JP2006298832A - High-purity o-(5,6,7,8-tetrahydro-2-naphthyl)-n-(6-methoxy-2-pyridyl)-n-methylthiocarbamate and its preparation method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a high-quality O-(5,6,7,8-tetrahydro-2-naphthyl)-N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate with a reduced amount of inorganic salts, which is used as a raw material for pharmaceutical products and conventionally contains a trace amount of inorganic salts and heavy metals. <P>SOLUTION: The O-(5,6,7,8-tetrahydro-2-naphthyl)-N-(6-methoxy-2-pyridyl)-N-methylthiocarbamate having an inorganic salt content of ≤300 ppm and a heavy metal content of <2 ppm is obtained by combining filtration by a fine filter and recrystallization performed at a temperature kept within a prescribed range. The obtained compound is especially suitable as the raw material for the pharmaceutical products with a low risk of inducing metal allergy. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to high-quality O- (5,6,7,8-tetrahydro-2-naphthyl) -N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate having a reduced inorganic salt content, and its It relates to a manufacturing method.

  O- (5,6,7,8-tetrahydro-2-naphthyl) -N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate represented by the following general formula (1) (hereinafter “target thiocarbamate”) Are abbreviated as “active ingredients” of antifungal agents. (For example, see Patent Document 1)

  In order to use the target thiocarbamate as a raw material for pharmaceutical products, the target thiocarbamate needs to have a high purity. In particular, the remaining inorganic salt is not preferred from the viewpoint of skin irritation, and is more inorganic than conventional products. There is a need for thiocarbamates with low target.

Conventionally, as a method for producing a target thiocarbamate having a small amount of inorganic salt, a raw material O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate is mixed in a C1-C3 alcohol-water mixed solvent. Reaction with 2-methoxy-6-methylaminopyridine in the presence of an excess of a dehydrohalogenating agent, or starting material N-methyl-N- (6-methoxy-) in a mixed solvent of C1-C3 alcohol-water 2-pyridyl) carbamoyl chloride was reacted with 5,6,7,8-tetrahydro-2-naphthol in the presence of an excess of a dehydrohalogenating agent, washed with water, and C1-C3 alcohols such as ethanol and isopropyl alcohol. It is known that the desired thiocarbamate can be obtained by recrystallization using (For example, see Patent Document 2)
However, the target thiocarbamate obtained by natural cooling by conventional continuous cooling has contained about 700 ppm of inorganic salt.

  On the other hand, metal materials such as stainless steel are generally used as industrial production equipment, and heavy metals such as trace amounts of iron may be eluted from them. Although these heavy metals remain together with inorganic salts as hydroxides or carbonates, it is not practical to carry out industrial production in production equipment made of non-metallic materials for all processes, and by devising production methods The problem was to reduce the heavy metal content.

JP-B-1-45449 Japanese Patent No. 3030724

  The present invention provides a high-quality target thiocarbamate with reduced inorganic salts and heavy metals for use as an active ingredient of pharmaceuticals, and a method for producing the same.

  As a result of intensive studies on reducing the metal content of the target thiocarbamate, the present inventors have found that O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate and 2-methoxy-6. Washing the target thiocarbamate obtained by the reaction of -methylaminopyridine or the reaction of N-methyl-N- (6-methoxy-2-pyridyl) carbamoyl chloride with 5,6,7,8-tetrahydro-2-naphthol , By dissolving in a solvent, filtering insolubles using a filter with a specific pore size, and then recrystallizing under a condition of holding in a temperature range of 50 to 70 ° C. for 1 hour or longer. It has been found that a target thiocarbamate having an inorganic salt content of 300 ppm or less and a heavy metal content of less than 2 ppm can be obtained, and the present invention has been completed. That.

  The present invention is described in detail below.

  As the impurities of the target thiocarbamate, the content of the inorganic salt of the target thiocarbamate used in the past was all 1000 ppm or less, but the lower limit was up to 300 ppm. It was not requested.

  The object thiocarbamate of the present invention has an inorganic salt content of 300 ppm or less, particularly preferably 100 ppm or less.

