JP3431218B2 - Preparation of chromancarboxylic acid derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel process for producing chromancarboxylic acid derivatives. The chromancarboxylic acid derivative is useful as an intermediate for physiologically active substances, especially agricultural chemicals.

[0002]

2. Description of the Related Art As a method for producing a chromancarboxylic acid derivative, J. Indian Chem. Soc. Vol. 45p200 (196
8) describes a method using Hagemann's ester as a raw material. However, it is not always an efficient production method because there are many reaction by-products. Further, it is not known that this compound is useful as an intermediate for agricultural chemicals.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have attempted to synthesize a large number of intermediates as raw materials in order to search for hydrazine derivatives having high insecticidal activity among agricultural chemicals. It has been found that a specific chromancarboxylic acid is an extremely excellent intermediate for a hydrazine derivative having high activity. However, there is no efficient method for producing the chromancarboxylic acid, and it has been necessary to develop a new method.

[0004]

Under these circumstances, various investigations have been made on reaction pathways. As a result, a compound represented by the following formula (1) is used as a starting material, and the target compound represented by the following formula (11) is expressed in 6 steps. It has been found that chromancarboxylic acid can be obtained in good yield. That is, the present invention is

[0005]

[Chemical 9]

(Wherein R ¹ represents a C _{1 to} C ₂ alkyl group or a halogen atom, R ² represents a C _{4 to} C ₆ tertiary alkyl group, and M represents an alkali metal atom). Compound in organic solvent

[Chemical 10] (Wherein R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a methyl group, and X is a halogen atom or OS.
O ₂ R ⁶ group, wherein R ⁶ represents a lower alkyl group or a phenyl group which may be substituted with a lower alkyl group).

[0007]

[Chemical 11]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ represents the same as above) (first step), and then this compound is (1) at high temperature in the presence or absence of an organic solvent or (2) an organic solvent and a Lewis acid. Rearrangement reaction is performed in the presence of a catalyst

[0009]

[Chemical 12]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ represents the same as the above) (second step), and then this compound is subjected to catalytic hydrogenation (reduction) reaction in a solvent in the presence of a hydrogenation catalyst in a hydrogen atmosphere, formula

[0011]

[Chemical 13]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ represents the same as the above) (third step), and this compound is then added to an organic solvent in the presence of a Lewis acid to form the formula CH ₃ COX ′ (6) (wherein X ′ is a halogen atom). A compound represented by the formula

[0013]

[Chemical 14]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ represents the same as the above) (4th step) This compound is then added to water or a mixed solvent of water and an organic solvent in the formula X'2 (8) (wherein X'is the above A compound of formula MOX ′ (9) (wherein M and X ′ are as defined above) in the presence of an alkali.

[0015]

[Chemical 15]

(Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ represents the same as above) (step 5) Finally, this compound was reacted with a Lewis acid in an organic solvent.

[0017]

[Chemical 16]

The present invention relates to a process for producing chromancarboxylic acid, which comprises producing a compound represented by the formula (wherein R ¹ , R ³ , R ⁴ and R ⁵ are the same as defined above) (step 6). The reaction route is as follows.

[0019]

[Chemical 17]

(In the figure, M, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above) First step, that is, from the compound of formula (1) to the compound of formula (3) Production: Examples of the organic solvent used include aromatic solvents such as benzene, toluene, xylene, orthochlorobenzene, and aprotic polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and preferably the aromatic solvents. It is desirable to use a mixture of 0.1 to 0.5 parts by weight of the aprotic polar solvent with respect to 1 part by weight in order to improve the yield and purity of the target product.
The reaction temperature is usually 0 to 50 ° C., preferably 10 to 2
It is 5 ° C. The compound of formula (2) is preferably used in an amount of 1 to 1.2 mol with respect to 1 mol of the compound of formula (1). In carrying out this reaction, a compound (phenol derivative) in which M is a hydrogen atom in the formula (1) is dissolved in the above aromatic solvent, and a salt-increasing agent such as sulfolane is preferably added to the compound. It is preferably 1.0 to 1.3 with respect to 1 mol of the derivative.
After adding a mole of a hydroxide of an alkali metal such as NaOH or KOH and dehydrating while preferably heating at 100 to 120 ° C. to obtain a compound of formula (1) (alkali metal salt of phenol derivative), this reaction is carried out. You can also do it.

