JP2002105066A - Method of producing guanidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily producing guanidine derivative [I] having excellent insecticidal effect in high yield in a large scale with industrial advantage. SOLUTION: A compound represented by formula [VI] (wherein R1 is a 1-3C alkyl, R2 is a 1-4C alkyl or the like, Q is a heterocyclic group which may be substituted, X is an electron-attractive group, n is 0 or 1) or a salt thereof is allowed to react with an amine or a salt thereof in an aqueous medium to produce the compound represented by formula [I] (wherein R3 is an amino group which may be substituted and the other signals have the same meanings as stated above) or salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for producing a guanidine derivative useful as an insecticide.

[0002]

[Prior art]

JP-A-3-157308 discloses a guanidine derivative having insecticidal activity and a method for producing the same. As an improved production method of the guanidine derivative, a method via an isothiourea derivative having an imide group as disclosed in the following scheme 1 is disclosed in JP-A-5-9173. Scheme 1

Embedded image (Wherein, R ¹ , R ² , R ^4a and R ^5a are the same or different and each represents hydrogen or an optionally substituted hydrocarbon group, and A ′ represents an optionally substituted divalent hydrocarbon group. Q ′ represents an optionally substituted heterocyclic group, X ′ represents an electron withdrawing group, Y ₁ and Y ₂ represent the same or different leaving groups, and n ′ represents 0 or 1. In addition, JP-A-2-288860 discloses a guanidine derivative having an insecticidal activity, and the production method thereof is disclosed as follows.

Embedded image (Wherein, the R ^{1 'and} R ^2' is hydrogen or _{C 1-4} alkyl group, a R ^{4 'is} _{C 1 -4} alkyl group, Z is optionally substituted with halogen or _{C 1-4} alkyl group A good 5- or 6-membered heterocyclic group having at least one nitrogen atom, and R ^{5 ′} and R ^{6 ′} represent hydrogen or a C _1-4 alkyl group.)

[0003]

[Problems to be solved by the invention]

In the production methods of these guanidine derivatives, thioisourea derivatives are specifically used as raw material compounds, and in the production process of the guanidine derivative as the final target compound, the formula RSH (where R is a substituted And a mercaptan compound represented by the formula (1): Under such circumstances, there is a demand for the development of a more industrially advantageous method for producing a guanidine derivative that is simple in reaction operation, has higher yield, and does not generate malodor.

[0004]

[Means for Solving the Problems]

 We achieve the above object by formula

Embedded image (Wherein, R ² is hydrogen or an optionally substituted hydrocarbon group, R ³ is an optionally substituted amino group, Q is an optionally substituted heterocyclic group, and X is an electron withdrawing atom. And n represents 0 or 1.) The roots of the guanidine derivative [I] represented by the formula As a result, the expression

Embedded image (Wherein, R ¹ represents an optionally substituted hydrocarbon group;
Is as defined above. )) Or an N-substituted-isourea derivative [II] or a salt thereof;

Embedded image (Wherein A represents a divalent hydrocarbon group which may be substituted, and Y ₁ and Y ₂ represent the same or different leaving groups). The equation is

Embedded image (The symbols in the formula are as defined above.)
The cyclic diacyl-N′-substituted-isourea derivative [IV] can be produced in high yield, and the compound [IV] and the formula Q- (CH ₂ ) _n -NH-R ² [V] Is as defined above.) With a compound [V] or a salt thereof represented by the formula:

Embedded image (The symbols in the formula are as defined above.) It was found that the compound [VI] or a salt thereof represented by the formula (1) can be produced in high yield. As a result of further study based on this finding, surprisingly, the compound [VI] or a salt thereof was reacted with an amine or a salt thereof in water or a mixed solvent of water and an organic solvent, whereby It has been discovered that the guanidine derivative [I] or a salt thereof can be produced in high yield. Furthermore, as a result of intensive studies based on these, the present invention was completed.

That is, the present invention provides:

Embedded image (Wherein, R ¹ represents a C _1-3 alkyl group, R ² represents hydrogen or a C _1-4 alkyl group, Q represents an optionally substituted heterocyclic group, X represents an electron withdrawing group, and n represents Represents a compound represented by formula (1) or a salt thereof, and a C _1-4 alkylamine or a salt thereof in water or a mixed solvent of water and an organic solvent.

Embedded image (Wherein, R ³ represents a C _1-4 alkylamino group, and other symbols have the same meanings as described above) or a salt thereof; (2) O-methyl-N- ( 1- (6-chloro-3-pyridylmethyl) -N'-nitroisourea or a salt thereof is reacted with methylamine or a salt thereof in water or a mixed solvent of water and an organic solvent. 6
-Chloro-3-pyridylmethyl) -3-methyl-2-nitroguanidine or a salt thereof; and (3) O-methyl-N- (2-chloro-5-thiazolylmethyl) -N'-nitroiso Reacting urea or a salt thereof with methylamine or a salt thereof in water or a mixed solvent of water and an organic solvent.
A process for producing (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine or a salt thereof;

