CN115043780A - Synthesis method and application of 4-hydroxy-5-fluoro-6-ethylpyrimidine - Google Patents
Synthesis method and application of 4-hydroxy-5-fluoro-6-ethylpyrimidine Download PDFInfo
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- BYTNEISLBIENSA-MDZDMXLPSA-N GW 4064 Chemical compound CC(C)C=1ON=C(C=2C(=CC=CC=2Cl)Cl)C=1COC(C=C1Cl)=CC=C1\C=C\C1=CC=CC(C(O)=O)=C1 BYTNEISLBIENSA-MDZDMXLPSA-N 0.000 title claims abstract description 47
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 38
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims abstract description 24
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 claims abstract description 24
- LELZLAXCAOPNFN-UHFFFAOYSA-N CCC(C1(F)F)NC=NC1=O Chemical compound CCC(C1(F)F)NC=NC1=O LELZLAXCAOPNFN-UHFFFAOYSA-N 0.000 claims abstract description 21
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims abstract description 7
- 238000006683 Mannich reaction Methods 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- 239000000243 solution Substances 0.000 claims description 19
- 239000002585 base Substances 0.000 claims description 11
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000003429 antifungal agent Substances 0.000 claims description 3
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 3
- 229960004740 voriconazole Drugs 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 238000000926 separation method Methods 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 3
- VOLSXIRVBOETBC-UHFFFAOYSA-N 2,4-dichloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC(Cl)=NC(Cl)=C1F VOLSXIRVBOETBC-UHFFFAOYSA-N 0.000 description 3
- GRYASYLFKKQPPF-UHFFFAOYSA-N 2-chloro-6-ethyl-5-fluoro-1h-pyrimidin-4-one Chemical compound CCC1=NC(Cl)=NC(O)=C1F GRYASYLFKKQPPF-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 description 3
- 150000004714 phosphonium salts Chemical class 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- ULNDTPIRBQGESN-UHFFFAOYSA-N ethyl 2-bromo-2-fluoroacetate Chemical compound CCOC(=O)C(F)Br ULNDTPIRBQGESN-UHFFFAOYSA-N 0.000 description 2
- ODPHSEIVAPWGAZ-UHFFFAOYSA-N ethyl 2-fluoro-3-oxopentanoate Chemical compound CCOC(=O)C(F)C(=O)CC ODPHSEIVAPWGAZ-UHFFFAOYSA-N 0.000 description 2
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Liquid Crystal Substances (AREA)
Abstract
The invention discloses a synthesis method and application of 4-hydroxy-5-fluoro-6-ethylpyrimidine, and belongs to the technical field of compound intermediate preparation. The synthesis method comprises the steps of taking ethyl difluoroacetate (I), propionaldehyde and formamidine acetate as initial raw materials, and synthesizing an intermediate (II) through a Mannich reaction, wherein the first step is reaction. After the reaction is finished, adding sodium methoxide as a strong base solution directly without separation to carry out ring closure reaction to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III), which is the second step of reaction. And (3) directly heating without separation to remove the hydrogen fluoride until the reaction is completely finished to generate the target product 4-hydroxy-5-fluoro-6-ethyl pyrimidine (IV), which is the third reaction step. The synthesis method only needs a three-step one-pot method to synthesize the target product, has extremely high yield and very low cost of ethyl difluoroacetate. The yield of the target product obtained by the synthesis method reaches 76.6 percent, and the purity is not lower than 98.3 percent.
Description
Technical Field
The invention belongs to the technical field of compound intermediate preparation, and particularly relates to a synthetic method and application of 4-hydroxy-5-fluoro-6-ethylpyrimidine.
Background
4-hydroxy-5-fluoro-6-ethyl pyrimidine is an important intermediate for synthesizing antifungal drug voriconazole. The related technology discloses that 5-fluorouracil (1) is used as a raw material, 2, 4-dichloro-5-fluoropyrimidine (2) is synthesized through phosphorus oxychloride chlorination, then 2, 4-dichloro-5-fluoro-6-ethylpyrimidine (3) is synthesized through Grignard reaction and oxidation reaction, 2-chloro-4-hydroxy-5-fluoro-6-ethylpyrimidine (4) is synthesized through sodium hydroxide hydrolysis, and a target product 4-hydroxy-5-fluoro-6-ethylpyrimidine (5) is obtained through palladium carbon hydrogenation. The synthetic route of the disclosed scheme has the disadvantages of expensive raw materials, complex process and high cost, and the synthetic flow is shown as the following formula.
