CN112745314B - Preparation and synthesis method of aromatic amine compound with specific HIF-2 alpha inhibition effect - Google Patents
Preparation and synthesis method of aromatic amine compound with specific HIF-2 alpha inhibition effect Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 title claims abstract description 16
- -1 aromatic amine compound Chemical class 0.000 title claims description 20
- 230000000694 effects Effects 0.000 title description 6
- 230000005764 inhibitory process Effects 0.000 title description 3
- 238000001308 synthesis method Methods 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 claims abstract description 17
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 16
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000003384 small molecules Chemical class 0.000 claims abstract description 14
- ORLGLBZRQYOWNA-UHFFFAOYSA-N 4-methylpyridin-2-amine Chemical compound CC1=CC=NC(N)=C1 ORLGLBZRQYOWNA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000012044 organic layer Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- QGXIKPKPVRZSGG-UHFFFAOYSA-N 2-[[benzyl(furan-2-ylmethyl)amino]methyl]-8-methylpyrido[1,2-a]pyrimidin-4-one Chemical compound C1=C(C)C=CN(C(C=2)=O)C1=NC=2CN(CC=1C=CC=CC=1)CC1=CC=CO1 QGXIKPKPVRZSGG-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- 239000010410 layer Substances 0.000 claims description 8
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 claims description 7
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- KUTREPQQCILHIM-UHFFFAOYSA-N [2-(furan-2-yl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1C1=CC=CO1 KUTREPQQCILHIM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 150000007529 inorganic bases Chemical group 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000007126 N-alkylation reaction Methods 0.000 abstract 1
- 238000007259 addition reaction Methods 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- ARYHUCZYDWUSAA-UHFFFAOYSA-N n-benzylfuran-2-amine Chemical compound C=1C=CC=CC=1CNC1=CC=CO1 ARYHUCZYDWUSAA-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- 102100035070 von Hippel-Lindau disease tumor suppressor Human genes 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a preparation method of a HIF-2 alpha small molecule inhibitor (2- ((benzyl (furan-2-methyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone). The compound is characterized in that: 4-methylpyridin-2-amine is taken as a starting material and cyclized with condensation to obtain 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone; and in addition, furfural is taken as an initial raw material to be subjected to addition reaction with benzylamine to obtain N-furbenylamine, and the obtained 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone and the N-furbenylamine are subjected to N-alkylation reaction to obtain the HIF-2 alpha small molecule inhibitor. The invention discloses a preparation method of a HIF-2 alpha small molecule inhibitor for the first time, which has the advantages of few steps, simple operation, rapid reaction, no need of high pressure, high yield and purity of the prepared compound, and easy obtainment of raw materials.
Description
Technical Field
The invention relates to a preparation method of a HIF-2 alpha small molecular compound inhibitor (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone), belonging to the technical field of biological pharmacy.
Background
At present, few reports on HIF-2 alpha inhibitors exist, only a small molecule PT2399 which can target and inhibit the HIF-2 alpha of kidney cancer cells lacking pVHL is found by Cho and the like, but no reports on HIF-2 alpha inhibitors with other tumor effects such as breast cancer, ovarian cancer and the like are found. Therefore, the research and development of the novel HIF-2 alpha inhibitor capable of targeting the tumor stem cell to specifically and highly express has important clinical significance for inhibiting the occurrence, metastasis and recurrence of tumors.
CN201810146778 discloses a HIF-2 alpha small molecule inhibitor and application thereof, in particular discloses a compound and a series of derivatives with high anti-tumor and anti-CSCs high activity and HIF-2 alpha inhibition effect, but does not disclose a preparation method of the compound. Based on the above, the invention provides a preparation method of a HIF-2 alpha small molecule inhibitor (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone).
