RU2177472C2 - Method of synthesis of derivatives of o-chloromethylphenyl-glycoxylic acid - Google Patents

Abstract

FIELD: organic chemistry, chemical technology. SUBSTANCE: invention relates to method of synthesis of compound of the formula (I)

where X means radical which is inert under reaction conditions; m = 0; R₃ means hydrogen atom, CH₃,CH₂F or CHF₂; Y means the group OR₄N(R₅)₂ or N(CH₃)OCH₃; R₄ and R₅ each and independently each of other mean hydrogen atom or C₁-C₈-alkyl, or (R₅)₂ in common with nitrogen atom to which they are bound form 5- or 6-membered unsubstituted or substituted ring in accordance with: (a) interaction of compound of the formula (II)

where X and m have values indicated for the formula (I) and R₁ and R₂ each and independently each of other mean C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-alkoxyalkyl or C₃-C₆-cyclo-alkyl, or R₁ and R₂ in common with nitrogen atom form unsubstituted or substituted 6- or 7-membered ring which except for said nitrogen atom can involve additional nitrogen atom with lithium-organic compound of the formula (III) Li-R₇ (III) where R₇ means organic anion-active radical and reaction is carried out in aprotonic solvent; (b) interaction of obtained lithium complex with compound of the formula (IV) Y₁-CO-CO-Y₁ where each of substitutes Y₁ can be similar or different and mean the group OR₄,N(R₆)₂ or N(CH₃)OCH₃; R₄ means C₁-C₈-alkyl; R₆ means C₁-C_8/ -alkyl or (R₆)₂ in common with nitrogen atom to which they are bound form 5- or 6-membered unsubstituted or substituted ring to yield the compound of the formula (V)

Description

где X обозначает радикал, который инертен в отношении реакций;
m обозначает 0-4;
R₃ обозначает водород, CH₃, CH₂F или CHF₂;
Y обозначает группу OR₄, N(R₅)₂ или N(CH₃)OCH₃;
R₄ и R₅ каждый независимо друг от друга обозначают водород или С₁-С₈алкил, или
(R₅)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо; причем в этом способе
а) проводят взаимодействие соединения формулы II

где
X и m имеют указанные для формулы I значения и
R₁ и R₂ каждый независимо друг от друга обозначают С₁-С₆алкил,
С₁-С₆алкенил, C₁-С₆алкоксиалкил или С₃-С₆циклоалкил, или же
R₁ и R₆ совместно с атомом азота образуют незамещенное или замещенное 6- или 7-членное кольцо, которое помимо этого атома азота может содержать дополнительный атом азота, в апротонном растворителе с литийорганическим соединением формулы III
Li-R₇, (III)
где R₇ обозначает органический анионоактивный радикал;
б) проводят взаимодействие полученного литиевого комплекса с соединением формулы IV
Y₁-CO-CO-Y₁, (IV)
где каждый из заместителей Y₁, которые могут быть одинаковыми или различными, представляет собой группу OR₄, N(R₆)₂ или N(CH₃)OCH₃, имидазол или галоген;
R₄ обозначает С₁-С₈алкил;
R₆ обозначает С₁1-С₈алкил; или же
(R₆)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо;
и затем, если Y₁ обозначает имидазол или галоген, эту группу замещают группой Y, где Y имеет значения, указанные для формулы I;
с получением соединения формулы V

в) это соединение в любом порядке
в1) подвергают оксимированию O-метилгидроксиламином или подвергают оксимированию гидроксиламином, а затем метилированию, фторметилированию или дифторметилированию;
в2) вводят во взаимодействие с эфиром хлормуравьиной кислоты.The invention relates to a method for producing a compound of formula I

where X is a radical that is inert to the reactions;
m is 0-4;
R ₃ is hydrogen, CH ₃ , CH ₂ F or CHF ₂ ;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently of one another are hydrogen or C ₁ -C ₈ alkyl, or
(R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring; moreover, in this method
a) carry out the interaction of the compounds of formula II

Where
X and m have the meanings indicated for formula I and
R ₁ and R ₂ each independently from each other are C ₁ -C ₆ alkyl,
C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl, or
R ₁ and R ₆ together with the nitrogen atom form an unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom, in an aprotic solvent with an organolithium compound of the formula III
Li-R ₇ , (III)
where R ₇ denotes an organic anionic radical;
b) carry out the interaction of the obtained lithium complex with the compound of formula IV
Y ₁ —CO — CO — Y ₁ , (IV)
where each of the substituents Y ₁ , which may be the same or different, represents a group OR ₄ , N (R ₆ ) ₂ or N (CH ₃ ) OCH ₃ , imidazole or halogen;
R ₄ is C ₁ -C ₈ alkyl;
R ₆ is C ₁ 1 -C ₈ alkyl; or
(R ₆ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
and then, if Y ₁ is imidazole or halogen, this group is replaced by a group Y, where Y has the meanings indicated for formula I;
to obtain the compounds of formula V

c) this connection in any order
c1) are subjected to oxymerization with O-methylhydroxylamine or subjected to oximeting with hydroxylamine, and then methylation, fluoromethylation or difluoromethylation;
B2) is introduced into interaction with chloroformic acid ester.

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

 Unless otherwise indicated, the above terms have the following meanings.

 The radical X may be any radical, provided that it is inert under the reaction conditions, for example, alkyl, alkenyl, phenyl, benzyl, nitro or alkoxy; m is preferably 0.

 Depending on the number of carbon atoms, the alkyl groups are straight chain 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.

 By the term “alkenyl” is meant straight-chain or branched alkenyl, in particular allyl, metall, 1-methylvinyl or but-2-en-1-yl. Alkenyl radicals whose chain contains 3-4 carbon atoms are preferred.

 Halogen is fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.

 Haloalkyls may contain the same or different halogen atoms, for example fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl and 3 , 3,3-trifluoropropyl.

 As alkoxy groups, for example, methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy groups are preferred; methoxy and ethoxy are preferred.

 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

 From Organic Reactions, 26, p. 1 ff., (1979), it is known that lithium can be introduced into the ortho position of tert-benzylamines using an organolithium compound, and this latter can be replaced at the ortho position by an electrophile. However, oxalic acid derivatives are not mentioned as electrophiles in this reference.

 In addition, in European patent 178826 on pages 48-75 there is a general indication that it is possible to react phenyl lithium compounds with oxalic esters to produce phenyl glyoxylic acid esters, but in the examples, phenyl lithium compounds substituted at the ortho position with an amino group are not illustrated. Moreover, a mixture of butyl lithium with potassium tert-butoxide is used for metallation.

 It was found that the interaction of benzylamines of formula II can be carried out with an organolithium compound, and then with an oxalic acid derivative of formula IV, to obtain phenylglyoxylic acid esters of formula V.

