TW201827436A - Crystal form of bisulfate of jak inhibitor and preparation method thereof - Google Patents
Crystal form of bisulfate of jak inhibitor and preparation method thereof Download PDFInfo
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
Description
本發明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽的III晶型及其製備方法，其在醫藥組成物中的應用以及該III晶型、組合物在製備治療和/或預防關節炎疾病藥物中的用途。 The present invention relates to (3 aR , 5 s , 6 aS )- N -(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7 H -pyrrolo[ III crystal form of 2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopenta[ c ]pyrrole-2( 1H )-carbenamide hydrogensulfate and preparation method thereof in medicine composition Use in the application and the use of the III crystal form, composition for the preparation of a medicament for the treatment and/or prevention of arthritic diseases.
關節炎是全世界最常見的慢性疾病，導致關節炎的原因很多，引起關節損傷的原因也各有不同。目前，Tofacitinib(CP-690550)是輝瑞公司研發的一種新型口服JAK通路抑制劑，Tofacitinib是用於類風濕性關節炎(rheumatoid arthritis)治療的首創藥物(first-in-class drug)。基於Tofacitinib的結構，WO2013091539公開了一系列具有體內、外活性，高吸收的JAK激酶抑制劑化合物。 Arthritis is the most common chronic disease in the world, causing many causes of arthritis, and the causes of joint damage are also different. Tofacitinib (CP-690550) is a new oral JAK pathway inhibitor developed by Pfizer Inc. Tofacitinib is a first-in-class drug for the treatment of rheumatoid arthritis. Based on the structure of Tofacitinib, WO2013091539 discloses a series of JAK kinase inhibitor compounds having in vivo and exogenous activity and high absorption.
專利申請WO2014194741中公開了式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽。 (3 aR , 5 s , 6 aS )- N -(3-methoxy-1,2,4-thiadiazol-5-yl)-5- represented by the formula (I) is disclosed in the patent application WO2014194741. (Methyl ( 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopenta[ c ]pyrrole-2( 1H )-carbenamide hydrogensulfate.
專利申請WO2016054959、WO2016070697分別公開了式(I)所示化合物的I晶型、II晶型。但上述晶型均存在溶解度較差的缺陷，需要深入摸索找到溶解度更好的晶型。 Patent applications WO2016054959 and WO2016070697 disclose Form I and Form II of the compound of formula (I), respectively. However, all of the above crystal forms have defects of poor solubility, and it is necessary to dig deeper to find a crystal form with better solubility.
本發明要解決的技術問題是提供一種(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽(如式(I)所示)的III晶型，該晶型具備良好的穩定性和溶解性。 The technical problem to be solved by the present invention is to provide a (3 aR , 5 s , 6 aS )- N -(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl group ( 7H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)hexahydrocyclopenta[ c ]pyrrole-2( 1H )-carbenamide hydrogensulfate (as in formula (I) The III crystal form shown) has good stability and solubility.
本發明的技術方案如下：本發明提供一種式(I)所示化合物的III晶型，其特徵在於：使用Cu-Kα輻射，得到以衍射角2θ角度表示的X-射線粉末衍射圖譜，其在7.43，9.60，11.19，18.18，19.31，19.64，21.25，22.80和25.63處有特徵峰，其中，每個特徵峰2θ的誤差範圍為±0.2，
在本發明的一個較佳實施例方案中，本發明提供一種式(I)所示化合物的III晶型，其特徵在於：使用Cu-Kα輻射，得到以衍射角2θ角度表示的X-射線粉末衍射圖譜，該III晶型在7.43，9.09，9.60，11.19，13.13，14.90，16.35，18.18，19.31，19.64，21.25，22.80，25.63和28.10處有特徵峰，其中，每個特徵峰2θ的誤差範圍為±0.2。 In a preferred embodiment of the present invention, the present invention provides a crystal form of a compound of the formula (I) characterized by using Cu-Kα radiation to obtain an X-ray powder expressed by a diffraction angle of 2θ. Diffraction pattern, the III crystal form has characteristic peaks at 7.43, 9.09, 9.60, 11.19, 13.13, 14.90, 16.35, 18.18, 19.31, 19.64, 21.25, 22.80, 25.63 and 28.10, wherein the error range of each characteristic peak 2θ Is ±0.2.
