JPH0239508B2 - CHIOKUROMANRUINOKAIRYOSEIHO - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the Wolff-Kishner reduction method, as shown in the reaction formula below.
The object of the present invention is to provide an improved technique for the known method of producing thiochromans by reduction. The aim is to produce thiochromans with high purity and high yield through simple operations. That is, the present invention provides general formula () A thiochroman-4-one compound represented by the formula () is reacted with hydrazine hydrate in a low-boiling alcohol to form the general formula (). A hydrazothiochroman compound represented by the formula is prepared, and then this reaction solution is dropped into a high-boiling alcohol solution containing an alkaline agent that has been heated to 120 to 150°C in advance to form a hydrazothiochroman compound represented by the general formula The present invention relates to an improved method for producing high-purity thiochromans, which is characterized in that the thiochromans are extracted from a high-boiling alcohol using benzene or toluene. However, in each of the above formulas, R represents a lower alkyl group or a lower alkoxy group, and n represents an integer of 1 or 2. The thiochromans obtained by the present invention are useful as intermediates for various industrial chemicals, including intermediates for pharmaceuticals. Among these, 6-methylthiochroman is particularly effective as an antihypertensive diuretic.
Methyl-7-sulfonamidothiochroman-1,
It is extremely useful as an intermediate in the synthesis of 1-diones. Until now, the methods for producing thiochromans have been as follows:
As shown in the following formula, a method for obtaining thiochroman-4-one (') by the Wolff-Xyuner reduction method is known. In this method, thiochroman-4-one ('), hydrazine, and an alkaline agent are heated to react at a high temperature of 100 to 190° C. using a high boiling point alcohol such as diethylene glycol as a solvent. However, this method has the disadvantage that it is accompanied by decomposition during the reaction and the yield is extremely low. As a method to improve such drawbacks, as shown in the following reaction formula, in JP-A-54-100393, 6-methylthiochromanone and hydrazine are mixed in a high-boiling alcohol at a temperature of 100°C or less. to obtain hydrazo-6-methylthiochroman, and then add an alkali agent to the reaction solution and react under high temperature conditions of 100°C or higher to decompose the hydrazo-6-methylthiochroman, thereby producing 6-methylthiochroman. A method for obtaining the is disclosed. Even in this method, when hydrazone is decomposed, nitrogen gas is generated and rapid bumping is likely to occur, and the process is not satisfactory for implementation on an industrial scale due to the problem of recovery of high-boiling alcohol. Reaction formula Conventional method (method described in JP-A-54-100393) [However, an alkaline agent (solid) is added to the compound of formula (')
] This invention [However, the compound of formula () is dropped into an alkali solution.] The present inventors conducted extensive research in view of the above circumstances, and as a result, completed the present invention. That is, the present invention is a method for producing thiochromans by the Wolff-Xyuner reduction method similar to that described in JP-A-54-100393, but the present invention further improves this method. First, the hydrazonation reaction of thiochroman-4-ones () is carried out in a low-boiling alcohol instead of the conventional high-boiling alcohol, and then a solid alkali agent is added to the reaction solution and heated as in the conventional method. Thiochromans () can be produced in high yield by dropping a low-boiling alcohol solution containing hydrazothiochromans () into a high-boiling alcohol solution such as diethine glycol in which an alkaline decomposer has been dissolved. can. Moreover,
In the present invention, since it is extremely easy to control the reaction that decomposes hydrazones (), bumping due to the generation of nitrogen gas does not occur, and it can be a safe method. Furthermore, after the reaction is complete, the high-boiling alcohol such as diethylene glycol and the alkali catalyst remain in the system as they are extracted using an inert solvent such as benzene or toluene that dissolves only the product thiochromans (). , can be used again in the next decomposition reaction. Therefore, in the production method of the present invention, thiochromans () can be produced by continuous reaction. In contrast, in the conventional method, the high-boiling alcohol cannot be used for the next reaction unless it is recovered and purified by operations such as distillation. Moreover, in the conventional method, the reaction solution containing the compound of formula (') was added to water, the alkali was neutralized with acid, and then extracted with a solvent such as trichlorethylene (trichlorethylene), but in this method, the reaction solution containing the compound of formula (') was extracted with a solvent such as trichlorethylene (trichlorethylene). The drawback was that impurities were mixed into the extraction solvent. However, according to the method of the present invention, impurities remain in the high-boiling alcohol and are not extracted into benzene or toluene, making it possible to obtain thiochromans () with high purity and a high yield of 90% or more. As described above, the present invention has been able to significantly improve the conventional production method in terms of safety, operability (continuity), and purification effect. The method for producing thiochromans of the present invention will be explained in more detail as follows. First, as the low-boiling alcohol, alcohols with relatively low boiling points such as methanol, ethanol, isopropanol, and secondary butanol are used. In this case, it is preferable to use one that can be easily distilled out at a reaction temperature of 120 to 150°C during the next decomposition reaction using an alkaline agent. The distilled low-boiling alcohol can be used as it is in the next reaction. Further, as the alkali decomposing agent for the hydrazothiochromans of formula (), in addition to sodium hydroxide and potassium hydroxide, alkali metal alcoholates such as sodium methylate and potassium ethylate are used. Further, as the high boiling point alcohol, solvents commonly used for Wolff-Xyuner reduction, such as ethylene glycol, diethylene glycol, triethylene glycol, etc., can be used. The hydrazonation reaction is carried out at the boiling point temperature of each solvent, but in order to facilitate post-treatment, it is necessary to
It is preferable to carry out the test at temperatures below ℃. This reaction is completed in about 2 hours regardless of which solvent is used. Also,
The hydrazothiochromans () produced by this reaction are converted into thiochromans () using an alkaline agent.
The reaction to decompose into
The reaction is smoothly carried out by dropping the low-boiling alcohol solution of the hydrazothiochromans () into a high-boiling alcohol solution in which an alkaline decomposing agent has been dissolved and which has been heated to 150°C. As this reaction progresses, nitrogen is gradually generated and, at the same time, the low-boiling alcohol of the solvent used in the hydrazonization reaction is distilled out and collected through a cooler. This recovered solvent is used as it is in the next reaction. Through such a decomposition reaction, the desired thiochromans () are produced almost quantitatively in the high-boiling alcohol. In order to recover the thiochromans () in high yield, the thiochromans () may be extracted by adding benzene or toluene.
During this extraction, most of the reaction impurities remain in the high-boiling alcohol, so if the extraction solvent benzene or toluene is distilled off, highly pure thiochromans () containing almost no impurities can be obtained. Note that the high-boiling alcohol solution containing the alkaline decomposing agent after being extracted with benzene or toluene can be used repeatedly for the alkaline decomposition reaction of hydrazones (2012). On the other hand, a solution containing thiochromans () extracted with benzene or toluene can be washed with water and then distilled off to obtain a highly pure product, which can be further purified by vacuum distillation or the like. From the above points, the method for producing thiochromans of the present invention is an excellent method that can be implemented on an industrial scale. Next, examples of the present invention will be shown, but the present invention is not limited only to the examples. Example 1

