TW202016099A - Crystalline form of opioid receptor agonist and manufacturing method thereof - Google Patents
Crystalline form of opioid receptor agonist and manufacturing 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
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
Abstract
Description
本公開提供(1S ,4S )-4-乙氧基-N -(2-((R )-9-(吡啶-2-基)-6-氧雜螺[4.5]癸-9-基)乙基)-1,2,3,4-四氫萘-1-胺富馬酸鹽的III晶型及製備方法，III晶型在藥物組合物中的應用以及該III晶型、組合物在製備治療和/或預防與鴉片類物質受體(MOR)激動劑有關疾病的藥物中的用途。The present disclosure provides (1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl )Ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine fumarate III crystal form and preparation method, application of the III crystal form in the pharmaceutical composition and the III crystal form and composition Use in the preparation of a medicament for the treatment and/or prevention of diseases associated with opioid receptor (MOR) agonists.
本申請要求申請日為2018/10/12的中國專利申請201811186743.7的優先權。本申請引用上述中國專利申請的全文。This application requires the priority of Chinese patent application 201811186743.7 with an application date of 2018/10/12. This application cites the entire text of the aforementioned Chinese patent application.
鴉片受體是一類重要的G蛋白偶聯受體(G protein coupled receptor, GPCR)，是內源性鴉片肽及鴉片類藥物結合的靶點，鴉片受體啟動後對神經系統免疫及內分泌系統具有調節作用，鴉片類藥物是目前最強且常用的中樞鎮痛藥。內源性鴉片肽是哺乳動物體內天然生成的鴉片類活性物質，目前已知的內源性鴉片肽大致分為腦啡肽、內啡肽、強啡肽和新啡肽幾類(Pharmacol Rev 2007; 59: 88-123)。中樞神經系統中存在其相應的鴉片受體，即μ(MOR)、δ(DOR)、κ(KOR)受體等。MOR是內源性腦啡肽和嗎啡等鴉片類鎮痛藥物的作用靶點。Opium receptors are an important class of G protein coupled receptors (GPCRs). They are targets for the binding of endogenous opioid peptides and opioids. After activation, the opioid receptors are immune to the nervous system and endocrine system. Regulatory effects, opioids are currently the strongest and most commonly used central analgesics. Endogenous opioid peptides are naturally-occurring opioid active substances in mammals, and currently known endogenous opioid peptides are roughly divided into enkephalins, endorphins, dynorphins, and neomorphins ( Pharmacol Rev 2007 ; 59: 88-123). There are corresponding opioid receptors in the central nervous system, namely μ (MOR), δ (DOR), and κ (KOR) receptors. MOR is the target of opioid analgesics such as endogenous enkephalin and morphine.
鴉片類藥物長期使用會產生耐受以及呼吸抑制、便秘等副作用，而這些副作用被證明與β-arrestin的功能密切相關。為了減小鴉片類藥物的副作用，可基於MOR的負性β-arrestin偏愛性配體設計藥物，使β
-arrestin介導的副作用降低，增強治療效果，對於本公開的氧雜螺環類衍生物在作為MOR選擇性藥物的研究中，TrevenaInc公司研究發現芳基苄位取代時活性較差(J. Med. Chem
. 2013, 56, 8019−8031)，但WO2017063509發現了一種芳基苄位成環後卻表現出高活性、Emax顯著提高、hERG明顯改善、單一構型的MOR化合物，結構如式(II)所示：
作為藥用活性成分的晶型結構往往影響到該藥物的化學和物理穩定性，結晶條件及儲存條件的不同有可能導致化合物的晶體結構的變化，有時還會伴隨著產生其他形態的晶型。一般來說，無定形的藥物產品沒有規則的晶體結構，往往具有其它缺陷，比如產物穩定性較差，過濾較難，易結塊，流動性差等。因此，改善式(II)所示化合物的各方面性質是很有必要的。The crystalline structure as a pharmaceutical active ingredient often affects the chemical and physical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other forms of crystalline form . In general, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy caking, and poor fluidity. Therefore, it is necessary to improve various properties of the compound represented by formula (II).