在本發明的一個較佳實施例方案中，本發明提供一種式(I)所示化合物的III晶型，其特徵在於，使用Cu-Kα輻射，得到以衍射角2θ角度表示的X-射線粉末衍射圖譜，該III晶型在7.43，9.09，9.60，11.19，12.27，13.13，13.95，14.90，16.35，17.76，18.18，19.31，19.64，21.25，21.82，22.45，22.80，23.43，24.42，25.63，26.37，27.49，28.10，29.07，30.07，31.32，32.13，32.90，33.50，34.64，35.73，36.69，37.70和38.48處有特徵峰，其中，每個特徵峰2θ的誤差範圍為±0.2。 In a preferred embodiment of the present invention, the present invention provides a crystal form of a compound of the formula (I), characterized in that X-ray powder represented by a diffraction angle 2θ angle is obtained by using Cu-Kα radiation. Diffraction pattern, the III crystal form is 7.43, 9.09, 9.60, 11.19, 12.27, 13.13, 13.95, 14.90, 16.35, 17.76, 18.18, 19.31, 19.64, 21.25, 21.82, 22.45, 22.80, 23.43, 24.42, 25.63, 26.37, 27.49, 28.10, 29.07, 30.07, 31.32, 32.13, 32.90, 33.50, 34.64, 35.73, 36.69, 37.70 and 38.48 have characteristic peaks, wherein the error range of each characteristic peak 2θ is ±0.2.
在本發明的一個較佳實施例方案中，本發明進一步提供一種製備式(I)所示化合物III晶型的方法，所述方法包括：(1)將式(I)所示化合物溶解於二甲基亞碸中，加入反溶 劑，攪拌析晶；(2)過濾，固體乾燥後即得目標III晶型。 In a preferred embodiment of the present invention, the present invention further provides a method for preparing a crystalline form of Compound III represented by Formula (I), which comprises: (1) dissolving a compound represented by Formula (I) in two In the methyl hydrazine, an anti-solvent is added, and the crystallization is stirred; (2) filtration, and the solid is dried to obtain the target III crystal form.
本發明所述反溶劑的加入方式為：多次加入或一次性加入；該多次加入較佳分十次加入(每次間隔10min)或分三次加入(每次間隔20min)。 The anti-solvent of the present invention is added in the following manner: multiple additions or one-time addition; the multiple additions are preferably added in ten portions (each time interval of 10 minutes) or three times (each interval of 20 minutes).
本發明所述反溶劑選自酯類、酮類、醚類、腈類或醇類溶劑，該酯類溶劑較佳為乙酸乙酯，該酮類溶劑較佳為丙酮或甲基異丁酮，該醚類溶劑較佳為四氫呋喃或1,4-二噁烷，該腈類溶劑較佳為乙腈，該醇類溶劑較佳為甲醇。 The anti-solvent of the present invention is selected from the group consisting of esters, ketones, ethers, nitriles or alcohol solvents, and the ester solvent is preferably ethyl acetate, and the ketone solvent is preferably acetone or methyl isobutyl ketone. The ether solvent is preferably tetrahydrofuran or 1,4-dioxane, and the nitrile solvent is preferably acetonitrile, and the alcohol solvent is preferably methanol.
本發明III晶型的DSC吸熱峰值為209.5℃至228℃，較佳為209.8℃至218℃，更佳為217.04℃。 The DSC endothermic peak of the crystal form of the present invention is from 209.5 ° C to 228 ° C, preferably from 209.8 ° C to 218 ° C, more preferably 217.04 ° C.
本發明進一步涉及式(I)所示化合物的III晶型的醫藥組成物，該醫藥組成物由III晶型與藥學上可接受的載體、稀釋劑或賦形劑組成。 The invention further relates to a pharmaceutical composition of the crystalline form III of the compound of formula (I) consisting of a crystalline form of III with a pharmaceutically acceptable carrier, diluent or excipient.
