CN116178239B - Synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde - Google Patents
Synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde Download PDFInfo
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- CN116178239B CN116178239B CN202211725702.7A CN202211725702A CN116178239B CN 116178239 B CN116178239 B CN 116178239B CN 202211725702 A CN202211725702 A CN 202211725702A CN 116178239 B CN116178239 B CN 116178239B
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- MQULPEUCGKEHEG-UHFFFAOYSA-N 5-(2-fluorophenyl)-1h-pyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1 MQULPEUCGKEHEG-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 23
- -1 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile Chemical compound 0.000 claims abstract description 18
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- 239000002808 molecular sieve Substances 0.000 claims abstract description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 11
- CBLLCYODFDSRQA-UHFFFAOYSA-N 2-bromo-2-fluoro-1-phenylethanone Chemical compound FC(Br)C(=O)C1=CC=CC=C1 CBLLCYODFDSRQA-UHFFFAOYSA-N 0.000 claims abstract description 10
- ZMMOYIXZGHJMNI-UHFFFAOYSA-N 3-oxopropanenitrile Chemical compound O=CCC#N ZMMOYIXZGHJMNI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 6
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229950003825 vonoprazan Drugs 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde. Firstly, carrying out substitution reaction on 2-fluoro-alpha-bromoacetophenone and 3-oxo-propionitrile under the action of an alkaline catalyst to obtain 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile; and then carrying out hydrogenation cyclization under the catalysis of an HZSM-5 molecular sieve and a Pd-C catalyst to obtain a target product 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde. The synthesis route has short steps, low cost, simple operation and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
Background
Vonoprazan fumarate (Vonoprazan fumarate), chemical name: 1- (5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine monofumarate is mainly used for treating gastric ulcer, duodenal ulcer and erosive gastroesophageal reflux disease, is a novel oral gastric acid resistant drug developed by Japanese Wuta-Makino pharmaceutical company, and is first marketed in Japan in 12 months in 2014 under the trade name Takecab.
5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde is of great interest as a key intermediate for Vonoprazan fumarate. The synthesis method mainly comprises the following steps:
(1) In Chinese patent CN102421753A, a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is disclosed, and the synthetic route is as follows:
the synthesis route has complicated steps, uses materials such as bromine with strong corrosiveness in the synthesis process, has high requirements on equipment, is extremely inflammable in palladium-carbon and Raney nickel used in the reduction dechlorination and cyano reduction processes, has great potential safety hazard, has high danger coefficient of industrial production operation and has great environmental protection pressure.
(2) In Chinese patent CN101300229A, a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is disclosed, and the synthetic route is as follows:
the synthesis route has complicated operation, requires low-temperature reaction (-78 ℃), uses expensive catalyst tetra-n-butyl ruthenium peroxide for alcohol oxidation to aldehyde, is not easy to control, adopts column purification in multiple steps, and is not beneficial to industrial production.
(3) In Chinese patent CN102421753A, a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is disclosed, and the synthetic route is as follows:
the synthesis route has complicated operation, and the product of the first step is extremely unstable, so that the reaction of oxidizing alcohol into aldehyde is not easy to control, and the industrial production is not facilitated.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a synthesis method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which takes 2-fluoro-alpha-bromoacetophenone as an initial raw material, carries out substitution reaction with 3-oxo-propionitrile to obtain 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, and then carries out hydrogenation cyclization under Pd-C catalysis to obtain a target compound 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde. The method has the advantages of short route steps, low cost, simple and convenient operation and high yield, and is suitable for industrial production.
The technical scheme of the invention is as follows: the synthesis method of the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps of:
1) 2-fluoro-alpha-bromoacetophenone and 3-oxo-propionitrile undergo substitution reaction under the action of an alkaline catalyst to obtain 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile;
2) 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile is subjected to hydrogenation cyclization under the catalysis of an HZSM-5 molecular sieve and a Pd-C catalyst to obtain a target product 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
The synthetic route is as follows:
the method specifically comprises the following steps:
1) Adding 2-fluoro-alpha-bromoacetophenone, an alkaline catalyst and 3-oxo-propionitrile into an organic solvent, reacting for 3-6 hours at 40-60 ℃, and obtaining 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile through post-treatment;
2) Adding 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, HZSM-5 molecular sieve and Pd-C catalyst into an organic solvent, stirring at 60-90 ℃ under normal pressure for reacting for 15-20H, and performing post-treatment to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
Preferably, the basic catalyst in the step 1) is triethylamine, K 2 CO 3 、Na 2 CO 3 One of, preferably K 2 CO 3 。
Preferably, the organic solvent in the step 1) is ethyl acetate, methyl acetate, acetone, etc., more preferably ethyl acetate; the organic solvent in the step 2) is 1, 4-dioxane, methanol, tetrahydrofuran or the like, and more preferably 1, 4-dioxane.
