JP3258043B2 - Method for producing benzoate derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing a novel benzoate derivative. More specifically, the present invention relates to a method for producing a benzoate derivative useful as a synthetic intermediate for agricultural chemicals, pharmaceuticals, and the like with a high yield.

[0002]

[Prior Art] General formula

Embedded image (Wherein R ₁ is a protecting group for a hydrogen atom or a hydroxyl group,
R ₂ , R ₃ and R ₄ are each a lower alkyl group, which may be the same or different.) The benzoate derivative represented by the formula (1) is useful as a synthetic intermediate for agricultural chemicals and pharmaceuticals, For example, a compound having a herbicidal activity previously found by the present inventors (Japanese Patent Laid-Open No. 4-140773).
JP-A No. 195/1992).

In general, when a butyllithium lithiation agent is reacted with a monosubstituted benzene having an unpaired electron such as oxygen or nitrogen in the substituent, the ortho position of the substituent is lithiated, and the electrophilic reagent It has been known for a long time that ortho derivatives can be obtained by the action of the compound [Chemistry, Vol. 45, p. 144 (1990).
Year); "Organic Reaction"
Reaction), Vol. 26, page 1 (197
9)). In this case, ether solvents such as ether and tetrahydrofuran are usually used as a reaction solvent, but when a hydrocarbon solvent such as hexane is used, a chelating agent for lithium ions such as tetramethylethylenediamine is required. Is also known.

Based on these findings, the present inventors have proposed a method for producing a benzoate derivative represented by the aforementioned general formula (I) in an ether-based solvent.

Embedded image (Wherein R ₁ , R ₃ and R ₄ have the same meanings as described above), butyllithium and a general formula XCOOR ₂ (III) (wherein X is a halogen atom and R ₂ is Have the same meaning as described above), but surprisingly, almost no benzoic acid derivative represented by the general formula (I) was formed.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel method for producing a benzoate derivative represented by the above general formula (I), which is useful as an intermediate for the synthesis of agricultural chemicals or pharmaceuticals, in a high yield. It was done for the purpose of doing.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, unexpectedly, an aliphatic or aromatic hydrocarbon was used as a solvent, and It has been found that a desired benzoate derivative can be obtained in good yield by sequentially reacting an alkyl lithium and a haloformate with the acetal derivative represented by the formula, and the present invention has been completed based on this finding.

That is, the present invention relates to a compound represented by the general formula (1) in the presence of an aliphatic or aromatic hydrocarbon solvent:

Embedded image (Wherein R ₁ , R ₃ and R ₄ have the same meaning as described above), alkyl lithium and general formula XCOOR ₂ (III) (wherein X and R ₂ have the same meanings as above) Wherein the haloformate represented by the general formula is sequentially reacted:

Embedded image (Wherein R ₁ , R ₂ , R _3, and R ₄ have the same meanings as described above).

[0008] In general formulas (I) and (II), R
₁ is a protecting group for a hydrogen atom or a hydroxyl group. The protecting group can be arbitrarily selected from those known as hydroxyl group protecting groups, and is not particularly limited.
Groups commonly used as protecting groups for hydroxyl groups include, for example, methyl, benzyl, substituted benzyl, methoxymethyl, ethoxyethyl, tert-
And a butyldimethylsilyl group.

Examples of the acetal derivative represented by the general formula (II) include 3-benzyloxyacetophenone dimethyl acetal, 3-benzyloxyacetophenone diethyl acetal, and 3-methoxymethoxyacetophenone dimethyl acetal. These acetal derivatives can be easily obtained by reacting the corresponding acetophenone derivative with an orthoformate.

According to the method of the present invention, the acetal derivative is reacted with an alkyl lithium and a haloformate represented by the general formula (III) sequentially in an aliphatic or aromatic hydrocarbon solvent, thereby obtaining the compound represented by the general formula (I) The benzoate derivative represented by the formula (1) is obtained in high yield and high selectivity.

The alkyllithium includes, for example, methyllithium, butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, and the like, and the haloformate includes, for example, methyl chloroformate, ethyl chloroformate, bromoformate. Methyl and the like. Further, examples of the aliphatic hydrocarbon used as the reaction solvent include hexane, cyclohexane, heptane and the like, and examples of the aromatic hydrocarbon include benzene and toluene. These solvents may be used alone or in combination of two or more.

