JPH0228582B2 - DAI2KYUAMINKAGOBUTSUNOSEIZOHOHO - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention provides a novel method for producing a secondary amine compound which is particularly useful as a medicine or agrochemical or its raw material or intermediate. (Problems to be solved by the prior art and the invention) The present inventors have long been involved in the synthesis of secondary amine compounds using Schiff's base compounds as raw materials and N-substituted amide compounds using the amine compounds as raw materials, and I have been conducting research on its activity. Conventionally, methods for synthesizing secondary amine compounds using Schiff base compounds as raw materials have generally involved hydrogen reduction in the presence of a catalyst and reduction using a metal hydride such as lithium aluminum hydride. However, the former hydrogen reduction requires the use of expensive or dangerous catalysts, and the reaction rate often becomes extremely slow when the catalyst becomes sterically bulky. Further, in the latter reduction with metal hydride, it was a major drawback that expensive and difficult-to-handle compounds such as lithium aluminum hydride had to be used. The present inventors have been synthesizing useful compounds having various activities for many years. For example, the present inventors have already published the general formula in JP-A-60-4181. (However, A is a halogen atom, an alkoxy group, or an alkylthio group, and R ₁ , R ₂ , and R ₃ are the same or different hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups, or alkylthio groups, respectively. It was proposed that the N-substituted-chloroacetanilide and the compound shown in ) are extremely useful as herbicides. The N-substituted-chloroacetanilide was generally synthesized by a two-step reaction as shown in the following formula. As is clear from the above reaction formula, the first step is a reduction reaction of Schiff's salt, and in this reduction reaction, expensive materials such as lithium aluminum hydride,
In some cases, it was necessary to use compounds that were difficult to handle. (Means and Effects for Solving the Problems) The present inventors have conducted intensive research on simple methods for synthesizing various secondary amine compounds, which are compounds useful as pharmaceuticals and agricultural chemicals, raw materials, and intermediates. Ta. As a result, they discovered that a secondary amine compound can be easily synthesized by reacting a Schiff base compound with a silane compound and then treating it with a proton donor. In particular, the present inventors have demonstrated that even in Schiff base compounds that are extremely difficult to reduce with conventional reducing agents, such as Schiff base compounds having bulky substituents around the C=N bond, The present inventors have discovered that the reduction reaction proceeds with good yield and has the advantage that the desired secondary amine compound can be obtained, and have completed and proposed the present invention. That is, the present invention has the general formula () (However, R ¹ and R ² are the same or different substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or an unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, and a substituted or unsubstituted heterocycloalkyl group. R ³ is a hydrogen atom or the above R ¹ , R ²
It is the same group as . ) is reacted with a silane compound represented by the general formula () H ₂ SiXY (where X and Y are the same or different hydrogen atoms or halogen atoms), and then reacted with a proton donor. By processing the general formula () (However, R ¹ , R ² , and R ³ are the same as above.) This is a method for producing a secondary amine compound, which is characterized by producing a secondary amine compound represented by the following. The Schiff base compound, which is one of the raw materials in the present invention, has the above general formula (), that is,

It is a compound represented by the formula: In the above general formula (),
Various organic groups are known as the groups represented by R ¹ , R ² , and R ³ , and these known organic groups can be used without particular limitation in the present invention.