本公開（The disclosure）提供一種式(I)所示化合物的III晶型，以衍射角2θ
角度表示的X-射線粉末衍射圖譜，在6.44、10.16、11.99、13.65、14.00、16.43、17.05、19.56、21.40和22.64處有特徵峰，
一些實施方案中提供所述的III晶型，以衍射角2θ
角度表示的X-射線粉末衍射圖譜，在6.44、10.16、11.99、13.22、13.65、14.00、14.38、16.08、16.43、17.05、17.63、17.98、18.90、19.56、20.12、20.58、21.40、22.64、22.91、23.94和29.26處有特徵峰。Some embodiments provide the crystalline form III according, X- ray powder diffraction pattern at the
一些實施方案中提供所述的III晶型，所述衍射角2θ
角在6.44、7.11、9.78、10.16、11.99、12.90、13.22、13.65、14.00、14.38、14.82、15.32、16.08、16.43、17.05、17.63、17.98、18.90、19.56、20.12、20.58、20.92、21.40、22.64、22.91、23.18、23.94、24.50、25.32、25.88、26.67、28.47、29.26、30.16、30.96、32.52、33.38、35.74、37.02、40.38、41.19和42.41處有特徵峰。Some embodiments provide the crystalline form III of the
另一些實施方案中提供所述的III晶型，以衍射角2θ
角度表示的X-射線粉末衍射圖譜如圖1所示。Some other embodiments provide Form III according, X- ray powder diffraction pattern at the
本公開還提供一種製備III晶型的方法，所述方法包括： 將式(I)所示化合物的游離態溶解於溶劑中，加入富馬酸，加熱至微沸，冷卻析晶得III晶型；所述微沸溫度選自40℃-溶劑沸點，所述溶劑優選醇類溶劑，所述醇類溶劑優選異丙醇。The present disclosure also provides a method of preparing the III crystal form, the method including: The free state of the compound represented by formula (I) is dissolved in a solvent, fumaric acid is added, heated to slightly boiling, and crystallized by cooling to obtain crystal form III; the slightly boiling temperature is selected from 40°C-the boiling point of the solvent, and the solvent is preferably An alcoholic solvent, the alcoholic solvent is preferably isopropyl alcohol.
另一方面，在一些實施方案中，本公開中晶型的製備方法中還包括過濾，洗滌或乾燥等步驟。On the other hand, in some embodiments, the method for preparing the crystalline form in the present disclosure further includes steps such as filtration, washing or drying.
本公開中提供了一種藥物組合物，由前述式(I)所示化合物III晶型，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑製備而成。例如，本公開的式(I)所示化合物的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 present disclosure provides a pharmaceutical composition prepared from the compound III crystal form represented by the aforementioned formula (I) and one or more pharmaceutically acceptable carriers, diluents or excipients. For example, the crystalline form III or pharmaceutical preparation of the compound represented by formula (I) of the present disclosure can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, injections Use sterile powders and concentrated solutions for injection), suppositories, inhalants or sprays.
此外，本公開所述藥物組合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，所述藥物組合物可製成口服製劑，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，所述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，所述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，所述藥物組合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，所述藥物製劑中可以不加入附加劑，也可根據藥物的性質加入適宜的附加劑。當用於直腸給藥時，所述藥物製劑可製成栓劑等。用於經肺給藥時，所述藥物製劑可製成吸入劑或噴霧劑等。在某些優選的實施方案中，本公開的式(I)所示的化合物的III晶型以治療和/或預防有效量存在於藥物組合物或藥物中。在某些優選的實施方案中，本公開式(I)所示的化合物的III晶型以單位劑量的形式存在於藥物組合物或藥物中。In addition, the pharmaceutical composition of the present disclosure can also be administered to patients or subjects in need of such treatment in any suitable manner of administration, such as oral, parenteral, rectal, pulmonary or local administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral mixtures Suspension, syrup, etc. When prepared as an oral preparation, the pharmaceutical preparation may also contain suitable fillers, binders, disintegrating agents, lubricants and the like. When used for parenteral administration, the pharmaceutical preparation can be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When prepared as an injection, the pharmaceutical composition can be produced using conventional methods in the existing pharmaceutical field. When preparing an injection, no additional agent may be added to the pharmaceutical preparation, or an appropriate additional agent may be added according to the nature of the drug. When used for rectal administration, the pharmaceutical preparation can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical preparations can be made into inhalants or sprays. In certain preferred embodiments, the crystalline form III of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in a therapeutically and/or prophylactically effective amount. In certain preferred embodiments, the crystalline form III of the compound represented by formula (I) of the present disclosure is present in the pharmaceutical composition or drug in unit dosage form.
本公開還提供了一種藥物組合物的製備方法，包括將前述III晶型或由前述方法製備獲得的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 present disclosure also provides a method for preparing a pharmaceutical composition, including the step of mixing the aforementioned III crystal form or the III crystal form obtained by the foregoing method with a pharmaceutically acceptable carrier, diluent or excipient.