The related technology also discloses that bromofluoroacetic acid ethyl ester (6) and tributylphosphine are used as initial raw materials to synthesize phosphonium salt (7), then the phosphonium salt and propionyl chloride react under the action of butyl lithium to generate 2-fluoro-3-oxopentanoic acid ethyl ester (8), and then the phosphonium salt and formamidine acetate are used for synthesizing a target compound 4-hydroxy-5-fluoro-6-ethylpyrimidine (5) in a sodium methoxide/methanol system. The synthetic route of the disclosed scheme has the disadvantages of expensive raw materials, harsh reaction conditions, ultra-low temperature reaction, extremely high cost and synthetic flow shown as the following formula.
The related technology also discloses that ethyl fluoroacetate (9) is used as an initial raw material, reacts with propionyl chloride in the presence of alkali to synthesize ethyl 2-fluoro-3-oxopentanoate (8), and then reacts with formamidine acetate in a sodium methoxide/methanol system to synthesize a target compound 4-hydroxy-5-fluoro-6-ethylpyrimidine (5). The ethyl fluoroacetate as the first raw material is reacted with propionyl chloride in the presence of alkali, wherein the alkali can be sodium hydride, sodium methoxide, sodium ethoxide and sodium hydroxide. The raw materials of the route are cheap, but the route has more side reactions, complicated treatment, low yield and low product purity, and the synthetic flow is shown as the following formula.
Disclosure of Invention
The invention aims to provide a synthesis method of 4-hydroxy-5-fluoro-6-ethylpyrimidine, which is used for solving the technical problems of complex synthesis method, high use cost of raw materials, harsh synthesis reaction conditions, low product yield and low product purity in the prior art.
The invention is realized by the following technical scheme:
a method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine comprises the following steps:
s1, Mannich reaction: mixing ethyl difluoroacetate, formamidine acetate, propionaldehyde, a solvent and an acid-base regulator, and reacting to generate an intermediate (II);
s2, ring closure reaction: the intermediate (II) reacts with a strong alkali solution to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III);
s3, heating the 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III) to remove hydrogen fluoride to generate 4-hydroxy-5-fluoro-6-ethylpyrimidine (IV);
the reaction formula of the synthesis method is as follows:
the synthesis method of the 4-hydroxy-5-fluoro-6-ethylpyrimidine is characterized in that ethyl difluoroacetate, propionaldehyde and formamidine acetate are used as initial raw materials, and an intermediate (II) is synthesized through Mannich reaction, which is the first step of reaction. After the reaction is completed, a strong base solution sodium methoxide is directly added without separation to carry out a ring closure reaction to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III)), which is the second reaction step. And (3) directly heating without separation, removing hydrogen fluoride until the reaction is completely finished to generate the target product 4-hydroxy-5-fluoro-6-ethyl pyrimidine (IV), which is the third step of reaction. The synthesis method only needs a three-step one-pot method to synthesize the target product, has extremely high yield and very low cost of ethyl difluoroacetate.
Preferably, the solvent is methanol;
preferably, the acid-base regulator is acetic acid;
preferably, the strong alkaline solution is a solution of sodium methoxide in methanol.
Sodium methoxide solution is selected as strong base so as to provide a strong reaction environment.
Preferably, the molar ratio of ethyl difluoroacetate, formamidine acetate and propionaldehyde is 1: 1.05-1.06: 1.10-1.11;
the addition amount of the acid-base regulator is until the formamidine acetate is completely dissolved.
Preferably, the mass ratio of the solvent to the ethyl difluoroacetate is 5.0-5.5: 1.
Preferably, the reaction temperature for generating the intermediate (II) is 55-60 ℃, and the reaction time is 120-140 min.
Preferably, the molar ratio of the strong base solution to ethyl difluoroacetate is 2.5: 1.
Preferably, the reaction temperature for producing 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III) is not higher than 10 ℃ and the reaction time is 30-40 min.