In the above formula, examples of the optionally substituted hydrocarbon group represented by R ¹ and R ² include a saturated or unsaturated aliphatic hydrocarbon group and an aromatic hydrocarbon group. Can be Preferred specific examples of the saturated or unsaturated aliphatic hydrocarbon group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, A C _1-15 alkyl group such as decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc., for example, a C _2-10 alkenyl group such as vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl; for example ethynyl methylphenol, 2-propynyl, _{C 2-10} alkynyl group of 3-hexynyl and the like, for example consequent Ropuropiru, cyclobutyl, cyclopentyl, _{C 3-10} cyclo alkyl such as cyclohexyl, for example cyclopropenyl, cyclopentenyl, cyclohexenylene Le _C etc. _3-10 Shikuroa Such as Kenyir group, and the like. Preferred specific examples of the aromatic hydrocarbon group include, for example, phenyl, naphthyl,
C _6-14 aryl groups such as azulenyl, anthryl and phenanthryl; and C _7-13 aralkyl groups such as benzyl, phenethyl and benzohydryl. Examples of the heterocyclic group of the optionally substituted heterocyclic group represented by Q include a 3- to 8-membered ring group containing 1 to 5 hetero atoms such as an oxygen atom, a sulfur atom and a nitrogen atom, or a condensed ring thereof. And specific examples thereof include, for example, 2- or 3-
Thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 2-, 3-
Or 4-pyridyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5
-Thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 3 -Or 5- (1,2,4-oxadiazolyl), 2
-Or 5- (1,3,4-oxadiazolyl), 3- or 5- (1,2,4
-Thiadiazolyl), 2- or 5- (1,3,4-thiadiazolyl), 4- or 5- (1,2,3-thiadiazolyl), 3- or 4- (1,2,5-thiadiazolyl), 1 -, 4- or 5- (1,2,3-triazolyl), 1-, 3
-Or 5- (1,2,4-triazolyl), 1- or 5- (1H-tetrazolyl), 2- or 5- (2H-tetrazolyl), N-oxide-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-,
4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N-
Oxid-3- or 4-pyridazinyl, triazinyl, oxotriazinyl,
Oxoimidazinyl, dioxotriazinyl, aziridinyl, azetidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperidino, pyranyl, thiopyranyl, 1,4-dioxanyl, morpholinyl, morpholino, 1,4-thiazinyl,
Heterocyclic groups such as 1,3-thiazinyl, piperazinyl, piperazino, indolyl, benzofuryl, benzothiazolyl, benzoxazolyl, imidazo [1,2-a]
Pyridinyl, tetrazolo [1,5-b] pyridazinyl, triazolo [4,5-
b] pyridazinyl, chromanyl, benzimidazolyl, quinolyl, isoquinolyl,
Cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl,
Condensed heterocyclic groups such as quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl and phenoxazinyl are used.

