CN107118153A - A kind of Rui Gefeini monohydrate crystal forms and preparation method thereof - Google Patents
A kind of Rui Gefeini monohydrate crystal forms and preparation method thereof Download PDFInfo
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- CN107118153A CN107118153A CN201511020292.6A CN201511020292A CN107118153A CN 107118153 A CN107118153 A CN 107118153A CN 201511020292 A CN201511020292 A CN 201511020292A CN 107118153 A CN107118153 A CN 107118153A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention provides a kind of Rui Gefeini hydrate novel crystal forms K, and the crystal formation preparation method.Rui Gefeini monohydrates K crystal formations provided by the present invention, compared with existing Rui Gefeini monohydrate crystal forms disclosed in prior art, with different DSC, TGA and X-ray diffracting spectrum.The K crystal formations product purity is more than 99.9%.Latent gene toxic impurities RG-5 content is only more than ten of ppm in product.The preparation technology is simple, and reaction condition is gentle, and post processing is simple.
Description
Technical field
The present invention relates to a kind of Rui Gefeini hydrate novel crystal forms and preparation method thereof.
Background technology
Rui Gefeini is developed by Bayer A.G, trade name " Stivarga ", this product belongs to the tyrosine kinase inhibitor of Mutiple Targets, the FDA of in September, 2012 ratifies it and listed in the U.S., in March, 2013 lists in Japan, in August, 2013 is listed in European Union, and this product is mainly used in treatment metastatic colorectal carcinoma and gastrointestinal stromal tumor.
Rui Gefeini, which is first, is used for the small-molecule drug for the treatment of of colorectal cancer, and compared to chemotherapeutics, adverse reaction is relatively fewer, and compared to monoclonal antibody medicine, price is lower.Because this product is new targeted drug, with convenient oral, efficiently, low toxicity the characteristics of, the therapeutic effect to GISTs and colorectal cancer is good, and good market prospect, and clinical demand is larger.
Bayer AG discloses compound Chinese patent 200480021091.1 and monohydrate patent 200780037680.2, and preparation method patent application 201180019150.1.
The feature and preparation method of the Zhong Gong Kailiao Rui Gefeini monohydrates of Chinese patent 200780037680.2 and polymorphic I, polymorphic I, which only has, is free of a molecular crystalline water in 1 absworption peak, and molecular structure.The DSC collection of illustrative plates of monohydrate shows 3 absworption peaks, wherein the 3rd peak is more than 200 DEG C, and DSC and TGA figures show that fusion and decomposition temperature is more than 200 DEG C.
The Zhong Gong Kailiao Rui Gefeini of Chinese patent 201180019150.1, the preparation method of its salt and monohydrate, the preparation method of wherein monohydrate is to be handled formula (IV) compounds having formula (V) compound, handled again with isocyanates and obtain the reactant mixture containing Rui Gefeini, preferred ethanol and chloroacetic chloride generation salt is added into above-mentioned reactant mixture, then preferably in 35 DEG C to 45 DEG C of temperature, salt is added to acetone, stirred in water and sodium hydrate aqueous solution, add Rui Gefeini monohydrate crystal seeds, it is cooled to 20 DEG C and adds a small amount of water, it is cooled to 3 DEG C, finally it is filtrated to get Rui Gefeini monohydrates, the DSC or x-ray diffraction pattern of monohydrate are not provided in that patent, we prepare monohydrate according to the patented method, and DSC and TGA measure is carried out to it, DSC figures show 3 absworption peaks, DSC and TGA figures show that its fusion and decomposition temperature is more than 200 DEG C.
Chinese patent 201410181182.7 discloses crystal formation of 3 kinds of acylates of Rui Gefeini and preparation method thereof, unrelated with Rui Gefeini monohydrates.
Chinese patent 201410300883.8 Zhong Gong Kailiao Rui Gefeini novel crystal forms A, B, C and preparation method thereof, and disclose the DSC and x-ray diffraction pattern of 3 kinds of crystal formations, DSC collection of illustrative plates shows that crystal formation A only has 1 absworption peak at 194 DEG C, crystal formation B has 2 absworption peaks at 113 DEG C and 207 DEG C, and crystal formation C contains 3 absworption peaks at 114 DEG C, 142 DEG C and 206 DEG C.
