JP2007099682A - Method for producing quazepam crystal - Google Patents
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- JP2007099682A JP2007099682A JP2005291619A JP2005291619A JP2007099682A JP 2007099682 A JP2007099682 A JP 2007099682A JP 2005291619 A JP2005291619 A JP 2005291619A JP 2005291619 A JP2005291619 A JP 2005291619A JP 2007099682 A JP2007099682 A JP 2007099682A
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本発明は、睡眠障害改善剤として有用な下式Ｉで示される一般名：クアゼパム（化学名：７−ｃｈｌｏｒｏ−５−（２−ｆｌｕｏｒｏｐｈｅｎｙｌ）−１，３−ｄｉｈｙｄｒｏ−１−（２，２，２−ｔｒｉｆｌｕｏｒｏｅｔｈｙｌ）−２Ｈ−１，４−ｂｅｎｚｏｄｉａｚｅｐｉｎｅ−２−ｔｈｉｏｎｅ）の工業的に有益な製造法に関するものである。
ＵＳＰ ２６（ＴＨＥ ＵＮＩＴＥＤ ＳＴＡＴＥＳ ＰＨＡＲＭＡＣＯＰＥＩＡ）によればクアゼパム原体の融点規格は１４６〜１５１℃である。
これに対して、クアゼパム結晶の製造方法としてはジクロロメタンとヘキサンの混合液から晶析する製造法が知られている。この方法により得られるのは融点１３９℃の結晶である。（特許文献１）
According to USP 26 (THE UNITED STATES PHARMOPEPEIA), the melting point standard of the quazepam base is 146 to 151 ° C.
On the other hand, as a method for producing a quazepam crystal, a method for producing a crystal from a mixed solution of dichloromethane and hexane is known. Crystals having a melting point of 139 ° C. are obtained by this method. (Patent Document 1)
医薬原体の物理化学的性質は薬効と重要な関係にあり、融点の違いは溶解速度、吸湿性、安定性、薬効に影響する重要な因子である。すなわち医薬品として許容されうるのは融点規格１４６〜１５１℃のクアゼパムだけである。これに対して前述の方法で得られるクアゼパム結晶は融点が１３９℃であり医薬品として使用できうるものではない。
工業的に結晶を得るための手段としては、所望の化合物を任意の溶媒と混合し、加熱と攪拌を加えて溶解せしめ、溶媒の蒸発や冷却等の操作により結晶を析出させるのが一般的である。所望の化合物を溶解する溶媒であれば結晶を得ることはできるが、工業的には、製品の歩留まりがよく、作業者の安全衛生上から扱いが容易（爆発性の低いこと、引火点が高いことなど）な溶媒の使用が求められる。
また医薬原体に使用する場合、溶媒の毒性が品質上重要となる。原体中に必ず溶媒は残存していることから結晶化に使用する溶媒は乾燥などの操作で除去が容易で、溶媒そのものの毒性が低いことが求められる。
したがって晶析による医薬原体製造法においては溶媒の選択が重要であるが、前述の要件を満たす溶媒を見出すことは画一的な溶媒のスクリーニングでは困難であり、溶媒種、溶媒量、晶析温度、晶析時間、乾燥方法（減圧乾燥、送風乾燥など）の各種条件を加味し適切な結晶製造法を決定する必要がある。
As a means for industrially obtaining crystals, a desired compound is generally mixed with an arbitrary solvent, dissolved by heating and stirring, and crystals are precipitated by operations such as evaporation and cooling of the solvent. is there. Crystals can be obtained if it is a solvent that dissolves the desired compound, but industrially, the yield of the product is good, and it is easy to handle from the safety and health of workers (low explosiveness, high flash point) Etc.) is required.
When used as a drug substance, the toxicity of the solvent is important in terms of quality. Since the solvent always remains in the raw material, the solvent used for crystallization is required to be easily removed by operations such as drying, and the solvent itself is required to have low toxicity.
Therefore, in the drug substance manufacturing method by crystallization, selection of the solvent is important, but finding a solvent that satisfies the above-mentioned requirements is difficult by uniform solvent screening, and the solvent type, solvent amount, crystallization It is necessary to determine an appropriate crystal production method in consideration of various conditions such as temperature, crystallization time, and drying method (vacuum drying, blow drying, etc.).
本発明の目的は、医薬品として有用なクアゼパム結晶の製造法を提供することにある。 The objective of this invention is providing the manufacturing method of a quazepam crystal | crystallization useful as a pharmaceutical.
