JP7426832B2 - Iguratimod with a novel crystal structure and its production method - Google Patents
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- ANMATWQYLIFGOK-UHFFFAOYSA-N Iguratimod Chemical compound CS(=O)(=O)NC1=CC=2OC=C(NC=O)C(=O)C=2C=C1OC1=CC=CC=C1 ANMATWQYLIFGOK-UHFFFAOYSA-N 0.000 title claims description 133
- 229950003909 iguratimod Drugs 0.000 title claims description 131
- 239000013078 crystal Substances 0.000 title claims description 129
- 238000004519 manufacturing process Methods 0.000 title claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 250
- 150000002576 ketones Chemical class 0.000 claims description 37
- 239000012453 solvate Substances 0.000 claims description 31
- 239000012046 mixed solvent Substances 0.000 claims description 21
- 238000002441 X-ray diffraction Methods 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- 238000002844 melting Methods 0.000 claims description 14
- 230000008018 melting Effects 0.000 claims description 14
- 230000005855 radiation Effects 0.000 claims description 2
- 238000005259 measurement Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- 238000000113 differential scanning calorimetry Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Chemical class 0.000 description 9
- 238000001878 scanning electron micrograph Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000004817 gas chromatography Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- MEPKWXDCDSQRNS-UHFFFAOYSA-N n-[5-hydroxy-4-[2-hydroxy-4-(methanesulfonamido)-5-phenoxybenzoyl]-2-phenoxyphenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(O)=C(C(=O)C=2C(=CC(NS(C)(=O)=O)=C(OC=3C=CC=CC=3)C=2)O)C=C1OC1=CC=CC=C1 MEPKWXDCDSQRNS-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003828 vacuum filtration Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 239000005453 ketone based solvent Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- -1 amine salt Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、新規な結晶構造を有するイグラチモド（化学名称：Ｎ－［３－（ホルミルアミノ）－４－オキソ－６－フェノキシ－４Ｈ－クロメン－７－イル］メタンスルホンアミド）及びその製造方法に関する。 The present invention relates to iguratimod (chemical name: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide) having a novel crystal structure and a method for producing the same. .
下記式（１） The following formula (1)
で示されるイグラチモド（化学名称：Ｎ－［３－（ホルミルアミノ）－４－オキソ－６－フェノキシ－４Ｈ－クロメン－７－イル］メタンスルホンアミド）は、優れた抗炎症作用、解熱鎮痛作用、抗関節炎作用および抗アレルギー作用を示す治療薬として非常に有用な化合物である（特許文献１参照）。以下、単に、「イグラチモド」とする場合もある。 Iguratimod (chemical name: N-[3-(formylamino)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide), represented by It is a very useful compound as a therapeutic agent that exhibits anti-arthritic and anti-allergic effects (see Patent Document 1). Hereinafter, it may be simply referred to as "iguratimod."
このイグラチモドは、結晶多形を有することが知られている（特許文献２参照）。ここで、結晶多形を有するとは、同一分子において結晶構造が異なる複数の結晶形が存在することを意味する。結晶多形における各結晶形間では、外観、結晶形状、溶解性、融点、溶出率、バイオアベイラビリティー、安定性、有効性などの医薬品としての品質に関係する特性が異なることが多い。 This iguratimod is known to have crystal polymorphism (see Patent Document 2). Here, having crystal polymorphism means that the same molecule has multiple crystal forms with different crystal structures. Characteristics related to pharmaceutical quality, such as appearance, crystal shape, solubility, melting point, dissolution rate, bioavailability, stability, and effectiveness, often differ between crystalline polymorphs.
イグラチモドは、通常、下記式（２） Iguratimod is usually administered by the following formula (2):
で示されるホルミルアミノメチル（２－ヒドロキシ－４－メチルスルホニルアミノ－５－フェノキシフェニル）ケトンを氷酢酸及びＮ，Ｎ－ジメチルホルムアミドジメチルアセタール存在下、環形成化反応に付すことによって合成される（特許文献３、４参照）。 It is synthesized by subjecting formylaminomethyl (2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl) ketone represented by to a ring-forming reaction in the presence of glacial acetic acid and N,N-dimethylformamide dimethyl acetal ( (See Patent Documents 3 and 4).
特許文献３および４には、環形成化反応を行った後、得られたイグラチモド粗体を水酸化カリウム存在下、含水アセトン中に溶解させ、塩酸で中和晶出してイグラチモドのα晶を取得する方法が記載されている。 Patent Documents 3 and 4 disclose that after performing a ring-forming reaction, the obtained crude iguratimod is dissolved in aqueous acetone in the presence of potassium hydroxide, and neutralized and crystallized with hydrochloric acid to obtain α-crystals of iguratimod. It describes how to do this.
また、特許文献２には、イグラチモドのα晶を２－ブタノン、ベンゼン、トルエン又はキシレンから再結晶することにより、吸湿性が低く、さらに帯電しにくく取り扱いが容易なβ晶へと変換する方法やアセトニトリル中で攪拌することにより吸湿性の低いγ晶へと変換する方法が記載されている。 Furthermore, Patent Document 2 describes a method of recrystallizing the α-crystal of iguratimod from 2-butanone, benzene, toluene, or xylene to convert it into a β-crystal that has low hygroscopicity and is less electrified and easier to handle. A method of converting it into γ crystals with low hygroscopicity by stirring in acetonitrile is described.
一般的に化合物を医薬品原薬として使用する場合には非常に高純度のものが望まれている。しかしながら、本発明者らが特許文献３、４に記載の方法でイグラチモドを合成したところ、環形成化反応中に下記式（３） Generally, when a compound is used as a drug substance, it is desired to have extremely high purity. However, when the present inventors synthesized iguratimod by the method described in Patent Documents 3 and 4, the following formula (3) was synthesized during the ring formation reaction.
で示されるイグラチモドのＮ－メチル体（化学名称：Ｎ－メチル－Ｎ－［３－（カルボキシアミド）－４－オキソ－６－フェノキシ－４Ｈ－１－ベンゾピラン－７－イル］メタンスルホンアミド）が一定量副生することが分かった。以下、単に、「Ｎ－メチル体」とする場合もある。 The N-methyl form of iguratimod (chemical name: N-methyl-N-[3-(carboxyamido)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide) represented by It was found that a certain amount is produced as a by-product. Hereinafter, it may be simply referred to as "N-methyl form".
