CN101200435A - Method for preparing tamibaroteneII crystal - Google Patents
Method for preparing tamibaroteneII crystal Download PDFInfo
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- CN101200435A CN101200435A CNA2006101670063A CN200610167006A CN101200435A CN 101200435 A CN101200435 A CN 101200435A CN A2006101670063 A CNA2006101670063 A CN A2006101670063A CN 200610167006 A CN200610167006 A CN 200610167006A CN 101200435 A CN101200435 A CN 101200435A
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- 239000013078 crystal Substances 0.000 title claims abstract description 39
- 238000000034 method Methods 0.000 title claims abstract description 32
- MUTNCGKQJGXKEM-UHFFFAOYSA-N tamibarotene Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1NC(=O)C1=CC=C(C(O)=O)C=C1 MUTNCGKQJGXKEM-UHFFFAOYSA-N 0.000 claims abstract description 62
- 229950010130 tamibarotene Drugs 0.000 claims abstract description 62
- 239000002904 solvent Substances 0.000 claims abstract description 33
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000019253 formic acid Nutrition 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 4
- 238000002425 crystallisation Methods 0.000 claims description 73
- 230000008025 crystallization Effects 0.000 claims description 73
- 230000015572 biosynthetic process Effects 0.000 claims description 25
- 238000001953 recrystallisation Methods 0.000 claims description 20
- 150000007524 organic acids Chemical class 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 15
- 238000010438 heat treatment Methods 0.000 abstract description 15
- 230000000704 physical effect Effects 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000007670 refining Methods 0.000 description 10
- 238000002386 leaching Methods 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 206010013786 Dry skin Diseases 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 241000345998 Calamus manan Species 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 208000035977 Rare disease Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000038009 orphan disease Diseases 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 235000012950 rattan cane Nutrition 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- -1 retinoid compounds Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for the preparation of tamibarotene II crystal which can be used to cure agranulosis. Any crystal or unformed tamibarotene solid is crystallized by acetic acid or formic acid and as well as the water solution of the acids to achieve tamibarotene II crystal. The achieved crystal has high purity and is stable during heating and physical actions; besides, the adopted crystal solvent is characterized in low toxicity and low residue. The tamibarotene II crystal prepared by the method can be better applied to clinic therapy.
Description
Technical field
The present invention relates to the specific high purity II type of pharmacy and organic chemistry, particularly Tamibarotene crystalline preparation method
Background technology
Tamibarotene (tamibarotene) is retinoid compounds (Jpn J Cancer Res 79:473-483,1988 of being found and being synthesized first by the first rattan professor in Tokyo University; J MedChem 31:2182-2192,1988 etc.).On November 27th, 1998, this medicine was owing to the usefulness that can estimate and effect to acute promyelocytic leukemia (marrow ball leukemia before acute) are designated as the orphan disease medication.2005, this medicine went through to go on the market in Japan.
Tamibarotene is a white crystalline powder, is soluble in DMF, is dissolved in methyl alcohol, ethanol etc., is insoluble in ether slightly, and it is fine, water insoluble to be insoluble in second.Indissoluble or not dissolving in various buffered soln (pH3～7).Early stage in the Tamibarotene research and development, the crystalline structure of the mixed crystallization of I type, II type and I type and II type (to call the III type in the following text) has obtained affirmation.The crystallization of I type is in 193 ℃ of fusings (referring to JP3001632B2), and is unstable usually, after (for example bump or heating) or long-time the placement, becomes II type or III type easily under physical action; The crystallization of II type is in 233 ℃ of fusings (referring to JP2000264733); The crystallization of III type is made with extra care from ethyl acetate/normal hexane mixed solvent and is got, at 205.5～206.5 ℃ of fusions (referring to US703110,1984).The I type in the III type and the content of II type are all inequality at every turn, do not have the fixed rule.
