TW200940485A - Preparing method of tamibarotene crystal form II - Google Patents

Abstract

The present invention relates to a method of preparing Tamibarotene crystal form II for the treatment of granulocytic leukaemia. The method comprises the step of crystallizing the Tamibarotene solid in an arbitrary crystal or amorphous form from acetic acid, formic acid or aqueous solution thereof to obtain the pure Tamibarotene crystal form II. The resulting crystal form has high purity, and is stable under heating and physical action, and moreover, the crystallization solvent used has low toxicity and residue. The Tamibarotene crystal form II prepared according to the present invention method can be more useful in clinical therapy.

Description

200940485 IX. Description of the invention: '[Technical field to which the invention belongs] 'The present invention relates to pharmacy and organic chemistry, in particular to the preparation of specific high purity type II crystals of Tamibarotene [Prior Art] Tamibarotene ) is an omental acid compound discovered by Professor Shinji Shun of the University of Tokyo and first synthesized (Jpn J Cancer Res 79: 473-483, 1988; J Med Chem 31: 2182-2192, 1988, etc.). In the year of November 27, 1998, the drug was designated as a rare disease drug due to its predictable efficacy and effect on acute promyelocytic leukemia (acute promyelocytic leukemia). In 2005, the drug was approved for marketing in Sakamoto. Hemibarrotin is a white crystalline powder, soluble in DMF, soluble in decyl alcohol, ethanol, etc., slightly insoluble in ether, insoluble in acetyl chloride, insoluble in water. It is poorly soluble or does not dissolve at all in various buffer solutions (pH 3 to 7). In the early development of his mibarotine, the crystal structure of mixed crystals of type I, type II, and type I and type II (hereinafter referred to as ΠΙ type) has been confirmed. Type I crystals melt at 193 ° C (see JP3001632B2), usually unstable, easily become type II or type III after physical action (such as impact or heating) or long time; type II crystal, melting at 233 ° C (See JP2000264733); Form III crystals are purified from a mixed solvent of ethyl acetate/n-hexane at 205.5 to 206.5. . Melting (see US 703110, 1984). The contents of type I and type II in type III are different each time, and there is no fixed law. The crystal melted at 193 ° C disclosed in JP 3 001 632 B1 can be prepared by using a mixture of decyl alcohol and water as a recrystallization solvent, although the crystal form of 5 94279 200940485 has such a characteristic that the residual methanol can be extremely lowered. However, the crystal melted at i93 ° C is easily converted into a crystal form by physical impact, and it is extremely difficult to prepare a homo-crystal, and is not suitable as a raw material for preparing a large-sized pharmaceutical product in a large amount. The ιη type crystal at 205.5 to 2〇6 5t: (iv) can be prepared by using a mixture of ethyl acetate and hexane as a recrystallization solvent. For this crystallization, further studies have shown that it is a mixed crystal form of crystalline form n and crystalline form ,, while the residual ratio of ethyl acetate and hexanyl acetate in the crystallization is 1200 _ and 190 ppm respectively. Residual solvent reference value (ethyl acetate · 5000 ppm or less; hexane · 2); compared to 233t molten TYPE crystal, not only has high stability against physical impact, but also heat, temperature, Light and the like are also highly stable. In the preparation method disclosed in jP20002647 (CN1449376), the crystals melted at 233 ° C can be prepared by using a mixture of ethanol and water as a recrystallization solvent, and the disadvantage is that it is difficult to prepare a high purity. Π-type crystallization. It is still necessary to use high-temperature heating conversion crystal form to obtain pure ruthenium crystallization. This method also has obvious defects, which is that the temperature of the heated conversion crystal form is very high. The usual conversion temperature is 180t^x. The invention relates to a system for preparing tamoxifen quinone crystals having a single endothermic peak in the vicinity of 233 art in differential scanning calorimetry. The method comprises the steps of crystallizing any crystalline or amorphous Tamibaro solid with an aqueous solution of a lower organic acid = or a lower organic acid to obtain a pure Tamibarotin π-type hydrazine. 9 94279 6 200940485 • wherein the lower acid refers to a lower organic acid having a carbon number of less than 6 and capable of volatilization and being used as a crystallization solvent, preferably formic acid' or a combination thereof. When the crystallization solvent is an aqueous solution of an organic acid, the ratio of both acid to water 'may be arbitrary, but is generally limited to 2 〇: 8 〇 to %: 2, preferably 50: 50 to 90: 1 。. Further comprising drying at 100 to 14 (TC, preferably 120 ° C) under reduced pressure to remove residual lower organic acids. In addition, the present invention relates to a rice having a single endothermic peak in the vicinity of differential scanning calorimetry. A method for preparing a Barrow type (4-) type crystal, which is characterized in that high-purity type II crystals can be obtained without mt: a high temperature range above which is easy to cause degradation. (Detailed Description of the Invention) The present invention provides selective preparation. ·Mibararo (4) The method of π-type 2 crystals is to use a low-toxic solvent to obtain a type II crystal which is melted at 233 ° C with a high content and a residual solvent residue. In order to solve the above-mentioned crystallization problem, the researcher has carried out extensive and in-depth Yan Nine. The inventors conducted a series of crystallization studies on commonly used solvents such as ethanol, methanol, isopropanol, acetone and their mixtures with water respectively, according to different design schemes, used as = Barrow (tetra) crystallization solvent. Two tests: point, differential scanning thermal analysis (DSC), and χ-diffraction map = two ΐ: whether it is pure solvent, or with the right amount of liquid 'for the refinement of Tamibarotene, very Rarely 94279 7 200940485