Generally, preferably used R ¹ and R ² are substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted A heteroaryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, or a substituted or unsubstituted heterocycloalkyl group. Further, as R ₃ , a hydrogen atom or the same group as shown in R ₁ and R ₂ above can be suitably used. More specific examples of the organic groups widely used industrially are as follows. Examples of the unsubstituted alkyl group include linear or branched alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. The substituted alkyl group includes fluoromethyl, trifluoromethyl, chloromethyl,
Straight or branched haloalkyl groups such as trichloromethyl, chloroethyl, bromoethyl, fluoropropyl, chloropropyl, chlorobutyl, bromopentyl, chlorohexyl, and fluorooctyl; methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl , methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl,
Straight or branched alkoxyalkyl groups such as propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, and pentoxyethyl; phenoxymethyl, phenoxyethyl, and chlorophenoxy Phenoxyalkyl groups such as propyl; cyanoalkyl groups such as cyanoethyl, cyanopropyl, and cyanobutyl; nitroalkyl groups such as nitroethyl, nitropropyl, and nitrohexyl; methylthiomethyl, methylthioethyl, methylthiopropyl, ethylthiomethyl, ethylthio Alkylthioalkyl groups such as ethyl, ethylthiobutyl, and propylthioethyl; arylalkyl groups such as phenylmethyl, phenylethyl, phenylpropyl, and methylphenylmethyl; thienylmethyl, thienylethyl, methoxythienylmethyl,
Heteroarylalkyl groups such as furylmethyl, furylethyl, chlorofurylmethyl, pyrrolylmethyl, and pyrazolylmethyl; cycloalkylalkyl groups such as cyclopropylmethyl and cyclohexylethyl; methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, and ethoxycarbonyl Examples include ethyl and alkoxycarbonylalkyl groups such as ethoxycarbonylpropyl. The unsubstituted alkenyl group includes ethenyl,
Alkenyl groups of various positional isomers such as propenyl, butenyl, pentenyl, hexenyl, and octenyl. Further, the substituted alkenyl group includes chloroethenyl, fluoroethenyl, bromopropenyl, chlorobutenyl, chloropetenyl,
and haloalkenyl groups such as fluorohexenyl;
Alkoxyalkenyl groups such as methoxyethenyl, methoxypropenyl, ethoxybutenyl, ethoxyhexenyl, and propoxybutenyl; cyanoethenyl, nitropropenyl, dimethylaminoethenyl, methylthiopropenyl, and the like. Furthermore, the unsubstituted alkynyl group includes alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Examples of the substituted alkynyl group include chloropropynyl, bromobutynyl, methoxybutynyl, cyanopropynyl, and methylthiobutynyl. Furthermore, the unsubstituted aryl group includes aryl groups such as phenyl, naphthyl, anthranyl, and phenanthrenyl. The substituted aryl groups include methylphenyl, dimethylphenyl, ethylphenyl, diethylphenyl, propylphenyl, dipropylphenyl, butylphenyl, pentylphenyl, hexylphenyl, methyl(ethyl)phenyl, methyl(propyl)phenyl, and Alkylphenyl groups such as ethyl(propyl)phenyl; halophenyl groups such as fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, iodophenyl, trichlorophenyl and chloro(fluoro)phenyl; methoxyphenyl, dimethoxyphenyl Alkoxyphenyl groups such as enyl, trimethoxyphenyl, ethoxyphenyl, diethoxyphenyl, propoxyphenyl, and butoxyphenyl; cyanophenyl, nitrophenyl, chloro(methyl)phenyl, chloro(ethoxy)phenyl, methyl(methoxy)phenyl , methylthiophenyl, trifluoromethylphenyl, bis(chloroethyl)aminophenyl, nitro(methyl)
Substituted phenyl groups such as phenyl and diphenyl;
Examples include substituted naphthyl groups such as methylnaphthyl, dimethylnaphthyl, ethylnaphthyl, chloronaphthyl, dichloronaphthyl, methoxynaphthyl, methylthionaphthyl, nitronaphthyl, and cyanonaphthyl. Furthermore, the unsubstituted heteroaryl group includes furyl, thienyl, pyrrolyl, pyridyl, pyrimidyl, benzofuryl, benzothienyl, indolyl, quinolyl, thiazolyl, pyrazolyl, benzothiazolyl, thiadiazolyl, and oxazolyl. Examples of the substituted heteroaryl group include substituted furyls such as methylfuryl, dimethylfuryl, ethylfuryl, propylfuryl, chlorofuryl, bromofuryl, methoxyfuryl, ethoxyfuryl, propoxyfuryl, methylthiofuryl, ethylthiofuryl, and nitrofuryl. Groups; Substituted thienyl groups such as methylthienyl, ethylthienyl, propylthienyl, butylthienyl, fluorothienyl, chlorothienyl, bromothienyl, iodothienyl, methoxythienyl, ethoxythienyl, propoxythienyl, methylthiothienyl, ethylthiothienyl, and nitrothienyl ;