Second step, ie, production of compound of formula (3) to compound of formula (4): As an organic solvent to be used,
For example, in the case of (1), a polyethylene glycol solvent such as diethylene glycol or triethylene glycol or an aromatic solvent such as N, N-dimethylaniline, N, N diethylaniline or o-dichlorobenzene may be mentioned, preferably N, N-diethylalinine. In the case of (2), an aromatic solvent such as toluene or dichlorobenzene or a chlorinated hydrocarbon solvent such as chloroform 1,1,1-trichloroethane may be mentioned, and o-dichlorobenzene is preferable. In the case of (1), the reaction temperature is usually 150 to 250 ° C., preferably 200 to 250 ° C.
It is 220 ° C. In the case of (2), it is usually room temperature to 200 ° C, preferably 150 to 180 ° C. The catalyst is usually a silver salt such as silver trifluoroacetate, a mercury salt such as mercury chloride, a copper salt such as copper chloride, a zinc salt such as zinc chloride, and usually 0.1 to 10 mol%, preferably 0.5. Use ~ 5 mol%.

Third step, ie, production from the compound of formula (4) to the compound of formula (5): The solvent used is an organic solvent or a mixed solvent thereof with water, and the organic solvent is, for example, methanol, ethanol or the like. Examples of the alcohol solvent include ether solvents such as tetrahydrofuran and dioxane, and these solvents may be mixed and used. The reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent, preferably 20 to 50 ° C. The catalyst is usually a hydrogenation catalyst such as palladium-activated carbon or Raney nickel, and the catalyst amount is usually 0.1 to 20 wt% with respect to the substrate,
Preferably 1 to 10 wt% is used. It is also preferable to use a hydrous catalyst to prevent the risk of ignition. The reaction may be carried out under normal pressure or under pressure, but usually the reaction is carried out under normal pressure. Hydrogen gas is filled in the reaction system, but if it is blown into the reaction solution, the reaction efficiency is improved. At that time, it is preferable to make the bubbles as fine as possible.

Fourth step, ie, production of compound of formula (5) to compound of formula (7): As an organic solvent to be used,
Examples thereof include aromatic solvents such as benzene and toluene, organic chlorine solvents such as dichloromethane and carbon tetrachloride, and carbon disulfide, and organic chlorine solvents are preferable. The reaction temperature is generally -20 ° C to 50 ° C, preferably -10 ° C.
~ 25 ° C. The Lewis acid is aluminum chloride, iron chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride, zinc chloride or the like, and preferably titanium tetrachloride. The amount used is usually 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, relative to the substrate. In addition, HF, sulfuric acid, polyphosphoric acid, etc. may also be used. The usage-amount of the compound shown by Formula (6) is 1.0-5.0 equivalent normally, Preferably it is 1.0-2.0 equivalent.

Fifth step, ie, production from compound of formula (7) to compound of formula (10): As the organic solvent to be used, either water-soluble organic solvent or hydrophobic organic solvent may be used. When using a water-soluble solvent, a uniform reaction with water,
Further, when a hydrophobic organic solvent is used, a two-phase system reaction with water occurs. In some cases, the reaction efficiency may be improved by adding a phase transfer catalyst. Examples of the water-soluble organic solvent include alcohol solvents such as methanol and ethanol, nitrile solvents such as acetonitrile, ether solvents such as tetrahydrofuran and dioxane, and dioxane is preferable. In the case of homogeneous reaction, the mixing ratio of water to the water-soluble organic solvent is usually 10: 1 to 1: 1 and preferably 3: 1 to 2: 1. Examples of the hydrophobic organic solvent include organic chlorine solvents such as dichloromethane, ester solvents such as ethyl acetate, and aromatic solvents such as toluene, and dichloromethane is preferable. When a phase transfer catalyst is added, it is preferably a quaternary ammonium salt such as tetra-n-butylammonium bromide. The reaction temperature is usually from 0 ° C to the boiling point of the solvent, preferably from 20 ° C to
It is 70 ° C. The amount of the compound represented by the formula (8) used is usually 3.0 to 6.0 equivalents, preferably 3.0.
~ 3.5 equivalents. The amount of the compound represented by the formula (9) used is usually 3.0 to 6.0 equivalents, preferably 3.0 to 4.0 equivalents.