 In addition, it is known that tert-benzylamines can be converted to the corresponding benzyl chlorides using chloroformate. For example, according to the Indian Journal of Chemistry, Volume 31B, p. 626 (1992), the corresponding benzyl chloride is prepared by reacting o-hydroxybenzyl diethylamine with ethyl chloroformate.

 It was also found that a similar interaction can be carried out in good yield, also using benzylamines that carry an 1,2-dioxo or 1-ketoximino-2-oxo group in the ortho position, this group being preserved, which is an unexpected fact, taking into attention to the reactivity of such a functional group.

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

 The individual reaction steps are preferably carried out as follows.

The reaction stage a)
Reaction temperature: 0-120 ^o C, preferably from 20 ^o C to the boiling point of the solvent.

 The organolithium compound of the formula III is butyl lithium, sec-butyl lithium, hexyl lithium, lithium diisopropylamide (DAL), lithium hexamethyldisilazide or lithium tetramethyl piperidide (TMPL); butyl lithium is particularly preferred.

 It is advisable to use 0.5-1.5 mol. organolithium compounds on the amount of the compounds of formula II.

As starting materials, it is preferable to use compounds of the formula II, where m is 0, R ₁ and R ₂ are C ₁ -C ₆ alkyl or R ₁ and R ₂ together with the nitrogen atom form piperidine.

The reaction stage b)
Reaction temperature: from -50 ^o C to the boiling point of the solvent, preferably from -20 to 30 ^o C.

 Use 0.9-4 mol. a derivative of oxalic acid of formula IV on the amount of the compound of formula II. Such an oxalic acid derivative, in particular ether, can also be used as a solvent.

 Suitable solvents for reaction stages a) and b) are ether, hydrocarbon or a mixture thereof, in particular hexane, benzene, toluene, xylene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, dimethoxyethane, diethoxyethane and diethoxymethane. Both reaction steps are preferably carried out in the same solvent mixture.

In the case where Y _{1 of} the oxalic acid derivative of the formula IV is halogen or imidazole, the glyoxylic acid halide or imidazole derivative of the formula V is reacted with HOR ₄ or HN (R ₅ ) ₂ under basic conditions to give the corresponding ester or amide. This glyoxylic acid ester can also be converted to the target glyoxylic acid amide by aminolysis with HN (R ₅ ) ₂ or transesterified with alcohol, in which case it is preferable to convert this ethyl ether to methyl or n-pentyl ether.

 As an oxalic acid derivative, it is preferable to use an ether, in particular ethyl ether.

 After carrying out the reaction step b), it is advisable to acidify the reaction mixture to a pH of 7 or less, for example with an aqueous solution of an acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with anhydrous acid, for example, a carboxylic acid, such as propionic acid or acetic acid acid, or ammonium salt. The organic phase is then washed thoroughly with water and the product of formula V is purified by distillation or crystallization. This product can also be purified by acid extraction of by-products. The reaction step b1) or b2) can also be carried out immediately after the reaction step b) without purification of intermediate V.

Reaction step b1)
Either the compound of formula V is reacted with O-methylhydroxylamine, or it is oximeted with hydroxylamine or its salt, for example, hydrochloride or sulfate, and then methylated, for example, with methyl iodide, methyl chloride or dimethyl sulfate, fluoromethylated using BrCH ₂ F or difluoromethylated with ClCHF ₂ in alkaline conditions.

Reaction step b2)
To replace the amino group with chlorine, it is preferable to use chloroformic acid ethyl ester.

Such a reaction can be carried out in an anhydrous aprotic solvent or without solvent; chloroformic acid ester can also be used as a solvent. Preferred solvents are hydrocarbons, halogenated hydrocarbons, esters, ethers, ketones, nitriles and chloroformate, in particular benzene, toluene, xylene, chlorobenzene, nitrobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, trichloromethane, dichloroethane and trih. chloroformate; ethyl acetate, tert-butyl methyl ether, methyl isobutyl ketone and acetonitrile are more preferred. The preferred reaction temperature is from 0 ^o C to the boiling point of the solvent, in particular 20-120 ^o C.

 In some cases, this reaction is expediently carried out in the presence of a base, which is used, for example, in an amount of 1-50 mol% based on the compound of formula V. Preferred bases are alkali metal and alkaline earth metal bicarbonates or carbonates.

 The chloroformate ester can be used in any desired excess, and the unreacted portion can be isolated; it is advisable to use in an amount of 100-200 mol.% of the amount of the compounds of formula V.

You can choose any alcohol residue of chloroformate ester, provided that it does not enter into any undesirable reactions; it is advisable that it contains no more than 8 carbon atoms, with optionally halogenated C ₁ -C ₄ alkyl ether, optionally halogenated C ₁ -C ₄ alkenyl ether, unsubstituted or substituted benzyl or phenyl ether is preferred, ethyl chloroformate is particularly preferred.

R ₁ and R _{2 are} preferably C ₁ -C ₆ alkyl or R ₁ and R ₂ together with the nitrogen atom form piperidine, piperazine, hexahydroazepine or tetrahydroisoquinoline, especially piperidine.

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

 Suitable bases are, for example, hydroxides, hydrides, amides, alkanolates, carbonates, dialkylamides or alkylsilylamides of alkali metals and alkaline earth metals, alkylamines, alkylenediamines, N-substituted and N-alkylated saturated and unsaturated cycloalkylamines, basic heterocyclic compounds, ammonium hydroxide as well as carbocyclic amines. Examples include hydroxide, hydride, amide, methanolate and sodium carbonate, tert-butanolate and potassium carbonate, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, calcium hydride, triethylamine, triethylene diamine, cyclohexylamine, N-cyclohexyl-N, N- dimethylamine, N, N-diethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, N-methylmorpholine, benzyltrimethylammonium hydroxide, as well as 1,8-diazabicyclo [5.4.0] undec-5-ene (DBU).

Во время переэтерификации С₂-С₈алкиловый эфир, прежде всего этиловый эфир, предпочтительно превращать с использованием метанола в соответствующий метиловый эфир.Reaction step g)
The reaction of a compound of formula I with a compound of formula HOR, wherein R is an organic radical, is carried out under basic conditions in a solvent in accordance with known methods. When Y is an OR ₄ group, the resulting compound of formula IX can, if necessary, be transesterified or amidated in accordance with well-known methods. In a particularly preferred embodiment, in the reaction step d), a compound of formula I is reacted where m is 0, R ₃ is methyl and Y is a methoxy or ethoxy group with a compound of formula A1 or A2

During the transesterification of a C ₂ -C ₈ alkyl ester, especially ethyl ester, it is preferable to convert, using methanol, to the corresponding methyl ester.

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

 Typical reaction conditions are presented in the examples.

