WO2017076286A1 - 二氢吡啶并环化合物的晶型、制备方法和中间体 - Google Patents

二氢吡啶并环化合物的晶型、制备方法和中间体 Download PDF

Info

Publication number
WO2017076286A1
WO2017076286A1 PCT/CN2016/104325 CN2016104325W WO2017076286A1 WO 2017076286 A1 WO2017076286 A1 WO 2017076286A1 CN 2016104325 W CN2016104325 W CN 2016104325W WO 2017076286 A1 WO2017076286 A1 WO 2017076286A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ethyl acetate
heptane
reaction
ethanol
Prior art date
Application number
PCT/CN2016/104325
Other languages
English (en)
French (fr)
Inventor
贺海鹰
周凯
李小林
王校飞
秦大琨
王星星
杨飞飞
王峥
李宗斌
Original Assignee
南京明德新药研发股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to EP16861554.0A priority Critical patent/EP3372606B1/en
Priority to CN201680063696.XA priority patent/CN108368113B/zh
Priority to ES16861554T priority patent/ES2794639T3/es
Priority to JP2018522961A priority patent/JP6523566B2/ja
Priority to CA3004147A priority patent/CA3004147C/en
Priority to US15/772,942 priority patent/US10253030B2/en
Publication of WO2017076286A1 publication Critical patent/WO2017076286A1/zh
Priority to PH12018500947A priority patent/PH12018500947B1/en
Priority to HK18110910.6A priority patent/HK1251555A1/zh

Links

Images

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystalline form of a dihydropyridocyclic compound, a process for its preparation and an intermediate.
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical characterizations in pathological morphology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • interferon Conventional agents that are approved for the treatment of chronic hepatitis are interferon and amifluudine.
  • interferon has only moderate activity and high toxic side effects; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often after stopping treatment. A rebound effect occurs, and the IC50 value of lamivudine (3-TC)> is 300 nM (Science, 299 (2003), 893-896).
  • heteroaryl ring-substituted dihydropyrimidine (HAP) compounds represented by Bay41_4109 and Bay39_5493, which are capable of inhibiting HBV replication by preventing the formation of normal nucleocapsids.
  • Bay41_4109 showed better drug metabolism parameters in clinical studies (Science, 299 (2003), 893-896).
  • Studies on its mechanism of action have revealed that heteroaryl ring-substituted dihydropyrimidines change the angle between the dimers forming the nucleocapsid by acting on the 113-143 amino acid residues of the core protein, resulting in the formation of no Stable expanded nucleocapsid accelerates degradation of core proteins (Biochem. Pharmacol. 66 (2003), 2273-2279).
  • the invention provides a preparation method of the compound 1,
  • This step reaction does not require the addition of an organic base or an inorganic base
  • the reaction solvent is selected from the group consisting of 1,4-dioxane or tetrahydrofuran;
  • the molar ratio of compound 12 to aminosulfonamide is selected from 1:1 to 20;
  • the reaction temperature is selected from the range of 60 ° C to reflux temperature
  • Compound 1 is purified by recrystallization from a mixed solvent of dichloromethane, ethyl acetate, isopropyl acetate, n-heptane, n-hexane, cyclohexane, petroleum ether or a solvent mixture of several solvents.
  • the molar ratio of the above compound 12 to the aminosulfonamide is selected from 1:10.
  • the above compound 1 is purified by recrystallization from a mixed solvent of dichloromethane or ethyl acetate / n-heptane.
  • the volume ratio of ethyl acetate to n-heptane is selected from 0.5:1 to 2.
  • the above preparation method includes the following steps,
  • the molar ratio of NMM to compound compound 4 is from 1 to 4:1, preferably from 2 to 3:1;
  • compound 8 is passed directly to the next reaction without isolation.
  • the above reaction results in a single solvent or a mixture of a mixture of the compound 9A and the compound 9B via ethyl acetate, isopropyl acetate, tetrahydrofuran, dioxane, cyclohexane, n-heptane.
  • the mixed solvent was recrystallized and purified to give Compound 9A.
  • the molar ratio of the NMM to the compound compound 4 is from 2 to 3:1.
  • the above-mentioned reaction gives a mixture of the compound 9A and the compound 9B, which is purified by recrystallization from ethyl acetate, tetrahydrofuran and n-heptane to give the compound 9A.
  • the volume ratio of the recrystallization solvent of the mixture of the above compound 9A and the compound 9B to n-heptane, ethyl acetate or tetrahydrofuran is (6 to 54): (2 to 18):1.
  • the volume ratio of the above n-heptane, ethyl acetate, tetrahydrofuran is 18:6:1.
  • the above preparation method comprises the following steps:
  • the condensing agent is selected from the group consisting of EDCI, DCC, DIC, DMC, HOBT, HATU, CDI;
  • the reaction temperature is selected from -20 ° C to 10 ° C;
  • Compound 3 is directly passed to the next reaction without isolation.
  • reaction temperature for the preparation of compound 3 above is selected from -10 ° C to 0 ° C.
  • the preparation method described above includes the following steps:
  • the reaction solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, ethyl acetate, toluene, a single solvent in xylene or a mixed solvent of several solvents.
  • the above reaction solvent for preparing compound 4 is selected from the group consisting of a mixed solvent of toluene and methanol.
  • the above compound 4 is stirred by a mixed solvent of methanol, ethanol, isopropanol, n-butanol, cyclohexane, n-hexane, n-heptane, petroleum ether or a solvent of several solvents. Purification by crystallization, beating or recrystallization.
  • the above compound 4 is purified by stirring, crystallization, beating or recrystallization from a mixed solvent of ethanol/cyclohexane, ethanol/n-hexane, ethanol/n-heptane or ethanol/petroleum ether.
  • the volume ratio of the above ethanol to cyclohexane, n-hexane, n-heptane or petroleum ether is selected from the group consisting of 1:1 to 3.
  • the volume ratio of the above ethanol to cyclohexane, n-hexane, n-heptane or petroleum ether is selected from the group consisting of 1:1 to 2.
  • the purification solvent of the above compound 4 is selected from the group consisting of ethanol/petroleum ether, and the volume ratio of ethanol to petroleum ether is 3:5.
  • the compound 4 is stirred or crystallized or purified at a temperature of from -5 ° C to 30 ° C.
  • the compound 4 is stirred or crystallized or purified at a temperature of 10 ° C to 20 ° C.
  • the above preparation method further includes the following steps:
  • the present invention provides Form I of Compound 1, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 15.50 ⁇ 0.2 °, 17.00 ⁇ 0.2 °, 20.86 ⁇ 0.2 °.
  • the above-mentioned Form I has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 11.04 ⁇ 0.2°, 15.50 ⁇ 0.2°, 17.00 ⁇ 0.2°, 18.57 ⁇ 0.2°, 19.36. ⁇ 0.2°, 20.19 ⁇ 0.2°, 20.86 ⁇ 0.2°, 22.68 ⁇ 0.2°.
  • the above-mentioned Form I has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 7.848°, 10.489°, 11.037°, 12.875°, 15.497°, 16.995°, 18.572°, 19.360, 19.697, 20.192, 20.861, 22.676, 22.972, 23.225, 23.583, 23.940, 24.571, 24.886, 25.162, 25.476, 25.710, 26.405, 27.393, 28.237 28.613°, 29.007°, 31.039°, 32.892°, 33.858°, 34.095°, 34.609°, 35.000°, 35.871°, 36.538°, 38.433°.
  • the present invention provides Form I of Compound 1, the XRPD pattern of which is shown in Figure 1.
  • the XRPD pattern analysis data for Form I is shown in Table-1.
  • the preparation method of Form I comprises the step of adding Compound 1 to a mixed solvent of ethyl acetate and petroleum ether to obtain a molar ratio of ethyl acetate to petroleum ether of 1:0.5-2.
  • the volume ratio of ethyl acetate to petroleum ether is 1:1.
  • Form I is prepared by adding Compound 1 to ethyl acetate, heating and refluxing, adding n-heptane dropwise, slowly cooling to 10 ° C to -10 ° C, and crystallization, acetic acid.
  • the volume ratio of ethyl ester to n-heptane is 1:0.5-2.
  • the volume ratio of ethyl acetate to n-heptane is selected from the group consisting of 1:1.
  • Another object of the present invention is to provide the use of Form I for the preparation of a medicament for the treatment of a disease associated with HBV receptors.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • DCM dichloromethane
  • PE petroleum ether
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • DMAC N,N-dimethylacetamide
  • DMSO dimethyl sulfoxide
  • EtOAc ethyl acetate
  • tol stands for toluene
  • THF tetrahydrofuran
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • NMP stands for N-methylpyrrolidone
  • 2-METHF stands for 2-methyltetrahydrofuran
  • Bn stands for benzyl
  • Cbz stands for benzyloxycarbonyl and is an amine protecting group
  • Boc stands for t-butylcarbonyl which is an amine protecting group
  • Fmoc fluorenylmethoxycarbonyl and is an amine a protecting group
  • XRPD X-ray powder diffractometer
  • Tube voltage 40kV
  • tube current 40mA
  • DSC Differential Scanning Calorimeter
  • Test conditions The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing at 25 ° C - 350 ° C and a heating rate of 10 ° C / min.
  • TGA Thermal Gravimetric Analyzer
  • Test conditions Samples (2 to 5 mg) were placed in a TGA platinum pot for testing at room temperature - 350 ° C and a heating rate of 10 ° C / min.
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form I.
  • Figure 2 is a DSC map of Form I.
  • Figure 3 is a TGA map of Form I.
  • the process for synthesizing compound 1 and its intermediates provided by the invention has the beneficial effects that the raw materials are cheap and easy to obtain, and the disadvantages of the reagents used are large, the reaction conditions are harsh, the separation and purification are difficult, and the industrialization is difficult.
  • the method for preparing compound 1 of the present invention is a conventional or common reagent, which is readily available on the market and is inexpensive;
  • the compound 4 of the obtained compound 4 is a low polar solvent such as ethanol and petroleum ether or n-heptane, n-hexane or cyclohexane. Stirring or beating, the operation is simple, and the product purity is high;
  • the present invention has high industrial application value and economic value in the case of the compound 1 and its intermediates.
  • the aqueous phase was further added with 13.25 kg of dichloromethane, 1.19 L of methanol, stirred, cooled to 5 degrees, and slowly added to about 4.4 kg of 3N sodium hydroxide to adjust the pH to 13 (about 20 minutes), and the organic phase was collected.
  • the aqueous phase was extracted once with a mixed solvent of 9.71 kg of dichloromethane and 0.58 kg of methanol (10/1). The organic phase was dried to give a crude product (yield: 94.19%).
  • Example 1 The crude product of Example 1 was dissolved under reflux with 4.76 kg of dichloromethane. The program is cooled to minus 30 degrees Celsius every 10 hours at 10 degrees Celsius. Maintain minus 20 degrees Celsius for 60 hours. A large amount of solid was precipitated, filtered, and the solid was slurried with 2.87 kg of dichloromethane. Filtration gave 790 g of solid. The solid was refluxed with 1.58 L of ethyl acetate until completely dissolved. 1.58 L of n-heptane was added dropwise, and the mixture was cooled to 50 ° C until a large amount of solid appeared. The procedure was cooled (100 minutes dropped to minus 10 degrees) and kept at minus 10 degrees for 10 hours. .
  • the configuration of the two chiral carbons in Compound 1 is consistent with the configuration of the two chiral carbons in Compound 14.
  • the absolute configuration of Compound 1 can also be determined by single crystal data of Compound 14.
  • the X-Ray of Compound 14 is shown in Figure 4.
  • the HBV DNA content in HepG2.2.15 cells was measured by real-time quantitative qPCR assay (real time-qPCR), and the inhibitory effect of the compound on HBV was evaluated by the EC 50 value of the compound.
  • HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330057; 10% serum, Invitrogen-10099141; 100 units/ml penicillin and 10 ⁇ g/ml streptomycin, Invitrogen-15140122; 1% non-essential amino acids, Invitrogen-11140076; 2 mM L-GLUTAMINE, Invitrogen-25030081: 300 ⁇ g/ml Geneticin, Invitrogen-10131027
  • HepG2.2.15 cells 4 x 10 4 cells/well were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 .
  • Upstream primer sequence GTGTCTGCGGCGTTTTATCA
  • 3.2 PCR reaction conditions were: heating at 95 ° C for 10 minutes; then denaturation at 95 ° C for 15 seconds, 60 ° C extension for 1 minute, a total of 40 cycles.
  • %Inh. [1-(DNA copy number in sample -1 ⁇ M DNA copy number in GLS4) / (DNA copy number in DMSO control -1 ⁇ M DNA copy number in GLS4)] x100.
  • Biological activity definition A: EC 50 ⁇ 100 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明公开了一种二氢吡啶并环化合物的晶型及其制备方法和中间体。