本發明還涉及一種製備上述醫藥組成物的方法，其特徵在於，該方法包括由III晶型與藥學上可接受的載體、稀釋劑或賦形劑混合的步驟。 The invention further relates to a process for the preparation of a pharmaceutical composition as described above, characterized in that it comprises the step of mixing the crystalline form III with a pharmaceutically acceptable carrier, diluent or excipient.
本發明進一步涉及式(I)所示化合物的III晶型或III晶型的醫藥組成物在製備治療與JAK激酶有關疾病藥物中的用途，該疾病選自風濕及類風濕性關節炎。 The invention further relates to the use of a pharmaceutical composition of Form III or Form III of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease associated with JAK kinase selected from rheumatoid arthritis and rheumatoid arthritis.
藉由X-射線粉末衍射圖譜(XRPD)、差示掃描量熱分析(DSC)對所得到式(I)所示化合物的III晶型進行結構測定、晶型研究。 The crystal form of the III crystal form of the obtained compound of the formula (I) was subjected to structure measurement and crystal form analysis by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
再結晶的方法没有特別限定，可以用通常的再結晶操作方法進行。例如，可以用原料式(I)所示化合物在有機溶劑中溶解後加入反溶劑析晶，結晶完成後，經過濾乾燥，即可得到所需要的結晶。 The method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method. For example, the compound of the formula (I) can be dissolved in an organic solvent and then added to an anti-solvent to crystallize. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
本發明析晶的方法有室温析晶、冷却析晶等。 The method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, and the like.
本發明晶型製備方法中所用的起始原料可以是任意形式的式(I)所示化合物，具體形式包括但不限於：無定形、任意晶型等。 The starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.
在本申請的說明書和申請專利範圍中，除非另有說明，否則本文中使用的科學和技術名詞具有本領域技術人員所通常理解的含義。然而，為了更好地理解本發明，下面提供了部分相關術語的定義和解釋。另外，當本申請所提供的術語的定義和解釋與本領域技術人員所通常理解的含義不一致時，以本申請所提供的術語的定義和解釋為准。 In the description and claims of this application, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, unless otherwise indicated. However, for a better understanding of the present invention, definitions and explanations of some related terms are provided below. In addition, when the definitions and explanations of the terms provided by the present application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and explanations of the terms provided by the present application shall prevail.
本發明所述的“酮類溶劑”是指羰基(-C(O)-)與兩個烴基相連的化合物，根據分子中烴基的不同，酮可分為脂肪酮、脂環酮、芳香酮、飽和酮和不飽和酮，具體實例包括，但不限於：丙酮、甲基丁酮或甲基異丁酮。 The "ketone solvent" as used in the present invention means a compound in which a carbonyl group (-C(O)-) is bonded to two hydrocarbon groups, and the ketone can be classified into an aliphatic ketone, an alicyclic ketone, an aromatic ketone according to a hydrocarbon group in the molecule. Saturated ketones and unsaturated ketones, specific examples include, but are not limited to, acetone, methyl butanone or methyl isobutyl ketone.
本發明所述的“酯類溶劑”是指含碳原子數為1至4個的低級有機酸與含碳原子數為1至6個的低級醇的結合物，具體實例包括，但不限於：乙酸乙酯、乙酸異丙酯或乙酸丁酯。 The "ester solvent" as used in the present invention means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to: Ethyl acetate, isopropyl acetate or butyl acetate.
本發明所述的“醚類溶劑”是指含有醚鍵-O-且碳原子 數為1至10個的鏈狀化合物或環狀化合物，具體實例包括，但不限於：丙二醇甲醚、四氫呋喃或1,4-二氧六環。 The "ether solvent" as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or 1,4-dioxane.
本發明所述的“醇類溶劑”是指一個或多個“羥基”取代“C1-6烷基”上的一個或多個氫原子所衍生的基團，該“羥基”和“C1-6烷基”如前文所定義，具體實例包括，但不限於：甲醇、乙醇、丙醇或2-丙醇。 The "alcohol solvent" as used in the present invention means a group derived from one or more "hydroxyl groups" substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", and the "hydroxyl group" and "C 1 " -6 alkyl" is as defined above, and specific examples include, but are not limited to, methanol, ethanol, propanol or 2-propanol.
