JPH0415783B2 - - Google Patents

Description

Claim 1 Formula where _R9 is N or CH; _R1 is _C1 - _C4 alkyl; _R2 is _C1 - _C4 alkyl or _C3-
C ₆ cycloalkyl; and R ₁ and R ₂ are
When taken together with the carbon to which they are attached, they can represent C ₃ -C ₆ cycloalkyl, optionally substituted with methyl, and when R ₁ and R ₂ are not the same, their optical isomers ;W is O
or S; X is hydrogen or _C1 - _C4 alkyl; Y is hydrogen, halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy, trifluoromethyl,
Trichloromethyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro,
phenyl or phenoxy, said phenyl and phenoxy optionally one C ₁ -C ₄ alkyl,
Optionally substituted with _C1 - _C4 alkoxy or halogen; Z is hydrogen, _C1 - _C4 alkyl, trifluoromethyl, trichloromethyl, phenyl,
or phenyl substituted with one _C1 - _C4 alkyl, _C1 - _C4 alkoxy or halogen;
And Y and Z, when taken together, can form a ring, where YZ has the structure: -(CH) _o -
where n is an integer from 3 to 5, where X is hydrogen; or YZ is , where L, M, Q and R ₇ are each hydrogen,
halogen, _C1 - _C4 haloalkyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro, phenyl, phenoxy or monosubstituted phenyl or phenoxy, where the substituents are _C1 - _C4 alkoxy or _{2- ( 5 _ _} , 5-disubstituted-4-oxo (or thiono)-2-imidazolin-2-yl) nicotinic acids, 3-quinolinecarboxylic acids or benzoic acids, the structure where R ₉ , X, Y, Z, W, R ₁ and R ₂ are as described above, and R ₃ is

or CN, with 2 to 20 molar equivalents of aqueous or aqueous alcoholic sodium hydroxide or potassium hydroxide and 0 to 10 molar equivalents of 30 to 90% aqueous hydrogen peroxide at 25 to 100°C. A method for producing a compound of the formula (), which comprises reacting the compound at a temperature of 100 to 100, and then acidifying the reaction mixture thus formed to a pH of 2 to 4 with a strong acid to obtain an acid of the formula (). 2 The concentration of aqueous or hydroalcoholic base is 10
% or more. 3 The concentration of base in the total reaction mixture by weight is
10. A process according to claim 1, wherein the amount is between 10 and 40% and is used in an amount sufficient to provide between 2 and 6 molar equivalents of base per equivalent of product of formula (a). 4 Structure In the formula, _R9 is N or CH, X is hydrogen or _C1 - _C4 alkyl, and Y is hydrogen, halogen,
_C1 - _C4 alkyl, _C1 - _C4 alkoxy, trifluoromethyl, trichloromethyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro, phenyl or phenoxy, where the phenyl and phenoxy are appropriately one
Optionally substituted with _C1 - _C4 alkoxy or halogen, Z is hydrogen, _C1 - _C4 alkyl, trifluoromethyl, trichloromethyl, phenyl,
or phenyl substituted with one _C1 - _C4 alkyl, _C1 - _C4 alkoxy or halogen;
And Y and Z, when taken together, can form a ring, where YZ has the structure: -(CH ₂ ) _o -
where n is an integer from 3 to 5, where X is hydrogen, or YZ is , where L, M, Q and R ₇ are each hydrogen,
halogen, _C1 - _C4 haloalkyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro, phenyl, phenoxy or monosubstituted phenyl or phenoxy, where the substituents are _C1 - _C4 alkoxy or halogen; provided that only one of L, M, Q and R ₇ can represent a substituent other than hydrogen, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, and W is O or S and R ₁ is C ₁ -C ₄ alkyl, with 2 to 20 molar equivalents of sodium hydroxide or potassium hydroxide per mole of compounds of formulas (a) and (b). an aqueous solution or an aqueous _C1 - _C4 alcoholic solution, and 25
reacting at a temperature of ~110 °C, acidifying the reaction mixture thus formed with hydrochloric acid or sulfuric acid to pH 2-4, extracting the acidified reaction mixture with an organic solvent,
and 2-(5,5-disubstituted-4-oxo(or thiono)-2-imidazolin-2-yl)nicotinic acids, quinolinecarboxylic acids or benzoic acids, characterized in that an acid product of formula (A) is obtained. Acid production method. 5 formula In the formula, R ₉ , X, Y and Z are defined in claim 1.
