CN113845459B - Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde - Google Patents
Preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde Download PDFInfo
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- CN113845459B CN113845459B CN202111197834.2A CN202111197834A CN113845459B CN 113845459 B CN113845459 B CN 113845459B CN 202111197834 A CN202111197834 A CN 202111197834A CN 113845459 B CN113845459 B CN 113845459B
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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 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000001914 filtration Methods 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 18
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000006722 reduction reaction Methods 0.000 claims abstract description 18
- MAEGBEZYSAHLLL-UHFFFAOYSA-N 2-(2-fluorobenzoyl)propanedinitrile Chemical compound Fc1ccccc1C(=O)C(C#N)C#N MAEGBEZYSAHLLL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 238000005406 washing Methods 0.000 claims abstract description 11
- 229960000583 acetic acid Drugs 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000004537 pulping Methods 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 238000005070 sampling Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000012544 monitoring process Methods 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 4
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 9
- 239000000243 solution Substances 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
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- 238000005580 one pot reaction Methods 0.000 abstract description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 10
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000005485 electric heating Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 230000007704 transition Effects 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- QMATYTFXDIWACW-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1F QMATYTFXDIWACW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- 238000001704 evaporation Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 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 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001914 gastric parietal cell Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- 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
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- 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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Abstract
The invention relates to a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which comprises the following steps: dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing hydrogen, heating, and performing a first reduction reaction; after the reaction is finished, cooling, filtering, adding Raney nickel and water into the reaction solution, vacuumizing, replacing with hydrogen, preserving heat, and carrying out a second reduction reaction; and after the reaction is finished, filtering, concentrating the filtrate under reduced pressure, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde. The method takes 2- (2-fluorobenzoyl) malononitrile as a raw material to synthesize the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by a one-pot method, avoids the separation process of multi-step intermediates, reduces the generation of three wastes, is environment-friendly, reduces the cost, is beneficial to industrial mass production, and has high yield and purity of the obtained product.
Description
Technical Field
The invention relates to the field of chemical pharmaceutical preparations, and in particular relates to a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
Background
Fu Nuola crude fumaric acid, chemical name: 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate is a potassium ion competitive acid blocker developed by Wuta, japan (Takeda), a new drug application is filed in 3 months in 2014 in Tokyo province, the drug has a strong and durable gastric acid secretion inhibition effect, and simultaneously has an early termination effect on gastric acid secretion by inhibiting the binding effect of K on H, K-ATP enzyme (proton pump) in the last step of gastric acid secretion of gastric parietal cells, and the drug is used for treating gastric ulcer, duodenal ulcer, reflux esophagitis and the like.
The 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is an important intermediate of Voranolan fumarate, so that a new synthesis process is developed, the cost is reduced, the operation is simplified, the yield is improved, and the method has important significance for realizing industrial production, and has the following structure:
the synthesis methods for preparing the compound I in the prior art mainly comprise the following two methods:
scheme (1) patent EP2327692 reports a process for the preparation of compound I, which synthetic scheme is as follows:
scheme (2) patent WO2010098351 also reports a process for the preparation of compound I, which is synthesized as follows:
in the route (1), o-fluoro acetophenone is used as a starting material, and the compound I is obtained through bromination, substitution condensation, palladium-carbon dechlorination, DIBAL reduction and oxidation.
Route (2) also uses o-fluoro acetophenone as starting material, and unlike the above method, cyano group is used to replace ethyl ester group, and the target product is directly obtained by Raney nickel reduction. The method is still long, although the steps are reduced. The method has the advantages of long steps, generation of a large amount of organic solvent waste liquid, low total yield, high cost and no contribution to industrial mass production.
The comparison of the two routes shows that although the reaction steps are reduced in the route (2), the operation steps are more generally, a large amount of organic solvent waste liquid is generated, the total yield is low, the cost is higher, and the method is not beneficial to industrial mass production.
Disclosure of Invention
In order to solve the problems in the background art, the invention provides a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
The invention provides a preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde, which comprises the following steps:
dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, heating, and performing a first reduction reaction;
after the first reduction reaction is finished, cooling to below 30 ℃, filtering to remove the metal catalyst, transferring the reaction liquid into a clean reaction kettle, adding Raney nickel and water, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, preserving heat, and carrying out the second reduction reaction;
and after the second reduction reaction is finished, filtering to remove Raney nickel, washing the Raney nickel by tetrahydrofuran, concentrating the filtrate under reduced pressure until a large amount of solids appear, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
The reaction route of the invention is as follows:
preferably, the plastid ratio of the 2- (2-fluorobenzoyl) malononitrile to the solvent in the step (1) is 1:5, the solvent is one or more of tetrahydrofuran, acetonitrile, acetone, pyridine and dimethyl sulfoxide, and the metal catalyst is one or more of 10% palladium carbon, platinum carbon, palladium hydroxide and zinc powder.
