CN113307810A - Synthetic method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile - Google Patents
Synthetic method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile Download PDFInfo
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- XMMFKXRGHKXAGG-UHFFFAOYSA-N 3-fluoro-1h-pyrrole Chemical compound FC=1C=CNC=1 XMMFKXRGHKXAGG-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000001308 synthesis method Methods 0.000 claims abstract description 18
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 95
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- 239000007787 solid Substances 0.000 claims description 36
- 235000019439 ethyl acetate Nutrition 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 26
- 239000003208 petroleum Substances 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000010898 silica gel chromatography Methods 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000012452 mother liquor Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000005227 gel permeation chromatography Methods 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000012363 selectfluor Substances 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000036772 blood pressure Effects 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000007832 Na2SO4 Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 238000011282 treatment Methods 0.000 abstract description 7
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 206010020772 Hypertension Diseases 0.000 description 6
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 6
- 230000001631 hypertensive effect Effects 0.000 description 6
- LPMXVESGRSUGHW-UHFFFAOYSA-N Acolongiflorosid K Natural products OC1C(O)C(O)C(C)OC1OC1CC2(O)CCC3C4(O)CCC(C=5COC(=O)C=5)C4(C)CC(O)C3C2(CO)C(O)C1 LPMXVESGRSUGHW-UHFFFAOYSA-N 0.000 description 5
- LPMXVESGRSUGHW-GHYGWZAOSA-N Ouabain Natural products O([C@@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1)[C@H]1C[C@@H](O)[C@@]2(CO)[C@@](O)(C1)CC[C@H]1[C@]3(O)[C@@](C)([C@H](C4=CC(=O)OC4)CC3)C[C@@H](O)[C@H]21 LPMXVESGRSUGHW-GHYGWZAOSA-N 0.000 description 5
- 244000166550 Strophanthus gratus Species 0.000 description 5
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 5
- 229960003343 ouabain Drugs 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 230000035488 systolic blood pressure Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile, which provides a synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile, aims at developing a brand-new synthesis method, solves the defects of more reaction byproducts, low conversion rate, complicated post-treatment operation, low product purity and the like in a preparation method of an intermediate synthetic compound of a drug for treating cardiovascular disorders, develops a novel general, economic, efficient, green and environment-friendly synthesis method, and accordingly achieves a product synthesis principle that raw materials are easy to obtain, the price is low, the operation is simple, the pollution is low, and the final preparation yield reaches more than 8%.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile.
Background
The present invention relates to novel active ingredient combinations which consist of other known active ingredients, known as pyridine-3-carbonitrile, as intermediate synthetic compounds for the production of medicaments, in particular for the production of medicaments for the treatment and/or prophylaxis of cardiovascular disorders.
CN201180042458.8 describes a process for the preparation of 5-fluoro-1H-pyrazolo [3, 4-b ] pyridine-3-carbonitriles of the formula which are useful as intermediate compounds in the synthesis of medicaments, in particular for the manufacture of medicaments for the treatment and/or prevention of cardiovascular disorders.
The active ingredients and active ingredient combinations described in the prior art have good activity but are in some cases not ideal at low application rates.
It is therefore an object of the present invention to provide a novel compound having improved activity.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile, aims at developing a brand-new synthesis method to overcome the defects of more reaction byproducts, low conversion rate, complicated post-treatment operation, low product purity and the like in a preparation method of an intermediate synthetic compound of a medicine for treating cardiovascular disorders, and develops a novel, general, economic, efficient, green and environment-friendly synthesis method, so that the product synthesis principle of easily available raw materials, low price, simple operation and less pollution is achieved, and the final preparation yield reaches more than 8%.
In order to realize the purpose, the invention adopts the technical scheme that:
a method for synthesizing 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is shown as a formula (I):
comprises the following steps:
the method comprises the following steps: CuI was added to Compound 1 at room temperature under nitrogen
And Pd (PPh)3)4In a mixture in toluene, compound 2 is added
Et3N and TBAF, and the mixture of the three was stirred at the same temperature for 17 h; after the reaction was complete, the mixture was filtered and the filtrate was evaporated in vacuo; the residue was purified by recrystallization from an organic mixed solvent to give compound 3.