Sixth step, ie, a method for producing the compound of formula (11) from the compound of formula (10): An aromatic hydrocarbon such as toluene or xylene is used as the organic solvent to be used, but in some cases, nitromethane Nitro compounds such as nitrobenzene, carbon disulfide, and organic chlorine solvents such as dichloromethane may be used. Toluene is preferred. Examples of the Lewis acid include aluminum chloride, iron chloride, titanium tetrachloride and the like, and aluminum chloride is preferable. The amount of Lewis acid used is usually 1.0 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents. The reaction temperature is usually from 0 ° C to the boiling point of the solvent, preferably from 0 to 25 ° C. Formulas (1) to (6) of the present invention
In the above, R ¹ is, for example, a methyl, ethyl group, chlorine, bromine or iodine atom, and R ² is, for example, a tert-butyl, 1,1,2-trimethylpropyl or 1,1-dimethylpropyl group. , R ³ , R
Examples of ⁴ and R ⁵ include hydrogen atom and methyl group, and examples of X and X ′ include chlorine, bromine and iodine atoms,
_{-OSO 2 CH 3, -OSO 2 C} 2 H 5 or -OSO ₂
C ₆ H ₄ CH ₃ groups can be mentioned, and M can be, but is not limited to, Li, Na or Ka atoms.

Examples of preferred compounds of the formula (1) in the present invention include 2-t-butyl-5-methylphenol, and examples of compounds of the formula (3) include 2-t-butyl-5-methyl. Phenyl propargyl ether can be mentioned. An example of the compound of the formula (4) is 8-t-butyl-5-methyl-2H-chromene. An example of a compound of the formula (5) is 8-t-butyl-5-methyl. Examples of compounds of formula (7) include chroman and 6-acetyl-8-t-butyl-5-methylchroman. Examples of compounds of formula (10) include 8-t-butyl-5-methylchroman- 6-carboxylic acid may be mentioned, and as an example of the compound of the formula (11), 5-methylchroman-6
-Carboxylic acids.

[0027]

INDUSTRIAL APPLICABILITY According to the present invention, an intermediate, which is a raw material of a hydrazine derivative having a high insecticidal activity, can be produced with high purity.

[0028]

EXAMPLES The present invention will be described below with reference to examples. Example 1 Preparation of 2-t-butyl-5-methylphenylpropargyl ether: 2-t-butyl-5-methylphenol (300 g, 1.83 mol) was dissolved in 1.5 l of toluene and sulfolane 18 was added as a salt increasing agent. .3 ml was added. The reaction solution is heated to about 100 ° C., and potassium hydroxide (95
%, 130 g, 2.2 mol) were added in 10 batches under vigorous reflux. After the theoretical amount of dehydration was completed, the reaction solution was cooled to 25 ° C. and 360 l of N, N-dimethylformamide was added. Further, while keeping the temperature at 25 ° C, propargyl bromide (146 ml, 1.9 m
ol) was slowly added dropwise and the mixture was stirred for 30 minutes to complete the reaction. To the reaction solution, 500 ml of toluene was added, transferred to a separating funnel, washed with water and brine, and then the toluene layer was dried with sodium sulfate. After filtration and evaporation of the solvent, the target product (367
g, 94% GC purity) was obtained as a brown oil. ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm): 1.00 (S. 9H), 2.35 (S. 3H) 2.55 (t. J = 2.4Hz, 1H) 4.76 (d, J = 2.4Hz, 2H) 6.75 (d, J = 8.0Hz, 1H) 6.88 (S, 1H) 7.22 (d, J = 8.0Hz, 1H)

Example 2 Preparation of 8-t-butyl-5-methyl-2H-chromene:
2-t-Butyl-5-methylphenylpropargyl ether (367 g, 1.82 mol) was dissolved in 900 ml of N, N-diethylaniline, and the mixture was heated with stirring in an oil bath at 220 ° C for 2 hours. After confirming the disappearance of the raw material peaks by GC, the reaction solution was cooled, ethyl acetate (1.5 l) was added, the mixture was transferred to a separating funnel, and N, N was added with a 10% aqueous hydrochloric acid solution (1 l x 2).
N-diethylaniline was removed from the organic layer. After further washing the organic layer with water and brine until neutral,
Glauber's salt dried. The desired product (36
3 g, GC purity 93.7%) was obtained as a brown oil. ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm): 1.35 (S, 9H) 2.25 (S, 3H) 4.65 (dd, 2H, J = 1.6Hz, 4.0Hz) 5.86 (dt, 1H, J = 4.0 Hz, 9.9Hz) 6.62 (dt, 1H, J = 1.6Hz, 9.9Hz) 6.67 (d, 1H, J = 8.2Hz) 7.03 (d, 1H, J = 8.2Hz)