Preferably, the feeding amount of the metal catalyst in the step (1) is 3-5% of the feeding amount of the 2- (2-fluorobenzoyl) malononitrile.
Preferably, the mass ratio of the 2- (2-fluorobenzoyl) malononitrile to the glacial acetic acid in the step (1) is 1.2-1.6.
Preferably, the temperature of the first reduction reaction in the step (1) is 45-50 ℃, and the reaction time is 8-9 h.
Preferably, the judgment of the completion of the first reduction reaction in the step (2) comprises sampling for reaction monitoring, and the 2- (2-fluorobenzoyl) malononitrile is remained below 0.5%.
Preferably, the input amount of the raney nickel in the step (2) is 3-7% of the input amount of the 2- (2-fluorobenzoyl) malononitrile.
Preferably, the temperature of the second reduction reaction in the step (2) is 15-25 ℃, and the reaction time is 15-16 h.
Preferably, the determination of the completion of the second reduction reaction in step (3) includes sampling for reaction monitoring, and the generated intermediate state is less than or equal to 0.2%.
Preferably, the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution in the step (3) is 1:5, the temperature range of reduced pressure concentration is 40-45 ℃, the heat preservation temperature is 20-30 ℃, and the pulping time is 3-4 h.
In summary, the invention has the following beneficial technical effects:
the invention uses the intermediate 2- (2-fluorobenzoyl) malononitrile as a raw material to carry out the process for synthesizing the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by the one-pot method, avoids the separation process of multi-step intermediates, greatly reduces the generation of three wastes, is environment-friendly, improves the yield, reduces the cost, simplifies the steps, is beneficial to industrial mass production, and has high yield and purity of the obtained product.
Drawings
FIG. 1 is a high performance liquid chromatogram of example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of example 2 of the present invention;
FIG. 3 is a high performance liquid chromatogram of example 3 of the present invention;
FIG. 4 is a hydrogen spectrum of example 1 of the present invention;
FIG. 5 is a primary mass spectrum of example 1 of the present invention;
FIG. 6 is a secondary mass spectrum of example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
Adding 20g of 2- (2-fluorobenzoyl) malononitrile (compound II), 100mL of tetrahydrofuran, 25g of glacial acetic acid and 1g of 10% palladium-carbon into a 250mL reaction kettle, vacuumizing and replacing for 3 times, hydrogenating by using a double-layer balloon under the pressure of 0.01Mpa, heating to 47 ℃, and preserving heat for reacting for 9 hours; sampling for reaction monitoring, wherein the compound II is 0.12% remained, cooling to below 30 ℃, filtering to remove palladium carbon, transferring the reaction solution into a clean reaction kettle, adding 1g of Raney nickel and 20ml of purified water, vacuumizing and replacing for 3 times, pressurizing to 0.01Mpa, keeping the temperature at 20 ℃, and reacting for 16 hours; sampling and detecting, wherein 0.09% of intermediate transition state is remained, the purity of the reaction liquid is 96.23%, filtering to remove Raney nickel, washing with 10ml of tetrahydrofuran, decompressing and concentrating the filtrate at 40 ℃, evaporating until no liquid flows out basically, cooling to 30 ℃, dropwise adding tetrahydrofuran aqueous solution of 20ml of tetrahydrofuran and 100ml of purified water, keeping the temperature at 20 ℃, stirring for 4H, filtering, washing the filter cake with 20ml of water to obtain 25.32g of brown yellow solid wet product, and drying by electric heating and blowing at 50 ℃ to obtain 17.58g of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde (compound I), the molar yield is 87.42%, the purity is detected by high performance liquid chromatography, the chromatogram is shown in figure 1, the detected purity is 99.49%, the primary mass spectrogram is shown in figure 5, the secondary mass spectrogram is shown in figure 6, and the hydrogen is shown in figure 4.