Preferably, when the 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III) is heated to remove hydrogen fluoride, the heating temperature is 55-60 ℃; the reaction time is 2.5-3 h.
4-hydroxy-5-fluoro-6-ethyl pyrimidine (IV) is prepared by adopting a synthesis method of 4-hydroxy-5-fluoro-6-ethyl pyrimidine.
The application of 4-hydroxy-5-fluoro-6-ethylpyrimidine (IV) is used as an intermediate in synthesizing antifungal drug voriconazole.
Compared with the prior art, the invention at least has the following technical effects:
1. the invention provides a synthesis method of 4-hydroxy-5-fluoro-6-ethylpyrimidine, which is characterized in that ethyl difluoroacetate (I), propionaldehyde and formamidine acetate are used as initial raw materials, and an intermediate (II) is synthesized through Mannich reaction, and the first step of reaction is reaction. After the reaction is completed, a strong base solution sodium methoxide is directly added without separation to carry out a ring closure reaction to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III)), which is the second reaction step. And (3) directly heating without separation, and removing hydrogen fluoride until the reaction is completely finished to generate the target product 4-hydroxy-5-fluoro-6-ethyl pyrimidine (IV), which is the third step of reaction.
2. The synthesis method only needs a three-step one-pot method to synthesize the target product, has extremely high yield and very low cost of ethyl difluoroacetate.
3. The yield of the 4-hydroxy-5-fluoro-6-ethyl pyrimidine obtained by the synthesis method reaches 76.6 percent, and the purity of the 4-hydroxy-5-fluoro-6-ethyl pyrimidine is not lower than 98.3 percent.
Drawings
FIG. 1 shows the NMR spectrum of 4-hydroxy-5-fluoro-6-ethylpyrimidine.
Detailed Description
Embodiments of the present invention will be described in detail with reference to the following examples, but those skilled in the art will understand that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention, and that the specific conditions not specified in the examples are carried out according to conventional conditions or conditions suggested by the manufacturer, and that the reagents or equipment used are not specified by the manufacturer, and are all conventional products available through commercial purchase.
The technical scheme of the invention is as follows:
adding methanol into a four-neck flask provided with a nitrogen guide pipe, a thermometer, a stirrer, a dropping device and a reflux device, starting stirring, adding formamidine acetate, propionaldehyde and acetic acid, adding ethyl difluoroacetate after the formamidine acetate is completely dissolved, and measuring the pH value to be 6.0. The temperature is increased, and the reaction is detected to be complete by gas chromatography (no ethyl difluoroacetate peak). Cooling, dropwise adding a methanol solution of sodium methoxide (the sodium methoxide is dissolved in methanol), controlling the temperature to be not more than 10 ℃ when dropwise adding is carried out, finishing dropwise adding after about 10 minutes, preserving the temperature for 30 minutes below 10 ℃ after dropwise adding is finished, and detecting complete reaction by thin-layer chromatography (TLC) (the TLC condition is that petroleum ether PE/ethyl acetate EA is 3/1) to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone. The reaction was warmed and checked by TLC (TLC conditions: methanol MeOH/dichloromethane DCM ═ 1/10, ammonia added) to give 4-hydroxy-5-fluoro-6-ethylpyrimidine. Cooling to room temperature, and dropwise adding glacial acetic acid until the reaction system is neutral. The reaction solution was spin-dried, the remaining white solid was extracted 4 times (50 ml. times.4) with ethyl acetate, the solid was filtered off each time, and the extracts were combined and spin-dried. And adding ethyl acetate, stirring, cooling, filtering, washing a filter cake with a small amount of ethyl acetate, and drying in the air. A white solid was obtained.
