TW202115027A - Tyrosine kinase inhibitor with low impurity content - Google Patents
Tyrosine kinase inhibitor with low impurity content Download PDFInfo
- Publication number
- TW202115027A TW202115027A TW109129417A TW109129417A TW202115027A TW 202115027 A TW202115027 A TW 202115027A TW 109129417 A TW109129417 A TW 109129417A TW 109129417 A TW109129417 A TW 109129417A TW 202115027 A TW202115027 A TW 202115027A
- Authority
- TW
- Taiwan
- Prior art keywords
- formula
- compound represented
- pharmaceutically acceptable
- solvent
- acceptable salt
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本發明要求申請日為2019年8月30日的中國專利申請CN201910812526.2的優先權。本發明引用上述中國專利申請的全文。The present invention claims the priority of the Chinese patent application CN201910812526.2 whose filing date is August 30, 2019. The present invention quotes the full text of the aforementioned Chinese patent application.
本發明屬於醫藥領域,關於低雜質含量的酪胺酸激酶抑制劑、藥物組合物及製備方法。The invention belongs to the field of medicine and relates to a tyrosine kinase inhibitor with low impurity content, a pharmaceutical composition and a preparation method.
受體酪胺酸激酶是一類參與訊號傳遞的跨膜蛋白,在多種細胞中表現,調節細胞的生長、分化和新生血管生成。研究表明,超過50%的原癌基因和癌基因產物都具有酪胺酸激酶活性,它們的異常表現將導致腫瘤發生,另外還與腫瘤的侵襲和轉移、腫瘤新生血管的生成、腫瘤的化療抗性密切相關。WO2011029265公開了一種有效的酪胺酸激酶抑制劑及其製備方法,其結構如式I所示,。Receptor tyrosine kinase is a type of transmembrane protein involved in signal transmission. It is expressed in a variety of cells and regulates cell growth, differentiation and angiogenesis. Studies have shown that more than 50% of proto-oncogenes and oncogene products have tyrosine kinase activity, and their abnormal performance will lead to tumorigenesis, in addition to tumor invasion and metastasis, tumor angiogenesis, tumor chemotherapy resistance Sex is closely related. WO2011029265 discloses an effective tyrosine kinase inhibitor and a preparation method thereof, the structure of which is shown in formula I, .
該化合物具有明顯的藥效優勢。CN102933574A中描述了該化合物的二馬來酸鹽形式,其具有改善的理化性質、藥代動力學性質以及良好的生物利用度。CN103974949A描述了該化合物的二馬來酸鹽的I晶型。WO2017186140描述了該化合物的製備方法。The compound has obvious pharmacodynamic advantages. CN102933574A describes the dimaleate salt form of the compound, which has improved physicochemical properties, pharmacokinetic properties, and good bioavailability. CN103974949A describes the crystalline form I of the dimaleate salt of this compound. WO2017186140 describes the preparation method of this compound.
經研究發現,現有的式I所示化合物的製備過程會產生多種雜質,而式I所示化合物在放置過程中也會產生降解雜質等多種雜質,可能的雜質數量超過了20種,且大部分都難以除去。在工業化生產過程中,往往需要單次投入大量原料製備產品以降低成本,單次原料的投入量可達幾百克、幾千克甚至數十數百千克。若產品中的雜質無法有效去除,則在大批量生產時極易導致產品的雜質含量易超標等問題。若減小生產規模,則會嚴重影響生產效率。Studies have found that the existing preparation process of the compound represented by formula I will produce a variety of impurities, and the compound represented by formula I will also produce a variety of impurities such as degradation impurities during the placing process, the number of possible impurities exceeds 20, and most of them It is difficult to remove. In the industrial production process, it is often necessary to invest a large amount of raw materials at a time to prepare products to reduce costs, and the input amount of raw materials at a time can reach several hundred grams, several kilograms, or even tens of hundreds of kilograms. If the impurities in the product cannot be effectively removed, it is very easy to cause problems such as the impurity content of the product easily exceeding the standard during mass production. If the scale of production is reduced, production efficiency will be seriously affected.
本發明提供了一種式I所示化合物或其可藥用鹽,, 其雜質含量低於0.2%。The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, , Its impurity content is less than 0.2%.