[0007] These hydrocarbon groups and heterocyclic groups are substituted at substitutable positions.
It may have 1 to 5, preferably 1 to 3, identical or different substituents.
No. When the substituent is a halogen atom, the maximum possible value of the hydrocarbon group and the heterocyclic group is as follows.
May be substituted up to the number. Preferred specific examples of the substituent include, for example, methyl
, Ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undec
, Dodecyl, tridecyl, tetradecyl, pentadecyl, etc._1-15Archi
Groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
Etc. C_3-10Cycloalkyl groups such as vinyl, allyl, 2-methylallyl,
C such as 2-butenyl, 3-butenyl, 3-octenyl and the like_2-10Alkenyl group, example
For example, C, such as ethynyl, 2-propynyl, 3-hexynyl, etc._2-10Alkynyl group,
For example, C such as cyclopropenyl, cyclopentenyl, cyclohexenyl, etc._3-10
A cycloalkenyl group such as phenyl, naphthyl, etc._6-10Aryl group, example
For example, C such as benzyl and phenylethyl_7-11Aralkyl, nitro, nitro
Sodium, hydroxyl, mercapto, cyano, oxo, thioxo, carbamoyl
Groups such as mono- or di-C such as methylcarbamoyl, dimethylcarbamoyl, etc.
_1-6Alkyl-carbamoyl groups such as C_6-14
Aryl-carbamoyl group, carboxyl group such as methoxycarbonyl, eth
C such as xycarbonyl_{1 -4} Alkoxy-carbonyl groups, such as phenoxy
C such as Bonyl_6-14Aryloxy-carbonyl, sulfo, e.g.
Halogen atoms such as nitrogen, chlorine, bromine and iodine such as methoxy, ethoxy and propoxy
Si, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.
C_1-4Alkoxy group, for example, C such as phenoxy_6-10Aryloxy group,
For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio
C such as e, isobutylthio, s-butylthio, t-butylthio, etc._1-4Alkylthio
A group such as C such as phenylthio_6-10Arylthio groups such as methylsulfi
Nil, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl
Butylsulfinyl, isobutylsulfinyl, s-butylsulfinyl, t
C such as -butylsulfinyl_1-4Alkylsulfinyl groups such as phenyls
C such as rufinil_{6-1 0} Arylsulfinyl groups such as methylsulfonyl,
Ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulf
Phonyl, isobutylsulfonyl, s-butylsulfonyl, t-butylsulfonyl
Etc. C_1-4Alkylsulfonyl groups such as C-phenylsulfonyl and the like;_6-10
Arylsulfonyl groups such as methoxysulfonyl, ethoxysulfonyl,
Poxysulfonyl, isopropyloxysulfonyl, butoxysulfonyl, iso
Butyloxysulfonyl, s-butoxysulfonyl, t-butoxysulfonyl, etc.
C_1-4An alkoxysulfonyl group such as C
_6-10Aryloxysulfonyl group, amino group such as acetylamino, propio
C such as nilamino, benzoylamino, etc._1-11Carboxylic acylamino groups, for example
Methylamino, ethylamino, propylamino, isopropylamino, butyl
Mono- or di-C such as amino, dimethylamino, diethylamino, etc._1-4Archi
Amino group such as cyclohexylamino_3-6Cycloalkylamino
A group such as C, such as anilino _6-10 Arylamino groups such as trimethylsilyl,
t-butyldimethylsilyl, triphenylsilyl, t-butylmethoxyphenyl
Tri-substituted silyl groups such as silyl, for example, C such as formyl, acetyl, benzoyl, etc.
_1-11Acyl carboxylate groups such as 2- or 3-thienyl, 2- or 3-phenyl;
Ryl, 1-, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-,
4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 1-, 3-,
4- or 5-pyrazolyl, 1-, 2-, 4- or 5-imidazolyl, 3-,
4- or 5-isooxoazolyl, 3-, 4- or 5-isothiazolyl, 1,
2,3- or 1,2,4-triazolyl, 2-, 4- or 5-pyrimidini
Benzothiazolyl, benzoxazolyl, triazinyl, oxiranyl,
Ridinyl, pyrrolidinyl, piperidinyl, morpholinyl, benzimidazolyl,
Oxygen atoms such as quinolyl and isoquinolyl, and hetero atoms such as sulfur and nitrogen
A group selected from a 3- to 6-membered cyclic ring group containing 1 to 5 or a condensed ring group thereof is used.
It is. When two or more substituents are used, two of these
For example, C_{1- 6} Alkylene (eg, methylene, ethylene, trimethylene
, Tetramethylene, propenylene), 3-oxapentamethylene, vinylene,
Benzylidene, methylenedioxy, 2-thiatrimethylene, oxalyl, maloni
, Succinyl, maleoyl, phthaloyl, oxygen, sulfur, imino, azo, hydrazo
May form a divalent group such as When these substituents are, for example, aryl, ara
Alkyl, cycloalkyl, cycloalkenyl, aryloxy, arylthio,
Arylsulfinyl, arylsulfonyl, arylcarbamoyl, aryl
Oxycarbonyl, aryloxysulfonyl, arylamino, cycloalkyl
Amino, carboxylate, acylamino carboxylate, trisubstituted silyl, hetero
When it is a cyclic group, a divalent group, etc., it further includes, for example, fluorine, chlorine, bromine, iodine, etc.
Halogen atom, hydroxyl group, nitro group, cyano group such as methyl, ethyl, propyl
C, such as butyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, etc._1-4A
Alkyl groups such as vinyl, allyl, etc._2-4Alkenyl groups such as ethynyl,
C such as 2-propynyl_{2 -4} Alkynyl group, phenyl group such as methoxy, eth
C such as Kishi_1-4Alkoxy group, phenoxy group such as methylthio, ethylthio
Etc. C_1-41 to 5 alkylthio groups, phenylthio groups and the like may be substituted.
In the case of a halogen atom, even if the substituent is substituted up to the maximum possible number,
Good. When the substituent is alkyl, alkenyl, alkynyl, alkoxy, alkyl
Thio, alkylsulfinyl, alkylsulfonyl, alkylcarbamoyl,
Alkoxycarbonyl, alkoxysulfonyl, amino, alkylamino, etc.
In such a case, a halogen atom, a hydroxyl group, a nitro group, a cyano group, a C
_1-4Alkoxy group, C_{1 -4} 1 to 5 alkylthio groups or the like may be substituted
In the case of a halogen atom, the substituent may be particularly substituted to the maximum possible number.
No. Examples of the electron-withdrawing group represented by X include a nitro group and a cyano group such as acetyl.
, Trichloroacetyl, trifluoroacetyl, pentafluoropropioni
And 1 to 5 halogens such as benzoyl and benzoyl (eg, fluorine, chlorine, bromine, iodine, etc.)
C which may be replaced_{1 -10} Acyl carboxylate groups such as nicotinoyl, furo
Ring atoms such as oxygen, sulfur, nitrogen, etc.
A 3- to 6-membered heterocyclic carbonyl group containing 1 to 4 carbon atoms,
C such as toxicoxycarbonyl and ethoxycarbonyl_1-4Alkoxy-carbonyl
A group such as C, such as phenoxycarbonyl, etc._6-10An aryloxy-carbonyl group,
For example, ring-constituting atoms such as pyridyloxycarbonyl and thienyloxycarbonyl
3 to 6 membered groups containing 1 to 4 heteroatoms such as oxygen, sulfur, nitrogen, etc.
Prime ring oxycarbonyl group, carbamoyl group such as methylsulfonyl-thiocar
C such as Bamoyl_1-4An alkylsulfonyl-thiocarbamoyl group such as methyl
Halogen such as sulfonyl, ethylsulfonyl and trifluoromethylsulfonyl
(Fluorine, chlorine, bromine, iodine, etc.)._1-4Al
Kylsulfonyl group, sulfamoyl group such as C such as diethoxyphosphoryl
_1-4A dialkoxyphosphoryl group or the like is used.

As the divalent hydrocarbon group of the optionally substituted divalent hydrocarbon group represented by A, for example, C 2 such as ethylene, propylene and trimethylene
_1-4 alkylene groups, for example, C _2-4 alkenylene groups such as vinylene and propenylene, for example, C _2-4 alkenylene groups such as 1,2-cyclopentylene and 1,2-cyclohexylene;
_3-10 cycloalkylene group, for example, C such as 1-cyclopropene-1,2-ylene, 1-cyclohexene-1,2-ylene, 4-cyclohexene-1,2-ylene, etc.
_{A 3-10} cycloalkenylene group, for example, a C _6-10 arylene group such as O-phenylene or the like is used. The substituent of the above divalent hydrocarbon group, for example such as those described above as the substituent of the optionally substituted carbon hydrocarbon group represented by R ¹ are used.

