CN110256445B - Method for synthesizing DNA-PK inhibitor STL127705 - Google Patents
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Abstract
The invention discloses a method for synthesizing a DNA-PK inhibitor STL 127705. The invention adopts inverse synthesis analysis, takes 2-methyl sulfide-4-chloropyrimidine-5-ethyl formate as a starting material, and prepares a target compound by 6 steps of reactions such as ammoniation, hydrolysis, amide condensation, cyclization, oxidation, substitution and the like, the total yield is 36.8 percent, the purity reaches 95.5 percent, and the product structure is obtained by1H‑NMR、13C-NMR, MS and the like, and the correct structure is proved.
Description
Technical Field
The invention belongs to the field of biology, and relates to a method for synthesizing a DNA-PK inhibitor STL 127705.
Background
DNA-dependent protein kinase (DNA-PK) is a protein complex consisting of a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and a Ku protein (an isoform consisting of Ku70 and Ku 80) which functions to initiate nonhomologous end-joining repair of DNA double strand breaks (NHEJ)[1-4]. DNA damage inducers and radiotherapy have been widely used in clinical tumor therapy, and the anti-tumor mechanism is to induce lethal DNA Double Strand Break (DSB) of tumor cells, the DSB is mainly repaired by non-homologous end connection, so that the inhibitor of DNA-PK playing a key role in the repair process has the effect of enhancing the sensitivity of radiotherapy and chemotherapy[5,6]. Olaparib is an inhibitor of adenosine polyphosphate ribopolymerase (PARP) which blocks enzymes involved in the repair of damaged DNA[7-9]. In 2014, the us FDA approved olaparib for use in the treatment of BRCA gene deficiency-related ovarian cancer. With the clinical approval of olaparib, DNA repair inhibitors have attracted the attention of a large number of researchers, and more novel DNA repair inhibitors have been developed and put into clinical trials. Studies find that STL127705 is an inhibitor of DNA-PK with a pyrimido-pyrimidinedione skeleton structure, has little killing effect on tumor cells, but can greatly enhance the anti-tumor effect of DNA damage inducers or radiotherapy by blocking DNA repair pathways[10]。
The synthesis method of the STL127705 is not reported before, and the STL127705 can be prepared by condensing 3, 4-dimethoxyphenethylamine and a derivative containing a pyrimidopyrimidinedione structure through chemical structure analysis; the pyrimidopyrimidinedione compound can be prepared by a 4-aminopyrimidine-5-amide derivative structural ring reaction; the 4-aminopyrimidine-5-amide derivatives can be prepared by esterification condensation of the corresponding 4-amino-5-pyrimidinecarboxylic acid derivatives with 3-fluoroaniline (FIG. 1).
Disclosure of Invention
The invention aims to provide a method for synthesizing a DNA-PK inhibitor STL 127705.
The invention claims a method of synthesizing STL127705, as shown in fig. 2, comprising: carrying out substitution reaction on the compound 5 and 3, 4-dimethoxy phenethylamine in an organic solvent to obtain the STL127705 after the reaction is finished;
in the method, the feeding molar ratio of the compound 5 to the 3, 4-dimethoxyphenethylamine is 1: 1-4; specifically 1: 1.5;
in the step of substitution reaction, the temperature is 20-100 ℃; in particular 80 ℃; the time is 1-6 h; in particular for 2 h;
the organic solvent is at least one selected from N, N-Dimethylacetamide (DMA), N-Dimethylformamide (DMF) and dioxane.
The present invention also claims intermediate compounds used in the synthesis of STL127705, namely compound 5,
the present invention provides a process for preparing compound 5 comprising: carrying out oxidation reaction on the compound 4 in the presence of an oxidant to obtain a compound 5 after the reaction is finished;
in the method, the oxidant is at least one selected from m-chloroperoxybenzoic acid (m-CPBA), hydrogen peroxide, potassium permanganate and potassium dichromate;
the feeding molar ratio of the compound 4 to the oxidant is 1: 2-10; specifically 1: 5;
in the oxidation reaction step, the temperature is 0-80 ℃; in particular room temperature; the time is 4-24 h; in particular 12 h;
the reaction is carried out in an organic solvent; the organic solvent is specifically selected from at least one of dichloromethane, tetrahydrofuran and acetone.
The invention adopts inverse synthesis analysis, takes 2-methyl sulfide-4-chloropyrimidine-5-ethyl formate as a starting material, and prepares a target compound by 6 steps of reactions such as ammoniation, hydrolysis, amide condensation, cyclization, oxidation, substitution and the like, the total yield is 36.8 percent, the purity reaches 95.5 percent, and the product structure is obtained by1H-NMR、13C-NMR, MS and the like, and the correct structure is proved.