在某些實施方式中,所述化合物的雜質含量可以低於0.19%、0.18%、0.17%、0.16%、0.15%、0.14%、0.13%、0.12%、0.11%、0.10%、0.09%、0.08%、0.07%、0.06%、0.05%或更低,優選低於0.18%,更優選低於0.15%,最優選低於0.1%。In some embodiments, the impurity content of the compound may be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08% %, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
在某些實施方式中,本發明所述的式I所示化合物或其可藥用鹽中,式I所示化合物的可藥用鹽為馬來酸鹽,優選二馬來酸鹽。In some embodiments, in the compound represented by formula I or a pharmaceutically acceptable salt thereof according to the present invention, the pharmaceutically acceptable salt of the compound represented by formula I is maleate, preferably dimaleate.
在某些實施方式中,本發明所述化合物的粒徑D90小於20μm,例如小於15μm,或小於14μm,或小於13μm,或小於12μm,或小於10μm,或小於9μm,或小於8μm,或小於7μm,或小於6μm,或小於5μm,或小於4μm,或小於3μm。In some embodiments, the particle size D90 of the compound of the present invention is less than 20 μm, such as less than 15 μm, or less than 14 μm, or less than 13 μm, or less than 12 μm, or less than 10 μm, or less than 9 μm, or less than 8 μm, or less than 7 μm , Or less than 6μm, or less than 5μm, or less than 4μm, or less than 3μm.
在某些實施方式中,所述化合物的粒徑D50小於5μm,優選小於4μm,或小於3μm,或小於2μm,或小於1μm。In some embodiments, the particle size D50 of the compound is less than 5 μm, preferably less than 4 μm, or less than 3 μm, or less than 2 μm, or less than 1 μm.
本發明另一方面還提供了一種式I所示化合物或其可藥用鹽的製備方法,包括使用溶劑將式I所示化合物或其可藥用鹽重結晶的步驟,所述溶劑可以是甲醇與其他溶劑的混合溶劑,所述其他溶劑選自丙酮、乙酸乙酯和四氫呋喃中的一種或多種,優選丙酮和/或四氫呋喃。In another aspect, the present invention also provides a method for preparing the compound represented by formula I or its pharmaceutically acceptable salt, which comprises the step of recrystallizing the compound represented by formula I or its pharmaceutically acceptable salt using a solvent, and the solvent may be methanol. A mixed solvent with other solvents, the other solvent is selected from one or more of acetone, ethyl acetate and tetrahydrofuran, preferably acetone and/or tetrahydrofuran.
在某些實施方式中,所述化合物的雜質含量低於0.2%,例如可以低於0.19%、0.18%、0.17%、0.16%、0.15%、0.14%、0.13%、0.12%、0.11%、0.10%、0.09%、0.08%、0.07%、0.06%、0.05%或更低,優選低於0.18%,更優選低於0.15%,最優選低於0.1%。In some embodiments, the impurity content of the compound is less than 0.2%, for example, it can be less than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%. %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or less, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
在某些實施方案中,甲醇與其他溶劑的體積比可以是1:1~1:50,優選1:3~1:20。In some embodiments, the volume ratio of methanol to other solvents may be 1:1 to 1:50, preferably 1:3 to 1:20.
在某些實施方案中,式I所示化合物或其可藥用鹽與溶劑的體積比的範圍可以是1:5~1:200。In some embodiments, the volume ratio of the compound represented by formula I or its pharmaceutically acceptable salt to the solvent may range from 1:5 to 1:200.
重結晶的方法沒有特別限定,可以用通常的重結晶操作方法進行。例如,可以用原料在有機溶劑加熱溶解後慢慢冷卻靜置析晶,也可採取攪拌析晶,結晶完成後,經過濾乾燥,即可得到所需要的結晶。通過採用包含甲醇溶劑的重結晶的方法,重結晶過程可在常溫下進行,無需加熱,很大程度上避免了式I所示化合物的降解,確保了式I所示化合物或其可藥用鹽和藥物組合物的穩定性及生產過程的可操作性。另外,制得的式I所示化合物的鹽粒徑較小,便於製劑製備。式I所示化合物在其他溶劑中,例如,在乙醇或異丙醇中雖然較易溶解,但基本上僅能在加熱條件下才能完全溶解,極易引起式I所示化合物的降解,導致純度降低。The method of recrystallization is not particularly limited, and it can be performed by a usual recrystallization operation method. For example, the raw materials can be heated and dissolved in an organic solvent and then slowly cooled and allowed to stand for crystallization, or stirring and crystallization can be adopted. After the crystallization is completed, the desired crystals can be obtained by filtering and drying. By adopting the method of recrystallization containing methanol solvent, the recrystallization process can be carried out at room temperature without heating, which largely avoids the degradation of the compound represented by formula I and ensures that the compound represented by formula I or its pharmaceutically acceptable salt And the stability of the pharmaceutical composition and the operability of the production process. In addition, the prepared salt of the compound represented by formula I has a small particle size, which is convenient for preparation of the formulation. Although the compound represented by formula I is relatively soluble in other solvents, for example, ethanol or isopropanol, it can basically only be completely dissolved under heating conditions, which can easily cause degradation of the compound represented by formula I, resulting in purity reduce.