Example 1:
80ml of methanol was put into a four-necked flask equipped with a nitrogen introduction tube, a thermometer, a stirrer, a dropping device and a reflux device, and stirred, and formamidine acetate (10.9g, 105mmol), propionaldehyde (6.38g, 110mmol) and acetic acid (1.0ml) were added, and after formamidine acetate was completely dissolved, ethyl difluoroacetate (12.4g, 100mmol) was added to measure the pH to 6.0. The temperature is raised to 60 ℃, the reaction is carried out for 120 minutes, and the reaction is completely detected by gas chromatography (no ethyl difluoroacetate peak). Cooling to below 10 ℃, dropwise adding a methanol solution of sodium methoxide (13.5g of sodium methoxide is dissolved in 40ml of methanol, 250mmol), controlling the temperature to be below 10 ℃ when dropwise adding is carried out, finishing dropwise adding within about 10 minutes, preserving the temperature below 10 ℃ for 30 minutes after finishing dropwise adding, and detecting complete reaction by Thin Layer Chromatography (TLC) (TLC condition: petroleum ether PE/ethyl acetate EA ═ 3/1) to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone. The temperature was raised to 60 ℃ for 2.5 h, and the completion of the reaction was detected by TLC (TLC conditions: MeOH/dichloromethane DCM. RTM. 1/10, aqueous ammonia was added) to give 4-hydroxy-5-fluoro-6-ethylpyrimidine. Cooling to room temperature, and dropwise adding glacial acetic acid until the reaction system is neutral. The reaction solution was spin-dried, the remaining white solid was extracted 4 times (50 ml. times.4) with ethyl acetate, the solid was filtered off each time, and the extracts were combined and spin-dried. Then 30ml ethyl acetate is added, stirred for 10 minutes and cooled to below 10 ℃, filtered, and the filter cake is washed by a small amount of ethyl acetate and dried. 9.5g of a white solid was obtained in 76.6% yield and 98.1% purity.
Example 2:
85ml of methanol was put into a four-necked flask equipped with a nitrogen introduction tube, a thermometer, a stirrer, a dropping device and a reflux device, stirring was started, formamidine acetate (11.0g, 106mmol), propionaldehyde (6.44g, 111mmol) and acetic acid (1.0ml) were added, and after formamidine acetate was completely dissolved, ethyl difluoroacetate (12.4g, 100mmol) was added to measure the pH to 6.0. The temperature was raised to 55 ℃ and the reaction was carried out for 140 minutes and was completed by gas chromatography (no ethyl difluoroacetate peak). Cooling to below 10 ℃, dropwise adding a methanol solution of sodium methoxide (13.5g of sodium methoxide is dissolved in 40ml of methanol, 250mmol), controlling the temperature to be below 10 ℃ when dropwise adding is carried out, finishing dropwise adding within about 10 minutes, preserving the temperature for 30 minutes below 10 ℃ after dropwise adding is finished, and detecting complete reaction by Thin Layer Chromatography (TLC) (TLC condition: petroleum ether PE/ethyl acetate EA: 3/1) to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone. The temperature was raised to 60 ℃ for 2.5 h, and the completion of the reaction was detected by TLC (TLC conditions: MeOH/dichloromethane DCM. RTM. 1/10, aqueous ammonia was added) to give 4-hydroxy-5-fluoro-6-ethylpyrimidine. Cooling to room temperature, and dropwise adding glacial acetic acid until the reaction system is neutral. The reaction solution was spin-dried, the remaining white solid was extracted 4 times (50 ml. times.4) with ethyl acetate, the solid was filtered off each time, and the extracts were combined and spin-dried. Then 30ml ethyl acetate is added, stirred for 10 minutes and cooled to below 10 ℃, filtered, and the filter cake is washed by a small amount of ethyl acetate and dried. 9.4g of white solid is obtained, the yield is 75.8 percent, and the purity is more than or equal to 98.3 percent.