Application number 200480017139 discloses pyrido [1,2-a ] pyrimidinyl compounds and a process for their preparation, which comprises several tens of steps, is complicated to operate, and the excessive use of raw materials and the large number of steps have adverse effects on the purity and yield of the final product, and the formation of excessive by-products is detrimental to the safety of the final product in subsequent use.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a HIF-2 alpha small molecule inhibitor (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone), which comprises the following specific preparation steps:
(1) Preparation of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Mixing 4-methylpyridine-2-amine, ethyl chloroacetoacetate and polyphosphoric acid, heating to 100-130 ℃, stirring, reacting for 4-8 hours, adding water and chloroform, pulping, extracting to obtain an organic layer A, and extracting a water layer with chloroform to obtain an organic layer B; the organic phases were combined, the layers were collected after washing with saturated brine, the organic layers were dried over anhydrous sodium sulfate, and purified by column chromatography to give a white powder.
Wherein, 4-methylpyridin-2-amine: ethyl chloroacetoacetate: the molar ratio of polyphosphoric acid is 1: (1-2): (5-10).
(2) Preparation of N-furanbenzylamine
Dissolving furfural in a solvent, placing the solvent in room temperature in an ice bath, slowly adding sodium borohydride while stirring after the temperature of the reaction liquid is reduced to 0 ℃, removing the ice bath after no bubbles exist, placing the ice bath at room temperature, adding benzylamine, mixing and stirring, reacting at room temperature for 1-4h, filtering, evaporating the solvent, and purifying by column chromatography to obtain oily matter.
Wherein, the molar ratio of furfural: sodium borohydride: benzylamine=1: (1-2): (1-1.5).
Wherein the solvent is one or more of acetone, chloroform, dichloromethane, anhydrous methanol, anhydrous ethanol and isopropanol.
(3) Preparation of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Dissolving 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone in the step (1) in a solvent A, adding an acid binding agent and a catalyst, stirring for 15min, adding N-furbenamine obtained in the step (2), reacting for 1-2H at 50-80 ℃, and adding water to stop the reaction; then adding solvent B, pulping for 5min, collecting an organic layer a, extracting the water layer for 2 times to obtain an organic phase B, then combining the organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, and purifying by column chromatography to obtain a light yellow oily substance.
Wherein the acid-binding agent is inorganic base or organic base, wherein the inorganic base is one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, potassium dihydrogen phosphate and sodium dihydrogen phosphate, and the inorganic base is one or more of triethylamine and pyridine; wherein the molar ratio of the addition amount of the acid binding agent to the 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone is 1:1.
Wherein the catalyst is potassium iodide, and the specific addition amount is 0.1 of the amount of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone.
Wherein the solvent A is one or more of acetone, dichloromethane, chloroform, ethyl acetate, N-dimethylformamide and tetrahydrofuran.
Wherein the solvent B is one or more of ethyl acetate, dichloromethane and chloroform.
Wherein the room temperature is 17-25 ℃.
The invention has the beneficial effects that.
(1) The invention discloses a preparation method of a HIF-2 alpha small molecule inhibitor (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone) for the first time.
(2) The preparation method is simple, and the 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone prepared by the method has the characteristics of high purity and good yield.
(3) The preparation method disclosed by the invention only comprises 3 steps, is simple and quick to operate, does not need high pressure, is convenient to obtain raw materials, has little environmental pollution and few byproducts, and can save resources.
Drawings
FIG. 1 is a schematic illustration of (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] of the present invention]Pyrimidin-4-one) 13 C spectrogram。
FIG. 2 is a schematic illustration of (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] of the present invention]Pyrimidin-4-one) 1 H spectrum.
FIG. 3 is a high performance liquid report of (2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one) of the present invention.
FIG. 4 is a chemical reaction scheme of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one of the invention.
Detailed Description
Example 1.
(1) Preparation of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
4-methylpyridin-2-amine (10 g,0.09 mol), ethyl chloroacetoacetate (18.2 g,0.135 mol) and 70g polyphosphoric acid were added to a 500ml eggplant-shaped bottle, the mixture was heated to 110℃in an oil bath, stirred for 3 hours, the oil bath was removed, cooled to room temperature, water was added, extraction was performed 3 times with chloroform, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after column chromatography, 9.36g of white powder was obtained, yield: 50.0%.
(2) Preparation of N-furanbenzylamine.
