JPS6237629B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an indole compound,
More specifically, the present invention relates to a method for producing 5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)indole.

5-alkoxy or 5-benzyloxy-3-(hydanto-5'-
ylmethyl)indole is an industrially useful organic intermediate that is a raw material for producing 5-hydroxytryptophan and the like.

Conventionally, as a method for producing 5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)indole, β-(hydant-5-yl)propionaldehyde and p-alkoxy or p-benzyloxyphenyl A method of reacting hydrazine or its acid addition salt in the presence of a strong acid of 0.5N or less in a mixed solvent of water and a hydrophilic organic solvent of 1.5 to 3.0 times the volume (Japanese Patent Publication No. 50-28958) ) is publicly known. However, this known method has the following drawbacks. (1) Since the amount of hydrophilic organic solvent used is 1.5 to 3.0 times that of water, a step of recovering the hydrophilic organic solvent is required, and furthermore, heating during solvent recovery reduces the purity of the indole compound. (2) The yield of 5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)indole is about 80%, so using this as a starting material, 5-hydroxytryptophan can be produced with high purity. For efficient production, this indole compound must be isolated and purified. The above-mentioned known methods therefore still leave room for improvement when implemented on an industrial scale.

The present inventors have improved the above conventional method to
-5-alkoxy or 5-benzyloxy-3- as a starting material for hydroxytryptophan etc.
We have conducted extensive research on a method to efficiently produce (hydant-5'-ylmethyl)indole with high purity, and by appropriately selecting the acid concentration of the reaction solution and keeping the reaction temperature low, we have avoided the use of hydrophilic organic solvents. They also discovered that the compound also reacts in an aqueous solvent, leading to the completion of the present invention.

That is, the present invention reacts β-(hydant-5-yl)propionaldehyde with p-alkoxy or p-benzyloxyphenylhydrazine or an acid addition salt thereof to form a 5-alkoxy or 5-benzyloxy-3-(hydanthyl) -5′-ylmethyl)indole is produced by adding an acid-salt to buffer the pH of the reaction solution in water or a water-low-boiling organic solvent mixture, and reacting at 50 to 90°C. The present invention provides a method for producing 5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)indole.

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

(However, in the formula, X represents an inorganic acid or an organic acid.) The method of the present invention was developed from a detailed study of Japanese Patent Publication No. 50-28958. That is,
It is not a necessary condition to carry out the reaction in a homogeneous system in which p-alkoxy or p-benzyloxyphenylhydrazine is dissolved using a hydrophilic organic solvent as disclosed in Japanese Patent Publication No. 50-28958. −
Even if alkoxy or p-benzyloxyphenylhydrazine is in a slurry state, by appropriately selecting the acid concentration of the reaction solution and keeping the reaction temperature low, 5-alkoxy or p-benzyloxy-3- The present invention was made based on the knowledge that (hydant-5'-ylmethyl)indole can be obtained. This cannot be easily predicted from known technology.

One embodiment of the method of the present invention is shown below. first,
Add p-benzyloxyphenylhydrazine hydrochloride to water, heat and stir at 50 to 90°C, and add dropwise an aqueous β-(hydant-5-yl)propionaldehyde solution containing an acid salt such as sulfuric acid-ammonium sulfate. . The reaction is carried out at 50 to 90°C for 3 hours while buffering the pH of the reaction solution to 1.5 to 3.0. After the reaction is completed, the reaction solution is cooled with water to precipitate crystals of 5-benzyloxy-3-(hydant-5'-ylmethyl)indole. The target product, 5-benzyloxy-3-(hydant-5'-ylmethyl)indole, is obtained in a yield of over 95%.

β-(hydanto-5-
propionaldehyde can be easily and inexpensively produced by known methods. That is, cyanoethylhydantoin may be semi-hydrogenated in an acidic aqueous solution of sulfuric acid using a hydrogenation catalyst, and then hydrolyzed. The alkoxy group of the other raw material p-alkoxy or p-benzyloxyphenylhydrazine or its acid addition salt is,
Examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, and t-butoxy group, and acid addition salts include, for example, hydrochloride, hydrobromide, Selected from inorganic acid salts such as sulfates, phosphates, nitrates, or organic acid salts such as acetates, oxalates, challatates, toluenesulfonates.

In the method of the present invention, always maintaining the pH of the reaction solution at 1.5 to 3.0 is an essential condition along with the reaction temperature. The method of keeping the pH of the reaction solution constant is not particularly limited, but a method of buffering the reaction solution by adding an acid-salt is preferred. As a method of buffering the pH of the reaction solution,
Koltoff's buffer (citric acid - potassium dihydrogen citrate), Michaelis' buffer (chlorite acid - potassium hydrogen phthalate), Clark-Lubs buffer (0.2N hydrochloric acid - 0.2M potassium hydrogen phthalate), etc. A commonly known buffering acid salt such as β-
Sulfuric acid and ammonium sulfate as a by-product are present in the aqueous solution of β-(hydant-5-yl)propionaldehyde, which is added to the aqueous solution of (hydant-5-yl)propionaldehyde or obtained by the above-mentioned known production method. Therefore, this product may be used as a raw material solution as it is.