Example 3:
to a four-necked flask equipped with a nitrogen inlet, a thermometer, a stirrer, a dropping device, and a reflux device, 80ml of methanol was introduced, stirring was started, formamidine acetate (10.9g, 105mmol), propionaldehyde (6.38g, 110mmol), and acetic acid (2ml) were added, and after formamidine acetate was completely dissolved, ethyl difluoroacetate (12.4g, 100mmol) was added. The pH was measured to be 6.0. The temperature is raised to 60 ℃, the reaction is carried out for 120 minutes, and the reaction is completely detected by gas chromatography (no ethyl difluoroacetate peak). Cooling to below 10 ℃, dropwise adding a methanol solution of sodium methoxide (13.5g of sodium methoxide is dissolved in 40ml of methanol, 250mmol), controlling the temperature to be below 10 ℃ when dropwise adding is carried out, finishing dropwise adding within about 10 minutes, preserving the temperature below 10 ℃ for 30 minutes after finishing dropwise adding, and detecting complete reaction by Thin Layer Chromatography (TLC) (TLC condition: petroleum ether PE/ethyl acetate EA ═ 3/1) to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone. The temperature was raised to 60 ℃ for 2.5 h, and the completion of the reaction was detected by TLC (TLC conditions: MeOH/dichloromethane DCM. RTM. 1/10, aqueous ammonia was added) to give 4-hydroxy-5-fluoro-6-ethylpyrimidine. Cooling to room temperature, and dropwise adding glacial acetic acid until the reaction system is neutral. The reaction solution was spin-dried, the remaining white solid was extracted 4 times (50 ml. times.4) with ethyl acetate, the solid was filtered off each time, and the extracts were combined and spin-dried. Then 30ml ethyl acetate is added, stirred for 10 minutes and cooled to below 10 ℃, filtered, and the filter cake is washed by a small amount of ethyl acetate and dried. 9.4g of white solid is obtained, the yield is 75.8 percent, and the purity is more than or equal to 98.2 percent.
Example 4: 80ml of methanol was put into a four-necked flask equipped with a nitrogen introduction tube, a thermometer, a stirrer, a dropping device and a reflux device, and stirred, and formamidine acetate (10.9g, 105mmol), propionaldehyde (6.38g, 110mmol) and acetic acid (1.0ml) were added, and after formamidine acetate was completely dissolved, ethyl difluoroacetate (12.4g, 100mmol) was added to measure the pH to 6.0. The temperature is raised to 60 ℃, the reaction is carried out for 120 minutes, and the reaction is completely detected by gas chromatography (no ethyl difluoroacetate peak). Cooling to below 10 ℃, dropwise adding a methanol solution of sodium methoxide (13.5g of sodium methoxide dissolved in 40ml of methanol, 250mmol), controlling the temperature to be below 10 ℃ when dropwise adding, finishing dropwise adding after about 10 minutes, preserving the temperature for 40 minutes below 10 ℃ after dropwise adding, and detecting the reaction completion by thin-layer chromatography (TLC) (TLC condition: petroleum ether PE/ethyl acetate EA ═ 3/1) to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone. The temperature was raised to 55 ℃ for 3 hours and the reaction was checked by TLC (TLC conditions: methanol MeOH/dichloromethane DCM ═ 1/10, ammonia added) to give 4-hydroxy-5-fluoro-6-ethylpyrimidine. Cooling to room temperature, and dropwise adding glacial acetic acid until the reaction system is neutral. The reaction solution was spin-dried, the remaining white solid was extracted 4 times (50 ml. times.4) with ethyl acetate, the solid was filtered off each time, and the extracts were combined and spin-dried. Then 30ml ethyl acetate is added, stirred for 10 minutes and cooled to below 10 ℃, filtered, and the filter cake is washed by a small amount of ethyl acetate and dried. 9.5g of a white solid was obtained in 76.6% yield and 98.3% purity.
Shown in figure 1, is the nuclear magnetic resonance hydrogen spectrum of 4-hydroxy-5-fluoro-6-ethyl pyrimidine.
Finally, it should be noted that: the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine is characterized by comprising the following steps:
s1, Mannich reaction: mixing ethyl difluoroacetate (I), formamidine acetate, propionaldehyde, a solvent and an acid-base regulator, and reacting to generate an intermediate (II);
s2, ring closure reaction: the intermediate (II) reacts with a strong alkali solution to generate 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III);
s3, heating the 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidone (III) to remove hydrogen fluoride to generate 4-hydroxy-5-fluoro-6-ethylpyrimidine (IV);
the reaction formula of the synthesis method is as follows:
2. the method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein the solvent is methanol;
preferably, the acid-base regulator is acetic acid;
preferably, the strong alkaline solution is a solution of sodium methoxide in methanol.
3. The method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein the molar ratio of ethyl difluoroacetate, formamidineacetate, and propionaldehyde is 1: 1.05-1.06: 1.10-1.11;
the addition amount of the acid-base regulator is until the formamidine acetate is completely dissolved.