Description

二氢吡啶并环化合物的晶型、制备方法和中间体 技术领域
本发明涉及一种二氢吡啶并环化合物的晶型及其制备方法和中间体。
背景技术
乙型肝炎病毒属于肝病毒科。它可引起急性的和或持续/渐进的慢性病。乙型肝炎病毒还引起病理形态中的许多其他的临床表征一尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。另外,与丁型肝炎的共同感染在疾病的发展过程中会产生不利影响。
被许可用于治疗慢性肝炎治疗的常规药剂是干扰素和拉米夫定(Iamivudine)。然而,干扰素只具有中等的活性,并具有较高的毒副反应;虽然拉米夫定(Iamivudine)具有良好的活性,但其耐药性在治疗过程中增幅迅速,并在停止治疗之后常常出现反弹效应,拉米夫定(3-TC)>的IC5tl值为300nM(Science,299(2003),893-896)。
Deres等报道了以Bay41_4109、Bay39_5493为代表的杂芳环取代的二氢嘧啶类(HAP)化合物,该类化合物能够通过阻止正常核衣壳的形成起到抑制HBV复制的作用。Bay41_4109在临床研究中表现了较好的药物代谢参数(Science,299(2003),893-896)。对其作用机制的研究发现,杂芳环取代的二氢嘧啶类化合物通过与核心蛋白的113-143氨基酸残基作用,改变了形成核衣壳的二聚体之间的夹角,导致形成不稳定的膨胀核衣壳,加速核心蛋白的降解(Biochem.Pharmacol.66(2003),2273-2279)。
Figure PCTCN2016104325-appb-000001
目前仍然需要有新的能够有效地用作抗病毒药物的化合物,尤其是用作治疗和/或预防乙型肝炎的药物。
发明内容
本发明提供了化合物1的制备方法,
Figure PCTCN2016104325-appb-000002
其包含如下步骤:
Figure PCTCN2016104325-appb-000003
其中,
该步反应不需要加入有机碱或无机碱;
反应溶剂选自1,4-二氧六环或四氢呋喃;
化合物12与氨基磺酰胺的摩尔比选自1∶1~20;
反应温度选自60℃~回流温度;
任选地,化合物1通过二氯甲烷、乙酸乙酯、乙酸异丙酯、正庚烷、正己烷、环己烷、石油醚中的一种单一溶剂或几种溶剂的混合溶剂重结晶纯化。
本发明的一些方案中,上述化合物12与氨基磺酰胺的摩尔比选自1∶10。
本发明的一些方案中,上述化合物1通过二氯甲烷或乙酸乙酯/正庚烷的混合溶剂重结晶纯化。
本发明的一些方案中,上述化乙酸乙酯/正庚烷的混合溶剂中,乙酸乙酯与正庚烷的体积比选自0.5∶1~2。
本发明的一些方案中,上述制备方法,其包括如下步骤,
Figure PCTCN2016104325-appb-000004
其中,
NMM与化合物化合物4的摩尔比为1~4∶1,优选自2~3∶1;
任选地,化合物8不经分离,直接投入下一步反应。本发明的一些方案中,上述反应得到化合物9A和化合物9B混合物经乙酸乙酯、乙酸异丙酯、四氢呋喃、二氧六环、环己烷、正庚烷中的一种单一溶剂或几种溶剂的混合溶剂重结晶拆分纯化,得化合物9A。
本发明的一些方案中,上述NMM与化合物化合物4的摩尔比为2~3∶1。
本发明的一些方案中,上述反应得到化合物9A和化合物9B混合物经乙酸乙酯、四氢呋喃、正庚烷的混合溶剂重结晶拆分纯化,得化合物9A。
本发明的一些方案中,上述化合物9A和化合物9B混合物的重结晶溶剂正庚烷、乙酸乙酯、四氢呋喃的体积比为(6~54)∶(2~18)∶1。
本发明的一些方案中,上述正庚烷、乙酸乙酯、四氢呋喃、的体积比为18∶6∶1。
本发明的一些方案中,上述制备方法,其包括如下步骤:
Figure PCTCN2016104325-appb-000005
缩合剂选自EDCI、DCC、DIC、DMC、HOBT、HATU、CDI;
反应温度选自-20℃~10℃;
任选地,化合物3不经分离,直接投入下一步反应。
本发明的一些方案中,上述制备化合物3的反应温度选自-10℃~0℃。
本发明的一些方案中,上述述制备方法,其包括如下步骤:
Figure PCTCN2016104325-appb-000006
反应溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃、乙酸乙酯、甲苯、二甲苯中的一种单一溶剂或几种溶剂的混合溶剂。
本发明的一些方案中,上述制备化合物4的反应溶剂选自甲苯与甲醇的混合溶剂。
本发明的一些方案中,上述化合物4经甲醇、乙醇、异丙醇、正丁醇、环己烷、正己烷、正庚烷、石油醚中的一种单一溶剂或几种溶剂的混合溶剂搅拌析晶、打浆或重结晶纯化。
本发明的一些方案中,上述化合物4经乙醇/环己烷、乙醇/正己烷、乙醇/正庚烷或乙醇/石油醚的混合溶剂搅拌析晶、打浆或重结晶纯化。
本发明的一些方案中,上述乙醇与环己烷、正己烷、正庚烷或石油醚的体积比选自1∶1~3。
本发明的一些方案中,上述乙醇与环己烷、正己烷、正庚烷或石油醚的体积比选自1∶1~2。
本发明的一些方案中,上述化合物4的纯化溶剂选自乙醇/石油醚,乙醇和石油醚的体积比为3∶5。
本发明的一些方案中,上述化合物4搅拌析晶或打浆纯化温度为-5℃~30℃。
本发明的一些方案中,上述化合物4搅拌析晶或打浆纯化温度为10℃~20℃。
本发明的一些方案中,上述制备方法,其还包括如下步骤:
Figure PCTCN2016104325-appb-000007
Figure PCTCN2016104325-appb-000008
本发明提供了化合物1的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.50±0.2°,17.00±0.2°,20.86±0.2°。
本发明的一些方案中,上述的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:11.04±0.2°,15.50±0.2°,17.00±0.2°,18.57±0.2°,19.36±0.2°,20.19±0.2°,20.86±0.2°,22.68±0.2°。
本发明的一些方案中,上述的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.848°、10.489°、11.037°、12.875°、15.497°、16.995°、18.572°、19.360°、19.697°、20.192°、20.861°、22.676°、22.972°、23.225°、23.583°、23.940°、24.571°、24.886°、25.162°、25.476°、25.710°、26.405°、27.393°、28.237°、28.613°、29.007°、31.039°、32.892°、33.858°、34.095°、34.609°、35.000°、35.871°、36.538°、38.433°。
本发明提供了化合物1的晶型I,其XRPD图谱如图1所示。
本发明的一些方案中,晶型I的XRPD图谱解析数据如表-1所示。
表-1图1的XRPD图谱解析数据
NO. 2-Theta I% NO. 2-Theta I%
1 7.848 12.1 19 25.162 5.0
2 10.489 9.6 20 25.476 5.8
3 11.037 25.4 21 25.710 7.8
4 12.875 5.3 22 26.405 7.2
5 15.497 100.0 23 27.393 1.9
6 16.995 65.0 24 28.237 7.7
7 18.572 26.0 25 28.613 9.4
8 19.360 25.8 26 29.007 2.9
