JPH0529388B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a method for producing a 4- or 7-acyloxyindene compound, which is attracting attention as an intermediate for pharmaceutical production.

For more details, see Pharmaceutical Journal, Vol. 92, No. 11, 1358-1363.
Indenolol hydrochloride, a drug for arrhythmia, described in pages and Japanese Patent Publication No. 46-25731, etc., Fundamentals and Clinical Practice Vol. 19, 9.
4- or 7- which is an important manufacturing intermediate constituting the basic skeleton of inderoxazine hydrochloride, a brain metabolic function improving agent described in
The present invention relates to a method for producing acyloxyindene.

(Prior art) As a conventional method for producing 4- or 7-acyloxyindene, as shown in Japanese Patent Publication No. 49-11218, 1,4-diacyloxyindane is heated with a catalytic amount of iodine and thermally decomposed. A method for producing by chlorinating the 1-position hydroxyl group of 4-acyloxy-1-hydroxyindan with thionyl chloride, followed by dehydrochlorination, and JP-A-56-108723 As shown in Japanese Patent Publication No. 1, a method for producing a hydrazone derivative by reacting 4-acyloxy-1-indanone with a hydrazine compound and decomposing the derivative is known. However, there are many problems in manufacturing these on an industrial scale, and it is actually extremely difficult.

The thermal decomposition method using iodine as a catalyst is a two-step reaction in which 1,4-dihydroxyindane is converted to diacetate and then acetic acid is removed to form 4- or 7-acetoxyindene. In addition, since the catalytic ability of iodine is too high, side reactions such as polymerization and decomposition cannot be avoided, and controlling this by adjusting the amount of catalyst added and reaction time is difficult, especially when using crude raw materials on an industrial scale. In some cases, it is extremely difficult.
Therefore, even in good cases, the yield of 4- or 7-acetoxyindene by this method is very low in both steps.
It is about 70%.

The dehydrochlorination method involves converting 1,4-dihydroxyindan into 4-acetoxy-1-hydroxyindan, isolating this, chlorinating it, and then dehydrochlorinating it, so the process is divided into three steps. Therefore, the operation is complicated and the process takes a long time, but
The yield of 4- or 7-acetoxyindene is 60-
Only 65%.

The method via hydrazone derivatives involves reacting 4-acetoxy-1-indanone with p-toluenesulfonyl hydrazide to isolate hydrazone, and then using dangerous reagents such as metallic sodium, metallic potassium, and sodium ethoxide. and disassemble it. For this reason, it is an industrially difficult manufacturing method, and the yield is extremely low at 30%, making it impractical.

(Problems to be Solved by the Invention) The present inventors have solved the problems of conventional methods such as low yield, unstable yield, complicated operations, and use of dangerous reagents, and have achieved industrial improvement. The present invention has been completed as a result of intensive research to develop a manufacturing method that is fully applicable to the present invention.

(Means for Solving the Problems) That is, the present invention provides a method for producing 4- or 7-acyloxyindene, which is characterized by subjecting 1,4-dihydroxyindan and carboxylic acid anhydride to a heating reaction in the presence of magnesium chloride. A manufacturing method is provided.

The reaction of the present invention is expressed by the following formula.

(Structure) The carboxylic anhydride of the present invention is an aliphatic carboxylic anhydride such as acetic anhydride, propionic anhydride, and butyric anhydride.

The acyloxy group of the 4- or 7-acyloxyindene of the present invention is preferably an inexpensive and versatile lower carboxyl group, such as an acetyl group, a propionyl group, a butyryl group, and the like.

In addition, the amount of carboxylic acid anhydride used in the reaction is
It is sufficient to use at least twice the mole of 1,4-dihydroxyindan, preferably 2 to 5 times the mole.

Heating in the present invention preferably ranges from 80° C. to 120° C., and the reaction may be carried out under reduced pressure of 50 Torr to 500 Torr in order to remove carboxylic acid by-produced during heating.

Magnesium chloride may be added in an amount of 0.1 mol% or more, but usually 5 to 15 mol% is sufficient. It may also contain crystal water.

The reaction is carried out by mixing 1,4-dihydroxyindan, a carboxylic acid anhydride, and magnesium chloride, and stirring the mixture under heating for about 3 hours. This makes it possible to obtain 4- or 7-acyloxyindene in one step. After completion of the reaction, the reaction mixture may be extracted and washed with water and then distilled, or may be directly concentrated and distilled.

(Effects) The present invention overcomes the problems of the conventional method at once by using easily available and safe magnesium chloride as a catalyst.

First, 4- or 7-acyloxyindene can be easily obtained in a short time through a one-step operation of mixing raw materials and magnesium chloride and heating.

Second, 4- or 7-acyloxyindene can be obtained with high purity and high yield, with a purity of 99% or higher and a yield of 90% or higher.

Thirdly, there is no side reaction such as polymerization even when the alkaline earth metal halide is added excessively or when heated for a long time, and the alkaline earth metal halide is
-It is also possible to directly distill and isolate 7-acyloxyindene.