Disclosedly among the Japanese Patent JP3001632B1 can prepare as recrystallization solvent with the mixture of methyl alcohol and water 193 ℃ of fused crystallizations, although having, this crystal formation can make residual methanol drop to extremely low such feature, yet, because of making crystalline form, physical impact transforms easily 193 ℃ of fused crystallizations, there is the utmost point to be difficult to prepare the such problem of homogeneous crystallization, not too is suitable for raw material as a large amount of preparation homogeneous specification pharmaceuticals.Can prepare as recrystallization solvent with the mixture of ethyl acetate and hexane in the crystallization of 205.5～206.5 ℃ of fused III types.For this crystallization, studies have shown that further it is the mixing crystal formation of crystal form II and crystal form II I, the residual rate of ethyl acetate and normal hexane is respectively 1200ppm and 190ppm in the crystallization simultaneously, and the residual solvent benchmark value (ethyl acetate: below the 5000ppm that is difficult to satisfy the pharmacopeia regulation is arranged; Hexane: 290ppm) such problem; By comparison, at 233 ℃ of fused II type xln, not only physical impact is had high stability, and heat, temperature, light etc. are also had high stability.In the disclosed preparation method of JP20002647 (CN1449376), can prepare as recrystallization solvent with the mixture of ethanol and water 233 ℃ of fused crystallizations, shortcoming is to be difficult to prepare the crystallization of highly purified II type.Still the method that needs to transform crystal formation with heat obtains pure II type crystallization, the open defect that this method also exists, and the temperature of Here it is thermal conversion crystal formation is very high, and invert point is more than 180 ℃ usually; And high temperature has caused producing degraded.
Summary of the invention
The present invention relates near a kind of Tamibarotene II type crystalline preparation method that single endotherm(ic)peak is arranged 233 ℃ in differential scanning calorimeter, this method comprises any crystal formation or unformed tamibarotene solid is obtained pure Tamibarotene II type crystalline step with rudimentary organic acid or the crystallization of the rudimentary organic acid aqueous solution.
Wherein, described lower acid refers to carbon atom quantity less than the 6 rudimentary organic acids that simultaneously can volatilize and can be used as recrystallisation solvent, is preferably acetate or formic acid, or their combination.
When the recrystallisation solvent of selecting for use was the organic acid aqueous solution, the ratio of acid and water can be arbitrarily, but generally be limited to 20: 80 to 98: 2, in preferred 50: 50 to 90: 10.
This method comprises further under reduced pressure that at 100-140 ℃ preferred 120 ℃ are carried out dry to remove residual rudimentary organic acid.
On the other hand, the present invention relates in differential scanning calorimeter, near 233 ℃, have the Tamibarotene II type crystalline preparation method of single endotherm(ic)peak, not needing it is characterized in that to obtain the crystallization of highly purified II type through causing the pyrolytic conversion process more than 180 ℃ of degraded easily.
Detailed Description Of The Invention
Content of the present invention provides the method that selectivity prepares the II type xln of Tamibarotene, makes every effort to use low-toxic solvent, obtain content height, dissolvent residual low in the crystallization of 233 ℃ of fused II types.
The inventor has carried out extensive and deep research in order to solve above-mentioned crystallization problem.The inventor to solvent commonly used such as ethanol, methyl alcohol, Virahol, acetone and they respectively with the mixture of water, by different designs, the recrystallisation solvent as Tamibarotene has carried out a series of Study on Crystallization work; Measure by surveying fusing point, differential scanning calorimeter (DSC) and X-diffracting spectrum, the Tamibarotene xln that obtains has been carried out crystal formation research.The inventor finds, above solvent no matter be pure solvent, still and the aqueous solution formed of the water of an amount of ratio, when being used for Tamibarotene refining, all is difficult to obtain pure II type Tamibarotene crystallization; In these solvents, optionally obtained known purer with the mixture of methyl alcohol and water in the crystallization of 193 ℃ of fused I types.And other solvent, perhaps their aqueous solution but can not get purer I type crystallization or the crystallization of II type during as the recrystallisation solvent of Tamibarotene.Although the inventor notices also among the patent CN1449376A that disclosed mixture with ethanol and water carries out recrystallization and optionally prepares 233 ℃ of fused II type crystalline methods, but experimental result shows, these above solvents, perhaps their aqueous solution, be difficult to obtain the high II type crystallization of purity during as the recrystallisation solvent of Tamibarotene, in differential scanning calorimeter (DSC) collection of illustrative plates, still see near the absorption peak 193 ℃ more or less, this means that these resulting crystal formations remain the mixing crystal formation.