Step two: at room temperature to compound 3
At DAdding CuO and Et3N to a stirred solution in MA; the reaction mixture was stirred at 130 ℃ for 17 h; after cooling to room temperature, the mixture was diluted with water and extracted three times with ethyl acetate; the combined organic layers were dried over anhydrous sodium sulfate; after filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give crude compound 4 as a pale yellow solid.
Step three: compound 4 is
Zn(CN)2And Pd (PPh)3)4The mixture in DMF was heated to 90 ℃ for 17 h; after the reaction was complete, it was cooled to room temperature, diluted with water, extracted three times with ether and Na2SO4Drying; after filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give compound 5.
Step four: mixing the compound 5
And Selectfluor in CH3CN and CH3The COOH mixed solution is heated to 80 ℃ for reaction for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature and saturated NH was added thereto4Quench with Cl solution, extract 3 times with EtOAc and over Na2And drying the SO 4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6: 1) to give compound 6
I.e. 2, 4-fluoro-pyrrolo [1,2]]Pyrimidine-7 carbonitrile.
Further, in the synthesis method, the organic mixed solvent in the step one is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 10: 1.
Furthermore, the solvent used in the gel chromatography in the second step of the synthesis method is a mixture of petroleum ether and ethyl acetate, and the volume ratio is 20: 1.
Further, the solvent used in the gel chromatography in the third step is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5: 1.
Further, the solvent used in the fourth step of the synthesis method by the mesogel chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 6: 1.
Further, the synthesis method comprises the steps of dissolving the crude compound 6 obtained in the step four in a solution of n-heptane and ethyl acetate in a ratio of 3:1, adding DCM for dissolution assistance, filtering the solution by silica gel, washing the materials by using a solvent of n-heptane and EA 3:1, concentrating eluent until a large amount of solids are separated out, cooling and filtering to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, filtering to obtain solids, continuously concentrating the secondary mother liquor until solids are separated out, and filtering to obtain the solid compound 6.
Further, the synthesis method comprises the step of carrying out suction filtration on the obtained solid compound 3, wherein the yield is over 85%; solid compound 4, yield more than 30%; solid compound 5, yield over 75%; the yield of the solid compound 6 is more than 8%.
Use of 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile for the treatment of cardiovascular disorders for lowering blood pressure.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method is a four-step reaction, the yield is not lower than 8%, and the 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is synthesized for the first time, and meanwhile, the production procedures and the cost are reduced.
(2) The method has the advantages of easily obtained raw materials and reagents, mild reaction conditions, easy operation of post-treatment and purification, and large-scale production.
Detailed Description
The description is to be construed as illustrative and explanatory only and is not intended to limit the scope of the present invention, as defined in the appended claims.
Example 1
A method for synthesizing 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is shown as a formula (I):
comprises the following steps:
the method comprises the following steps: synthesis of Compound 3
CuI (7.2g, 39mmol) was added to a mixture of compound 1(36g, 126.5mmol) and Pd (PPh3)4(7.3g, 6.5mmol) in toluene (240mL) at room temperature under nitrogen. Then, compound 2(18.6 mL, 126.5mmol), Et3N (58.5mL, 405mmol) and TBAF (126.5mL, 126.5mmol, 1M in THF) were added and the mixture was stirred at the same temperature for 17 h. After the reaction was complete, the mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by recrystallization from a mixed solvent of petroleum ether/ethyl acetate (about 10: 1 by volume) to give compound 3 as a white solid (29.8g, 85% yield). 1H NMR (400MHz, CDCl3): delta 2.08(s,3H),8.70(s,2H). EI-MS:196,169,117,104,90,64,52. m.p.:98-100 ℃.