The content of the invention
The present invention provides a kind of Rui Gefeini hydrate novel crystal forms K, and the crystal formation preparation method.
Rui Gefeini monohydrates K crystal formations provided by the present invention, compared with all existing Rui Gefeini monohydrate crystal forms that background section is analyzed, with different DSC, TGA and X-ray diffracting spectrum, particularly the 3rd peak is less than 200 DEG C in its DSC collection of illustrative plates.
The preparation technology of the K crystal formations is simple, and reaction condition is gentle, and post processing is simple, and product purity is more than 99.9%.
Especially latent gene toxic impurities RG-5 content is only more than ten of ppm, and well below the content of RG-5 in Rui Gefeini monohydrates of the Yuan Yan companies disclosed in its patent 200780037680.2, specific experiment refers to embodiments of the invention 6.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided, it is characterised in that the fusion and decomposition temperature of the K crystal formations is 186-195 DEG C.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided, it is characterised in that its means of differential scanning calorimetry (DSC) is shown at 86-119 DEG C, have endothermic peak at 143-149 DEG C and at 186-195 DEG C.Means of differential scanning calorimetry figure is shown in accompanying drawing 2.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided, it is characterised in that x-ray diffraction pattern shows that 2 θ angles have peak at 14.8 degree, and is highest peak, and 2 θ angles have time strong peak at 25.9 degree, and 11.8 degree have three strongest peak.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided, it is characterised in that the K crystal formations X-ray powder diffraction collection data are：
The θ angles of 1 Rui Gefeini K crystal formation XRPD diffraction patterns of table 2 and relative intensity
| 2 θ angles (°) | Relative intensity (Area%) |
| 5.9 | 5.2 |
| 11.8 | 17.2 |
| 14.8 | 100.0 |
| 16.1 | 5.1 |
| 17.2 | 5.6 |
| 17.7 | 5.6 |
| 21.1 | 8.1 |
| 23.7 | 6.5 |
| 25.9 | 18.2 |
| 26.2 | 9.1 |
| 27.2 | 10.9。 |
The Rui Gefeini monohydrate K crystal formations that the present invention is provided, it is characterised in that the K crystal formations have X-ray powder diffraction figure as shown in Figure 1.
Due to the difference of measuring condition, the 2 θ angles at each peak and relative intensity can change on XRPD diffraction patterns, and general 2 θ angles change is within ± 0.2 °, and relative intensity is considered reasonable error within ± 0.2%.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided are characterised by, quality loss of weight 3.7% between its thermogravimetric analysis (TGA) is shown in 83-125 DEG C, calculated according to molecular weight 500.83, show the crystallization water containing a molecule, thermogravimetric analysis figure is shown in accompanying drawing 3.
The Rui Gefeini monohydrate K crystal formations that the present invention is provided are characterised by that itself DSC and TAG figure shows that 186-195 DEG C is fusion and decomposition temperature.
The present invention also provides the preparation method of Rui Gefeini monohydrate K crystal formations, comprises the following steps：
Rui Gefeini crude products are added in organic solvent a, hydrochloric acid and acetone is added, stirring and crystallizing, filtering obtains solid matter,
Solid matter, which is added in organic solvent b and sodium hydroxide solution, to be dissolved,
Add water stirring and crystallizing, and solution temperature and recrystallization temperature are preferred 20-25 DEG C, get Rui Gefeini monohydrate K crystal formations,
Qi Zhong Suo Shu Rui Gefeini crude products are Rui Gefeini or its monohydrate or other crystal formations of Rui Gefeini such as I crystal formation, A crystal formations, B crystal form or C crystal form.
Wherein described organic solvent a is tetrahydrofuran, and organic solvent b is acetone.
Other crystal formations of Rui Gefeini such as I crystal formation, A crystal formations, B crystal form or C crystal form etc. are prepared with reference to existing patent, and purity more than 99.0%.
The Rui Gefeini monohydrate K crystal formation preparation technologies that the present invention is provided, reaction condition is gentle, and post processing is simple, and product purity is more than 99.9%, essentially free of latent gene toxic impurities RG-5.
" essentially free of " mentioned here refers to not detect under described testing conditions, or less than 10ppm.
