CN113307810B - Synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile - Google Patents
Synthesis method and application of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 24
- XMMFKXRGHKXAGG-UHFFFAOYSA-N 3-fluoro-1h-pyrrole Chemical compound FC=1C=CNC=1 XMMFKXRGHKXAGG-UHFFFAOYSA-N 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 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 89
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- 239000007787 solid Substances 0.000 claims description 35
- 235000019439 ethyl acetate Nutrition 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 29
- 239000003208 petroleum Substances 0.000 claims description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 238000010898 silica gel chromatography Methods 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 239000012452 mother liquor Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 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
- 239000011259 mixed solution Substances 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 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
- 229920006395 saturated elastomer Polymers 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
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 239000000463 material 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
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 6
- 238000007865 diluting Methods 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000003791 organic solvent mixture Substances 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 238000011282 treatment Methods 0.000 abstract description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 7
- 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
- 238000004519 manufacturing process Methods 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
- 206010020772 Hypertension Diseases 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000001631 hypertensive effect Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance 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
- 229940125782 compound 2 Drugs 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
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000035488 systolic blood pressure Effects 0.000 description 2
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- SJXRUKHJNKEFEC-UHFFFAOYSA-N 5-fluoro-2h-pyrazolo[3,4-b]pyridine-3-carbonitrile Chemical compound FC1=CN=C2NN=C(C#N)C2=C1 SJXRUKHJNKEFEC-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method and application of 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile, and provides a synthesis method of 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile, which is based on the development of a brand-new synthesis method to solve the defects of more reaction byproducts, low conversion rate, complex post-treatment operation, low product purity and the like in the preparation method of pharmaceutical intermediate synthesis compounds of cardiovascular disorders, and a novel general, economic, efficient and environment-friendly synthesis method is developed, 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%.
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a synthesis method and application of 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile.
Background
The present invention relates to novel active ingredient combinations consisting of other known active ingredients, known as methods of pyridine-3-carbonitrile, which compounds are useful as intermediate synthesis 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-carbonitrile of formula (la), which is useful in the synthesis of intermediate compounds of medicaments, in particular in the production of medicaments for the treatment and/or prophylaxis of cardiovascular disorders.
The active ingredients and active ingredient compositions described in the prior art have good activity but are not ideal in some cases at low application rates.
It is therefore an object of the present invention to provide novel compounds with 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, which is based on the development of a brand-new synthesis method to solve the defects of more reaction byproducts, low conversion rate, complex post-treatment operation, low product purity and the like in the preparation method of an intermediate synthetic compound of a cardiovascular disorder drug, and develops a novel general, economic, efficient and environment-friendly synthesis method, thereby achieving the product synthesis principle of easily available raw materials, low price, simple operation and less pollution, and the final preparation yield reaches more than 8 percent.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is characterized in that the reaction formula is shown as formula (I):
Comprises the following steps:
Step one: adding CuI to Compound 1 at room temperature under nitrogen And Pd (mixture of PPh 3)4 in toluene), adding Compound 2Et 3 N and TBAF, and stirring the mixture of the three at the same temperature for 17h; after the reaction was completed, 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: to Compound 3 at room temperatureTo the stirred solution in DMA, cuO and Et 3 N were added; the reaction mixture was stirred at 130 ℃ for 17h; 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 isZn (CN) 2 and Pd (mixture of PPh 3)4 in DMF was heated to 90 ℃ for 17h, after the reaction was completed, it was cooled to room temperature, diluted with water, extracted three times with diethyl ether and dried over Na 2 SO4, after filtration, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give compound 5.
Step four: compound 5And a selective fluorine reagent (SelectFluor) were heated to 80℃in a mixed solution of CH 3 CN and CH 3 COOH for 0.5h. After the reaction was cooled to room temperature, quenched with saturated NH 4 Cl solution, extracted 3 times with EtOAc and dried over Na 2SO4. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, wherein petroleum ether/ethyl acetate=6:1, to give compound 6I.e. 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile.
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.
In the synthesis method, the solvent used in the silica gel chromatography in the second step is a mixture of petroleum ether and ethyl acetate, and the volume ratio is 20:1.