Substituted pyrrolyl groups such as N-methylpyrrolyl, N-ethylpyrrolyl, methyl-N-methylpyrrolyl, chloro-N-ethylpyrrolyl, methoxy-N-methylpyrrolyl, methoxyprolyl, ethylprolyl, and chloroprolyl; methylpyridyl, ethylpyridyl, chloropyridyl and methoxy Substituted pyridyl groups such as pyridyl; substituted benzofuryl groups such as methylbenzofuryl, chlorobenzofuryl, ethoxybenzofuryl, and nitrobenzofuryl; substituted benzothienyl such as ethylbenzothienyl, fluorobenzothienyl, methoxybenzothienyl, and nitrobenzothienyl Group; methylquinolyl,
Substituted quinolyl groups such as ethylquinolyl, chloroquinolyl, and methoxyquinolyl; methylthiazolyl groups, and the like. Furthermore, the unsubstituted cycloalkyl group includes cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the substituted cycloalkyl group include methylcyclopropyl, ethylcyclopropyl, propylcyclopropyl, chlorocyclopropyl, methoxycyclopropyl, ethoxycyclopropyl, methylcyclobutyl, bromocyclobutyl, methylthiocyclobutyl, chlorocyclopentyl, and methylcyclohexyl. , ethylcyclohexyl, chlorocyclohexyl, methoxycyclohexyl, propoxycyclohexyl, and the like. Examples of unsubstituted cycloalkenyl groups include cyclobutenyl, cyclopentenyl, and cyclohexenyl. Examples of the substituted cycloalkenyl group include methylcyclobutenyl, chlorocyclopentenyl, methoxycyclopentenyl, methylcyclohexenyl, ethylcyclohexenyl, chlorocyclohexenyl, methoxycyclohexenyl, and ethoxycyclohexenyl. Furthermore, examples of the unsubstituted heterocycloalkyl group include tetrahydrofuryl, tetrahydrothienyl, pyrrolidyl, tetrahydropyryl, tetrahydrothiopyryl, and piperidyl.
The substituted heterocycloalkyl group is
N-methylpyrrolidyl, N-ethylpyrrolidyl,
Examples include N-methylpiperidyl and N-ethylpiperidyl. Compounds having the groups listed above often exist in various positional isomers, but they can be used in the present invention without particular limitation. For example, the methylphenyl group includes o-methylphenyl group, m
-methylphenyl group, p-methylphenyl group, butyl group includes n-butyl group,
Examples include sec-butyl group and tert-butyl group. Furthermore, the substituents are not limited to the above specific examples, and can be appropriately selected and used as necessary, as long as the desired amine compound can be obtained by the production method of the present invention. Moreover, X and Y in the silane compound represented by the general formula ()H ₂ SiXY are not particularly limited as long as they are hydrogen atoms or halogen atoms. Examples of compounds that are generally preferably used include:
Examples include H ₂ SiCl ₂ , H ₂ SiBr ₂ , H ₃ SiCl, and H ₃ SiBr. Further, as the proton donor, any compound having a proton source such as water, mineral acid, organic acid, alcohol, phenol, and thiol can be used without particular limitation. In particular, water, mineral acids and organic acids are preferably used industrially. The most commonly used proton donors include: water; mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, benzoic acid, and oxalic acid; ethanesulfonic acid, benzenesulfone acids, sulfonic acids such as toluenesulfonic acid and chlorosulfonic acid; phosphoric acids such as orthophosphoric acid, metaphosphoric acid and pyrophosphoric acid; alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, benzyl alcohol, allyl alcohol, and ethylene glycol; phenols; Phenols such as cresol and naphthol; thiols such as methanethiol and ethanethiol; and the like. The greatest feature of the present invention is that a specific silane compound represented by the general formula () is used for the reduction reaction of the Schiff base compound represented by the general formula (). Although the reaction between the Schiff base compound and the silane compound can be carried out without a solvent, it is generally preferable to carry out the reaction in a solvent. The solvent is not particularly limited as long as it is an inert organic solvent that does not interact with both compounds. For example, hexane, ether, benzene, chloroform, acetonitrile, and the like are preferably used.