Drawings
FIG. 1 is a reverse synthetic route analysis of target compound STL 127705.
Fig. 2 is a synthetic route of the target compound STL127705 provided by the present invention.
Fig. 3 shows tautomerism of the target compound.
FIG. 4 is a mass spectrum of Compound 1.
FIG. 5 is a mass spectrum of Compound 2.
Fig. 6 is a hydrogen spectrum of compound 2.
Fig. 7 is a hydrogen spectrum of compound 3.
FIG. 8 is a mass spectrum of Compound 4.
FIG. 9 is a hydrogen spectrum of Compound 4.
FIG. 10 is a mass spectrum of Compound 5.
FIG. 11 is a hydrogen spectrum of Compound 5.
Fig. 12 is a mass spectrum of target compound STL 127705.
Fig. 13 shows a hydrogen spectrum (room temperature) of the target compound STL 127705.
FIG. 14 shows a hydrogen spectrum (80 ℃ C.) of the objective compound STL 127705.
Fig. 15 shows the purity of target compound STL 127705.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Examples 1,
1 experimental part
1.1 instruments and reagents
In the experiment, related chemical reagents are all domestic analytical reagents, and the anhydrous solvent is dried by a conventional method. The reaction was monitored by TLC using a thin layer chromatography silica gel plate model 0.25mm E.Merck (GF)254) (ii) a The column chromatography separation and purification adopts a rapid preparation instrument Biotage Isolera I, and the used silica gel is 300-400 mesh. The reaction yield was calculated after column purification. Melting point was measured using an X4 type micro melting point apparatus, mass spectrum was LCQ-Deca XP/Ad type (Thermo Electron), ion source was electrospray ionization (ESI),1H-NMR and13C-NMR A400 MHz Bruker Avance III NMR spectrometer was used.
1.2 Experimental methods
1.2.1 Synthesis of Compound 1 5.00g (21.5mmol) of ethyl 2-dimethylsulfide-4-chloropyrimidine-5-carboxylate were dissolved in 20mL of tetrahydrofuran, 5mL of 25% aqueous ammonia was added to the reaction mixture, the reaction was carried out at room temperature for 2 hours, the reaction was monitored by TLC, after the reaction was completed, 30mL of saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, extraction was carried out with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was purified by column separation (PE/EA,1:1) to give 4.12g of a white solid, with a yield of 89.3%, a melting point of 130-. ESI-MS M/z 214.0[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ8.61(s,1H,H-4),7.84(s,2H,-NH2),3.47–3.41(q,J＝6.8Hz,2H,-OCH2CH3),2.45(s,3H,-SCH3),1.04–1.00(t,J＝6.8Hz,3H,-OCH2CH3) Mass spectra are shown in figure 4.
1.2.2 Synthesis of Compound 2 4.12g (19.3mmol) of Compound 1 was dissolved in 15mL of methanol, 3mL of 0.50g/mL aqueous lithium hydroxide solution was added dropwise to the reaction mixture, the reaction was carried out at 50 ℃ for 5 hours, the progress of the reaction was monitored by TLC, and after the reaction was completed, 30mL of saturated ammonium chloride solution was added to the reaction mixture to quench the reactionExtraction with ethyl acetate (20 mL. times.3), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and column separation and purification of the residue (PE/EA,1:3) gave 3.25g of a white solid in 91.0% yield, mp 122-. ESI-MS M/z 183.9[ M-H ]]-.1H NMR(400MHz,DMSO-d6)δ13.17(s,1H,-COOH),8.54(s,1H,H-4),7.89(s,1H,-NH2),7.82(s,1H,-NH2),2.47(s,3H,-SCH3) The mass spectrum and hydrogen spectrum of compound 2 are shown in fig. 5 and 6.
1.2.3 Synthesis of Compound 3 3.25g (17.6mmol) of Compound 2 and 8.01g (21.1mmol) of 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) were dissolved in 20mL of dry N, N-Dimethylformamide (DMF), 4.6mL (26.4mmol) of N, N-Diisopropylethylamine (DIPEA) was added to the reaction mixture under nitrogen protection at room temperature, after completion of the dropwise addition reaction for 10min, 2.40g (21.1mmol) of 3-fluoroaniline was added to the reaction mixture, after 12 hours at room temperature, the reaction was monitored by TLC, after completion of the reaction, 30mL of a saturated ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (20 mL. times.4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column separation (PE/EA,2:3) to give 4.55g of a pale yellow solid in a yield of 93.0%, melting point 145-147 ℃. ESI-MS M/z 279.4[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ10.33(s,1H,-CONH-),8.65(s,1H,H-4),7.82(s,2H,-NH2),7.65(dt,J＝11.8,2.2Hz,1H,H-2’),7.49–7.43(m,1H,H-6’),7.39(dt,J＝15.0,7.5Hz,1H,H-4’),6.94(ddd,J＝8.1,2.5,1.8Hz,1H,H-5’),2.48(s,3H,-SCH3) The hydrogen spectrum of compound 3 is shown in figure 7.