Preferably, the Pd-C catalyst in the step 2) is Pd-C/H 2 、Pd-C/HCOOH、Pd-C/NaH 4 PO 3 One of them, preferably 10% Pd-C/H 2 。
Preferably, in the step 1), the molar ratio of the 2-fluoro-alpha-bromoacetophenone to the 3-oxo-propionitrile to the basic catalyst is 1:1.0 to 1.2:1.1 to 1.3, preferably 1:1.1:1.2.
preferably, the mass ratio of 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, HZSM-5 molecular sieve and 10% Pd-C in the step 2) is 1:0.5 to 0.8:0.05 to 0.2, preferably 1:0.6:0.1.
the post-treatment of the step 1) is as follows: cooling after the reaction is finished, and dropwise adding a hydrochloric acid solution to quench the reaction; separating, washing and drying an organic phase, concentrating filtrate under reduced pressure until the filtrate is dried, adding a mixed solvent of isopropyl alcohol and water (the volume ratio is preferably 1:1), removing impurities, carrying out suction filtration, and drying to obtain the 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile.
The post-treatment of the step 2) is as follows: after the reaction is finished, cooling to room temperature, filtering Pd-C and molecular sieve, dripping water into the filtrate, cooling to 0-10 ℃, stirring for crystallization, filtering, and drying to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
The invention has the technical effects that: the method obtains the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde through two steps of reactions, has short route steps, low cost, simple and convenient operation and high yield, and is suitable for industrial production.
Drawings
FIG. 1 shows 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde prepared in example 1 of the present invention 1 H NMR spectrum;
FIG. 2 is a liquid phase diagram of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde prepared in example 1 of the present invention.
Detailed Description
The invention will be further described with reference to examples and figures.
Example 1
1) Synthesis of 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile
3.5g of 3-oxo-propionitrile, 40mL of ethyl acetate and 7.6g of potassium carbonate are added into a 250mL reaction bottle, stirring is started, ethyl acetate (40 mL) solution of 2-fluoro-alpha-bromoacetophenone (10 g) is dropwise added, and the temperature is raised to 50 ℃ for reaction for 5-6 h. After the reaction was completed, the temperature was lowered to 0℃and 30mL of 5% HCl was added dropwise to quench the reaction. Separating the organic phase with saturated NaHCO in sequence 3 Washing with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, concentrating the filtrate under reduced pressure until the filtrate is dried, adding 10mL of isopropanol and 10mL of water into the concentrate, stirring for 1h at 15-25 ℃, carrying out suction filtration, and drying to obtain 8.3g of light yellow solid, wherein the yield is 88.0%, and the purity is 99.1%.
2) Synthesis of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
To a 250mL reaction flask, 8g of 4- (2-fluorophenyl) -2-formyl-4-oxobutyronitrile, 4.8g of HZSM-5, 100mL of 1, 4-dioxane and 0.8g of 10% palladium on carbon were charged, stirring was started, nitrogen was replaced 3 times, and the reaction was stirred at 80℃for 18 hours under a hydrogen atmosphere (1 atm). After the reaction is finished, the temperature is reduced to room temperature, pd-C and molecular sieve are filtered, 100mL of water is dripped into the filtrate, the temperature is controlled between 15 and 25 ℃, the mixture is stirred for 1h, the temperature is reduced to between 0 and 10 ℃, the mixture is stirred and crystallized for 1h, the mixture is filtered and dried, and 6.8g of pale yellow solid is obtained, the yield is 92.2 percent, and the purity is 99.42 percent (shown in figure 2).
As shown in FIG. 1, the product 1 H NMR(400MHz,DMSO)δ12.17(s,1H),9.77(s,1H),7.83(d,J＝1.5Hz,1H),7.82-7.74(m,1H),7.43-7.15(m,3H),6.91(dd,J＝2.8,1.6Hz,1H)。
Example 2
1) Synthesis of 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile
To a 250mL reaction flask, 4.2g of 3-oxopropionitrile, 50mL of ethyl acetate and 7.0g of sodium carbonate were added, stirring was started, and a solution of 2-fluoro-alpha-bromoacetophenone (12 g) in ethyl acetate (50 mL) was added dropwise, and the temperature was raised to 50℃to react for 5-6 hours. After the reaction was completed, the temperature was lowered to 0℃and 40mL of 5% HCl was added dropwise to quench the reaction. Separating the organic phase with saturated NaHCO in sequence 3 Washing with saturated NaCl solution, anhydrous Na 2 SO 4 Drying, concentrating the filtrate under reduced pressure until the filtrate is dried, adding 15mL of isopropanol and 15mL of water into the concentrate, stirring for 1h at the temperature of 18-25 ℃, carrying out suction filtration, and drying to obtain 10.2g of light yellow solid, wherein the yield is 89.9%, and the purity is 99.0%.