Step two: synthesis of Compound 4
To a stirred solution of compound 3(6g, 30.5mmol) in 128mL DMA at room temperature were added CuO (2.4g, 30.5mmol) and Et3N (18mL, 125 mmol). The reaction mixture was stirred at 130 ℃ for 17 h. After cooling to room temperature, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 20: 1) to give crude compound 4 as a light yellow solid (1.8g, 30% yield). 1H NMR (400MHz, CDCl3): δ 6.66(d, J ═ 4.0Hz,1H),6.96(d, J ═ 0.8Hz,1H),7.16(t, J ═ 1.2Hz,1H), 8.03(d, J ═ 2.8Hz,1H),8.31(dd, J1 ═ 1.2Hz, J1 ═ 2.0Hz,1H), EI-MS:196, 117,90,64,52.m.p.: 107-.
Step three: synthesis of Compound 5
A mixture of compound 4(3.95g, 40mmol), Zn (CN)2(7.0g, 60mmol) and Pd (PPh3)4(5.8g, 5mmol) in 75mL DMF was heated to 90 deg.C for 17 h. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted three times with ether and dried over Na2SO 4. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 5: 1) to give compound 5(2.15g, 75% yield) as a light yellow solid. 1H NMR (400MHz, CDCl3): δ 6.78(d, J ═ 4.0Hz,1H),7.15(t, J ═ 32.0Hz,1H),7.31(d, J ═ 2.4Hz,1H),8.13(d, J ═ 2.4Hz,1H),8.59(d, J ═ 1.2Hz,1H), EI-MS:143,116,89,65,51.m.p.: 156-.
Step four: synthesis of Compound 6
Compound 5(214.5mg, 1.5mmol) and Selectfluor (1.1g, 3.15mmol) were heated to 80 ℃ in a mixed solution of CH3CN (30mL) and CH3COOH (6mL) for 0.5 h. After the reaction was complete the mixture was cooled to room temperature, quenched with saturated NH4Cl solution, extracted 3 times with EtOAc and dried over Na2SO 4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6: 1) to give 21.5mg of compound 6, 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile in 8% yield as a light yellow solid. 1H NMR (400MHz, CDCl3): δ 6.49(d, J ═ 2.8Hz,1H),7.89(s,1H),8.32(s,1H), 19F NMR (376MHz, CDCl3): δ -164.65(d, J ═ 16.9Hz,1F), -145.4(d, J ═ 18.0Hz,1F), 13C NMR (100MHz, CDCl3): δ 88.2(s),88.4(s),88.4(s),88.5(s),94.6(s),114.8(s), 131.1(s),137.8(t) — MS:120,105,91,77,65,58,51.HPLC: 93.9%. m.p.:86-88 ℃.
Example 2
A method for synthesizing 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is shown as a formula (I):
comprises the following steps:
the method comprises the following steps: synthesis of Compound 3
CuI (4.8g, 25.3mmol) was added to a mixture of compound 1(24g, 84.3mmol) and Pd (PPh3)4(4.87g, 4.3mmol) in toluene (160mL) at room temperature under nitrogen. Then, compound 2(12.4mL, 84.3mmol), Et3N (39mL, 270mmol) and TBAF (84.3mL, 84.3mmol, 1M in THF) were added and the mixture was stirred at the same temperature for 17 h. After the reaction was complete, the mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by recrystallization from a mixed solvent of petroleum ether/ethyl acetate (about 10: 1 by volume) to give compound 3 as a white solid (33.53g, 90% yield). 1H NMR (400MHz, CDCl3): delta 2.08(s,3H),8.70(s,2H), EI-MS:196,169,117,104,90,64,52. m.p.:98-100 ℃.
Step two: synthesis of Compound 4
To a stirred solution of compound 3(4g, 20.3mmol) in 256mL DMA at room temperature were added CuO (1.6g, 20.3mmol) and Et3N (12mL, 83.3 mmol). The reaction mixture was stirred at 130 ℃ for 17 h. After cooling to room temperature, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate: 20: 1) to give crude compound 4 as a light yellow solid (1.2g, 30% yield). 1H NMR (400MHz, CDCl3): δ 6.66(d, J ═ 4.0Hz,1H),6.96(d, J ═ 0.8Hz,1H),7.16(t, J ═ 1.2Hz,1H), 8.03(d, J ═ 2.8Hz,1H),8.31(dd, J1 ═ 1.2Hz, J1 ═ 2.0Hz,1H), EI-MS:196, 117,90,64,52.m.p.: 107-.