本公開還提供所述的III晶型、III晶型的藥物組合物在製備治療與鴉片類物質受體(MOR)激動劑介導的相關疾病的藥物中的用途。The present disclosure also provides the use of the crystalline form III and the crystalline form III pharmaceutical composition in the preparation of a medicament for treating diseases related to opioid receptor (MOR) agonists.
本公開所述的用途，其中所述MOR受體激動劑介導的相關疾病選自疼痛、免疫功能障礙、炎症、食管回流、神經和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸道疾病，優選疼痛。The use described in the present disclosure, wherein the related diseases mediated by the MOR receptor agonist are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases, Pain is preferred.
本公開還提供式(I)所示化合物的III晶型、III晶型的藥物組合物在製備預防或治療疼痛和疼痛相關疾病的藥物中的用途。The present disclosure also provides use of the crystalline form III and the crystalline form III of the compound represented by formula (I) in the preparation of a medicament for preventing or treating pain and pain-related diseases.
本公開所述的疼痛選自術後疼痛、癌症引起的疼痛、神經性疼痛、創傷性疼痛或炎症引起的疼痛。The pain described in this disclosure is selected from postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, or inflammation-induced pain.
本公開所述的癌症選自乳腺癌、子宮內膜癌、子宮頸癌、皮膚癌、***癌、卵巢癌、輸卵管腫瘤、卵巢瘤、血友病和白血病。The cancer described in the present disclosure is selected from breast cancer, endometrial cancer, cervical cancer, skin cancer, prostate cancer, ovarian cancer, fallopian tube tumor, ovarian tumor, hemophilia, and leukemia.
本公開還提供式(I)所示化合物的III晶型、III晶型的藥物組合物在製備激動或拮抗MOR受體的藥物中用途。此外，本申請還提供了一種抑制與鴉片類物質受體(MOR)激動劑有關的疾病的方法，其包括給有此需要的受試者施用治療和/或預防有效量的本公開式(I)化合物的III晶型，或者本公開的藥物組合物。The present disclosure also provides the use of the crystalline form III and the crystalline form III of the compound represented by formula (I) in the preparation of a medicament for agonizing or antagonizing the MOR receptor. In addition, the present application also provides a method of inhibiting a disease associated with an opioid receptor (MOR) agonist, which includes administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of the formula (I ) Compound III crystal form, or the pharmaceutical composition of the present disclosure.
在某些優選的實施方案中，所述疾病為與鴉片類物質受體(MOR)激動劑有關的疾病，選自疼痛。In certain preferred embodiments, the disease is a disease associated with an opioid receptor (MOR) agonist, selected from pain.
通過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 X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC) were used to determine the structure and crystal form of the III crystal form of the obtained compound represented by formula (I).
III晶型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 of the III crystal form is not particularly limited, and it can be carried out by a general recrystallization operation method. For example, the compound represented by the formula (I) as a raw material can be dissolved in an organic solvent and then added to an anti-solvent for crystallization. After the crystallization is completed, the desired crystal can be obtained by filtration and drying.
本公開析晶的方法有室溫析晶、冷卻析晶、加入晶種誘導析晶等。The crystallization methods of the present disclosure include room temperature crystallization, cooling crystallization, adding seed crystals to induce crystallization, and the like.
本公開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 crystal form preparation method of the present disclosure may be any form of the compound represented by formula (I), and specific forms include, but are not limited to, amorphous, any crystal form, and the like.
披露詳述：Disclosure details:
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，為了更好地理解本公開，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準。In the description and patent application scope of this application, unless otherwise stated, the scientific and technical terms used herein have the meaning commonly understood by those skilled in the art. However, in order to better understand the present disclosure, definitions and explanations of some related terms are provided below. In addition, when the definitions and interpretations of the terms provided in this application are inconsistent with the meanings generally understood by those skilled in the art, the definitions and interpretations of the terms provided in this application shall prevail.
本公開所述“C1-6 烷基”表示直鏈或支鏈的含有1-6個碳原子的烷基，具體實例包括但不限於：甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、異己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。The "C 1-6 alkyl group" in the present disclosure means a linear or branched alkyl group containing 1-6 carbon atoms, and specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl Group, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.
本公開所述“羥基”是指-OH等基團。The "hydroxyl group" in the present disclosure refers to a group such as -OH.
本公開所述“氰基”是指-CN等基團。The "cyano" in this disclosure refers to a group such as -CN.
