n-utility in hexane (15%; of 92.7 g; to 0.22 mole) is added over a period of 10-15 min in a solution and 24.1 g of N-benzyldimethylamine (0,175 mol) in 60 ml of diethyl ether, and this mixture was kept at the temperature of reflux distilled 50-55oC for about 3 hours CME n-pentyloxide in 160 ml of diethyl ether. The mixture is stirred for 30 min and during this time the temperature is allowed to rise to 30oC. At a temperature of from -20 to 0oC add a mixture of 10 g (0,31 mol) of methanol and 32.5 g of triethylamine (0.31 in mol), after which the reaction mixture is stirred at RT overnight and concentrated by evaporation in a vacuum. The residue is dissolved in 200 ml of methylene chloride and 150 ml of water. The organic phase is separated and concentrated by evaporation. In this way get to 98.5 g of the product (basic substance content: 32%; yield: 65%).

Example 4: Methyl ester o-chloromethyloxirane acid VIIa

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15.9 g of methylchloroform (165 mmol) at 20-25oC added to a solution of 18.3 g of methyl ester of o-(N,N-dimethylaminomethyl)- phenylglyoxylic acid Va (basic substance content: 88,6%; 73,3 mol) in 100 ml of toluene. The reaction mixture was stirred at RT overnight, incubated at 60oC for 1 h, cooled and concentrated by evaporation in a vacuum. In this way gain of 15.3 g of the product (basic substance content: 83%; yield: 82%).

Example 5: Ethyl ester of o-chloromethyloxirane acid VIIb

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11.5g of methylchloroform (119 mmol) at 20-25oC added to a solution of 10.3 g of etiolog the l of toluene. Stirring is carried out at RT over night. The reaction mixture is concentrated by evaporation in a vacuum, getting to 10.1 g of the product (the content of the basic substance: 85%; yield: 94%).

Example 6: O-methyloxime methyl ester o-(N,N-dimethylaminomethyl)phenylglyoxylic acid VIa

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14,4 g keeeper Va (basic substance content: 72%; 46,9 mmole) is added to a mixture of 4.2 g of O-methylhydroxylamine (49,3 mmole), 100 g of toluene, 20 ml of methanol and 0.4 g of p-toluenesulfonic acid. The reaction mixture was maintained at 50-55oC for 10 h, and then concentrated by evaporation in a vacuum. The salts are dissolved in 100 ml of methylene chloride and 8 g of sodium carbonate, salt is filtered off and the solution concentrated by evaporation in a vacuum. Obtain 11.9 g of product (basic substance content: 82%; yield: 83%).

Example 7: O-methyloxime n-pentalofos ether o-chloromethyloxirane acid Ic

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A solution of 10.1 g of keeeper VIIb (approximately 80%; 36 mmol) and 0.18 g (1 mmol) of the monohydrate of p-toluenesulfonic acid in 39 g of n-pentanol maintained at 90-95oC for 4 h Then evaporated to approximately 6 g of the solvent and replace pentanol and the reaction is complete. After cooling to CT add 3.7 g (44.5 mmole) label is in a mixture of 60 g of ice and 40 g of water. The resulting mixture is neutralized aqueous solution of NaHCO3and the organic phase is separated, washed with 30 ml of water and concentrated by evaporation in a vacuum. In the form of a mixture pentalofos ether Ic (approximately 50%) with ethyl ether Ia (about 30%) are obtained 10.3 g of crude product.

Example 8: Ethyl ester of o-piperidinecarboxylate acids Ve

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A solution of n-utility in toluene (20%; 65,6 g; of 0.20 mol) for 10-15 minutes added to a solution of 31 g of N-benzylpiperidine (0,175 mol) in 60 ml of tert-butyl methyl ether. The reaction mixture is maintained at 55-60oC for about 18 h and then at RT add in cold (-20oC) a solution of 50.1 g diethyloxalate (at 0.42 mole) in 160 ml of toluene. The mixture is heated to CT and stirred at 20-25oC for 30 minutes Then to this reaction mixture was added to 12.6 g of 100% (of 0.21 mol) of acetic acid and a mixture of 50 g of powdered ice with 100 g of water. The phases are separated, the organic phase is washed with 50 ml of water and concentrated by evaporation in a vacuum. In this way get to 43.2 g of the product (basic substance content: 89%; yield: 80%).