(Alternative method) 2-t-butyl-5-methylphenylpropargyl ether (2.0 g, 10 mmol) was dissolved in o-dichlorobenzene, and copper bromide (2
0 mg, about 1 wt%) was added and heated at 180 ° C. for 10 hours. The end point of the reaction was confirmed by GC, and the reaction solution was cooled. Toluene was added to the reaction solution, washed twice with brine,
Glauber's salt dried. After filtration, toluene and o-dichlorobenzene were removed by distillation under reduced pressure to obtain the desired product (1.8 g GC purity).
90.1%) was obtained as a brown oil.

Example 3 Preparation of 8-t-butyl-5-methylchroman: 8-t-
Butyl-5-methyl-2H-chromene (336 g, 1.
66 mol) was dissolved in 1.1 l of methanol, and 1,4-
120 ml of dioxane was added. To this, 74 g of 10% palladium-activated carbon catalyst (50% hydrous product) was added to methanol 1
Suspended in 00 ml and added slowly. Reaction mixture 5
After heating to 0 ° C. and blowing hydrogen gas into the system in an amount of (1 l / min), the catalyst was removed by filtration, the solvent was distilled off, and a pale yellow oil was obtained. . This oil contains some water, so 1 liter of n-hexane
, Magnesium sulfate was added for dehydration, filtration, and removal of the solvent by distillation to obtain the desired product (330 g, GC purity 97.3).
%) As a yellow oil. If the raw material contains Harz, it can be cleaned up by adding silica gel (300mesh, about 200g) when dissolving it in n-hexane in the post-treatment, leaving it as it is overnight, and filtering. . ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm): 1.35 (S, 9H) 2.00 (m, 9H) 2.15 (S, 3H) 2.63 (t, 2H, J = 6.6Hz) 4.11 (t, 2H, J = 6.6Hz) 6.65 (d, 1H, J = 7.9Hz) 7.01 (d, 1H, J = 7.9Hz)

Example 4 Preparation of 6-acetyl-8-t-butyl-5-methylchroman: A solution of titanium tetrachloride (177 ml, 1.62 mol) in carbon tetrachloride (750 ml) was cooled with ice and acetyl chloride (115 ml). , 1.62 mol) was added dropwise to about 1
Stir for 5 minutes. Under ice cooling, 8-t-butyl-6-methylchroman (300 g, 1.47 mol) was added thereto.
Carbon tetrachloride (100 ml) solution of was added dropwise while maintaining the temperature at 10 ° C or lower, and the mixture was stirred at that temperature for 30 minutes. The reaction solution was poured into diluted hydrochloric acid and stirred for a while to quench titanium tetrachloride. The solution was transferred to a separating funnel, dichloromethane (1 l) was added, and the mixture was extracted. The organic layer was further washed with water and brine, and dried with mirabilite. After filtration and evaporation of the solvent, the target product (359 g, GC purity 97.5%) was obtained as white crystals. ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm): 1.37 (S, 9H) 2.03 (m. 2H) 2.34 (S. 3H) 2.54 (S, 3H) 2.69 (t, 2H, J = 6.6Hz) 4.17 (t, 2H, J = 5.3Hz) 7.46 (S, 1H)

Example 5 Preparation of 8-t-butyl-5-methylchroman-6-carboxylic acid: Sodium hydroxide (552g, 13.1mo)
Bromine (244 ml, 4.57 mol) was added dropwise to a solution prepared by dissolving l) in water (1.45 l) under ice-cooling, and the mixture was stirred for 30 minutes as it was. After returning the reaction solution to room temperature and adding 1,4-dioxane (300 ml),
A solution of 6-acetyl-8-t-butyl-5-methylchroman (359 g, 1.45 mol) in 1,4-dioxane (300 ml) was added dropwise little by little. When the reaction solution was slightly warmed in a warm bath, it gradually generated heat and reached 80 ° C. After that, when the liquid temperature drops, the reaction is stopped, dioxane is concentrated, and the solution is transferred to a separating funnel together with toluene.
Unreacted impurities were extracted into the toluene layer. When the aqueous layer was neutralized with hydrochloric acid, crude benzoic acid crystals were precipitated. This was separated by filtration, the crystals were thoroughly washed with water and hexane, and air-dried. The desired product was obtained as white crystals (330 g, HPLC purity 95%). ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm): 1.37 (S, 9H) 2.05 (m. 2H) 2.50 (S. 3H) 2.72 (t, 2H, J = 6.6Hz) 4.19 (t, 2H, J = 5.3Hz) 7.88 (S, 1H) 11.0 (bs, 1H)

