JPS63145251A - Production of beta-substituted atropic acid - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a raw material for producing medicines and agricultural chemicals in good yield by simple reaction operation, by reacting a beta-substituted atropic acid amide with an alkali nitrite in an acidic solvent. CONSTITUTION:beta-Substituted atropic acid amides expressed by formula I (R1 is 1-4C lower alkyl; R2 is H or 1-4C lower alkyl or R1 and R2 may link to form a carbocyclic ring; R3 is H, halogen or 1-4C lower alkyl; Ph is phenylene) are reacted with an alkali nitrite in an acidic solvent, e.g. acetic acid-sulfuric acid, etc., at 10-50 deg.C. The reaction is carried out by using the alkali nitrite in a molar amount of 1-2 times based on the amides expressed by formula I and the solvent in an amount of 10-50 times based on the amides expressed by formula I to afford the aimed substance expressed by formula II.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing β-substituted atropic acids.

Conventionally, 2-aryl-substituted alkene nitriles such as 3-methyl-2-→→--→-2-butenenitrile have been known, and these nitriles can be converted into the corresponding amides to obtain It has been described in the literature that amides (β-substituted atropic acid-resistant amides) can be converted into the corresponding carboxylic acids (β-substituted atropic acids) by known methods (for example, Japanese Patent Application Laid-Open No. 53-23947).

[Problems to be Solved by the Invention] The present inventors hydrolyzed a β-substituted atropic acid into a β-substituted atropic acid by a conventional method using an acid-resistant amic acid or an alkali under various conditions. However, it was found that the β-substituted atropybutyric acid amide either did not react at all or the double bond was cleaved, making it extremely difficult to obtain the desired carboxylic acid.

[Means for Solving the Invention] As a result of various studies, the present inventors have discovered that β-substituted atrobittaic acid can be converted into β-substituted atrobittaic acid in good yield by reacting it with β-substituted atrobitbutyric acid amide nitrous acid. Heading, we arrived at the present invention. That is, the present invention relates to the general formula, R3-Ph-C-CONH2(1) (wherein, R1 represents a lower alkyl group having 1 to 4 carbon atoms, and R2 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. and R1 and R2 may be combined to form a carbon ring. R3 represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 4 carbon atoms. Ph represents a phenylene group.) The β-substituted atropybutyric acid amide shown in the formula (2) is characterized by reacting with an alkali nitrite salt in an acidic solvent. It has the same meaning as in case.] is required in the 'tA production method of β-substituted atropic acids.

In general formulas (1) and (2), R1, R2 and R
Examples of the lower alkyl group having 1 to 4 carbon atoms in 3 include a methyl group, an ethyl group, and an isopropyl group.

R1 and R2 may be combined to form an alkylene group -+CH2 → carbon dioxide (n is usually 4 to 6) and form a carbocyclic ring together with a carbon atom; examples of this ring include a cyclopentane ring and a cyclohexane ring. It will be done.

Of R1 and R2, a methyl group is preferred.

The β-substituted atropybutyric acid amide represented by the general formula (1) can be easily obtained by hydrolyzing the corresponding nitrile by a known method.

As the acidic solvent used in the reaction, acetic acid, sulfuric acid, and a mixed acid thereof are usually used, and a mixed acid of acetic acid and sulfuric acid is particularly suitable.

In the present invention, commercially available sodium nitrite or potassium nitrite can be used as the alkali nitrite salt.

The amount of alkali nitrite used is usually 1 to 2 times the amount of the amides on a molar basis, but preferably 1.
1 to 1.5 times older.

The amount of the solvent used is usually 10 to 50 times the amount of the amide represented by the general formula (1) on a weight basis. If the amount is less than 1 o (= amount), the viscosity of the reaction liquid will be high, making it difficult to stir during the reaction, making the reaction non-uniform and reducing the yield.
If the amount is more than 0 times, it will be inefficient in terms of productivity, and post-processing will also be a problem.

The reaction is generally carried out by dissolving the β-substituted atropic tamide in an acidic solvent, and adding an alkali nitrite salt with a small amount of water (the amount of water added is 1 to 10 (8 f
This is done by dissolving the solution in <fi> and adding it little by little.