重結晶的過程中,任選地可加入晶種加快析晶的速度。During the recrystallization process, seed crystals can optionally be added to accelerate the speed of crystallization.
在某些實施方案中,所述式I所示化合物或其可藥用鹽為式I所示化合物的馬來酸鹽,所述方法還包括將式I所示化合物或其可藥用鹽與馬來酸、溶劑混合的步驟。In certain embodiments, the compound represented by formula I or a pharmaceutically acceptable salt thereof is the maleate salt of the compound represented by formula I, and the method further comprises combining the compound represented by formula I or a pharmaceutically acceptable salt thereof with The step of mixing maleic acid and solvent.
在某些實施方案中,所述式I所示化合物或其可藥用鹽為式I所示化合物的二馬來酸鹽。In some embodiments, the compound represented by formula I or a pharmaceutically acceptable salt thereof is the dimaleate salt of the compound represented by formula I.
在某些實施方案中,所述混合步驟中的溶劑選自甲醇、乙醇、異丙醇、丙酮、乙酸乙酯或四氫呋喃中的一種或多種,優選甲醇。式I所示化合物在甲醇中的溶解度較高,溶解速度較快,且溶解後的式I所示化合物不易在甲醇中析出,有利於工業化生產。In some embodiments, the solvent in the mixing step is selected from one or more of methanol, ethanol, isopropanol, acetone, ethyl acetate, or tetrahydrofuran, preferably methanol. The compound represented by the formula I has high solubility in methanol, and the dissolution rate is relatively fast, and the dissolved compound represented by the formula I is not easy to precipitate in methanol, which is beneficial to industrial production.
在某些實施方案中,所述製備方法包括: (1)將式I所示化合物或其可藥用鹽與馬來酸、甲醇混合製備式I所示化合物的二馬來酸鹽; (2)使用溶劑將式I所示化合物的二馬來酸鹽重結晶,其中所述溶劑選自甲醇與其他溶劑的混合溶劑,所述其他溶劑選自丙酮、乙酸乙酯和四氫呋喃中的一種或多種,優選丙酮和/或四氫呋喃。In some embodiments, the preparation method includes: (1) Mixing the compound represented by formula I or its pharmaceutically acceptable salt with maleic acid and methanol to prepare the dimaleate salt of the compound represented by formula I; (2) Using a solvent to recrystallize the dimaleate salt of the compound represented by formula I, wherein the solvent is selected from a mixed solvent of methanol and other solvents, and the other solvent is selected from one of acetone, ethyl acetate and tetrahydrofuran Or more, preferably acetone and/or tetrahydrofuran.
在某些實施方式中,方法還包括分離式I所示化合物或其可藥用鹽的晶體的步驟,優選分離得到的式I所示化合物或其可藥用鹽的雜質含量低於0.2%,例如可以低於0.19%、0.18%、0.17%、0.16%、0.15%、0.14%、0.13%、0.12%、0.11%、0.10%、0.09%、0.08%、0.07%、0.06%、0.05%或更低,優選低於0.18%,更優選低於0.15%,最優選低於0.1%。In some embodiments, the method further includes the step of separating crystals of the compound represented by formula I or its pharmaceutically acceptable salt. Preferably, the isolated compound represented by formula I or its pharmaceutically acceptable salt has an impurity content of less than 0.2%, For example, it can be lower than 0.19%, 0.18%, 0.17%, 0.16%, 0.15%, 0.14%, 0.13%, 0.12%, 0.11%, 0.10%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05% or more Low, preferably less than 0.18%, more preferably less than 0.15%, most preferably less than 0.1%.