N • to 屯 type II Tamibaro > T crystal; in these solvents, a relatively pure one is known to be obtained with an object at 193. With melting = crystallization. However, other solvents, or aqueous solutions thereof, are used as the crystallization solvent of > butyl but no pure crystalline or π-type junction f is obtained. The inventors of the German tube also noted the method of selectively recrystallizing a 23 rc blended crucible by recrystallization from a mixture of ethanol and water disclosed in the patent CN1449376A, but the experimental results show that the above solvents, or It, it is difficult to obtain pure π-type crystals when used as a crystallization solvent for his Mibarol, and in the differential scanning calorimetry (DSC) map, it is still more or less seen at 193t. The nearby absorption peaks mean that these crystal forms are still mixed crystal forms. According to the wire, in a certain sense, according to the method disclosed in the patent CN1449376A, only a solvent of ethanol is used as a solvent for the crystallization of Tamibarotene, and it is difficult to obtain a single pure type 11 crystallization. Patent cN1449376A also discloses an auxiliary method for the preparation of pure type II crystals of Tamibarotene, which can be heated at a temperature of about 2 Torr, so that in differential scanning thermal analysis 193t: The crystal of Tamibaro diced with an endothermic peak near and near 233aC can be heated and the crystal form is transformed to obtain pure Form II crystal. This method is feasible, but the inventors have also found obvious defects in the method in the research, which is the degradation problem caused by high temperature; the inventors have high purity (HpLC99 85%, single impurity is less than the rice The barotene mixed crystal sample was subjected to a crystal form conversion test. After heating at a temperature of 2 Torr to 205 C for 2 hours, the purity of the sample was reduced to "5〇%, and a pre-mixed amount reached 0.1% or more. A pre-mixed amount of 0.2% or more. 8 94279 200940485 In order to find a better preparation of the rice, the hair: a wide and in-depth study of the various types of rice used for his mirbaro _ crystal. The inventor was pleasantly surprised to find = human ; &: 2: class of falling agent, used for his mibaro _ crystal time full of people,,. Fruit. The resulting Mibararo; D: for the differential scanning thermal analysis in 2 'The present invention is a crystal of Tiba, but it is operated under the _ under / ^ near an endothermic peak of the end of the heat absorption peak [under, at 120 to 14 旳, preferably uot:, the acid and acetic acid are below 500ppm If the product is more satisfactory, if it is long enough, the residual formic acid and acetic acid can not be detected, turn: = the method does not need High-purity type II crystals can be obtained by a high-purity conversion which is liable to cause degradation. The present invention provides an anthracycline, v τ / or acetic acid B having an endothermic peak near 233t in differential scanning calorimetry. Crystals made of vinegar or ethanol, do not contain hexanes and preparations. As medicine, it can be used:: Residue = agent is characterized by 'can be used in medicine', in the treatment of cardiomyopathy of myeloid leukemia. 々 月 月 方 方 可 可 可 可 可 可 可 可 可 可 可 他 他 他 他 他 他 他 他 他 他 他 他 他 他 他 他 他 他 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 」 It can also be carried out by the enthalpy-ray diffraction measurement. The melting point measured by the capillary method can also be used as an important reference. The heat of the above-mentioned type 1 crystal and type II crystal is not described in the above. In the patent literature, it is to be noted that the experimental error in ... point measurement or differential scanning thermal analysis, etc. is about C. 9 94279 200940485 is usually within 2 ° C, preferably within rC. Characteristic Using a lower organic acid, preferably an organic carboxylic acid having a carbon number of less than 6, which can be volatilized and used as a crystallization solvent, or a mixture thereof; more preferably acetic acid or formic acid or a mixture thereof, or a mixture thereof with water The mixture is used as a recrystallization solution of the mibarol-ordered crystal. When the sa is analyzed, pure acetic acid or formic acid may be used, or a mixed solvent of acid and water may be used, and the ratio of the ratio of the acid to the water is not limited, and may be any , generally limited to 20: 80 to 98: 2, but if the ratio of acid is too low, the volume of the crystallization solvent is increased to a large extent, so it is more preferably 5 〇: 5 〇 to 9 〇: 10. Of course, it can also be used. Pure organic acid. The method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method. For example, the raw material tamibarotene crystal can be completely dissolved in the pure acetate compound, and then slowly cooled and crystallized, and then the crystal is pulverized; in order to crystallize the object with high efficiency, it is also possible to add: The number of the two seed crystals is not particularly limited; the crystals to be taken are usually at a pressure of about 100 to 140 ° C, preferably 12 (drying under heating of TC, to achieve the effect of removing the recrystallization solvent. The tamibarotene crystals prepared according to the method of the present invention contain only a relatively low content of acetic acid or formic acid. The third type of low toxic solvent in the residual solvent of acetic acid and medicinal products of lysine may be better due to crystallization. The present invention is not limited to the present invention. The present invention will be described in more detail with reference to the embodiments. Only the technical solutions of the present invention will be described. 200940485 Quality Test instrument used in the experiment 1. DSC spectrum instrument model: Perkin-Elmer Pyris 7 Series Thermal Analysis System Purge gas: Nitrogen heating rate: l〇.〇°C/min Temperature range: 50 to 250°C © 2. X-ray diffraction spectrum instrument model: D/Max-RA Japan Rigaku X-ray powder diffractometer ray: Monochrome Cu-Κα ray (λ=1.5418 A) Scanning method: Θ/2Θ, scanning Range: 3 - 40°