当該Ｎ－メチル体は構造がイグラチモドと非常に類似していることから、特許文献３、４に記載の含水アセトン溶媒から中和晶出した場合も除去が困難であり、高純度のイグラチモドを得るためには繰り返して精製操作を行う必要があった。また、前記製法で取得したイグラチモドのα晶を用いて特許文献２に記載の精製方法によってβ晶やγ晶を合成したところ、同様に前記Ｎ－メチル体の除去効率は低く、且つ、晶析操作を実施するためには多量の有機溶媒が必要であることが分かった。さらに、前記製造方法によって得られるイグラチモドのα晶、β晶、γ晶は図５、８、１０に示すようにすべて針状結晶であり、帯電し易く、且つ取り扱いが非常に困難であることから、操作性の点からも大きな問題であった。 Since the structure of the N-methyl compound is very similar to that of iguratimod, it is difficult to remove even when crystallized by neutralization from the aqueous acetone solvent described in Patent Documents 3 and 4, and highly pure iguratimod is obtained. This required repeated purification operations. Further, when β crystals and γ crystals were synthesized by the purification method described in Patent Document 2 using the α crystal of iguratimod obtained by the above production method, the removal efficiency of the N-methyl form was similarly low, and the crystallization It was found that large amounts of organic solvent were required to carry out the operation. Furthermore, the α, β, and γ crystals of iguratimod obtained by the above production method are all needle-shaped crystals as shown in FIGS. 5, 8, and 10, and are easily charged and extremely difficult to handle. This was also a big problem from the point of view of operability.
したがって、本発明の目的は、Ｎ－メチル体の含有量が低減され、且つ帯電しにくく、取り扱いが容易な新規な結晶形を有するイグラチモドの結晶、およびその製造方法を提供することにある。 Therefore, an object of the present invention is to provide crystals of iguratimod having a new crystal form that has a reduced content of N-methyl forms, is less likely to be charged, and is easy to handle, and a method for producing the same.
本発明者らは、上記課題に対して鋭意検討を行った。具体的には、様々な溶媒を用いてイグラチモドの再結晶を行った。その結果、Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒を使用して、イグラチモドの結晶化を行ったところ、Ｎ－メチル体を含むイグラチモドの不純物を効率的に低減できることが分かった。加えて、得られたイグラチモドの結晶は、その結晶形が既知の結晶形とは異なる新規の結晶形であり、既知の結晶形と比較して、帯電しにくく、且つ取り扱いが容易な結晶であることを見出し、本発明を完成するに至った。 The inventors of the present invention have conducted extensive studies on the above-mentioned problems. Specifically, iguratimod was recrystallized using various solvents. As a result, when we crystallized iguratimod using N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones, we found that impurities in iguratimod, including the N-methyl compound, were efficiently removed. It was found that it was possible to reduce the In addition, the obtained iguratimod crystals have a new crystal form that is different from known crystal forms, and are less likely to be charged and easier to handle than known crystal forms. This discovery led to the completion of the present invention.
Ｎ－メチル体を含むイグラチモドの不純物を効率的に低減できる理由については明らかではないが、本発明によって得られるイグラチモドの新規結晶は既知結晶形と比較してアスペクト比が小さな板状結晶であることから、ろ過が容易となり、不純物を含む母液が結晶に残存しにくくなったため、効率的に精製ができているものと考えられる。 Although it is not clear why impurities in iguratimod, including the N-methyl form, can be efficiently reduced, the new crystals of iguratimod obtained by the present invention are plate-shaped crystals with a smaller aspect ratio compared to known crystal forms. Therefore, it is thought that filtration is easier and mother liquor containing impurities is less likely to remain in the crystals, resulting in efficient purification.
即ち、第一の本発明は、イグラチモドをＮ，Ｎ－ジメチルホルムアミド又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒中で結晶化させることを特徴とするイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶の製造方法である。 That is, the first invention provides an N,N-dimethylformamide solvent for iguratimod, which is characterized in that iguratimod is crystallized in N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones. This is a method for producing Japanese crystals.
また、第二の本発明は、Ｃｕ－Ｋα線を用いるＸ線回折により、少なくとも２θ＝１５．９±０．２°、１９．４±０．２°、２２．７±０．２°、２６．５±０．２°に特徴的なピークを与える結晶構造を有するイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶である。 Further, the second invention provides at least 2θ=15.9±0.2°, 19.4±0.2°, 22.7±0.2°, This is a crystal of the N,N-dimethylformamide solvate of iguratimod having a crystal structure giving a characteristic peak at 26.5±0.2°.
さらに、第二の本発明のイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物は、少なくとも、１００～１１０℃の温度範囲、および２４０～２５０℃の温度範囲に融点を有する化合物の結晶となることが好ましい。 Furthermore, the N,N-dimethylformamide solvate of iguratimod of the second invention can form crystals of a compound having a melting point in the temperature range of at least 100 to 110°C and 240 to 250°C. preferable.
本発明の方法によれば、Ｎ－メチル体が容易に除去でき、既知の結晶形とは異なる新規の結晶形を有するイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得ることができる。本発明の方法により得られるイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は、Ｎ－メチル体の含有量が低減された高純度な結晶であり、且つ新規な結晶構造を有しており、帯電しにくく、取り扱いが容易な結晶である。そのため、特に高純度の原薬を必要とする医薬品等の中間体として、最適に利用することが出来る。 According to the method of the present invention, the N-methyl compound can be easily removed and crystals of the N,N-dimethylformamide solvate of iguratimod having a new crystal form different from known crystal forms can be obtained. The crystals of N,N-dimethylformamide solvate of iguratimod obtained by the method of the present invention are highly pure crystals with a reduced content of N-methyl forms, and have a novel crystal structure. , it is a crystal that is difficult to charge and easy to handle. Therefore, it can be optimally used as an intermediate for pharmaceutical products that require particularly high purity drug substances.
本発明は、イグラチモドをＮ，Ｎ－ジメチルホルムアミド又はＮ，Ｎ－ジメチルホルムアミドとケトン類の混合溶媒中で結晶化させることを特徴とするイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の製造方法である。以下、順を追って説明する。 The present invention provides a method for producing an N,N-dimethylformamide solvate of iguratimod, which comprises crystallizing iguratimod in N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones. be. The following is a step-by-step explanation.
（対象イグラチモド）
本発明において使用されるイグラチモドは、特に制限されず、公知の方法で製造されたものを使用することができる。例えば、特許文献３及び４に記載の方法で製造することができる。イグラチモドの合成ルートを以下に示す。
(Target iguratimod)
Iguratimod used in the present invention is not particularly limited, and those produced by known methods can be used. For example, it can be manufactured by the methods described in Patent Documents 3 and 4. The synthetic route for iguratimod is shown below.
具体的には、Ｎ，Ｎ－ジメチルホルムアミド中、氷酢酸存在下、ホルミルアミノメチル（２－ヒドロキシ－４－メチルスルホニルアミノ－５－フェノキシフェニル）ケトンとＮ，Ｎ－ジメチルホルムアミドジメチルアセタールを反応温度１５～２０℃で５時間反応させることにより、イグラチモドを製造することができる（特許文献３、実施例５、及び特許文献４、実施例６を参照）。 Specifically, in the presence of glacial acetic acid in N,N-dimethylformamide, formylaminomethyl (2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl) ketone and N,N-dimethylformamide dimethyl acetal were reacted at a temperature Iguratimod can be produced by reacting at 15 to 20° C. for 5 hours (see Patent Document 3, Example 5, and Patent Document 4, Example 6).