The equivalent of the compound of formula In the formula, R ₁ , R ₂ and W are as described in claim 1. 60℃
The structure is formed by reacting in a nitrogen atmosphere at a temperature of Compounds of formula (a) and structures having An isomer mixture of a compound of formula (XVb) having the formula (XVb), wherein R ₉ , X, Y, Z, W, R ₁ and R ₂ are as defined in claim 1, is formed The reaction product is reacted with an aqueous solution or an aqueous C ₁ -C ₄ alcoholic solution of 2 to 10 molar equivalents of sodium hydroxide or potassium hydroxide per mole of compounds of formulas (a) and (b) at 25 to 110°C. and acidifying the reaction mixture thus formed with hydrochloric acid or sulfuric acid to a pH of 2 to 4, extracting the acidified reaction mixture with an organic solvent, and obtaining the acid product of formula (A). 2. The method according to claim 1 for producing a compound of the formula, wherein R ₉ , X, Y, Z, W, R ₁ and R ₂ are as described in claim 1. 6 formula In the formula, R ₉ , X, Y and Z are defined in claim 1.
The equivalent of the compound of formula wherein R ₁ and R ₂ are as described in claim 1, and in the presence of a solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, acetonitrile or a low boiling halogenated hydrocarbon,
Structures (a) and (b) were obtained by reacting in a nitrogen atmosphere at temperatures between 20 and 60°C.

【formula】 and

[Formula] wherein R ₉ , X, Y, Z, W, R ₁ and R ₂ are as described in claim 1. 2 to 10 molar equivalents per mole of compounds of formulas (a) and (b) in aqueous or aqueous
Treat with _C1 - _C4 alcoholic sodium hydroxide or potassium hydroxide and 2-5 moles of 30-90% aqueous hydrogen peroxide at a temperature of 25-110 °C, and the reaction mixture thus formed has a pH of 2-4. Structure (B) consisting of acidifying with hydrochloric acid or sulfuric acid, extracting the acidified reaction mixture with an organic solvent, and obtaining the acid product of formula (B). 2. The method according to claim 1 for producing a compound of the formula, wherein R ₉ , X, Y, Z, W, R ₁ and R ₂ are as described in claim 1. 7 R ₁ is methyl; R ₂ is isopropyl; W is O; X is hydrogen; Y is hydrogen,
Halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy,
Trifluoromethyl, trichloromethyl, difluoromethoxy, di-lower alkylamino, C ₁ -C ₄
alkylthio, nitro, phenyl or phenoxy, said phenyl and phenoxy optionally substituted with one C ₁ -C ₄ alkoxy or halogen, Z is hydrogen, C ₁ -C ₄ alkyl,
2. The method of claim 1, wherein the phenyl is trifluoromethyl, trichloromethyl, phenyl, or phenyl substituted with one _C1 - _C4 alkyl, _C1 - _C4 alkoxy or halogen. 8 (+)-2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-
Claim 1 for producing 3-quinolinecarboxylic acid
The method described in. 9. The method according to claim 1 for producing (+)-2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid. 10 Compound 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)
-p-toluic acid and 6-(5-isopropyl-5-methyl-4-oxo-2-imidazoline-
2. A process according to claim 1 for producing a mixture of 2-yl)-m-toluic acids. SUMMARY OF THE INVENTION The present invention comprises a structure 2-(5,5-disubstituted-4 of formula () with
-Oxo (or thiono)-2-imidazoline-
2-yl) nicotinic acids, 3-quinolinecarboxylic acids or benzoic acids with the structure A method for producing by base-catalyzed cyclization of 2-carbamoylnicotinic acid or 2-carbamoyl 3-quinolinecarboxylic acid of formula (a), in which R ₉ is N or CH; R ₁ is C _1