Although the molar ratio of the raw materials to be charged in the reaction is not particularly limited, it is usually preferable to use the silane compound in a ratio of 1 to 2 moles per mole of Schiff's base. The reaction mode of the reaction is not particularly limited, but when the silane compound has a low boiling point, a method in which the silane compound does not come out of the reaction system is preferred. For this purpose, it is preferable to use, for example, a reactor equipped with a dry ice cooler, a pressure-resistant reactor, or the like. Furthermore, although the reaction can be carried out in the atmosphere, it is preferably carried out in an inert gas such as helium, nitrogen, or argon. Furthermore, the reaction temperature in this reaction is not particularly limited and can be selected within a wide temperature range, but it is preferable to carry out the reaction in a suitable temperature range taking into consideration the reactivity of the raw materials and the stability of the product. . For example -
A temperature between 20°C and 150°C is suitable. The reaction time varies depending on the reaction temperature, but can be selected from several minutes to several days, generally from 10 minutes to 30 hours. The reaction progresses easily even without a catalyst, but
When a catalyst is used, it is possible to lower the reaction temperature and shorten the reaction time. As the catalyst, chloroplatinic acid, benzoyl peroxide, triethylamine, boron trifluoride etherate, etc. are preferably used. However, when an active catalyst is used, the silane compound may be added to the double bond or triple bond in the Schiff base compound. Therefore, when using a catalyst, it is best to check its reactivity beforehand. Furthermore, the Schiff base compound that is the raw material for the reaction does not need to be isolated or purified. That is, the silane compound may be directly added to a solution in which a Schiff base compound is synthesized by dehydration condensation of an amine and an aldehyde or ketone. As a treatment method using a proton donor after reacting a Schiff base compound and a silane compound,
The proton donor or a solution of the proton donor in an inert solvent may be gradually added to the reaction solution of the Schiff base compound and the silane compound as it is or after distilling off the low-boiling point compounds from the reaction solution.
The temperature of the reaction solution during this treatment is not particularly limited, and may be carried out within a suitable temperature range. Generally -
A temperature between 10°C and 100°C is suitable. Furthermore, if a violent reaction is expected due to the treatment, -10℃~
It is preferable to carry out the reaction at a temperature between 30°C. Although the processing time is not particularly limited, it may generally be selected from several minutes to several days, for example, from 5 minutes to 5 days. If the amine compound is obtained as a solid after treatment, it may be filtered, but generally water may be added to the treatment solution to extract the organic layer. The extraction solvent is not particularly limited as long as it is an organic solvent that is immiscible with water, but ether, benzene, hexane, chloroform, carbon tetrachloride, and the like are suitable. By adding a base to the system to make it alkaline during extraction, the target amine compound can be efficiently extracted. As the base to be added, potassium hydroxide, sodium hydroxide, ammonia, soda carbonate, etc. are preferably used. Also preferably used is a method in which a silane compound and a Schiff base are reacted and then treated with a mineral acid in a gas or solution state to obtain the desired amine as a mineral acid salt. If the amine mineral salt precipitates as a solid, it can be purified by filtration and washing. If the mineral acid salt is not obtained as a precipitate, it can be purified by removing low-boiling substances and washing the obtained solid. Further, the desired amine compound can be obtained by neutralizing the obtained mineral acid salt. In the present invention, an amine compound can be easily obtained by reacting a Schiff base compound and a silane compound and then treating the reaction with a proton donor. The method for purifying the obtained amine compound is not particularly limited. In general, after distilling off the extraction solvent from the extract, it is sufficient to perform normal pressure, reduced pressure, or vacuum distillation, and if necessary, washing, recrystallization,
Alternatively, a chromatographic purification method can be used. (Operations and Effects of the Invention) The chemical formula of the reaction of the present invention is as follows. Although the reaction mechanism of the above reaction is not clear, it is inferred as follows. First, a Schiff base compound and a silane compound react to form a silane adduct.

[Formula] is formed, and the desired amine compound is thought to be formed by reacting the stem adduct with a proton donor. The secondary amine compound obtained by the present invention is useful, for example, as agrochemicals such as herbicides, insecticides, and fungicides, or as pharmaceuticals. It is also a very useful substance as an intermediate for these raw materials. As described above, the present invention is an excellent method for synthesizing secondary amine compounds useful as pharmaceuticals and agrochemicals or raw material intermediates from the corresponding Schiff base compounds in good yield under mild conditions. . Furthermore, the product can be easily isolated and purified after the reaction is completed. Therefore, it can be said that the present invention is extremely excellent from an industrial perspective. (Examples) Examples are given below to specifically explain the present invention, but the present invention is not limited to these Examples. Example 1 In a 100ml glass autoclave, N-[2
-(3-methoxy)-thienylmethylidene]-
A solution of 2',6'-dimethylaniline (2.4 g) in dry benzene (15 ml) was added, and the mixture was cooled to -78°C under nitrogen. Next, dichlorosilane (2.81 g) was introduced into the autoclave, and the autoclave was then closed. After the autoclave was returned to room temperature, it was heated and stirred at 50°C for 8 hours. The reaction vessel was cooled to room temperature, opened under nitrogen,
The reaction solution was taken out. Cool the reaction solution to 10°C,
While stirring, a KOH-methanol aqueous solution was gradually added to make it basic. After stirring at room temperature for 2 hours, water was added, the organic layer was extracted with ether, and the extract was dried over anhydrous sodium sulfate. By removing the ether and distilling the residual colored liquid (2.33 g), N-[2
-(3-methoxy)-thienylmethyl]-2',
6′-dimethylaniline was obtained. Example 2 N-[2-(3-methoxy)-thienylmethylidene]-2',6'-dimethylaniline (5.02 g) was placed in a three-necked flask equipped with a dry ice cooler.
Dry acetonitrile (20 ml) and dichlorosilane (6.11 g) were added. After stirring at room temperature for 1 hour, the mixture was heated and stirred in an oil bath (65°C) for 5 hours. The reaction solution cooled to room temperature was gradually dropped into permanent water.
After dropping, add sodium carbonate to make it basic 2
Stir for hours. Water was added and the organic layer was extracted with ether. After drying the extract over anhydrous sodium sulfate, the ether was removed to obtain N-[2-(3-methoxy)-thienylmethyl]-2',6'-dimethylaniline (4.60 g) as a red colored liquid. . Example 3 A solution of n-pentylidene-ethylamine (3.05 g) in dry benzene (15 ml) was placed in a 100 ml glass autoclave and cooled to -78°C under nitrogen. Next, dichlorosilane (5.30 g) was introduced into the autoclave, and the autoclave was then closed. After the autoclave was returned to room temperature, it was heated and stirred at 40°C for 6 hours. After cooling to room temperature, the container was opened under nitrogen and the reaction solution was taken out. The reaction solution was cooled to 10° C., and HCl gas was introduced while stirring. By filtering the formed solid and washing with benzene, the melting point is 196℃.
(N-ethyl)-n-pentylamine hydrochloride (3.40 g) was obtained as a white solid. Example 4 Similar to the methods described in Examples 1 to 3, various amine compounds were synthesized using dichlorosilane as the silane compound. The structural formula and physical properties of the obtained amine compound are listed in Table 1.

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[Table] Example 5 Amine compounds were synthesized using various Schiff base compounds, various silane compounds, and various proton donors. The structural formula is shown in Table 2.

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Claims (1)

[Claims] 1 General formula () (However, R ¹ and R ² are the same or different substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or an unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, and a substituted or unsubstituted heterocycloalkyl group. R ³ is a hydrogen atom or the above R ¹ , R ²
It is the same group as . ) is reacted with a silane compound represented by the general formula () H ₂ SiXY (where X and Y are the same or different hydrogen atoms or halogen atoms), and then reacted with a proton donor. By processing the general formula () (However, R ¹ , R ² , and R ³ are the same as above.) A method for producing a secondary amine compound, characterized by producing a secondary amine compound represented by the following.