2) Synthesis of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
To a 250mL reaction flask, 10g of 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, 6g of HZSM-5, 100mL of 1, 4-dioxane and 1g of 10% palladium on carbon were added, stirring was started, nitrogen was replaced 3 times, and the reaction was stirred at 80℃for 18 hours under a hydrogen atmosphere (1 atm). After the reaction is finished, cooling to room temperature, filtering Pd-C and molecular sieve, dripping 100mL of water into the filtrate, stirring for 1h at 15-25 ℃, cooling to 0-10 ℃, stirring for crystallization for 1h, filtering, and drying to obtain 8.5g of pale yellow solid, wherein the yield is 91.9%, and the purity is 99.5%.
Claims (10)
1. The synthesis method of the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps of:
1) 2-fluoro-alpha-bromoacetophenone and 3-oxo-propionitrile undergo substitution reaction under the action of an alkaline catalyst to obtain 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile;
2) 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile is subjected to hydrogenation cyclization under the catalysis of an HZSM-5 molecular sieve and a Pd-C catalyst to obtain a target product 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
2. The synthesis method according to claim 1, characterized in that it comprises the following steps:
1) Adding 2-fluoro-alpha-bromoacetophenone, an alkaline catalyst and 3-oxo-propionitrile into an organic solvent, reacting for 3-6 hours at 40-60 ℃, and obtaining 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile through post-treatment;
2) Adding 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, HZSM-5 molecular sieve and Pd-C catalyst into an organic solvent, stirring at 60-90 ℃ under normal pressure for reacting for 15-20H, and performing post-treatment to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
3. The synthesis method according to claim 1 or 2, wherein the basic catalyst in step 1) is triethylamine, K 2 CO 3 、Na 2 CO 3 One of them.
4. The synthetic method according to claim 1 or 2, wherein the Pd-C catalyst in step 2) is Pd-C/H 2 、Pd-C/HCOOH、Pd-C/NaH 4 PO 3 One of them.
5. The synthesis method according to claim 2, wherein the organic solvent in the step 1) is one or more of ethyl acetate, methyl acetate and acetone.
6. The synthesis method according to claim 2, wherein the organic solvent in the step 2) is one or more of 1, 4-dioxane, methanol and tetrahydrofuran.
7. The synthesis method according to claim 2, wherein in step 1), the molar ratio of 2-fluoro-alpha-bromoacetophenone, 3-oxopropionitrile to basic catalyst is 1:1.0 to 1.2:1.1 to 1.3.
8. The synthesis method according to claim 2, wherein in step 2), the mass ratio of 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile, HZSM-5 molecular sieve and 10% pd-C is 1:0.5 to 0.8:0.05 to 0.2.
9. The synthesis method according to claim 2, wherein the post-treatment of step 1) is: cooling after the reaction is finished, and dropwise adding a hydrochloric acid solution to quench the reaction; separating, washing and drying an organic phase, concentrating filtrate under reduced pressure until the filtrate is dried, adding a mixed solvent of isopropyl alcohol and water for removing impurities, carrying out suction filtration, and drying to obtain the 4- (2-fluorophenyl) -2-formyl-4-oxo-butyronitrile.
10. The synthesis method according to claim 2, wherein the post-treatment of step 2) is: after the reaction is finished, cooling to room temperature, filtering Pd-C and molecular sieve, dripping water into the filtrate, cooling to 0-10 ℃, stirring for crystallization, filtering, and drying to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
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| CN116178239B true CN116178239B (en) | 2024-03-29 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN112194607A (en) * | 2020-08-27 | 2021-01-08 | 河北科博莱特医药科技有限公司 | Synthetic method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
| CN113651746A (en) * | 2021-08-16 | 2021-11-16 | 杭州煌森生物科技有限公司 | Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102421753A (en) * | 2009-02-25 | 2012-04-18 | 武田药品工业株式会社 | Process for producing pyrrole compound |
| CN112194607A (en) * | 2020-08-27 | 2021-01-08 | 河北科博莱特医药科技有限公司 | Synthetic method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
| CN113651746A (en) * | 2021-08-16 | 2021-11-16 | 杭州煌森生物科技有限公司 | Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde |
Non-Patent Citations (1)
| Title |
|---|
| "Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmetha namine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)";Arikawa, Yasuyoshi, et al.;《Journal of Medicinal Chemistry》;20120418;第55卷(第9期);第4446-4456页 * |
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