在某些實施方式中,將所述步驟(1)中的包含式I所示化合物的二馬來酸鹽的甲醇溶液與步驟(2)中的與其他溶劑混合進行重結晶。在某些實施方式中,所述步驟(1)不包含除去甲醇溶劑的操作。In some embodiments, the methanol solution containing the dimaleate salt of the compound represented by formula I in the step (1) is mixed with other solvents in the step (2) for recrystallization. In some embodiments, the step (1) does not include the operation of removing the methanol solvent.
本發明所述的分離式I所示化合物或其可藥用鹽的方法為本領域常規的分離方法,例如可以是離心、過濾等等。The method for separating the compound represented by formula I or its pharmaceutically acceptable salt according to the present invention is a conventional separation method in the art, such as centrifugation, filtration and the like.
本發明另一方面還提供了一種藥物組合物,包含本發明所述的式I所示化合物或其可藥用鹽。藥物組合物還可包含其他藥學上可接受的輔料。In another aspect of the present invention, there is also provided a pharmaceutical composition comprising the compound represented by formula I of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may also contain other pharmaceutically acceptable excipients.
本發明另一方面還提供了一種藥物組合物,其由本發明所述的或本發明所述的方法制得的式I所示化合物或其可藥用鹽,與一種或多種藥學上可接受的輔料混合製得。Another aspect of the present invention also provides a pharmaceutical composition, the compound of formula I or a pharmaceutically acceptable salt thereof prepared by the method of the present invention or the method of the present invention, and one or more pharmaceutically acceptable Made by mixing auxiliary materials.
本發明所述雜質或物質含量均可通過HPLC檢測獲得。The impurities or substance content of the present invention can be obtained through HPLC detection.
HPLC法(中國藥典2015年版四部通則0512)檢測條件:十八烷基矽烷鍵合矽膠為填充劑(Waters symmetry C18,規格:4.6*250mm,5μm),以磷酸二氫鈉溶液和乙腈溶液為流動相進行洗脫,其中分別對系統適應性溶液、供試品溶液及1%對照溶液進行測定,按下式計算雜質百分含量: 其中,各雜質的相對保留時間為:雜質-A 0.31min;雜質-B 1.08min;雜質-C 0.86min。HPLC method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512) detection conditions: octadecyl silane bonded silica as filler (Waters symmetry C18, specification: 4.6*250mm, 5μm), with sodium dihydrogen phosphate solution and acetonitrile solution as flowing Phase is eluted, and the system adaptability solution, test solution and 1% control solution are measured respectively, and the percentage of impurities is calculated by the following formula: Among them, the relative retention time of each impurity is: impurity-A 0.31min; impurity-B 1.08min; impurity-C 0.86min.
本發明所述的雜質相對於式I所示化合物或其可藥用鹽的比例為重量比。本發明所述的「D10」是指一個樣品的累計粒度分佈百分數達到10%時所對應的粒徑。「D50」是指一個樣品的累計粒度分佈百分數達到50%時所對應的粒徑。「D90」是指一個樣品的累計粒度分佈百分數達到90%時所對應的粒徑。The ratio of the impurities in the present invention to the compound represented by formula I or its pharmaceutically acceptable salt is a weight ratio. The "D10" in the present invention refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 10%. "D50" refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 50%. "D90" refers to the particle size when the cumulative particle size distribution percentage of a sample reaches 90%.
實施例1Example 1
取式I化合物游離鹼2kg(根據WO2017186140實施例3方法製備)、馬來酸800g於50L配料桶中,加入6L無水甲醇,攪拌溶解,過濾除去不溶物,濾液轉移至玻璃反應釜中,加入30L丙酮,攪拌均勻,加入2g式I化合物二馬來酸鹽I晶型晶種,攪拌析晶,抽濾,濾餅用丙酮洗滌,濾餅40℃減壓乾燥24小時,得式I化合物二馬來酸鹽共2.408kg,收率為86.0%。Take 2kg of free base of formula I compound (prepared according to the method in Example 3 of WO2017186140) and 800g of maleic acid in a 50L batching tank, add 6L of anhydrous methanol, stir to dissolve, filter to remove insolubles, transfer the filtrate to a glass reactor, add 30L Acetone, stir evenly, add 2g of the compound of formula I dimaleate salt crystal form I seed crystals, stir to crystallize, filter with suction, wash the filter cake with acetone, and dry the filter cake under reduced pressure at 40°C for 24 hours to obtain the compound of formula I dimaleate The total lysate was 2.408 kg, and the yield was 86.0%.