本發明所述的“腈類溶劑”是指一個或多個“氰基”取代“C1-6烷基”上的一個或多個氫原子所衍生的基團，該“氰基”和“C1-6烷基”如前文所定義，具體實例包括，但不限於：乙腈或丙腈。 The "nitrile solvent" as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted "C 1-6 alkyl", the "cyano" and " C 1-6 alkyl" is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
本發明所述的“X-射線粉末衍射圖譜或XRPD”是指根據布拉格公式2d sin θ=nλ(式中，λ為X射線的波長，λ=1.54056Å，衍射的級數n為任何正整數，一般取一級衍射峰，n=1)，當X射線以掠角θ(入射角的餘角，又稱為布拉格角)入射到晶體或部分晶體樣品的某一具有d點陣平面間距的原子面上時，就能滿足布拉格方程，從而測得了這組X射線粉末衍射圖。 The "X-ray powder diffraction pattern or XRPD" according to the present invention means that according to the Bragg formula 2d sin θ = nλ (where λ is the wavelength of the X-ray, λ = 1.540556 Å, the order of diffraction n is any positive integer Generally, taking the first-order diffraction peak, n=1), when the X-ray is incident on the crystal or a part of the crystal sample with a d-dot plane spacing by the sweep angle θ (the complementary angle of the incident angle, also called the Bragg angle) On the surface, the Bragg equation is satisfied, and the X-ray powder diffraction pattern is measured.
本發明所述的“差示掃描量熱分析或DSC”是指在樣品升溫或恒溫過程中，測量樣品與參考物之間的溫度差、熱流差，以表徵所有與熱效應有關的物理變化和化學變化，得到樣品的相變資訊。 The "differential scanning calorimetry or DSC" as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change, get the phase change information of the sample.
本發明所述的“2θ或2θ角度”是指衍射角，θ為布拉格角，單位為°或度，2θ的誤差範圍為±0.1至±0.5，較佳±0.1至±0.3，更佳±0.2。 The "2θ or 2θ angle" as used in the present invention means a diffraction angle, θ is a Bragg angle, and the unit is ° or degree, and the error range of 2θ is ±0.1 to ±0.5, preferably ±0.1 to ±0.3, more preferably ±0.2. .
本發明所述的“晶面間距或晶面間距(d值)”是指空間點陣選擇3個不相平行的連結相鄰兩個點陣點的單位向量a，b，c，它們將點陣劃分成並置的平行六面體單位，稱為晶面間距。空間點陣按照確定的平行六面體單位連線劃分，獲得一套直線網格，稱為空間格子或晶格。點陣和晶格是分別用幾何的點和線反映晶體結構的週期性，不同的晶面，其面間距(即相鄰的兩個平行晶面之間的距離)各不相同；單位為Å或埃。 The "plane spacing or interplanar spacing (d value)" according to the present invention means that the spatial lattice selects three non-parallel unit vectors a, b, c connecting adjacent two lattice points, which will point The parallelepiped unit, which is divided into juxtapositions, is called the interplanar spacing. The spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice. The lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel planes) is different; the unit is Å Or ang.
本發明還涉及，包括式(I)所示的化合物的III晶型，以及任選的一種或多種藥用載體和/或稀釋劑的醫藥組成物。該醫藥組成物可以製成藥學上可接受的任一劑型。例如，本發明的III晶型或藥物製劑可以配製為片劑、膠囊劑、丸劑、顆粒劑、溶液劑、混懸劑、糖漿劑、注射劑(包括注射液、注射用無菌粉末與注射用濃溶液)、栓劑、吸入劑或噴霧劑。 The invention further relates to a pharmaceutical composition comprising a crystalline form of the compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents. The pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms. For example, the III crystalline form or pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection). ), suppositories, inhalants or sprays.