1H-NMR(600MHz,DMSO)，δ(ppm)：6.9(dd,J＝1.8Hz,J＝2.4Hz,1H),7.27-7.35(m,3H),7.77(td,J＝7.8Hz,J＝1.8Hz,1H)7.82(d,J＝1.8Hz,1H)9.76(s,1H)12.14(brs,1H)。
Example 2
Adding 200g of a compound II into a 2L high-pressure kettle, adding 1000mL of acetonitrile and 320g of glacial acetic acid, adding 10g of platinum carbon, vacuumizing, replacing 3 times with nitrogen, then vacuumizing, pressurizing hydrogen to 0.10Mpa, heating to 45 ℃, preserving heat, reacting for 8 hours, and pressurizing to 0.1Mpa when the pressure is reduced to 0.01 Mpa; sampling for reaction monitoring, wherein the compound II is 0.09 percent remained, the reaction liquid is cooled to below 30 ℃, filtering is carried out to remove platinum and carbon, the reaction liquid is transferred into a clean reaction kettle, 14g of Raney nickel and 200ml of purified water are added, vacuumizing is carried out for 3 times by replacing with nitrogen, vacuumizing is carried out again, hydrogen is pressurized to 0.10Mpa, the temperature is kept at 25 ℃, the reaction is carried out for 15 hours, and when the hydrogen pressure is reduced to 0.02Mpa, the pressure is pressurized to 0.10Mpa; sampling and detecting, wherein 0.08% of intermediate transition state is remained, the purity of the reaction liquid is 96.63%, raney nickel is removed by filtering, after 100ml of tetrahydrofuran is used for washing, the filtrate is decompressed and concentrated at 45 ℃, the liquid is evaporated till no liquid flows out basically, the temperature is reduced to 30 ℃,200ml of tetrahydrofuran and 1000ml of purified water are added dropwise, the temperature is kept at 30 ℃, the mixture is stirred for 4 hours, the filtering is carried out, the filter cake is washed by 200ml of water, 257.78g of brown yellow solid wet product is obtained, and after 50 ℃, electric heating forced air drying is carried out, compound I177.45 g is obtained, the molar yield is 88.24%, the purity is detected by high performance liquid chromatography, as shown in a chromatogram 2, and the detected purity is 99.41%.
Example 3
Adding 1kg of compound II into a 10L high-pressure kettle, adding 5L of acetone and 1.3kg of glacial acetic acid, adding 30g of palladium hydroxide, vacuumizing, replacing 3 times with nitrogen, vacuumizing again, pressurizing hydrogen to 0.25Mpa, heating to 50 ℃, preserving heat, reacting for 8 hours, and pressurizing to 0.25Mpa when the pressure of the hydrogen is reduced to 0.02 Mpa; sampling for reaction monitoring, wherein the compound II is 0.08 percent remained, cooling to below 30 ℃, filtering to remove palladium hydroxide, transferring the reaction solution into a clean high-pressure kettle again, adding 30g of Raney nickel and 1kg of purified water, vacuumizing, replacing for 3 times by nitrogen, vacuumizing again, pressurizing hydrogen to 0.25Mpa, preserving the temperature at 15 ℃, reacting for 16h, and pressurizing to 0.25Mpa when the hydrogen pressure is reduced to 0.02 Mpa; sampling and detecting, wherein 0.06% of intermediate transition state is remained, the purity of the reaction solution is 95.33%, filtering to remove Raney nickel, washing with 500ml of tetrahydrofuran, decompressing and concentrating the filtrate at 40 ℃, evaporating until no liquid flows out basically, cooling to 25 ℃, dropwise adding 1L of tetrahydrofuran and 5L of tetrahydrofuran aqueous solution of purified water, keeping the temperature at 25 ℃, stirring for 3h, filtering, washing the filter cake with 500ml of water to obtain 1021.21g of brown yellow solid wet product, and drying by electric heating blowing at 50 ℃ to obtain 889.56g of compound I, the molar yield is 88.47%, detecting the purity by high performance liquid chromatography, and the chromatogram is shown in figure 3, and the detected purity is 99.19%.