本発明において使用されるイグラチモドは、一旦溶液状態とするため、その結晶形などは特に限定されず、たとえば特許文献２に記載の他の結晶形（β晶、γ晶）、アモルファス、有機／無機アミン塩またはこれらが混合した形態であってもよく、粉末、塊状物、またはこれらが混合した形状であってもよく、無水物、水和物、溶媒和物またはこれらが混合した形態であってもよい。水和物または溶媒和物であるときの水または溶媒の分子数は特に制限されない。また、イグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の製造時にＮ，Ｎ－ジメチルホルムアミド又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒を用いることから、Ｎ，Ｎ－ジメチルホルムアミド又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒を含む湿体であってもよい。その他の溶媒についても、結晶化の際に影響を及ぼさない範囲で含んでいてもよい。具体的には、当該イグラチモドの湿体の３０質量％以下の量で残留していてもよいが、Ｎ，Ｎ－ジメチルホルムアミド又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒以外の溶媒を含まないことが最も好ましい。また、使用するイグラチモドの純度は特に制限されず、上記製造方法によって得られたものをそのまま使用することができる。ただし、最終的に得られるイグラチモドの結晶の純度をより高くするために、一般的な精製方法、例えば再結晶やリスラリー、カラムクロマトグラフィーなどの方法により、必要に応じて１回以上精製したものを、イグラチモドとして利用することもできる。 Since iguratimod used in the present invention is once in a solution state, its crystal form is not particularly limited. For example, other crystal forms (β crystal, γ crystal), amorphous, organic/inorganic It may be in the form of an amine salt or a mixture thereof; it may be in the form of a powder, a lump, or a mixture thereof; it may be an anhydride, a hydrate, a solvate, or a mixture thereof; Good too. The number of water or solvent molecules in a hydrate or solvate is not particularly limited. In addition, since N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones is used in the production of N,N-dimethylformamide solvate of iguratimod, N,N-dimethylformamide or N,N-dimethylformamide and ketones are used. A wet body containing a mixed solvent of N-dimethylformamide and ketones may be used. Other solvents may also be included as long as they do not affect crystallization. Specifically, solvents other than N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones may remain in an amount of 30% by mass or less of the wet iguratimod. Most preferably, it does not. Further, the purity of iguratimod used is not particularly limited, and the one obtained by the above production method can be used as is. However, in order to further increase the purity of the final iguratimod crystals, they may be purified one or more times as necessary using general purification methods such as recrystallization, reslurry, and column chromatography. , can also be used as iguratimod.
具体的には、下記の実施例で記載した高速液体クロマトグラフィー（ＨＰＬＣ）の条件で測定した際、イグラチモドのピーク面積割合が９５％以上であるイグラチモドを対象とすることが好ましい。また、Ｎ－メチル体の低減を目的とするのではなく操作性の高い結晶を得ることを目的として、前記ＨＰＬＣの純度測定において、イグラチモドのピーク面積割合が１００％となるものを使用することもできる。 Specifically, it is preferable to target iguratimod whose peak area ratio is 95% or more when measured under the high performance liquid chromatography (HPLC) conditions described in the Examples below. In addition, for the purpose of obtaining crystals with high operability, rather than for the purpose of reducing the N-methyl form, a product with a peak area ratio of 100% of iguratimod may be used in the HPLC purity measurement. can.
（イグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の製造方法）
（溶媒；Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒）
本発明においては、前記対象イグラチモドの純度を高くし、かつ結晶形を取り扱いが容易な新規結晶形へ変形させるためには、対象イグラチモドを、Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒中で結晶化させる必要がある。Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒を使用することにより、２－ブタノン、ベンゼン、トルエン、キシレン又はアセトニトリルを用いた従来の方法と比べて、イグラチモドのＮ－メチル体等の不純物を効率よく低減することができ、さらに、従来の結晶とは異なる新規の結晶構造を有するイグラチモドを得ることができる。
(Process for producing N,N-dimethylformamide solvate of iguratimod)
(Solvent: N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones)
In the present invention, in order to increase the purity of the target iguratimod and transform the crystal form into a new crystal form that is easy to handle, the target iguratimod is treated with N,N-dimethylformamide or N,N-dimethylformamide. It is necessary to crystallize in a mixed solvent of and ketones. By using N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones, iguratimod is Impurities such as N-methyl forms can be efficiently reduced, and iguratimod having a new crystal structure different from conventional crystals can be obtained.
本発明で使用する溶媒は、Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒であり、Ｎ，Ｎ－ジメチルホルムアミドとケトン類との合計の容積を１００としたとき、Ｎ，Ｎ－ジメチルホルムアミドの容積比率が１００～５０％、ケトン類の容積比率が０～５０％となるものが好ましい。本発明者等の検討によれば、容積比率５０％以下の範囲でケトン類を含む場合であっても、ケトン類を含まない（Ｎ，Ｎ－ジメチルホルムアミドのみの）場合と同様に、新規の結晶形を取得できることが分かった。そのため、使用するＮ，Ｎ－ジメチルホルムアミドの容積比率よりも、ケトン類の容積比率が大きくならない範囲であれば、対象イグラチモド中のケトン類の残量を厳密に管理する必要がない。そのため、対象イグラチモドがケトン類を含む湿体である場合には、そのケトン類の残量を測定して、使用するＮ，Ｎ－ジメチルホルムアミドの量を調整してやればよい。また、対象イグラチモドがＮ，Ｎ－ジメチルホルムアミド又はケトン類以外の他の溶媒を含む湿体である場合には、湿体に含まれる他の溶媒の合計量を測定し、算出される対象イグラチモドの純分に対して溶媒量を決定すればよいが、他の溶媒の含有量は溶媒の全量に対して２０ｖｏｌ％以下であることが好ましい。 The solvent used in the present invention is N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones, and the total volume of N,N-dimethylformamide and ketones is 100. In this case, it is preferable that the volume ratio of N,N-dimethylformamide is 100 to 50% and the volume ratio of ketones is 0 to 50%. According to the studies of the present inventors, even when ketones are included in a volume ratio of 50% or less, the new It turns out that it is possible to obtain a crystalline form. Therefore, as long as the volume ratio of ketones does not become larger than the volume ratio of N,N-dimethylformamide used, it is not necessary to strictly control the remaining amount of ketones in the target iguratimod. Therefore, when the target iguratimod is a wet substance containing ketones, the amount of the remaining ketones may be measured and the amount of N,N-dimethylformamide used may be adjusted. In addition, if the target iguratimod is a wet body containing N,N-dimethylformamide or other solvents other than ketones, the total amount of other solvents contained in the wet body is measured, and the target iguratimod is calculated by measuring the total amount of other solvents contained in the wet body. Although the amount of solvent may be determined based on the pure content, it is preferable that the content of other solvents is 20 vol% or less based on the total amount of solvent.