  Furthermore, the content of heavy metal contained in the object thiocarbamate of the present invention is preferably less than 2 ppm, particularly preferably less than 0.9 ppm.

  Next, a method for producing the object thiocarbamate of the present invention will be described.

  The object thiocarbamate of the present invention is a reaction of O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate with 2-methoxy-6-methylaminopyridine, or N-methyl-N- ( 6-Methoxy-2-pyridyl) carbamoyl chloride and 5,6,7,8-tetrahydro-2-naphthol crude thiocarbamate obtained by washing with water, dissolving in a solvent, and filtering insoluble matter The recrystallization is performed under the condition that the recrystallization is maintained in a temperature range of 50 to 70 ° C. for 1 hour or more.

O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate, N-methyl-N- (6-methoxy-2-pyridyl) carbamoyl chloride, 2-methoxy-6-methyl used as raw material Aminopyridine, 5,6,7,8-tetrahydro-2-naphthol can be produced by a known method. (For example, refer to Japanese Patent No. 1364461, Japanese Patent No. 2086706, etc.)
The reaction conditions of these raw materials may be conventional conditions, and typical conditions are exemplified in Patent Document 1 or Patent Document 2, for example.

  The crude crystals obtained by the above reaction are first washed with water, but the water used for the water washing needs to have an amount that allows the crude crystals obtained after the reaction to be sufficiently dispersed and washed in a suspended state. The amount is preferably 5 times (weight ratio) or more with respect to the crystal. On the other hand, even if a large amount of water is used, no further effect can be obtained, and it may cause a decrease in yield due to the outflow of the crude crystals. Therefore, a range of 6 to 10 times the amount (weight ratio) is sufficient. is there.

  Next, the crude crystals washed with water are purified by filtration and recrystallization in a solvent, but the solvent used for the recrystallization is not particularly limited. For example, (1) linear chain having C1 to C3 and chain having side chains (2) a combination of a C1-C3 linear and side chain aliphatic carboxylic acid and a C1-C3 linear and side chain aliphatic alcohol (3) ) Combinations of C4-C18 linear and side chain aliphatic hydrocarbons and aromatic hydrocarbons such as benzene, toluene, o-, m-, p-xylene, ethylbenzene, 4) Nitriles such as acetonitrile can be exemplified as preferred solvents. Among these solvents, it is particularly preferable to use C1 to C3 alcohols from the viewpoints of the purification effect in recrystallization of the thiocarbamate of the present invention, industrial availability, and use as a single component.

  For example, in the case of a C1-C3 alcohol, the amount of the solvent used is preferably four times (weight ratio) or more with respect to the target thiocarbamate crystals to be purified. On the other hand, if the solvent is used in a large amount, the yield of the final purified product is reduced, so it is not economical, and 4 to 8 times (weight ratio) is appropriate.

  The temperature at which the thiocarbamate crystals to be purified are dissolved in the solvent varies depending on the type and boiling point of the organic solvent to be used. For example, when the solvent is a C1-C3 alcohol, it is possible to dissolve all thiocarbamate crystals at 70 ° C. or higher. .

  The method of filtration is not particularly limited, but the insoluble matter is filtered using a hollow fiber filter or filter paper attached to a filter such as a glass filter or a membrane filter or a filter at a temperature at which crystals do not crystallize from the dissolved solution. Can be illustrated. The pore size of the filter is preferably 20 μm or less, particularly preferably 0.1 to 1 μm. On the other hand, those having a large pore diameter exceeding 20 μm decrease the removal rate of inorganic salts.

  In order to obtain the object thiocarbamate of the present invention, temperature control of recrystallization is important. At low temperatures where the initial temperature of recrystallization does not reach 50 ° C., crystallization rapidly proceeds and purity decreases, so that the target thiocarbamate of the purity of the present invention cannot be obtained. On the other hand, when the initial temperature of recrystallization exceeds 100 ° C., the target thiocarbamate melts and partially decomposes, so that impurities are easily taken in, and the particle diameters are also likely to be uneven. Therefore, in order to obtain the object thiocarbamate of the present invention, it is preferable that the recrystallization start temperature starts from a range of 50 ° C to 100 ° C.