本公開所述的“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：四氫呋喃、***、丙二醇甲醚、甲基第三丁基醚或1,4-二氧六環。The "ether solvent" described in the present disclosure refers to a chain compound or a cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include but are not limited to: tetrahydrofuran, diethyl ether, and propylene glycol methyl ether , Methyl tert-butyl ether or 1,4-dioxane.
本公開所述的“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，所述“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、異丙醇、正丙醇、異戊醇或三氟乙醇。The "alcoholic solvent" described in the present disclosure refers to a group derived from one or more "hydroxyl groups" in place of one or more hydrogen atoms on a "C 1-6 alkyl group". The "hydroxyl group" and "C "1-6 alkyl" is as defined above, and specific examples include, but are not limited to: methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol, or trifluoroethanol.
本公開所述的“混合溶劑”是指一種或多種不同種類的有機溶劑按照一定比例混合而成的溶劑，或有機溶劑與水按照一定比例混合而成的溶劑；所述混合溶劑優選為醇類與醚類的混合溶劑；所述醇類與醚類的混合溶劑優選為甲醇與***的混合溶劑，所述比例優選1:10。The "mixed solvent" in the present disclosure refers to a solvent in which one or more different kinds of organic solvents are mixed in a certain ratio, or a solvent in which an organic solvent and water are mixed in a certain ratio; the mixed solvent is preferably an alcohol A mixed solvent with ethers; the mixed solvent of alcohols and ethers is preferably a mixed solvent of methanol and ether, and the ratio is preferably 1:10.
本公開中所述的“X-射線粉末衍射圖譜”為使用Cu-Kα輻射測量得到，其中，λ=1.5418 Å。The “X-ray powder diffraction pattern” described in this disclosure is measured using Cu-Kα radiation, where λ=1.5418 Å.
本公開所述的“X-射線粉末衍射圖譜或XRPD”是指根據布拉格公式2d sinθ = nλ (式中，λ為X射線的波長，λ=1.5418Å，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" mentioned in this disclosure refers to the Bragg formula 2d sin θ = nλ (where λ is the wavelength of X-ray, λ=1.5418Å, and the order of diffraction n is any positive integer , Generally take the first-order diffraction peak, n=1), when X-rays enter the crystal or part of the crystal sample with a d-lattice plane spacing at a grazing angle θ (coincidence of the incident angle, also called Bragg angle) On the surface, the Bragg equation can be satisfied, so that this group of X-ray powder diffraction patterns are measured.
本公開所述的“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" described in this disclosure refers to the measurement of the temperature difference and heat flow difference between the sample and the reference substance during the sample heating or constant temperature process to characterize all physical changes and chemistry related to the thermal effect Change, get the phase change information of the sample.
本公開所述的“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±0.3，可以為-0.30、-0.29、-0.28、-0.27、-0.26、-0.25、-0.24、-0.23、-0.22、-0.21、-0.20、-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、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.30，更優選±0.2。The "2 θ or 2 θ angle" mentioned in this disclosure refers to the diffraction angle , θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.3, which can be -0.30, -0.29, -0.28, -0.27 , -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -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, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10 , 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, more preferably ±0.2.
本公開所述的“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 "crystal plane spacing or crystal plane spacing ( d value)" described in this disclosure means that the spatial lattice selects three non-parallel unit vectors a, b, and c that connect two adjacent lattice points, and they will point The array is divided into juxtaposed parallelepiped units, called interplanar spacing. The spatial lattice is divided according to the determined parallel hexahedral unit connection to obtain a set of linear grids, called spatial grids or lattices. The lattice and lattice reflect the periodicity of the crystal structure with geometric dots and lines, respectively. Different crystal planes have different surface spacings (ie, the distance between two adjacent parallel crystal planes); the unit is Å Or Egypt.
本公開中所述乾燥溫度一般為25℃~100℃，優選40℃~70℃，可以常壓乾燥，也可以減壓乾燥。優選的，乾燥在減壓下乾燥。The drying temperature in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and can be dried under normal pressure or under reduced pressure. Preferably, the drying is done under reduced pressure.