The characteristic for the Rui Gefeini monohydrate K crystal formations that the present invention is provided.
(1) character：This product is off-white color crystalline powder.
(2) dissolubility：Determined with reference to Chinese Pharmacopoeia two notes on the use of version in 2010 on deliquescent
Method：The product that Example 1 is obtained is appropriate, is separately added into each solvent, every strength shaking in 5 minutes 30 seconds, observes the dissolving situation in 30 minutes, produces.It the results are shown in Table 2
The dissolubility test result of table 2
(3) stability
1st, hot test
Product that Example 1 is obtained is appropriate, is placed in open measuring cup, spreads out into≤thick 5mm thin layer, is placed 10 days at 60 DEG C and 40 DEG C respectively, in the 0th, samples within 5,10 days, is detected by stability high spot reviews project, the results are shown in Table 3.
Table 3 high temperature, 60 DEG C of result of the tests
Remarks：Melting point data is determined by melting point apparatus in stability, and DSC is determined and slightly had deviation.
2nd, high wet test
Product that Example 1 is obtained is appropriate, is placed in open measuring cup, spreads out into≤thick 5mm thin layer, is placed 10 days 92.5%, in the 0th, sampling in 5,10 days, is detected by stability high spot reviews project, the results are shown in Table 4.
The result of the test of 4 high humidity of table 92.5%
3rd, exposure experiments to light
Product that Example 1 is obtained is appropriate, is placed in open measuring cup, spreads out into≤thick 5mm thin layer, it is placed in the lighting box equipped with fluorescent lamp, illumination is 4500Lx ± 500Lx, is placed 10 days, in the 0th, sampling in 5,10 days, detected by stability high spot reviews project, the results are shown in Table 5.
The exposure experiments to light result of table 5
4th, accelerated test
The product that Example 1 is obtained, using double casing, inner packing is medicinal low density polyethylene (LDPE) bag, outer packing is aluminium foil bag, the sample is placed in 40 DEG C ± 2 DEG C, under the conditions of 75 ± 5% place 6 months, 0th month during testing, 1 month, 2 months, 3 months, 6 months it is separately sampled once, by stability high spot reviews item detection, 6 are the results are shown in Table.
The accelerated test result of table 6
5th, long term test
The product that Example 1 is obtained, using double casing, inner packing is medicinal low density polyethylene (LDPE) bag, outer packing is aluminium foil bag, the sample is placed in 25 DEG C ± 2 DEG C, placed under the conditions of 60 ± 10% 6 months, sampling in every 3 months is once, detected respectively at -+0 month, 3 months, 6 months by stability high spot reviews project, the results are shown in Table 7.
The long-term test results of table 7
Result of the test shows：The Rui Gefeini monohydrate K crystal formations of the present invention are relatively stablized under illumination, high temperature, super-humid conditions, and relevant material, content, moisture are substantially unchanged；Accelerated test and long-term test results also indicate that the Rui Gefeini monohydrate K stable crystal forms of the present invention.
The beneficial effects of the invention are as follows：K crystal formations are easily prepared, with good stability；Impurity content is low, and long-term placement quality is more stable, security is higher.
Brief description of the drawings
The XRPD figures of Rui Gefeini monohydrate K crystal formations prepared by the embodiment 1 of accompanying drawing 1.
The DSC figures of Rui Gefeini monohydrate K crystal formations prepared by the embodiment 1 of accompanying drawing 2.
The TGA figures of Rui Gefeini monohydrate K crystal formations prepared by the embodiment 1 of accompanying drawing 3.
Embodiment
Following examples are that the present invention is illustrated, and the scope of the present invention should not be construed as limiting.
Embodiment 1：The preparation of Rui Gefeini monohydrate K crystal formations
12.0g Rui Gefeini crude products and 300ml tetrahydrofurans are added in reaction bulb, hydrochloric acid 40ml and acetone 500ml, 20 DEG C of stirring 8h is added, filter to dry, solid is added in reaction bulb, 500ml acetone and 5% sodium hydrate aqueous solution 450ml, plus purified water 600ml is added, 20 DEG C of stirring and crystallizing 12h, filtration drying, obtains product Rui Gefeini monohydrate K crystal formation 10.04g, purity 99.95%, yield 83.7%, 192-195 DEG C of fusing point.XRPD, DSC and TGA (referring to accompanying drawing 1-3) of the product are detected, it is really K crystal formations to determine products obtained therefrom.