  On the other hand, in the method of the present invention, recrystallization is performed under the condition that the recrystallization is maintained in a temperature range of 50 to 70 ° C. for 1 hour or more. Although it is not clear why the inorganic salt contained in the target thiocarbamate is reduced by holding at a certain temperature in the temperature range of 50 to 70 ° C. for 1 hour or more, the target thiocarbamate is maintained at this temperature range. It is considered that carbamate is selectively precipitated and has an effect of reducing inorganic salts. A holding temperature of 1 hour or more is sufficient, but it is preferably about 2 to 10 hours. Even if the holding time is longer than this, the effect of reducing the inorganic salt of the target thiocarbamate reaches a peak and the productivity is lowered, so the upper limit of the holding time is about 10 to 50 hours.

  In the recrystallization of the present invention, there are no particular limitations on the temperature decrease rate other than maintaining a constant temperature, and the target thiocarbamate with a low metal content can be obtained even if the temperature is decreased at a relatively high rate as long as the temperature control of the present invention is performed. It is done. The target thiocarbamate with a sufficiently low metal content can be obtained when the temperature lowering time to room temperature other than the holding temperature at 50 to 70 ° C. is about 1 to 20 hours and 2 to 10 hours in total. The method of the present invention, which may be subjected to rapid temperature reduction as a whole, is excellent in terms of productivity as long as it is maintained in a temperature range of 50 to 70 ° C. for 1 hour or longer.

  By combining filtration using a filter having a small pore size and recrystallization maintained within a certain temperature range, a target thiocarbamate having an inorganic salt content of 300 ppm or less and a heavy metal content of less than 2 ppm can be produced. Thiocarbamate, which has few inorganic salts and heavy metals, is particularly excellent as a pharmaceutical raw material without risk of metal allergy.

  EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

  The inorganic ions in the obtained thiocarbamate were analyzed using ion chromatography. The inorganic salt was confirmed by UV using the Japanese Pharmacopoeia ignition residue test method, and for the heavy metal limit test, the Japanese Pharmacopoeia heavy metal test method No. 4. Furthermore, the ICP method was used for detailed analysis of each heavy metal, but the detection limit of each metal at the time of measurement by the ICP method varies depending on the metal, and 0.5 ppm, nickel, molybdenum, aluminum, lead for iron, chromium, and copper, respectively. And zinc were 1 ppm, and manganese was 0.1 ppm. In all of the examples, the isolated yield was used.

Example 1
First, removal of inorganic salts by recrystallization was examined using a glass flask.

  While stirring 14.0 g (0.10 mol) of 2-methoxy-6-methylaminopyridine and 10.6 g (0.10 mol) of sodium carbonate together with a mixed solvent of 285 g of isopropyl alcohol and 15.0 g of water, the mixture was stirred. 22.0 g (0.097 mol) of O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate was added dropwise. Next, after filtration and washing with 150 g of water, 87.7 g of a crude thiocarbamate was obtained. As a result of measuring the obtained crude crystal with a thermobalance, the water content was 65%. A small amount was sampled, dried, and analyzed by liquid chromatography. As a result, the purity was 99.8%. Moreover, in the inorganic ion analysis by ion chromatography, 460 ppm of chlorine ions, 260 ppm of carbonate ions, and 370 ppm of sodium ions were contained.

  87.7 g of the obtained crude thiocarbamate was purified and dissolved in 215 g of isopropyl alcohol, which is about 2.5 times the amount of the water-containing cake, at 80 ° C., filtered while hot using a filter having a pore size of 0.5 μm, and cooled. The temperature was further lowered under the condition of holding at 50 ° C. to 60 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature, centrifuged and then dried to obtain 30.0 g of target thiocarbamate crystals (yield 94%).

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Table 1 shows the measurement results of the chlorine ion concentration and the carbonate ion concentration and the sodium ion concentration of the crude product and the refined product together with the dissolving operation and the cooling operation.