本発明者らはクアゼパム結晶の製造法を鋭意検討した結果、エタノールまたはトルエン溶媒にクアゼパムを加え、加温溶解せしめ得られたクアゼパム溶液を冷却することによって、クアゼパム原体の融点規格１４６〜１５１℃を満たすクアゼパム結晶が得られることを見出し本発明を完成するに至った。 As a result of intensive studies on a method for producing quazepam crystals, the inventors of the present invention added quazepam to ethanol or toluene solvent, and cooled the quazepam solution obtained by heating to dissolve, whereby the melting point specification 146 to 151 ° C. The inventors have found that a quazepam crystal satisfying the above can be obtained, and have completed the present invention.
すなわち本発明は以下の手段によって達成される。
トルエンまたはエタノールを晶析溶媒とすることを特徴とする式Ｉで表されるクアゼパム結晶の製造法。
A method for producing a quazepam crystal represented by the formula I, wherein toluene or ethanol is used as a crystallization solvent.
本発明によれば、医薬品として有用なクアゼパム結晶を製造できる。 According to the present invention, quazepam crystals useful as pharmaceuticals can be produced.
クアゼパムは特公昭５６−２８９１４に記載の方法により製造できる化合物である。クアゼパムの結晶製造に使用するクアゼパム粗製物は粉体でもオイル状でも使用できるが、不純物の存在は得られる結晶の物理化学的特性に影響を与えることから９８％以上の液体クロマトグラフィー純度であることが望ましい。 Quazepam is a compound that can be produced by the method described in Japanese Patent Publication No. 56-28914. The crude zeazepam used for the production of crystals of quazepam can be used in the form of powder or oil, but the presence of impurities affects the physicochemical properties of the crystals obtained, so that it should have a liquid chromatographic purity of 98% or higher. Is desirable.
溶媒はトルエンまたはエタノールである。溶媒使用量はクアゼパム粗製体に対して２〜３倍容量で行うことができる。 The solvent is toluene or ethanol. The amount of the solvent used can be 2 to 3 times the volume of the crude quazepam.
溶媒とクアゼパムを混合し、攪拌しながら溶解する。溶解時の温度は５０℃〜７０℃である、溶解時の温度が低いと結晶が完全に溶解しないため、不均一なクアゼパム結晶となるため好ましくない。溶解温度が高いとクアゼパムの分解により、クロマトグラフィー純度が低下する。結晶を溶解せしめた溶液を３０℃以下まで徐冷する。より低温のほうが歩留まりが向上するが、あまり低温になるとクアゼパム粗製に由来する不純物が析出しクアゼパム結晶の品質低下を招くことから０℃程度までが好ましい。 Mix solvent and quazepam and dissolve with stirring. The temperature at the time of dissolution is from 50 ° C. to 70 ° C. If the temperature at the time of dissolution is low, the crystals are not completely dissolved, which is not preferable because nonuniform quazepam crystals are formed. If the dissolution temperature is high, the chromatographic purity decreases due to the decomposition of quazepam. The solution in which the crystals are dissolved is gradually cooled to 30 ° C. or lower. The yield is improved at a lower temperature. However, when the temperature is too low, impurities derived from the crude zeazepam are precipitated and the quality of the quazepam crystals is lowered.
冷却によって結晶が析出しスラリー状になる。冷却、攪拌を続けて十分に結晶を析出せしめた後、ろ過により結晶とろ液を分離する。湿結晶からの溶媒除去は送風乾燥、減圧乾燥などによって実施可能である。医薬品としての品質を満足するレベルまで容易に溶媒を除去することができる。 Crystals are precipitated by cooling to form a slurry. After cooling and stirring are continued to sufficiently precipitate crystals, the crystals and the filtrate are separated by filtration. Solvent removal from the wet crystal can be performed by air drying, drying under reduced pressure, or the like. The solvent can be easily removed to a level satisfying the quality as a pharmaceutical product.
以下、実施例によって本発明を具体的に説明するが、本発明は、これらの実施例に限定されるものではない。
実施例における液体クロマトグラフィー純度は、下記条件にて液体クロマトグラフィー分析を行い、各成分ピークの面積％を用いたものであり純度の指標とした。
装置：ＬＣ−２０００Ｐｌｕｓ ｓｅｒｉｅｓ（日本分光株式会社）
カラム：ＹＭＣＰＡＣＫ ＯＤＳ−ＡＭ
移動層：アセトニトリル／水／メタノール＝１１／５／４の混合液
検出波長：２２０ｎｍ
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples.