本発明において、使用するＮ，Ｎ－ジメチルホルムアミド、及びケトン類の溶媒は、特に制限されず市販のものをそのまま使用することができる。ケトン類の溶媒について、具体的に例示すれば、アセトン、メチルエチルケトン、メチルイソブチルケトン、ジイソブチルケトン、シクロヘキサノン等が挙げられる。この中でも、収率および溶媒の汎用性を考慮すると、アセトンを選択することがより好ましい。また、これらのケトン類は１種類を使用することもできるし、複数種類を混合して使用することもできる。複数種類のケトン類を混合して使用する場合には、使用したケトン類の合計容量が容積比率５０％以下であればよい。本発明において、ケトン類を使用する場合には、Ｎ，Ｎ－ジメチルホルムアミドの容積比率が９９～５０、ケトン類の容積比率が１～５０となるものが好ましく、Ｎ，Ｎ－ジメチルホルムアミドの容積比率が９９～７０、ケトン類の容積比率が１～３０となるものが最も好ましい。 In the present invention, the N,N-dimethylformamide and ketone solvents used are not particularly limited, and commercially available ones can be used as they are. Specific examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, and cyclohexanone. Among these, acetone is more preferably selected in consideration of yield and versatility of the solvent. Furthermore, these ketones can be used alone or in combination. When a mixture of multiple types of ketones is used, the total volume of the ketones used may be 50% or less by volume. In the present invention, when using ketones, it is preferable that the volume ratio of N,N-dimethylformamide is 99 to 50, and the volume ratio of ketones is 1 to 50. Most preferably, the ratio is 99 to 70, and the volume ratio of ketones is 1 to 30.
Ｎ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒を使用する場合、ケトン類の容積比率をなるべく少なくすることで、使用する溶媒量を低減することができる。 When using a mixed solvent of N,N-dimethylformamide and ketones, the amount of solvent used can be reduced by reducing the volume ratio of ketones as much as possible.
（結晶化の方法）
使用するＮ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒の使用量は、特に制限されるものではないが、前記対象イグラチモドの結晶１ｇに対して、２～２０ｍｌとすることが好ましく、さらに３～１０ｍｌとすることがより好ましい。なお、使用する溶媒の前記体積は、２３℃における体積である。また、混合溶媒を使用する場合には、基準となる溶媒の量は、Ｎ，Ｎ－ジメチルホルムアミドおよびケトン類の合計量である。
(Crystallization method)
The amount of N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones to be used is not particularly limited, but is 2 to 20 ml per 1 g of target iguratimod crystals. The amount is preferably 3 to 10 ml, and more preferably 3 to 10 ml. Note that the volume of the solvent used is the volume at 23°C. Furthermore, when a mixed solvent is used, the standard amount of solvent is the total amount of N,N-dimethylformamide and ketones.
再結晶の方法としては、Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドおよびケトン類の混合溶媒中に前記対象イグラチモドを溶解させ、好ましくは、得られる溶液を６０～９０℃に加熱し、次いで、１０～３０℃／時間の冷却速度で冷却し、好ましくは０～３０℃、さらに好ましくは－１０～３０℃、特に好ましくは－１０～２０℃の温度範囲で一定時間保持することが好ましい。なお、イグラチモドに対してケトン類の溶媒は溶解度が低いため、対象となるイグラチモドはＮ，Ｎ－ジメチルホルムアミド中に溶解することが好ましい。Ｎ，Ｎ－ジメチルホルムアミドのみに溶解させることによって、より少ない溶媒量で対象イグラチモドを溶解することができ、高収率でイグラチモドを回収することが可能となる。なお、Ｎ，Ｎ－ジメチルホルムアミドとケトン類の混合溶媒中からイグラチモドを結晶化させる場合には、一度、Ｎ，Ｎ－ジメチルホルムアミドに溶解させた後にケトン類の溶媒を追加すればよい。 The recrystallization method involves dissolving the target iguratimod in N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones, and preferably heating the resulting solution to 60 to 90°C. Then, it is cooled at a cooling rate of 10 to 30 °C/hour, and maintained for a certain period of time at a temperature range of preferably 0 to 30 °C, more preferably -10 to 30 °C, particularly preferably -10 to 20 °C. preferable. Note that since the solubility of ketones in solvents is low for iguratimod, it is preferable that the target iguratimod be dissolved in N,N-dimethylformamide. By dissolving only in N,N-dimethylformamide, the target iguratimod can be dissolved with a smaller amount of solvent, making it possible to recover iguratimod in a high yield. When crystallizing iguratimod from a mixed solvent of N,N-dimethylformamide and ketones, the ketone solvent may be added after dissolving it in N,N-dimethylformamide.
また、イグラチモドとジメチルホルムアミドとを混合して溶液を調整すれば良く、混合する方法や順序も特に制限されない。 Further, a solution may be prepared by mixing iguratimod and dimethylformamide, and the method and order of mixing are not particularly limited.
（イグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶）
本発明のイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は、Ｃｕ－Ｋα線を用いるＸ線回折により、少なくとも２θ＝１５．９±０．２°、１９．４±０．２°、２２．７±０．２°、２６．５±０．２°に特徴的なピークを有する化合物である。このイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶のＸ線回折測定結果を図１に示した。また、前記イグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は、図２に示すようにその結晶形態は板状結晶であり、特許文献２、３、４で得られる既知のイグラチモド結晶と比較して、アスペクト比が低く、取り扱いが容易な結晶となる。
(Crystals of N,N-dimethylformamide solvate of iguratimod)
Crystals of the N,N-dimethylformamide solvate of iguratimod of the present invention were determined by X-ray diffraction using Cu-Kα radiation to have 2θ=15.9±0.2°, 19.4±0.2°, This compound has characteristic peaks at 22.7±0.2° and 26.5±0.2°. The results of X-ray diffraction measurements of the crystals of the N,N-dimethylformamide solvate of iguratimod are shown in FIG. In addition, the crystal form of the N,N-dimethylformamide solvate of iguratimod is a plate-like crystal as shown in FIG. 2, and compared with known iguratimod crystals obtained in Patent Documents 2, 3, and 4. As a result, the crystal has a low aspect ratio and is easy to handle.