(Alternative method) hypochlorous acid aqueous solution (effective chlorine 12
%, 26.0 g, 4 equivalents) and 50% aqueous sodium hydroxide solution (3.36 g, 4 equivalents) were mixed, and 6-acetyl-
8-t-butyl-5-methylchroman (2 g, 0.01
A solution of 05 mol) of 1,4-dioxane (5 ml) was added dropwise at room temperature. This is stirred for 30 minutes and then triethylbenzylammonium chloride (TEBAC, 2
00 mg) was added. The reaction solution was stirred at 60 ° C for 2 hours,
After cooling, it was poured into water. 50 ml of ether was added to extract impurities. When hydrochloric acid was added to the aqueous layer, crude crystals of benzoic acid were precipitated. This was filtered, and the crystals were washed with water and n-hexane and air dried to obtain the desired product (1.52 g, HPLC).
Purity 99%) was obtained as white crystals.

Example 8 Preparation of 5-methylchroman-6-carboxylic acid: Aluminum chloride (213 g, 1.6 mol) was added to toluene (1.
3 l) and suspended under ice cooling, 8-t-butyl-5-methylchroman-6-carboxylic acid (330 g, 1.33 m)
ol) was added little by little while paying attention to the temperature rise. The reaction solution turned brown. The mixture was stirred as it was for 2 hours, and after confirming the disappearance of the raw materials, 5% hydrochloric acid (700 ml) was added to the reaction solution.
While paying attention to heat generation, the mixture was added dropwise under ice cooling. The resulting slurry was dissolved in ethyl acetate, the separated aqueous layer was removed, 5% aqueous sodium hydroxide solution was added to the ethyl acetate layer, and the carboxylic acid was back-extracted into the aqueous layer. The aqueous layer was subjected to acid precipitation with hydrochloric acid under ice cooling, and the crystals were filtered off and dried under reduced pressure to give the desired product (198 g, purity 99.0% -HPLC area ratio, Y: 7)
7.5%) was obtained as white crystals. ¹ H-NMR (90MHz, CDCl ₃ ) δ (ppm) 2.00 (m, 2H) 2.49 (S, 3H) 2.69 (t, 2H, J = 6.6Hz) 4.14 (t, 2H, J = 5.3Hz) 6.65 (D, 1H, J = 8.5 Hz) 7.63 (d, 1H, J = 8.5 Hz) 9.43 (bs, 1H)

─────────────────────────────────────────────────── ─── Continuation of front page (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 311/58 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The formula: (Wherein R ¹ represents a C _{1 to} C ₂ alkyl group or a halogen atom, R ² represents a C _{4 to} C ₆ tertiary alkyl group, and M represents an alkali metal atom). Formula in a solvent (Wherein R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom or a methyl group, and X is a halogen atom or OS.
An O ₂ R ⁶ group, wherein R ⁶ represents a lower alkyl group or a phenyl group which may be substituted with a lower alkyl group). (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and then the compound is prepared in the presence or absence of (1) an organic solvent. The rearrangement reaction is carried out at a high temperature below or in the presence of (2) an organic solvent and a Lewis acid catalyst. (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and the compound is then added to a solvent in a hydrogen atmosphere in the presence of a hydrogenation catalyst. Catalytic hydrogenation (reduction) reaction is performed under the following formula: (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and the compound is then added to an organic solvent in the presence of a Lewis acid to form a compound of formula CH ₃ COX '(6) by reacting with a compound represented by the formula (X' represents a halogen atom); (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and the compound is then added to water or a mixed solvent of water and an organic solvent to give a compound of the formula A compound of the formula X'2 (8) (wherein X'represents the same as above), or a compound of the formula MOX '(9) (wherein M and X'represent the same as above) Reaction with a compound in the presence of an alkali (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above), and finally the compound is reacted with a Lewis acid in an organic solvent. 8] A process for producing chromancarboxylic acid, which comprises producing a compound represented by the formula (wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as above). 2. The method according to claim 1, wherein R ¹ is a methyl group, R ² is a t-butyl group, and R ³ , R ⁴ and R ⁵ are each a hydrogen atom.