To sum up said, say in a sense, according to disclosed method among the patent CN1449376A, only do the crystallization of solvent as Tamibarotene with aqueous ethanolic solution, be difficult to obtain single pure II type crystallization.Pure a kind of householder method of II type crystalline as the preparation Tamibarotene is also disclosed among the patent CN1449376A simultaneously, promptly can heat in the temperature about 200 ℃, make in differential scanning calorimeter near 193 ℃ and near the crystal energy of Tamibarotene that endotherm(ic)peak arranged 233 ℃ through the method for heating, crystal formation changes, and obtains pure II type crystallization.This method is feasible, but the present inventor has also found the open defect that this method exists under study for action, degradation problem that high temperature causes that Here it is; The present inventor is with high purity (HPLC99.85%, single mixing less than 0.1%) Tamibarotene mixes crystal form samples and does the crystal formation conversion test, after heating 2 hours under 200～205 ℃ the temperature condition, the purity of sample has dropped to 99.50%, assorted reaching more than 0.1% before one, assorted reaching more than 0.2% before another.
In order to seek better preparation Tamibarotene II type crystalline method, the present inventor has carried out more extensive and deep research to being applicable to each kind solvent of Tamibarotene II type crystalline.The inventor finds that pleasantly surprisedly the rudimentary organic acid solvent as recrystallisation solvent when being used for the crystallization of Tamibarotene, has gratifying result.Resulting Tamibarotene crystallization when differential scanning calorimeter, has single endotherm(ic)peak near 233 ℃; And then, the invention provides the crystallization of the Tamibarotene of single endotherm(ic)peak is arranged near 233 ℃ in differential scanning calorimeter, under reduced pressure, at 120～140 ℃, preferred 120 ℃, carry out drying after, residual formic acid and acetate are all below 500ppm, more satisfied situation is, if time of drying during sufficiently long, residual formic acid and acetate can not detect.And this method does not need can obtain highly purified II type xln through causing the pyrolytic conversion process more than 180 ℃ of degraded easily.
The invention provides has the Tamibarotene of single endotherm(ic)peak II type crystalline xln near 233 ℃ in differential scanning calorimeter, be feature not contain hexane and/or ethyl acetate or ethanol as residual solvent, can be used for the medicine preparation.Can be used for the treatment of diseases such as acute preceding marrow ball leukemia as medicine.
The Tamibarotene crystalline kind that can be used as the raw material use in the inventive method is not particularly limited, and can use the crystallization or the unformed solid of any crystal formation.
The affirmation of crystallization shape except that differential scanning calorimeter, can also positively be carried out by carrying out powder x-ray diffraction mensuration, and the fusing point data that capillary tube technique is measured also can be used as important reference.Crystallization of above-mentioned I type and the hot analytical results of II type crystalline are recorded in respectively in the above-mentioned patent documentation.Here be noted that the experimental error in fusing point test or the differential scanning calorimeter etc. is about several ℃, usually in 2 ℃, more fortunately in 1 ℃.
The inventive method is characterised in that uses rudimentary organic acid, and preferred carbon atom quantity is less than organic carboxyl acid 6, that can volatilize and can be used as simultaneously recrystallisation solvent, or their mixture; More preferably acetate or formic acid or their mixture, or the mixture of they and water is as Tamibarotene crystalline recrystallization solvent.Can be with pure acetate or formic acid during crystallization, also can use the mixed solvent of acid and water, the ratio ratio of acid and water also without limits, can be arbitrarily, generally be limited to 20: 80 to 98: 2, if but the ratio of acid is low excessively, then can increase the volume of recrystallisation solvent greatly, so more preferably 50: 50 to 90: 10.Certainly, also can use pure organic acid.
The method of recrystallization is not particularly limited, and can carry out with common recrystallization working method.For example, can be with raw material Tamibarotene crystallization cooling crystallization slowly after the dissolving fully in the mixture of pure acetate or acetate and water, the leaching crystallization of separating out then; In order to make object crystallization expeditiously, also can add crystal seed, crystal seed quantity is not particularly limited; The xln of institute's leaching usually under reduced pressure about 100～140 ℃, carries out drying under the preferred 120 ℃ heating, just can reach the effect of removing recrystallization solvent.