Voltage: 30 KV Current: 50 mA Comparative Example 1 _ - 2.0 g of Tamibarotene was added to a mixture U of 20 ml of decyl alcohol and 20 ml of water, dissolved by heating, and cooled to room temperature. The precipitated crystals were collected by filtration, and dried at 110 to 1.120 ° C under reduced pressure to give 1.52 g of crystals. When performing differential scanning calorimetry on this crystal, a single endothermic peak is given near 193 ° C (see Figure 1-1). Further, this crystal powder X-ray diffraction pattern (see Fig. 1-2) is identical to the powder X-ray diffraction pattern shown in Fig. 5 of Japanese Patent JP3001632, and it can be confirmed that it is type I crystal. Comparative Example 2 2.0 g of Tamibarotene was added to a mixture of 1 ethanol of 20 m and water of 20 ml, dissolved by heating, and then cooled to room temperature. The precipitated crystals were collected by filtration and dried at 1 94 279 200940485 •• repeatedly at 1 WC to obtain crystals i6g. For such stations • Line differential scanning thermal analysis, ^93. 〇和如. Give ^^ near C (see Figure 2-1). The capillary method was used to determine the melting point of 2〇4 5 to φ. It can also be 204 from the differential thermal analysis map. (; There is also a smaller endothermic peak, which is obtained by the method of the endothermic peak, and has not been reported in the literature. 1... The mixed type of crucible (HPLC99.85〇/〇, single miscellaneous) Less than © gentleman 曰m to 205 c heated for 2 hours. For the obtained ',, 曰 曰 曰 不 不 不 不 不 不 不 不 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 233 It can be set to ·1·» 3 π (1) to confirm that it is a quinoid crystal. The HPLC test sample, ', has dropped to 50%, the pre-mix has reached 0.1% or more, and the other pre-mix has reached 0.2% or more. Example 1 ... Adding (tetra) Luo, T 1Q.Qg to human acetic acid (13Gml), heating and dissolving, then cooling and cooling; taking out the precipitated crystals. The obtained crystals are dried under reduced pressure for 4 hours to obtain crystals. ^. For this crystallization difference, when scanning thermal analysis, a single peak is given near 23yc. Capillary method to determine the melting point 23, acetic acid solvent residue 42 〇 ppm, and then continue the sample at 14 〇 M pressure After drying for 2 () hours, the acetic acid solvent residue was not detected. The crystallized powder x-ray diffraction pattern (see Figure 4-2) and Comparative Example 2 The powder χ ray diffraction pattern obtained after the temperature conversion (see the figure) is consistent, and it can be confirmed that it is a D-type crystallization. Example 2 Adding Tamibaro 'Ding 10·0 § to 400 ml of acetic acid and 200 ml of water mixed 12 94279 200940485