Example 2
The reaction was performed in the same manner as in Example 1, filtered, and washed with 150 g of water to obtain 60.0 g of a crude thiocarbamate. As a result of measuring the obtained crude crystal with a thermobalance, the water content was 48%. A small amount was sampled, dried, and analyzed by liquid chromatography. As a result, the purity was 99.9%. In addition, inorganic ion analysis by ion chromatography contained 530 ppm of chlorine ions, 300 ppm of carbonate ions, and 410 ppm of sodium ions.

  The obtained crude target thiocarbamate was dissolved as it was in 375 g of isopropyl alcohol, which was approximately 6.3 times the amount of the water-containing cake, at 75 ° C., filtered while hot using a filter having a pore size of 0.5 μm, cooled and further cooled to 45 The temperature was lowered under the condition of maintaining at 650C to 65C for 2 hours. Thereafter, the mixture was cooled to room temperature, filtered and dried to obtain 30.2 g (yield 95%) of the desired thiocarbamate crystals.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Table 1 shows the measurement results of the chlorine ion concentration and the carbonate ion concentration and the sodium ion concentration of the crude product and the refined product together with the dissolving operation and the cooling operation.

Example 3
Next, the examination results on an industrial scale are shown.

  39 kg (283 mol) of 2-methoxy-6-methylaminopyridine and 28.7 kg (271 mol) of sodium carbonate were put in a mixed solvent of 793 kg of isopropyl alcohol and 42 kg of water, and O- (5,6,7 with stirring. , 8-Tetrahydro-2-naphthyl) chlorothioformate 61 kg (269 mol) was added dropwise. Subsequently, after centrifugal filtration and washing with 1,226 kg of water, 107.0 kg of the resulting crude thiocarbamate was heated and dissolved in 573 kg of isopropyl alcohol at 72 ° C. and heated using a filter having a pore size of 0.5 μm. After time filtration, the mixture was cooled and further cooled under a condition of maintaining at 55 to 65 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature, filtered and dried to obtain 77.1 kg (yield 87%) of the desired thiocarbamate crystals.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Further, Table 2 shows the results of the ignition residue and the heavy metal limit test together with the cooling operation. Further, detailed analysis results of heavy metals are shown in Table 3.

  From the result of the ignition residue, removal of inorganic salts was confirmed. Moreover, it was confirmed that heavy metal is also less than 2 ppm.

Example 4
The reaction was carried out in the same manner as in Example 3, centrifugally filtered, washed with 1,217 kg of water, and 111.0 kg of the resulting crude thiocarbamate was dissolved in 573 kg of isopropyl alcohol by heating at 74 ° C. After hot filtration using a 0.5 μm filter, the mixture was cooled and further cooled down at 57 ° C. to 70 ° C. for 1.3 hours. Thereafter, the mixture was cooled to room temperature, filtered and dried to obtain 75.2 kg (yield 85%) of the desired thiocarbamate.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Further, Table 2 shows the results of the ignition residue and the heavy metal limit test together with the cooling operation. Further, detailed analysis results of heavy metals are shown in Table 3.

  From the result of the ignition residue, removal of inorganic salts was confirmed. Moreover, it was confirmed that heavy metal is also less than 2 ppm.

Example 5
After reacting in the same manner as in Example 3, centrifugal filtration, washing with 1,317 kg of water, 110.5 kg of the crude thiocarbamate obtained was directly dissolved in 573 kg of isopropyl alcohol by heating at 70 ° C. After hot filtration using a 0.5 μm filter, the mixture was cooled and further cooled under a condition of maintaining at 57 ° C. to 65 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature, filtered and dried to obtain 75.0 kg (yield 85%) of the desired thiocarbamate crystals.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Further, Table 2 shows the results of the ignition residue and the heavy metal limit test together with the cooling operation. Further, detailed analysis results of heavy metals are shown in Table 3.

  From the result of the ignition residue, removal of inorganic salts was confirmed. Moreover, it was confirmed that heavy metal is also less than 2 ppm.