さらに、本発明におけるイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は少なくとも融点が２つ存在する、新規な結晶形である。中でも、Ｎ，Ｎ－ジメチルホルムアミド、又はＮ，Ｎ－ジメチルホルムアミドとケトン類との混合溶媒中で結晶化させて得られるイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は、実施例で示した示差走査熱量測定の条件で測定した融点が、少なくとも１００～１１０℃、２４０～２５０℃に観察される。示差走査熱量測定の結果を図３に示した。なお、本発明において、該示差走査熱量（ＤＳＣ）測定で決定される融点は測定により得られた吸熱ピークのピークトップ温度を指す。 Furthermore, the crystals of the N,N-dimethylformamide solvate of iguratimod in the present invention are a novel crystal form that has at least two melting points. Among them, crystals of N,N-dimethylformamide solvate of iguratimod obtained by crystallization in N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones are as shown in Examples. The melting point measured under differential scanning calorimetry conditions is at least 100 to 110°C and 240 to 250°C. The results of differential scanning calorimetry are shown in FIG. 3. In the present invention, the melting point determined by the differential scanning calorimetry (DSC) measurement refers to the peak top temperature of the endothermic peak obtained by the measurement.
得られた結晶がイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶であることは、５０℃で２４時間乾燥して、重量変化がなくなった結晶がＸ線回折－示差走査熱量同時測定（ＸＲＤ－ＤＳＣ）により、１００～１１０℃付近でβ晶に転移すること、ガスクロマトグラフィー（ＧＣ）によりＮ，Ｎ－ジメチルホルムアミドが検出されることから確認できる。ＤＳＣの１００～１１０℃のピークは溶媒和物由来であり、当該温度で溶媒和物がＮ，Ｎ－ジメチルホルムアミドをリリースしてβ晶に転移している。 The obtained crystals are N,N-dimethylformamide solvate crystals of iguratimod, which are confirmed by simultaneous X-ray diffraction and differential scanning calorimetry (XRD) when the crystals show no change in weight after drying at 50°C for 24 hours. -DSC), it can be confirmed that it transitions to a β crystal at around 100 to 110°C, and that N,N-dimethylformamide is detected by gas chromatography (GC). The DSC peak at 100 to 110°C is derived from the solvate, and at this temperature the solvate releases N,N-dimethylformamide and transforms into β crystals.
本発明において得られるイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶は、Ｎ－メチル体の含有量が低減された高純度な結晶であり、且つ新規な結晶構造を有しており、取り扱いが容易な結晶である。そのため、特に高純度の原薬を必要とする医薬品等の中間体として、そのまま利用することが出来る。 The crystals of N,N-dimethylformamide solvate of iguratimod obtained in the present invention are highly pure crystals with a reduced content of N-methyl forms, and have a novel crystal structure, making them easy to handle. is an easy crystal. Therefore, it can be used as is, especially as an intermediate for pharmaceutical products that require highly pure drug substances.
以下、実施例を挙げて本発明を更に具体的に説明するが、本発明はこれらの実施例によって何等制限されることはない。 EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples in any way.
なお、製造例、実施例、比較例で得られるイグラチモドの純度測定、Ｎ－メチル体の含有量の測定、粉末Ｘ線回折（ＸＲＤ）の測定、示差走査熱量計（ＤＳＣ）を用いた融点の測定、走査型電子顕微鏡（ＳＥＭ）を用いた結晶形状の測定は、以下の方法でおこなった。 In addition, the purity measurement of iguratimod obtained in the production examples, examples, and comparative examples, the measurement of the content of N-methyl form, the measurement of powder X-ray diffraction (XRD), and the measurement of the melting point using differential scanning calorimeter (DSC) Measurement: The crystal shape was measured using a scanning electron microscope (SEM) in the following manner.
＜イグラチモドの純度、Ｎ－メチル体の含有量の測定＞
装置：高速液体クロマトグラフィー（ＨＰＬＣ）
機種：２６９５－２４８９－２９９８（Ｗａｔｅｒｓ社製）
検出器：紫外吸光光度計（測定波長：２４０ｎｍ）
カラム：Ｋｉｎｅｔｅｘ Ｃ１８、内径４．６ｍｍ、長さ２５ｃｍ（粒子径５μｍ）（Ｐｈｅｎｏｍｅｎｅｘ社製）
カラム温度：３０℃一定
サンプル温度：２５℃一定
移動相Ａ：アセトニトリル
移動相Ｂ：１５ｍＭリン酸二水素カリウム水溶液（ｐＨ＝２．５ リン酸にて調整）
移動相の送液：移動相Ａ，Ｂの混合比を表１のように変えて濃度勾配制御する
<Measurement of purity of iguratimod and content of N-methyl form>
Equipment: High performance liquid chromatography (HPLC)
Model: 2695-2489-2998 (manufactured by Waters)
Detector: Ultraviolet absorption photometer (measurement wavelength: 240 nm)
Column: Kinetex C18, inner diameter 4.6 mm, length 25 cm (particle size 5 μm) (manufactured by Phenomenex)
Column temperature: 30°C constant Sample temperature: 25°C constant Mobile phase A: Acetonitrile Mobile phase B: 15mM potassium dihydrogen phosphate aqueous solution (pH = 2.5, adjusted with phosphoric acid)
Mobile phase delivery: Control the concentration gradient by changing the mixing ratio of mobile phases A and B as shown in Table 1.
流速：０．８ｍＬ／分
測定時間：４５分
Flow rate: 0.8mL/min Measurement time: 45 minutes
なお、上記ＨＰＬＣの測定条件において、前記ホルミルアミノメチル（２－ヒドロキシ－４－メチルスルホニルアミノ－５－フェノキシフェニル）ケトンは約５．６分、前記イグラチモドは約８．２分、前記Ｎ－メチル体は約１０．３分にピークが確認される。 In addition, under the above HPLC measurement conditions, the formylaminomethyl (2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl) ketone took about 5.6 minutes, the iguratimod took about 8.2 minutes, and the N-methyl For the body, a peak is observed at approximately 10.3 minutes.
以下の実施例、比較例において、イグラチモドの純度、Ｎ－メチル体の含有量は共に、上記条件で測定したピーク面積％の値である。 In the following Examples and Comparative Examples, both the purity of iguratimod and the content of N-methyl form are the values of peak area % measured under the above conditions.
＜イグラチモドの結晶形の測定＞
装置：Ｘ線回折装置（ＸＲＤ）
機種：ＳｍａｒｔＬａｂ（株式会社リガク製）
測定方法：ＡＳＣ６ ＢＢ Ｄｔｅｘ
Ｘ 線出力：４０ｋＶ－３０ｍＡ
波長：ＣｕＫａ／１．５４１８８２Å
<Measurement of crystal form of iguratimod>
Equipment: X-ray diffraction device (XRD)
Model: SmartLab (manufactured by Rigaku Co., Ltd.)