The reaction in the method of the invention is carried out at 50 to 90°C, preferably
It is carried out at a temperature range of 70 to 75°C. The reaction temperature is an important factor that determines the success or failure of the reaction of the present invention.
If the reaction temperature exceeds 90°C in the conventional method, the target product will hardly be obtained and a resin-like product will be obtained, whereas if the reaction temperature is below 50°C, p-alkoxy or p-benzyloxyphenylhydrazine will be converted to 5-alkoxy or 5-
The ring-closing reaction to benzyloxy-3-(hydant-5'-ylmethyl)indole does not proceed.

The reaction solvent in the method of the present invention may be water alone, or may be a mixed solvent in which a low-boiling organic solvent is added to water for the purpose of controlling the reaction temperature constant within the range of 50 to 90°C. When a low boiling point organic solvent is used in combination, it is not used for the purpose of dissolving p-alkoxy or p-benzyloxyphenylhydrazine as disclosed in Japanese Patent Publication No. 50-28958, so It is not necessary to use an organic solvent in an amount 1.5 to 3.0 times the amount of water, and it is sufficient to use an amount equal to or less than the amount of water. Examples of low-boiling organic solvents that can be used include methanol, ethanol, n-propanol, isopropanol, and tetrahydrofuran.
The reaction temperature is kept constant within the above range by appropriately selecting the blending amount of the organic solvent so that the boiling point of the organic solvent-water mixture or the azeotropic boiling point of the organic solvent and water is in the range of 50 to 90°C. be able to.

Although the details of the reason why the method of the present invention is superior are not clear, if the PH of the reaction solution and the reaction temperature are carried out outside the range of the present invention, β-
(hydant-5-yl)propionaldehyde,
Hydrolysis of p-alkoxy or p-benzyloxyphenylhydrazine (acid addition salt) and β-
A condensation reaction of (hydant-5-yl)propionaldehyde to the indole nucleus also occurs, resulting in a significant decrease in the yield of the target product.

5 from the reaction mixture obtained by the method of the present invention.
-alkoxy or 5-benzyloxy-3-
To isolate (hydant-5'-ylmethyl)indole, only filtration is necessary. To purify it, it can be recrystallized from a solvent such as methanol, but
Since 5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)indole produced by the method of the present invention can be obtained with a yield of 95% or more, 5-hydroxytryptophan can be obtained without purification. It can be used as a raw material such as In addition,
To produce 5-hydroxytryptophan,
5-alkoxy or 5-benzyloxy-3-(hydant-5'-ylmethyl)-
Indole may be hydrolyzed with an alkali to give 5-alkoxy or 5-benzyloxytryptophan, and the protecting group for the 5-position hydroxyl group may be removed by reduction.

The present invention will be explained in more detail with reference to Examples below.

Example 1 Preparation of β-(hydant-5-yl)propionaldehyde aqueous solution 5-(β-cyanoethyl)hydantoin 220Kg
(Wet product, purity 80%, 1093 mol) was dissolved in water to make a total volume of 870, and the solution was charged into an autoclave equipped with an airtight stirrer. Furthermore, 20 kg of lead-poisoned Raney nickel and 130 kg of 10N sulfuric acid were added, and while stirring, the inside of the apparatus was purged with nitrogen, and then replaced with hydrogen to bring the hydrogen pressure to 1.5 to 1.7 kg/cm ² . The temperature was gradually increased and reduction was carried out at 50°C for 110 minutes. Hydrogen absorption rate is 5-(β
-cyanoethyl)hydantoin, the reaction was stopped, cooled and the catalyst was filtered. The thus obtained β-(hydant-5-yl)propionaldehyde aqueous solution (hereinafter abbreviated as CH reducing solution) contained 132.9 g/Kg (0.85 mol/) of β-(hydant-5-yl)propionaldehyde and ammonium sulfate. It contained 65g/Kg and 9.2g/Kg of sulfuric acid, and the pH was 1.8.

Preparation of 5-benzyloxy-3-(hydant-5'-ylmethyl)indole In a 3.5 ^m3 reactor, 719 g of water and 60 g of methanol were added.
70Kg of p-benzyloxyphenylhydrazine hydrochloride (hereinafter abbreviated as BOPH)
(280 mol) and gradually heated while stirring to 75 mol.
℃. When the liquid temperature reached 75°C, 339 kg (288.4 mol) of CH reducing solution was added dropwise over 1 hour. After the dropwise addition, the reaction was carried out at 75°C for 3 hours. During this time, the pH of the reaction solution was maintained at 2.1 due to the buffering action of sulfuric acid-ammonium sulfate contained in the CH reducing solution. The appearance of the reaction solution during the reaction gradually became transparent as the CH reducing solution was added dropwise to the BOPH solution, which was initially in a suspended state, and became transparent when the entire amount of the CH reducing solution was added. After that, the reaction solution was mixed with 5-benzyloxy-3-(hydanto-5'-
Crystals of ylmethyl)indole (hereinafter abbreviated as BHN) began to precipitate and became suspended again. After cooling with water, it was centrifuged, washed with water, and dried to obtain 90.9 kg of golden BHN crystals (yield: 97.2%). The obtained crystals were confirmed by matching the infrared absorption spectrum of the standard product with the thin layer chromatogram.
The melting point of this product is 196.5-200.6℃, and the neutralization value is 164.1.
It was hot.