In the synthesis method, the solvent used in the silica gel chromatography in the step three is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 5:1.
In the synthesis method, the solvent used in the silica gel chromatography in the fourth step is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 6:1.
Further, in the synthesis method, the crude compound 6 obtained in the step four is dissolved in a solution of n-heptane and ethyl acetate 3:1, DCM is added for assisting dissolution, the solution is filtered by silica gel, the material is washed by a solvent of n-heptane and EA3:1 until a large amount of solids are separated out, the eluent is concentrated until the solid is obtained by cooling and suction filtration, the obtained mother liquor is concentrated until the solid is separated out, the suction filtration is carried out after the solid is separated out, the secondary mother liquor is further concentrated and the solid is separated out, and the solid compound 6 is obtained by suction filtration.
Further, the synthesis method has the advantages that the yield of the solid compound 3 is more than 85%; solid compound 4, yield more than 30%; solid compound 5, yield more than 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 preparation of a medicament for use in cardiovascular disorders.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention is a four-step reaction, the yield is not lower than 8%, 2, 4-fluoro-pyrrole [1,2] pyrimidine-7 carbonitrile is synthesized for the first time, the production procedures are reduced, and the cost is reduced.
(2) The invention has the advantages of easily obtained raw materials and reagents, mild reaction conditions, easy operation of post-treatment and purification and mass production.
Detailed Description
In order that those skilled in the art may better understand the technical solution of the present invention, the description of this section is merely exemplary and explanatory and should not be construed as limiting the scope of the present invention in any way.
Example 1
A synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile, the reaction formula is shown as formula (I):
Comprises the following steps:
Step one: synthesis of Compound 3
CuI (7.2 g,39 mmol) was added to a mixture of compound 1 (36 g,126.5 mmol) and Pd (PPh 3)4 (7.3 g,6.5 mmol) in toluene (240 mL) at room temperature under nitrogen, then compound 2 (18.6 mL,126.5 mmol), et 3 N (58.5 mL,405 mmol) and TBAF (126.5 mL,126.5mmol,1M in THF) were added, and the mixture was stirred at the same temperature for 17H after the reaction was completed, the mixture was filtered and the filtrate was evaporated in vacuo to give compound 3 as a white solid (29.8 g,85% yield). 1HNMR (400 MHz, CDCl 3). Delta.2.08 (s, 3H), 8.70 (s, 2H). EI-MS:196, 117,104, 52, 64.98-100.100 ℃.
Step two: synthesis of Compound 4
To a stirred solution of compound 3 (6 g,30.5 mmol) in 128mLDMA at room temperature was added CuO (2.4 g,30.5 mmol) and Et 3 N (18 mL,125 mmol). The reaction mixture was stirred at 130℃for 17h. 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 (1.8 g,30% yield) as a pale yellow solid.
1HNMR(400MHz,CDCl3):δ6.66(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.:107-109℃.
Step three: synthesis of Compound 5
A mixture of Compound 4 (3.95 g,40 mmol), zn (CN) 2 (7.0 g,60 mmol) and Pd (PPh 3)4 (5.8 g,5 mmol) in 75 mM MF was heated to 90℃for 17h after completion of the reaction, cooled to room temperature, diluted with water, extracted three times with diethyl ether and dried over Na 2SO4 after filtration the filtrate was evaporated under reduced pressure and the residue purified by silica gel chromatography (Petroleum ether/ethyl acetate=5:1) to give Compound 5 (2.15 g,75% yield) as a pale yellow solid .1HNMR(400MHz,CDCl3):δ6.78(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.:156-158℃.
Step four: synthesis of Compound 6
Compound 5 (214.5 mg,1.5 mmol) and SelectFluor (1.1 g,3.15 mmol) were reacted in a mixed solution of CH 3 CN (30 mL) and CH 3 COOH (6 mL) heated to 80℃for 0.5h. After the reaction was cooled to room temperature, quenched with saturated NH 4 Cl solution, extracted 3 times with EtOAc and dried over Na 2SO4. 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 pale yellow solid.
