JPH058702B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing 2-alkylindoles from acyl-O-toluidine and sodium toluide.

2-Methylindole is a compound useful as a pressure-sensitive dye intermediate, and other 2-alkylindoles are useful as raw materials for various organic synthesis intermediates.

BACKGROUND TECHNIQUES Conventionally proposed methods for producing 2-alkylindoles include, for example, a method for synthesizing 2-methylindole by heating a mixture of acetyl-O-toluidine and sodium amide in ether. Are known. ("New Experimental Chemistry Course"
Vo. 14P1964) USP 2006713 also states that in the presence of an inert solvent such as diethylaniline, acetyl-O-
A method is described in which a mixture of toluidine and sodium metal is obtained by heating, preferably in the presence of a catalyst of copper powder.

Problems to be Solved by the Invention In the method based on the reaction of acetyl-O-toluidine and sodium amide as described in the above-mentioned "New Experimental Chemistry Course", both of these raw materials are solid at room temperature, Due to insufficient mixing during raw material preparation and during reaction, as the heating ring-closing reaction progresses, the system becomes heterogeneous and solidifies, making stirring difficult even if a solvent such as ether is present in the system. It has drawbacks such as the inability to maintain a uniform temperature due to the accompanying solid phase reaction, unreacted sodium amide remaining, and the need to remove metallic sodium by adding alcohol or the like after the reaction is complete.

Also, as in the method described in USP, acetyl-O
- When metallic sodium is directly added to an inert solvent in which toluidine is dissolved and a ring-closing reaction is carried out by heating, a heterogeneous reaction between a solid phase and a liquid phase is inevitable, and it is necessary to add metallic sodium to improve the yield. It is necessary to use a 2 to 3 times molar excess relative to acetyl-O-toluidine. Therefore, unreacted sodium metal remains in the reaction product, and it is necessary to remove the metal sodium by adding alcohol or the like as in the above cited example.

Means for Solving the Problems The present inventors have developed an acyl-O-toluidine solution that does not contain sodium in the reaction product after the completion of the thermal ring-closing reaction, and that the reaction is carried out in a homogeneous system under mild conditions. We have conducted intensive studies on methods for producing 2-alkylindoles and have solved the problems of known methods.

That is, the present invention synthesizes sodium toluid by subjecting sodium metal to a heating reaction in the presence of an excess amount of O-toluidine, and adds solid or molten acyl-O-toluidine to an O-toluidine solution containing the same. This method is characterized by adding and further heating to perform a ring-closing reaction.

The reaction formula of the method of the present invention is as follows.

In the reaction of the present invention (1), the reaction is usually carried out in an excess amount of O-toluidine, about twice the molar amount of sodium metal, so that the added metal sodium reacts completely and the resulting sodium toluidine reacts completely. The id is completely dissolved in O-toluidine. By adding acyl-O-toluidine to this, in reaction (2), the ring-closing reaction is carried out in the presence of O-toluidine liberated by the reaction, so the system becomes viscous as the reaction progresses. The reaction can be carried out while maintaining a uniform liquid phase state, and the temperature can be easily kept constant.

Acyl-O-toluidine used in the method of the present invention can be easily obtained by a known method. That is, O-
If toluidine is reacted dropwise with an equimolar amount of a lower fatty anhydride such as acetic anhydride, propionic anhydride, or butyric anhydride, the corresponding acylated product can be obtained.

Moreover, the synthesis reaction of sodium toluide of the present invention and the subsequent ring-closing reaction performed by adding acyl-O-toluidine are carried out as follows.

A mixed solution of O-toluidine in an amount of about 1.5 to 2 moles, preferably 1.6 to 1.8 moles, of sodium metal and ferric oxide added in a small amount as a catalyst is heated to 100 to 200°C, preferably 170 to 200°C. The mixture is heated to 0.degree. C., solid or liquid sodium metal is added in portions under stirring in a nitrogen stream, and the mixture is allowed to react for several hours. After confirming that the metallic sodium has dissolved, acyl-O-toluidine is added to the dissolved sodium toluide by about 0.5 times the mole, preferably in a molten state.
Raise the temperature to a reaction temperature of 240-350℃, preferably 240-350℃
The ring-closing reaction is carried out at 290°C for 0.5 to 20 hours, usually 1 to 5 hours. The reaction time depends on the type of raw materials and reaction temperature.

