CN111217758A - Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine - Google Patents
Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine Download PDFInfo
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- CN111217758A CN111217758A CN202010193055.4A CN202010193055A CN111217758A CN 111217758 A CN111217758 A CN 111217758A CN 202010193055 A CN202010193055 A CN 202010193055A CN 111217758 A CN111217758 A CN 111217758A
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- chloropyrimidine
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- LKTGVRWVTAJGMS-UHFFFAOYSA-N 4-chloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC(Cl)=C1F LKTGVRWVTAJGMS-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000002994 raw material Substances 0.000 claims abstract description 20
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims abstract description 16
- WCXWRFSKLBACLE-UHFFFAOYSA-N 5-chloro-6-ethyl-1h-pyrimidin-4-one Chemical compound CCC1=NC=NC(O)=C1Cl WCXWRFSKLBACLE-UHFFFAOYSA-N 0.000 claims abstract description 15
- ZEMRCKIJEFNNCO-UHFFFAOYSA-N 6-ethyl-5-fluoro-1h-pyrimidin-4-one Chemical compound CCC=1NC=NC(=O)C=1F ZEMRCKIJEFNNCO-UHFFFAOYSA-N 0.000 claims abstract description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000011698 potassium fluoride Substances 0.000 claims abstract description 8
- 235000003270 potassium fluoride Nutrition 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims description 14
- 238000005660 chlorination reaction Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 6
- GEMFOQNVIPGLNR-UHFFFAOYSA-N ethyl 2-chloro-3-oxopentanoate Chemical compound CCOC(=O)C(Cl)C(=O)CC GEMFOQNVIPGLNR-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical group Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- HQKDHMCNAMQTFI-UHFFFAOYSA-N methyl 2-chloro-3-oxopentanoate Chemical compound CCC(=O)C(Cl)C(=O)OC HQKDHMCNAMQTFI-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 18
- 230000008901 benefit Effects 0.000 abstract description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 abstract description 3
- -1 after ring closing Substances 0.000 abstract description 2
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 abstract description 2
- 229960001372 aprepitant Drugs 0.000 abstract description 2
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 2
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 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 description 4
- 229960004740 voriconazole Drugs 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical class C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 241000041810 Mycetoma Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- CCUTVTFBCKCUPH-UHFFFAOYSA-N ethyl 4-chloro-3-oxopentanoate Chemical compound CCOC(=O)CC(=O)C(C)Cl CCUTVTFBCKCUPH-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- BRKFQVAOMSWFDU-UHFFFAOYSA-M tetraphenylphosphanium;bromide Chemical compound [Br-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BRKFQVAOMSWFDU-UHFFFAOYSA-M 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- 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
- C07D239/30—Halogen atoms or nitro radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine, which comprises the following steps: preparing 6-ethyl-5-chloro-4-hydroxypyrimidine; preparing 6-ethyl-5-fluoro-4-hydroxypyrimidine; finally, 6-ethyl-5-fluoro-4-chloropyrimidine is obtained. The invention takes cheap a-chloro propionyl ethyl acetate or a-chloro propionyl methyl acetate as raw materials, after ring closing, potassium fluoride is used for fluoro, and finally thionyl chloride is used for chloro to obtain high-yield 6-ethyl-5-fluoro-4-chloropyrimidine, the reaction steps are simple, easy to control and suitable for industrial production, thereby providing a more valuable synthetic route for preparing aprepitant, bringing good social benefit and economic benefit and having great economic value potential.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine for synthesizing voriconazole intermediates.
Background
The voriconazole developed by the American Ginese corporation is a fluconazole derivative, is used for treating acute and chronic deep fungal infection, has good antibacterial activity on acute invasive aspergillus, severe invasive candida of fluconazole resistance, esophagococcus, mycetoma and fusarium, has the characteristics of wide antibacterial spectrum and strong antibacterial effect, and is widely concerned as a novel broad-spectrum triazole antifungal medicine.