本公開的有益效果：The beneficial effects of this disclosure:
與現有技術相比，本公開的技術方案具有以下優點： 經研究表明，本公開製備的式(I)所示化合物的III晶型熔點較高、溶解性良好、純度較高，在高溫、高濕、光照的條件下晶型經XRPD檢測均未發生改變、晶型穩定性良好；本公開技術方案得到的式(I)所示化合物的III晶型能夠滿足生產運輸儲存的藥用要求，生產工藝穩定、可重複可控，能夠適應於工業化生產。Compared with the prior art, the technical solution of the present disclosure has the following advantages: Studies have shown that the compound III of the formula (I) prepared by the present disclosure has a high melting point, good solubility, and high purity, and the crystal form has not been changed by XRPD detection under the conditions of high temperature, high humidity, and light. The crystal form has good stability; the III crystal form of the compound represented by formula (I) obtained by the technical scheme of the present disclosure can meet the pharmaceutical requirements for production, transportation and storage, and the production process is stable, repeatable and controllable, and can be adapted to industrial production.
為讓本發明之上述和其他目的、特徵和優點能更明顯易懂，下文特舉實施例，並配合所附圖式，作詳細說明如下。To make the above and other objects, features, and advantages of the present invention more comprehensible, embodiments are described below in conjunction with the accompanying drawings, which are described in detail below.
以下將結合實施例更詳細地解釋本公開，本公開的實施例僅用於說明本公開的技術方案，並非限定本公開的實質和範圍。Hereinafter, the present disclosure will be explained in more detail in conjunction with embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.
實驗所用儀器的測試條件：
1、差示掃描量熱儀(Differential Scanning Calorimeter, DSC)
儀器型號：TA Q2000
吹掃氣：氮氣(50mL/min)
升溫速率：10.0℃/min
溫度範圍：30-300℃
2、X-射線粉末衍射譜(X-ray Powder Diffraction, XRPD)
儀器型號：Rigaku UltimaIV X-射線粉末衍射儀
射線：單色Cu-Kα射線(λ=1.5418 Å)
掃描方式：θ /2θ，掃描範圍：3-45o
電壓：40kV，電流：40mA
3、熱重分析儀(Thermogravimetric Analysis, TGA)
儀器型號：Mettler Toledo TGA2 STARe
System
吹掃氣：氮氣
升溫速率：10.0℃/min
溫度範圍：20-250℃Test conditions of the instrument used in the experiment: 1. Differential Scanning Calorimeter (DSC) Instrument model: TA Q2000 Purge gas: nitrogen (50mL/min) Heating rate: 10.0℃/min Temperature range: 30-300
對比例1：(1S
,4S
)-4-乙氧基-N
-(2-((R
)-9-(吡啶-2-基)-6-氧雜螺[4.5]癸-9-基)乙基)-1,2,3,4-四氫萘-1-胺(化合物19的無定形)的製備
第一步，(S )-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (11a)The first step, ( S )-1,2,3,4-Tetrahydronaphthalene-1-carbamic acid third butyl ester (11a)
將(S )-1,2,3,4-四氫-1-萘胺10a (3 g，20.41 mmol，採用“Angewandte Chemie-International Edition, 45(28), 4641-4644, 2006”公開的方法製備而得)溶解於100 mL二氯甲烷中，加入三乙胺(5.7 mL，40.82 mmol)，加入二第三丁基二碳酸酯(4.9 g，22.45 mmol)，攪拌反應12小時。反應液依次用水(100 mL)，飽和碳酸氫鈉溶液洗滌(100 mL)，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，得到粗品標題產物11a (5.6 g，淡黃色油狀物)，產物不經純化直接進行下步反應。( S )-1,2,3,4-Tetrahydro-1-naphthylamine 10a (3 g, 20.41 mmol, using the method disclosed in " Angewandte Chemie-International Edition, 45(28), 4641-4644, 2006" Prepared) was dissolved in 100 mL of dichloromethane, triethylamine (5.7 mL, 40.82 mmol) was added, di-tert-butyl dicarbonate (4.9 g, 22.45 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was washed successively with water (100 mL), saturated sodium bicarbonate solution (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 11a (5.6 g, light yellow oil) The product was directly subjected to the next reaction without purification.
MS m/z (ESI): 248.3 [M+1]。MS m/z (ESI): 248.3 [M+1].
