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 PDFInfo
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- 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
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- ethyl acetate
- heptane
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- HGPLRZDHSVWCMZ-AYVTZFPOSA-N COC(C1=C(C[C@@H](C2)NS(N)(=O)=O)N2C(c2ncc[s]2)=N[C@H]1c(c(F)c1F)ccc1F)=O Chemical compound COC(C1=C(C[C@@H](C2)NS(N)(=O)=O)N2C(c2ncc[s]2)=N[C@H]1c(c(F)c1F)ccc1F)=O HGPLRZDHSVWCMZ-AYVTZFPOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline 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.
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Abstract
Description
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 |
供试样品 | HBV的50%抑制浓度(EC50)值 |
化合物1 | A |
Claims (13)
- 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°。
- 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°。
- 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°。
- 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。
- 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。
- 根据权利要求7所述制备方法,其包括如下步骤: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。
- 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。
- 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。
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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 |
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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 |
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