1.2.4 Synthesis of Compound 4 in 30mL dry tetrahydrofuran under nitrogen and ice bath conditions, 4.55g (16.4mmol) of Compound 3 and 20g (65.6mmol) of bis (trichloromethyl) carbonate were dissolved, 5.7mL (32.8mmol) of DIPEA was added dropwise to the reaction mixture, after 2h reaction, TLC was used to monitor the reaction, after the reaction was completed, 50mL saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, extraction was performed with ethyl acetate (30 mL. times.4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was passed through an ice bathColumn isolation purification (PE/EA,1:1) gave 4.43g of a pale yellow solid in 88.9% yield, mp 139-. ESI-MS M/z 305.5[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ12.48(s,1H,H-7),8.93(s,1H,H-4),7.60–7.50(m,1H,H-4’),7.35–7.24(m,2H,H-2’,H-5’),7.21(d,J＝7.9Hz,1H,H-6’),2.61(s,3H,-SCH3) The mass spectrum and hydrogen spectrum of compound 4 are shown in fig. 8 and 9.
1.2.5 Synthesis of Compound 5 in ice bath conditions, 4.43g (14.6mmol) of Compound 4 was dissolved in 30mL of dry dichloromethane, 14.8g (73.0mmol) of 85% m-chloroperoxybenzoic acid (m-CPBA) was slowly added to the reaction mixture, after the solid was dissolved, the ice bath was removed, oxidation was carried out at room temperature for 12 hours, TLC was carried out to monitor the reaction, after the reaction was completed, 50mL of saturated sodium bicarbonate solution was added to the reaction mixture to quench the reaction, extraction was carried out with dichloromethane (30 mL. times.4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column separation (PE/EA,1:2) to give 3.45g of a yellow solid, yield 70.4%, melting point 142. sup. 143 ℃. ESI-MS M/z 337.0[ M + H ]]+.1H NMR(400MHz,DMSO-d6)δ13.18(s,1H,H-7),9.32(s,1H,H-4),7.58(dd,J＝14.7,8.0Hz,1H,H-4’),7.39–7.30(m,1H,H-5’),7.26(d,J＝9.5Hz,1H,H-2’),7.22(d,J＝8.0Hz,1H,H-6’),3.48(s,3H,-SO2CH3) The mass spectrum and hydrogen spectrum of compound 5 are shown in fig. 10 and 11.
1.2.6 Synthesis of the target Compound STL127705 in the presence of nitrogen, 3.45g (10.3mmol) of Compound 5 and 2.85g (15.5mmol) of 3, 4-dimethoxyphenethylamine were dissolved in 10mL of N, N-Dimethylacetamide (DMA), and after a substitution reaction at 80 ℃ for 2 hours, the progress of the reaction was monitored by TLC, 30mL of water was added to the reaction mixture after the reaction was completed to quench the reaction, followed by extraction with dichloromethane (30 mL. times.4), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column separation (PE/EA,1:2) to give 3.50g of a yellow solid, a yield of 77.8%, a melting point of 212-. HRMS (ESI) calcd for C22H20FN5O4(M+H)+:437.4256Found:437.4216,(△-3.6ppm,-4.9mDa).1H NMR(400MHz,DMSO-d6)δ11.51(s,1H,H-7),8.70(s,1H,H-4),7.80(s,1H,H-9”),7.51(dd,J＝15.1,7.7Hz,1H,H-4’),7.29–7.10(m,3H,H-2’,H-5’,H-6’),6.89(d,J＝8.4Hz,2H,H-2”,H-5”),6.81(d,J＝7.3Hz,1H,H-6”),3.79(s,3H,-OCH3),3.77(s,3H,-OCH3),3.67–3.61(dd,J＝7.1,6.8Hz,2H,H-8”),2.87(t,J＝7.3Hz,2H,H-7”).13C NMR(101MHz,DMSO-d6) δ 173.70,167.52,162.23,161.61,160.16,150.38,149.83,148.82,147.15,137.91,127.82,123.96,122.33,117.25,116.98,113.26,112.81,103.86,57.82,57.73,45.62, 33.96. Fig. 12 is a mass spectrum of target compound STL 127705. Fig. 13 shows a hydrogen spectrum (room temperature) of the target compound STL 127705. FIG. 14 shows a hydrogen spectrum (80 ℃ C.) of the objective compound STL 127705. Fig. 15 shows the purity of target compound STL 127705. From the above, it was found that the compound has a correct structure and is a target compound.