Next, an example of a preferred embodiment of the present invention will be described. First, the acetal derivative and alkyllithium are added to the above-mentioned solvent at a normal equivalence ratio of 1: 1 to 1: 2. After stirring for about several hours in the vicinity, haloformate was added thereto at a ratio such that the equivalent ratio to the acetal derivative was about 1 to 2,
The reaction is carried out at a temperature in the range from 10 to 50C. After completion of the reaction, excess alkyllithium is inactivated using water or the like, and then operations such as extraction, washing, and solvent distillation are performed to isolate a high-purity benzoate derivative.

The benzoate derivative of the present invention thus obtained can easily remove an acetal group by the action of a weak acid.

[0014]

The benzoate derivative obtained by the method of the present invention is useful as a synthetic intermediate for agrochemicals and pharmaceuticals, for example, a herbicidally active compound previously discovered by the present inventors (JP-A-4-134073). Official Gazette).

According to the present invention, the benzoate derivative can be easily produced with high yield and high selectivity.

[0016]

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

Example 1 Production of 3-benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal In a nitrogen stream, 8.16 g (30 mmol) of 3-benzyloxyacetophenone dimethyl acetal was added to toluene 8
0 ml, and n-butyllithium 1 at 0-5 ° C.
21 ml of a 5 wt% hexane solution (n-butyl lithium 3
3 mmol) was added dropwise. After stirring at 20 ° C. for 2 hours, the reaction solution was recooled, and methyl chloroformate was 3.12 g.
(33 mmol) was added dropwise at 5-10 ° C. After stirring at 20 ° C. for 2 hours, 10 ml of ethyl acetate was added, and then the reaction solution was washed with water, and the solvent was distilled off to obtain 10.0 g of an oily substance.
I got

The oil was analyzed by gas chromatography to find that
-Benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal is produced in a yield of 73 mol%,
It was found that 16 mol% of unreacted raw materials remained.
Next, this oil was purified by column chromatography to obtain 3.0 g of an analytical sample of 3-benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal.

The infrared absorption spectrum, N
When the MR spectrum and the refractive index at 20 ° C. were determined, the following results were obtained. IR (neat): 1730, 1580, 1440, 1
260 cm ^-1 NMR (CDCl ₃ ): δ 1.6 (s, 3H), 3.2
(S, 6h), 3.8 (s, 3H), 5.1 (s, 2
H), 6.7~7.6 (m, 8H ) n D 20: 1.5413

Example 2 Preparation of 3-benzyloxy-2-methoxycarbonylacetophenone dimethyl acetal The reaction was carried out in the same manner as in Example 1 except that n-hexane was used as a solvent instead of toluene. The product was analyzed by gas chromatography and found to be 3-benzyloxy-2.
-Methoxycarbonylacetophenone dimethyl acetal was produced in a yield of 60 mol%, and the raw material remained at 24 mol%.

Example 3 Preparation of 3-Berdyloxy-2-methoxycarbonylacetophenone dimethyl acetal The reaction was carried out in the same manner as in Example 1 except that cyclohexane was used as a solvent instead of toluene.
The product was analyzed by gas chromatography. As a result, 3-belzyloxy-2-methoxycarbonylacetophenone dimethyl acetal was produced in a yield of 83 mol%, and 6 mol% of the raw material remained.

Example 4 Preparation of 3-hydroxy-2-methoxycarbonylacetophenone dimethyl acetal In a 50 ml four-necked reaction flask, 3-verzyloxy-
1.0 g (3.0 mmol) of 2-methoxycarbonylacetophenone dimethyl acetal, 0.1 g of 5 wt% palladium-carbon, 5 ml of methanol and 1 ml of toluene
And subjected to catalytic hydrogenation treatment at room temperature. After 8 hours, the palladium-carbon was filtered off, and the solvent was distilled off to obtain 0.5 g of an oil. The oil was analyzed by ¹ H-NMR to find that the composition of 3-hydroxy-2-methoxycarbonylacetophenone dimethyl acetal was 67 mol% and the deacetalized 3-hydroxy-2-methoxycarbonyl acetophenone was 33 mol%. there were.

A small amount of an analytical sample of 3-hydroxy-2-methoxycarbonylacetophenone dimethyl acetal was obtained and analyzed. The following data was obtained. IR (neat): 1710, 1590, 1470, 1
_{^{440,1300cm -1 NMR (CDC1 3):}} δ1.7 (s, 3H), 3.2
(S, 6H), 3.9 (s, 3H), 6.5-7.7.
^{_{(M, 4H) n D 20}} : 1.5150

Comparative Example A reaction was carried out in the same manner as in Example 1 except that diethyl ether was used instead of toluene as a solvent, and gas chromatographic analysis showed that 3-benzyloxy-2.
Only 2 mol% of -methoxycarbonylacetophenone dimethyl acetal was formed.