Example 9: n-Pentalogy ether o-piperidinecarboxylic acid Vf

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From a solution of 51.8 g (0,2 mol) of 92% Ve connection and 0.57 g of 95% continuously distilled ethanol (with a coefficient of irrigation 1: 20). After approximately 2 hours the mixture is cooled to CT and poured into a mixture of 50 g of ice with 50 g of water and 0.6 g of acetic acid. The phases are separated, the organic phase is washed with 50 ml of water and concentrated by evaporation in a vacuum. In this way get to 59.4 g of the product (the content of the basic substance: 86,5%; yield: 98%).

Example 10: Methyl ester of 2-(-chloromethylene)-2-methoxybenzoate acid Ia

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In a 100-ml flask for sulphurization of 15.7 g of ether methoxybenzeneboronic acid VIa (pereg., 91.3 percent; 49,4 mmole) was dissolved in 20 ml of toluene and added 0.3 g (2,15 mmole) of powdered potassium carbonate. Then when CT dropwise quickly add and 7.1 ml of ethyl ether of Harborview acid (74,6 mmole), and within 10 minutes the temperature rises from CT to the 41oC. After attenuation of the exothermic reaction the mixture is heated to 95oC and using gas chromatography to determine the conversion rate is 86%. Next add an additional 1,41 ml of ethyl ether of Harborview acid (14,8 mmole) and after 1/4 h again determine the conversion rate, which is 98%. After a total of 1 h reaction time the reaction mixture is cooled, poured into brine and slightly acidified with 1 N. hydrochloric acid. After the first oil gain of 22.4 g of crude product.

For accurate determination of the output of the isomers [E/Z] chromatography carried out on silica gel at a ratio of ethyl acetate/hexane 1:6 and in high vacuum with gentle heating distilled 7,18 g of the carbamate, which was made.

Output: 11,81 g of a viscous yellow product in the form of oil or 99% of theoretical yield; purity: 96.5 percent; total yield: 95.4 percent of theoretical yield; the ratio [E/Z] according to the gas chromatography is 80:20.

In this example, using 4 mol.% potassium carbonate and 180 mol.% ethyl ether of Harborview acid from the amount of starting material.

Isomerization

When standing within nights, in the oily product crystallized [E]-form and can be filtered, washed methylcyclohexane-tert-butylmethylamine ether, and then dried in high vacuum to constant weight.

1st crystallized: 6,37 g of white crystals.

5,44 g [E/Z]-a mixture of stock solution dissolved in hot condition in 20 ml of methylcyclohexane, the solution is cooled to room temperature and for 5 hours to enter a weak stream of gaseous hydrogen chloride. The solution, which is initially painted in a dark purple color, becoming dark green and in the sediment falls [E]-isomer, comfortably]-isomer: 9,63 g or 81% of theoretical yield.

Example 11: Ethyl ester of 2-(-chloromethylene)-2 - methoxyimino-acetic acid Ib

< / BR>
20 g chloromethylketone ether (0,071 mole) is placed in a sulphonation flask together with 6.6 g of o-methylhydroxylamine (0,08 mol) and 30 g of absolute ethanol and the mixture is heated to 50-55oC. After exposure for 3 h with stirring at 50-55oC at the same temperature for 30 minutes give 10 g of gaseous hydrogen chloride, or 0.27 mol). After stirring for 17 h at 50-55oC to complete the reaction, the reaction mixture is cooled to 0-5oC and pH by adding sodium hydroxide solution was adjusted to 7-9. The resulting product is filtered and washed three times with 10 ml of cold water. Next, wet the crude product is dried in a drying chamber under vacuum at 30oC. the Product, i.e., the ethyl ester of 2-(chloromethylene)methoxybenzoate acid, is obtained in 87% (theoretical) yield and content of the basic substance 90,5% (consisting of 82.8% of E-isomer and 7.7% Z-isomer). By recrystallization of the content of the E-isomer can be increased to more than 95%. The melting point of 99% E-isomer is 73oC. Z-isomer at room temperature is a liquid.