The acetate or the formic acid that do not contain or only contain lower aq according to the Tamibarotene crystallization of method preparation of the present invention.Acetate and formic acid are the 3rd class low poison solvents in the pharmaceutical prod residual solvent of state-promulgated pharmacopoeia regulation, thereby crystallization of the present invention can be used as medical effective constituent preferably.
Description of drawings:
Fig. 1-1: the DSC spectrum (methanol-water is refining) of Tamibarotene I crystal formation
Fig. 1-2: the X-ray powder diffraction spectrum (methanol-water is refining) of Tamibarotene I crystal formation
Fig. 2-1: the DSC spectrum (alcohol-water is refining) of Tamibarotene III crystal formation
Fig. 2-2: the X-ray powder diffraction spectrum (alcohol-water is refining) of Tamibarotene III crystal formation
Fig. 3-1: the DSC spectrum of Tamibarotene II crystal formation (the refining heating of alcohol-water changes brilliant)
Fig. 3-2: the X-ray powder diffraction spectrum of Tamibarotene II crystal formation (the refining heating of alcohol-water changes brilliant)
Fig. 4-1: the DSC spectrum (purification of acetic acid) of Tamibarotene II crystal formation
Fig. 4-2: the X-ray powder diffraction spectrum (purification of acetic acid) of Tamibarotene II crystal formation
Fig. 5-1: the DSC spectrum (formic acid is refining) of Tamibarotene II crystal formation
Fig. 5-2: the X-ray powder diffraction spectrum (formic acid is refining) of Tamibarotene II crystal formation
Embodiment
Explain the present invention in more detail below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Test used testing tool
1.DSC spectrum
Instrument model: Perkin-Elmer Pyris 7Series Thermal Analysis System
Sweep gas: nitrogen
Temperature rise rate: 10.0 ℃/min
Temperature range: 50-250 ℃
2.X-ray diffraction spectra
Instrument model: D/Max-RA Japan RigakuX-ray powder diffraction instrument
Ray: monochromatic Cu-K alpha-ray (λ=1.5418
)
Scan mode: θ/2 θ, sweep limit: 3-40 °
Voltage: 30KV electric current: 50mA
The comparative example 1
Tamibarotene 2.0g is added in the mixed solution of methyl alcohol 20ml and water 20ml, the dissolving postcooling of heating is to room temperature.The crystallization that leaching is separated out under reduced pressure in 110～120 ℃ of dryings, obtains crystallization 1.52g.When differential scanning calorimeter is carried out in this crystallization, near 193 ℃, provide single endotherm(ic)peak (seeing accompanying drawing 1-1).And then this crystalline x-ray diffractogram of powder (seeing accompanying drawing 1-2) is consistent with the x-ray diffractogram of powder shown in Figure 5 of Japanese Patent JP3001632, can be confirmed to be the crystallization of I type.
The comparative example 2
Tamibarotene 2.0g is added in the mixed solution of 1 ethanol 20m and water 20ml, the dissolving postcooling of heating is to room temperature.The crystallization that leaching is separated out under reduced pressure in 110～120 ℃ of dryings, obtains crystallization 1.6g.When differential scanning calorimeter is carried out in this crystallization, near 193 ℃ and 233 ℃, provide endotherm(ic)peak (seeing accompanying drawing 2-1).Capillary tube technique is measured 204.5-208.5 ℃ of fusing point.Can be confirmed to be the mixed type crystallization.Also can find out near 204 ℃ to also have a less endotherm(ic)peak from the differential scanning calorimeter collection of illustrative plates, the crystal formation of this endotherm(ic)peak representative can't obtain, and does not see also that at present document reports for work.
The above-mentioned mixed type crystallization that obtains (HPLC99.85%, single assorted less than 0.1%) is under reduced pressure in 200～205 ℃ of heating 2 hours.When differential scanning calorimeter is carried out in resulting crystallization, near 233 ℃, provide single endotherm(ic)peak (seeing accompanying drawing 3-1).Can be confirmed to be the crystallization of II type.Assorted reaching more than 0.1% before the purity of HPLC test sample has dropped to 99.50%, one, assorted reaching more than 0.2% before another.