9 19.697 6.2 27 31.039 18.5
10 20.192 24.8 28 32.892 3.6
11 20.861 28.4 29 33.858 5.2
12 22.676 19.0 30 34.095 3.2
13 22.972 5.8 31 34.609 2.9
14 23.225 9.9 32 35.000 2.9
15 23.583 6.6 33 35.871 2.2
16 23.940 10.6 34 36.538 7.1
17 24.571 12.3 35 38.433 7.3
18 24.886 5.0      
本发明的一些方案中,晶型I的制备方法,包括将化合物1加入到乙酸乙酯、石油醚的混合溶剂重结晶制得,乙酸乙酯与石油醚体积比为1∶0.5~2。
本发明的一些方案中,上述晶型I的制备方法中,乙酸乙酯与石油醚的体积比为1∶1。
本发明的一些方案中,晶型I的制备方法为将化合物1加入到乙酸乙酯中加热回流溶解,滴加正庚烷后,缓慢降温至10℃~-10℃,析晶制得,乙酸乙酯与正庚烷的体积比为1∶0.5~2。
本发明的一些方案中,上述晶型I的制备中,乙酸乙酯与正庚烷的体积比选自1∶1。
本发明的另一个目的在于提供晶型I在制备治疗与HBV受体有关疾病的药物中的应用。
定义和说明:
除非另有说明,本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文出现商品名时,旨在指代其对应的商品或其活性成分。
本发明的中间体化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明具体实施方式的化学反应是在合适的溶剂中完成的,所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物,有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本发明中的氨基)选择合适的保护基。对于经过训练的从业者来说,Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本发明引用的所有参考文献整体上并入本发明。
下面会通过实施例具体描述本发明,这些实施例并不意味着对本发明的任何限制。
本发明所使用的所有溶剂是市售的,无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上,化学位移以四甲基硅烷低场处的(ppm)表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD:SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词:DCM代表二氯甲烷;PE代表石油醚;EA代表乙酸乙酯;DMF代表N,N-二甲基甲酰胺;DMAC代表N,N-二甲基乙酰胺;DMSO代表二甲亚砜;EtOAc代表乙酸乙酯;tol代表甲苯;THF代表四氢呋喃;EtOH代表乙醇;MeOH代表甲醇;NMP代表N-甲基吡咯烷酮;2-METHF代表2-甲基四氢呋喃;i-PrOH代表2-丙醇;Bn代表苄基;Cbz代表苄氧羰基,是一种胺保护基团;Boc代表叔丁基羰基是一种胺保护基团;Fmoc代表笏甲氧羰基,是一种胺保护基团;Alloc代表烯丙氧羰基,是一种胺保护基团;Teoc代表三甲基硅乙氧羰基,是一种胺保护基团;Boc2O代表二-叔丁基二碳酸酯;HCl(g)代表氯化氢气体;H2SO4代表硫酸;HOAc代表乙酸;TFA代表三氟乙酸;DIPEA代表二异丙基乙基胺;DIEA代表二异丙基乙基胺;NMM代表N-甲基吗啡啉;DBU代表1,8-二氮杂二环十一碳 -7-烯;Et3N代表三乙胺;LDA代表二异丙基胺锂;NaHMDS代表双(三甲基硅基)氨基钠;KHMDS代表双(三甲基硅基)氨基钾;LiAlH4代表四氢铝锂;t-BuOK代表叔丁醇钾;H2O2代表过氧化氢;NH4Cl代表氯化铵;BaSO4代表硫酸钡;CaCO3代表碳酸钙;SnCl2代表氯化亚锡;Zn(BH4)2代表硼氢化锌;PPh3代表三苯基膦;HMDS代表六甲基二硅胺烷;Pd/C代表钯碳;PtO2代表二氧化铂;Pd(OH)2代表氢氧化钯;Pd2(dba)3代表三(二亚苄基丙酮)二钯;Pd(PPh3)4代表四三苯基膦钯;Pd(dppf)Cl2代表1,1′-双(二苯基磷)二茂铁氯化钯;Pd(PPh3)2Cl2代表二氯双(三苯基膦)钯(II);Pd(OAc)2代表醋酸钯;PdCl2代表氯化钯;CuI代表碘化亚铜;CuBr代表溴化亚铜;CuCl代表氯化亚铜;Cu代表铜粉;Cu2O代表氧化亚铜;Xantphos代表4,5-双(二苯基磷)-9,9-二甲基氧杂蒽;Sphos代表2-二环己基亚膦基-2′,6′-二甲氧基联苯;Xphos代表2-二环己基磷-2′,4′,6′-三异丙基联苯;Ruphos代表2-双环己基膦-2′,6′-二异丙氧基-,1,1′-联苯;Brettphos代表2-(二环己基膦基)-3,6-二甲氧基-2′-4′-6′-三异丙基-1,1′-联苯。
化合物经手工或者
Figure PCTCN2016104325-appb-000009
软件命名,市售化合物采用供应商目录名称。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号:布鲁克D8 advance X-射线衍射仪
测试条件:详细的XRPD参数如下:
X-ray发生器:Cu,kα,
Figure PCTCN2016104325-appb-000010
管电压:40kV,管电流:40mA.
发射狭缝:1deg.
限高狭缝:10mm
散射狭缝:1deg.
接受狭缝:0.15mm
单色器:固定的单色器
扫描范围:4-40deg.
扫描速度:10deg/min
本发明差热分析(Differential Scanning Calorimeter,DSC)方法
仪器型号:TA Q2000差示扫描量热仪
测试条件:取样品(~1mg)置于DSC铝锅内进行测试,方法为:25℃-350℃,升温速率为10℃/min。
本发明热重分析(Thermal Gravimetric Analyzer,TGA)方法
仪器型号:TA Q5000IR热重分析仪
测试条件:取样品(2~5mg)置于TGA铂金锅内进行测试,方法为:室温-350℃,升温速率为10℃/min。
附图说明
图1为晶型I的Cu-Kα辐射的XRPD谱图。
图2为晶型I的DSC图谱。
图3为晶型I的TGA图谱。
图4为化合14的单分子立体结构椭球图。
技术效果:
本发明给出的合成化合物1及其中间体的工艺,有益效果为:原料价格便宜易得,克服所用试剂毒害大,反应条件苛刻,分离纯化困难以及不易工业化等缺点。
具体地:
1)本发明制备化合物1方法原料为常规或常见试剂,在市场上容易获得且价格低廉;
2)在化合物4的制备中,使用EDCI,DCC,DIC等作为缩合剂,反应条件温和,所得化合物4化合物4使用乙醇和石油醚或正庚烷、正己烷或环己烷等低极性溶剂搅拌析晶或打浆,操作简单,产物纯度高;
3)在化合物8的制备中采用化合物4、化合物6和化合物7为原料,合成化合物8,反应条件温和,收率较高,W化合物8可不经分离,直接投入下步反应,操作简单;
4)反应制得的化合物9A和化合物9B的混合物经乙酸乙酯、四氢呋喃和正庚烷的混合溶剂重结晶。可直接得到化合物9A,纯度达95%以上,De大于96%。
5)化合物1的制备步骤中,不需要加入无机碱或有机碱的条件下,用二氧六环做溶剂,大概10当量的氨基磺酰胺与化合物12在回流情况下反应,得到的产物干净,后处理方便简单。
6)化合物1的晶型I性质稳定,具有良好的成药前景。