-C4 alkyl; _R2 is _C1 - _C4 alkyl or _C3 - _C6 cycloalkyl; and _R1 and _R2 , when taken together with the carbon to which they are attached, are optionally substituted with methyl. C ₃ −C ₆ which may be
can represent cycloalkyl and R ₁
and when R ₂ are not the same, their optical isomers; W is O or S; X is hydrogen or
C ₁ -C ₄ alkyl; Y is hydrogen, halogen,
_C1 - _C4 alkyl, _C1 - _C4 alkoxy, trifluoromethyl, trichloromethyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro, phenyl, phenoxy, and one _C1 - _C4 alkyl, _C1 - _C4 alkoxy or phenyl or phenoxy substituted with halogen; Z is hydrogen, _C1 - _C4 alkyl, trifluoromethyl, trichloromethyl, phenyl, or one _C1 - _C4 alkyl; C ₁ -C ₄ alkoxy or halogen substituted phenyl; and Y and Z, when taken together, can form a ring, where YZ is represented by the structure: -(CH) _o -. , where n is an integer selected from 3 to 5, where X is hydrogen; or YZ is , where L, M, Q and R ₇ are each hydrogen,
Halogen, _C1 - _C4 alkyl, _C1 - _C4 alkoxy,
_C1 - _C4 haloalkyl, difluoromethoxy, di-lower alkylamino, _C1 - _C4 alkylthio, nitro, phenyl, phenoxy, or monosubstituted phenyl or phenoxy, where the substituents are
_C1 - _C4 alkyl, _C1 - _C4 alkoxy or halogen; provided that only one of L, M, Q and _R7 is hydrogen, halogen, _C1 - _C4 alkyl or
Substituents other than C ₁ -C ₄ alkoxy can be represented. This base-catalyzed cyclization method carbamoylnicotinic acid or carbamoyl 3-quinolinecarboxylic acid of formula (a), where X, Y, Z, W, R ₁ and R ₂ are as defined above;
1 to 20 mol, preferably 2 to 6 mol of aqueous or hydroalcoholic sodium hydroxide or potassium hydroxide per mole of acid of formula (a);
It involves reacting at a temperature of ~110<0>C, i.e. at reflux temperature. Then, the reaction mixture was adjusted to PH2
Acidified to ~4 to give formula () in high yield and purity 2-(5,5-disubstituted-4-oxo(or thiono)-2-imidazoline-) having the structure, where X, Y, Z, W, _R1 and _R2 are as described above 2-yl) nicotinic acid or 3-quinolinecarboxylic acid. Advantageously, the method of the invention also comprises the formula (
2-(5,
5-Disubstituted-4-oxo (or thiono)-2-
imidazolin-2-yl) nicotinic acid and 3-
It is carried out to produce quinoline carboxylic acid. According to the method of the invention, carbamoylnicotinic acid or quinolinic acid of formula (a) and carbamoylnicotinic acid or quinolinic acid of formula (
The isomer mixture containing carbamoylpicolinic acid or quinaldic acid of b) is heated to a temperature of 25 to 110°C (i.e. reflux temperature) with about 2 to 20 molar equivalents of an aqueous or aqueous alcohol ( _C1 - _C4 -alcohol). ) with 2 to 6 molar equivalents of said base, preferably at a concentration of greater than 10% by weight, in an atmosphere of an inert gas, such as nitrogen or argon. The mixture is then cooled to about 25°C and treated with a strong acid, such as hydrochloric acid or sulfuric acid, to a pH of 2-4.
to produce a herbicidally effective product of formula () in greater than 95% yield. Formula (a)
When the product is water-insoluble, it can be precipitated and recovered by filtration. When the product is water-soluble, the mixture is extracted with an organic solvent, such as ether or methylene chloride, and the extract is then concentrated to give the herbicidally effective 2-(5,5 -disubstituted-4-oxo(or thiono)-2-imidazolin-2-yl)
Nicotinic acid or 3-quinolinecarboxylic acid is obtained. A.Kjaer, Acta.Chemica.Scand7, 889, using dilute 1.0N (4%) aqueous sodium hydroxide.