Example 4
Adding 500L of tetrahydrofuran into a 1000L reaction kettle, adding 100kg of a compound II under stirring, adding 3kg of 10% palladium carbon and 135kg of glacial acetic acid, vacuumizing, replacing for 3 times by nitrogen, vacuumizing again, pressurizing to 0.20Mpa by hydrogen, heating to 45 ℃, preserving heat, stirring, reacting, pressurizing to 0.20Mpa when the pressure is reduced to 0.02Mpa, and preserving heat for 9 hours; sampling for reaction monitoring, wherein the compound II is 0.10% in rest, cooling to below 30 ℃, filtering to remove palladium carbon, transferring the reaction solution into a clean reaction kettle, adding 3kg of Raney nickel and 100kg of purified water, vacuumizing, replacing for 3 times with nitrogen, vacuumizing again, pressurizing hydrogen to 0.20MPa, keeping the temperature at 25 ℃, keeping the temperature, stirring and reacting for 15 hours, and pressurizing to 0.2MPa when the pressure of the hydrogen is reduced to 0.02 MPa; sampling and detecting, wherein 0.06% of intermediate transition state is remained, the purity of reaction liquid is 96.13%, raney nickel is removed by filtering, after 40kg of tetrahydrofuran is used for washing, the filtrate is subjected to reduced pressure concentration at 45 ℃, evaporated until no liquid flows out basically, the temperature is reduced to 30 ℃, a tetrahydrofuran aqueous solution of 87kg of tetrahydrofuran and 500kg of purified water is dripped, the use time is about 2 hours, the temperature is kept at 30 ℃, stirring is carried out for 4 hours, filtering is carried out, a filter cake is washed by 200kg of water, a brown yellow solid wet product is obtained by 93kg, electric heating forced air drying is carried out at 50 ℃, 87.5kg of a compound I is obtained, the molar yield is 87.02%, and the detected purity is 99.26%.
From the examples 1 to 4, it can be seen that the method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde by the one-pot method provided by the invention is simple and convenient in technological operation, less in three wastes generated in the preparation process, less in environmental pollution, lower in cost, easy for large-scale production of products, higher in product yield and purity, more than 85% of product yield, and more than 99% of product purity.
The present embodiment is only for explaining the present invention, and it is not limited to the present invention, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present invention.
Claims (4)
1. A preparation method of 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is characterized by comprising the following steps:
(1) Dissolving 2- (2-fluorobenzoyl) malononitrile in a solvent, adding a metal catalyst and glacial acetic acid, vacuumizing, replacing with nitrogen for 3 times, pressurizing with hydrogen, heating, and carrying out a first reduction reaction at the temperature of 45-50 ℃ for 8-9 hours; the solvent is one or more of tetrahydrofuran, acetonitrile and acetone, and the mass ratio of the 2- (2-fluorobenzoyl) malononitrile to the solvent is 1:5; the metal catalyst is one or more of 10% palladium carbon, platinum carbon and palladium hydroxide, and the feeding amount of the metal catalyst is 3-5% of that of the 2- (2-fluorobenzoyl) malononitrile; the mass ratio of the 2- (2-fluorobenzoyl) malononitrile to the glacial acetic acid is 1.2-1.6;
(2) After the first reduction reaction is finished, cooling to below 30 ℃, filtering to remove the metal catalyst, transferring the reaction liquid into a clean reaction kettle, adding raney nickel and water, vacuumizing, replacing for 3 times with nitrogen, pressurizing with hydrogen, preserving heat, and carrying out a second reduction reaction at the temperature of 15-25 ℃ for 15-16 h; the feeding amount of the raney nickel is 3-7% of that of the 2- (2-fluorobenzoyl) malononitrile;
(3) And after the second reduction reaction is finished, filtering to remove Raney nickel, washing the Raney nickel by tetrahydrofuran, concentrating the filtrate under reduced pressure until a large amount of solids appear, cooling, adding a tetrahydrofuran aqueous solution, preserving heat, stirring and pulping, filtering, washing with water, and drying to obtain the 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde.
2. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: and (3) judging the completion of the first reduction reaction in the step (2) comprises sampling for reaction monitoring, wherein the 2- (2-fluorobenzoyl) malononitrile is remained to be less than 0.5%.
3. The process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde according to claim 1, wherein: and (3) judging the completion of the second reduction reaction in the step (3) comprises sampling and carrying out reaction monitoring, wherein the generated intermediate state is less than 0.2 percent.
4. The method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde according to claim 1, wherein: in the step (3), the volume ratio of tetrahydrofuran to water in the tetrahydrofuran aqueous solution is 1:5, the temperature range of decompression concentration is 40-45 ℃, the temperature of heat preservation is 20-30 ℃, and the pulping time is 3-4 h.
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