因此,本发明在化合物1及其中间体方面,具有很高的工业应用价值和经济价值。
具体实施方式
为了更好的理解本发明的内容,下面结合具体实施例来做进一步的说明,但具体的实施方式并不是对本发明的内容所做的限制。
实施例1:化合物1粗品的制备
Figure PCTCN2016104325-appb-000011
第一步:化合物4的制备
在50L的反应釜中加入12L的DCM。加入起始原料(5.00kg,15.46mol)。加入DMAP(2.83kg,23.20mol),搅拌10min。加入化合物2(2.23kg,15.46mol),反应釜温度降至0℃。将EDCI(4.45kg,23.20mol)分批溶于DCM(20L)中,形成悬浊液。缓慢滴加,滴加过程中控制内部温度低于0℃。滴加完毕, 反应液在0℃下搅拌16小时。取样检测,TLC(PE∶EtOAc=1∶1)和LCMS检测原料消失,反应完毕。将反应液用NaHCO3饱和溶液洗涤(20L*2)。TLC(PE∶EtOAc=0∶1)检测无DMAP,且LCMS确认无DMAP。用NaCl饱和溶液(15L),洗涤1次。减压浓缩,旋干后加入3L甲苯。继续减压浓缩得化合物3。分离重量6.95kg,分离收率87.7%,纯度85%。
1H NMR(400MHz,CHLOROFORM-d)ppm 1.42(s,8H)1.65-1.76(m,5H)3.54-3.72(m,2H)4.85(d,J=6.02Hz,1H)5.07-5.25(m,2H)5.35(d,J=8.28Hz,1H)7.29-7.40(m,5H)
LCMS:m/z:472.1[M+Na+]
在50L反应釜中,加入无水甲苯(20L)。加入化合物3(6.95kg,15.46mol)。机械搅拌下,加入无水MeOH(6.26L,154.6mol)。控制内温为70℃,搅拌16h。取样检测。TLC(PE∶EtOAc=1∶1),LCMS检测反应完成。将反应液减压浓缩,得到红棕色粘稠液体。将粗产品溶解在6L EtOH,10L石油醚中。溶液在13℃下搅拌30分钟,有白色固体析出。搅拌2小时,静置过夜,过滤,固体用石油醚(5L)洗涤三次后晾干,得白色产品(4.2kg,11.07mol)。将过滤母液降温至-11℃,过滤得白色产品(600g,1.58mol)。分离重量共4.8kg,两步分离收率81.7%,纯度98%。
1H NMR(400MHz,CHLOROFORM-d)ppm 1.43(s,9H)3.07-3.16(m,1H)3.22-3.33(m,1H)3.44(s,2H)3.72(s,3H)4.51-4.62(m,1H)5.16(s,2H)5.48(d,J=8.03Hz,1H)7.29-7.40(m,5H)
LCMS:m/z:402.1[M+Na+]
第二步:化合物6的制备
在50L的反应釜中加入12L的MeOH。加入化合物5(2200g,20.00mol,1eq)。加入NaOMe(54g,1mol,0.05eq),10℃下,搅拌0.5h。取样检测,TLC(PE∶EtOAc=2∶1),原料消失,中间体生成。加入NH4Cl(1296g,24.00mol,1.2eq),于65℃下搅拌16h。取样检测,TLC(PE∶EtOAc=2∶1),中间体消失,反应完毕。将反应液过滤得到210g NH4Cl固体,将滤液旋干得到粗品。用20L EtOAc对粗品进行打浆2h过滤得3200g产品化合物6,纯度98%,Q-NMR测的有效含量NMR 95%,分离收率93%。
1H NMR(400MHz,DMSO-d6)ppm 8.26(d,J=2.76Hz,1H)8.38(d,J=3.01Hz,1H)9.81(br.s.,1H)LCMS:m/z:127.9[M+H+]
第三步:化合物9A的制备
在30L夹套反应瓶中加入化合物4(1140g,3mol),无水THF(7.5L),搅拌。加入化合物6(566g,3.45mol),化合物7(502g,1.1mol)和NMM(760g,7.5mol)。反应回流(60℃)20h,HPLC监测 中间体羧酸含量,降温到5-10℃,滴加入氯甲酸异丁酯(492g,3.6mol,溶于500mLTHF),5,10℃下反应1h。TLC和HPLC显示反应中间体羧酸反应完全。加入H2O(3L)淬灭反应。加入EtOAc(9L)萃取,有机溶剂加入H2O(3L)洗涤1次。浓缩有机溶剂得到母液2.2kg。母液溶于EtOAc(3L),加入THF(500mL),缓慢滴加正庚烷(约9L),15℃搅拌过夜,固体析出。过滤得到固体粗品,purity 95%,De=85%。粗品重结晶:按照固体每100g加THF/EtOAc(500/500mL)于50℃溶解,滴加正庚烷(1L),搅拌1h。逐渐降温至25℃搅拌过夜。过滤固体可得化合物9A白色固体500g,产物纯度可达到96%,De>96%。产率27%
1H NMR(400MHz,CHLOROFORM-d)ppm 1.46(s,9H)3.11(dd,J=17.82,8.03Hz,1H)3.70(s,3H)3.86-4.03(m,1H)4.46(d,J=7.78Hz,1H)5.30(d,J=6.27Hz,1H)6.02(s,1H)6.89-7.00(m,1H)7.01-7.12(m,1H)7.49(d,J=3.26Hz,1H)7.90(d,J=3.01Hz,1H)
LCMS:m/z:523.1[M+H+]
第四步:化合物10的制备
在10升反应瓶中加入200mL H2O,再加入NaBH4(39.2g,1.03mol)溶解,在0℃,在化合物9(270.0g,0.52mol)中加入4.0升THF溶解,然后缓慢滴入反应瓶中,控制温度0-5℃反应3h。取样检测,反应完毕。在反应液中加入750mLHCl(1mol/L),调节pH=7。反应液浓缩得到粗品,粗品中加入200mL水。用乙酸乙酯(500mL*3)萃取,合并有机相。有机相用Na2SO4干燥。浓缩得299g粗品,纯度为97.23%,分离收率>100%(粗品),有效含量90%,产率96%。
1H NMR(400MHz,DMSO-d6)ppm 1.14(s.9H)2.61-2.69(m,1H)3.38(br.s.,2H)3.52-3.59(m,4H)3.84-3.94(m,1H)4.81(t,J=5.65Hz,1H)5.86(s,1H)6.40(d,J=9.54Hz,1H)7.15-7.25(m,2H)7.94(d,J=3.26Hz,1H)8.01(d,J=3.01Hz,1H)9.71(s,1H)
LCMS:m/z:527.1[M+H+]
第五步:化合物11的制备
在5L反应瓶中加入化合物10(269.0g,0.51mol),加入1.2L二氯甲烷溶解。再加入DMAP(187.4g,1.53mol),搅拌10min使内温降到0℃。滴加甲烷磺酰氯(118.09g,1.03mol)的DCM(50mL)溶液,滴加过程中控制内部温度,滴加完毕后,控制反应温度为0℃条件下搅拌反应20min。升高温度为35℃条件下搅拌反应。反应16h,取样检测,反应完毕。在反应液中加入500mL,1mol/LHCl,调节pH=2~3。反应液中加入500mL水,用二氯甲烷(700mL*3)萃取,合并有机相。有机相检测几乎没有DMAP,水相检测,水相中无目标产物。再在有机相中加入50mL,2mol/L HCl,并用饱和NaCl洗涤(500mL*2)。有机相检测几乎没有DMAP,水相用二氯甲烷(100mL*3)萃取,合并有机相,有机相用1MNaHCO3(300 mL*2)洗涤,无水Na2SO4干燥。浓缩得270g黄色固体,分离重量270g,分离收率85.7%,纯度88.56%。1H NMR(400MHz,DMSO-d6)ppm 1.38(s,9H)3.01(dd,J=17.82,6.27Hz,1H)3.35(dd,J=17.82,7.53Hz,1H)3.53(s,3H)4.06-4.29(m,2H)4.40(dd,J=11.04,6.78Hz,1H)5.89(s,1H)7.21-7.27(m,2H)7.39(d,J=6.02Hz,1H)7.89(d,J=3.26Hz,1H)7.96(d,J=3.26Hz,1H)