此外，本發明的該醫藥組成物還可以以任何合適的給藥方式，例如口服、腸胃外、直腸、經肺或局部給藥等方式施用於需要這種治療的患者或受試者。當用於口服給藥時，該醫藥組成物可製成口服製劑，例如口服固體製劑，如片劑、膠囊劑、丸劑、顆粒劑等；或，口服液體製劑，如口服溶液劑、口服混懸劑、糖漿劑等。當製成口服製劑時，該藥物製劑還可包含適宜的填充劑、粘合劑、崩解劑、潤滑劑等。當用於腸胃外給藥時，該藥物製劑可製成注射劑，包括注射液、注射用無菌粉末與注射用濃溶液。當製 成注射劑時，該醫藥組成物可採用現有製藥領域中的常規方法來進行生產。當配製注射劑時，該藥物製劑中可以不加入添加劑，也可根據藥物的性質加入適宜的添加劑。當用於直腸給藥時，該藥物製劑可製成栓劑等。用於經肺給藥時，該藥物製劑可製成吸入劑或噴霧劑等。在某些較佳的實施方案中，本發明的III晶型以治療和/或預防有效量存在於醫藥組成物或藥物中。在某些較佳的實施方案中，本發明的III晶型以單位劑量的形式存在於醫藥組成物或藥物中。 Furthermore, the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be formulated into an oral preparation, for example, an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral suspension. Agent, syrup, and the like. When formulated into an oral preparation, the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like. When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. When an injection is prepared, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field. When the injection is formulated, the pharmaceutical preparation may be added without an additive, and a suitable additive may be added depending on the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be formulated into a suppository or the like. For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray. In certain preferred embodiments, the Form III of the invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the Form III of the invention is present in a pharmaceutical composition or drug in unit dosage form.
本發明式(I)化合物的III晶型可用於製備治療與JAK激酶有關疾病藥物中的用途。因此，本申請還涉及，本發明式(I)化合物的III晶型用於製備藥物的用途，該藥物用於治療與JAK激酶有關的疾病的藥物中的用途。此外，本申請還涉及，一種抑制與JAK激酶有關的疾病的方法，其包括給有此需要的受試者施用治療和/或預防有效量的本發明式(I)化合物的III晶型，或者本發明的醫藥組成物。 The crystalline form III of the compound of the formula (I) of the present invention can be used for the preparation of a medicament for treating a disease associated with JAK kinase. Accordingly, the present application also relates to the use of the crystalline form III of the compound of the formula (I) of the present invention for the preparation of a medicament for use in a medicament for the treatment of a disease associated with JAK kinase. Further, the present application relates to a method of inhibiting a disease associated with JAK kinase, which comprises administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a crystalline form III of a compound of the formula (I) of the present invention, or A pharmaceutical composition of the present invention.
在某些較佳的實施方案中，該疾病為與JAK激酶有關的疾病，選自風濕及類風濕性關節炎。 In certain preferred embodiments, the disease is a disease associated with JAK kinase selected from the group consisting of rheumatoid and rheumatoid arthritis.
與現有技術相比，本發明的技術方案具有以下優點：經研究表明，本發明製備的式(I)所示化合物的III晶型溶解性優、純度較高，在光照、高温、高濕的條件下晶型經XRPD檢測均未發生改變、晶型穩定性良好；HPLC純度變化小、化學穩定性高；本發明技術方案得到的式(I) 所示化合物的III晶型能够滿足生產運輸儲存的藥用要求，生產工藝穩定、可重複可控，能够適應於工業化生產。 Compared with the prior art, the technical scheme of the present invention has the following advantages: the research shows that the III crystal form of the compound of the formula (I) prepared by the invention has excellent solubility and high purity, and is light, high temperature and high humidity. Under the condition, the crystal form has not changed by XRPD detection, and the crystal form stability is good; the HPLC purity change is small, and the chemical stability is high; the III crystal form of the compound of the formula (I) obtained by the technical scheme of the present invention can satisfy the production transportation and storage. The medicinal requirements, the production process is stable, repeatable and controllable, and can be adapted to industrial production.