Prima is 7.0 g of 3-triftoratsetofenona (A) (0,034 mole) in 8 ml of dimethylacetamide. When 55-70oC and 250-50 mbar 3.5 ml distilled solvent. After addition of 0.07 g of potassium iodide for 20 min at 55-65oC add a 9.25 g of 90% ethyl ester of 2-(-chloromethylene)-2-methoxybenzoate acid Ib (to 0.032 mole), dissolved in 12 ml of dimethylacetamide. After stirring for 3 h to complete the reaction the reaction mixture at 20-25oC for 30 min add in a mixture of 30 ml of water, 18 ml of toluene, and the addition of 32% hydrochloric acid the pH was adjusted to 4-5. Water, the lower phase is extracted twice using each time 10 ml of toluene. The combined organic phases are extracted with 10 ml of water. The solvent is distilled off in vacuum at 60oC. thus obtain 14.8 g of a crude product of compound IXb in the form of oil, containing 78% of the basic substance. After cleaning, get a solid substance with a melting point 47oC and basic substance content of 95%.

This reaction can also be carried out, for example, DMF or N-organic in the same conditions or in acetonitrile, using as the Foundation of potassium carbonate.

Example 13: Transesterification

< / BR>
A solution of 14.8 g telefonnogo compound IXb (basic substance content: 78%; or 0.027 mol) in 53 ml of methanol and 1.5 g of 30% metaplay in a mixture of 53 ml of toluene, 10 ml of water and 1 g of 32% hydrochloric acid, maintaining the pH level of 3-3 .5 by the addition of hydrochloric acid. After separation of the phases the aqueous phase is extracted twice, using each time 10 ml of toluene. The combined organic phases are extracted twice, using each time in 16 ml of water. After evaporation of the organic solvent in vacuum at 60-65oC gain of 13.4 g of crude product which is dissolved at 55-60oC in 27 ml of methylcyclohexane. During cooling to 0-5oC precipitated product is filtered and washed with 0-5oC methylcyclohexanol. After drying in vacuum at 40oC obtain 9 g of the product IXa with a melting point of 69-71oC.

1. The method of obtaining the compounds of formula I

< / BR>
where X denotes an organic radical inert to the reaction conditions;

m denotes 0;

R3denotes hydrogen, CH3CH2F or CHF2;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl, or (R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

when is rmula I values;

R1and R2each independently of one another denote WITH1-C6alkyl,

WITH1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl or

R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom,

in an aprotic solvent with an organolithium compound of formula III

Li-R7III

where R7denotes an organic anionic radical,

b) spend the interaction of the obtained lithium complex with the compound of the formula IV

Y1-CO-CO-Y1IV

where each of the substituents Y1that may be the same or different, represents a group OR4N(R6)2or N(CH3)OCH3;

R4represents C1-C8alkyl;

R6stands WITH1-C8alkyl,

or (R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring,

obtaining the compounds of formula V

< / BR>
in this connection, in any order B1) are occimiano O-methylhydroxylamine; B2) enter into interaction with the ether of Harborview acid.

2. The method according to p. 1, where the reaction stage a) is carried out at 0-120oC, and the reaction stage b) is carried out at a temperature from -50 to +30oC.

3. The method according to p. 1, where the solvent on the reaction stages (a) and (b) use a simple ether, a hydrocarbon or a mixture thereof.