[0009] Y₁And Y₂Examples of the leaving group represented by
(Eg, fluorine, chlorine, bromine, iodine)
Good C_1-4Alkyl sulfonyloxy (eg, methanesulfonyloxy, eth
Sulfonyloxy, trifluoromethanesulfonyloxy, etc.), halogen and
And C_1-4Substituted with 1 to 4 alkyl groups (eg, methyl, ethyl, etc.)
C that may be_{6-1 0} Arylsulfonyloxy (eg, benzenesulfonyl
Oxy, p-bromobenzene benzenesulfonyloxy, mesitylenesulfonyloxy
Etc.), C 1-3 optionally substituted with halogen_1-6Acyloxy carboxylate
(Eg, acetyloxy, trifluoroacetyloxy, etc.), C_6-10Aryl
-Carbonyloxy (eg, benzoyloxy, etc.), C_1-4Alkylthio (eg,
Methylthio, ethylthio, etc.), 1 to 5 carbon atoms optionally substituted by halogen
_6-10Arylthio (eg, phenylthio, pentachlorophenylthio, etc.), ring configuration
Containing from 1 to 4 heteroatoms such as oxygen, sulfur, nitrogen, etc.
6-membered heterocyclic thio (eg, 2-pyridylthio, 2-benzothiazolylthio, etc.) is used
Can be Also, Y₁And Y ₂ And may represent an oxygen atom or a sulfur atom.

[0010] Examples of the amines include ammonia and primary amines.
And secondary amines. Preferred specific examples of the amines include, for example,
Equation R⁴R⁵NH (wherein, R⁴And R⁵Are the same or different and are hydrogen or substituted
A hydrocarbon group which may be⁴And R⁵Are adjacent to each other
A cyclic amino group is shown together with an elementary atom. ) Is used. R⁴And
And R⁵Examples of the optionally substituted hydrocarbon group represented by¹You
And R²The above-mentioned hydrocarbon groups which may be substituted and represented by
And the substituent is used. R⁴And R⁵Together with the adjacent nitrogen atom
As the cyclic amino group shown, for example, aziridino, azetidino, pyridino, morpho
Lino and thiomonolholino groups. R³May be replaced by
Examples of the amino group include an amino group and a secondary or tertiary amino group.
The amino group includes a compound of the formula R ⁴ R⁵N- (wherein, R⁴And R⁵Has the same meaning as above.
I do. ).

[0011] Preferably aliphatic saturated or unsaturated hydrocarbon group as R ^1, further _{C 1-15} alkyl group. Particularly, a C _1-3 alkyl group is preferable, and a methyl group is particularly preferable. R ² is preferably hydrogen or a saturated or unsaturated aliphatic hydrocarbon group, more preferably hydrogen or a C _1-15 alkyl group. Particularly, hydrogen or a _C1-4 alkyl group is preferable, and hydrogen is particularly preferable. As R ³ , a secondary amino group is preferable, and a C _1-4 alkyl-amino group is more preferable. Among them, a methylamino group is particularly preferred. As amines, primary amines are preferred, and C _1-4 alkyl-amines are more preferred.
Among them, methylamine is particularly preferred. A is C _1-4 alkylene, C _2-4
Alkenylene and _{C 6 -14} arylene are preferred, _{C 6-14} arylene are preferred. Particularly, ethylene, trimethylene, vinylene or O-phenylene is preferable, and an O-phenylene group is particularly preferable. As Q, a 5- to 6-membered aromatic heterocyclic group containing at least one nitrogen atom or sulfur atom which may be halogenated is preferable. In particular, a halogenated pyridyl group and a halogenated thiazolyl group are preferred, and among them, a 6-chloro-3-pyridyl group and a 2-chloro-
A 5-thiazolyl group is particularly preferred. n is preferably 1. X is preferably nitro or cyano, and particularly preferably nitro. Both Y ₁ and Y ₂ are preferably halogen, and among them, chlorine is particularly preferable.

[0012] Guanidine derivatives [I], compounds [II], [V], [VI]
And amine salts may be any salts that are acceptable in agrochemicals, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and perchloric acid; Formic acid, acetic acid, tartaric acid, malic acid, citric acid, oxalic acid, succinic acid, benzoic acid,
Organic acids such as picric acid, methanesulfonic acid and p-toluenesulfonic acid may be used. When the guanidine derivative [I], the compounds [II], [V], [VI] and amines have an acidic group such as a carboxyl group, they may form a salt with a base. For example, inorganic bases such as sodium, potassium, lithium, calcium, magnesium, and ammonia, and organic bases such as pyridine, collidine, dimethylamine, triethylamine, and triethanolamine are used. When the compounds [III] and [IV] have a basic group such as an amino group, for example, they may form a salt with the above-mentioned inorganic or organic acid. Compound (II)
When I] and [IV] have an acidic group such as a carboxyl group, for example, they may form a salt with the above-mentioned inorganic base or organic base.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION

The production method of the present invention can be carried out, for example, according to the reaction conditions described below. When the product is obtained as a free compound by the following production method, it can be converted into a salt as described above, and when the product is obtained in the form of a salt, it can be converted into a free compound according to a conventional method. When the starting compound can be a salt as described above, it can be used as a salt as well as free. Therefore,
The raw material compounds and products used in the following production methods include salts thereof (for example, salts with acids or bases as described in the above guanidine derivative [I]).

(A) Compound [IV] is produced by reacting compound [II] with compound [III].