2 results and discussion
From the target compound STL1277051Tautomerism of the final product was observed in H-NMR data, and the possible site of tautomerism was an intra-cyclic amide bond in the molecular structure, which can undergo enol tautomerism from a keto form (fig. 3). A dynamic equilibrium exists between the two isomers, the interconversion rate is relatively slow at low temperature, two sets of peaks can be detected by nuclear magnetism, and when the temperature is increased, the interconversion rate is fast, and the two sets of peaks are fused into one set of peaks. Thus the temperature rise was tested for the final product1H-NMR (80 ℃ C.), and the spectrum result shows a set of peaks, which confirms the conjecture of the applicant.
Intermediate 4 and intermediate 5 likewise present a cyclic amide bond, but in1No two distinct sets of peaks were observed in H-NMR, probably due to the fact that the stable isomer accounts for a much larger proportion than its tautomer. Intermediates 4 and 5 must exist tautomeric, except that the two isomers are very different in stability, and the equilibrium may be 99% biased towards one of the stable structures,1H-NMR will show only one set of peaks. The structure of the target compound is changed, the change of the molecular structure influences the deviation of balance, the stability of two isomers is close, and the stability of the two isomers is observed at room temperature1H-NMR will show both hydrogen signals, so two sets of peaks.
3 conclusion
The invention provides a simple and effective synthesis method of a DNA-PK inhibitor STL 127705. The method takes commercially available chemical raw materials as starting materials, and obtains a target product with the yield of 36.8 percent and the purity of 95 percent through 6 steps of reaction. The preparation method has mild conditions, does not need harsh reaction conditions, is simple, has high technical feasibility, and lays a theoretical foundation for the synthesis research of a novel DNA-PK inhibitor with a pyrimidopyrimidinedione structure.
Claims (5)
1. A method of synthesizing an STL127705, comprising: (1) taking 2-methyl sulfide-4-chloropyrimidine-5-ethyl formate as a starting raw material, and sequentially carrying out ammoniation, hydrolysis, amide condensation and cyclization to obtain a compound 4;
(2) carrying out oxidation reaction on the compound 4 in the presence of an oxidant to obtain a compound 5 after the reaction is finished;
the oxidant is at least one selected from m-chloroperoxybenzoic acid (m-CPBA), hydrogen peroxide, potassium permanganate and potassium dichromate;
(3) carrying out substitution reaction on the compound 5 and 3, 4-dimethoxyphenethylamine in an organic solvent to obtain the STL127705 after the reaction is finished;
in the step of substitution reaction, the temperature is 20-100 ℃; the time is 1-6 h.
2. The method of claim 1, wherein: the feeding molar ratio of the compound 5 to the 3, 4-dimethoxyphenethylamine is 1: 1-4;
in the step of substitution reaction, the temperature is 80 ℃; the time is 2 h;
the organic solvent is at least one selected from N, N-dimethylacetamide, N-dimethylformamide and dioxane.
3. The method of claim 2, wherein: the feeding molar ratio of the compound 5 to the 3, 4-dimethoxyphenethylamine is 1: 1.5.
4. The method of claim 1, wherein: the feeding molar ratio of the compound 4 to the oxidant is 1: 2-10;
in the oxidation reaction step, the temperature is 0-80 ℃; the time is 4-24 h;
the reaction is carried out in an organic solvent.
5. The method of claim 4, wherein: the feeding molar ratio of the compound 4 to the oxidant is 1: 5;
in the step of oxidation reaction, the temperature is room temperature; the time is 12 h;
the organic solvent is at least one selected from dichloromethane, tetrahydrofuran and acetone.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048388A (en) * | 2004-08-31 | 2007-10-03 | 阿斯利康(瑞典)有限公司 | Quinazolinone derivatives and their use as B-Raf inhibitors |
| WO2017031116A1 (en) * | 2015-08-18 | 2017-02-23 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Small molecule inhibitors of ku70/80 and uses thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048388A (en) * | 2004-08-31 | 2007-10-03 | 阿斯利康(瑞典)有限公司 | Quinazolinone derivatives and their use as B-Raf inhibitors |
| WO2017031116A1 (en) * | 2015-08-18 | 2017-02-23 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Small molecule inhibitors of ku70/80 and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| "A novel small molecule inhibitor of the DNA repair protein Ku70/80";Eric Weterings et al.;《DNA Repair》;20160407;第43卷;第98-106页 * |
| "Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells";Ahmed Malki et al.;《Journal of Enzyme Inhibition and Medicinal Chemistry》;20151218;第31卷(第6期);第1286-1299页 * |
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