4. The method according to p. 3, where a represents a hydrocarbon hexane, benzene, toluene or xylene, and a simple ether is tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, dimethoxyethane, diethoxyethane or diethoxymethane.

5. The method according to p. 1, where the organolithium compound of formula III is used utility, second-utility, exility, diisopropylamide lithium (DAL), hexamethyldisilazide lithium or tetramethylpiperidine lithium (TMPL).

6. The method according to p. 5, where organolithium compound of formula III is utility.

7. The method according to p. 1 where in the compound of formula IV, Y1indicates OR3first of all OS2H5.

8. The method according to p. 1 where in the compound of formula II, m is 0 and R1and R2each independently of one another denote C1-Cactionnow stage a) use 0.5 to 1.5 mol. EQ. organolithium compounds of the formula III, the amount of compounds of formula II.

10. The method according to p. 1, where the reaction stage b) using a 0.9-4 mol. EQ. derivative of oxalic acid of formula IV from the amount of the compounds of formula II.

11. The method according to p. 1, where after the implementation of the reaction stage b) the pH value of the reaction mixture is adjusted to 7 or less.

12. The method according to p. 1, where the reaction stage B2) using ethyl ether of Harborview acid.

13. The method of obtaining the compounds of formula V

< / BR>
where X denotes a radical which is inert at the reaction;

m denotes 0;

R1and R2each independently of one another denote WITH1-C6alkyl, C1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl or R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl, or (R5)2somesite in this way a) in an aprotic solvent spend the interaction of the compounds of formula II

< / BR>
where X, m, R1and R2have the meanings specified for formula V,

with organolithium compound of formula III

Li-R7III

where R7denotes an organic anionic radical;

b) spend the interaction of the obtained lithium complex with the compound of the formula IV

Y1-CO-CO-Y1IV

where each of the substituents Y1that may be the same or different, represents a group OR4N(R6)2or N(CH3)OCH3;

R4stands WITH1-C8alkyl;

R6represents C1-C8alkyl or

(R6)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring,

obtaining the compounds of formula V.

14. The method of obtaining the compounds of formula I

< / BR>
where X denotes a radical which is inert in respect of reactions;

m denotes 0;

R3denotes hydrogen, CH3CH2F or CHF2;

Y denotes a group OR4N(R5)2or N'(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl, or (R5)2with
moreover, in this method, the compound of formula V

< / BR>
where X, m and Y have the meanings stated for formula I;

R1and R2each independently of one another denote C1-C6alkyl, C1-C6alkenyl,1-C6alkoxyalkyl or3-C6cycloalkyl or R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom,

in any order B1) are occimiano O-methylhydroxylamine or are occimiano hydroxylamine, and then methylated, formatierung or diftormetilirovaniya; B2) enter into interaction with the ether of Harborview acid.

15. The compound of formula V.

< / BR>
where X denotes a radical which is inert in relation to the reactions as described in paragraph 1;

m denotes 0;

Y denotes a group OR4N(R5)2or N(CH3)OCH3;

R4and R5each independently of one another denote hydrogen or C1-C8alkyl or (R5)2together with the nitrogen atom to which they are bound, form a 5 - or 6-membered unsubstituted or substituted ring;

R11-C6alkoxyalkyl or3-C6cycloalkyl or R1and R2together with the nitrogen atom form an unsubstituted or substituted 6 - or 7-membered ring which in addition to the nitrogen atom may contain an additional nitrogen atom.

16. Connection on p. 15, where m denotes 0; Y denotes a group OR4; R4stands WITH1-C8alkyl; R1and R2each independently of one another denote C1-C6alkyl, or R1and R2together with the nitrogen atom form a piperidine.

17. Connection on p. 16, where R4represents ethyl; R1and R2denote methyl.

Priority points:

03.01.1996 - PP.1-13 and 15-17;

26.07.1996 - p. 14.

 

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< / BR>
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