Embedded image (The symbols in the formulas have the same meanings as described above.) Compound [III] is used in about 0.8 to 5 equivalents, preferably about 1 to 1.5 equivalents, relative to compound [II]. May be used in large excess. This reaction can be performed advantageously in the presence of a base. Such bases include, for example, alkali metal bicarbonates (eg, sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonates (eg, sodium carbonate, potassium carbonate, etc.), alkali metal hydroxides (eg, sodium hydroxide) , Potassium hydroxide, etc.), alkaline earth metal hydroxides (eg, calcium hydroxide, etc.), alkyl lithium (eg, butyl lithium, etc.), aryl lithium (eg, phenyl lithium, etc.), alkali metal amides (eg, Sodium amide, lithium diisopropylamide), alkali metal hydride (eg, sodium hydride, potassium hydride, etc.), alkali metal alkoxide (eg, sodium methoxide, sodium ethoxide, etc.), alkali metal (eg, metal sodium hydride) , Metal potassium, etc.), for example, triethylamine, Tributylamine, N, N-dimethylaniline, pyridine, picoline,
Lutidine, collidine, 5-ethyl-2-methylpyridine, 4- (dimethylamino) pyridine, 1,8-diazabicyclo [5,4,0] undecene-7 (hereinafter abbreviated as DBU)
Organic bases such as are used. The organic base can itself be used as a solvent. The base is used in an amount of about 0.5 to 20 equivalents, preferably about 1.8 to 4 equivalents, relative to compound [III]. The reaction may be carried out without a solvent, but is usually carried out in a solvent that does not adversely influence the reaction. Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride, and hexane, heptane and cyclohexane. Saturated hydrocarbons, diethyl ether, tetrahydrofuran (hereinafter abbreviated as THF), ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide (hereinafter referred to as DMSO and Abbreviations), acid amides such as N, N-dimethylformamide (hereinafter abbreviated as DMF), N, N-dimethylacetamide, esters such as ethyl acetate and butyl acetate, methanol and ethanol. Alcohols such as alcohol, propanol and isopropanol; And water are used. These solvents can be used alone or, if necessary, two or more of them in an appropriate ratio,
For example, they may be mixed and used at a ratio of about 1: 1 to 1:10 (volume ratio). When the reaction mixture is not homogeneous, for example, quaternary ammonium salts such as triethylbenzylammonium chloride, tri-n-octylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium bromide, and cetylpyridinium bromide, and interphases such as crown ethers The reaction may be performed in the presence of a transfer catalyst. The reaction temperature is usually about −20 to 250 ° C., preferably about −10 to 50 ° C. The reaction time usually ranges from about 10 minutes to 50 hours, preferably from about 10 minutes to 10 hours. In this reaction,
After the reaction, a lower alcohol having 1 to 4 carbon atoms, such as methanol or ethanol, is added to decompose the remaining compound [III] into the corresponding ester, so that the post-treatment operation becomes simpler. In some cases, a compound [IV] having high purity may be obtained. It is particularly preferable to use methanol as such a lower alcohol. It is preferable to use about 0.1 to 5.0 equivalents of the lower alcohol with respect to the compound [III]. The decomposition time is preferably about 10 minutes to 5 hours. Decomposition temperature is about 0-50 ℃
Is preferred.

(B) Compound [VI] is produced by reacting compound [IV] with compound [V].

Embedded image (The symbols in the formula are as defined above.) The compound [V] is used in about 0.8 to 5 equivalents, preferably about 1 to 1.5 equivalents, relative to the compound [IV]. A large excess may be used. This reaction is usually carried out without a base, but in some cases, for example, the reaction can be advantageously carried out in the presence of the base used in the above method (A). The reaction is usually performed in a solvent that does not adversely influence the reaction. Examples of the solvent include the solvents used in the above method (A). When the reaction mixture is not a homogeneous phase, the phase transfer catalyst used in the above method (A) may be used. The reaction temperature is usually
The range is from about -20 to 200 ° C, preferably from about -10 to 50 ° C. Reaction times generally range from about 10 minutes to 50 hours, preferably from about 10 minutes to 10 hours. In this reaction, the formula

Embedded image (Wherein, A has the same meaning as described above), as a by-product. Compound (VII) can often be separated using a known means such as a difference in solubility in a solvent or column chromatography.
In some cases, 1) a method in which the reaction mixture is dissolved in a basic aqueous solution and the compound [VI] and the compound [VII] are separately precipitated while neutralizing the reaction mixture little by little with an acid,
2) By stirring in a basic aqueous solution at about 0 to 50 ° C. for about 30 minutes to 5 hours, the compound [VII] is decomposed into a substance (dicarboxylic acid monoamide, etc.) which is harder to precipitate, and then acidified. Separation is also possible by a method of precipitating compound [VI] by neutralization. The base used in such a separation method is, for example, the base described in the method (A), and the acid is, for example, the acid described above as a salt of the guanidine derivative [I] or the like.

(C) The guanidine derivative [I] is produced by reacting the compound [VI] with an amine.

Embedded image (The symbols in the formula have the same meanings as described above.) The amines have the same meanings as described above. Compound (V
The amines are used in about 0.8 to 10 equivalents, preferably about 1 to 4 equivalents to I], but may be used in a large excess if the reaction is not hindered. This reaction may be advantageously carried out, for example, in the presence of a base as described in the method (A), but the reaction usually proceeds without a base. The reaction is usually carried out, for example, in a solvent as described in method (A). When the reaction mixture is not a homogeneous phase, a phase transfer catalyst as described in the method (A) may be used. In this reaction, guanidine derivative [I] can be produced in high yield especially by using water or a mixed solvent of water and the above-mentioned organic solvent. As the organic solvent in the mixed solvent, the above-mentioned halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane are particularly preferable. Reaction temperatures are usually in the range of about -20 to 200 ° C, preferably about -10 to 50 ° C. Reaction times usually range from about 10 minutes to 50 hours, preferably from about 10 minutes to 10 hours. The starting compound [VI] of this reaction can be produced by the method of the above method (B) or a method analogous thereto, and once isolated can be used. It is also possible to use. For example, 1) a method of reacting in water or a mixed solvent of water and the above-mentioned organic solvent under the conditions of the method (B), followed by adding amines and reacting as it is, and 2) a method of reacting the compound (B) in an organic solvent After the reaction under the conditions of (1) and (2), water may be added to the reaction solution to form a two-phase system, and then amines may be added for the reaction. The latter 2)
In the case of the above, by-product compound [VII] may be precipitated after the reaction in the first half, and this may be removed by filtration. Of course, it is also possible to react without removing. The compound [IV], [VI] and the guanidine derivative [I] or a salt thereof obtained in this manner can be obtained by known means, for example, concentration, concentration under reduced pressure, distillation, fractionation,
It can be isolated and purified by solvent extraction, liquid conversion, transfusion, chromatography, crystallization, recrystallization and the like. Guanidine derivatives (I), compounds (II), (IV) and (V
I] or their salts give rise to cis- and trans-stereoisomers with respect to the position of the substituent X, and the guanidine derivatives [I], compounds [II] and [VI] are theoretically dependent on the substituent. Although it produces tautomers, all its isomers are included in the corresponding guanidine derivatives [I], compounds [II], [IV] and [VI] or salts thereof.