Tamibarotene 10.0g is added in the acetate (130ml) the slowly cooling of dissolving back of heating, the crystallization that leaching is separated out.Resulting crystallization under reduced pressure in 120～130 ℃ of dryings 4 hours, obtains crystallization 7.5g.When differential scanning calorimeter is carried out in this crystallization, near 233 ℃, provide single endotherm(ic)peak.Capillary tube technique is measured 231-3 ℃ of fusing point, and the residual 420ppm of acetic acid solvent continues sample then 140 ℃ of drying under reduced pressure 20 hours, and acetic acid solvent is residual not to be detected.In this crystalline x-ray diffractogram of powder (seeing accompanying drawing 4-2) and the comparative example 2 after the pyrolytic conversion resulting x-ray diffractogram of powder (seeing accompanying drawing 3-2) consistent, can be confirmed to be the crystallization of II type.
Tamibarotene 10.0g is added in the mixed solution of acetate 400ml and water 200ml the slowly cooling of dissolving back of heating, the crystallization that leaching is separated out.Resulting crystallization under reduced pressure in 120～130 ℃ of dryings 2 hours, obtains crystallization 8g.Differential scanning calorimeter is carried out in this crystallization, near 233 ℃, provide single endotherm(ic)peak.Capillary tube technique is measured 231.3 ℃ of fusing points, and this crystalline x-ray diffractogram of powder is consistent with resulting x-ray diffractogram of powder among the embodiment 1, can be confirmed to be the crystallization of II type.
Tamibarotene 10.0g is added among the formic acid 120ml the slowly cooling of dissolving back of heating, the crystallization that leaching is separated out.Resulting crystallization under reduced pressure in 120～130 ℃ of dryings 4 hours, obtains crystallization 7g.When differential scanning calorimeter is carried out in this crystallization, near 233 ℃, provide single endotherm(ic)peak (seeing accompanying drawing 5-2).Capillary tube technique is measured 231-3 ℃ of fusing point, the residual 470ppm of formic acid solvent.This crystalline x-ray diffractogram of powder (seeing accompanying drawing 5-2) is consistent with resulting x-ray diffractogram of powder (seeing accompanying drawing 4-2) among the embodiment 1, can be confirmed to be the crystallization of II type.
Tamibarotene 10.0g is added in the mixed solution of formic acid 300ml and water 200ml the dissolving back cooling slowly of heating, the crystallization that leaching is separated out.Resulting wet crystallization under reduced pressure in 120～130 ℃ of dryings 3 hours, obtains crystallization 7.2g.When differential scanning calorimeter is carried out in this crystallization, near 233 ℃, provide single endotherm(ic)peak.Capillary tube technique is measured 231-4 ℃ of fusing point, and this crystalline x-ray diffractogram of powder spectrum is consistent with resulting x-ray diffractogram of powder among the embodiment 3, can be confirmed to be the crystallization of II type.
The preparation of subordinate list 1. Tamibarotene different crystal forms and corresponding spectrogram result
| Experimental example | Crystallization preparation method | Refining solvent | DSC spectrum endothermic peak (℃) | The X-ray powder diffraction | Crystal formation |
| Reference example 1 | JP3001632 | Methanol-water | 194.061 204.607 see accompanying drawing 1-1 | See accompanying drawing 1-2 | The I type |
| Reference example 2 | JP3001632 CN1449376A | Alcohol-water | 193.374 204.070,232.767 see accompanying drawing 2-1 | See accompanying drawing 2-2 | III type mixed type |
| Reference example 2 | CN1449376A | Crystal formation is changeed in heating | 233.144 see accompanying drawing 3-1 | See accompanying drawing 3-2 | The II |
| Embodiment | |||||
| 1 | Acetate | 234.023 see accompanying drawing 4-1 | See accompanying drawing 4-2 | The II | |
| Embodiment | |||||
| 3 | Formic acid | 233.546 see accompanying drawing 5-1 | See accompanying drawing 5-2 | The II type |
Claims (8)
1. near Tamibarotene II type crystalline preparation method that single endotherm(ic)peak is arranged 233 ℃ in differential scanning calorimeter, this method comprise any crystal formation or unformed tamibarotene solid are obtained pure Tamibarotene II type crystalline step with rudimentary organic acid or the crystallization of the rudimentary organic acid aqueous solution.
2. Tamibarotene II type crystalline preparation method according to claim 1, wherein said lower acid refers to carbon atom quantity can volatilize and can be used as recrystallisation solvent less than 6 whiles rudimentary organic acid, when the recrystallisation solvent of selecting for use is the organic acid aqueous solution, the ratio of acid and water can be arbitrarily.