где X, m, R₁ и R₂ имеют значения, указанные для формулы V, с литийорганическим соединением формулы III
Li-R₇, (III)
где R₇ обозначает органический анионоактивный радикал;
б) проводят взаимодействие полученного литиевого комплекса с соединением формулы IV
Y₁-CO-CO-Y₁, (IV)
где каждый из заместителей Y₁, которые могут быть одинаковыми или различными, представляет собой группу OR₄, N(R₆)₂ или N(CH₃)OCH₃, имидазол или галоген;
R₄ обозначает С₁-С₈алкил;
R₆ обозначает С₁-С₈алкил или же
(R₆)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо;
и затем, если Y₁ обозначает имидазол или галоген, эту группу замещают группой Y, где Y имеет значения, указанные для формулы I
с получением соединения формулы V.The invention also relates to a method for producing a compound of formula V

where X is a radical that is inert to the reaction;
m is 0-4;
R ₁ and R ₂ each independently from each other are C ₁ -C ₆ alkyl,
C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl, or
R ₁ and R ₂ together with the nitrogen atom form an unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom,
Y represents a group OR ₄ N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently of one another are hydrogen or C ₁ -C ₈ alkyl, or
(R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
moreover, in this method
a) in an aprotic solvent, the compounds of formula II are reacted

where X, m, R ₁ and R ₂ have the meanings indicated for formula V, with an organolithium compound of the formula III
Li-R ₇ , (III)
where R ₇ denotes an organic anionic radical;
b) carry out the interaction of the obtained lithium complex with the compound of formula IV
Y ₁ —CO — CO — Y ₁ , (IV)
where each of the substituents Y ₁ , which may be the same or different, represents a group OR ₄ , N (R ₆ ) ₂ or N (CH ₃ ) OCH ₃ , imidazole or halogen;
R ₄ is C ₁ -C ₈ alkyl;
R ₆ is C ₁ -C ₈ alkyl or
(R ₆ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
and then, if Y ₁ is imidazole or halogen, this group is replaced by a group Y, where Y has the meanings indicated for formula I
to obtain the compounds of formula V.

где X обозначает радикал, который инертен в отношении реакций;
m обозначает 0-4;
R₃ обозначает водород, CH₃, CH₂F или CHF₂;
Y обозначает группу OR₄, N(R₅)₂ или N(CH₃)OCH₃;
R₄ и R₅ каждый независимо друг от друга обозначают водород или С₁-C₈алкил, или
(R₅)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо;
причем в этом способе соединение формулы V

где X, m и Y имеют значения, указанные для формулы I, и
R₁ и R₂ каждый независимо друг от друга обозначают C₁-С₆алкил, C₁-С₆алкенил, С₁-С₆алкоксиалкил или С₃-С₆циклоалкил или же
R₁ и R₂ вместе с атомом азота образуют незамещенное или замещенное 6- или 7-членное кольцо, которое помимо этого атома азота может содержать дополнительный атом азота,
в любом порядке
в1) подвергают оксимированию O-метилгидроксиламином или подвергают оксимированию гидроксиламином, а затем метилированию, фторметилированию или дифторметилированию;
в2) вводят во взаимодействие с эфиром хлормуравьиной кислоты.The invention also relates to a method for producing a compound of formula I

where X is a radical that is inert to the reactions;
m is 0-4;
R ₃ is hydrogen, CH ₃ , CH ₂ F or CHF ₂ ;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently of one another are hydrogen or C ₁ -C ₈ alkyl, or
(R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
moreover, in this method, the compound of formula V

where X, m and Y have the meanings indicated for formula I, and
R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl or
R ₁ and R ₂ together with the nitrogen atom form an unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom,
in any order
c1) are subjected to oxymerization with O-methylhydroxylamine or subjected to oximeting with hydroxylamine, and then methylation, fluoromethylation or difluoromethylation;
B2) is introduced into interaction with chloroformic acid ester.

где X обозначает радикал, который инертен в отношении реакций;
m обозначает 0-4;
Y обозначает группу OR₄, N(R₅)₂ или N(CH₃)OCH₃;
R₄ и R₅ каждый независимо друг от друга обозначают водород или С₁-С₈алкил, или
(R₅)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо;
R₁ и R₂ каждый независимо друг от друга обозначают С₁-С₆алкил,
С₁-С₆алкенил, С₁-С₆алкоксиалкил или С₃-С₆циклоалкил, или же
R₁ и R₂ вместе с атомом азота образуют незамещенное или замещенное 6- или 7-членное кольцо, которое помимо этого атома азота может содержать дополнительный атом азота.The invention also relates to new compounds of formulas V and VII.

where X is a radical that is inert to the reactions;
m is 0-4;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently of one another are hydrogen or C ₁ -C ₈ alkyl, or
(R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
R ₁ and R ₂ each independently from each other are C ₁ -C ₆ alkyl,
C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl, or
R ₁ and R ₂ together with the nitrogen atom form an unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom.

Compounds in which
m is 0;
Y represents an OR ₄ group;
R ₄ is C ₁ -C ₈ alkyl, especially ethyl;
R ₁ and R ₂ each independently from each other are C ₁ -C ₆ alkyl, especially methyl, or
R ₁ and R ₂ together with the nitrogen atom form piperidine.

Изобретение относится также к соединениям формулы I

где X обозначает радикал, который инертен в отношении реакций;
m обозначает 0-4;
R₃ обозначает водород, CH₃, CH₂F или CHF₂;
Y обозначает группу OR₄, N(R₅)₂ или N(CH₃)OCH₃;
R₄ обозначает С₂-С₄алкил;
каждый из заместителей R₅ независимо друг от друга обозначает водород или С₁-С₈алкил, или
(R₅)₂ совместно с атомом азота, с которым они связаны, образуют 5- или 6-членное незамещенное или замещенное кольцо;
предпочтительно к соединениям, в которых
m обозначает 0;
R₃ обозначает CH₃;
Y обозначает группу OR₄;
R₄ обозначает С₂-С₄алкил, прежде всего этил.Particularly preferred compounds of formulas Vb and VIIb

The invention also relates to compounds of the formula I

where X is a radical that is inert to the reactions;
m is 0-4;
R ₃ is hydrogen, CH ₃ , CH ₂ F or CHF ₂ ;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ is C ₂ -C ₄ alkyl;
each of the substituents R ₅ independently from each other denotes hydrogen or C ₁ -C ₈ alkyl, or
(R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
preferably to compounds in which
m is 0;
R ₃ is CH ₃ ;
Y represents an OR ₄ group;
R ₄ is C ₂ -C ₄ alkyl, especially ethyl.

Примеры получения
Аббревиатуры: КТ обозначает комнатную температуру; ТГФ обозначает тетрагидрофуран; ч обозначает часы, мин обозначает минуты.In addition, the invention relates to new compounds of the formulas

Production Examples
Abbreviations: CT stands for room temperature; THF is tetrahydrofuran; h is hours, min is minutes.