The compound [II] or a salt thereof is a partially known compound (for example, see Rec. Trav. Chim., Vol. 81, p. 69 (1962)).

Embedded image (Wherein, R ¹ has the same meaning as described above.)
It can be produced by nitrating the isourea derivative [VIII] or a salt thereof. As the nitrating agent, 60 to 100% nitric acid is widely used. For example, alkali metal nitrates such as sodium nitrate and potassium nitrate, alkyl nitrates such as ethyl nitrate and amyl nitrate, and nitronium tetrafluoroborate ( NO ₂ B
F ₄ ), nitronium trifluoromethanesulfonate (NO ₂ CF ₃ SO ₃ ), or the like may be used. The nitrating agent can be used in an amount of about 1.0 to 20 equivalents to the compound [VIII], and preferably about 1.5 to 10 equivalents when nitric acid is used. This reaction may be carried out without solvent, but is usually carried out using sulfuric acid, acetic acid, acetic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic acid or the like as a solvent. In some cases, a solvent as described in the above method (A) or a mixture thereof may be used.
A particularly preferred solvent is sulfuric acid. The reaction temperature of this reaction is generally in the range of about -500C to 100C, preferably about -20C to 30C. Reaction times range from about 10 minutes to 10 hours, preferably from about 30 minutes to 3 hours. Compound [III] is commercially available, or can be produced by a method known per se or a method analogous thereto. The method is described in, for example, The Chemistry o Derivatives Part 1 (The Chemistry o
f acid derivatives, Part 1), John Willey & Sons (1979), Chapter 7; The Chemistry of acid Derivatives Part 2
derivatives, Part2), John Willey & Sons (1979), Chapter 11; The Chemistry of acyl halides, John Wiley
& Sons (1972), Chapter 2.

Compound [V] or a salt thereof can be produced according to a method known per se or a method analogous thereto. The method includes, for example, Organic Function Group Preparations (Organic Functiona).
l Group Preparations), Academic Press, Volume 1, Chapter 13 (1968);
Vol. 10, Chapter (1972); a method described in JP-A-2-171. The compound [V] or a salt thereof is not isolated and can be used as a reaction mixture. The amines or salts thereof are commercially available or can be produced according to a method known per se or a method analogous thereto. The method includes, for example, Survey of Organic Synthesis, Wiley-Interscience (197
0), and the method described in Chapter 8.

Guanidine derivative [I] produced by the production method of the present application
And salts thereof have an excellent insecticidal effect as described in JP-A-3-157308, and can be used as an insecticidal composition.

[0020]

【Example】

Next, the present invention will be described in more detail with reference to Examples, but the present invention should not be construed as being limited to these Examples. The proton NMR spectra of Examples and Reference Examples were measured with a Bruker AC-200P type spectrometer, and all δ values were shown in ppm using tetramethylsilane as an internal standard. The abbreviations used in the following Reference Examples and Examples have the following meanings. s:
Singlet, br: broad (broad), d: doublet, t: triplet,
m: Multiplet, dd: Double doublet, J: Coupling constant, Hz: Hertz, DMSO-d
6: heavy DMSO,%: weight%, Mp. : Melting point. Room temperature means about 15 to 25 ° C. Reference Example 1 Sulfate O-methylisourea (5.00 g, 29.0 mmol)
Was dissolved in 97% sulfuric acid (15.2 ml, 10 equivalents) at room temperature with 61% nitric acid (15.2 ml).
ml, 7 equivalents) was added dropwise over 10 minutes. After stirring for 1 hour, the reaction solution was added to ice (100 g).
After neutralization by adding a 40% aqueous sodium hydroxide solution, the mixture was extracted with ethyl acetate (300 ml). Dry over anhydrous magnesium sulfate and concentrate under reduced pressure to give 2.80 g of O-methyl-N-
Nitroisourea was obtained in a yield of 82.4%. 1H-NMR (DMSO-d6): 3.76 (3H, s), 8.60-
9.20 (2H, br. S). Mp. 107-109 ° C.

Reference Examples 2 to 5 The following Reference Examples 2 to 5 were carried out in the same manner as in Reference Example 1 to produce O-methyl-N-nitroisourea.

[Table 1] Reference Example 6 A mixture of O-methylisourea sulfate (1031 g, 5.99 mol) dissolved in 97% sulfuric acid (940 ml, 3 equivalents) was mixed with 98% nitric acid (760 ml, 3 equivalents) under ice-cooling for 2 hours. It was dropped. After stirring at room temperature for 2 hours, the reaction solution was added to ice (5000 g). -
After cooling to 15 ° C., the mixture was allowed to stand for 0.5 hour, and the generated crystals were collected by filtration. The crystals are converted to water (1000 m
l), a 40% aqueous sodium hydroxide solution (160 ml) was added to adjust the pH to 8, and the mixture was stirred at room temperature for 0.5 hour. The mixture was further stirred for 0.5 hour under ice cooling, and the precipitated crystals were collected by filtration. After drying, 542.7 g of O-methyl-N-nitroisourea was obtained with a yield of 76.1%.