Example 5 Preparation of 3-benzyloxy-2-ethoxycarbonylacetophenone diethyl acetal Under a nitrogen stream, 9.0 g (30 mmol) of 3-benzyloxyacetophenone diethyl acetal was dissolved in 60 ml of cyclohexane, and the solution was dissolved at 0 to 5 ° C. Then, 21 ml of a 15 wt% hexane solution of n-butyllithium (33 mmol of n-butyllithium) was added dropwise. After stirring at 20 ° C. for 2 hours, the reaction solution was recooled, and ethyl chloroformate 3.58 was obtained.
g (33 mmol) were added dropwise at 5-10 ° C. 20 ° C
After stirring for 2 hours, add 10 ml of ethyl acetate,
Then, the reaction solution was washed with water and the solvent was distilled off to obtain an oily substance 11.0.
g was obtained.

The oily substance was analyzed by gas chromatography to find that
-Berdyloxy-2-ethoxycarbonylacetophenone diethyl acetal is produced in a yield of 73 mol%,
It was found that 15 mol% of unreacted raw materials remained.
Next, this oily product was purified by column chromatography to obtain 6.8 g of 3-verdyloxy-2-ethoxycarbonylacetophenone diethyl acetal. The yield was 61 mol%. The analytical data of this is shown below. IR (neat): 1720, 1580, 1440, 1
260, 1050 cm ^-1 NMR (CDCl ₃ ): δ 1.2 (t, J = 7 Hz, 6
H), 1.3 (t, J = 7 Hz, 3H), 1.6 (s,
3H), 3.5 (q, J = 7 Hz, 4H), 4.3
(Q, J = 7 Hz, 2H), 5.0 (s, 2H), 6.
_{7~7.5 (m, 8H) n D} 20: 1.5288

Example 6 Preparation of 3-hydroxy-2-ethoxycarbonylacetophenone diethyl acetal In a 50 ml four-necked reaction flask, 3-verzyloxy-
2-ethoxycarbonylacetophenone diethyl acetal 3.0 g (8.0 mmol), 5 wt% palladium-carbon 0.3 g, methanol 20 ml and toluene 2 m
and subjected to catalytic hydrogenation treatment at room temperature. After 8 hours, the palladium-carbon was filtered off, and the solvent was distilled off to obtain 1.7 g of crystals.

The crystals were analyzed by ¹ H-NMR. As a result, 83 mol% of 3-hydroxy-2-ethoxycarbonylacetophenone diethyl acetal and 17 mol% of deacetalized 3-hydroxy-2-ethoxycarbonylacetophenone were obtained. It was a composition.

The crystals were recrystallized from 15 ml of hexane to obtain 0.5 g of 3-hydroxy-2-ethoxycarbonylacetophenone diethyl acetal as an analytical sample. Its melting point was 71-74 ° C. The analysis data is shown below. IR (KBr): 1700, 1580, 1460, 12
90,1260 cm ^-1 NMR (CDCl ₃ ): δ 1.0 to 1.5 (m, 9
H), 1.7 (s, 3H), 3.4 (q, J = 7 Hz,
4H), 4.4 (q, J = 7 Hz, 2H), 6.8-
7.4 (m, 4H)

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshikazu Kimura 2256 Nakanosato, Fujikawa-cho, Anbara-gun, Shizuoka Pref. Ihara Chemical Industry Co., Ltd. (56) References JP-A-4-368361 (JP, A) JP-A Heisei 4-134080 (JP, A) JP-A-4-1344073 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 69/84 C07C 67/36 C07C 69/92 CA (STN ) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) In the presence of an aliphatic or aromatic hydrocarbon solvent, a compound represented by the general formula: (Wherein R ₁ is a protecting group for a hydrogen atom or a hydroxyl group,
R ₃ and R ₄ are each a lower alkyl group, which may be the same or different from each other. An alkyl lithium and a general formula XCOOR ₂ (where X is a halogen atom, R ₂ is a lower alkyl group), characterized by sequentially reacting a haloformate represented by the following general formula: (Wherein R ₁ , R ₂ , R ₃ and R ₄ have the same meaning as described above).