第1圖為式(I)所示化合物III晶型的XRPD圖譜。 Figure 1 is an XRPD pattern of the crystalline form of Compound III of formula (I).
第2圖為式(I)所示化合物III晶型的DSC圖譜。 Figure 2 is a DSC chart of the crystalline form of Compound III of formula (I).
第3圖為式(I)所示化合物無定形的XRPD圖譜。 Figure 3 is an amorphous XRPD pattern of the compound of formula (I).
第4圖為式(I)所示化合物無定形的DSC圖譜。 Figure 4 is an amorphous DSC pattern of the compound of formula (I).
以下將結合實施例更詳細地解釋本發明，本發明的實施例僅用於說明本發明的技術方案，並非限定本發明的實質和範圍。 The invention is explained in more detail below with reference to the embodiments, which are intended to illustrate the technical scope of the invention and not to limit the scope and scope of the invention.
實驗所用儀器的測試條件： Test conditions for the instruments used in the experiment:
儀器型號：Mettler Toledo DSC 1 STARe System Instrument model: Mettler Toledo DSC 1 STAR e System
吹掃氣：氮氣 Purge gas: nitrogen
升溫速率：10.0℃/min Heating rate: 10.0 ° C / min
溫度範圍：40-300℃ Temperature range: 40-300 ° C
儀器型號：Bruker D8 Focus X-射線粉末衍射儀 Instrument model: Bruker D8 Focus X-ray powder diffractometer
射線：單色Cu-Kα射線(λ=1.5406) Ray: Monochrome Cu-Kα ray (λ=1.5406)
掃描方式：θ/2θ，掃描範圍：2-40° Scanning mode: θ/2θ, scanning range: 2-40°
電壓：40kV，電流：40mA Voltage: 40kV, current: 40mA
將(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺(140g，0.34mol)加入反應瓶中，加入無水甲醇(350g)、二氯甲烷(2.0kg)，懸浮攪拌，室溫下緩慢滴加硫酸(34.8g，0.36mol)，反應液澄清，攪拌反應30min。過濾除去不溶物，濾液減壓濃縮，乾燥，得目標產物(168g，產率90%)。該樣品的X-射線衍射譜圖見第3圖，顯示無晶型特徵吸收峰，DSC譜圖見第4圖，在300℃以下未見熔融特徵吸收峰，據此確定產物為無定形固體。 (3 aR , 5 s , 6 aS )- N -(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7 H -pyrrolo[2, 3- d ]pyrimidin-4-yl)amino)hexahydrocyclopenta[ c ]pyrrole-2( 1H )-carbenamide (140 g, 0.34 mol) was added to a reaction flask, and anhydrous methanol (350 g) was added. Dichloromethane (2.0 kg) was stirred and stirred, and sulfuric acid (34.8 g, 0.36 mol) was slowly added dropwise at room temperature, the reaction solution was clarified, and the reaction was stirred for 30 min. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to give the desired product (168 g, yield: 90%). The X-ray diffraction spectrum of the sample is shown in Fig. 3, showing the characteristic peak of the amorphous form. The DSC spectrum is shown in Fig. 4. No melting characteristic absorption peak is observed below 300 ° C, and the product is determined to be an amorphous solid.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)加入反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入乙酸乙酯(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥後得固體樣品，經XRPD檢測衍射角2θ在7.44(11.87)，9.10(9.72)，9.61(9.20)，11.20(7.89)，12.28(7.20)，13.14(6.73)，13.96(6.34)，14.91(5.94)，16.35(5.42)，17.76(4.99)，18.19(4.87)，19.31(4.59)，19.66(4.51)，21.27(4.17)，21.82(4.07)，22.47(3.95)，22.80(3.90)，23.44(3.79)，24.44(3.64)，25.65(3.47)，26.38(3.38)，27.49(3.24)，28.13(3.17)，29.10(3.07)，30.08(2.97)，31.34(2.85)，32.15(2.78)，32.91 (2.72)，33.50(2.07)，34.63(2.59)，35.73(2.51)，36.73(2.45)，37.64(2.39)和38.47(2.34)處有特徵峰，將此晶型定義為III晶型。 A sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was added to a reaction flask, DMSO (150 μL) was added thereto, and the mixture was stirred and dissolved at 25 ° C, and ethyl acetate (1 mL) was gradually added thereto, and 100 μL each was added. The middle interval is about 10 min. After the addition, the heating is turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate is vacuum dried to obtain a solid sample. The diffraction angle 2θ is detected by XRPD at 7.44 (11.87), 9.10 (9.72), 9.61 (9.20). , 11.20 (7.89), 12.28 (7.20), 13.14 (6.73), 13.96 (6.34), 14.91 (5.94), 16.35 (5.42), 17.76 (4.99), 18.19 (4.87), 19.31 (4.59), 19.66 (4.51) , 21.27 (4.17), 21.82 (4.07), 22.47 (3.95), 22.80 (3.90), 23.44 (3.79), 24.44 (3.64), 25.65 (3.47), 26.38 (3.38), 27.49 (3.24), 28.13 (3.17) , 29.10 (3.07), 30.08 (2.97), 31.34 (2.85), 32.15 (2.78), 32.91 (2.72), 33.50 (2.07), 34.63 (2.59), 35.73 (2.51), 36.73 (2.45), 37.64 (2.39) And 38.47 (2.34) has a characteristic peak, which is defined as the III crystal form.