Reference Example 7 60.0 g (0.49 mol) of O-methylisourea 1/2 sulfate was added to 98
56.5 g of fuming nitric acid (98%) was added to a mixture of 176.5 g (1.76 mol) of sulfuric acid.
(0.85 mol, 1.7 equivalents) was added dropwise at 4-8 ° C over 1 hour. After stirring at 25 ° C. for 2.5 hours, the reaction solution was added to a mixture of 400 g of ice and 440 ml of water. After cooling to -12 ° C and standing for 1.5 hours,
The precipitated crystals were collected by filtration. Add 168 ml of water and 30% aqueous sodium hydroxide 8.
The pH was adjusted to 8 by adding 0 g, and the mixture was stirred at 10 ° C for 1 hour. The crystals were collected by filtration and dried to obtain 38.4 g (yield 66.2%) of the target O-methyl-N-nitroisourea.

Reference Example 8 O-methyl-N-nitroisourea (46.2 g, 0.388 mol) was dissolved in a mixture of dichloromethane (460 ml) and pyridine (92 g, 1.16 mol). The mixture cooled to -15 ° C in an ice-methanol bath was added to phthaloyl chloride (9
5.0 g, 0.468 mol) was added dropwise over 10 minutes. After stirring for 2 hours, add methanol (12.
5 g) was added and stirred for 15 minutes. The reaction solution was concentrated hydrochloric acid (80 ml) and ice water (400 ml)
And the organic layer was separated. The crude product obtained by vacuum concentration was treated with methanol 20
The mixture was stirred at room temperature for 30 minutes and under ice cooling for 30 minutes. 71.8 g
O-methyl-N-nitro-N′-phthaloylisourea was obtained in a yield of 74.3%. 1H-NMR (C
DC13): 4.15 (3H, s), 7.80-8.15 (4H, m). Mp. 137-138.5 ° C.

Reference Example 9 O-methyl-N-nitro-N′-phthaloylisourea (2.00 g,
8.03 mmol) was suspended in methanol (10 ml), and the mixture was suspended at 0 ° C in 5- (aminomethyl) -2-
Chlorothiazole (1.20 g, 8.07 mmol) was added dropwise over 15 minutes. After stirring at room temperature for 30 minutes, water (20 ml) was added under ice cooling. The resulting crystals were collected by filtration, dissolved in a 10% aqueous sodium hydroxide solution (10 ml), and stirred for 30 minutes. The pH was adjusted to 4 by adding hydrochloric acid. The precipitated crystals are collected by filtration and dried, and then O-methyl-N- (2-chloro-5-thiazolylmethyl) -N '
1.70 g (yield 85.0%) of -nitroisourea was obtained. 1H-NMR (DMSO-d6): 3.87 (3H,
s), 4.61 (2H, d, J = 5.5 Hz), 7.61 (1H, s), 9.90 (1H, br. t, J = 5.5 Hz). M
p. 133-135 ° C.

Reference Example 10 A reaction was carried out in the same manner as in Reference Example 9 except that acetone was used as a reaction solvent, and a target product was obtained with a yield of 74.0%. Reference Example 11 A reaction was carried out in the same manner as in Reference Example 9 except that acetonitrile was used as a reaction solvent, to obtain a target product in a yield of 78.0%. Example 1 O-methyl-N- (2-chloro-5-thiazolylmethyl) -N'-nitroisourea (1.00 g, 4.00 mmol) was suspended in water (10 ml), and a 40% aqueous methylamine solution ( 0.77 g, 9.92 mmol) was added dropwise. After stirring at room temperature for 14 hours, the precipitated crystals were collected by filtration. After washing with water (10 ml) and drying, 0.92 g of 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine was obtained in a yield of 92.0%.

Example 2 O-methyl-N-nitro-N′-phthaloylisourea (4.57 g, 1
To a mixture of 8.3 mmol) and methanol (54 ml), 5- (aminomethyl) -2-chlorothiazole (2.96 g, 19.9 mmol) was added dropwise over 30 minutes while stirring at 3 ° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into 50 g of ice water. After stirring for 10 minutes, the precipitated crystals were collected by filtration and washed with water. Crystals are 10% sodium hydroxide solution (60 ml)
And stirred at room temperature for 0.5 hour. This solution was washed with chloroform (100 ml). The pH of the solution was adjusted to pH 4 by adding concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. After washing with water, crystal and water (4
0%) of the mixture was stirred at room temperature while stirring with a 40% aqueous methylamine solution (3.78 g, 48.8 g).
mmol) was added. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration. After washing with water and drying, 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine was added to 2.56
g (56.0%). Mp. 173.5-176.5 ° C.

Example 3 O-methyl-N-nitro-N′-phthaloylisourea (2.90 g, 1
1.6 mmol) and dichloromethane (30 ml) while stirring at 3 ° C with 5- (aminomethyl) -2-chlorothiazole (1.90 g, 12.8 mmol) in dichloromethane (15 ml).
ml) solution was added dropwise over 25 minutes. After stirring at room temperature for 1 hour, the precipitated crystals were separated by filtration. The crystals were washed with 12 ml of dichloromethane. A 40% aqueous solution of methylamine (1.89 g, 24.3 mmol) was added to a mixture of the filtrate, the washings and water (30 ml) at room temperature with stirring over 5 minutes. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration. After washing with water and drying,
2.15 g of (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine (74.
0%).

Example 4 O-methyl-N-nitro-N′-phthaloylisourea (2.89 g, 1
1.6 mmol) and water (20 ml) while stirring at 3 ° C with 5- (aminomethyl) -2.
-Chlorothiazole (1.79 g, 12.0 mmol) was added dropwise at a time. Acetonitrile
(1 ml), the dropping funnel was washed, and the washing solution was added to the reaction solution. After stirring at room temperature for 2 hours, a 40% aqueous solution of methylamine (3.97 g, 5.11 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. The precipitated crystals were collected by filtration and washed with water. The crystals were stirred in acetonitrile (10 ml) for 15 minutes and collected by filtration to obtain 1.50 g (51.8%) of 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine.