Measurement method: ASC6 BB Dtex
X-ray output: 40kV-30mA
Wavelength: CuKa/1.541882Å
＜イグラチモドの融点の測定＞
装置：示差走査熱量計（ＤＳＣ）
機種：ＤＳＣ６２００（エスアイアイ・ナノテクノロジー社製）
昇温条件：５℃／分
ガス：アルゴン
<Measurement of melting point of iguratimod>
Equipment: Differential scanning calorimeter (DSC)
Model: DSC6200 (manufactured by SII Nanotechnology)
Temperature raising conditions: 5℃/min Gas: Argon
＜イグラチモドの結晶形の温度依存性の測定＞
装置：Ｘ線回折－示差走査熱量同時測定装置（ＸＲＤ－ＤＳＣ）
機種：ＳｍａｒｔＬａｂ、ＤＳＣアタッチメント（株式会社リガク製）
測定方法：ＡＳＣ６ ＢＢ Ｄｔｅｘ
Ｘ 線出力：４０ｋＶ－３０ｍＡ
波長：ＣｕＫａ／１．５４１８８２Å
昇温条件：１０℃／分
<Measurement of temperature dependence of crystalline form of iguratimod>
Equipment: X-ray diffraction-differential scanning calorimetry simultaneous measurement equipment (XRD-DSC)
Model: SmartLab, DSC attachment (manufactured by Rigaku Co., Ltd.)
Measurement method: ASC6 BB Dtex
X-ray output: 40kV-30mA
Wavelength: CuKa/1.541882Å
Temperature rising conditions: 10℃/min
＜イグラチモドの溶媒量の測定＞
測定方法：ガスクロマトグラフィー（ＧＣ）
装置：島津製作所製 ＧＣ－２０１０ Ｐｌｕｓ
検出器：水素炎イオン化検出器（ＦＩＤ）
カラム：アジレント・テクノロジー社製 ＤＢ－６２４（長さ３０ｍ、内径０．５
３０ｍｍ、膜厚：３．００μｍ）
カラム温度：４０℃付近の一定温度で注入後、５分間維持し、次いで毎分１０℃で１１０℃まで昇温し、その後、毎分２０℃で２３０℃まで昇温し、２３０℃で５分間維持した。
注入口温度：２５０℃
検出器温度：３００℃
キャリアーガス：Ｈｅ
カラム圧力：３．８４ｐｓｉ
上記条件において、Ｎ，Ｎ－ジメチルホルムアミドは約１１．０分にピークが確認される。
<Measurement of the amount of iguratimod solvent>
Measurement method: Gas chromatography (GC)
Equipment: Shimadzu GC-2010 Plus
Detector: Flame ionization detector (FID)
Column: Agilent Technologies DB-624 (length 30m, inner diameter 0.5
30mm, film thickness: 3.00μm)
Column temperature: Maintain a constant temperature around 40°C for 5 minutes after injection, then increase the temperature to 110°C at 10°C per minute, then increase the temperature to 230°C at 20°C per minute, and then 5 minutes at 230°C. Maintained.
Inlet temperature: 250℃
Detector temperature: 300℃
Carrier gas: He
Column pressure: 3.84psi
Under the above conditions, a peak of N,N-dimethylformamide is observed at about 11.0 minutes.
＜イグラチモドの結晶形状の測定＞
装置：走査型電子顕微鏡（ＳＥＭ）
機種：Ｓ－３４００Ｎ（日立社製）
試料を白金コーティング（１０ｎｍ）後に測定を行った。
<Measurement of crystal shape of iguratimod>
Equipment: Scanning electron microscope (SEM)
Model: S-3400N (manufactured by Hitachi)
Measurements were performed after the sample was coated with platinum (10 nm).
製造例１
（イグラチモドの製造：特許文献３，４）
直径１０ｃｍの２枚撹拌翼を備えた１０００ｍＬ四つ口フラスコにＮ，Ｎ－ジメチルホルムアミド１５０ｍＬ、Ｎ，Ｎ－ジメチルホルムアミドジメチルアセタール４０．９ｇ（３４３ｍｍｏｌ）を加えて、撹拌しながら１０℃まで冷却した。そこに氷酢酸８．２ｇ（１３７ｍｍｏｌ）及びホルミルアミノメチル（２－ヒドロキシ－４－メチルスルホニルアミノ－５－フェノキシフェニル）ケトン５０．０ｇ（１３７ｍｍｏｌ）を順次加えて、２０℃まで昇温した後、同温度で５時間反応を行った。反応懸濁液に塩化メチレン２５０ｍＬを加えて得られた溶液に水５００ｍＬを滴下した。１０％の塩酸水溶液を用いてｐＨを５に調整した後、２０℃で１時間攪拌した。得られた析出晶を分取し、塩化メチレン５０ｍＬ、水５０ｍＬ、エタノール５０ｍＬで順次洗浄した後、５０℃で１２時間乾燥した。次いで、得られた結晶を水酸化カリウム７．７ｇ（１３７ｍｍｏｌ）、水７５０ｍＬ、アセトン７５０ｍＬの混合溶媒中に溶解した後、２Ｎ塩酸水で中和し、得られた析出晶を分取した。次いで、水５０ｍＬで洗浄した後、５０℃で１２時間乾燥して、４２．８ｇのイグラチモドを得た（イグラチモド純度：９９．７２％、Ｎ－メチル体：０．２３％）。
Manufacturing example 1
(Manufacture of iguratimod: Patent Documents 3 and 4)
150 mL of N,N-dimethylformamide and 40.9 g (343 mmol) of N,N-dimethylformamide dimethyl acetal were added to a 1000 mL four-necked flask equipped with two stirring blades with a diameter of 10 cm, and the mixture was cooled to 10°C while stirring. . 8.2 g (137 mmol) of glacial acetic acid and 50.0 g (137 mmol) of formylaminomethyl (2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl) ketone were sequentially added thereto, and the temperature was raised to 20°C. The reaction was carried out at the same temperature for 5 hours. 250 mL of methylene chloride was added to the reaction suspension, and 500 mL of water was added dropwise to the resulting solution. After adjusting the pH to 5 using a 10% aqueous hydrochloric acid solution, the mixture was stirred at 20°C for 1 hour. The obtained precipitated crystals were collected, washed successively with 50 mL of methylene chloride, 50 mL of water, and 50 mL of ethanol, and then dried at 50° C. for 12 hours. Next, the obtained crystals were dissolved in a mixed solvent of 7.7 g (137 mmol) of potassium hydroxide, 750 mL of water, and 750 mL of acetone, and then neutralized with 2N hydrochloric acid water, and the obtained precipitated crystals were collected. Next, after washing with 50 mL of water, it was dried at 50° C. for 12 hours to obtain 42.8 g of iguratimod (iguratimod purity: 99.72%, N-methyl form: 0.23%).