將式(I)化合物(按實施例1的方法製備)樣品(500mg)置於反應瓶中，加入DMSO(1.5mL)，60℃下攪拌溶解，加入甲醇(10mL)，關閉加熱，攪拌析晶，過濾，真空乾燥得固體樣品393mg，收率78.6%。將此晶型定義為III晶型，該結晶樣品的XRPD圖譜見第1圖，其DSC譜圖見第2圖，熔點在217.04附近，起始熔化溫度為209.82℃，其特徵峰位置如下表所示：
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入丙酮(1mL)，每次加入100μL，中間間隔約10min；加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and acetone (1 mL) was gradually added thereto, and 100 μL each was added. The interval was about 10 min; after the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入丙酮(1mL)，分三次加入，分別為300μL、300μL、400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌 約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and acetone (1 mL) was gradually added thereto, and added in three portions, respectively. 300 μL, 300 μL, 400 μL, with an interval of about 20 min. After the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，一次性加入丙酮(1mL)，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, acetone (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating was turned off, stirring was carried out for about 40 hours, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入四氫呋喃(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, and DMSO (150 μL) was added thereto, and the mixture was stirred and dissolved at 25 ° C, and tetrahydrofuran (1 mL) was gradually added thereto, and 100 μL each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入四氫呋喃(1mL)，分三次加入，分別為300μL，300μL，400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and tetrahydrofuran (1 mL) was gradually added thereto, and added in three portions, respectively. 300 μL, 300 μL, 400 μL, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置 於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入1,4-二噁烷(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was gradually added. Add 100 μL each time, the interval is about 10 min, add up, heat off after 1.5 h, stir for about 40 h, filter, and the precipitate is vacuum dried to obtain a solid. The XRPD pattern and DSC spectrum of the crystal sample are compared by study to confirm that the product is III. Crystal form.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入1,4-二噁烷(1mL)，分三次加入，分別為300μL，300μL，400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was gradually added. It was added in three portions, 300 μL, 300 μL, 400 μL, and the interval was about 20 min. After the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. XRPD pattern and DSC pattern of the crystal sample were studied. The product was determined to be a crystalline form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，一次性加入1,4-二噁烷(1mL)，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was added in one portion. After the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入乙腈(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾 燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and acetonitrile (1 mL) was gradually added thereto, and 100 μL each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入乙腈(1mL)，分三次加入，分別為300μL，300μL，400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and acetonitrile (1 mL) was gradually added thereto, and added in three portions, respectively. 300 μL, 300 μL, 400 μL, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入甲基異丁酮(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and methyl isobutyl ketone (1 mL) was gradually added thereto. Add 100 μL, the interval is about 10 min, add up, heat off after 1.5 h, stir for about 40 h, filter, and the precipitate is vacuum dried to obtain a solid. The XRPD pattern and the DSC spectrum of the crystal sample are compared by study to confirm that the product is a crystal form III. .