Embodiment 2：The preparation of Rui Gefeini monohydrate K crystal formations
Rui Gefeini I crystal 8.0g and 240ml tetrahydrofurans are added in reaction bulb, hydrochloric acid 32ml and acetone 350ml, 23 DEG C of stirring 8h is added, filter to dry, solid is added in reaction bulb, 300ml acetone and 5% sodium hydrate aqueous solution 300ml, plus purified water 350ml is added, 23 DEG C of stirring and crystallizing 9h, filtration drying, get Rui Gefeini monohydrate K crystal formation 6.66g, purity 99.94%, yield 83.3%, 192-195 DEG C of fusing point.XRPD, DSC and TGA of the product are detected, it is really K crystal formations to determine products obtained therefrom.
Embodiment 3：The preparation of Rui Gefeini monohydrate K crystal formations
Rui Gefeini A crystal formation 12.0g and 260ml tetrahydrofurans are added in reaction bulb, hydrochloric acid 42ml and acetone 500ml, 21 DEG C of stirring 8h is added, filter to dry, solid is added in reaction bulb, 450ml acetone and 5% sodium hydrate aqueous solution 450ml, plus purified water 500ml is added, 21 DEG C of stirring and crystallizing 10h, filtration drying, get Rui Gefeini monohydrate K crystal formation 9.8g, purity 99.95%, yield 81.7%, 192-195 DEG C of fusing point.XRPD, DSC and TGA of the product are detected, it is really K crystal formations to determine products obtained therefrom.
Embodiment 4：The preparation of Rui Gefeini monohydrate K crystal formations
Rui Gefeini B crystal form 9.0g and 360ml tetrahydrofurans are added in reaction bulb, hydrochloric acid 30ml and acetone 450ml, 25 DEG C of stirring 8h is added, filter to dry, solid is added in reaction bulb, 400ml acetone and 10% sodium hydrate aqueous solution 200ml, plus purified water 460ml is added, 25 DEG C of stirring and crystallizing 9h, filtration drying, get Rui Gefeini monohydrate K crystal formation 7.51g, purity 99.96%, yield 83.4%, 192-195 DEG C of fusing point.XRPD, DSC and TGA of the product are detected, it is really K crystal formations to determine products obtained therefrom.
Embodiment 5：The preparation of Rui Gefeini monohydrate K crystal formations
Rui Gefeini C crystal form 10.0g and 400ml tetrahydrofurans are added in reaction bulb, hydrochloric acid 35ml and acetone 450ml, 22 DEG C of stirring 8h is added, filter to dry, solid is added in reaction bulb, 450ml acetone and 10% sodium hydrate aqueous solution 250ml, plus purified water 500ml is added, 22 DEG C of stirring and crystallizing 10h, filtration drying, get Rui Gefeini monohydrate K crystal formation 8.27g, purity 99.95%, yield 82.7%, 192-195 DEG C of fusing point.XRPD, DSC and TGA of the product are detected, it is really K crystal formations to determine products obtained therefrom.Embodiment 6：Rui Gefeini monohydrate K crystal formations prepare monohydrate contrast test contrast test with the method for patent 200780037680.2 and used with a collection of Rui Gefeini crude products (purity 99.13%), prepare sample 1, sample 2, sample 3 and sample 4 respectively by the following method, wherein sample 1 and sample 2 are the Rui Gefeini monohydrate K crystal formations of the method preparation of embodiments in accordance with the present invention 1, sample 3 and sample 4 are the Rui Gefeini monohydrates prepared according to the method for the embodiment 1.1 of patent 200780037680.2, the results are shown in Table 8 and table 9.
80 days comparative test results of table
The long-term comparative test result in March of table 9
As a result show, do not detect the malicious impurity RG-5 of latent gene in the Rui Gefeini monohydrate K crystal formations prepared according to the present invention, and RG-5 is not also detected in the experiment of long-term 3 months.And containing the malicious impurity RG-5 of latent gene in the Rui Gefeini monohydrate crystals prepared according to the method for patent 200780037680.2, and after the long-term stable experiment by 3 months, its content has increased.