Пример 1.1
Раствор н-бутиллития в гексане (15%-ный; 107,6 г; 0,25 моля) при КТ добавляют в течение 20 мин в раствор N-бензилдиметиламина IIa (24,1 г; 0,175 моля) в 60 мл диэтилового эфира и смесь выдерживают при температуре дефлегмации приблизительно 50^oC в течение 3 ч. Далее эту смесь при -50^oC добавляют в 50,1 г (0,42 моля) диметилоксалата в 160 мл ТГФ и нагревают до КТ, добавляют 20,3 г (0,21 моля) метилхлорформиата, смесь перемешивают при КТ в течение 1,5 ч и концентрируют упариванием в вакууме. К остатку добавляют по 100 мл хлористого метилена и воды, органическую фазу отделяют и концентрируют упариванием. Таким путем получают 38,1 г продукта (содержание основного вещества: 80%; выход: 79%).Example 1: O- (N, N-dimethylaminomethyl) phenylglyoxylic acid methyl ester Va

Example 1.1
A solution of n-butyllithium in hexane (15%; 107.6 g; 0.25 mol) at RT was added over 20 minutes to a solution of N-benzyldimethylamine IIa (24.1 g; 0.175 mol) in 60 ml of diethyl ether and the mixture was kept at a reflux temperature of approximately 50 ^° C. for 3 hours. Next, this mixture was added at -50 ^° C. to 50.1 g (0.42 mol) of dimethyl oxalate in 160 ml of THF and heated to RT, 20.3 g ( 0.21 mol) of methyl chloroformate, the mixture was stirred at RT for 1.5 h and concentrated by evaporation in vacuo. 100 ml of methylene chloride and water are added to the residue, the organic phase is separated and concentrated by evaporation. In this way, 38.1 g of product are obtained (basic substance content: 80%; yield: 79%).

Example 1.2
A solution of n-butyllithium in toluene (20%; 82.3 g; 0.26 mol) is added over 10-15 minutes to a solution of 24.1 g of N-benzyldimethylamine (0.175 mol) in 60 ml of tert-butyl methyl ether. The mixture was kept at 55-60 ^° C. for 3 hours, cooled to RT, and 50.1 g (0.42 mol) of dimethyl oxalate in 138.7 g of toluene was added to a solution of -50 ^° C. The reaction mixture is heated to RT and stirred for 13 hours at approximately 25 ^° C., 20.3 g (0.21 mol) of methyl chloroformate are added, the mixture is stirred at RT for 1 hour and concentrated by evaporation in vacuo. 100 ml of methylene chloride and 100 ml of water were added to the residue, and the organic phase was separated. In this way, 26.6 g of product are obtained (basic substance content: 87%; yield: 69%).

Example 1.3
A solution of n-butyllithium in hexane (15%; 89.7 g; 0.21 mol) was added over 10-15 minutes to a solution of 24.1 g of N-benzyldimethylamine (0.17 mol) in 60 ml of diethyl ether. The mixture was kept at a reflux temperature of approximately 55 ^° C. for 3 hours. This mixture was cooled to RT and 66.3 g (0.52 mol) of methyloxalyl chloride pre-cooled to -20 ^° C. in 160 ml of diethyl ether were added to the solution. After stirring for 30 minutes at a temperature of from -10 to 0 ^° C, the reaction mixture was again cooled to -20 ^° C and diluted with 100 ml of diethyl ether. Maintaining the temperature in the range from -20 to -10 ^o C, add a solution of sodium methanolate in methanol (30%; 56.8 g; 0.31 mol). The mixture was heated to RT, 200 ml of methylene chloride was added, and the mixture was stirred overnight. The salts are filtered off, the concentrate is dissolved in 200 ml of toluene and the salts that remain are filtered off and washed with 50 ml of toluene. 23.1 g of product are obtained as filtrate (basic substance content: 72%; yield: 43%).

Example 1.4
A solution of n-butyllithium in hexane (15%; 52 g; 0.12 mol) is added over 10-15 minutes to a solution of 13.8 g (0.10 mol) of N-benzyldimethylamine in 60 ml of diethyl ether. The resulting mixture was kept at a reflux temperature of 40-45 ^o C for about 3 hours and then cooled to CT. Next, this mixture at a temperature of from -20 to -10 ^o C is added to the prepared mixture of 31 g of triethylamine (0.30 mol) and 37.9 g of methyloxalyl chloride (0.30 mol) in 160 ml of diethyl ether. The resulting mixture was cooled to -20 ^o C and add 32 g of methanol, and during this operation, the temperature rises to CT. The mixture was stirred at RT overnight, followed by filtration, washing twice with 100 ml of diethyl ether and concentration by evaporation in vacuo. The residue was dissolved in 100 ml of methylene chloride and 50 ml of water, and the organic phase was separated and concentrated by evaporation. In this case, 16.4 g of product are obtained (basic substance content: 69%; yield: 51%).

Пример 2.1
Раствор н-бутиллития в гексане (15%-ный; 183,8 г; 0,43 моля) добавляют в течение 15 мин в раствор 48,3 г N-бензилдиметиламина (0,35 моля) в 120 мл метил-трет-бутилового эфира. Эту смесь выдерживают при 50-55^oC в течение 4 ч, а затем в течение 30 мин добавляют в охлажденную до -20^oC суспензию 124 г (0,84 моля) диэтилоксалата в 320 мл метил-трет-бутилового эфира. Далее эту реакционную смесь нагревают до КТ и добавляют 25,2 г (0,42 моля) 100%-ной уксусной кислоты, а затем смесь 100 г истолченного льда с 200 г воды. Фазы разделяют и органическую фазу промывают 100 мл воды и концентрируют упариванием в вакууме. При этом получают 78 г продукта (содержание основного вещества: 86,4%; выход: 82%).Example 2: Ethyl ester of o- (N, N-dimethylaminomethyl) phenylglyoxylic acid Vb

Example 2.1
A solution of n-butyllithium in hexane (15%; 183.8 g; 0.43 mol) is added over 15 minutes to a solution of 48.3 g of N-benzyldimethylamine (0.35 mol) in 120 ml of methyl tert-butyl ether. This mixture was kept at 50-55 ^° C for 4 hours, and then a suspension of 124 g (0.84 mol) of diethyl oxalate in 320 ml of methyl tert-butyl ether was added to the suspension cooled to -20 ^° C. This reaction mixture is then heated to RT and 25.2 g (0.42 mol) of 100% acetic acid are added, followed by a mixture of 100 g of crushed 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 vacuo. In this case, 78 g of product are obtained (basic substance content: 86.4%; yield: 82%).

Example 2.2
The procedure is similar to that described in the previous example, except that instead of butyllithium in hexane, butyllithium in toluene (20%) is used. Yield: 72 g (basic substance content: 84.8%; yield: 74%).