(1953) gives significantly lower yields (less than 10-15%). The present invention also provides carbamoylnicotinic acid and quinoline carbonate of formulas (a) and (b) by reacting an appropriately substituted anhydride of formula () with aminocarboxamide or aminothiocarboxamide of formula (a). A herbicidally effective compound of the formula ()2-(5,5-disubstituted-4-
Oxo (or thiono)-2-imidazoline-2
-yl) nicotinic acid, 3-quinolinecarboxylic acid,
and a method for producing benzoic acid. The reaction is preferably carried out using equivalent amounts of an anhydride of formula () and a carboxamide or thiocarboxamide of formula (a) in an inert organic solvent, such as a low boiling ether (diethyl ether, tetrahydrofuran or dimethoxyethane), It is carried out in the presence of acetonitrile, ethyl acetate or a halogenated hydrocarbon such as methylene chloride. The reaction is generally carried out at a temperature of 20 DEG to 80 DEG C., preferably 30 DEG to 60 DEG C., in an atmosphere of an inert gas such as nitrogen or argon. This reaction is expressed by the formula (
An isomer mixture of carbamoylnicotinic acid, 3-quinolinecarboxylic acid or benzoic acid of formula (a) and carbamoylpicolinic acid or quinaldic acid of formula (b) is produced. The isomer mixture is then treated as described above to obtain the herbicidally effective formula (A).
2-(5,5-disubstituted-4-oxo(or thiono)-2-imidazolin-2-yl)nicotinic acid, 3-quinolinecarboxylic acid or benzoic acid can be recovered. The foregoing reaction is graphically illustrated in Flow Diagram I. Herbicidal 2- produced according to the method of the present invention
(5,5-disubstituted-4-oxo-2-imidazolin-2-yl)nicotinic acid and quinoline-3-
Carboxylic acid is Marinus Los
published December 16, 1981, Publication No. 81/50, European Patent Application No. 0041623. Herbicidal benzoic acid is described in US Pat. No. 4,188,487 (1980) by Marinus Los.
(2013) and exemplified. where X, Y, Z, W, R ₁ and R ₂ are as described above, and R ₉ is N or CH. Conveniently, the process of the present invention directly converts nitriles into imidazolinyl- Also suitable for producing quinolinic, nicotinic and benzoic herbicides. In the formula, R ₉ , X, Y, Z, R ₁ and R ₂ are as described above. The reaction is carried out at 0-100° C. in water, a mixture of water and a water-miscible solvent such as a C ₁ -C ₄ alcohol or water and a water-immiscible solvent such as dichloromethane, 1,2-dichloroethane, chlorobenzene,
It can be carried out in a mixture with toluene, xylene and ethyl ether. The reaction can also be carried out in a _C1 - _C4 alcohol without the addition of water. 60～
Reaction in water at 100° C. is preferred because cyclization to the desired imidazolinyl product is more rapid at elevated temperatures and does not require disposal or recovery of organic solvents. The use of aqueous 30-90% hydrogen peroxide with alkali metal hydroxides results in faster conversion of acid amidonitriles to alkali metal cation salts of acid diamides and less by-product formation. The amount of peroxide is 0 to 1 mole of acid amide nitrile.
It can be used in a molar ratio of 10 mol, preferably 2 to 5 mol. Both aqueous and aqueous-alcoholic alkali metal hydroxides such as KOH, NaOH or Ca(OH) ₂ are added by weight per mole of acid amidonitrile.
1 to 10 moles, preferably 2 to 6 moles, at a concentration of 10% or more
Used in mole ratios. The product imidazolinyl-acids are amphoteric;
And it can act as either an acid or a base. Thus, they can be isolated as alkali metal cation salts, as free acids and, when treated with strong acids such as hydrochloric, sulfuric and hydrobromic acids, as acid addition salts. Acid amidonitriles suitable for use as starting materials are disclosed in U.S. Patent Application No. 381,812, filed May 25, 1982, incorporated herein by reference.