このイグラチモドを試料として、ＸＲＤを測定すると、図４に示すように２θ＝６．９°、１０．９°、１７．６°、１９．５°に特徴的なピークを与えるイグラチモドのα晶であることが分かった。また、ＤＳＣ測定による融点は、２４２．８℃であった（図６）。さらに、得られたイグラチモドのＳＥＭ画像を図５に示したが、イグラチモドのα晶はアスペクト比が高い針状晶であることが分かった。 When XRD was measured using this iguratimod as a sample, as shown in Figure 4, it was the alpha crystal of iguratimod that gave characteristic peaks at 2θ = 6.9°, 10.9°, 17.6°, and 19.5°. I found out something. Furthermore, the melting point determined by DSC measurement was 242.8°C (FIG. 6). Furthermore, the SEM image of the obtained iguratimod was shown in FIG. 5, and it was found that the α crystal of iguratimod was a needle crystal with a high aspect ratio.
実施例１
（Ｎ，Ｎ－ジメチルホルムアミド中での結晶化）
直径２．５ｃｍの２枚撹拌翼を備えた１００ｍＬ三つ口フラスコに製造例１で得られたイグラチモド（α晶）５ｇを量りとり、Ｎ，Ｎ－ジメチルホルムアミド１５ｍＬを加え、７０℃で加熱溶解した。得られた溶液を５℃まで冷却した後、同温度で終夜撹拌した。次いで、減圧濾過して析出した結晶を分取し、５０℃で２４時間乾燥して、４．９ｇのイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得た（イグラチモド純度：９９．９１％、Ｎ－メチル体：０．０５％）。
Example 1
(Crystallization in N,N-dimethylformamide)
Weigh out 5 g of iguratimod (α crystal) obtained in Production Example 1 into a 100 mL three-necked flask equipped with two stirring blades with a diameter of 2.5 cm, add 15 mL of N,N-dimethylformamide, and dissolve by heating at 70°C. did. The resulting solution was cooled to 5°C, and then stirred at the same temperature overnight. Next, the precipitated crystals were collected by vacuum filtration and dried at 50°C for 24 hours to obtain 4.9 g of crystals of iguratimod N,N-dimethylformamide solvate (iguratimod purity: 99.91 %, N-methyl form: 0.05%).
この結晶を試料として、ＸＲＤを測定すると、図１に示すように２θ＝１５．９°、１９．４°、２２．７°、２６．５°に特徴的なピークを与えた。ＤＳＣ測定による融点は、１０２．８℃及び２４３．９℃であった（図３）。ＸＲＤ－ＤＳＣ測定の結果、１００℃付近で結晶形がβ晶に変化していた。また、ＧＣにより、この結晶は、Ｎ，Ｎ－ジメチルホルムアミドを含んでいることが確認できた。 When XRD was measured using this crystal as a sample, characteristic peaks were given at 2θ=15.9°, 19.4°, 22.7°, and 26.5°, as shown in FIG. The melting points measured by DSC were 102.8°C and 243.9°C (Figure 3). As a result of XRD-DSC measurement, the crystal form changed to β crystal at around 100°C. Furthermore, it was confirmed by GC that this crystal contained N,N-dimethylformamide.
さらに、得られた結晶のＳＥＭ画像を図２に示したが、イグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶はアスペクト比が低い板状晶であった。 Further, a SEM image of the obtained crystals is shown in FIG. 2, and the crystals of the N,N-dimethylformamide solvate of iguratimod were plate-like crystals with a low aspect ratio.
実施例２
（Ｎ，Ｎ－ジメチルホルムアミド及びアセトンの混合溶媒中での結晶化）
直径２．５ｃｍの２枚撹拌翼を備えた１００ｍＬ三つ口フラスコに製造例１で得られたイグラチモド５ｇを量りとり、Ｎ，Ｎ－ジメチルホルムアミド１５ｍＬを加え、７０℃で加熱溶解した。得られた溶液を５０℃まで冷却した後、アセトン１５ｍＬを加えて、さらに５℃まで冷却し、同温度で終夜撹拌した。次いで、減圧濾過して析出した結晶を分取し、５０℃で２４時間乾燥して、４．９ｇのイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得た（イグラチモド純度：９９．９０％、Ｎ－メチル体：０．０６％）。
Example 2
(Crystallization in a mixed solvent of N,N-dimethylformamide and acetone)
5 g of iguratimod obtained in Production Example 1 was weighed into a 100 mL three-necked flask equipped with two stirring blades with a diameter of 2.5 cm, 15 mL of N,N-dimethylformamide was added, and the mixture was dissolved by heating at 70°C. After the obtained solution was cooled to 50°C, 15 mL of acetone was added, further cooled to 5°C, and stirred at the same temperature overnight. Next, the precipitated crystals were collected by vacuum filtration and dried at 50°C for 24 hours to obtain 4.9 g of crystals of iguratimod N,N-dimethylformamide solvate (iguratimod purity: 99.90 %, N-methyl form: 0.06%).
このイグラチモドを試料として、ＸＲＤを測定すると、２θ＝１５．８°、１９．３°、２２．７°、２６．５°に特徴的なピークを与えた。また、ＤＳＣ測定による融点は、１０３．１℃及び２４２．９℃であった。 When XRD was measured using this iguratimod as a sample, characteristic peaks were given at 2θ=15.8°, 19.3°, 22.7°, and 26.5°. Furthermore, the melting points measured by DSC were 103.1°C and 242.9°C.
実施例３
（Ｎ，Ｎ－ジメチルホルムアミド及びメチルエチルケトンの混合溶媒中での結晶化）
実施例２において、使用したアセトンをメチルエチルケトンに変更した以外は、実施例２と同様の操作を行い、４．８ｇのイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得た（イグラチモド純度：９９．９０％、Ｎ－メチル体：０．０６％）。
Example 3
(Crystallization in a mixed solvent of N,N-dimethylformamide and methyl ethyl ketone)
In Example 2, the same operation as in Example 2 was performed except that the acetone used was changed to methyl ethyl ketone, and 4.8 g of crystals of N,N-dimethylformamide solvate of iguratimod was obtained (iguratimod purity: 99.90%, N-methyl form: 0.06%).
このイグラチモドを試料として、ＸＲＤを測定すると、２θ＝１５．９°、１９．３°、２２．６°、２６．６°に特徴的なピークを与えた。また、ＤＳＣ測定による融点は、１０３．３℃及び２４３．８℃であった。 When XRD was measured using this iguratimod as a sample, characteristic peaks were given at 2θ=15.9°, 19.3°, 22.6°, and 26.6°. Furthermore, the melting points measured by DSC were 103.3°C and 243.8°C.