Furthermore, due to its excellent catalytic ability, the yield is stable regardless of the purity of the raw materials. These points are far superior to conventional methods, and the method has become fully applicable on an industrial scale.

Therefore, the present invention is an excellent method for producing 4- or 7-acetoxyindene, which is an intermediate for indenolol hydrochloride and inderoxazine hydrochloride.

Example 1 60.0 g of 1,4-dihydroxyindan, 163 g of acetic anhydride and 3.80 g of magnesium chloride were mixed.
Heat and stir at 110°C for 3 hours. Toluene after the reaction
Add 60ml and 30ml of water, separate and wash with water. When toluene is concentrated and the residue is distilled under reduced pressure, the boiling point is 180℃/
67.5 g of 4- or 7-acetoxyindene (purity 99%) exhibiting 5 Torr was obtained. (Yield 96%) Example 2 30.0 g of 1,4-dihydroxyindan, 81.6 g of acetic anhydride and 1.90 g of magnesium chloride were mixed.
Heat and stir at 110°C for 3 hours. After the reaction was completed, acetic anhydride and the like were directly distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain 33.7 g of 4- or 7-acetoxyindene (purity 99%) having a boiling point of 108°C/5 Torr. (Yield 96%) Example 3 30.0 g of 1,4-dihydroxyindan, 104 g of propionic anhydride, and 1.90 g of magnesium chloride
Mix and heat and stir at 120°C for 4 hours. After the reaction is complete,
Add 30ml of toluene and 15ml of water, separate and wash with water. When toluene is concentrated and the residue is distilled under reduced pressure, the boiling point is 119
34.2 g of 4- or 7-propionyloxyindene (purity 99%) exhibiting a temperature of 0.degree. C./5 Torr was obtained.
(Yield 90%) Example 4 30.0 g of 1,4-dihydroxyindan, 126 g of butyric anhydride and 1.90 g of magnesium chloride were mixed.
Heat and stir at 120°C for 4 hours. After the reaction is complete, add 30 ml of toluene and 15 ml of water, separate and wash with water. When toluene is concentrated and the residue is distilled under reduced pressure, the boiling point is 114℃/
36.7 g of 4- or 7-butyryloxyindene (purity 99%) exhibiting 3 Torr was obtained. (Yield 90%) Comparative Example Comparative Example 1 Method of decomposition with iodine
11218) 1st stage: 1,4-dihydroxyindan 15g
(0.1 mol) and 15.3 g (0.15 mol) of acetic anhydride were mixed and heated under reflux for 30 minutes. By vacuum distillation,
20.1 g of 1,4-diacetoxyindan exhibiting a temperature of 180°C/1 mmHg was obtained. (Yield 86%) 2nd stage: 23.4 g of 1,4-diacetoxyindan
Add a large amount of iodine and heat at 150℃ for 5 minutes. After the reaction is completed, the temperature is reduced to 142℃/22mm by vacuum distillation.
14.0g of 7-acetoxyindene of Hg was obtained.
(Yield: 80.5%) Through the above two steps, the yield of 1,4-dihydroxyindane→7-acetoxyindene was 69.2%.

Comparative Example 2 Dehydrochlorination method (Special Publication Act 1977-
11218) 1st stage: 1,4-dihydroxyindan 15g
(0.1 mol) was dissolved in an aqueous solution of 4.0 g (0.1 mol) of NaOH, and 10.2 g (0.1 mol) of acetic anhydride was added under ice cooling.
Add. After the reaction is complete, extract with ethyl acetate, concentrate and distill under reduced pressure to obtain a boiling point of 130-132.
17.6 g of 4-acetoxy-1-indanol having a temperature of 0.4 mmHg was obtained. (Yield: 92%) 2nd and 3rd stage: 53 g of 4-acetoxy-1-indanol was added to a large amount of pyridine in benzene, and the mixture was stirred with 37 g of thionyl chloride at room temperature for 1 hour. Concentration gave 4-acetoxy-1-chloroindanone, which was heated at 150°C/40°C in a _N2 stream.
Heat in mmHg for 1 hour. Distill the reaction solution under reduced pressure
34 g of 7-acetoxyindene having a temperature of 140°C/22 mmHg was obtained. (Yield: 70.5%) Through the above three steps, the yield of 1,4-dihydroxyindan→7-acetoxyindene was 64.9%.

Comparative Example 3 Method via hydrazone (Unexamined Japanese Patent Publication No. 1983-
No. 108723) 18 g (0.05 mol) of 4-acetoxy-1-indanone-p-toluenesulfonylhydrazone was treated with 0.16 mol of sodium ethoxide dissolved in 100 ml of ethylene glycol at room temperature for 30 minutes.
Heated at 160°C for 1 hour. 2.6 g of 7-acetoxyindel was obtained. The yield was 30%.

Claims (1)

[Claims] 1. A method for producing 4- or 7-acyloxyindene, which comprises reacting 1,4-dihydroxyindane and a carboxylic acid anhydride by heating in the presence of magnesium chloride.