It is conveniently prepared by first reacting methyl isopropyl ketone with hydrogen cyanide in aqueous ammonium hydroxide, as described by Stepek and Matthew Nigro). This compound is then reacted with a suitable anhydride to form the acid amidonitrile. This production is under US Patent No. 4017510
listed in the number. 2- of formula (A) produced by the present invention
(5,5-disubstituted-4-oxo (or thiono)-
2-imidazolin-2-yl)nicotinic acid, 3-
Quinoline carboxylic acid, and benzoic acid, are highly effective herbicides useful in controlling a wide variety of monocots and dicots. They are also useful as herbicides for aquatic plants and are preferably applied to water containing leaves, soil, or seeds, or other propagating organs of plants such as tubers, rhizomes or bracts, from about 0.025 to 8.0 Kg/ha, preferably is about
It is unique in its effectiveness in suppressing plants when applied at a rate of 0.032-4.0 Kg/ha. The following examples illustrate certain details of the invention. The invention is not limited except as defined in the claims. Example 1 Production of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid To a stirred suspension of 2,3-pyridinecarboxylic anhydride (30 g) in 150 ml of acetonitrile was added 2-amino-2,
Add a solution of 3-dimethylbutylamine (28g) to 25~
Add at 30°C. Stir this mixture for 2 hours. The solvent is removed under reduced pressure at 50°C. The remaining gum is dissolved in 230 ml of 2.6N sodium hydroxide and heated to 80° C. for 1.5 hours. The mixture was cooled to 25°C and diluted with 65ml of 37% hydrochloric acid.
Acidify to PH3. The resulting solution is extracted twice with 200 ml of methylene chloride each time. The extract was concentrated and a residue of 33 g of the desired product, mp 160-165
℃ is obtained. After standing overnight, the aqueous layer contained 3.8 g of picolinic acid isomer,
Melting point: 155-157°C (decomposition), precipitates. Example 2 2-(4-oxo-1,3-diazaspiro[4,
5] Production of dec-2-en-2-yl)nicotinic acid To a stirred solution of 7.1 g of 1-aminocyclohexanecarboxamide in 60 ml of methylene chloride is added 7.5 g of 2,3-pyridinecarboxylic anhydride. This mixture becomes warm and forms a solution. Stirring is continued for 2 hours, at which time a colorless solid precipitates. A mixture of monoacids is collected,
12.0g, melting point 168-178°C (decomposition). This material is dissolved in 45 ml of 2.7N sodium hydroxide and heated to 80-85°C for 1 hour. It is then cooled, acidified with 10.3 ml of 37% hydrochloric acid and extracted twice with 25 ml of methylene chloride each time. Concentration of the extract gave 7.5 g of the desired product, which was recrystallized from aqueous methanol to give 2-(4-oxo-1,3-diazaspiro[4.5]dec-2-
(en-2-yl) nicotinic acid, melting point 186-189℃,
is obtained. Example 3 6-isopropyl-2-(5-isopropyl-
5-methyl-4-oxo-2-imidazoline-2
-yl)nicotinic acid production To a stirred solution of the anhydride (15.1 g) in 125 ml of THF under nitrogen atmosphere is added 11.4 g of 2-amino-2,3-dimethylbutyramide.
Stir this mixture overnight. The solvent is removed in vacuo and the resulting oil (consisting of a mixture of isomeric pyridine monoacid products) is dissolved in 66 ml of 6N NaOH. This solution was heated to 70 °C in a nitrogen atmosphere for 3.5 h, then cooled and the pH of this solution was reduced to 6N.