1HNMR(400MHz,CDCl3):δ6.49(d,J2.8Hz,1H),7.89(s,1H),8.32(s,1H).19FNMR(376MHz,CDCl3):δ-164.65(d,J＝16.9Hz,1F),-145.4(d,J＝18.0Hz,1F).13CNMR(100MHz,CDCl3):δ88.2(s),88.4(s),88.4(s),88.5(s),94.6(s),114.8(s),131.1(s),137.8(t).EI-MS:120,105,91,77,65,58,51.HPLC:93.9％.m.p.:86-88℃.
Example 2
A synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile, the reaction formula is shown as formula (I):
Comprises the following steps:
Step one: synthesis of Compound 3
CuI (4.8 g,25.3 mmol) was added to a mixture of compound 1 (24 g,84.3 mmol) and Pd (PPh 3)4 (4.87 g,4.3 mmol) in toluene (160 mL) at room temperature under nitrogen, then compound 2 (12.4 mL,84.3 mmol), et 3 N (39 mL,270 mmol) and TBAF (84.3 mL,84.3mmol,1M in THF) were added, and the mixture was stirred at the same temperature for 17H after the reaction was completed, the mixture was filtered and the filtrate was evaporated in vacuo.
Step two: synthesis of Compound 4
To a stirred solution of compound 3 (4 g,20.3 mmol) in 256mLDMA at room temperature were added CuO (1.6 g,20.3 mmol) and Et 3 N (12 ml,83.3 mmol). The reaction mixture was stirred at 130℃for 17h. 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 (1.2 g,30% yield) as a pale yellow solid ).1HNMR(400MHz,CDCl3):δ6.66(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.:107-109℃.
Step three: synthesis of Compound 5
A mixture of compound 4 (2.63 g,13.3 mmol), zn (CN) 2 (4.67 g,40 mmol) and Pd (PPh 3)4 (3.87 g,3.33 mmol) in 50mL DM F was heated to 90℃for 17h after the reaction was completed, cooled to room temperature, diluted with water, extracted three times with diethyl ether and dried over Na 2SO4 after filtration the filtrate was evaporated under reduced pressure and the residue purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give compound 5 (1.68 g,88% yield) as a pale yellow solid.
1HNMR(400MHz,CDCl3):δ6.78(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.:156-158℃.
Step four: synthesis of Compound 6
Compound 5 (143 mg,1 mmol) and SelectFluor (0.73 g,2.1 mmol) were reacted in a mixed solution of CH 3 CN (20 mL) and CH 3 COOH (4 mL) heated to 80℃for 0.5h. After the reaction was cooled to room temperature, quenched with saturated NH 4 Cl solution, extracted 3 times with EtOAc and dried over Na 2SO4. 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 pale yellow solid .1HNMR(400MHz,CDCl3):δ6.49(d,J＝2.8Hz,1H),7.89(s,1H),8.32(s,1H).19FNMR(376MHz,CDCl3):δ-164.65(d,J＝16.9Hz,1F),-145.4(d,J＝18.0Hz,1F).13CNMR(100MHz,CDCl3):δ88.2(s),88.4(s),88.4(s),88.5(s),94.6(s),114.8(s),131.1(s),137.8(t).EI-MS:120,105,91,77,65,58,51.HPLC:93.9％.m.p.:86-88℃.
And simultaneously, dissolving the crude compound 6 obtained in the step four in a solution of n-heptane and ethyl acetate 3:1, adding DCM to assist in dissolving, filtering the solution by using silica gel, washing the material by using a solvent of n-heptane and EA3:1 until a large amount of solids are separated out, cooling and suction-filtering the eluent to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, suction-filtering the mother liquor to obtain solids, continuously concentrating the secondary mother liquor, separating out solids, and suction-filtering the solid compound 6.