4. The method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein the mass ratio of the solvent to ethyl difluoroacetate is 5.0-5.5: 1.
5. The method as claimed in claim 1, wherein the reaction temperature for the reaction to form intermediate (II) is 55-60 ℃ and the reaction time is 120-140 min.
6. The method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein a molar ratio of the strong base solution to ethyl difluoroacetate is 2.5: 1.
7. The method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein the reaction temperature for producing 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone (III) is not higher than 10 ℃ and the reaction time is 30 to 40 min.
8. The method for synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to claim 1, wherein when hydrogen fluoride is removed by heating 6-ethyl-5, 5-difluoro-5, 6-dihydro-4-pyrimidinone (III), the heating temperature is 55-60 ℃; the reaction time is 2.5-3 h.
9. 4-hydroxy-5-fluoro-6-ethylpyrimidine (IV) prepared by the method of synthesizing 4-hydroxy-5-fluoro-6-ethylpyrimidine according to any one of claims 1 to 8.
10. The application of 4-hydroxy-5-fluoro-6-ethylpyrimidine is characterized in that 4-hydroxy-5-fluoro-6-ethylpyrimidine (IV) is used as an intermediate and is applied to synthesizing antifungal drug voriconazole.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0395977A1 (en) * | 1989-04-24 | 1990-11-07 | Lonza Ag | Process for the preparation of 4-hydroxy-6-polyfluoroalkylpyrimidines |
| WO2008146914A1 (en) * | 2007-06-01 | 2008-12-04 | Mitsubishi Tanabe Pharma Corporation | Heterocyclic compound |
| US20110110957A1 (en) * | 2008-04-22 | 2011-05-12 | Stamford Andrew W | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use |
| CN102190628A (en) * | 2010-03-03 | 2011-09-21 | 浙江海翔药业股份有限公司 | Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole |
| CN103864697A (en) * | 2012-12-11 | 2014-06-18 | 润泽制药(苏州)有限公司 | Preparation method of rosuvastatin intermediate main chain alcohol |
| CN103896855A (en) * | 2014-03-17 | 2014-07-02 | 巨化集团技术中心 | Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine |
| WO2019044868A1 (en) * | 2017-08-30 | 2019-03-07 | あすか製薬株式会社 | Pyrimidine derivative |
| CN111217758A (en) * | 2020-03-18 | 2020-06-02 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine |
-
2022
- 2022-07-11 CN CN202210814955.5A patent/CN115043780B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0395977A1 (en) * | 1989-04-24 | 1990-11-07 | Lonza Ag | Process for the preparation of 4-hydroxy-6-polyfluoroalkylpyrimidines |
| WO2008146914A1 (en) * | 2007-06-01 | 2008-12-04 | Mitsubishi Tanabe Pharma Corporation | Heterocyclic compound |
| US20110110957A1 (en) * | 2008-04-22 | 2011-05-12 | Stamford Andrew W | Phenyl-substituted 2-imino-3-methyl pyrrolo pyrimidinone compounds as bace-1 inhibitors, compositions, and their use |
| CN102190628A (en) * | 2010-03-03 | 2011-09-21 | 浙江海翔药业股份有限公司 | Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole |
| CN103864697A (en) * | 2012-12-11 | 2014-06-18 | 润泽制药(苏州)有限公司 | Preparation method of rosuvastatin intermediate main chain alcohol |
| CN103896855A (en) * | 2014-03-17 | 2014-07-02 | 巨化集团技术中心 | Method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine |
| WO2019044868A1 (en) * | 2017-08-30 | 2019-03-07 | あすか製薬株式会社 | Pyrimidine derivative |
| CN111217758A (en) * | 2020-03-18 | 2020-06-02 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine |
Non-Patent Citations (2)
| Title |
|---|
| XIAOHONG CHEN ET AL.: "Regiodivergent Halogenation of Vinylogous Esters: One-Pot, Transition-Metal-Free Access to Differentiated Haloresorcinols", 《ORGANIC LETTERS》, vol. 17, pages 378 - 381 * |
| 杨 帆 等: "氟嘧菌胺的合成与生物活性", 《农 药》, vol. 52, no. 12, pages 868 - 870 * |
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