第二步，(S )-4-羰基-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (11b)The second step, ( S )-4-carbonyl-1,2,3,4-tetrahydronaphthalene-1-carbamic acid third butyl ester (11b)
將粗品(S )-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (11a) (5.6 g，20.41 mmol)溶解於90 mL丙酮和水(V/V = 2:1)混合溶劑中，加入硫酸鎂(5.5 g，45.66 mmol)，攪拌下緩慢加入高錳酸鉀(7.22 g，45.66 mmol)，攪拌反應12小時。反應液減壓濃縮，用矽膠柱色譜法以正己烷和乙酸乙酯為洗脫劑純化所得殘餘物，得到標題產物11b (3.1 g，類白色固體)，產率：52%。Dissolve crude ( S )-1,2,3,4-tetrahydronaphthalene-1-carbamic acid third butyl ester (11a) (5.6 g, 20.41 mmol) in 90 mL of acetone and water (V/V = 2: 1) To the mixed solvent, magnesium sulfate (5.5 g, 45.66 mmol) was added, potassium permanganate (7.22 g, 45.66 mmol) was slowly added with stirring, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane and ethyl acetate as eluents to obtain the title product 11b (3.1 g, off-white solid), yield: 52%.
MS m/z (ESI): 262.3 [M+1]。MS m/z (ESI): 262.3 [M+1].
第三步，(1S ,4S )-4-羥基-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (14a)The third step, (1 S ,4 S )-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid third butyl ester (14a)
將(S
)-4-羰基-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (11b) (100 mg，0.883 mmol)溶解於5 mL甲苯中，降溫至0℃，加入(R
)-2-甲基-CBS-
MS m/z (ESI): 208.3 [M-55]。MS m/z (ESI): 208.3 [M-55].
第四步，(1S ,4S )-4-乙氧基-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (19a)The fourth step, (1 S ,4 S )-4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid third butyl ester (19a)
將粗品(1S )-4-羥基-1,2,3,4-四氫萘-1-氨基甲酸第三丁酯 (14a) (850 mg，3.23 mmol)，氧化銀(76 mg，0.33 mmol)和碘乙烷(1.3 mL，16.15 mmol)溶解於二氯甲烷(30 mL)中，攪拌反應48小時。過濾，濾液減壓濃縮，得到粗品標題產物19a (800 mg，黃色油狀物)，產物不經純化直接進行下步反應。The crude (1 S )-4-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carbamic acid tert-butyl ester (14a) (850 mg, 3.23 mmol), silver oxide (76 mg, 0.33 mmol ) And ethyl iodide (1.3 mL, 16.15 mmol) were dissolved in dichloromethane (30 mL), and the reaction was stirred for 48 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude title product 19a (800 mg, yellow oil). The product was directly subjected to the next reaction without purification.
MS m/z (ESI): 236.1 [M-55]。MS m/z (ESI): 236.1 [M-55].
第五步，(1S ,4S )-4-乙氧基-1,2,3,4-四氫萘-1-胺 (19b)The fifth step, (1 S ,4 S )-4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-amine (19b)
將粗品化合物19a (698 mg，2.4 mmol)溶解於4 mL二氯甲烷中，加入8 mL 4M 氯化氫的1, 4-二氧六環溶液，攪拌反應2小時。反應液減壓濃縮，乙酸乙酯打漿(30 mL)，過濾，濾餅溶於二氯甲烷和甲醇(20 mL，V:V = 5:1)的混合溶劑中，用飽和碳酸氫鈉溶液調節反應液pH為7~8，反應液減壓濃縮，用二氯甲烷和甲醇(V:V=5:1)的混合溶劑洗滌(30 mL×2)，過濾，濾液減壓濃縮，得到粗品標題產物19b(310 mg，黃色液體)，產物不經純化直接進行下步反應。The crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 mL of dichloromethane, 8 mL of 4 M hydrogen chloride in 1,4-dioxane was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, slurried with ethyl acetate (30 mL), filtered, and the filter cake was dissolved in a mixed solvent of dichloromethane and methanol (20 mL, V:V = 5:1), adjusted with saturated sodium bicarbonate solution The pH of the reaction solution was 7-8. The reaction solution was concentrated under reduced pressure, washed with a mixed solvent of dichloromethane and methanol (V:V=5:1) (30 mL×2), filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title Product 19b (310 mg, yellow liquid). The product was directly subjected to the next reaction without purification.
MS m/z (ESI): 191.1 [M+1]。MS m/z (ESI): 191.1 [M+1].