實施例2Example 2
根據實施例1的方法,投入式I化合物 0.5kg,得式I化合物二馬來酸鹽共601.8g,收率為86%。According to the method of Example 1, 0.5 kg of compound of formula I was added to obtain a total of 601.8 g of compound of formula I dimaleate, with a yield of 86%.
實施例3Example 3
取式I化合物5.0g、馬來酸2.0g於反應瓶中,加入15ml無水甲醇,攪拌溶解,加入75ml四氫呋喃,攪拌析晶。抽濾,濾餅40℃真空乾燥得固體6.384g,收率為91.2%。Take 5.0 g of the compound of formula I and 2.0 g of maleic acid in a reaction flask, add 15 ml of anhydrous methanol, stir to dissolve, add 75 ml of tetrahydrofuran, and stir to crystallize. After suction filtration, the filter cake was vacuum dried at 40°C to obtain 6.384 g of solid, with a yield of 91.2%.
實施例4Example 4
將式I化合物游離鹼11.78kg、無水甲醇65.00kg加入到反應釜中,再加入4.68kg馬來酸,攪拌溶解,過濾除去不溶物,濾液在45℃減壓濃縮至無明顯液滴流下,加入93.00kg異丙醇與46.00kg丙酮,加熱回流至全部溶清。溶清後再加入晶種4.7g,繼續回流0.5小時,攪拌下冷卻析晶,過濾,濾餅用丙酮洗滌,40℃減壓乾燥,得式I化合物二馬來酸鹽共13.60kg,收率為82.58%。Add 11.78kg of free base of formula I compound and 65.00kg of anhydrous methanol into the reaction kettle, then add 4.68kg of maleic acid, stir to dissolve, filter to remove insolubles, and concentrate the filtrate at 45°C under reduced pressure until there is no obvious droplet flow. 93.00kg of isopropanol and 46.00kg of acetone, heated to reflux until all dissolved. After dissolving, add 4.7 g of seed crystals, continue to reflux for 0.5 hours, cool and crystallize under stirring, filter, wash the filter cake with acetone, and dry under reduced pressure at 40°C to obtain the compound of formula I dimaleate with a total yield of 13.60 kg. It is 82.58%.
實施例5Example 5
取各實施例製備的式I化合物二馬來酸鹽產品,測定其雜質含量,如下表1所示。
表1
採用甲醇溶劑重結晶的式I化合物二馬來酸鹽產品的雜質含量較其他溶劑製備的產品的雜質含量明顯降低。The impurity content of the dimaleate product of the formula I compound recrystallized with methanol solvent is significantly lower than that of products prepared from other solvents.
實施例6Example 6
取各實施例1、2製備的式I化合物二馬來酸鹽產品,測定其粒徑情況,如下表2所示。
表2
雖然以上描述了本發明的具體實施方式,但是本發明所屬技術領域中具通常知識者應當理解,這些僅是舉例說明,在不背離本發明的原理和實質的前提下,可以對這些實施方式做出多種變更或修改。因此,本發明的保護範圍由所附申請專利範圍限定。Although the specific embodiments of the present invention are described above, those with ordinary knowledge in the technical field of the present invention should understand that these are only examples, and these embodiments can be made without departing from the principle and essence of the present invention. Various changes or modifications have been made. Therefore, the scope of protection of the present invention is limited by the scope of the attached patent application.