Example 2.3
A solution of n-butyllithium in hexane (15%; 54.2 g; 0.13 mol) is added over 10-15 minutes to a solution of 13.8 g of N-benzyldimethylamine (0.10 mol) in 60 ml of diethyl ether and the mixture was kept at a reflux temperature of 35-45 ^° C for 3 hours. This reaction mixture was cooled to RT and 42.2 g (0.30 mol) of ethyl oxalyl chloride in 160 ml were added to a solution pre-cooled to -20 ^° C. diethyl ether. The reaction mixture was stirred for 30 minutes at 30 ^° C. and then cooled to -20 ^° C. At a temperature of from -20 ^° to 0 ^° C., 46 g of ethanol (1.0 mol) and 36.4 g of triethylamine (0.35) were successively added. praying). After this, the reaction mixture was heated to RT and stirred for 1 h, the salts were filtered off and washed with 3 portions of 50 ml of diethyl ether. The combined filtrates were concentrated by evaporation in vacuo. The residue was dissolved in 200 ml of methylene chloride and 50 ml of water, and the organic phase was separated and concentrated by evaporation. In this way, 19.3 g of product are obtained (basic substance content: 77%; yield: 63%).

Пример 3.1
Методика аналогична описанной в примере 1.1, за исключением того, что вместо диметилоксалата используют ди-н-пентилоксалат. Выход: 62%.Example 3: n- Pentyl ether o- (N, N-dimethylaminomethyl) phenylglyoxylic acid Vc

Example 3.1
The procedure is similar to that described in example 1.1, except that di-n-pentyloxalate is used instead of dimethyl oxalate. Yield: 62%.

Example 3.2
A solution of n-butyllithium in hexane (15%; 92.7 g; 0.22 mol) is added over 10-15 minutes to a solution of 24.1 g of N-benzyldimethylamine (0.175 mol) in 60 ml of diethyl ether and this mixture incubated at a reflux temperature of 50-55 ^o C for approximately 3 hours. The mixture is cooled to CT and within 5 minutes a solution of 93.8 g (0.52 mol) of n-pentyloxalyl chloride in 160 ml is added to a pre-cooled to -20 ^o C diethyl ether. The mixture is stirred for 30 minutes and during this time period the temperature is allowed to rise to 30 ^° C. At a temperature of from -20 to 0 ^° C., a mixture of 10 g (0.31 mol) of methanol and 32.5 g of triethylamine (0.31) is added. mole), after which the reaction mixture was stirred at RT overnight and concentrated by evaporation in vacuo. 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, 98.5 g of product are obtained (basic substance content: 32%; yield: 65%).

15,9 г метилхлорформиата (165 ммолей) при 20-25^oC добавляют в раствор 18,3 г метилового эфира о-(N,N-диметиламинометил)- фенилглиоксиловой кислоты Va (содержание основного вещества: 88,6%; 73,3 моля) в 100 мл толуола. Реакционную смесь перемешивают при КТ в течение ночи, выдерживают при 60^oC в течение 1 ч, охлаждают и концентрируют упариванием в вакууме. Таким путем получают 15,3 г продукта (содержание основного вещества: 83%; выход: 82%).Example 4: O-chloromethylphenylglyoxylic acid methyl ester VIIa

15.9 g of methyl chloroformate (165 mmol) at 20-25 ^° C. are added to a solution of 18.3 g of o- (N, N-dimethylaminomethyl) phenylglyoxylic acid methyl ester Va (basic substance content: 88.6%; 73.3 mole) in 100 ml of toluene. The reaction mixture was stirred at RT overnight, kept at 60 ^° C. for 1 hour, cooled and concentrated by evaporation in vacuo. 15.3 g of product are obtained in this way (basic substance content: 83%; yield: 82%).

11,5 г метилхлорформиата (119 ммолей) при 20-25^oC добавляют в раствор 10,3 г этилового эфира о-(N,N-диметиламинометил)фенилглиоксиловой кислоты Vb (содержание основного вещества: 91,3%; 40 ммолей) в 40 мл толуола. Перемешивание проводят при КТ в течение ночи. Реакционную смесь концентрируют упариванием в вакууме, получая 10,1 г продукта (содержание основного вещества: 85%; выход: 94%).Example 5: Ethyl o-chloromethylphenylglyoxylic acid VIIb

11.5 g of methyl chloroformate (119 mmol) at 20-25 ^° C are added to a solution of 10.3 g of o- (N, N-dimethylaminomethyl) phenylglyoxylic acid Vb ethyl ester (basic substance content: 91.3%; 40 mmol) in 40 ml of toluene. Stirring is carried out at RT overnight. The reaction mixture was concentrated by evaporation in vacuo to give 10.1 g of product (basic substance content: 85%; yield: 94%).

14,4 г кетоэфира Va (содержание основного вещества: 72%; 46,9 ммоля) добавляют в смесь 4,2 г O-метилгидроксиламингидрохлорида (49,3 ммоля), 100 г толуола, 20 мл метанола и 0,4 г п-толуолсульфокислоты. Реакционную смесь выдерживают при 50-55^oC в течение 10 ч, а затем концентрируют упариванием в вакууме. Полученные соли растворяют в 100 мл хлористого метилена и 8 г карбоната натрия, соли отфильтровывают и раствор концентрируют упариванием в вакууме. Получают 11,9 г продукта (содержание основного вещества: 82%; выход: 83%).Example 6: O- (N, N-dimethylaminomethyl) phenylglyoxylic acid methyl ester O-methyloxime VIa

14.4 g of Va ketoester (basic substance content: 72%; 46.9 mmol) are added to the mixture of 4.2 g of O-methylhydroxylamine hydrochloride (49.3 mmol), 100 g of toluene, 20 ml of methanol and 0.4 g of p- toluenesulfonic acid. The reaction mixture was kept at 50-55 ^° C. for 10 hours and then concentrated by evaporation in vacuo. The resulting salts were dissolved in 100 ml of methylene chloride and 8 g of sodium carbonate, the salts were filtered off and the solution was concentrated by evaporation in vacuo. 11.9 g of product are obtained (basic substance content: 82%; yield: 83%).

Раствор 10,1 г кетоэфира VIIb (приблизительно 80%-ный; 36 ммолей) и 0,18 г (1 ммоль) моногидрата п-толуолсульфокислоты в 39 г н-пентанола выдерживают при 90-95^oC в течение 4 ч. Далее отгоняют приблизительно 6 г растворителя и заменяют пентанолом и реакцию завершают. После охлаждения до КТ добавляют 3,7 г (44,5 ммоля) метоксиламингидрохлорида и реакционную смесь перемешивают при 60^oC в течение 20 ч, охлаждают до КТ и добавляют в смесь 60 г льда и 40 г воды. Образовавшуюся смесь нейтрализуют водным раствором NaHCO₃ и органическую фазу отделяют, промывают 30 мл воды и концентрируют упариванием в вакууме. В виде смеси пентилового эфира Ic (приблизительно 50%) с этиловым эфиром Ia (примерно 30%) получают 10,3 г сырого продукта.Example 7: O-methyloxy n-pentyl ester o-chloromethylphenylglyoxylic acid Ic

A solution of 10.1 g of ketoester VIIb (approximately 80%; 36 mmol) and 0.18 g (1 mmol) of p-toluenesulfonic acid monohydrate in 39 g of n-pentanol is maintained at 90-95 ^° C. for 4 hours. approximately 6 g of solvent and replaced with pentanol and the reaction is completed. After cooling to RT, 3.7 g (44.5 mmol) of methoxylamine hydrochloride are added and the reaction mixture is stirred at 60 ^° C. for 20 hours, cooled to RT and 60 g of ice and 40 g of water are added to the mixture. The resulting mixture was neutralized with an aqueous solution of NaHCO ₃ and the organic phase was separated, washed with 30 ml of water and concentrated by evaporation in vacuo. In the form of a mixture of pentyl ether Ic (approximately 50%) with ethyl ether Ia (approximately 30%), 10.3 g of crude product are obtained.