Impurity RG-5, chemical name 4- [(4- amino -3- fluorophenoxies)-uride]-N- picoline -2- formamides, RG-5 is not only process contaminants, while being also catabolite, and the impurity contains the malicious structure fragment of latent gene, therefore its limit need to strictly be controlled.According to EMEA guidelines《GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES》, formula is calculated as follows：
9.4ppm should be according to EMEA guideline computational methods RG-5 limit.Impurity RG-5 is not detected in the Rui Gefeini monohydrate K crystal formations that the present invention is provided, meet prescribed limit, and this limit of impurities has gone beyond the limit requirement in monohydrate prepared by the method for patent 200780037680.2, therefore the Rui Gefeini monohydrate K crystal formation impurity that the present invention is provided is lower, and security is higher.
Claims (10)
1. a kind of K crystal formations of Rui Gefeini monohydrates, it is characterised in that the fusion and decomposition temperature of the K crystal formations is
186-195℃。
2. the K crystal formations of Rui Gefeini monohydrates as claimed in claim 1, it is characterised in that the DSC of the K crystal formations
Fisrt feature peak is at 86-119 DEG C in collection of illustrative plates, and second feature peak is at 143-149 DEG C, and third feature peak is at 186-195 DEG C.
3. the K crystal formations of Rui Gefeini monohydrates as claimed in claim 1, it is characterised in that the X- of the K crystal formations is penetrated
Line powder diffraction spectrum shows that 2 θ angles have highest peak at 14.8 °, and 2 θ angles have time strong peak at 25.9 °, and 11.8 ° have three strongest peak,
Error is ± 0.2 °.
4. the K crystal formations of Rui Gefeini monohydrates as claimed in claim 1, it is characterised in that the K crystal formations X-ray powder
Last diffracting spectrum data are：
5. the K crystal formations of Rui Gefeini monohydrates as claimed in claim 1, it is characterised in that the K crystal formations have as schemed
X-ray powder diffraction figure shown in 1.
6. the K crystal formations of Rui Gefeini monohydrates as claimed in claim 1, it is characterised in that the TGA figures of the K crystal formations
Mass lost 3.7% between spectrum is shown in 83-125 DEG C.
7. a kind of method for preparing Rui Gefeini monohydrates K crystal formations as claimed in claim 1, comprises the following steps：
Rui Gefeini crude products are added in organic solvent a, hydrochloric acid and acetone, stirring and crystallizing is added, obtains solid matter,
Solid matter, which is added in organic solvent b and sodium hydroxide solution, to be dissolved,
Add water stirring and crystallizing, and solution temperature and recrystallization temperature are preferred 20-25 DEG C, dries, and get Rui Gefeini monohydrates K is brilliant
Type,
Qi Zhong Suo Shu Rui Gefeini crude products be Rui Gefeini or its monohydrate or other crystal formations of Rui Gefeini such as I crystal formation, A crystal formations,
B crystal form or C crystal form.
8. the preparation method of Rui Gefeini monohydrates K crystal formations as claimed in claim 7, it is characterised in that described organic molten
Agent a is tetrahydrofuran, and organic solvent b is acetone.
9. the preparation method of Rui Gefeini monohydrates K crystal formations as claimed in claim 7, it is characterised in that the Rui Gefei
The purity of Buddhist nun's crude product is more than 99.0%.
10. the preparation method of Rui Gefeini monohydrates K crystal formations as claimed in claim 7, it is characterised in that the Rui Gefeini
The purity more than 99.9% of monohydrate K crystal formations, essentially free of latent gene toxic impurities RG-5.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110294706A (en) * | 2019-07-25 | 2019-10-01 | 李斌 | Anti-tumor drug and its preparation method and purposes |
| CN111995571A (en) * | 2020-08-07 | 2020-11-27 | 天津理工大学 | Eutectic crystal of regorafenib and maleic acid and preparation method thereof |
| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
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| CN114315710A (en) * | 2022-01-07 | 2022-04-12 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
| CN114315710B (en) * | 2022-01-07 | 2024-04-26 | 江苏豪森药业集团有限公司 | Method for preparing or purifying regorafenib |
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Application publication date: 20170901 |