Adjust to ₉ with _H2SO4 . The mixture is extracted twice with ether and the organic extract is discarded. PH of aqueous phase
Adjust to 3 with 6N H ₂ SO ₄ . The resulting precipitate is filtered off, washed with water and dried to give 13.25 g of the desired product. A sample was recrystallized from methylene chloride-hexane and then from ether-hexane to yield 6-isopropyl-2-(5-isopropyl-5-methyl-4-oxo-2-imidazoline-
An analytically pure sample of 2-yl) nicotinic acid, melting point 131-133.5°C, is obtained. Using essentially the same procedure but substituting the appropriate substituted pyridine-2,3-dicarboxylic anhydride and also optionally using the optically active 2-amino-2,3-dicarboxylic anhydride The following nicotinic acids were prepared by substituting dimethylbutyramide or 2-amino-2,3-dimethylthiobutyramide for 2-amino-2,3-dimethylbutyramide.

【table】

【table】

Melting point: 182-184°C Example 4 Production of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid 2-amino-2 in 500 ml acetonitrile,
To a stirred solution of 3-dimethylbutyramide (40 g) is added 60 g of 2,3-quinolinedicarboxylic anhydride in portions over about 45 minutes. The mixture was heated to 50-60°C for 2 hours, cooled to room temperature,
73.7 g of a mixture of carbamoylquinolinecarboxylic acids are obtained. This solid is dissolved in 435 ml of 1.5N sodium hydroxide and heated to 80-85°C for 2 hours. The solution is cooled and acidified with 57 ml of 37% hydrochloric acid. The desired product is filtered off and dried. This solid was recrystallized from methanol to yield 49 g of 2-
(5-isopropyl-5-methyl-4-oxo-
2-imidazolin-2-yl)-3-quinolinecarboxylic acid, melting point 240-242°C, is obtained. The next step 1 of the above procedure yields 2-carbamoyl-3-quinolinecarboxylic acid with the following structure: In the formula, L, M, Q and R ₇ are as described below.

[Table] Step 2 of the above procedure, i.e. carbamoyl-
Base-catalyzed cyclization of 3-quinolinecarboxylic acid produces 2-(5-isopropyl-5-methyl-4-oxo-2-imidazoline-
2-yl)-3-quinolinecarboxylic acid: In the formula, L, M, Q and R ₇ are as described below.

[Table] Example 5 Production of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoic acid To a stirred solution of 13.4 g of 2-amino-2,3-dimethylbutyramide in 200 ml of methylene chloride is added 13.4 g of phthalic anhydride. The mixture is heated to reflux for several minutes, then allowed to cool and stir overnight. The clear solution is then stirred with 160 ml of 0.8N sodium hydroxide for 15 minutes. The aqueous layer is separated and treated with another 12.1 g of 50% aqueous sodium hydroxide and the alkaline solution is heated to 75° C. for 2.5 hours. The solution is then cooled to 25° C. and neutralized with 23 ml of 37% aqueous hydrochloric acid. The colorless product is separated, collected and dried to yield 13.8 g, mp 158-162°C.
Concentrate the solution under reduced pressure to a volume of 50 ml and add another 10.0
g of product, melting point 150-170°C, are obtained. The total yield of crude product is 23.8 g or 91.5% yield. Example 6 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-p-toluic acid and 6-(5-isopropyl-5-methyl-4-oxo-imidazolin-2-yl) -il)-m
-Production of toluic acid In a solution of 14.4 g of 2-amino 2,3-dimethylbutyramide in 75 ml of acetonitrile, 16.2 g
of 4-methylphthalic anhydride. The solution was heated to 60°C for 2 hours and then concentrated under reduced pressure to 31.3
g of residue is obtained. This residue is dissolved in 80 ml of 3N sodium hydroxide and heated to 80-85°C for 3 hours. Then cool it to 25℃ and add 23.5ml of 37%
Neutralize with aqueous hydrochloric acid. Near the end of neutralization,