Раствор н-бутиллития в толуоле (20%-ный; 65,6 г; 0,20 моля) в течение 10-15 мин добавляют в раствор 31 г N-бензилпиперидина (0,175 моля) в 60 мл трет-бутилметилового эфира. Реакционную смесь выдерживают при 55-60^oC в течение приблизительно 18 ч и затем при КТ добавляют в холодный (-20^oC) раствор 50,1 г диэтилоксалата (0,42 моля) в 160 мл толуола. Смесь нагревают до КТ и перемешивают при 20-25^oC в течение 30 мин. Далее в эту реакционную смесь добавляют 12,6 г 100%-ной (0,21 моля) уксусной кислоты и смесь 50 г истолченного льда со 100 г воды. Фазы разделяют, органическую фазу промывают 50 мл воды и концентрируют упариванием в вакууме. Таким путем получают 43,2 г продукта (содержание основного вещества: 89%; выход: 80%).Example 8: Ethyl o-piperidinomethylphenylglyoxylic acid Ve

A solution of n-butyllithium in toluene (20%; 65.6 g; 0.20 mol) is added over 10-15 minutes to a solution of 31 g of N-benzylpiperidine (0.175 mol) in 60 ml of tert-butyl methyl ether. The reaction mixture was kept at 55-60 ^° C for approximately 18 hours and then, at RT, 50.1 g of diethyl oxalate (0.42 mol) in 160 ml of toluene was added to a cold (-20 ^° C). The mixture is heated to RT and stirred at 20-25 ^° C. for 30 minutes. Then, 12.6 g of 100% (0.21 mol) of acetic acid and a mixture of 50 g of crushed ice with 100 g of water are added to this reaction mixture. The phases are separated, the organic phase is washed with 50 ml of water and concentrated by evaporation in vacuo. In this way, 43.2 g of product are obtained (basic substance content: 89%; yield: 80%).

Из раствора 51,8 г (0,2 моля) 92%-ного соединения Ve и 0,57 г 95%-ного (10 ммолей) метоксида натрия в 180 г н-пентанола при температуре дефлегмации (70-75^oC) в вакууме (200 мбар) непрерывно отгоняют этанол (при коэффициенте орошения 1: 20). По истечении приблизительно 2 ч смесь охлаждают до КТ и сливают в смесь 50 г льда с 50 г воды и 0,6 г уксусной кислоты. Фазы разделяют, органическую фазу промывают 50 мл воды и концентрируют упариванием в вакууме. Таким путем получают 59,4 г продукта (содержание основного вещества: 86,5%; выход: 98%).Example 9: n-pentyl ester of o-piperidinomethylphenylglyoxylic acid Vf

From a solution of 51.8 g (0.2 mol) of 92% Ve compound and 0.57 g of 95% (10 mmol) sodium methoxide in 180 g of n-pentanol at reflux temperature (70-75 ^o C) in in a vacuum (200 mbar) ethanol is continuously distilled off (with an irrigation coefficient of 1: 20). After approximately 2 hours, the mixture is cooled to RT 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 vacuo. In this way, 59.4 g of product are obtained (basic substance content: 86.5%; yield: 98%).

-хлорметилфенил)-2-метоксиминоуксусной кислоты Ia

В 100-миллилитровой колбе для сульфирования 15,7 г эфира метоксиминокарбоновой кислоты VIa (перег., 91,3%; 49,4 ммоля) растворяют в 20 мл толуола и добавляют 0,3 г (2,15 ммоля) порошкообразного карбоната калия. Затем при КТ по каплям быстро добавляют 7,1 мл этилового эфира хлормуравьиной кислоты (74,6 ммоля), причем в течение 10 мин температура повышается от КТ до 41^oC. После затухания экзотермической реакции смесь нагревают до 95^oC и с помощью газовой хроматографии определяют, что конверсия составляет 86%. Далее добавляют дополнительно 1,41 мл этилового эфира хлормуравьиной кислоты (14,8 ммоля) и по истечении 1/4 ч вновь определяют конверсию, которая составляет 98%. По истечении в общей сложности 1 ч реакционного времени реакционную смесь охлаждают, сливают в соляной раствор и слегка подкисляют 1 н. соляной кислотой. После этого проводят завершающую экстракцию этилацетатом и эксперимент ведут обычным путем. При этом в виде оранжевого масла получают 22,4 г сырого продукта.Example 10: Methyl ether 2- (

-chloromethylphenyl) -2-methoxyiminoacetic acid Ia

In a 100 ml sulphonation flask, 15.7 g of methoxyiminocarboxylic acid ester VIa (dist., 91.3%; 49.4 mmol) was dissolved in 20 ml of toluene and 0.3 g (2.15 mmol) of powdered potassium carbonate was added. Then, at CT, 7.1 ml of chloroformic acid ethyl ester (74.6 mmol) was quickly added dropwise, and the temperature increased from 10 to 41 ^° C over 10 minutes. After the exothermic reaction was quenched, the mixture was heated to 95 ^° C and using gas chromatography determines that the conversion is 86%. An additional 1.41 ml of chloroformic acid ethyl ester (14.8 mmol) is added, and after 1/4 h the conversion is again determined, which is 98%. After a total of 1 h of reaction time, the reaction mixture was cooled, poured into brine and slightly acidified with 1N hydrochloric acid. After that, the final extraction with ethyl acetate is carried out and the experiment is conducted in the usual way. In this case, 22.4 g of crude product are obtained in the form of an orange oil.

 To accurately determine the yield of [E / Z] isomers, chromatography was carried out on silica gel with an ethyl acetate / hexane ratio of 1: 6 and 7.18 g of carbamate, which was introduced, was distilled off under high vacuum with careful heating.

 Yield: 11.81 g, viscous yellow product as an oil or 99% of theoretical yield; purity: 96.5%; total yield: 95.4% of theoretical yield; the ratio [E / Z] according to gas chromatography is 80:20.

 In this example, 4 mol.% Potassium carbonate and 180 mol.% Ethyl chloroformate are used based on the amount of starting material.

Isomerization
When standing overnight in the oily product, the [E] -form crystallizes and can be filtered off, washed with methylcyclohexane-tert-butyl methyl ether, and then dried in high vacuum to constant weight.