O-toluidine is always present in the system as a solvent during the ring-closing reaction, including the excess amount at the time of charging and the reaction product liberated during the ring-closing reaction, but at the end of the reaction, about 80% of the fraction is usually removed from the system. It is discharged outside, leaving about 20% remaining.

The reaction product thus obtained is subjected to a hydrolysis step according to a conventional method. Hydrolysis is usually carried out by cooling the reaction product to 50-100°C.
In the method of the present invention, it is preferable that O-toluidine is newly added before cooling and then subjected to hydrolysis. After the obtained hydrolysis reaction liquid is separated, the oil layer is separated from the aqueous layer, and O-toluidine is separated from the oil layer by a method such as distillation to obtain the target product 2-alkylindole in high yield. It will be done.

Further, O-toluidine decomposed in the reaction step and distillation step can be recovered and used as it is in the synthesis reaction of sodium toluide.

Functions and Effects As mentioned above, by using O-toluidine solution of sodium toluide as a ring-closing agent in the process for producing 2-alkylindole from acyl-O-toluidine, the reaction can maintain a uniform liquid phase state. , not only can the desired product be obtained in high yield, but the reaction operation is easy, and metallic sodium does not remain in the ring-closing reaction product at all, so there is no risk of ignition due to reaction with water during the hydrolysis process. Can be directly hydrolyzed with water.

In addition, since the only solvent used is O-toluidine produced during the reaction, there is no need to separate ether, diethylaniline, etc. in the recovery process as in known methods, which simplifies the distillation process and is of great importance in industrial implementation. has advantages.

〔Example〕

O-toluidine was added to a flask equipped with a thermometer, _N2 gas inlet tube, condenser and stirrer.
428g (4.0mol) and ferric oxide 0.24g (0.0015mol)
was charged, heated and stirred while flowing N ₂ gas at a flow rate of 100 ml per minute. Metallic sodium at about 100℃
11.75g was added and the temperature was continued to rise.

When the internal temperature reached 195-200℃, hydrogen gas was observed to be generated and it was confirmed that the reaction had started, so the internal temperature was lowered to 170-180℃ and 40g of metallic sodium was added.
10g of sodium was charged in portions at 30 minute intervals, and a total of 51.75g (2.25 moles) of metallic sodium was finally charged. When the temperature was further kept at 200°C and the reaction was carried out under reflux, the metallic sodium completely disappeared in about 1 hour, and no hydrogen was generated.

Next, acetyl-O-toluidine was added to this reaction solution.
149.2 g (1.0 mol) was added, and the temperature was continued to rise while stirring. The temperature was raised to 280°C over 2 hours, and heating and stirring were continued at this temperature for 3 hours to complete the reaction. During this time, the inside of the system became viscous as the amount of O-toluidine distilled increased, but it was possible to stir sufficiently and uniformly until the reaction was completed. The amount of O-toluidine distilled out during the reaction was 382 g.

Next, start cooling while continuing to stir, and cool to 200 ml.
200g of O-toluidine was added at 100°C, and 200g of water was added when the temperature reached 100°C, but no generation of hydrogen gas was observed.

After the hydrolyzate is allowed to stand still, the oil layer is separated from the water layer,
Perform vacuum distillation to obtain 241.9g of O-toluidine as a fraction up to 20mmHg and 110℃, and 20mHg140-155
105.1 g of main fraction at ℃ was obtained. This main fraction was confirmed to be 2-methylindole by gas chromatography. (yield 80.0% vs. acetyl)
O-toluidine) A total of 623.9 g (recovery rate 99.3%) of O-toluidine was recovered from the reaction step and distillation step, which could be reused.

Claims (1)

[Claims] 1. Metallic sodium is reacted in the presence of an excess amount of O-toluidine, and the resulting O-toluidine solution containing sodium toluid is added to the formula (). (In the formula, R is a lower alkyl group having 4 or less carbon atoms)
Formula () characterized by adding and reacting acyl-O-toluidine represented by (In the formula, R is the same as R in the formula ()) A method for producing a 2-alkylindole represented by the following. 2. The method according to claim 1, wherein the 2-alkylindole represented by formula () is 2-methylindole. 3 Reaction between O-toluidine and metallic sodium
The method according to claim 1, which is carried out at 170 to 200°C in the presence of ferric oxide. 4. The method according to claim 1, wherein the reaction between sodium toluide and acyl-O-toluidine is carried out at 240 to 290°C.