LCMS:m/z:509.2[M+H+]
第六步:化合物12的制备
往30L釜R1中加入化合物11(1.1kg,2.1mol,重量含量97.14%),9.9kg乙酸乙酯和0.87kg浓盐酸。25度下搅拌3小时,取样检测,反应完毕。加入4.4kg水,分液萃取,弃去乙酸乙酯相。水相用分别用6.82kg二氯甲烷洗涤两次,分液,弃去二氯甲烷相。水相再加入13.25kg二氯甲烷,1.19L甲醇,搅拌,冷至5度,慢慢加入约4.4kg 3N氢氧化钠调节PH值至13(约需20分钟),分液,收集有机相。水相用9.71kg二氯甲烷和0.58kg甲醇(10/1)的混合溶剂萃取一次。有机相旋干得到0.85kg粗品(重量含量:94.19%)。
1H NMR(400MHz,DMSO-d6)ppm 1.84(br.s.,2H)2.84(dd.J=17.57,6.02Hz,1H)3.26(dd,J=17.57,6.78Hz,1H)3.55(s,3H)3.63(m,J=6.15Hz,1H)4.00(dd,J=10.92,5.65Hz,1H)4.29(dd,J=11.04,6.27Hz,1H)5.90(s,1H)7.14-7.31(m,2H)7.89(d,J=3.26Hz,1H)7.97(d,J=3.26Hz,1H)
LCMS:m/z:409.1[M+H+]
第七步:化合物1的制备
依次往30L反应釜中加入化合物12(0.82kg,1.89mol,重量含量94.19%),1,4-二氧六环(8.2L),氨基磺酰胺(1.89kg,2.35mol),氮气置换。回流下反应2小时。取样反应基本完全。反应液旋干,加4.4kg乙酸乙酯,用12.3kg自来水洗涤一遍。有机相加入6.5kg二氯甲烷,用(3*12.3kg)去离子水洗涤三次,有机相浓缩至干得化合物1粗品。
实施例2化合物1的晶型I的制备
将实施例1的粗品用4.76kg二氯甲烷回流状态下溶解。每半小时10摄氏度程序降温至零下30摄氏度。维持零下20摄氏度60小时。析出大量固体,过滤,固体用2.87kg二氯甲烷打浆。过滤,得790g固体。固体用1.58L乙酸乙酯回流至全部溶解,滴加1.58升正庚烷,冷至50℃状态下搅拌至大量固体出现,程序降温(100分钟降至零下10度),保持零下10度10小时。过滤,用0.79升乙酸乙酯和0.79升正庚烷的混合溶剂洗涤固体,真空烘箱拉干,得0.61kg化合物1的晶型I,纯度为98.5%。
1H NMR(400MHz,DMSO-d6)ppm 3.07(dd,J=17.69,6.90Hz,1H)3.48(dd,J=17.82,7.53Hz,1H) 3.55(s,3H)4.10(m,J=6.88Hz,1H)4.20(dd,J=11.29,6.27Hz,1H)4.51(dd,J=11.29,6.78Hz,1H)5.91(s,1H)6.76(s,2H)7.17(d,J=7.28Hz,1H)7.22-7.29(m,2H)7.89(d,J=3.26Hz,1H)7.98(d,J=3.26Hz,1H)
LCMS:m/z:488.1[M+H+]。
X-Ray检测分析:化合物1不易培养单晶,为了确证化合物1的绝对构型,通过将化合物12与甲磺酰氯反应,得到化合物14,对化合物14培养单晶,路线如下,
该取代反应发生在N上,且所用碱TEA的碱性较弱,化合物12中两个手性碳的构型不会发生翻转。因此,
化合物1中两个手性碳的构型与化合物14中两个手性碳的构型一致。通过化合物14的单晶数据,亦可以确定化合物1的绝对构型。化合物14的X-Ray见附图4。
实施例3:化合物1的晶型I的制备
将实施例1中所得化合物1粗品经硅胶柱纯化,流动相:二氯甲烷/甲醇=100∶1,纯化所得产物经乙酸乙酯/石油醚混合溶剂(体积比1∶1)重结晶两次,得化合物1的晶型I。
HBV体外测试定量qPCR试验
1实验目的:
通过实时定量qPCR试验(real time-qPCR)检测HepG2.2.15细胞内的HBV DNA含量,以化合物的EC50值为指标,来评价化合物对HBV的抑制作用。
2实验材料:
2.1细胞系:HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12,Invitrogen-11330057;10%血清,Invitrogen-10099141;100units/ml青霉素和10μg/ml链霉素,Invitrogen-15140122;1%非必需氨基酸,Invitrogen-11140076;2mM L-GLUTAMINE,Invitrogen-25030081:300μg/ml Geneticin,Invitrogen-10131027
2.2试剂:
胰酶(Invitrogen-25300062)
DPBS(Hyclone-SH30028.01B)
DMSO(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96 DNA Blood Kit,Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master,Roche-04914058001)
2.3耗材与仪器:
96孔细胞培养板(Corning-3599)
CO2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500 real time PCR system)
1.实验步骤和方法:
3.1种HepG2.2.15细胞(4x104细胞/孔)到96孔板,在37℃,5%CO2培养过夜。
3.2第二天,稀释化合物,共8个浓度,3倍梯度稀释。加不同浓度化合物到培养孔中,双复孔。培养液中DMSO的终浓度为1%。1μM GLS4作为100%inhibition对照;1%的DMSO作为0%inhibition对照。
3.3第五天,更换含有化合物的新鲜培养液。
3.4第八天收取培养孔中的培养液,使用高通量DNA纯化试剂盒(Qiagen-51162)提取DNA,具体步骤参照该产品说明书。
3.5 PCR反应液的配制如表1所示:
表1 PCR反应液的配制
Figure PCTCN2016104325-appb-000013
上游引物序列:GTGTCTGCGGCGTTTTATCA
下游引物序列:GACAAACGGGCAACATACCTT
探针序列:5′+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA-3′
3.1在96孔PCR板中每孔加入15μl的反应混合液,然后每孔加入10μl的样品DNA或HBV DNA的标准品。
3.2 PCR的反应条件为:95℃加热10分钟;然后95℃变性15秒,60℃延伸1分钟,共40个循环。
3.3数据分析:
3.8.1计算抑制百分比:%Inh.=【1-(样品中DNA拷贝数-1μM GLS4中DNA拷贝数)/(DMSO对照中DNA拷贝数-1μM GLS4中DNA拷贝数)】x100。
3.8.2计算EC50:使用GraphPad Prism软件计算化合物对HBV的50%抑制浓度(EC50)值。
4实验结果
实验结果见表-3:
表-3 qPCR实验检测EC50测试结果
供试样品 HBV的50%抑制浓度(EC50)值
化合物1 A
生物活性定义:A:EC50≤100nM。
结论:化合物1对HBV DNA的抑制作用显著。