 1st crystallizate: 6.37 g of white crystals.

 5.44 g of the [E / Z] mixture from the mother liquor is dissolved hot in 20 ml of methylcyclohexane, the solution is cooled to room temperature and a weak stream of gaseous hydrogen chloride is introduced over 5 hours. The solution, which is initially colored dark purple, becomes dark green and the [E] isomer precipitates, which can be filtered off.

 2nd crystallizate: 3.26 g of dark green crystals.

 Total yield of [E] -isomer: 9.63 g or 81% of theoretical yield.

20 г хлорметилкетоэтилового эфира (0,071 моля) помещают в колбу для сульфирования совместно с 6,6 г о-метилгидроксиламингидрохлорида (0,08 моля) и 30 г абсолютного этанола и смесь нагревают до 50-55^oC. После выдержки в течение 3 ч с перемешиванием при 50-55^oC при этой же температуре в течение 30 мин вводят 10 г газообразного хлористого водорода (0,27 моля). После перемешивания в течение 17 ч при 50-55^oC до завершения реакции реакционную смесь охлаждают до 0-5^oC и pH добавлением раствора гидроксида натрия доводят до 7-9. Полученный продукт отфильтровывают и трижды промывают порциями по 10 мл холодной воды. Далее влажный сырой продукт сушат в сушильной камере в вакууме при 30^oC. Продукт, т.е. этиловый эфир 2-(хлорметилфенил)метоксиминоуксусной кислоты, получают с 87%-ным (от теоретического) выходом продукта и содержанием основного вещества 90,5% (состоящего из 82,8% E-изомера и 7,7% Z-изомера). Перекристаллизацией содержание E-изомера можно повысить до более чем 95%. Температура плавления 99%-ного E-изомера составляет 73^oC. Z-изомер при комнатной температуре представляет собой жидкость.Example 11: 2- (α-Chloromethylphenyl) -2-methoxyimino-acetic acid ethyl ester Ib

20 g of chloromethyl ketoethyl ether (0.071 mol) are placed in a sulfonation flask together with 6.6 g of o-methylhydroxylamine hydrochloride (0.08 mol) and 30 g of absolute ethanol and the mixture is heated to 50-55 ^o C. After exposure for 3 hours stirring at 50-55 ^o C at the same temperature for 30 min, 10 g of hydrogen chloride gas (0.27 mol) are introduced. After stirring for 17 h at 50-55 ^o C until the reaction is complete, the reaction mixture is cooled to 0-5 ^o C and the pH is adjusted to 7-9 by adding sodium hydroxide solution. The product obtained is filtered off and washed three times with 10 ml of cold water each time. The wet crude product is then dried in a drying chamber in vacuo at 30 ^° C. The product, i.e. ethyl 2- (chloromethylphenyl) methoxyiminoacetic acid, obtained with 87% (theoretical) yield of the product and a basic substance content of 90.5% (consisting of 82.8% E-isomer and 7.7% Z-isomer). By recrystallization, the content of the E-isomer can be increased to more than 95%. The melting point of the 99% E-isomer is 73 ^° C. The Z-isomer at room temperature is a liquid.

6,1 г 30%-ного раствора метанолята натрия в метаноле по каплям в течение 10 мин добавляют в раствор 7,0 г 3-трифторметилацетофеноноксима (A) (0,034 моля) в 8 мл диметилацетамида. При 55-70^oC и 250-50 мбар отгоняют 3,5 мл растворителя. После добавления 0,07 г иодида калия в течение 20 мин при 55-65^oC добавляют 9,25 г 90%-ного этилового эфира 2-(

-хлорметилфенил)-2-метоксиминоуксусной кислоты Ib (0,032 моля), растворенного в 12 мл диметилацетамида. После перемешивания в течение 3 ч до завершения реакции реакционную смесь при 20-25^oC в течение 30 мин добавляют в смесь 30 мл воды с 18 мл толуола, причем добавлением 32%-ной соляной кислоты pH доводят до 4-5. Водную, нижнюю фазу дважды экстрагируют с использованием каждый раз по 10 мл толуола. Объединенные органические фазы экстрагируют 10 мл воды. Растворитель отгоняют в вакууме при 60^oC. При этом получают 14,8 г сырого продукта соединения IXb в виде масла, содержащего 78% основного вещества. После очистки получают твердое вещество с температурой плавления 47^oC и содержанием основного вещества 95%.Example 12

6.1 g of a 30% solution of sodium methanolate in methanol are added dropwise over a period of 10 minutes to a solution of 7.0 g of 3-trifluoromethylacetophenone oxime (A) (0.034 mol) in 8 ml of dimethylacetamide. At 55-70 ^° C. and 250-50 mbar, 3.5 ml of solvent are distilled off. After adding 0.07 g of potassium iodide over a period of 20 minutes at 55-65 ^° C., 9.25 g of 90% ethyl ester 2- (

-chloromethylphenyl) -2-methoxyiminoacetic acid Ib (0.032 mol) dissolved in 12 ml of dimethylacetamide. After stirring for 3 hours until completion of the reaction, the reaction mixture is added to a mixture of 30 ml of water and 18 ml of toluene at 20-25 ^° C. over 30 minutes, the pH being adjusted to 4-5 by adding 32% hydrochloric acid. The aqueous lower phase is extracted twice using 10 ml of toluene each time. The combined organic phases are extracted with 10 ml of water. The solvent is distilled off in vacuo at 60 ^° C. This gives 14.8 g of the crude product of compound IXb in the form of an oil containing 78% of the basic substance. After purification, a solid is obtained with a melting point of 47 ^° C. and a basic substance content of 95%.

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

Раствор 14,8 г этилэфирного соединения IXb (содержание основного вещества: 78%; 0,027 моля) в 53 мл метанола и 1,5 г 30%-ного метанолята натрия в метаноле перемешивают в течение 2 ч при 40-45^oC. Эту реакционную смесь при 20-25^oC добавляют в смесь 53 мл толуола, 10 мл воды и 1 г 32%-ной соляной кислоты, поддерживая значение pH на уровне 3-3,5 добавлением соляной кислоты. После разделения фаз водную фазу дважды экстрагируют, используя каждый раз по 10 мл толуола. Объединенные органические фазы дважды экстрагируют, используя каждый раз по 16 мл воды. После выпаривания органического растворителя в вакууме при 60-65^oC получают 13,4 г сырого продукта, который растворяют при 55-60^oC в 27 мл метилциклогексана. Во время охлаждения до 0-5^oC выпадает в осадок продукт, его отфильтровывают и промывают при 0-5^oC метилциклогексаном. После сушки в вакууме при 40^oC получают 9 г продукта IXa с температурой плавления 69-71^oC.Example 13: Transesterification

A solution of 14.8 g of ethyl ester compound IXb (basic substance content: 78%; 0.027 mol) in 53 ml of methanol and 1.5 g of 30% sodium methanolate in methanol was stirred for 2 hours at 40-45 ^° C. This reaction the mixture at 20-25 ^o C is added to the mixture 53 ml of toluene, 10 ml of water and 1 g of 32% hydrochloric acid, maintaining the pH value at the level of 3-3.5 by the addition of hydrochloric acid. After phase separation, the aqueous phase is extracted twice, using 10 ml of toluene each time. The combined organic phases are extracted twice using 16 ml of water each time. After evaporation of the organic solvent in vacuo at 60-65 ^° C, 13.4 g of crude product are obtained, which is dissolved at 55-60 ^° C in 27 ml of methylcyclohexane. During cooling to 0-5 ^° C, the product precipitates, it is filtered off and washed at 0-5 ^° C with methylcyclohexane. After drying in vacuo at 40 ^° C., 9 g of product IXa are obtained with a melting point of 69-71 ^° C.