In the liquid mixture, it was slowly dissolved by heating, and the precipitated crystals were collected by filtration. The obtained f crystal was dried under reduced pressure at 12 to 13 (TC was dried for 2 hours to obtain 8 g of crystals. Differential scanning calorimetry was performed on this crystal, and a single endothermic peak was given in the vicinity of 233t: Point 2313. That is, the crystal powder X-ray diffraction pattern and the powder X-ray diffraction pattern obtained in Example i - can be confirmed to be quinoid crystals. Example 3 • Tamibarotene 10.0 § After adding 12 〇 ml of citric acid, it was dissolved by heating, and then slowly cooled, and the precipitated crystals were collected by filtration. The obtained crystal was dried under reduced pressure at 12 〇f 13 (TC for 4 hours to obtain crystals). When scanning, ,, and knife analysis, a single endothermic peak is given near 233 C (see Figure 5-2). The capillary method is used to determine the melting point of 231_3t: and the formic acid solvent remains 47. Melon. The final X-ray diffraction pattern (see Fig. 5-2) is identical to the powder X-ray diffraction pattern obtained in Example 1 (see Fig. 4-2), and it can be confirmed that it is a quinoid crystal. ❾ Example 4 Tamibaol > Ding l〇〇g is added to a mixture of formic acid 3, such as water and 2 〇〇ml, after heating and dissolving The precipitated crystals were cooled by cooling, and the obtained wet crystals were dried under reduced pressure at 12 to 13 passages for 3 hours to obtain crystals of 72 g. For differential scanning calorimetry of the crystals of the species, at 233 (:: The end point (4) endothermic peak. The capillary point 2mc was determined by capillary method, and the powder X-ray diffraction pattern of the crystal was consistent with the powder χ ray diffraction pattern obtained in Example 3, and it was confirmed that it was jj type crystal. 94279 13 200940485 Table 1. Preparation of different crystal forms of Tamibarotene and corresponding spectrum results Experimental example Crystallization preparation method Refined solvent DSC spectrum endothermic peak (°C) X-ray powder diffraction crystal form Reference example 1 JP3001632 sterol-water 194.061 204.607 See Figure 1-1 Figure 1-2 Figure I Type Reference Example 2 JP3001632 CN1449376 A Ethanol-water 193.374, 204.070, 232.767 See Figure 2-1 for Figure 2-2 Figure m-type hybrid reference example 2 CN1449376 A Heated crystal form 233.144 See Figure 3-1 Figure 3-2 Figure π Type Example 1 Acetic acid 234.023 See Figure 4-1 See Figure 4-2 Figure π Type Example 3 Tannic acid 233.546 See section 5-1 See Figure 5-2 for the figure [Simplified illustration] Figure 1-1: DSC spectrum of his mibarotine I crystal form (refined with decyl alcohol-water) ❿ Figure 1-2: X-ray powder diffraction spectrum of his rice barostatin I crystal form (methanol-water) Refined) Figure 2-1: DSC spectrum of his mibarotine III crystal form (refined by ethanol-water) Figure 2-2: X-ray powder diffraction spectrum of his mibarotine III crystal form (ethanol one Water refining) Figure 3-1: DSC spectrum of the crystalline form of Tamibarotin II (ethanol-water 1 refined heating and crystallizing) 14 94279 200940485 3_2 Figure · X-ray of his mibarotine π crystal form Powder diffraction spectrum (ethanol-water refining heating and crystal transformation) Figure 4·1: DS of Tamibarotene η crystal form (: spectrum (acetic acid refining) acid essence ^) 4 2 Tetami Baro Π crystal form Χ·ray powder diffraction spectrum (B