Claims (13)

  1. 化合物1的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:15.50±0.2°,17.00±0.2°,20.86±0.2°。
  2. 根据权利要求1所述的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:11.04±0.2°,15.50±0.2°,17.00±0.2°,18.57±0.2°,19.36±0.2°,20.19±0.2°,20.86±0.2°,22.68±0.2°。
  3. 化合物1的晶型I,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.848°、10.489°、11.037°、12.875°、15.497°、16.995°、18.572°、19.360°、19.697°、20.192°、20.861°、22.676°、22.972°、23.225°、23.583°、23.940°、24.571°、24.886°、25.162°、25.476°、25.710°、26.405°、27.393°、28.237°、28.613°、29.007°、31.039°、32.892°、33.858°、34.095°、34.609°、35.000°、35.871°、36.538°、38.433°。
  4. 化合物1的晶型I,其XRPD图谱如图1所示,
    Figure PCTCN2016104325-appb-100001
  5. 根据权利要求1-4任意一项所述的晶型I,其特征在于:所述晶型具有如图2所示的DSC图谱。
  6. 根据权利要求1-4任一项所述的晶型I,其特征在于:所述晶型具有如图3所示的TGA图谱。
  7. 化合物1的制备方法,
    其包含如下步骤:
    Figure PCTCN2016104325-appb-100002
    其中,
    该反应步骤不需要加入有机碱或无机碱;
    反应溶剂选自1,4-二氧六环或四氢呋喃;
    化合物12与氨基磺酰胺的摩尔比选自1∶1~20,优选1∶10;
    反应温度选自60℃~回流温度;
    任选地,化合物1通过二氯甲烷、乙酸乙酯、乙酸异丙酯、正庚烷、正己烷、环己烷、石油醚中的一种单一溶剂或几种溶剂的混合溶剂重结晶纯化。
  8. 根据权利要求7所述的制备方法,其包括如下步骤,
    Figure PCTCN2016104325-appb-100003
    其中,
    NMM与化合物4的摩尔比为1~4∶1,优选自2~3∶1;
    任选地,化合物8不经分离,直接投入下一步反应;
    任选地,反应得到化合物9A和化合物9B混合物经乙酸乙酯、乙酸异丙酯、四氢呋喃、二氧六环、环己烷、正庚烷中的一种单一溶剂或几种溶剂的混合溶剂重结晶拆分纯化,得化合物9A;
    优选地,重结晶溶剂选自乙酸乙酯、四氢呋喃、正庚烷的混合溶剂;
    更优选地,所述混合溶剂中正庚烷、乙酸乙酯、四氢呋喃的体积比为(6~54)∶(2~18)∶1,更优选为18∶6∶1。
  9. 根据权利要求7所述制备方法,其包括如下步骤:
    Figure PCTCN2016104325-appb-100004
    缩合剂选自EDCI、DCC、DIC、DMC、HOBT、HATU、CDI;
    反应温度选自-20℃~10℃,优选自-10℃~0℃;
    任选地,化合物3不经分离,直接投入下一步反应。
  10. 根据权利要求7所述制备方法,其包括如下步骤:
    Figure PCTCN2016104325-appb-100005
    反应溶剂选自甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃、乙酸乙酯、甲苯、二甲苯中的一种单一溶剂或几种溶剂的混合溶剂,优选自甲苯与甲醇的混合溶剂;
    任选地,化合物4经甲醇、乙醇、异丙醇、正丁醇、环己烷、正己烷、正庚烷、石油醚中的一种单一溶剂或几种溶剂的混合溶剂搅拌析晶、打浆或重结晶纯化;
    化合物4搅拌析晶温度或打浆纯化温度为-5℃~30℃,优选10℃~20℃;
    优选地,化合物4经乙醇/环己烷、乙醇/正己烷、乙醇/正庚烷或乙醇/石油醚的混合溶剂搅拌析晶、打浆或重结晶纯化;
    更优选地,所述混合溶剂中乙醇与环己烷、正己烷、正庚烷或石油醚的体积比选自1∶1~3;
    更优选地,所述混合溶剂选自乙醇/石油醚,乙醇和石油醚的体积比为3∶5。
  11. 根据权利要求7所述制备方法,其还包括如下步骤:
    Figure PCTCN2016104325-appb-100006
    Figure PCTCN2016104325-appb-100007
  12. 根据权利要求4所述晶型I的制备方法,包括将化合物1加入到乙酸乙酯、石油醚的混合溶剂重结晶制得,乙酸乙酯与石油醚体积比为1∶0.5~2,优选自1∶1;或
    将化合物1加入到乙酸乙酯中加热回流溶解,滴加正庚烷后,缓慢降温至10℃~-10℃,析晶制得,乙酸乙酯与正庚烷的体积比为1∶0.5~2,优选自1∶1。
  13. 根据权利要求1-4任一项所述的晶型I在制备治疗与HBV有关疾病的药物中的应用。
PCT/CN2016/104325 2015-11-04 2016-11-02 二氢吡啶并环化合物的晶型、制备方法和中间体 WO2017076286A1 (zh)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP16861554.0A EP3372606B1 (en) 2015-11-04 2016-11-02 Crystal form, preparation method and intermediate of dihydropyrido ring compound
CN201680063696.XA CN108368113B (zh) 2015-11-04 2016-11-02 二氢吡啶并环化合物的晶型、制备方法和中间体
ES16861554T ES2794639T3 (es) 2015-11-04 2016-11-02 Forma cristalina, método de preparación y compuesto intermedio de compuesto con anillo dihidropirido
JP2018522961A JP6523566B2 (ja) 2015-11-04 2016-11-02 ジヒドロピリド環化合物の結晶形、製造方法および中間体
CA3004147A CA3004147C (en) 2015-11-04 2016-11-02 Crystal form, preparation method and intermediate of dihydropyrido ring compound
US15/772,942 US10253030B2 (en) 2015-11-04 2016-11-02 Crystal form, preparation method and intermediate of dihydropyrido ring compound
PH12018500947A PH12018500947B1 (en) 2015-11-04 2018-05-03 Crystal form, preparation method and intermediate of dihydropyrido ring compound
HK18110910.6A HK1251555A1 (zh) 2015-11-04 2018-08-23 二氫吡啶並環化合物的晶型、製備方法和中間體