第六步，(1S ,4S )-4-乙氧基-N -(2-((R )-9-(吡啶-2-基)-6-氧雜螺[4.5]癸烷-9-基)乙基)-1,2,3,4-四氫萘-1-胺 (19)The sixth step, (1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9 -Yl)ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine (19)
將(R )-2-(9-(吡啶-2-基)-6-氧雜螺[4.5]癸烷-9-基)乙醛 (5a) (500 mg，1.85 mmol，採用專利申請“WO2012129495”公開的方法製備而得)，粗品化合物19b (310 mg，1.85 mmol)溶解於二氯乙烷(30 mL)中，攪拌反應40分鐘，加入三乙醯氧基硼氫化鈉(980 mg，4.63 mmol)，攪拌反應2小時。依次用飽和碳酸氫鈉溶液(30 mL×3)，用飽和氯化鈉溶液洗滌(30 mL×3)，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用薄層色譜法以二氯甲烷和甲醇為洗脫劑純化所得殘餘物，得到標題產物19 (280 mg，黃色粘稠固體)，產率：35%。( R )-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)acetaldehyde (5a) (500 mg, 1.85 mmol, using the patent application "WO2012129495 "Prepared by the disclosed method), the crude compound 19b (310 mg, 1.85 mmol) was dissolved in dichloroethane (30 mL), the reaction was stirred for 40 minutes, and sodium triethoxyborohydride (980 mg, 4.63) was added mmol) and stirred for 2 hours. It was washed successively with saturated sodium bicarbonate solution (30 mL×3) and washed with saturated sodium chloride solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using methyl chloride and methanol as eluents to obtain the title product 19 (280 mg, yellow sticky solid), yield: 35%.
實施例1Example 1
(1S
,4S
)-4-乙氧基-N
-(2-((R
)-9-(吡啶-2-基)-6-氧雜螺[4.5]癸-9-基)乙基)-1,2,3,4-四氫萘-1-胺 富馬酸鹽(III晶型)的製備
將(1S ,4S )-4-乙氧基-N -(2-((R )-9-(吡啶-2-基)-6-氧雜螺[4.5]癸-9-基)乙基)-1,2,3,4-四氫萘-1-胺(2.6 g，5.96 mmol)溶於異丙醇(10 mL)中，升溫至80℃，將富馬酸(695 mg，5.96 mmol)和異丙醇(10 mL)加入另一反應瓶中，升溫至80℃攪拌溶清後滴加入上述溶液中，回流攪拌反應10分鐘，自然冷卻至40℃，溶液中有白色固體析出，再冷卻至室溫，攪拌反應1.5小時。反應液過濾，濾餅依次用異丙醇(2 mL×5)和乙酸乙酯(2 mL×3)淋洗，收集濾餅，真空乾燥得到白色固體產物(2.0 g，產率60%)，該結晶樣品的XRPD圖譜見圖1，其DSC譜圖見圖2，吸熱峰起始點在175.44℃附近，峰值約為176.65℃，TGA圖譜如圖3，表明III晶型為無水物；其特徵峰位置如下表1所示。(1 S ,4 S )-4-ethoxy- N -(2-(( R )-9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethane Base)-1,2,3,4-tetrahydronaphthalene-1-amine (2.6 g, 5.96 mmol) was dissolved in isopropanol (10 mL), warmed to 80 °C, fumaric acid (695 mg, 5.96 mmol) and isopropanol (10 mL) were added to another reaction flask. The temperature was raised to 80°C and stirred to dissolve. After dropping into the above solution, the reaction was stirred at reflux for 10 minutes and naturally cooled to 40°C. A white solid precipitated in the solution. After cooling to room temperature, the reaction was stirred for 1.5 hours. The reaction solution was filtered, and the filter cake was rinsed with isopropyl alcohol (2 mL×5) and ethyl acetate (2 mL×3) in sequence. The filter cake was collected and dried in vacuo to obtain a white solid product (2.0 g, yield 60%). The XRPD pattern of the crystalline sample is shown in Figure 1, and the DSC spectrum is shown in Figure 2. The starting point of the endothermic peak is near 175.44℃, and the peak value is about 176.65℃. The TGA pattern is shown in Figure 3, indicating that the crystal form III is anhydrous; its characteristics The peak positions are shown in Table 1 below.
MS m/z (ESI): 435.5 [M+1]。MS m/z (ESI): 435.5 [M+1].