Furfural (9.6 g,0.1 mol) and methanol (80 ml) were added to a 250ml eggplant-shaped bottle, and then stirred in an ice bath, after the temperature had fallen to 0 ℃, sodium borohydride (5.67 g,0.15 mol) was added a small number of times to the stirring after no bubbles had been formed, benzylamine (13.39 g,0.125 mol) was added, the ice bath was removed, stirring was carried out at room temperature for 5 hours, the solvent was evaporated, and 17.41g of an oil was obtained after column chromatography, the yield was 93.0%.
(3) Preparation of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one (2.08 g,0.01 mol), potassium carbonate (1.38 g,0.01 mol), potassium iodide (0.166 g,0.001 mol) and N, N-dimethylformamide 90ml prepared as described above were added to a 250ml eggplant-shaped bottle, stirred at room temperature for 15 minutes, N-furbenylamine (1.87 g,0.01 mol) was added thereto, stirred in an oil bath at 85℃for 1 hour, then the oil bath was removed, cooled to room temperature, dissolved in water, the aqueous layer was extracted 2 times with ethyl acetate, the organic phase was combined, the organic layer was collected after washing with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and an oily liquid was obtained after purification by column chromatography, the yield was 83.0%, and the HPLC detection purity was 96.00%.
Example 2.
(1) Preparation of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
4-methylpyridin-2-amine (10 g,0.09 mol), ethyl chloroacetoacetate (17.7 g,0.108 mol) and 50g polyphosphoric acid were added to a 500ml eggplant-shaped bottle, the mixture was heated to 100℃in an oil bath, stirred for 4 hours, the oil bath was removed, cooled to room temperature, water was added, extraction was performed 3 times with chloroform, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and a white powder of 5.62g was obtained after column chromatography, yield: 30.0%.
(2) Preparation of N-furanbenzylamine.
Furfural (9.6 g,0.1 mol) and methanol (90 ml) were added to a 250ml eggplant-shaped bottle, and then stirred in an ice bath, after the temperature had fallen to 0 ℃, sodium borohydride (3.78 g,0.1 mol) was added a small number of times to the stirring after no air bubbles had occurred, benzylamine (10.71 g,0.1 mol) was added, the ice bath was removed, stirring was carried out at room temperature for 6 hours, the solvent was evaporated, and 17.8g of an oil was obtained after column chromatography, the yield was 95.0%.
(3) Preparation of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one (5.2 g,0.025 mol), potassium carbonate (3.45 g,0.025 mol), potassium iodide (1.66 g,0.01 mol) and 80ml of N, N-dimethylformamide prepared as described above were added to a 250ml eggplant-shaped bottle, stirred at room temperature for 15 minutes, N-furbenylamine (4.68 g,0.025 mol) was added thereto, the mixture was heated to 85℃in an oil bath and stirred for 1 hour, the oil bath was removed, cooled to room temperature, dissolved in water, the aqueous layer was extracted 2 times with ethyl acetate, the organic phase was combined, the organic layer was collected after washing with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the oily liquid was obtained after column chromatography purification, the yield was 80.0%, and the HPLC detection purity was 96.00%.
Example 3.
(1) Preparation of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
4-methylpyridin-2-amine (10 g,0.09 mol), ethyl chloroacetoacetate (29.52 g,0.19 mol) and 100g polyphosphoric acid were added to a 500ml eggplant-shaped bottle, the mixture was heated to 120℃in an oil bath, stirred, after stirring for 3 hours, the oil bath was removed, cooled to room temperature, water was added, extraction was performed 3 times with chloroform, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and after column chromatography, 10.29g of white powder was obtained, yield: 55.0%.
(2) Preparation of N-furanbenzylamine.
Furfural (19.22 g,0.2 mol) and methanol (200 ml) were added to a 500ml eggplant-shaped bottle, and then stirred in an ice bath, after the temperature had fallen to 0 ℃, sodium borohydride (7.56 g,0.2 mol) was added a small number of times during stirring, after no air bubbles had occurred, benzylamine (21.43 g,0.2 mol) was added, the ice bath was removed, stirring was carried out at room temperature for 6 hours, the solvent was evaporated, and after column chromatography 35.2g of oil was obtained in 94.0% yield.
(3) Preparation of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one.