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510742546.9 2015-11-04
CN201510742546 2015-11-04

Publications (1)

Publication Number Publication Date
WO2017076286A1 true WO2017076286A1 (zh) 2017-05-11

Family

ID=58661624

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/104325 WO2017076286A1 (zh) 2015-11-04 2016-11-02 二氢吡啶并环化合物的晶型、制备方法和中间体

Country Status (10)

Country Link
US (1) US10253030B2 (zh)
EP (1) EP3372606B1 (zh)
JP (1) JP6523566B2 (zh)
CN (1) CN108368113B (zh)
CA (1) CA3004147C (zh)
ES (1) ES2794639T3 (zh)
HK (1) HK1251555A1 (zh)
PH (1) PH12018500947B1 (zh)
TW (1) TWI715658B (zh)
WO (1) WO2017076286A1 (zh)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018196805A1 (zh) * 2017-04-28 2018-11-01 齐鲁制药有限公司 化合物的多晶型、其制备方法和用途
WO2019086141A1 (en) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Novel, highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2019086142A1 (en) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Novel, highly active pyrazolo-piperidine substituted indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089452A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[4,3-c]pyridines active against the hepatitis b virus (hbv)
WO2020089455A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089459A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines active against the hepatitis b virus (hbv)
WO2020089453A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089456A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines active against the hepatitis b virus (hbv)
WO2020089460A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv)
WO2020221824A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv)
WO2020221811A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel oxalyl piperazines active against the hepatitis b virus (hbv)
WO2020221816A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel phenyl and pyridyl ureas active against the hepatitis b virus (hbv)
WO2020221826A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2021031997A1 (zh) * 2019-08-16 2021-02-25 西藏天晟泰丰药业有限公司 二氢嘧啶衍生物及其用途