The liquid chromatography purity in the examples was obtained by performing liquid chromatography analysis under the following conditions and using the area% of each component peak, and was used as an index of purity.
Apparatus: LC-2000 Plus series (JASCO Corporation)
Column: YMCPACK ODS-AM
Moving layer: A mixture of acetonitrile / water / methanol = 11/5/4 Detection wavelength: 220 nm
実施例１
攪拌装置を備えた５００ｍＬ容器に液体クロマトグラフィー純度９８％以上のクアゼパム粗製１７２ｇ、トルエン２８０ｍＬを加え７０℃にて１時間攪拌し溶解させた。加温を止めて、３時間かけて１℃まで冷却した後、冷却温度を保持しながら１０時間攪拌した。吸引ろ過にてクアゼパム結晶とろ液を分離しケーキをトルエン６０ｍＬで洗浄した。結晶を５０℃にて１２時間送風乾燥し黄色のクアゼパム結晶１３５ｇを得た。収率７８．５％
液体クロマトグラフィー純度９９．８％
融点１４９．５℃（日本薬局方 融点測定法；第１法）
トルエン残量５００ｐｐｍ以下
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：４．２（１Ｈ，ｄ），４．４（１Ｈ，ｍ），５．５（１Ｈ，ｄ），６．３（１Ｈ，ｍ），７．１−７．７（７Ｈ，ｍ）
Example 1
In a 500 mL container equipped with a stirrer, 172 g of crude azeazepam having a liquid chromatography purity of 98% or more and 280 mL of toluene were added and stirred at 70 ° C. for 1 hour to dissolve. After stopping the heating and cooling to 1 ° C. over 3 hours, the mixture was stirred for 10 hours while maintaining the cooling temperature. The quazepam crystals and the filtrate were separated by suction filtration, and the cake was washed with 60 mL of toluene. The crystals were blown and dried at 50 ° C. for 12 hours to obtain 135 g of yellow quazepam crystals. Yield 78.5%
Liquid chromatography purity 99.8%
Melting point 149.5 ° C. (Japanese Pharmacopoeia Melting point measurement method: Method 1)
Toluene remaining amount 500ppm or less
1 H-NMR (CDCl 3 ) δ (ppm): 4.2 (1H, d), 4.4 (1H, m), 5.5 (1H, d), 6.3 (1H, m), 7 .1-7.7 (7H, m)
実施例２
攪拌装置を備えた２Ｌ容器に液体クロマトグラフィー純度９８％以上のクアゼパム粗製１７２ｇ、エタノール１３００ｍＬを加え７８℃にて１時間攪拌し溶解させた。加温を止めて、３時間かけて１℃まで冷却した後、冷却温度を保持しながら１０時間攪拌した。吸引ろ過にてクアゼパム結晶とろ液を分離しケーキをトルエン６０ｍＬで洗浄した。結晶を５０℃にて１２時間送風乾燥し黄色のクアゼパム結晶１２９ｇを得た。収率７５．０％
液体クロマトグラフィー純度９９．８％
融点１４８．７℃（日本薬局方 融点測定法；第１法）
乾燥減量０．１％
１Ｈ−ＮＭＲ（ＣＤＣｌ３）δ（ｐｐｍ）：４．２（１Ｈ，ｄ），４．４（１Ｈ，ｍ），５．５（１Ｈ，ｄ），６．３（１Ｈ，ｍ），７．１−７．７（７Ｈ，ｍ）
Example 2
To a 2 L vessel equipped with a stirrer, 172 g of quazepam crude having a liquid chromatography purity of 98% or higher and 1300 mL of ethanol were added and stirred for 1 hour at 78 ° C. to dissolve. After stopping the heating and cooling to 1 ° C. over 3 hours, the mixture was stirred for 10 hours while maintaining the cooling temperature. The quazepam crystals and the filtrate were separated by suction filtration, and the cake was washed with 60 mL of toluene. The crystals were blown and dried at 50 ° C. for 12 hours to obtain 129 g of yellow quazepam crystals. Yield 75.0%
Liquid chromatography purity 99.8%
Melting point 148.7 ° C. (Japanese Pharmacopoeia Melting point measurement method; Method 1)
Loss on drying 0.1%
1 H-NMR (CDCl 3 ) δ (ppm): 4.2 (1H, d), 4.4 (1H, m), 5.5 (1H, d), 6.3 (1H, m), 7 .1-7.7 (7H, m)
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| JPS5628914B1 (en) * | 1970-08-07 | 1981-07-04 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS5628914B1 (en) * | 1970-08-07 | 1981-07-04 |
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