Figure 5-1: He Mi Ba Luo, Ding No. 5-2: He Mibaro juice ^ Acid refining) [Main component symbol description] Crystalline DSC spectrum (formic acid purification) Crystalline X-ray Powder diffraction spectrum (A no. ❹ 94279 15

Claims (1)

200940485 X. Application for Patent Park: 1. One type in differential scanning thermal analysis at 233. In the vicinity of 〇, there is a preparation method of singular- and Barrow-type crystallization. The method-package=peak-form or amorphous tamoxifen solid is crystallized with an aqueous solution of lower hydrazine as a lower organic acid to obtain pure Or the step of crystal.己罗/丁Π型结结2. As claimed in the scope of the patent, the lower grade acid described in the crystal m is a lower level than when the number of carbon atoms is less than that of the month b and can be used as a crystallization solvent. When the organic solvent and the crystallization solvent used are an aqueous solution of an organic acid, both of the acid and water may be arbitrary. 3. 'Preparation method for the preparation of the mibaro μ-type crystal of the p range of the patents' When the crystal solvent selected is an aqueous solution of an organic acid, the ratio of the acid to the water is generally limited to 2〇: 8〇 to 98· · 2. >, 4·In the case of the patent application, the damage of the Tambarol and Ting π-type crystals is as follows: Method 'When the selected crystallization solvent is an aqueous solution of an organic acid, the ratio of acid to one or two water is limited. More preferably 5〇: 5〇 to 9〇: ι〇. " 5. A process for the preparation of a Tamibarotene-type crystal according to item 2 of the patent application, wherein the lower organic acid refers to acetic acid or citric acid, or a combination thereof. 6. The method of preparing a mibaro type crystal according to the first aspect of the patent application, the method further comprising drying at 100 to 14 ° C under reduced pressure to remove residual low-grade organic acid. A method of preparing a mibarrotin π-type crystal according to the fifth aspect of the patent application, wherein the drying is carried out at 120 ° C under reduced pressure to remove residual low-grade organic acid. 8. The preparation of the Mibarrotin II type crystal according to the first paragraph of the patent application can obtain a high-purity type II method, which is characterized in that it does not require a 180T: above temperature conversion process which is susceptible to degradation. Ie a曰e 17 94279