Biological experiments
The procedure for testing the antihypertensive activity of this compound in the above model was performed in hypertensive rats produced by chronic infusion of ouabain, as follows: systolic pressure (SBP) and Heart Rate (HR) were measured by the indirect tail sleeve (indirecttailcuff) method. Hypotension of the inventive composition 2,4 fluoro-pyrrolo [1,2] pyrimidine-7 carbonitrile was detected in hypertensive ouabain-sensitive rats. The compound was suspended in 0.3% (w/v) methylcellulose and administered orally for 3 weeks at a daily dose of 7 μg/kg/day. SBP and HR were detected 5 hours after treatment weekly. For comparison, hypertensive ouabain-sensitive rats and non-hypertensive rats, both treated with only 0.3% (w/v) methylcellulose. As shown in Table 1 below, the data were averaged and the blood pressure (170 mmHg) of the ouabain-sensitive rats treated with the compounds of the present invention was reduced almost to the level of the control rats (154 mmHg).
TABLE 1 systolic blood pressure decrease in the 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 have been described herein with reference to specific examples, the description of which is intended only to facilitate an understanding of the method of the present invention and its core ideas. The foregoing is merely illustrative of the preferred embodiments of this invention, and it is noted that there is objectively no limit to the specific structure disclosed herein, since numerous modifications, adaptations and variations can be made by those skilled in the art without departing from the principles of the invention, and the above-described features can be combined in any suitable manner; such modifications, variations and combinations, or the direct application of the inventive concepts and aspects to other applications without modification, are contemplated as falling within the scope of the present invention.
Claims (8)
1. A synthesis method of 2, 4-fluoro-pyrrole [1,2] pyrimidine-7-carbonitrile is characterized in that the reaction formula is shown as formula (I):
Comprises the following steps:
Step one: adding CuI to Compound 1 at room temperature under nitrogen And Pd (mixture of PPh 3)4 in toluene), adding Compound 2Et 3 N and TBAF, and stirring the mixture of the three at the same temperature for 17h; after the reaction was completed, the mixture was filtered and the filtrate was evaporated in vacuo; purifying the residue by recrystallization from an organic solvent mixture to give compound 3;
step two: to Compound 3 at room temperature To the stirred solution in DMA, cuO and Et 3 N were added; the reaction mixture was stirred at 130 ℃ for 17h; 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 Heating a mixture of Zn (CN) 2 and Pd (PPh 3)4 in DMF to 90 ℃ for 17h, cooling to room temperature after the reaction, diluting with water, extracting three times with diethyl ether, drying with Na 2SO4, filtering, evaporating the filtrate under reduced pressure, and purifying the residue by silica gel chromatography to obtain a compound 5;
step four: compound 5 And optionally fluorogenic reagent in a mixed solution of CH 3 CN and CH 3 COOH heated to 80 ℃ for 0.5h, after the reaction was completed and the mixture cooled to room temperature, it was quenched with saturated NH 4 Cl solution, extracted 3 times with EtOAc, dried over Na 2SO4, the solvent removed in vacuo and the residue purified by silica gel chromatography, wherein petroleum ether/ethyl acetate=6:1, to give the compound
6I.e. 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile.
2. The method for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: 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 for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: in the synthesis method, the solvent used in the silica gel chromatography in the second step is a mixture of petroleum ether and ethyl acetate, and the volume ratio is 20:1.
4. The method for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: in the synthetic method, the solvent used in the silica gel chromatography in the step three is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 5:1.
5. The method for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: in the synthesis method, the solvent used in the silica gel chromatography in the fourth step is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 6:1.
6. The method for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: dissolving the crude compound 6 obtained in the step four in a solution of n-heptane and ethyl acetate 3:1, adding DCM to assist dissolution, filtering the solution with silica gel, washing the material with a solvent of n-heptane and EA3:1 until a large amount of solids are separated out, cooling and suction-filtering the eluent to obtain solids, concentrating the obtained mother liquor until a large amount of solids are separated out, suction-filtering the obtained mother liquor to obtain solids, continuously concentrating the secondary mother liquor, separating out solids, and suction-filtering the secondary mother liquor to obtain the solid compound 6.
7. The method for synthesizing 2, 4-fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile according to claim 1, wherein: the synthesis method has the advantages that the yield of the solid compound 3 is more than 85%; solid compound 4, yield more than 30%; solid compound 5, yield more than 75%; the yield of the solid compound 6 is more than 8%.
Use of 8.2,4 fluoro-pyrrolo [1,2] pyrimidine-7-carbonitrile for the preparation of a medicament for use in cardiovascular disorders.
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