Example 6
Reaction was carried out in the same manner as in Example 3, centrifugal filtration was performed, and after washing with 1,217 kg of water, 110.7 kg of the crude thiocarbamate obtained was directly dissolved in 573 kg of isopropyl alcohol at 70 ° C. After hot filtration using a 0.5 μm filter, it was cooled and further cooled down under the condition of holding at around 65 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature, filtered and dried to obtain 75.1 kg (yield 85%) of the desired thiocarbamate crystals.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.9%. Further, Table 2 shows the results of the ignition residue and the heavy metal limit test together with the cooling operation. Further, detailed analysis results of heavy metals are shown in Table 3.

  From the result of the ignition residue, removal of inorganic salts was confirmed. Moreover, it was confirmed that heavy metal is also less than 2 ppm.

Comparative Example 1
The reaction was conducted in the same manner as in Example 1, filtered, and washed with 150 g of water to obtain 70.0 g of a crude thiocarbamate. As a result of measuring the obtained crude crystal with a thermobalance, the water content was 56%. A small amount was sampled, dried, and analyzed by liquid chromatography. As a result, the purity was 99.8%. Moreover, in the inorganic ion analysis by ion chromatography, 520 ppm of chlorine ions, 280 ppm of carbonate ions, and 380 ppm of sodium ions were contained.

  87.7 g of the resulting crude thiocarbamate is heated and dissolved as it is in 215 g of isopropyl alcohol at 80 ° C., and after hot filtration using a filter having a pore size of 0.5 μm, it is kept in the range of 50 to 70 ° C. Without lowering the temperature continuously. After cooling to 20 ° C. in 1 hour, centrifugal filtration and drying, 30.1 g of target thiocarbamate crystals (yield 94%) was obtained.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.8%. Further, when ion chromatography analysis was performed on chlorine ion, carbonate ion and sodium ion, they were 80 ppm, 200 ppm and 140 ppm, respectively, and a large amount of inorganic salt was observed. Table 1 shows the measurement results of the chlorine ion concentration, carbonate ion concentration and sodium ion concentration of the crude product and the refined product, together with the dissolving operation and the cooling operation.

Comparative Example 2
As in Example 1, 24.8 g (0.180 mol) of raw materials 2-methoxy-6-methylaminopyridine and 38.7 g of O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate (0.171 mol) was reacted in the presence of 18.2 g (0.171 mol) of sodium carbonate in a mixed solvent of 241 g of isopropyl alcohol and 15.3 g of water and filtered to obtain crude crystals. The obtained crude crystals were washed with 280 g of isopropyl alcohol and 980 g of water, dissolved in 196 g of isopropyl alcohol, added with 2 g of activated carbon, and filtered while hot using a filter having a pore size of 0.5 μm around 80 ° C. Without maintaining the range, it was continuously recrystallized in a cooled state to obtain 48.4 g (yield: 86.3%) of the desired thiocarbamate.

  As a result of analyzing the purity of the obtained target thiocarbamate by liquid chromatography, the purity was 99.8%. Further, Table 2 shows the results of the ignition residue and the heavy metal limit test together with the cooling operation.

  From the result of the ignition residue, the inorganic salt remained. Also, the heavy metal content was high compared to the examples and was not sufficient.

Claims (4)

O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) represented by the following general formula (1), wherein the inorganic salt content is 300 ppm or less ) -N-methylthiocarbamate.

O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N- according to claim 1, characterized in that the heavy metal content is less than 2 ppm. Methyl thiocarbamate. Reaction of O- (5,6,7,8-tetrahydro-2-naphthyl) chlorothioformate with 2-methoxy-6-methylaminopyridine, or N-methyl-N- (6-methoxy-2-pyridyl) O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl)-obtained by reaction of carbamoyl chloride with 5,6,7,8-tetrahydro-2-naphthol In a method for recrystallizing N-methylthiocarbamate to produce O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate, The insoluble matter is filtered through a filter having a thickness of 20 μm or less, and then recrystallized under a condition that the temperature is maintained at 50 to 70 ° C. for 1 hour or longer. O-(5,6,7,8-tetrahydro-2-naphthyl) N- preparation of (6-methoxy-2-pyridyl) -N- methyl thiocarbamates according to 2. The production method according to claim 3, wherein the pore size of the filter is less than 1 μm.