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入甲醇(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was gradually added thereto, and 100 μL each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，逐步加入甲醇(1mL)，分三次加入，分別為300μL，300μL，400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was gradually added thereto, and added in three portions, respectively. 300 μL, 300 μL, 400 μL, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，25℃下攪拌溶解，一次性加入甲醇(1mL)，加畢，1.5h後關閉加熱，攪拌約40h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating was turned off, stirring was carried out for about 40 hours, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，50℃下攪拌溶解，逐步加入丙酮(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約20h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 50 ° C, and acetone (1 mL) was gradually added thereto, and 100 μL each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 20 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，50℃下攪拌溶解，逐步加入甲醇(1mL)，每次加入100μL，中間間隔約10min，加畢，1.5h後關閉加熱，攪拌約20h，過濾，沉澱物真空乾 燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, and DMSO (150 μL) was added thereto, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was gradually added thereto, and 100 μL each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 20 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，50℃下攪拌溶解，逐步加入甲醇(1mL)，分三次加入，分別為300μL、300μL、400μL，中間間隔約20min，加畢，1.5h後關閉加熱，攪拌約20h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was gradually added thereto, and added in three portions, respectively. 300 μL, 300 μL, 400 μL, with an interval of about 20 min. After the addition, the heating was turned off after 1.5 h, stirred for about 20 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
將式(I)化合物(按實施例1的方法製備)樣品(50mg)置於反應瓶中，加入DMSO(150μL)，50℃下攪拌溶解，一次性加入甲醇(1mL)，加畢，1.5h後關閉加熱，攪拌約20h，過濾，沉澱物真空乾燥得固體，該結晶樣品的XRPD圖譜和DSC圖譜經研究比對，確定產物為III晶型。 A sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 μL) was added, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating, the heating was turned off, stirred for about 20 hours, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
將實施例1所得的無定形產物樣品和實施例3所得的III晶型產物樣品敞口平攤放置，考察在光照(4500Lux)、加熱(40℃、60℃)、高濕(RH75%、RH90%)條件下樣品的穩定性，考察取樣時間為5天和10天，HPLC檢測純度結果見表1。 The amorphous product sample obtained in Example 1 and the III crystal product sample obtained in Example 3 were placed in an open position, and examined under illumination (4,500 Lux), heating (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90). The stability of the sample under the condition of %) was investigated for 5 days and 10 days, and the purity of the HPLC was shown in Table 1.
試驗結果： test results:
由表2的穩定性考察結果顯示：在光照、高濕、高溫敞口放置條件下，高濕對兩者的影響不大，但是在光照、高溫的條件下，III晶型的穩定性顯著優於無定形樣品，經XRPD檢測晶型均未發生改變，說明本發明的III晶型穩定性顯著優於無定形。 The results of the stability study in Table 2 show that under the conditions of light, high humidity and high temperature open, the high humidity has little effect on the two, but under the conditions of illumination and high temperature, the stability of the III crystal form is significantly better. In the amorphous sample, the crystal form was not changed by XRPD, indicating that the stability of the III crystal form of the present invention is significantly better than that of amorphous.
供試品：晶型III(按照實施例3方法製備)、晶型I(可按照WO2016054959方法製備)、晶型II(可按照WO2016070697方法製備)。 Test sample: Form III (prepared according to the method of Example 3), Form I (which can be prepared according to the method of WO2016054959), Form II (which can be prepared according to the method of WO2016070697).
溶劑：水、0.1N HCl。 Solvent: water, 0.1 N HCl.
試驗結果： test results:
由表3實驗結果顯示：本發明晶型III在水或0.1N HCl中的飽和溶解度均大於晶型I或晶型II，本發明晶型III的溶解性更優。 The experimental results shown in Table 3 show that the saturated solubility of the crystalline form III of the present invention in water or 0.1 N HCl is larger than that of the crystalline form I or the crystalline form II, and the solubility of the crystalline form III of the present invention is superior.
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