Add 100 ml of methylene chloride to dissolve the separating gummy product. Separate the layers and extract the aqueous layer with an additional 65 ml of methylene chloride. The combined methylene chloride layers were concentrated to give 28.8 g of residual rubber, which contained 23.9 g of the two desired products as determined by quantitative high performance liquid chromatography. Therefore, the yield is 87%. Example 7 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolinyl-2-yl)-p-ylylic acid and 6-(5-isopropyl-5-methyl-4-oxo-2-imidazoline) -2-yl)-m-ylic acid production 32.0 g (0.116 mol) of N-(1-
To the cyano-1,2-dimethylpropyl)-4(and 5)-methylphthalamic acid is added 30.0 g (0.375 mol) of 50% sodium hydroxide. Maintain the temperature at 20-25 °C using external heating. 56.0
(0.494 mol) of 30% aqueous hydrogen peroxide is added in 30 min, maintaining the temperature between 20 and 30 °C. The solution is heated to 80°C and stirred at 80-90°C until the reaction is complete (approximately 2 hours) as determined by thin layer chromatography. The reaction mixture was cooled to 20-30°C, 125 ml of methylene chloride was added, then 19.2 g
Neutralize the mixture by adding (0.188 mol) of 96% sulfuric acid. Separate the organic layer and distill the solvent to give 31.7g
76.7% purity (76.0% yield) of solid 2-
(5-isopropyl-5-methyl-4-oxo-
2-imidazolin-2-yl)-p-toluic acid and 6-(5-isopropyl-5-methyl-4
-oxo-2-imidazolin-2-yl)-m-
Toluic acid is obtained. Example 8 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolinyl-2-yl)-p-toluic acid and 6-(5-isopropyl-5-methyl-4-oxo-2-imidazoline) -2-yl)-m-toluic acid production 29.5 g (0.108 mol) of N-(1
-Cyano-1,2-dimethylpropyl)-4(and 5)-methylphthalamic acid is added with 26.4 g (0.33 mol) of aqueous 50% sodium hydroxide. Maintain temperature at 20-25 °C using external cooling. Stir this mixture for 1 hour at 20-25°C, then at 80-90°C.
C. and stir until the reaction is complete (approximately 7 hours) as determined by thin layer chromatography analysis of the reaction mixture. Cool the reaction mixture to 20-30°C, add 125 ml of methylene chloride and 16.8 g
Neutralize the mixture by adding (0.165 mol) of 96% sulfuric acid. Separate the organic layer and remove the solvent in vacuo.
26.3 g of 69.3% pure (61.5% yield) solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-p-toluic acid and 6-(5 -isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-
m-Toluic acid is obtained. Example 9 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoic acid,
Production of hydrochloride 5.22 g (0.020 mol) N-(1-cyano-1,2-dimethylpropyl)phthalamic acid in a mixture of 35 ml isopropyl alcohol and 10 ml water to 6.41 g (0.080 mol) aqueous 50% water Add sodium oxide. Temperature 20~20 using external cooling
Hold at 30° C. and add 4.80 g (0.042 mol) aqueous 30% hydrogen peroxide. This mixture was heated to 80℃
Heat for 5 hours and then cool to 20-25°C. Adjust the pH to 1 by adding 36% aqueous hydrochloric acid. The volatile solvent was removed in vacuo to yield 8.35 g of solid 2-(5-
Isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)benzoic acid, hydrochloride is obtained. The solid is analyzed by high performance liquid chromatography. Actual yield is 60.3%. Example 10 Preparation of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid 7.83 to a stirred mixture of 20 ml of water and 8.40 g (0.105 mol) of a 50% sodium hydroxide solution.
g (0.030 mol) of 2-[(1-cyano-1,2-
Add dimethylpropyl)aminocarbonyl]nicotinic acid. Raise the temperature to 70-75°C using external heating and maintain it here for 5 hours. Cool the reaction mixture to 20-30 °C, add 50 ml of methylene chloride, and adjust the pH to 3.0 by adding 37% hydrochloric acid.
After separating the organic layer and removing the solvent by evaporation,
6.71 g of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid was obtained, which was 90% pure (77
% yield). Example 11 Preparation of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid 7.83 g into a stirred mixture of 20 ml of water and 840 g (0.105 mol) of 50% sodium hydroxide solution
(0.030 mol) of 2-[(1-cyano-1,2-dimethylpropyl)aminocarbonyl]-3-pyridinecarboxylic acid is added. Adjust the temperature using external heating
Raise to 35-40℃. Add 13.6g (0.120g) to this solution.