比較例１
（特許文献２に記載の方法によるイグラチモドβ晶の製造）
直径１０ｃｍの２枚撹拌翼を備えた１０００ｍＬ三つ口フラスコに製造例１で得られたイグラチモド（α晶）１５ｇを量りとり、２－ブタノン６００ｍＬを加え、還流温度で加熱撹拌した。得られた溶液を５℃まで冷却した後、同温度で終夜撹拌した。次いで、減圧濾過して析出した結晶を分取し、５０℃で乾燥して、６．３ｇのイグラチモドの結晶を得た（イグラチモド純度：９９．７９％、Ｎ－メチル体：０．２０％）。
Comparative example 1
(Production of iguratimod β crystal by the method described in Patent Document 2)
15 g of iguratimod (α crystal) obtained in Production Example 1 was weighed into a 1000 mL three-neck flask equipped with two stirring blades with a diameter of 10 cm, 600 mL of 2-butanone was added, and the mixture was heated and stirred at reflux temperature. The resulting solution was cooled to 5°C, and then stirred at the same temperature overnight. Next, the precipitated crystals were collected by vacuum filtration and dried at 50°C to obtain 6.3 g of iguratimod crystals (iguratimod purity: 99.79%, N-methyl form: 0.20%). .
このイグラチモドを試料として、ＸＲＤを測定すると、図７に示すように２θ＝６．０°、１０．６°、１７．５、１８．４°に特徴的なピークを与えるイグラチモドのβ晶であることが分かった。また、ＤＳＣ測定による融点は２４３．３℃であった。さらに、得られたイグラチモドのＳＥＭ画像を図８に示したが、当該結晶はアスペクト比が高い針状晶であった。 When XRD is measured using this iguratimod as a sample, it is found to be a β crystal of iguratimod that gives characteristic peaks at 2θ=6.0°, 10.6°, 17.5°, and 18.4°, as shown in Figure 7. That's what I found out. Further, the melting point as determined by DSC measurement was 243.3°C. Furthermore, the SEM image of the obtained iguratimod was shown in FIG. 8, and the crystals were needle-shaped crystals with a high aspect ratio.
比較例２
（特許文献２に記載の方法によるイグラチモドγ晶の製造）
直径１０ｃｍの２枚撹拌翼を備えた１０００ｍＬ三つ口フラスコに製造例１で得られたイグラチモド（α晶）１５ｇを量りとり、アセトニトリル６００ｍＬを加え、２５℃で終夜撹拌した。次いで、減圧濾過して析出した結晶を分取し、５０℃で乾燥して、１２．４ｇのイグラチモドの結晶を得た（イグラチモド純度：９９．８４％、Ｎ－メチル体：０．１９％）。
Comparative example 2
(Production of iguratimod γ crystals by the method described in Patent Document 2)
15 g of iguratimod (α crystal) obtained in Production Example 1 was weighed into a 1000 mL three-neck flask equipped with two stirring blades with a diameter of 10 cm, 600 mL of acetonitrile was added, and the mixture was stirred at 25° C. overnight. Next, the precipitated crystals were separated by vacuum filtration and dried at 50°C to obtain 12.4 g of iguratimod crystals (iguratimod purity: 99.84%, N-methyl form: 0.19%). .
このイグラチモドを試料として、ＸＲＤを測定すると、図９に示すように２θ＝１１．３°、１７．４°、１８．１°、２１．７°、２２．６°に特徴的なピークを与えるイグラチモドのγ晶であることが分かった。また、ＤＳＣ測定による融点は２４３．４℃であった。さらに、得られたイグラチモドのＳＥＭ画像を図１０に示したが、当該結晶はアスペクト比が高い針状晶であった。 When XRD is measured using this iguratimod as a sample, it gives characteristic peaks at 2θ=11.3°, 17.4°, 18.1°, 21.7°, and 22.6° as shown in Figure 9. It turned out to be gamma crystals of iguratimod. Moreover, the melting point as determined by DSC measurement was 243.4°C. Furthermore, the SEM image of the obtained iguratimod was shown in FIG. 10, and the crystals were needle-shaped crystals with a high aspect ratio.
実施例４（β晶からの変換）
比較例１で得られたイグラチモドのβ晶を使用した以外は、実施例１と同様の操作を行い、４．９ｇのイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得た（イグラチモド純度：９９．９２％、Ｎ－メチル体：０．０４％）。
Example 4 (conversion from β crystal)
The same operation as in Example 1 was carried out except that the β-crystal of iguratimod obtained in Comparative Example 1 was used to obtain 4.9 g of crystals of N,N-dimethylformamide solvate of iguratimod (Iguratimod purity :99.92%, N-methyl form: 0.04%).
このイグラチモドを試料として、ＸＲＤを測定すると２θ＝１５．９°、１９．４°、２２．６°、２６．６°に特徴的なピークを与えた。 When XRD was measured using this iguratimod as a sample, characteristic peaks were given at 2θ=15.9°, 19.4°, 22.6°, and 26.6°.
実施例５（γ晶からの変換）
比較例２で得られたイグラチモドのγ晶を使用した以外は、実施例１と同様の操作を行い、４．９ｇのイグラチモドのＮ，Ｎ－ジメチルホルムアミド溶媒和物の結晶を得た（イグラチモド純度：９９．９３％、Ｎ－メチル体：０．０４％）。
Example 5 (conversion from γ crystal)
The same operation as in Example 1 was performed except that the gamma crystals of iguratimod obtained in Comparative Example 2 were used to obtain 4.9 g of crystals of N,N-dimethylformamide solvate of iguratimod (iguratimod purity :99.93%, N-methyl form: 0.04%).
このイグラチモドを試料として、ＸＲＤを測定すると２θ＝１６．０°、１９．４°、２２．７°、２６．４°に特徴的なピークを与えた。 When XRD was measured using this iguratimod as a sample, characteristic peaks were given at 2θ=16.0°, 19.4°, 22.7°, and 26.4°.
Claims (3)
前記ケトン類は、アセトン及びメチルエチルケトンからなる群より選択される少なくとも１種であり、
前記混合溶媒において、前記Ｎ，Ｎ－ジメチルホルムアミドの容積比率は９９～５０％であり、前記ケトン類の容積比率は１～５０％である、製造方法。 The feature is that iguratimod is heated and dissolved in N,N-dimethylformamide at 60 to 70°C or lower, and then crystallized in N,N-dimethylformamide or a mixed solvent of N,N-dimethylformamide and ketones. A method for producing crystals of N,N-dimethylformamide solvate of iguratimod, comprising:
The ketones are at least one selected from the group consisting of acetone and methyl ethyl ketone,
In the mixed solvent, the volume ratio of the N,N-dimethylformamide is 99 to 50%, and the volume ratio of the ketones is 1 to 50%.
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