6-ethyl-5-fluoro-4-chloropyrimidine is a key intermediate for synthesizing voriconazole, and most of the current synthetic routes of voriconazole need to pass through the intermediate.
Regarding the synthesis method of 6-ethyl-5-fluoro-4-chloropyrimidine, the following are the most common in the prior literature: (1) WO9706160PCT published by the Perey company discloses that 5-fluorouracil is used as a raw material, phosphorus oxychloride is firstly used for chlorination, then ethyl is formed, then the raw material is oxidized into a pyrimidine ring, and then the 6-ethyl-5-fluoro-4-chloropyrimidine is obtained through catalytic dechlorination, and the method has the defects that: the reaction conditions are harsh, the price of the initial raw materials is high, the oxidation is difficult, noble metals are used, the cost of the route is high, the actual operation difficulty is large, and the industrialization is not suitable; (2) in EP0440372, ethyl levulinoacetate is used as a starting material, sodium methoxide is used as a base, and the starting material and formamidine acetate are directly cyclized to obtain 6-ethyl-5-fluoro-4-hydroxypyrimidine.
Disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine, which aims to solve the technical problems that: the preparation method of the 6-ethyl-5-fluoro-4-chloropyrimidine has the advantages of easily obtained raw materials, simple route, high yield, mild reaction conditions, easiness in control and suitability for large-scale industrialization.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine,
the synthesis path is as follows:
the preparation method comprises the following steps:
preparation of Q1, 6-ethyl-5-chloro-4-hydroxypyrimidine:
under the reaction temperature, performing cyclization reaction on a reaction raw material A which is ethyl 2-chloro-3-oxopentanoate and a reaction raw material B which is formamidine acetate in a reaction solvent under the action of alkali for 10-24 hours, and distilling, extracting and recrystallizing to obtain a product 6-ethyl-5-chloro-4-hydroxypyrimidine;
preparation of Q2, 6-ethyl-5-fluoro-4-hydroxypyrimidine:
reacting 6-ethyl-5-chloro-4-hydroxypyrimidine with potassium fluoride in a reaction solvent for 18-24 hours at 240-250 ℃, and distilling, extracting and recrystallizing to obtain 6-ethyl-5-fluoro-4-hydroxypyrimidine;
preparation of Q3, 6-ethyl-5-fluoro-4-chloropyrimidine:
the 6-ethyl-5-fluoro-4-hydroxypyrimidine and a chlorinated reagent are subjected to chlorination reaction in a reaction solvent and a catalyst to generate 6-ethyl-5-fluoro-4-chloropyrimidine, the chlorination reaction temperature is 80-90 ℃, the reaction time is 8-12 hours, and the 6-ethyl-5-fluoro-4-chloropyrimidine is obtained through the steps of extraction, drying and rectification.
In the technical scheme, in Q1, the reaction raw material A is 2-chloro-3-oxopentanoic acid methyl ester.
In the technical scheme, in the Q1, the reaction raw material B is formamidine hydrochloride.
In the above technical solution, in Q1, the reaction solvent is one of methanol, ethanol, and isopropanol or a mixture thereof in any proportion, and is preferably methanol.
In the above technical solution, in Q1, the base is sodium methoxide or sodium ethoxide, preferably sodium methoxide.
In the technical scheme, the molar ratio of the alkali to the reaction raw material A in the Q1 is 2-4: 1.
In the above technical scheme, in Q1, the extraction solvent is dichloromethane or ethyl acetate during the extraction.
In the above technical solution, in Q2, the reaction solvent is sulfolane.
In the technical scheme, in the Q2, the molar ratio of the potassium fluoride to the 6-ethyl-5-chloro-4-hydroxypyrimidine is 3-5: 1.
In the above technical scheme, in Q2, the extraction solvent is ethyl acetate.
In the above technical solution, in Q3, the reaction solvent is dichloromethane or toluene, preferably toluene.
In the above technical solution, in Q3, in the chlorination reaction, one of thionyl chloride, phosphorus oxychloride and triphosgene is used as the chlorinating reagent, and preferably thionyl chloride is used.