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016183266A1 (en) 2015-05-13 2016-11-17 Enanta Pharmaceuticals, Inc. Ehpatitis b antiviral agents
WO2017011552A1 (en) 2015-07-13 2017-01-19 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
CA3017020C (en) 2016-03-07 2024-01-16 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
WO2017214395A1 (en) 2016-06-10 2017-12-14 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
UY37861A (es) 2017-08-28 2019-03-29 Enanta Pharm Inc Agentes antivirales contra la hepatitis b
WO2019113175A1 (en) 2017-12-06 2019-06-13 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
TW201927789A (zh) * 2017-12-06 2019-07-16 美商因那塔製藥公司 B型肝炎抗病毒試劑
US11058678B2 (en) 2018-01-22 2021-07-13 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
WO2019191166A1 (en) 2018-03-29 2019-10-03 Enanta Pharmaceuticals, Inc. Hepatitis b antiviral agents
BR112021005091A2 (pt) 2018-09-21 2021-06-08 Enanta Pharmaceuticals, Inc. heterociclos funcionalizados como agentes antivirais
EP3883570A4 (en) 2018-11-21 2022-07-13 Enanta Pharmaceuticals, Inc. FUNCTIONALIZED HETEROCYCLES AS ANTIVIRAL AGENTS
WO2020247444A1 (en) 2019-06-03 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
WO2020247561A1 (en) 2019-06-04 2020-12-10 Enanta Pharmaceuticals, Inc, Hepatitis b antiviral agents
US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
WO2021007488A1 (en) 2019-07-11 2021-01-14 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
WO2021188414A1 (en) 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1297449A (zh) * 1998-04-18 2001-05-30 拜尔公司 新型2-杂环取代的二氢嘧啶
WO2001068641A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen
CN101104617A (zh) * 2006-07-10 2008-01-16 北京摩力克科技有限公司 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途
CN103570626A (zh) * 2012-08-06 2014-02-12 上海壹志医药科技有限公司 二氢嘧啶衍生物的盐
CN103724339A (zh) * 2012-09-27 2014-04-16 广东东阳光药业有限公司 二氢嘧啶衍生物的晶型

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101575318B (zh) * 2009-06-25 2012-02-08 中国人民解放军军事医学科学院毒物药物研究所 二氢嘧啶类化合物及其用于制备治疗和/或预防病毒性疾病的药物的用途
ES2687606T3 (es) * 2014-05-30 2018-10-26 Qilu Pharmaceutical Co., Ltd. Derivado de bucle de dihidropirimido como inhibidor de HBV

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1297449A (zh) * 1998-04-18 2001-05-30 拜尔公司 新型2-杂环取代的二氢嘧啶
WO2001068641A1 (de) * 2000-03-17 2001-09-20 Bayer Aktiengesellschaft 6-aminoalkyl-dihydroppyrimidine und ihre verwendung als arzneimittel gegen virale erkrankungen
CN101104617A (zh) * 2006-07-10 2008-01-16 北京摩力克科技有限公司 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途
CN103570626A (zh) * 2012-08-06 2014-02-12 上海壹志医药科技有限公司 二氢嘧啶衍生物的盐
CN103724339A (zh) * 2012-09-27 2014-04-16 广东东阳光药业有限公司 二氢嘧啶衍生物的晶型

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018196805A1 (zh) * 2017-04-28 2018-11-01 齐鲁制药有限公司 化合物的多晶型、其制备方法和用途
CN108794481A (zh) * 2017-04-28 2018-11-13 齐鲁制药有限公司 化合物的多晶型、其制备方法和用途
US10662198B2 (en) 2017-04-28 2020-05-26 Qilu Pharmaceutical Co., Ltd. Polymorphic form of compound, preparation method and use thereof
WO2019086141A1 (en) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Novel, highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2019086142A1 (en) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Novel, highly active pyrazolo-piperidine substituted indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089456A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines active against the hepatitis b virus (hbv)
WO2020089459A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines active against the hepatitis b virus (hbv)
WO2020089453A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089455A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2020089460A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv)
WO2020089452A1 (en) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Novel urea 6,7-dihydro-4h-pyrazolo[4,3-c]pyridines active against the hepatitis b virus (hbv)
WO2020221824A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv)
WO2020221811A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel oxalyl piperazines active against the hepatitis b virus (hbv)
WO2020221816A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel phenyl and pyridyl ureas active against the hepatitis b virus (hbv)
WO2020221826A1 (en) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Novel indole-2-carboxamides active against the hepatitis b virus (hbv)
WO2021031997A1 (zh) * 2019-08-16 2021-02-25 西藏天晟泰丰药业有限公司 二氢嘧啶衍生物及其用途

Also Published As

Publication number Publication date
US20180312512A1 (en) 2018-11-01
EP3372606B1 (en) 2020-04-08
ES2794639T3 (es) 2020-11-18
CA3004147C (en) 2019-09-10
JP6523566B2 (ja) 2019-06-05
EP3372606A4 (en) 2019-05-01
TWI715658B (zh) 2021-01-11
CN108368113A (zh) 2018-08-03
US10253030B2 (en) 2019-04-09
HK1251555A1 (zh) 2019-02-01
JP2018537436A (ja) 2018-12-20
PH12018500947A1 (en) 2018-11-12
PH12018500947B1 (en) 2018-11-12
TW201720825A (zh) 2017-06-16
EP3372606A1 (en) 2018-09-12
CN108368113B (zh) 2020-11-24
CA3004147A1 (en) 2017-05-11

Similar Documents

Publication Publication Date Title
WO2017076286A1 (zh) 二氢吡啶并环化合物的晶型、制备方法和中间体
JP5577099B2 (ja) アデニン化合物の製造方法
US8372822B2 (en) Polymorphs of eltrombopag and eltrombopag salts and processes for preparation thereof
JP6568221B2 (ja) ベンゾオキサゾールオキサジンケトン系化合物の製造方法及びその中間体と結晶形
WO2017133686A1 (zh) 一种吡咯并[3,2-d]嘧啶类化合物的制备方法及其中间体
US10399981B2 (en) Crystal form A of 7-(cyclopropylmethyl)-1-(((cis )-4-hydroxy-4-methylcyclohexyl)methyl)-3-methyl-1H-purine-2,6-(3H,7H)-dione for treating liver diseases
WO2017162204A1 (zh) 苯并呋喃类似物制备方法及其中间体和晶型
US11053259B2 (en) Crystal of cephalosporin intermediate 7α-methoxy cephalothin and method for preparing same
US20240059678A1 (en) Synthesis Method for Aminopyrimidine FAK Inhibitor Compound
CN111747949B (zh) Bcl-2选择性抑制剂的制备方法
US8093384B2 (en) Processes for the preparation of alfuzosin
CN108290859B (zh) 喹啉衍生物的盐型、晶型及其制备方法和中间体
JP6427695B2 (ja) 1,2,5−チアジアゾリジン−1,1−ジオキシドの塩形態、結晶形態及びその調製方法と中間体
TW202214658A (zh) 三氮唑並[1,5-a]吡嗪製備方法及其應用
WO2021139795A1 (zh) 吡咯烷基脲衍生物的制备方法
SK8893A3 (en) Process for preparing 2-carboxy-3-[2-(dimethylamino)-ethyl]-n- -methyl-1h-indole-5-methanesulfonamide and lower alkyl esters thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16861554

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15772942

Country of ref document: US

Ref document number: 2018522961

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 3004147

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 12018500947

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016861554

Country of ref document: EP