3. Tamibarotene II type crystalline preparation method according to claim 1, when the recrystallisation solvent of selecting for use was the organic acid aqueous solution, acid generally was limited to 20: 80 to 98: 2 with the ratio of water.
4. Tamibarotene II type crystalline preparation method according to claim 1, when the recrystallisation solvent of selecting for use was the organic acid aqueous solution, the limited proportion of acid and water was at more preferably 50: 50 to 90: 10.
5. Tamibarotene II type crystalline preparation method according to claim 2, wherein said rudimentary organic acid refers to acetate or formic acid, or their combination.
6. Tamibarotene II type crystalline preparation method according to claim 1, this method further comprise under reduced pressure carry out at 100-140 ℃ dry to remove residual rudimentary organic acid.
7. the preparation method of Tamibarotene II type xln according to claim 5 wherein under reduced pressure carries out dry to remove residual rudimentary organic acid at 120 ℃.
8. near the Tamibarotene II type crystalline preparation method that single endotherm(ic)peak is arranged 233 ℃ in differential scanning calorimeter not needing is characterized in that can obtaining the crystallization of highly purified II type through causing the pyrolytic conversion process more than 180 ℃ of degraded easily.
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|---|---|---|---|
| CN2006101670063A CN101200435B (en) | 2006-12-12 | 2006-12-12 | Method for preparing tamibaroteneII crystal |
| TW97109791A TW200940485A (en) | 2006-12-12 | 2008-03-20 | Preparing method of tamibarotene crystal form II |
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| CN2006101670063A CN101200435B (en) | 2006-12-12 | 2006-12-12 | Method for preparing tamibaroteneII crystal |
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| CN101200435B CN101200435B (en) | 2011-12-07 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009114966A1 (en) * | 2008-03-19 | 2009-09-24 | 江苏恒瑞医药股份有限公司 | The process for preparing tamibarotene ii type crystal |
| CN102633673A (en) * | 2012-03-30 | 2012-08-15 | 上海共价化学科技有限公司 | Synthesis method of tamibarotene |
| CN103822939A (en) * | 2014-02-28 | 2014-05-28 | 南京师范大学 | Thermal Analysis Method of Water-Assisted Low-Temperature Crystallization of TiO2 |
| WO2020205957A1 (en) * | 2019-04-02 | 2020-10-08 | Transgenex Nanobiotech, Inc. | Novel ternary molecular complex of tamibarotene for cancer stem cells treatment |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3580134D1 (en) * | 1984-07-07 | 1990-11-22 | Shudo Koichi Prof Dr Chem | BENZOESAEUR DERIVATIVES. |
| DK0478787T3 (en) * | 1990-03-20 | 1995-02-20 | Shionogi & Co | New method for preparing a benzoic acid derivative |
| TWI288129B (en) * | 2000-09-01 | 2007-10-11 | Toko Pharmaceuticals Ind Co Lt | Process for the production of crystals of a benzoic acid derivative |
-
2006
- 2006-12-12 CN CN2006101670063A patent/CN101200435B/en not_active Expired - Fee Related
-
2008
- 2008-03-20 TW TW97109791A patent/TW200940485A/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009114966A1 (en) * | 2008-03-19 | 2009-09-24 | 江苏恒瑞医药股份有限公司 | The process for preparing tamibarotene ii type crystal |
| CN102633673A (en) * | 2012-03-30 | 2012-08-15 | 上海共价化学科技有限公司 | Synthesis method of tamibarotene |
| CN103822939A (en) * | 2014-02-28 | 2014-05-28 | 南京师范大学 | Thermal Analysis Method of Water-Assisted Low-Temperature Crystallization of TiO2 |
| CN103822939B (en) * | 2014-02-28 | 2016-09-14 | 南京师范大学 | Thermal Analysis Method of Water-Assisted Low-Temperature Crystallization of TiO2 |
| WO2020205957A1 (en) * | 2019-04-02 | 2020-10-08 | Transgenex Nanobiotech, Inc. | Novel ternary molecular complex of tamibarotene for cancer stem cells treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| TW200940485A (en) | 2009-10-01 |
| CN101200435B (en) | 2011-12-07 |
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