The reaction temperature ranges from 10 to 50'C, especially from 15 to 50'C.
30°C is preferred. If the reaction temperature is less than io'c, stirring becomes difficult, although it depends on the amount of the reaction solvent, and if it is higher than 50°C, reaction heat and nitrogen gas are generated intensely, making reaction control difficult. The reaction time can be arbitrarily changed depending on the reaction temperature. When the alkaline nitrite aqueous solution is added, the reaction proceeds immediately, generating reaction heat and nitrogen gas. Therefore, the alkaline nitrite aqueous solution is added dropwise while controlling the reaction temperature. For example, when the reaction is carried out at 20 to 25°C, the reaction time is usually 30 minutes to 2 hours.

The progress of the reaction can be confirmed by checking the reactants using a gas chromatograph.

The β-substituted atropic acids obtained by the method of the present invention exhibit physiological activity and are useful as raw materials for pharmaceuticals and agricultural chemicals.

[Example] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 Process for producing β,β-dimethylatropic acid 26g of β,β-dimethylatropic acid amide was dissolved in 220ml of acetic acid and 50d of concentrated sulfuric acid, and 14g of sodium nitrite was added to 50ml of water while stirring in an IO'C. and warmed little by little. Nitrogen gas was generated along with the reaction heat. Gentle,
The reaction solution was kept at 20±5°C. After warming, the mixture was stirred at room temperature for 1 hour and poured into ice water to produce a colorless precipitate. I rinsed my mouth with water. Yield was 21 g (80%). When recrystallized from methanol-water, the melting point was 151-152°C.

Elemental analysis value <C11"1202) Calculated value: C
,74,98: H,8,88 Measured value: C,74
,91; H,6,80 cough magnetic resonance absorption (CD(13
, δppm >1.69.2.21 (6H,S,
CH3) 6.97-7.50 (5H, m, 0H
)11.35 (1H,s,C00H) Example 2 Process for producing p-chloro-β,β-dimethylatropic acid p-chloro-β,β-dimethylatropic acid amide 2
Dissolve 09 in acetic acid 40 (7) and sulfuric acid 200m,
Add 10g of sodium nitrite to 50% of water with stirring at °C.
He melted into power and became gentle. The temperature of the contents rose to 25° C. while generating nitrogen gas. 20-2
The temperature was maintained at 5°C. It took a gentle 15 minutes.

The mixture was stirred for 1 hour, added to ice water, and the precipitate was washed with water.

18 g of p-chloro-β,β-dimethylatropic acid was obtained. Methanol-melting point 147-1 when recrystallized from water
It was 48°C.

Elemental analysis value (as C11H11o2C!!) Calculated value:
C, 62, 72: H, 5, 2 et al. Measured value: C
,62,80: H,5,22 nuclear magnetic resonance absorption (CC
1g, δppm >1.73. 2.25 (6H,
s, CH3) 6.85-7.50 (4H, m,
0H) 12.44 (IH, s, COO171>Example 3 Method for producing 0-chloro-β,β-dimethylatropic acid 0-chloro-β,β-dimethylatropic acidiamide 109 acid 100d and sulfuric acid 50d Melt, 15°
Add sodium nitrite 59 to 15 ml of water while stirring at C.
It was dissolved in a mild manner. The temperature was maintained at 15-25°C. It took a gentle 15 minutes. After warming, the mixture was stirred for 2 hours, poured into ice water, and the resulting precipitate was rinsed with water and air-dried. Melting point 1
8.6 g of 0-chloro-β,β-dimethylatropic acid having a temperature of 40 to 141°C was obtained.

Methanol-melting point 142-143° when recrystallized from water
It was C.

Elemental analysis value (as C11H1102C1) Calculated value:
C, 62, 72: H, 5, 26 measurement value: C,
62,59; H,5,32 nuclear magnetic resonance absorption (CC1
4, δppm) 1.65. 2.29 (6H,s
, CH3) 8.90 ~ 7.57 (4H, m
, Qt1 )12.21 (11-(,S,
C00H) [Advantageous Effects of the Invention 1 The method of the present invention has a simple reaction operation and a high yield.

Therefore, it has become possible to industrially produce 3-substituted atropic acids, which have been difficult to synthesize in the past.

These effects can be obtained by reacting β-substituted atropic sulfur amides with alkali nitrite in an acidic solvent.
This is something that cannot be obtained using conventional methods.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) (In the formula, R_1 represents a lower alkyl group having 1 to 4 carbon atoms, and R_2 represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms. 4 represents a lower alkyl group, and R_1 and R_2 may be combined to form a carbon ring. R_3 represents a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 4 carbon atoms. Ph represents a phenylene group There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼(2) (formula wherein R_1, R_2 and R_3 have the same meanings as in general formula (1).] A method for producing a β-substituted atropic acid.