Example 2 Dimroth cooling pipe, thermometer, isobaric dropping funnel,
Then, 50.2 g (0.2 mol) of BOPH and 500 ml of water were added to a three-necked flask equipped with an airtight stirrer, and the mixture was gradually heated to 75° C. while stirring. Liquid temperature is 75℃
When the temperature reached, 222 ml of the CH reduced solution obtained according to Example 1 (containing 0.206 mol of β-(hydant-5-yl)propionaldehyde) was added dropwise from the dropping funnel over a period of 1 hour. After the dropwise addition, the reaction was carried out at 75°C for 3 hours. During this time, the pH of the reaction solution was maintained at 2.1. After the reaction was completed, it was cooled with water and the precipitated crystals were filtered.
The crystals were washed with water and dried to obtain 65.0 g of crystals (yield: 97.2%). This substance was confirmed to be BHN based on the agreement between the infrared absorption spectrum of the standard sample and the thin layer chromatogram. The crystal state was also good. As a result of analysis, this crystal had a melting point of 202.0 to 203.5°C, a neutralization value of 167.1, and a nitrogen content of 12.00%.

Comparative example 1 Add 50.2 BOPH to 500ml of water adjusted to PH1 with hydrochloric acid.
g (0.2 mol) and heated to 75° C. with stirring. Add 222 ml of CH reducing solution (β-(hydanto-5
(contains 0.206 mole of propionaldehyde)
was adjusted to pH 1 with concentrated hydrochloric acid and added dropwise. When the reaction temperature was further raised to 100°C and the reaction continued for 2 hours, most of the reaction product turned into a dark brown oil that adhered to the stirring rod and the walls of the vessel. An attempt was made to produce 5-hydroxytryptophan by a conventional method using this product, but 5-hydroxytryptophan could not be obtained.

Example 3 50 parts by volume of 0.2MKCl instead of 500ml of water:
The reaction was carried out in the same manner as in Example 2, except that 500 ml of a buffer solution prepared at a ratio of 10.6 parts by volume of 0.2 MHCl: 139.4 parts by volume of water was used, and the pH of the solution was maintained at 2.0. After the reaction, the same treatment as in Example 2 was carried out.
65.4 g (yield 98%) of BHN was obtained. When this product was analyzed, it had a melting point of 198.6 to 201.0°C and a neutralization value of 170.9.

Example 4 Instead of 500 ml of water, 8 parts by volume of 0.1N acetalic acid: 0.1M
The reaction was carried out in the same manner as in Example 2, except that 500 ml of a buffer solution adjusted to 1 part by volume of sodium charaterate was used, and the pH of the solution was maintained at 2.0. After the reaction, the same procedure as in Example 2 was carried out to obtain 64.1 g of BHN (yield:
96%). The analysis value of this substance is melting point:
The temperature was 196.5-200.6°C, and the neutralization value was 164.1.

Example 5 0.1M potassium dihydrogen citrate 25.0 instead of water
The reaction was carried out in the same manner as in Example 1, except that a buffer solution prepared at a ratio of 0.1NHCl24.85 parts by volume and 0.15 parts by volume of water was used, and 300 ml of ethanol was used instead of 600 ml of methanol. 90.3 kg (yield 96.6%) of BHN in a good crystalline state was obtained. The melting point of this product was 204-206°C.

Claims (1)

[Claims] 1 β-(hydant-5-yl)propionaldehyde and p-alkoxy or p-benzyloxyphenylhydrazine or its acid addition salt are reacted to form 5-alkoxy or 5-benzyloxy-3 -(hydant-5'-ylmethyl)indole is produced by 5-alkoxy or 5-benzyl, characterized in that the reaction is carried out in a solvent at 50 to 90°C while keeping the pH of the reaction solution always between 1.5 and 3.0. A method for producing oxy-3-(hydant-5'-ylmethyl)indole. 2. The method according to claim 1, wherein the p-benzyloxyphenylhydrazine acid addition salt is p-benzyloxyphenylhydrazine hydrochloride. 3 The pH of the reaction solution is 1.5 to 1.5 due to the presence of the acid-salt.
3.0. 4. The method according to claim 3, wherein the acid-salt is sulfuric acid-ammonium sulfate. 5. The method according to claim 1, wherein the solvent is water or a water-low-boiling organic solvent mixture.