Step three: synthesis of Compound 5
A mixture of compound 4(2.63g, 13.3mmol), Zn (CN)2(4.67g, 40mmol) and Pd (PPh3)4(3.87g, 3.33mmol) in 50mL DMF was heated to 90 ℃ for 17 h. After the reaction was complete, it was cooled to room temperature, diluted with water, extracted three times with ether and dried over Na2SO 4. After filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 5: 1) to give compound 5(1.68g, 88% yield) as a light yellow solid. 1H NMR (400MHz, CDCl3): δ 6.78(d, J ═ 4.0Hz,1H),7.15(t, J ═ 32.0Hz,1H),7.31(d, J ═ 2.4Hz,1H),8.13(d, J ═ 2.4Hz,1H),8.59(d, J ═ 1.2Hz,1H), EI-MS:143,116,89,65,51.m.p.: 156-.
Step four: synthesis of Compound 6
Compound 5(143mg, 1mmol) and Selectfluor (0.73g, 2.1mmol) were heated to 80 ℃ in a mixed solution of CH3CN (20mL) and CH3COOH (4mL) for 0.5 h. After the reaction was complete the mixture was cooled to room temperature, quenched with saturated NH4Cl solution, extracted 3 times with EtOAc and dried over Na2SO 4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6: 1) to give 16.13mg of the compound 6, 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile in 9% yield as a light yellow solid. 1H NMR (400MHz, CDCl3): δ 6.49(d, J ═ 2.8Hz,1H),7.89(s,1H),8.32(s,1H), 19F NMR (376MHz, CDCl3): δ -164.65(d, J ═ 16.9Hz,1F), -145.4(d, J ═ 18.0Hz,1F), 13C NMR (100MHz, CDCl3): δ 88.2(s),88.4(s),88.4(s),88.5(s),94.6(s),114.8(s), 131.1(s),137.8(t) — MS:120,105,91,77,65,58,51.HPLC: 93.9%. m.p.:86-88 ℃.
And meanwhile, dissolving the crude compound 6 obtained in the fourth step in a solution of n-heptane and ethyl acetate 3:1, adding DCM for assisting dissolution, filtering the solution by using silica gel, washing the material by using n-heptane and an EA 3:1 solvent until the material is completely washed, concentrating eluent until a large amount of solids are separated out, cooling and filtering to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, filtering to obtain solids, continuously concentrating the secondary mother liquor until the solids are separated out, and filtering to obtain the solid compound 6.
Biological experiments
The test was carried out in hypertensive rats generated by chronic infusion of ouabain, and the procedure used to test the antihypertensive activity of this compound in the above model was as follows: systolic Blood Pressure (SBP) and Heart Rate (HR) were measured by indirect tail-cap (indiect tailcuff) method. The hypotensive effect of the 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile, a composition of the invention, was tested in hypertensive ouabain-sensitive rats. The compound was suspended in 0.3% (w/v) methylcellulose and administered orally at a dose of 7. mu.g/kg/day for 3 weeks daily. SBP and HR were measured weekly 5 hours after treatment. For comparison, hypertensive ouabain-sensitive rats and non-hypertensive rats, both treated with methylcellulose only 0.3% (w/v) were used. As shown in table 1 below, the data were averaged and the blood pressure of hypertensive ouabain-sensitive rats treated with the compound of the present invention (170mmHg) was reduced almost to the level of control rats (154 mmHg).
TABLE 1 systolic blood pressure drop in hypertensive ouabain-sensitive rats.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The principles and embodiments of the present invention are explained herein using specific examples, which are presented only to assist in understanding the method and its core concepts of the present invention. The foregoing is only a preferred embodiment of the present invention, and it should be noted that there are objectively infinite specific structures due to the limited character expressions, and it will be apparent to those skilled in the art that a plurality of modifications, decorations or changes may be made without departing from the principle of the present invention, and the technical features described above may be combined in a suitable manner; such modifications, variations, or combinations, or other applications of the inventive concept or technique directly without modification, are intended to be within the scope of the present invention.