1
H-NMR (400 MHz, DMSO-d 6
) δ 8.49-8.61 (m, 1H), 7.68-7.80 (m, 1H), 7.41-7.53 (m, 1H), 7.28-7.37 (m, 1H), 7.15-7.28 (m, 4H), 6.51 (s, 2H), 4.25-4.38 (m, 1H), 3.88-4.01 (m, 1H), 3.51-3.69 (m, 3H), 3.40-3.51 (m, 1H), 2.52-2.64 (m, 1H), 2.29-2.46 (m, 2H), 2.08-2.22 (m, 1H), 1.85-2.08 (m, 3H), 1.23-1.85 (m, 12H), 1.11 (t, 3H), 0.92-1.03 (m, 1H), 0.56-0.71 (m, 1H)。
表1、III晶型特徵峰
實施例2、III晶型影響因素穩定性考察Example 2. Stability of factors affecting the III crystal form
將實施例1所得的III晶型樣品敞口平攤放置，考察在光照(4500Lux)、高溫(40℃，60℃)、高濕(RH75%，RH90%)條件下樣品的化學穩定性，考察取樣時間為10天、17天，考察樣品化學純度和手性純度，HPLC檢測純度見下表。Place the III crystal sample obtained in Example 1 flat and open to investigate the chemical stability of the sample under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH90%). The sampling time is 10 days and 17 days. The chemical purity and chiral purity of the samples are investigated. The HPLC detection purity is shown in the table below.
試驗結果：
表2、III晶型樣品的影響因素穩定性(HPLC純度)
試驗結論：Test Conclusions:
III晶型在光照、高溫(40℃，60℃)條件下敞口放置17天，化學純度和手性純度下降明顯，在高濕(RH75%，RH90%)條件下敞口放置17天，化學純度和手性純度變化較小；XRPD檢測III晶型在光照(4500Lux)、高溫(40℃，60℃)、高濕(RH75%，RH90%)條件下放置17天，晶型均未發生改變，說明III晶型穩定性較好。The III crystal form is exposed to light and high temperature (40°C, 60°C) for 17 days, and the chemical purity and chiral purity decrease significantly. Under high humidity (RH75%, RH90%), it is placed for 17 days, chemical The purity and chiral purity change little; XRPD detection III crystal form is placed under light (4500Lux), high temperature (40℃, 60℃), high humidity (RH75%, RH90%) conditions for 17 days, the crystal form has not changed , Indicating that the III crystal form has better stability.
實施例3、III晶型長期、加速穩定性考察Example 3, Long-term and accelerated stability of III crystal form
將實施例1所得的III晶型樣品避光、密封平攤放置，考察在長期(25℃、60%RH) 和加速(40℃、75%RH)下樣品的穩定性，考察取樣時間為0.5個月、1個月、2個月、3個月，XRPD檢測晶型是否發生轉變。The III crystal sample obtained in Example 1 was protected from light and placed in a sealed flat position, and the stability of the sample under long-term (25°C, 60%RH) and acceleration (40°C, 75%RH) was investigated. The sampling time was 0.5 Months, 1 months, 2 months, 3 months, XRPD detects whether the crystal form has changed.
試驗結果：
表3、III晶型樣品的穩定性(HPLC純度)
試驗結論：Test Conclusions:
III晶型在避光、密封情況下長期(25℃、60%RH)、加速(40℃、75%RH)條件下放置3個月穩定性良好，25℃、60%RH放置3個月的XRPD圖譜見圖4，40℃、75%RH放置3個月的XRPD圖譜見圖5，III晶型的XRPD峰型基本未發生變化，晶型穩定。The crystal form III has good stability under long-term (25°C, 60%RH) and accelerated (40°C, 75%RH) conditions when protected from light and sealed for 3 months. The XRPD pattern is shown in Fig. 4, and the XRPD pattern at 40°C, 75%RH for 3 months is shown in Fig. 5. The XRPD peak shape of the III crystal form is basically unchanged, and the crystal form is stable.
雖然本發明已以實施例揭露如上，然其並非用以限定本發明，本發明所屬技術領域中具有通常知識者，在不脫離本發明之精神和範圍內，當可作些許之更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。Although the present invention has been disclosed as above with examples, it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention belongs can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the scope defined in the appended patent application.
無no
圖1為式(I)所示化合物III晶型的XRPD圖譜。 圖2為式(I)所示化合物III晶型的DSC圖譜。 圖3為式(I)所示化合物III晶型的TGA圖譜。 圖4為式(I)所示化合物III晶型在25℃、60%RH條件下放置3個月的的XRPD圖譜。 圖5為式(I)所示化合物III晶型在40℃、75%RH條件下放置3個月的的XRPD圖譜。FIG. 1 is an XRPD pattern of the compound III crystal form represented by formula (I). FIG. 2 is a DSC pattern of the compound III crystal form represented by formula (I). Fig. 3 is a TGA pattern of the compound III crystal form represented by formula (I). FIG. 4 is an XRPD pattern of the compound III crystal form represented by formula (I) at 25° C. and 60% RH for 3 months. FIG. 5 is an XRPD pattern of the compound III crystal form represented by formula (I) at 40° C. and 75% RH for 3 months.
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