2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one (10.4 g,0.05 mol), potassium carbonate (6.91 g,0.05 mol), potassium iodide (0.83 g,0.005 mol) and 80ml of N, N-dimethylformamide prepared as described above were added to a 250ml eggplant-shaped bottle, stirred at room temperature for 15 minutes, N-furylbenzylamine (9.362 g,0.05 mol) was added thereto, stirred at 80℃for 1 hour in an oil bath, then the oil bath was removed, cooled to room temperature, dissolved in water, the aqueous layer was extracted 2 times with ethyl acetate, the organic phase was combined, the organic layer was collected after washing with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and an oily liquid was obtained after purification by column chromatography, the yield was 85.0%, and the HPLC detection purity was 96.00%.
Claims (7)
1. A method for preparing a HIF-2 alpha small molecule inhibitor 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one, comprising the steps of:
(1) Preparation of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Mixing 4-methylpyridine-2-amine, ethyl chloroacetoacetate and polyphosphoric acid, heating to 100-130 ℃, stirring for 4-8h, adding water and chloroform, pulping, and extracting to obtain an organic layer A; extracting the water layer with chloroform to obtain an organic layer B; combining the organic layers A and B, washing, layering, collecting the organic layers, drying the organic layers, and purifying by column chromatography to obtain white powder, namely 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-ketone;
(2) Preparation of N-furanbenzylamine
Dissolving furfural in a solvent, then cooling to 0 ℃, slowly adding sodium borohydride while stirring, and naturally heating to room temperature after no bubbles; then adding benzylamine, stirring, reacting for 1-4 hours at room temperature, filtering, evaporating the solvent, and purifying by column chromatography to obtain oily substance, namely N-furbenylamine;
(3) Preparation of 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one
Dissolving the white powder in the step (1) in the solvent A, adding an acid binding agent and a catalyst, stirring, adding the oily substance obtained in the step (2), reacting for 1-2h at 50-80 ℃, and adding water to stop the reaction; adding a solvent B, pulping, taking an organic layer a for later use, extracting a water layer to obtain an organic phase B, combining the organic phases a and B, washing, drying, and purifying by column chromatography to obtain a light yellow oily substance, namely 2- ((benzyl (furan-2-ylmethyl) amino) methyl) -8-methyl-4H-pyrido [1,2-a ] pyrimidine-4-one, wherein the solvent A is one or more of acetone, dichloromethane, chloroform, ethyl acetate, N-dimethylformamide and tetrahydrofuran; the solvent B is one or more of ethyl acetate, dichloromethane and chloroform; the acid binding agent is inorganic base or organic base, wherein the inorganic base is one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, monopotassium phosphate and sodium dihydrogen phosphate, and the organic base is one or two of triethylamine and pyridine; the catalyst is potassium iodide.
2. The method of preparing HIF-2 a small molecule inhibitors according to claim 1, wherein in the step (1), the combined organic layers a and B are washed with saturated saline; the organic layer was dried over anhydrous sodium sulfate; the molar ratio of the 4-methylpyridin-2-amine, the ethyl chloroacetoacetate and the polyphosphoric acid is 1:1-2:5-10.
3. The method of preparing HIF-2 a small molecule inhibitors according to claim 1, wherein in step (2), the molar ratio of furfural, sodium borohydride and benzylamine is 1:1-2:1 to 1.5; the solvent is one or more of acetone, chloroform, dichloromethane, anhydrous methanol, anhydrous ethanol and isopropanol.
4. The method of preparing HIF-2 a small molecule inhibitors according to claim 1, wherein in the step (3), the combined organic phases a and b are washed with saturated saline; the organic layer was dried over anhydrous magnesium sulfate.
5. The method for preparing a HIF-2 a small molecule inhibitor according to claim 1, wherein the molar ratio of the acid binding agent to 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one is 1:1.
6. The method for preparing a HIF-2 a small molecule inhibitor according to claim 1, wherein the catalyst is added in an amount of 0.1 of the amount of 2-chloro-8-methyl-4H-pyrido [1,2-a ] pyrimidin-4-one substance.
7. The method of claim 1, wherein the room temperature is in the range of 17-25 ℃.
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