30% (mol) hydrogen peroxide is added over 30 minutes, during which time the temperature is maintained at 35-40°C by external cooling. After 1.5 hours at 35-40°C, the mixture is heated to 70°C and held at that temperature for 2 hours. 20
After cooling to ~30 °C, add 50 ml of methylene chloride and adjust the pH to 3.0 by addition of 37% hydrochloric acid.
After separating the organic layer and evaporating the solvent, 7.57 g
(87% yield) of solid 2-(5-isopropyl-
5-methyl-4-oxo-2-imidazoline-2
-yl) nicotinic acid is obtained. Example 12 Preparation of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid To a stirred solution of 1.69 g (0.042 mol) solid sodium hydroxide in 11 ml water, 4.00 g
(0.013 mol) of 2-[(1-cyano-1,2-dimethylpropyl)-2-aminocarbonyl]-3-quinolinecarboxylic acid is added. Raise the temperature to 80-83 °C using external heating. Add 4.37g to this solution.
(0.039 mol) of 30% hydrogen peroxide is added over 30 minutes, maintaining the temperature at 80-83 °C. After the hydrogen peroxide addition is complete, 1.04 g (0.026 mole) of solid sodium hydroxide is added. 1 hour later, additional 1.04
g (0.026 mol) of solid sodium hydroxide is added. After a total reaction time of 2 hours, the solution is cooled in an ice-water bath and the PH is adjusted to 2.0 by addition of 37% hydrochloric acid. After filtering, washing and drying the precipitate,
3.90 g (85% yield) of solid 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid was obtained, which was 87.5% It is purity. Example 13 Effect of base stoichiometry and concentration on the formation of 2-(5,5-disubstituted-4-oxo-2-imidazolin-2-yl) compounds Three samples (1.3 g, 0.005 mol) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid were treated with 2, 3, and 4 molar equivalents of sodium hydroxide. Contains 3
Dissolve in 30% aqueous basic solution. Each of these solutions was heated to 60°C for 3 hours, and the solution was purified by high performance liquid chromatography to determine 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid and 2 - [(1
The equilibrium concentration of -carbamoyl-1,2-dimethylpropyl)carbamoyl]nicotinic acid is analyzed. Sufficient water is then added to each solution to adjust the base concentration to 15% and the equilibrium concentration is determined as above. Finally, adjust the base concentration to 10% and measure the equilibrium concentration. The results of these experiments, illustrated graphically below, are (2-imidazolin-2-yl)
We demonstrate the importance of sufficient base concentration and stoichiometry for efficient formation of compounds. Example 14 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-p-toluic acid and 6-(5-isopropyl-5-methyl-4-oxo-2-imidazoline) -2-yl)
-Production of m-toluic acid A mixture of [(1-carbamoyl-1,2-dimethylpropyl)carbamoyl] meta and para-toluic acids (5.83 g, 0.02 mol) is dissolved in 15% aqueous sodium hydroxide (0.4 mol, 20 molar equivalents). The solution is heated to 80° C. for 2 hours and then cooled to room temperature. Analysis of the reaction mixture by high performance liquid chromatography revealed that 94% of 2-(5
-isopropyl-5-methyl-4-oxo-2-
imidazolin-2-yl)-p-toluic acid and 6
-(5-isopropyl-5-methyl-4-oxo-imidazolin-2-yl)-m-toluic acid. Example 15 Effect of base concentration on the formation of 2-(5,5-disubstituted-4-oxo-2-imidazolin-2-yl) compounds 2-[(1-carbamoyl-1,2-dimethylpropyl) -carbamoyl] Nicotinic acid, meta and para-toluic acid samples are dissolved in 3.42 molar equivalents of aqueous sodium hydroxide at varying concentrations of 4%, 10% and 20%. Heat the resulting solution to 80-85℃
Heat for 2-3 hours and analyze the solution for the desired cyclized (imidazolin-2-yl) product. The results of these experiments are shown in the table below. As is clear from these results, product formation increases significantly at base concentrations of 10% and above on a weight basis.

【table】