Method for producing [Formula] 267.5 g (1.5 mol) of 6-methylthiochroman-4-one is placed in a 1-volume four-necked flask and dissolved in 400 ml of methanol. Add 141 g (2.25 moles) of 80% hydrazine hydrate and heat slowly.
The mixture is refluxed at 65°C for 2 hours to carry out the hydrazonation reaction.
Separately, 1 diethylene glycol and 120 g (3 mol) of sodium hydroxide are charged into a 2-capacity four-necked flask equipped with a distiller, and heated to 130°C. The hydrazonation reaction solution was gradually added dropwise to this while maintaining the temperature at 130°C. After the completion of the dropwise addition, a boost reaction is carried out for 3 hours to complete the reaction. After cooling the reaction solution to room temperature, it was extracted twice using 700 ml of toluene each time, and the resulting toluene layer was washed with water and the toluene was distilled off, resulting in 6-
255.1 g (crude yield) of methylthiochroman was obtained [yield (Y) 103.5%, purity (P) 93.7%]. Further vacuum distillation of this yields 227.1g of the same compound.
[Purity (P) 99.8%, Yield (Y)]
92.2%, pure product yield 92% (YP), bp80℃/3
mmHg, n ^15.4 _D 1.5960]. Example 2

Production method of [Formula] In a 1-capacity four-necked flask, 6-ethyl-8-
Methylthiochroman-4-one 206g (1 mol)
Dissolve in 400ml of isopropanol. Add 125g (2 moles) of hydrazine hydrate to it and heat it.
React at 83°C for 2 hours. In addition, diethylene glycol 800 ml and potassium hydroxide 112.2 g (2 mol) were added to a 2-capacity four-necked flask equipped with a distiller.
is added and heated to 150°C, and the previously reacted isopropanol solution is gradually added dropwise thereto. After the completion of the dropwise addition, a boost reaction is performed for 4 hours to complete the reaction. After cooling the reaction solution to room temperature, it was extracted twice using 500 ml of toluene each time, and the resulting toluene layer was washed with water and the toluene was distilled off, yielding 198.5 g (crude) of 6-ethyl-8-methylthiochroman. Yield) Obtained [Yield (Y) 103.2%, Purity (P)
93.0%]. When this was further vacuum distilled, 175.7 g of the above compound was obtained [purity (P) 99.6%,
Yield (Y) 91.4% Pure product conversion yield (YP) 91%, b.
p.165.5℃/13mmHg, n ^22.8 _D 1.5843]. Example 3