Claims (8)
1. A method for synthesizing 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is characterized in that the reaction formula is shown as the formula (I):
comprises the following steps:
the method comprises the following steps: CuI was added to Compound 1 at room temperature under nitrogen
And Pd (PPh)3)4In a mixture in toluene, compound 2 is added
Et3N and TBAF, and the mixture of the three was stirred at the same temperature for 17 h; after the reaction was complete, the mixture was filtered and the filtrate was evaporated in vacuo; the residue was purified by recrystallization from an organic mixed solvent to give compound 3.
Step two: at room temperature to compound 3
To a stirred solution in DMA, CuO and Et3N were added; the reaction mixture was stirred at 130 ℃ for 17 h; after cooling to room temperature, the mixture was diluted with water and extracted three times with ethyl acetate; the combined organic layers were dried over anhydrous sodium sulfate; after filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give crude compound 4 as a pale yellow solid.
Step three: compound 4 is
Zn(CN)2And Pd (PPh)3)4The mixture in DMF was heated to 90 ℃ for 17 h; after the reaction was complete, it was cooled to room temperature, diluted with water, extracted three times with ether and Na2SO4Drying; after filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give compound 5.
Step four: mixing the compound 5
And Selectfluor in CH3CN and CH3Heating the COOH mixed solution to 80 ℃ to react for 0.5 h. After the reaction was completed, the mixture was cooled to room temperature and saturated NH was added thereto4Quench with Cl solution, extract 3 times with EtOAc and over Na2And drying the SO 4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6: 1) to give compound 6
I.e. 2, 4-fluoro-pyrrolo [1,2]]Pyrimidine-7 carbonitrile.
2. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: in the synthesis method, the organic mixed solvent in the step one is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 10: 1.
3. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: in the synthesis method, the solvent used in the gel chromatography in the step two is a mixture of petroleum ether and ethyl acetate, and the volume ratio is 20: 1.
4. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: the synthesis method comprises the step three, wherein the solvent used in the gel chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5: 1.
5. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: the synthesis method comprises the step four, wherein the solvent used in the gel chromatography is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 6: 1.
6. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: dissolving the crude compound 6 obtained in the fourth step in a solution of n-heptane and ethyl acetate 3:1, adding DCM for assisting dissolution, filtering the solution by silica gel, washing the materials by using the n-heptane and the EA 3:1 until the materials are completely washed, concentrating eluent until a large amount of solids are separated out, cooling and filtering to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, filtering to obtain solids, continuously concentrating the secondary mother liquor until the solids are separated out, and filtering to obtain the solid compound 6.
7. The method of synthesizing 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile according to claim 1, characterized in that: the synthesis method comprises the steps of carrying out suction filtration on the obtained solid compound 3, wherein the yield is over 85%; solid compound 4, yield more than 30%; solid compound 5, yield over 75%; the yield of the solid compound 6 is more than 8%.
Use of 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile in cardiovascular disorders for lowering blood pressure.
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| WO2015132133A1 (en) * | 2014-03-04 | 2015-09-11 | Syngenta Participations Ag | Microbiocidal heterobicyclic derivatives |
| WO2018068739A1 (en) * | 2016-10-13 | 2018-04-19 | 深圳市塔吉瑞生物医药有限公司 | Alkynyl heterocyclic compound for inhibiting protein kinase activity |
| WO2018116072A1 (en) * | 2016-12-20 | 2018-06-28 | Pi Industries Ltd. | Heterocyclic compounds |
| CN112574211A (en) * | 2019-09-29 | 2021-03-30 | 山东轩竹医药科技有限公司 | Heterocyclic kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015132133A1 (en) * | 2014-03-04 | 2015-09-11 | Syngenta Participations Ag | Microbiocidal heterobicyclic derivatives |
| WO2018068739A1 (en) * | 2016-10-13 | 2018-04-19 | 深圳市塔吉瑞生物医药有限公司 | Alkynyl heterocyclic compound for inhibiting protein kinase activity |
| WO2018116072A1 (en) * | 2016-12-20 | 2018-06-28 | Pi Industries Ltd. | Heterocyclic compounds |
| CN112574211A (en) * | 2019-09-29 | 2021-03-30 | 山东轩竹医药科技有限公司 | Heterocyclic kinase inhibitors |
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