無no
無no
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910812526 | 2019-08-30 | ||
CN201910812526.2 | 2019-08-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202115027A true TW202115027A (en) | 2021-04-16 |
Family
ID=74685178
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW109129417A TW202115027A (en) | 2019-08-30 | 2020-08-28 | Tyrosine kinase inhibitor with low impurity content |
Country Status (2)
Country | Link |
---|---|
TW (1) | TW202115027A (en) |
WO (1) | WO2021037185A1 (en) |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102675287A (en) * | 2011-03-11 | 2012-09-19 | 江苏恒瑞医药股份有限公司 | Pharmaceutically acceptable salts of (E)-N-(4-((3-chloro-4-(2-pyridyl methoxy) phenyl) amino)-3-cyano-7-ethyoxyl-6-quinolyl)-3-((2R)-1-methyl pyrrolidine-2-propyl)-2-acrylamide, preparation method and application of salts in medicines |
CN103539783A (en) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | I-type crystal of dimaleate of tyrosine kinase inhibitor and preparation method thereof |
EP3447051B1 (en) * | 2016-04-28 | 2021-12-15 | Jiangsu Hengrui Medicine Co., Ltd. | Method for preparing tyrosine kinase inhibitor and derivative thereof |
CA3079916A1 (en) * | 2017-10-24 | 2019-05-02 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing quinoline derivative |
US10857146B2 (en) * | 2018-08-21 | 2020-12-08 | Jiangsu Hengrui Medicine Co., Ltd. | Method for preventing or treating tumor diseases with a combination of tyrosine kinase inhibitor and CDK4/6 inhibitor |
CN110960529A (en) * | 2018-09-30 | 2020-04-07 | 江苏恒瑞医药股份有限公司 | Tyrosine kinase inhibitor bulk drug with reduced toxic impurity content |
EP3872072A4 (en) * | 2018-10-22 | 2022-07-13 | Jiangsu Hengrui Medicine Co., Ltd. | Crystal form of maleate of tyrosine kinase inhibitor and preparation method therefor |
-
2020
- 2020-08-28 TW TW109129417A patent/TW202115027A/en unknown
- 2020-08-28 WO PCT/CN2020/111995 patent/WO2021037185A1/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2021037185A1 (en) | 2021-03-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7973045B2 (en) | Anhydrous form of dasatinib and process for preparation thereof | |
US8933114B2 (en) | Polymorphic forms of asenapine maleate and processes for their preparation | |
US20190337908A1 (en) | Crystalline forms of ozanimod and ozanimod hydrochloride, and processes for preparation thereof | |
WO2011095059A1 (en) | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof | |
NO329618B1 (en) | New crystalline forms of the compound ZD1839, solvate thereof, processes for the preparation thereof and pharmaceutical preparations containing such | |
JP2020530473A (en) | Polymorphs and co-crystals of Lokidustat | |
US20180346506A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
KR102522895B1 (en) | Crystal Form of JAK Kinase inhibitor Bisulfate and a preparation method therefor | |
US11111248B2 (en) | Crystal form of 2-(6-methyl-pyridin-2-yl)-3-yl-[6-amido-quinolin-4-yl]-5,6-dihydro-4H-pyrrolo[1,2-B]pyrazole, preparation method therefor and pharmaceutical composition thereof | |
CN109438370B (en) | Methylpyrazine derivative anhydrous crystal form | |
WO2019028689A1 (en) | Odm-201 crystalline form, preparation method therefor, and pharmaceutical composition thereof | |
WO2015003571A1 (en) | Novel crystal form of dabrafenib mesylate and preparation method thereof | |
CN109574975B (en) | Crystal form of 7,8-dihydroxyflavone derivative, and preparation method and application thereof | |
CN102070625A (en) | Iloperidone crystallizing method | |
TW202115027A (en) | Tyrosine kinase inhibitor with low impurity content | |
JP2005506969A (en) | Novel modification of trometamol salt of R-thioctic acid and its production | |
KR20220141251A (en) | Novel polymorphs of 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl-N-(tetrahydro-2H-pyran-4-yl)-1H-indol-7-amine | |
WO2019200502A1 (en) | Crystal form of abemaciclib mesylate, preparation method therefor and pharmaceutical composition thereof | |
WO2023123742A1 (en) | SEMI-FUMARATE CRYSTAL OF PI3Kδ/γ DUAL INHIBITOR COMPOUND, AND PREPARATION METHOD THEREFOR | |
US20070225507A1 (en) | Process for preparing a crystalline form of Tegaserod maleate | |
WO2023125419A1 (en) | Adipate crystal and preparation method therefor | |
US20230106142A1 (en) | Crystals of alkynyl-containing compound, salt and solvate thereof, preparation method, and applications | |
CN112225732B (en) | Crystal form of pirone hydrochloride hydrate and preparation method thereof | |
CN113121456B (en) | Acipimox urea eutectic | |
US11358966B2 (en) | Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |