WO2017054755A1 - 4H-吡唑并[1, 5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体 - Google Patents

4H-吡唑并[1, 5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体 Download PDF

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WO2017054755A1
WO2017054755A1 PCT/CN2016/100821 CN2016100821W WO2017054755A1 WO 2017054755 A1 WO2017054755 A1 WO 2017054755A1 CN 2016100821 W CN2016100821 W CN 2016100821W WO 2017054755 A1 WO2017054755 A1 WO 2017054755A1
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group
compound
acid
metal catalyst
solvent
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PCT/CN2016/100821
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English (en)
French (fr)
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王学海
丁照中
沈洁
陈曙辉
李莉娥
李刚
许勇
王才林
涂荣华
王继猛
乐洋
邓彪
陈海靓
刘辉
孙文洁
王聪
黄璐
王铮
李卫东
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湖北生物医药产业技术研究院有限公司
人福医药集团股份公司
南京明德新药研发股份有限公司
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Priority to CN201680056833.7A priority Critical patent/CN108137598B/zh
Priority to KR1020187010733A priority patent/KR102664193B1/ko
Priority to ES16850379T priority patent/ES2901152T3/es
Priority to AU2016333293A priority patent/AU2016333293B2/en
Priority to US15/763,676 priority patent/US10428073B2/en
Priority to CA3003122A priority patent/CA3003122C/en
Application filed by 湖北生物医药产业技术研究院有限公司, 人福医药集团股份公司, 南京明德新药研发股份有限公司 filed Critical 湖北生物医药产业技术研究院有限公司
Priority to EP16850379.5A priority patent/EP3357925B1/en
Priority to JP2018516694A priority patent/JP6858762B2/ja
Publication of WO2017054755A1 publication Critical patent/WO2017054755A1/zh
Priority to IL258451A priority patent/IL258451B/en
Priority to HK19101057.7A priority patent/HK1258757A1/zh
Priority to US16/548,303 priority patent/US10941150B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a salt form, a crystal form of a 4H-pyrazolo[1,5- ⁇ ]benzimidazole compound, a preparation method thereof and an intermediate.
  • Patent No. 201410144173.0 describes a new class of PARP inhibitors that can be used as an independent therapy for tumor types of BRCA1 and BRCA2 deletion types of DNA repair mechanisms. It can also be used in combination with many types of anticancer therapies such as DNA alkylating agents, platinum drugs, topoisomerase inhibitors and radiation therapy to enhance the anti-tumor efficacy of first-line chemotherapy drugs. Its structure is as shown in formula (B-1):
  • Velibari (ABT-888), an anticancer drug developed by Abbeville, is a novel poly(ADP-ribose) polymerase (PARP) inhibitor, and poly ADP-ribosyltransferase (poly ADP-ribose polymerase (PARP) is a DNA repair enzyme that plays a key role in DNA repair pathways.
  • PARP poly ADP-ribose polymerase
  • Veliparib is a novel, highly selective PARP inhibitor that acts by interfering with DNA repair processes in cells, which makes tumors more sensitive to DNA-damaging chemotherapeutic drugs.
  • the present invention provides a process for the preparation of a compound of formula (I),
  • R is selected from the group consisting of optionally C 1-5 alkyl
  • R 1 is an amino protecting group
  • X is a halogen
  • the metal catalyst is selected from the group consisting of a palladium metal catalyst, a platinum metal catalyst, and/or a copper metal catalyst;
  • the ligand is selected from a phosphine-containing ligand coordinated to a palladium metal catalyst and/or a nitrogen-containing ligand coordinated to a copper metal catalyst;
  • the base is selected from the group consisting of alkali metal bases, alkaline earth metal bases, organic bases and/or organometallic bases.
  • R is selected from the group consisting of methyl, ethyl, isopropyl or t-butyl.
  • the above R 1 is selected from the group consisting of an alkoxycarbonylamino protecting group and/or a benzylic amino protecting group.
  • R 1 is selected from the group consisting of Bn, Cbz, Boc, Fmoc, Alloc, Teco, methoxycarbonyl or ethoxycarbonyl.
  • the palladium metal catalyst is selected from the group consisting of Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 and/ Or PdCl 2 .
  • the platinum metal catalyst is selected from the group consisting of PtO 2 .
  • the copper metal catalyst is selected from the group consisting of CuI, CuBr, CuCl, Cu, and/or Cu 2 O.
  • the phosphine-containing ligand coordinated to the palladium metal catalyst is selected from the group consisting of Xantphos, Sphos, Xphos, Ruphos, and/or Brettphos.
  • the nitrogen-containing ligand coordinated to the copper metal catalyst is selected from the group consisting of 1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, and/or 1,10-phenanthrenequinone. Porphyrin.
  • the alkali metal base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and/or potassium phosphate. .
  • the alkaline earth metal base is selected from the group consisting of sodium hydride, potassium hydride, and/or calcium hydride.
  • the above organic base is selected from the group consisting of triethylamine, DIPEA, NMM, and/or DBU.
  • the organometallic base is selected from the group consisting of sodium methoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and/or aluminum isopropoxide.
  • the molar ratio of the compound (II) to the base is from 1:1 to 5, specifically from 1:2 to 3.
  • the molar ratio of the compound (II) to the metal catalyst is from 1:0.05 to 0.1.
  • the molar ratio of the metal catalyst to the ligand is 1:1 to 2.
  • the reaction temperature of the above reaction is from 100 to 150 ° C, specifically from 120 to 140 ° C.
  • the reaction time of the above reaction is from 5 to 12 hours, specifically from 5 to 6 hours.
  • the above reaction is carried out in a reaction solvent selected from the group consisting of amide solvents.
  • the amide solvent is selected from the group consisting of DMF, DMAC, NMP, and/or DMSO.
  • the amount of the above reaction solvent is from 5 to 20 times, more preferably from 8 to 12 times the weight of the compound (II).
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • Metal catalysts, ligands and bases are as defined above;
  • the ammonia source is selected from the group consisting of HMDS and/or formamide;
  • the reaction solvent for the reaction is selected from the group consisting of amide solvents, specifically selected from DMF, DMAC, NMP and/or DMSO;
  • the carbon monoxide pressure of the reaction is 0.1 to 2 MPa, specifically 0.8 to 1 MPa;
  • the molar ratio of the compound (III) to the base is 1:1 to 5, specifically 1:2 to 3;
  • the molar ratio of the compound (III) to the metal catalyst is 1:0.05 to 0.1;
  • the molar ratio of the compound (III) to the ammonia source is 1:1.2-10, specifically 3-5;
  • the molar ratio of the metal catalyst to the ligand is 1:1 to 2;
  • the amount of the reaction solvent is 5 to 20 times, specifically 8 to 12 times the weight of the compound (III);
  • the reaction temperature of the reaction is 80 to 110 ° C, specifically 100 to 110 ° C;
  • the reaction time of the reaction is from 12 to 24 hours, specifically from 18 to 20 hours.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • HB is selected from organic or inorganic acids
  • the molar ratio of the compound (IV) to the acid is 1:1 to 10, specifically 1:5 to 8;
  • the reaction solvent is selected from the group consisting of water, glacial acetic acid, an alcohol solvent, an ether solvent, an ester solvent, and/or any mixture thereof;
  • the amount of the reaction solvent is 3 to 20 times, specifically 5 to 10 times the weight of the compound (IV);
  • the reaction temperature of the reaction is -10 to 30 ° C;
  • the reaction time of the reaction is 2 to 3 hours.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, and/or isopropanol.
  • the ether solvent is selected from the group consisting of THF, 2-METHF, and/or dioxane.
  • the ester solvent is selected from the group consisting of ethyl acetate.
  • the organic acid is selected from the group consisting of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, maleic acid or fumaric acid.
  • the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, and phosphoric acid.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the molar ratio of the compound (V) to the base is 1:1 to 5, specifically 1:1 to 2;
  • the reaction solvent is selected from the group consisting of water, an alcohol solvent, and/or any mixture thereof;
  • the reaction solvent is used in an amount of 5 to 20 times, specifically 8 to 12 times, the weight of the compound (V);
  • the reaction temperature of the reaction is 0 to 10 ° C, specifically 0 to 5 ° C.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the hydrogen source is selected from the group consisting of hydrogen, cyclohexene and/or ammonium formate;
  • R aldehyde is selected from the group consisting of formaldehyde, acetaldehyde, and isobutyraldehyde;
  • R ketone is selected from isopropanone
  • the reaction solvent is selected from an amide solvent
  • the reaction solvent is used in an amount of 5 to 20 times, more preferably 8 to 12 times the weight of the compound (VI);
  • the molar ratio of the compound (VI) to the reaction reagent R is 1:10, specifically 1:5 to 10;
  • the molar ratio of the compound (VI) to the metal catalyst is 1:0.05 to 0.1;
  • the hydrogen pressure of the reaction is 0.1 to 2 MPa, specifically 0.8 to 1 MPa;
  • the reaction temperature of the reaction is 60 to 100 ° C, specifically 60 to 70 ° C.
  • the amide solvent is selected from the group consisting of DMF, DMAC, NMP, and/or DMSO, more preferably NMP.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the HA is selected from an organic or inorganic acid
  • the reaction solvent is selected from the group consisting of an alcohol solvent and/or a mixed solvent containing an alcohol solvent and water;
  • the volume ratio of the alcohol solvent to water is 1:0.05 to 0.1;
  • the amount of the reaction solvent is 5 to 20 times, specifically 8 to 12 times the weight of the compound (VII);
  • the molar ratio of the compound (VII) to the reagent reagent HA is 1:0.5 to 2, specifically 1:1.05 to 1.2;
  • the reaction temperature of the reaction is 50 to 100 ° C, specifically 60 to 80 ° C;
  • organic acid, inorganic acid and alcohol solvent are as defined above.
  • the method for preparing the compound of the above formula (I) further comprises the following reaction:
  • the present invention also provides an intermediate for preparing the compound (I), which has the following structure:
  • the invention also provides a preparation method of the intermediate (II), which comprises the following reaction:
  • the molar ratio of the compound (f) to the compound (h) is 1:1 to 1.2;
  • the molar ratio of the compound (f) to the base is 1:1 to 5;
  • the reaction solvent is selected from the group consisting of methanol, ethanol, isopropanol, THF, 2-METHF, acetonitrile, NMP, DMF and/or DMAc;
  • the solvent is used in an amount of 5 to 20 times the weight of the above compound (f);
  • the reaction temperature of the reaction is 50 to 100 ° C;
  • the base is as defined above.
  • the present invention also provides a compound 2 of the formula:
  • the present invention also provides Form A of Compound 3, the XRPD pattern of which is shown in Figure 1.
  • the XRPD pattern analysis data of the above A crystal form is as shown in Table 1:
  • Table 1 XRPD pattern analysis data of Form A
  • the differential scanning calorimetry curve of the above A crystal form has an end point of an endothermic peak at 85.44 ° C, an onset point of an endothermic peak at 162.95 ° C, and an endothermic peak at 205.63 ° C. The starting point.
  • the DSC pattern of the above Form A is shown in Figure 2.
  • thermogravimetric analysis curve of the above A crystal form has a weight loss of 3.740% at 129.34 ° C; a weight loss of 0.4250% at 194.30 ° C; and a loss of 13.59 % at 245.46 ° C.
  • the TGA pattern of the above Form A is shown in Figure 3.
  • the present invention also provides a method for preparing a crystalline form A, which comprises preparing a compound of the formula 1 in any form and adding maleic acid to a solvent, wherein
  • the molar ratio of maleic acid to compound 1 is 1:1.05 to 1.2;
  • the solvent is used in an amount of 8 to 12 times the weight of the compound 1;
  • the reaction solvent is selected from an alcohol solvent and/or a mixed solvent containing an alcohol solvent and water.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, and/or isopropanol.
  • the mixed solvent of the above alcohol solvent and water is selected from the group consisting of a mixed solvent of methanol, ethanol, isopropanol and water.
  • the volume ratio of the solvent of the alcohol to the water is from 1:0.05 to 0.1.
  • Another object of the present invention is to provide a use of the crystalline form A of Compound 2 or Compound 3 for the preparation of a medicament for treating a disease associated with a PARP receptor.
  • 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
  • the invention provides the process for synthesizing the compound of the formula (I) and the intermediate thereof, and has the beneficial effects that the starting material is cheap and easy to obtain, and overcomes the disadvantages of large poisoning, harsh reaction conditions, difficulty in separation and purification, and difficulty in industrialization.
  • the method for preparing the compound of the formula (I) of the present invention is a conventional or common reagent, which is readily available on the market and is inexpensive;
  • the reagents used in the reaction of each step are small molecules and easy to be purified.
  • the present invention has high industrial application value and economic value in the preparation of the compound of the formula (I) and its intermediate.
  • XRPD X-ray powder diffractometer
  • 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 A.
  • Figure 2 is a DSC pattern of Form A.
  • Figure 3 is a TGA pattern of Form A.
  • Fig. 5 is a view showing a cell packing pattern of the A crystal form along the b-axis direction.
  • Step 1 4-(1-Cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 4-(1-Cyano-2-ethoxy-2-oxoethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester
  • Step 4 4-(cyanomethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester
  • Step 5 4-(1-Cyano-2-oxoethyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester
  • Step 7 4-(5-Amino-1-(2,6-dibromo-4-fluorophenyl)-1H-pyrazol-4-yl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester
  • ⁇ RTI ID 0.0> ⁇ /RTI> ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; The mixture was extracted with EtOAc (EtOAc)EtOAc. The white solid was collected by filtration to give the title compound (3.5 g, yield: 87.5%, purity: 99.84%).
  • 1H NMR (400MHz, CHLOROFORM-d) ppm 1.32 (s, 3H), 1.48 (s, 9H), 1.57-1.63 (m, 2H), 2.03-2.14 (m, 2H), 3.30 (br.s., 4H) ), 3.67 (d, J 13.30 Hz, 2H), 7.41 - 7.52 (m, 3H).
  • Step 1 4-(8-Bromo-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1-carboxylic acid Tert-butyl ester
  • Step 2 4-(8-carbamoyl-6-fluoro-4H-benzo[4,5]imidazo[1,2-B]pyrazol-3-yl)-4-methylpiperidine-1 - tert-butyl formate
  • Step 4 6-Fluoro-3-(1-isopropyl-4-methylpiperidin-4-yl)-4H-benzo[4,5]imidazo[1,2-b]pyrazole-8 -formamide
  • HCC1937 cells were seeded in 965-well plates at 4 x 104 cells/well and cultured overnight in a 37 °C incubator. The cells were treated with the test compound for 30 minutes and then treated with 1 mM hydrogen peroxide for 10 minutes. Cells were washed twice with 200 UL pre-cooled PBS and fixed with 100 ul of pre-cooled methanol/acetone (7:3) for 30 minutes in an ice bath. After air drying, the cells were blocked with PBS-Tween-20 blocking solution (0.05%) in 5% skim milk powder for 30 minutes at room temperature.
  • the cells and the anti-PAR 10H antibody were incubated at a ratio of 1:100 in blocking solution for 1 hour at room temperature, then washed three times with PBS-Tween-20, and then fluorescein-5(6)-different containing goat anti-mouse was added.
  • the thiocyanate (FITC)-conjugated secondary antibody and 1 ⁇ g/mL DAPI blocking solution were incubated for 1 hour at room temperature in the dark. After rinsing three times with PBS-Tween-20, the data was analyzed using a fluorescent microplate counter (Flexstation III, Molecular Device).
  • PARP enzyme assay accordinging to the HT Universal PARP1 Colorimetric Assay Kit).
  • Histones were packaged in 96-well plates and incubated overnight at 4 °C. After washing the plate 3 times with 200UL PBST solution, it was blocked with a blocking solution, incubated at room temperature for 30 minutes, and then washed 3 times with a PBST solution.
  • the test compound was treated to be added to the well plate, and then 20 ml of diluted PARP1 (1 nM) or 20 ml of PARP2 (3 nM) solution was added to the reaction system for 1 or 2 hours.
  • a mixture of 50 ⁇ l streptavidin-HRP (1:50) was added to the well plate and incubated for 30 minutes at room temperature, and washed three times with PBST buffer. 100 ml (HRP) (chemiluminescent substrate A and substrate B (1:1)) were added to the well plates. Immediately read on a microplate reader (Envision, PerkinElmer).
  • MDA-MB-436 and MDA-MB-231 cells were seeded in 96-well plates at a density of 500 and 2000 cells per well, respectively, and cultured overnight.
  • the medium was RPMI 1640 containing 10% (V/V) FBS and 1% (V/V) penicillin-streptomycin. After the test compound was added, it was treated for 8 days.
  • Cell viability was measured by the CCK8 kit. Specifically, 10 UL CCK8 reagent was added to each well, and incubated at 37 ° C in a 5% CO 2 incubator for 3 hours. After shaking for 10 minutes, the light absorption value (OD value) was measured with a Flexstation III (Molecular Device) 450 nm.
  • PF50 [IC 50 of test compound] / [IC50 of the compound at a fixed DNA damage drug concentration].
  • TMZ temozolomide
  • Compound 1 showed strong inhibitory effect on BRAC mutant MDA-MB-436 cell line, and showed synergistic effect with TMZ.

Abstract

本发明公开了一种4H-吡唑并[1，5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体。

Description

4H-吡唑并[1,5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体 技术领域
本发明涉及一种4H-吡唑并[1,5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体。
背景技术
申请号或专利号201410144173.0记载了一类全新的PARP抑制剂，对于BRCA1和BRCA2缺失类型的DNA修复机制的肿瘤类型而言，可作为一个独立的疗法。亦可与许多类型的抗癌疗法例如DNA烷化剂、铂类药物、拓扑异构酶抑制剂和放射治疗联用，起到增敏剂效果，能大大提高了一线化疗药物的抗肿瘤功效。其结构如式(B-1)所示：
Figure PCTCN2016100821-appb-000001
艾伯维研发的抗癌药物维利帕尼(Veliparib,ABT-888)是一种新型的聚腺苷二磷酸核糖聚合酶(PARP)抑制剂，而聚腺苷酸二磷酸核糖转移酶(poly ADP-ribose polymerase，PARP)是一种DNA修复酶，在DNA修复通路中起关键作用。veliparib是一种新型高选择PARP抑制剂，通过干扰细胞中DNA修复过程而起作用，这将使得肿瘤对损坏DNA的化疗药物变得更加敏感。
发明内容
本发明提供了式(Ⅰ)化合物的制备方法，
Figure PCTCN2016100821-appb-000002
其包含如下步骤：
Figure PCTCN2016100821-appb-000003
其中，
R选自任选C1-5烷基；
R1为氨基保护基；
X为卤素；
金属催化剂选自钯金属催化剂、铂金属催化剂和/或铜金属催化剂；
配体选自与钯金属催化剂配位的含膦配体和/或与铜金属催化剂配位的含氮配体；
碱选自碱金属碱、碱土金属碱、有机碱和/或有机金属碱。
本发明的一些方案中，上述R选自甲基、乙基、异丙基或叔丁基。
本发明的一些方案中，上述R1选自烷氧羰基类氨基保护基和/或苄基类氨基保护基。
本发明的一些方案中，上述R1选自Bn、Cbz、Boc、Fmoc、Alloc、Teco、甲氧羰基或乙氧羰基。
本发明的一些方案中，上述钯金属催化剂选自Pd2(dba)3、Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2和/或PdCl2。
本发明的一些方案中，上述铂金属催化剂选自PtO2。
本发明的一些方案中，上述铜金属催化剂选自CuI、CuBr、CuCl、Cu和/或Cu2O。
本发明的一些方案中，上述与钯金属催化剂配位的含膦配体选自Xantphos、Sphos、Xphos、Ruphos和/或Brettphos。
本发明的一些方案中，上述与铜金属催化剂配位的含氮配体选自1,2-环己二胺、N,N'-二甲基乙二胺和/或1,10-菲啰啉。
本发明的一些方案中，上述碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾和/或磷酸钾。
本发明的一些方案中，上述碱土金属碱选自氢化钠、氢化钾和/或氢化钙。
本发明的一些方案中，上述有机碱选自三乙胺、DIPEA、NMM和/或DBU。
本发明的一些方案中，上述有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝。
本发明的一些方案中，上述化合物(II)与所述碱的摩尔用量比为1:1～5,具体为1:2～3。
本发明的一些方案中，上述化合物(II)和金属催化剂摩尔用量比为1:0.05～0.1。
本发明的一些方案中，上述金属催化剂和配体摩尔用量比为1:1～2。
本发明的一些方案中，上述反应的反应温度为100～150℃，具体为120～140℃。
本发明的一些方案中，上述反应的反应时间为5～12小时，具体为5～6小时。
本发明的一些方案中，上述反应在反应溶剂中进行，所述反应溶剂选自酰胺类溶剂。
本发明的一些方案中，上述酰胺类溶剂选自DMF、DMAC、NMP和/或DMSO。
本发明的一些方案中，上述反应溶剂用量为化合物(II)重量的5～20倍，更优选为8～12倍。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000004
其中，
金属催化剂、配体和碱如上述所定义；
氨源选自HMDS和/或甲酰胺；
反应的反应溶剂选自酰胺类溶剂，具体地选自DMF、DMAC、NMP和/或DMSO；
反应的一氧化碳压力为0.1～2MPa，具体为0.8～1MPa；
化合物(III)与碱的摩尔用量比为1:1～5,具体为1:2～3；
化合物(III)和金属催化剂摩尔用量比为1:0.05～0.1；
化合物(III)和氨源摩尔用量比为1:1.2～10，具体为3～5；
金属催化剂和配体摩尔用量比为1:1～2；
反应溶剂用量为化合物(III)重量的5～20倍，具体为8～12倍；
反应的反应温度为80～110℃，具体为100～110℃；
反应的反应时间为12～24小时，具体为18～20小时。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000005
其中，
HB选自有机或无机酸；
化合物(IV)与所述酸的摩尔用量比为1:1～10,具体为1:5～8；
反应溶剂选自选自水、冰醋酸、醇类溶剂、醚类溶剂、酯类溶剂和/或其任意混合物；
反应溶剂用量为化合物(IV)重量的3～20倍，具体为5～10倍；
反应的反应温度为-10～30℃；
反应的反应时间为2～3小时。
本发明的一些方案中，上所述醇类溶剂选自甲醇、乙醇和/或异丙醇。
本发明的一些方案中，上述醚类溶剂选自THF、2-METHF和/或二氧六环。
本发明的一些方案中，上述酯类溶剂选自乙酸乙酯。
本发明的一些方案中，上述有机酸选自三氟乙酸、甲基磺酸、对甲苯磺酸、柠檬酸、马来酸或富马酸。
本发明的一些方案中，上述无机酸选自盐酸、氢溴酸、磷酸
和或硫酸。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000006
其中，碱如上述所定义；
化合物(V)与碱的摩尔用量比为1:1～5,具体为1:1～2；
反应溶剂选自水、醇类溶剂和/或其任意混合物；
所述反应溶剂用量为化合物(V)重量的5～20倍，具体为8～12倍；
所述反应的反应温度为0～10℃，具体为0～5℃。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000007
其中，
氢源选自氢气、环己烯和/或甲酸铵；
R醛选自甲醛、乙醛、异丁醛；
R酮选自异丙酮；
反应溶剂选自酰胺类溶剂；
反应溶剂用量为化合物(VI)重量的5～20倍，更优选为8～12倍；
化合物(VI)与所述反应试剂R的摩尔用量比为1:10,具体为1:5～10；
化合物(VI)和金属催化剂摩尔用量比为1:0.05～0.1；
反应的氢气压力为0.1～2MPa，具体为0.8～1MPa；
反应的反应温度为60～100℃，具体为60～70℃。
本发明的一些方案中，上述酰胺类溶剂选自DMF、DMAC、NMP和/或DMSO，更优选为NMP。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000008
本发明的一些方案中，上述HA选自有机或无机酸；
反应溶剂选自醇类溶剂和/或含有醇类溶剂和水的混合溶剂；
醇类溶剂和水的体积比为1:0.05～0.1；
反应溶剂用量为化合物(VII)重量的5～20倍，具体为8～12倍；
化合物(VII)与所述反应试剂HA的摩尔用量比为1:0.5～2,具体为1:1.05～1.2；
反应的反应温度为50～100℃，具体为60～80℃；
有机酸、无机酸和醇类溶剂如上述所定义。
本发明的一些方案中，上述式(Ⅰ)化合物的制备方法还包含如下反应：
Figure PCTCN2016100821-appb-000009
本发明还提供了制备化合物(Ⅰ)的中间体，其结构如下：
Figure PCTCN2016100821-appb-000010
本发明还提供了中间体(II)的制备方法，其包含如下反应：
Figure PCTCN2016100821-appb-000011
其中，
化合物(f)与化合物(h)的摩尔用量比为1:1～1.2；
化合物(f)与碱的摩尔用量比为1:1～5；
反应溶剂选自甲醇、乙醇、异丙醇、THF、2-METHF、乙腈、NMP、DMF和/或DMAc；
溶剂用量为上述化合物(f)重量的5～20倍；
反应的反应温度为50～100℃；
碱如上述所定义。
本发明还提供了下式所示化合物2：
Figure PCTCN2016100821-appb-000012
本发明还提供了化合物3的A晶型，其XRPD图谱如图1所示，
Figure PCTCN2016100821-appb-000013
本发明的一些方案中，上述A晶型的XRPD图谱解析数据如表1所示：
表1:A晶型的XRPD图谱解析数据
NO. 2-Theta d(A) I％ NO. 2-Theta d(A) I％
1 5.718 15.4432 3.2 11 21.513 4.1272 13.6
2 8.773 10.0706 68.9 12 22.776 3.9011 9.6
3 9.286 9.5154 100.0 13 24.315 3.6575 2.7
4 11.512 7.6804 11.0 14 24.672 3.6054 1.8
5 16.051 5.5172 10.0 15 25.401 3.5036 2.1
6 16.622 5.3289 2.4 16 26.327 3.3824 6.6
7 17.136 5.1704 8.3 17 28.436 3.1362 5.7
8 18.575 4.7727 18.1 18 31.001 2.8823 5.5
9 19.780 4.4848 3.2 19 34.572 2.5923 1.3
10 20.332 4.3642 7.5 20 35.618 2.5185 3.0
本发明的一些方案中，上述A晶型的差示扫描量热曲线在85.44℃处具有吸热峰的起始点，在162.95℃处具有吸热峰的起始点,在205.63℃处具有吸热峰的起始点。
本发明的一些方案中，上述A晶型的的DSC图谱如图2所示。
本发明的一些方案中，上述A晶型的热重分析曲线在129.34℃处失重达3.740％；在194.30℃处失重达0.4250％；在245.46℃失重达13.59％。
本发明的一些方案中，上述A晶型的TGA图谱如图3所示。
本发明还提供了A晶型的制备方法，包括将任意一种形式的式化合物1与马来酸加入到溶剂中结晶制得，其中，
马来酸与化合物1摩尔比为1:1.05～1.2；
溶剂用量为化合物1重量的8～12倍；
反应溶剂选自醇类溶剂和/或含有醇类溶剂和水的混合溶剂。
本发明的一些方案中，上述醇类溶剂选自甲醇、乙醇和/或异丙醇。
本发明的一些方案中，上述醇类溶剂和水的混合溶剂选自甲醇、乙醇、异丙醇和水的混合溶剂。
本发明的一些方案中，上诉醇类溶剂和水的体积比为1:0.05～0.1。
本发明的另一个目的在于提供化合物2或化合物3的A晶型在制备治疗与PARP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***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；TMZ代表替莫唑胺。
化合物经手工或者
Figure PCTCN2016100821-appb-000014
软件命名，市售化合物采用供应商目录名称。
本发明给出的合成式(Ⅰ)化合物及其中间体的工艺，有益效果为：起始原料价格便宜易得，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)本发明制备式(Ⅰ)化合物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)中间体化合物(IV)巧妙利用中间体化合物(II)的两个卤族基团经金属催化以及插羰氨化反应成功的构造了三环结构以及酰胺药效团，并有效的提高了反应收率；
3)本发明制备式(Ⅰ)中异丙基的引入利用廉价易得的丙酮经还原氢化后制得；
4)各步骤反应中所使用试剂均为小分子，易于纯化。
因此，本发明在制备式(Ⅰ)化合物及其中间体方面，具有很高的工业应用价值和经济价值。
本发明粉末X-射线衍射(X-ray powder diffractometer,XRPD)方法
仪器型号：布鲁克D8advance X-射线衍射仪
测试条件：详细的XRPD参数如下：
光管：Cu,kα,
Figure PCTCN2016100821-appb-000015
光管电压：40kV，光管电流：40mA
发散狭缝：0.60mm
探测器狭缝：10.50mm
防散射狭缝：7.10mm
扫描范围：4-40deg
步径：0.02deg
步长：0.12秒
样品盘转速：15rpm
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A晶型的Cu-Kα辐射的XRPD谱图。
图2为A晶型的DSC图谱。
图3为A晶型的TGA图谱。
图4为化合物3单分子的立体结构椭球图。
图5为A晶型沿b轴方向的晶胞堆积图。
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3的制备
流程1:
Figure PCTCN2016100821-appb-000016
步骤1：4-(1-氰基-2-乙氧基-2-氧代亚乙基)哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000017
4-氧代哌啶-1-羧酸叔丁酯(3公斤，15.05摩尔)的甲苯溶液(24升)加热升温至95℃，依次一次性加入乙酸(446克，7.43摩尔)，乙基-2-氰基乙酸酯(1.68公斤，14.85摩尔)，乙酸铵(571克，7.41摩尔)。外温升至130℃，内温102℃时开始回流分水，当内温达到114℃时，HPLC检测原料完毕，大约用时3小时。冷却至室温，依次用水(10L)，10％Na2CO3水溶液(8L)，饱和盐水(5L X 2)洗涤有机相，水相合并用乙酸乙酯(5L X 2)萃取，合并有机相减压蒸除溶剂后，得到4.5公斤残余物。残余物用PE/EtOAc＝10/1(9L)打浆纯化。白色固体通过过滤收集，得到标题化合物(1.5公斤，收率：33.84％，纯度：98.62％)。(滤液浓缩后可进一步纯化得标题化合物)1H NMR(400MHz,CHLOROFORM-d)δppm 1.38(t,J＝7.15Hz,3H),1.50(s,9H),2.79(t,J＝5.90Hz,2H),3.15(t,J＝5.83Hz,2H),3.56(t,J＝5.71Hz,2H),3.63(t,J＝5.83Hz,2H),4.31(q,J＝7.15Hz,2H).LCMS(ESI)m/z:295(M+1).
步骤2：4-(1-氰基-2-乙氧基-2-氧代乙基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000018
在-50～-40℃氮气保护下,向碘化亚铜(1.29公斤，6.78摩尔)的无水四氢呋喃(16升)混合物中滴加入3M甲基溴化镁***溶液(5.66升，16.98摩尔)(滴加速度以内温不超过-40℃为宜)。滴加完毕后在-5℃～0℃下搅拌1小时，降温至-50～-40℃，滴加4-(1-氰基-2-乙氧基-2-氧代亚乙基)哌啶-1-甲酸叔丁酯(2公斤，6.79摩尔)的四氢呋喃(4L)溶液(滴加速度以内温不超过-40℃为宜)，滴加完毕后混合物缓慢升温至室温，搅拌15小时后，降温至0～5℃用饱和氯化铵水溶液/水(W/W＝1:1)(2升)淬灭，淬灭完毕后硅藻土过滤，滤液分层，滤渣用EtOAc(5升×2)洗涤，将合并的有机层用饱和氯化铵水溶液(5升X2)，盐水(5升X2)洗涤，蒸发，得到粗标题化合物(2.1公斤)，为黄色油状物，将其直接用于下一步骤而无需进一步纯化。
步骤3：2-(1-(叔丁氧基羰基)-4-甲基哌啶-4-基)-2-氰基乙酸
Figure PCTCN2016100821-appb-000019
0℃下，向4-(1-氰基-2-乙氧基-2-氧代乙基)-4-甲基哌啶-1-甲酸叔丁酯(2公斤，粗，6.44摩尔)的 THF/MeOH＝10:1(3.52升)混合溶液中滴加入氢氧化钠(1.03公斤，25.75摩尔)的水(2.6升)溶液，滴加速度控制内温在0～10℃度为宜。滴加完毕后混合物在室温搅拌2小时后，TLC监测(原料&产品220nm吸收弱)原料反应完毕，加入EtOAc(2升)/叔丁基甲醚(4升)混合溶液搅拌，静置分出水层，有机相用水(1升×3)洗涤。合并水层用叔丁基甲醚(1升×2)萃取后，用1N盐酸调节pH至3～4，DCM(5升×2)萃取。将合并的二氯甲烷有机层用盐水(5升×2)洗，蒸发，得到粗标题化合物(1.5公斤)，为白色固体，将其直接用于下一步骤而无需进一步纯化。
步骤4：4-(氰基甲基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000020
2-(1-(叔丁氧基羰基)-4-甲基哌啶-4-基)-2-氰基乙酸(4公斤，粗，14.17摩尔)和Cu2O(405.45克，2.83摩尔)的乙腈(20升)混合物在85℃下搅拌2小时，TLC监测(原料&产品220nm吸收弱)原料反应完毕，冷却至室温后，过滤滤除不溶物，滤液蒸干，残余物用乙酸乙酯(20升)溶解，依次用0.5N盐酸(10升×2)，饱和盐水(20升×2)洗涤，蒸发至干，残余物用PE/EtOAc＝10/1(16升)打浆纯化。白色固体通过过滤收集，得到标题化合物(2.5公斤，收率：74.03％，纯度：因产品220nm吸收弱，纯度以加等摩尔比内标判断)。1H NMR(400MHz,CHLOROFORM-d)ppm 1.16(s，3H)，1.43-1.54(m,13H),2.31(s,2H),3.23(ddd,J＝13.68,8.78,4.39Hz,2H),3.52-3.70(m,2H).LCMS(ESI)m/z:239(M+1).
步骤5：4-(1-氰基-2-氧代乙基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000021
在-60～-50℃氮气保护下，向4-(氰基甲基)-4-甲基哌啶-1-甲酸叔丁酯(1公斤，4.2摩尔)的THF(8L)混合物中滴加2M LDA(3.15升，6.3摩尔)。在-60～-50℃搅拌1小时后，滴加甲酸乙酯(622克，8.4摩尔)，滴加完毕后缓慢升温至室温下再搅拌15小时。反应完毕后降温至-30～-20℃，用1N盐酸水溶液(5L)淬灭，水层用EtOAc(2升×3)萃取，合并的有机层用0.5N盐酸(5升×2)，盐水(5升×2)洗涤后，蒸发至干，得到残余物用PE/EtOAc＝10/1(2升)打浆纯化。白色固体通过过滤收集，得到标题化合物(900克，收率：80.46％，纯度：100％)。1H NMR(400MHz,CHLOROFORM-d)ppm 1.22(s,3H),1.47-1.55(m,11H),1.73-2.07(m,4H),3.38-3.48(m,4H),6.97(s,1H),7.55-8.14(m,1H).LCMS(ESI)m/z:289(M+23).
步骤6：(2,6-二溴-4-氟苯基)肼盐酸盐
Figure PCTCN2016100821-appb-000022
-5～0℃下,向2,6-二溴-4-氟苯胺(500克，1.86摩尔)的浓盐酸(1.8升)溶液中缓慢滴入亚硝酸钠(141克，2.05摩尔)的水(1.8升)溶液。滴加完毕后在零下-5～0℃搅拌40分钟后，在-10～-5℃下将上述反应混合物滴加入二水合氯化亚锡(629克，2.79摩尔)的浓盐酸(2升)溶液中，滴加速度以内温不超过-5℃为宜，所得混合物缓慢升温至20℃左右并搅拌12小时，固体通过过滤收集，用异丙醇(0.5升×4)洗涤后真空干燥，得到标题化合物(430克，收率：72％，纯度：97.75％)灰白色固体，可用下一步骤而无需进一步纯化。1H NMR(400MHz,DMSO-d6)δppm 2.37-2.68(m,1H),6.94-7.28(m,1H),7.80(d,J＝8.03Hz,2H),10.13(br.s.,3H).
步骤7：4-(5-氨基-1-(2,6-二溴-4-氟苯基)-1H-吡唑-4-基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000023
醋酸钾(1.11公斤，11.27摩尔)和(2,6-二溴-4-氟苯基)肼盐酸盐(2.65公斤，8.27摩尔)的乙醇(25L)混合物在室温下搅拌0.5小时后，加入4-(1-氰基-2-氧代乙基)-4-甲基哌啶-1-甲酸叔丁酯(2公斤，7.51摩尔)，混合物在60℃下搅拌2小时。反应完成后向该混合物中分批加入NaHCO3(1.89公斤，22.5摩尔)，并在80～90℃下再搅拌15小时，冷却至室温后，将所得混合物蒸发，残余物加水(20L)，用EtOAc(10L×2)萃取，将合并的有机层用盐水(10升×2)洗涤，蒸发，残余物用PE/EtOAc＝10/1(6L)打浆纯化。白色固体通过过滤收集，以提供标题化合物(3.5公斤，收率：87.5％，纯度：99.84％)。1H NMR(400MHz,CHLOROFORM-d)ppm 1.32(s，3H)，1.48(s，9H)，1.57-1.63(m,2H),2.03-2.14(m,2H),3.30(br.s.,4H),3.67(d,J＝13.30Hz,2H),7.41-7.52(m,3H).
流程2:
Figure PCTCN2016100821-appb-000024
步骤1：4-(8-溴-6-氟-4H-苯并[4,5]咪唑并[1,2-B]吡唑-3-基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000025
氮气保护下，4-(5-氨基-1-(2,6-二溴-4-氟苯基)-1H-吡唑-4-基)-4-甲基哌啶-1-甲酸叔丁酯(2.1公斤，3.95摩尔)，Pd2(dba)3(289.37克，0.316摩尔)，Xantphos(365.69克，0.632摩尔)和碳酸铯(2.57公斤，7.9摩尔)的DMF(16.8升)混合物在125～135℃下搅拌5～6小时。冷却至室温后，将所得混合物硅藻土过滤，滤液用EtOAc(20L)和水(40升)稀释后搅拌分层，水相用乙酸乙酯(20升×2)萃取，有机相减压蒸发至干，提供粗品标题化合物(2.68公斤)，可用于下一步骤而无需进一步纯化。LCMS(ESI)m/z:451,453(M,M+2).
步骤2：4-(8-氨基甲酰基-6-氟-4H-苯并[4,5]咪唑并[1,2-B]吡唑-3-基)-4-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2016100821-appb-000026
向10L高压釜中加入4-(8-溴-6-氟-4H-苯并[4,5]咪唑并[1,2-B]吡唑-3-基)-4-甲基哌啶-1-甲酸叔丁酯(535克，1.19摩尔)、HMDS(956.55克，5.93摩尔)、Pd(dppf)Cl2(43.37克，0.0593摩尔)、Xantphos(34.29克，0.0593摩尔)、DIPEA(306.40克，2.37摩尔)和DMF(5L)，一氧化碳置换3次，加压到0.8～1MPa，升温至100～110℃搅拌下18-20小时。冷却至室温后，将混合物硅藻土过滤，滤液用乙酸乙酯(5L)和水(15升)稀释后搅拌分层，水相用乙酸乙酯(5升×2)萃取，有机相用食盐水(5升) 洗涤后，减压浓缩至干得到标题化合物粗品(552克，粗品)，可用于下一步骤而无需进一步纯化。LCMS(ESI)m/z:416(M+1).
步骤3：6-氟-3-(4-甲基哌啶-4-基)-4H-苯并[4,5]咪唑并[1,2-b]吡唑-8-甲酰胺
Figure PCTCN2016100821-appb-000027
在-10～0℃下，将4M HCl(g)/MeOH溶液(11L)缓慢滴加入4-(8-氨基甲酰基-6-氟-4H-苯并[4,5]咪唑并[1,2-B]吡唑-3-基)-4-甲基哌啶-1-甲酸叔丁酯(2.7公斤，6.5摩尔)的MeOH(10升)溶液中，滴加完毕升温至20～25℃下搅拌2-3小时。反应完毕后将所得混合物浓缩到5L，过滤得到固体。将固体分散至水(12L)中，混合液降温至0～5℃，缓慢滴加20％氢氧化钠溶液(1L)至pH 9～10，滴加完毕后，在0～5℃搅拌1小时，过滤，滤饼水洗至中性后烘干得到标题化合物(1.03公斤，收率：82％，纯度：99.72％)，淡黄色固体。1H NMR(400MHz,DMSO-d6)ppm 1.31(s，3H)，1.68-1.85(m,2H),2.27(d,J＝14.81Hz,2H),2.83(t,J＝9.79Hz,2H),3.00-3.13(m,2H),7.42(dd,J＝8.66,2.51Hz,1H),7.53(dd,J＝11.11,2.57Hz,1H),7.78(s,1H),8.06(s,1H),10.66(s,1H).LCMS(ESI)m/z:316(M+1).
步骤4：6-氟-3-(1-异丙基-4-甲基哌啶-4-基)-4H-苯并[4,5]咪唑并[1,2-b]吡唑-8-甲酰胺
Figure PCTCN2016100821-appb-000028
向10L高压釜中加入6-氟-3-(4-甲基哌啶-4-基)-4H-苯并[4,5]咪唑并[1,2-b]吡唑-8-甲酰胺(505克，1.6摩尔)、10％Pd/C(51克)、丙酮(930.12克，16摩尔)和NMP(5L)，氢气置换3次，加压到0.8～1MPa，升温至60～70℃搅拌18-20小时。冷却至室温后，将混合物硅藻土过滤，滤液倾倒入水(20升)搅拌过滤，滤饼水洗至中性后烘干得到标题化合物淡黄色固体(405克，收率：78.8％，纯度：99.05％)。1H NMR(400MHz,DMSO-d6)ppm 0.92(d,J＝6.53Hz,6H),1.26(s,3H),1.58-1.75(m,2H),1.86-1.93(m,1H),2.09-2.20(m,2H),2.35(t,J＝7.72Hz,2H),2.63-2.74(m,2H),7.43(dd,J＝8.41,2.64Hz,1H),7.59(dd,J＝11.11,2.57Hz,1H),7.76(s,1H),8.12(s,1H),10.62(s,1H).LCMS(ESI)m/z:358(M+1).
步骤5：6-氟-3-(1-异丙基-4-甲基哌啶-4-基)-4H-苯并[4,5]咪唑并[1,2-b]吡唑-8-甲酰胺.马来酸盐一水合物
Figure PCTCN2016100821-appb-000029
6-氟-3-(1-异丙基-4-甲基哌啶-4-基)-4H-苯并[4,5]咪唑并[1,2-b]吡唑-8-甲酰胺(0.404公斤，1.13摩尔)、马来酸(0.137公斤，1.18摩尔)的95％甲醇(5.25升)加热回流2小时后热滤，滤液静置冷却，过滤得白色结晶(420克，收率：78.2％，纯度：99.66％)。1H NMR(400MHz,DMSO-d6)ppm 0.63-1.70(m,10H),1.81-2.32(m,3H),2.82(br.s.,1H),3.11-3.36(m,4H),6.04(s,2H),7.52(dd,J＝8.28,2.51Hz,1H),7.62(dd,J＝11.04,2.51Hz,1H),7.77-7.98(m,1H),8.16(s,1H),8.91(br.s.,1H),10.54(br.s.,1H),12.20(br.s.,1H).LCMS(ESI)m/z:358(M+1).
A晶型在不同溶剂中的稳定性试验
称取50mg的A晶型多份，分别加入0.3-0.4mL的下表中的单一或混合溶剂，25℃条件下搅拌。搅拌3天后，离心样品，收集所有样品中的固体，XRPD检测其晶型状态。结果见表2。
表2：A晶型在不同溶剂中的稳定性实验
序号 溶剂 外观(3天) 结果
1 甲醇 混悬液 A晶型
2 乙醇 混悬液 A晶型
3 异丙醇 混悬液 A晶型
4 丙酮 混悬液 A晶型
5 乙酸乙酯 混悬液 A晶型
6 甲醇:水＝3:1 混悬液 A晶型
7 乙醇:水＝3:1 混悬液 A晶型
8 乙腈:水＝1:1 混悬液 A晶型
9 丙酮:水＝1:2 混悬液 A晶型
10 异丙醇:水＝1:1 混悬液 A晶型
A晶型在高温，高湿及强光照条件下的固体稳定性试验
称取A晶型样品约10mg，置于玻璃样品瓶的底部，摊成薄薄一层。60℃及92.5％相对湿度条件下放置的样品用铝箔纸封瓶口，并在铝箔纸上扎些小孔，保证样品能与环境空气充分接触；强光照(5Klux)条件下放置的样品用螺纹瓶盖密封。不同条件下放置的样品于第10天取样检测，检测结果与0天的初始检测结果进行比较，试验结果见下表3所示：
表3：A晶型的固体稳定性试验
试验条件 取样时间(天) 外观 含量(％) 总杂质(％)
- 0 白色粉末 98.9 0.10
60℃(敞口) 10 白色粉末 98.5 0.11
92.5％RH(敞口) 10 白色粉末 99.5 0.10
强光照(密闭) 10 白色粉末 99.4 0.11
体外活性评价
细胞PARylation分析
HCC1937细胞接种到965孔板，4×104个细胞/孔，37℃培养箱中培养过夜。细胞用被测试化合物处理30分钟后，用1mM过氧化氢处理10分钟。细胞用200UL预冷的PBS洗两次，并用100ul预先冷却的甲醇/丙酮(7:3)在冰浴下固定30分钟。风干后，用溶有5％脱脂奶粉的PBS-Tween-20封闭液(0.05％)在室温下封闭30分钟。细胞和anti-PAR 10H抗体按1：100比例在封闭液中室温下温育1小时，然后用PBS-Tween-20冲洗三次，然后加入含有羊抗小鼠的荧光素-5(6)-异硫氰酸酯(FITC)-联用的二抗和1μg/mL DAPI的封闭液中室温下避光温育1小时。PBS-Tween-20冲洗三次后，用荧光微型版计数器(Flexstation III，Molecular Device)分析数据。PARP酶试验(依照HT通用PARP1比色法分析试剂盒说明书)。组蛋白被包在96孔板中并4℃孵育过夜。用200UL PBST溶液洗涤该板3次后，将其用封闭液封闭，室温孵育30分钟后，用PBST溶液洗涤3次。将被测试化合物处理加入孔板中，之后将20ml稀释的PARP1(1nM)或20ml PARP2(3nM)溶液中加入到反应体系中孵育1或2小时。50μl链霉亲和素-HRP(1:50)的混合液加入到孔板中并室温孵育30分钟后，PBST缓冲液洗涤三次。100ml(HRP)(化学发光底物A和底物B(1:1))加入孔板。立即到酶标仪(Envision，PerkinElmer)上读数。
抗增殖试验
MDA-MB-436和MDA-MB-231细胞分别以每孔500和2000细胞的密度接种于96孔板中,过夜培养。培养基为RPMI 1640，内含有10％(V/V)FBS和1％(V/V)青霉素-链霉素.加入待测化合物后，处理8天。细胞生存力通过CCK8试剂盒测量。具体方法为10UL CCK8试剂加入到每个孔中，37℃在5％CO2培养箱并孵育3小时。振摇10分钟后，用Flexstation III(Molecular Device)450nm测定光吸收值(OD值)。
针对化合物组合试验(与DNA损伤药物联用)，PF50值被用来计算药物的协同作用。PF50＝[被测化合物的IC 50]/[该化合物在固定DNA损伤药物浓度时的IC50]。在本研究中替莫唑胺(TMZ)被用作DNA损伤的药物。
化合物1和ABT888单一用药及与TMZ协同作用对MDA-MB-231/436细胞增殖的抑制检测IC50数据在如下表4所示：
表4：本发明化合物体外筛选试验结果
Figure PCTCN2016100821-appb-000030
结论：化合物1对BRAC突变的MDA-MB-436细胞系显示出较强的抑制作用，并且与TMZ联用显现出较好的协同效用。

Claims (14)

  1. 式(Ⅰ)化合物的制备方法，
    Figure PCTCN2016100821-appb-100001
    其包含如下步骤：
    Figure PCTCN2016100821-appb-100002
    其中，
    R选自任选C1-5烷基；
    R1为氨基保护基；
    X为卤素；
    金属催化剂选自钯金属催化剂、铂金属催化剂和/或铜金属催化剂；
    配体选自与钯金属催化剂配位的含膦配体和/或与铜金属催化剂配位的含氮配体；
    碱选自碱金属碱、碱土金属碱、有机碱和/或有机金属碱。
  2. 根据权利要求1所述的制备方法，其包含如下步骤：
    Figure PCTCN2016100821-appb-100003
    其中，氨源选自HMDS和/或甲酰胺。
  3. 根据权利要求1或2的制备方法，其包括如下步骤：
    Figure PCTCN2016100821-appb-100004
    Figure PCTCN2016100821-appb-100005
    其中，
    HB选自有机或无机酸；
    HA选自有机或无机酸；
    R醛选自甲醛、乙醛、异丁醛；
    R酮选自异丙酮；
    氢源选自氢气、环己烯和/或甲酸铵。
  4. 根据权利要求3所述的制备方法，其中，所述有机酸选自三氟乙酸、甲基磺酸、对甲苯磺酸、柠檬酸、马来酸或富马酸；或
    无机酸选自盐酸、氢溴酸、磷酸和或硫酸。
  5. 根据权利要求1或2所述的制备方法，其中，R选自甲基、乙基、异丙基或叔丁基；
    R1自烷氧羰基类氨基保护基和/或苄基类氨基保护基；
    钯金属催化剂选自Pd2(dba)3、Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2和/或PdCl2；
    铜金属催化剂选自CuI、CuBr、CuCl、Cu和/或Cu2O；
    铂金属催化剂选自PtO2；
    与钯金属催化剂配位的含膦配体选自Xantphos、Sphos、Xphos、Ruphos和/或Brettphos；
    与铜金属催化剂配位的含氮配体选自1,2-环己二胺、N,N'-二甲基乙二胺和/或1,10-菲啰啉；
    碱金属碱选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾和/或磷酸钾；
    碱土金属碱选自氢化钠、氢化钾和/或氢化钙；
    有机碱选自三乙胺、DIPEA、NMM和/或DBU；
    有机金属碱选自甲醇钠、叔丁醇锂、叔丁醇钠、叔丁醇钾、乙醇钠和/或异丙醇铝。
  6. 作为制备式(Ⅰ)化合物中间体的下式化合物：
    Figure PCTCN2016100821-appb-100006
  7. 下式所示化合物2：
    Figure PCTCN2016100821-appb-100007
  8. 化合物3的A晶型，其XRPD图谱如图1所示，
    Figure PCTCN2016100821-appb-100008
  9. 根据权利要求8所述的A晶型，其差示扫描量热曲线在85.44℃具有吸热峰的起始点，在162.95℃处具有吸热峰的起始点,在205.63℃±3℃处具有吸热峰的起始点。
  10. 根据权利要求8所述的A晶型，其中，该晶型的DSC图谱如图2所示。
  11. 根据权利要求8所述的A晶型，其热重分析曲线在129.34℃处失重达3.740％；在194.30℃处失重达0.4250％；在245.46℃失重达13.59％。
  12. 根据权利要求8所述的A晶型，其中，该晶型的TGA图谱如图3所示。
  13. 根据权利要求8所述A晶型的制备方法，包括将任意一种形式的式(1)化合物与马来酸加入到溶剂中结晶制得，其中，
    马来酸与式(1)化合物摩尔比为1:1.05～1.2；
    溶剂用量为式(1)化合物重量的8～12倍；
    反应溶剂选自醇类溶剂和/或含有醇类溶剂和水的混合溶剂；
    具体地，所述醇类溶剂选自甲醇、乙醇和/或异丙醇；
    具体地，所述醇类溶剂和水的混合溶剂选自甲醇、乙醇、异丙醇和水的混合溶剂；
    具体地，所述醇类溶剂和水的体积比为1:0.05～0.1。
  14. 根据权利要求7所述盐或权利要求8所述A晶型在制备治疗与PARP受体有关疾病的药物中的应用。
PCT/CN2016/100821 2015-09-30 2016-09-29 4H-吡唑并[1, 5-α]苯并咪唑类化合物的盐型、晶型及其制备方法和中间体 WO2017054755A1 (zh)

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