Example 5 O-methyl-N-nitro-N′-phthaloylisourea (4.70 g, 1
To a mixture of 8.9 mmol) and dichloromethane (25 ml) was added dropwise a solution of 5- (aminomethyl) -2-chlorothiazole (2.80 g, 18.9 mmol) in 2 ml of dichloromethane over 5 minutes while stirring at room temperature. After stirring at room temperature for 30 minutes, a 40% aqueous solution of methylamine (6.49 g, 83.6 mmol) was added to the reaction mixture to which 75 ml of water had been added over 2 minutes. At room temperature
After stirring for 1.5 hours, the precipitated crystals were collected by filtration and washed with water. After drying, 1-
3.49 g of (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine
5%).

Example 6 O-methyl-N-nitro-N′-phthaloylisourea 5.0 g (19.
46 mmol) in a mixture of dichloromethane (10 ml) and water (15 ml).
While stirring at 10 ° C, 3.25 g of 5- (aminomethyl) -2-chlorothiazole (20.69
(1.06 equiv.) in dichloromethane (5 ml) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 30 minutes. Add water (60 ml) and then 6.7 ml of methylamine (77.84 mm
ol, 4.00 equivalents). The mixture was stirred at room temperature for 1.5 hours. The crystals were collected by filtration and washed with water and methanol in that order. Dry the crystals to give 1- (2-chloro-5-thiazolylmethyl)
3.83 g (78.8%) of -3-methyl-2-nitroguanidine was obtained as white crystals.

Example 7 O-methyl-N-nitro-N′-phthaloylisourea 5.0 g (20.
0)) was suspended in dichloromethane (10 ml) and water (15 ml) and stirred at 10 ° C with 5- (aminomethyl) -2-chloropyridine 3.0 g (21.0 mmol, 1.05 equivalent) in dichloromethane ( (5 ml) The solution was added dropwise over 5 minutes. The mixture was stirred at room temperature for 30 minutes. water
(60 ml) was added followed by 6.7 ml (77.84 mmol, 4.0 equivalents) of methylamine. The mixture was stirred at room temperature for 1.5 hours. 20% aqueous sodium hydroxide solution 30 m to the reaction mixture
l was added, the layers were separated, and the aqueous layer was washed with dichloromethane. The aqueous layer was neutralized by adding concentrated hydrochloric acid to pH 3.0. The precipitated crystals were collected by filtration and washed with water and methanol in that order.
The crystals were dried to obtain 3.12 g (yield 64.0%) of 1- (6-chloro-3-pyridylmethyl) -3-methyl-2-nitroguanidine as white crystals. Mp 159-160 ° C. 1H-NMR (DMS
O-d6) δ: 2.85 (3H, d, J = 4.4 Hz), 4.44 (2H, d, J = 6.0 Hz), 7.49 (1H, d, J =
8.2 Hz), 7.80 (1H, dd, J = 8.2 Hz, 2.6 Hz), 7.90 (1H, br), 8.37 (1H, d, J =
2.6 Hz), 9.10 (1H, br). IR (nujol): 3300, 1620, 1570, 1380, 1340, 1240
(cm-1).

Example 8 47.2 g (0.164 mol) of O-methyl-N- (2-chloro-5-thiazolylmethyl) -N′-nitroisourea (purity 87%) was suspended in 410 ml of water. 25.5 g (0.328 mol, 2.0 equivalents) of a 40% aqueous methylamine solution was added dropwise at 23 ° C. After stirring at room temperature for 2 hours, 14.3 ml (0.168 mol) of 36% hydrochloric acid was added dropwise at 13 to 20 ° C under ice cooling. The crystals were collected by filtration to obtain 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine (39.1 g, yield 95.6%).

Table 2 shows the chemical structural formulas and yields of the compounds produced in Reference Examples 8 to 11 and Examples 1 to 8.

[0034]

【The invention's effect】

According to the production method of the present invention, a guanidine derivative [I] having excellent insecticidal activity and a salt thereof can be easily and industrially mass-produced in a high yield.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Jin Ishizuka 3-12-1, Matsushiro, Tsukuba-shi, Ibaraki Pref. 609 Takeda Matsushiro Residence (72) Inventor Yasuo Kamiya 1-2-6, Takezono, Tsukuba-shi, Ibaraki 2 Tsukuba Sakura Danchi 901-305 F term (reference) 4C033 AD06 4H011 AC01

Claims (3)

[Claims] (1) Formula (1) (Wherein, R ¹ represents a C _1-3 alkyl group, R ² represents hydrogen or a C _1-4 alkyl group, Q represents an optionally substituted heterocyclic group, X represents a nitro group or a cyano group, n represents 0 or 1.) The reaction of a compound represented by the formula (I) or a salt thereof with a _C1-4 alkylamine or a salt thereof in water or a mixed solvent of water and an organic solvent: (Wherein R ³ represents a C _1-4 alkylamino group and other symbols have the same meanings as described above) or a salt thereof. 2. O-methyl-N- (6-chloro-3-pyridylmethyl) -N′-nitroisourea or a salt thereof and methylamine or a salt thereof in water or a mixed solvent of water and an organic solvent. A process for producing 1- (6-chloro-3-pyridylmethyl) -3-methyl-2-nitroguanidine or a salt thereof. 3. O-methyl-N- (2-chloro-5-thiazolylmethyl) -N'-nitroisourea or a salt thereof and methylamine or a salt thereof in water or a mixed solvent of water and an organic solvent. A process for producing 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine or a salt thereof.