Claims (17)

1. The method of obtaining the compounds of formula I

where X is a radical inert under the reaction conditions;
m is 0;
R ₃ is hydrogen, CH ₃ , CH ₂ F or CHF ₂ ;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently represent hydrogen or C ₁ -C ₈ alkyl, or (R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring;
moreover, in this method a) the interaction of the compounds of formula II

where X and m have the meanings indicated for formula I;
R ₁ and R ₂ each independently from each other are C ₁ -C ₆ alkyl,
C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl or
R ₁ and R ₂ together with the nitrogen atom form an unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom,
in an aprotic solvent with an organolithium compound of the formula III
Li-R ₇ , III
where R ₇ denotes an organic anionic radical,
b) carry out the interaction of the obtained lithium complex with the compound of formula IV
Y ₁ -CO-CO-Y ₁ , IV
where each of the substituents Y ₁ , which may be the same or different, represents a group OR ₄ , N (R ₆ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ is C ₁ -C ₈ alkyl;
R ₆ is C ₁ -C ₈ alkyl,
or (R ₆ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring,
to obtain the compounds of formula V

c) this compound in any order c1) is subjected to oximeting with O-methylhydroxylamine or subjected to oximeting with hydroxylamine and then methylation, fluoromethylation or difluoromethylation; B2) is introduced into interaction with chloroformic acid ester. 2. The method according to claim 1, where the reaction stage a) is carried out at 0-120 ^o C, and the reaction stage b) is carried out at a temperature of from -50 to +30 ^o C.  3. The method according to claim 1, where as a solvent in the reaction stages a) and b) use an ether, a hydrocarbon or a mixture thereof.  4. The method of claim 3, wherein the hydrocarbon is hexane, benzene, toluene or xylene, and the ether is tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, dimethoxyethane, diethoxyethane or diethoxymethane.  5. The method according to claim 1, where butyllithium, sec-butyl lithium, hexyllithium, lithium diisopropylamide (DAL), lithium hexamethyldisilazide or lithium tetramethylpiperidide (TMPL) are used as an organolithium compound of formula III.  6. The method according to claim 5, where the organolithium compound of the formula III is butyl lithium. 7. The method according to claim 1, where in the compound of formula IV Y ₁ denotes OR ₃ , especially OS ₂ H ₅ . 8. The method according to claim 1, where in the compound of formula II, m is 0 and R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl or R ₁ and R ₂ form piperidine together with the nitrogen atom.  9. The method according to claim 1, where in the reaction stage a) use 0.5-1.5 mol. eq. organolithium compounds of formula III on the amount of the compounds of formula II.  10. The method according to claim 1, where in the reaction stage b) use of 0.9-4 mol. eq. a derivative of oxalic acid of formula IV on the amount of the compound of formula II.  11. The method according to claim 1, where after the implementation of the reaction stage b) the pH of the reaction mixture is adjusted to 7 or less.  12. The method according to p. 1, where in the reaction step b2) chloroformic acid ethyl ester is used. 13. The method of obtaining the compounds of formula V

where X is a radical that is inert to the reaction;
m is 0;
R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl or R ₁ and R ₂ together with the nitrogen atom form an unsubstituted or a substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently represent hydrogen or C ₁ -C ₈ alkyl, or (R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring,
moreover, in this method a) in an aprotic solvent, the compounds of formula II are reacted

where X, m, R ₁ and R ₂ have the meanings indicated for formula V,
with an organolithium compound of the formula III
Li-R ₇ , III
where R ₇ denotes an organic anionic radical;
b) carry out the interaction of the obtained lithium complex with the compound of formula IV
Y ₁ -CO-CO-Y ₁ , IV
where each of the substituents Y ₁ , which may be the same or different, represents a group OR ₄ , N (R ₆ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ is C ₁ -C ₈ alkyl;
R ₆ is C ₁ -C ₈ alkyl or
(R ₆ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring,
to obtain the compounds of formula V. 14. The method of obtaining the compounds of formula I

where X is a radical that is inert to the reactions;
m is 0;
R ₃ is hydrogen, CH ₃ , CH ₂ F or CHF ₂ ;
Y represents a group OR ₄ , N (R ₅ ) ₂ or N '(CH ₃ ) OCH ₃ ;
R ₄ and R ₅ each independently represent hydrogen or C ₁ -C ₈ alkyl, or (R ₅ ) ₂ together with the nitrogen atom to which they are attached form a 5- or 6-membered unsubstituted or substituted ring,
moreover, in this method, the compound of formula V

where X, m and Y have the meanings indicated for formula I;
R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl, or R ₁ and R ₂ together with a nitrogen atom form unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom,
in any order c1) is subjected to oximeting with O-methylhydroxylamine or subjected to oximeting with hydroxylamine and then methylation, fluoromethylation or difluoromethylation; B2) is introduced into interaction with chloroformic acid ester.  15. The compound of formula V.

where X is a radical that is inert with respect to the reactions as indicated in claim 1;
m is 0;
Y represents an OR ₄ group, N (R ₅ ) ₂ or N (CH ₃ ) OCH ₃ ;
R ₄ and R _{5 are} each independently hydrogen and C ₁ -C ₈ alkyl or (R ₅ ) _2, together with the nitrogen atom to which they are attached, form a 5- or 6-membered unsubstituted or substituted ring;
R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkoxyalkyl or C ₃ -C ₆ cycloalkyl, or R ₁ and R ₂ together with a nitrogen atom form unsubstituted or substituted 6- or 7-membered ring, which in addition to this nitrogen atom may contain an additional nitrogen atom. 16. The compound of claim 15, wherein m is 0; Y represents an OR ₄ group; R ₄ is C ₁ -C ₈ alkyl; R ₁ and R _{2 are} each independently C ₁ -C ₆ alkyl, or R ₁ and R ₂ together with a nitrogen atom form piperidine. 17. The compound according to clause 16, where R ₄ denotes ethyl; R ₁ and R ₂ are methyl. Priority on points:
01/03/1996 - according to claims 1-13 and 15-17;
07/26/1996 - according to item 14.

Images