Production method for [Formula] Dissolve 44.6 g (0.25 mol) of 8-methylthiochroman-4-one in 100 ml of ethanol in a 1-volume four-necked flask, and dissolve 23.5 g of 80% hydrazine hydrate.
(0.38 mol) was added and gradually heated to reflux at 80°C for 2 hours to carry out the hydrazonation reaction. Separately, 230 ml of triethylene glycol and 42.1 g (0.5 mol) of potassium ethylate were heated to 140°C in a 1-volume four-necked flask equipped with a distillation device, and the ethanol solution previously reacted was placed in this. Gradually drip. After the completion of the dropwise addition, a boost reaction is carried out for 3 hours to complete the reaction. After the reaction solution was cooled to room temperature, it was extracted twice with 100 ml of benzene each time, the resulting benzene layer was washed with water, and the benzene was distilled off to obtain 42.7 g (crude yield) of 8-methylthiochroman. Rate (Y)
104.1%, purity (P) 93.2%]. When this was further vacuum distilled, 37.9 g of the above compound was obtained [purity (P) 99.7%, yield (Y) 92.2%, pure product conversion yield (YP) 91.9%, bp 149-150℃/14mm
Hg〕. Example 4

Production method for [Formula] Dissolve 38.9 g (0.2 mol) of 6-methoxythiochroman-4-one in 80 ml of methanol in a 1-volume four-necked flask, and dissolve 18.8 g of 80% hydrazine hydrate.
(0.3 mol) was added and gradually heated to reflux at 65°C for 2 hours to carry out the hydrazonation reaction. Separately, 200 ml of triethylene glycol and 21.6 g (0.4 mol) of sodium methylate were heated to 120°C in a 1-volume four-necked flask equipped with a distillation device, and the methanol solution previously reacted was placed in this. Gradually drip. After the completion of the dropwise addition, a boost reaction is carried out for 3 hours to complete the reaction. After the reaction solution was cooled to room temperature, it was extracted twice with 80 ml of benzene each time, and the resulting benzene layer was washed with water, and then benzene was distilled off to obtain 37.0 g (crude yield) of 6-methoxythiochroman. Yield (Y) 102.6%, purity (P)
92.8%]. When this was further vacuum distilled, 33.1 g of the above compound was obtained [purity (P) 99.1%,
Yield (Y) 91.8%, pure product conversion yield (YP) 91%,
mp116-117℃]. Comparative example 1

Production method of [Formula] In a 1-capacity four-necked flask, 6-ethyl-8-
Methylthiochroman-4-one 103g (0.5mol),
62.5 g (1 mol) of 80% hydrazine hydrate, 400 ml of diethylene glycol and 56.1 g of potassium hydroxide
(1 mol) and gradually heated it to 135℃ for 5 minutes.
Allow time to react. Thereafter, this reaction solution was poured into ice water (Step 1), 500 ml of benzene was added thereto, and the benzene layer was separated. After washing with water, distilling off the benzene yields 6-ethyl-8-methylthiochroman.
70.8g (crude yield) was obtained [yield (Y) 73.6%,
Purity (P) 72.0%]. This was further vacuum distilled to obtain 47.0g of the above compound [purity (P) 98.2
%, yield (Y) 48.9% pure product conversion yield (YP) 48
%]. Comparative example 2

Production method for [Formula]: Add 89.2 g (0.5 mol) of 6-methylthiochroman-4-one, 47 g (0.75 mol) of 80% hydrazine hydrate, and 400 ml of diethylene glycol to a 1-volume four-necked flask and heat to 100°C. Perform hydrazonation reaction. After the reaction is complete, add sodium to the reaction solution.
Add 40g (1 mol) and gradually heat to 160°C. At this time, sufficient care must be taken to avoid bumping. Thereafter, a boost reaction is performed for 4 hours. Pour the reaction solution into ice water from step 1, neutralize with hydrochloric acid, add 500 ml of trichlene, separate the trichlene layer,
After washing with water, tricrene was distilled off to obtain 78.7 g (crude yield) of 6-methylthiochroman [yield (Y) 95.9%, purity (P) 77.2%]. Further, this was vacuum distilled to obtain 58.4 g of the above compound [purity (P) 98.5%, yield (Y) 71.1%, yield in terms of pure product (YP) 70%].

Claims (1)

[Claims] 1. General formula (In the formula, R represents a lower alkyl group or a lower alkoxy group, and n represents an integer of 1 or 2) by reacting a thiochroman-4-one compound with hydrazine hydrate in a low boiling alcohol, formula A hydrazothiochroman compound represented by (in the formula, R and n are as described above) is formed, and the resulting reaction solution is preliminarily heated to
A general formula characterized by adding dropwise into a high-boiling alcohol solution containing an alkaline agent heated to 150°C, and subsequently extracting from the high-boiling alcohol with benzene or toluene. An improved method for producing a thiochroman compound represented by the formula (wherein R and n are as described above).