In the above technical scheme, in the Q3, in the chlorination reaction, the catalyst is N, N-dimethylformamide or 4-N, N-lutidine.
The invention takes cheap a-chloro propionyl ethyl acetate or a-chloro propionyl methyl acetate as raw materials, after ring closing, potassium fluoride is used for fluoro, and finally thionyl chloride is used for chloro to obtain high-yield 6-ethyl-5-fluoro-4-chloropyrimidine, the reaction steps are simple, easy to control and suitable for industrial production, thereby providing a more valuable synthetic route for preparing aprepitant, bringing good social benefit and economic benefit and having great economic value potential.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
As a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine shown in the embodiment, a-chloro propionyl ethyl acetate or a-chloro propionyl methyl acetate is used as a raw material to generate 6-ethyl-5-fluoro-4-chloropyrimidine;
the synthesis path is as follows:
the preparation method comprises the following steps:
preparation of Q1, 6-ethyl-5-chloro-4-hydroxypyrimidine:
under the reaction temperature, selecting ethyl 2-chloro-3-oxopentanoate as a reaction raw material A, selecting formamidine acetate as a reaction raw material B, and carrying out cyclization reaction in a reaction solvent under the action of alkali for 10-24 hours; distilling, extracting and recrystallizing to obtain a product 6-ethyl-5-chloro-4-hydroxypyrimidine;
preparation of Q2, 6-ethyl-5-fluoro-4-hydroxypyrimidine:
reacting 6-ethyl-5-chloro-4-hydroxypyrimidine with potassium fluoride in a reaction solvent for 18-24 hours; the reaction temperature is 240-250 ℃, and 6-ethyl-5-fluoro-4-hydroxypyrimidine is obtained through distillation, extraction and recrystallization;
preparation of Q3, 6-ethyl-5-fluoro-4-chloropyrimidine:
carrying out chlorination reaction on 6-ethyl-5-fluoro-4-hydroxypyrimidine and phosphorus oxychloride or thionyl chloride in a reaction solvent and a catalyst to generate 6-ethyl-5-fluoro-4-chloropyrimidine, wherein the chlorination reaction temperature is 80-90 ℃; the reaction time is 8-12 hours, and the 6-ethyl-5-fluoro-4-chloropyrimidine is obtained through the steps of extraction, drying and rectification.
The following specific examples illustrate the technical scheme of the present invention using ethyl a-chloropropionylacetate and formamidine acetate as raw materials, wherein the methyl a-chloropropionylacetate and formamidine hydrochloride are similar:
step one, preparing 6-ethyl-5-chloro-4-hydroxypyrimidine:
the different preparation methods of 6-ethyl-5-chloro-4-hydroxypyrimidine are illustrated by examples in which the reaction solvent is methanol or ethanol and the base is sodium methoxide or sodium ethoxide:
A. adding 800mL of methanol into a 2L three-mouth reaction bottle under the protection of nitrogen, adding 103g of formamidine acetate, and cooling to 0 ℃. Adding 108g of sodium methoxide into a reaction liquid bottle, controlling the adding temperature to be 0-5 ℃, continuously stirring for 1 hour at the temperature, then slowly dropwise adding 178.5g of ethyl 2-chloro-3-oxopentanoate under stirring, controlling the temperature to be below 0 ℃, completing dropwise adding, slowly heating the reaction mixture to room temperature, continuously stirring for 12 hours, concentrating under reduced pressure, and adjusting the pH of a concentrated substrate to 5-6 by using concentrated hydrochloric acid. Filtration and washing of the filter cake with water 2 times followed by crystallization from isopropanol gave 136.7g of product in 86.2% yield.
B. Adding 800mL of methanol into a 2L three-mouth reaction bottle under the protection of nitrogen, adding 103g of formamidine acetate, and cooling to 0 ℃. To the reaction solution bottle was added 162g of sodium methoxide, and the addition temperature was controlled at 0 to 5 ℃ and stirring was continued at that temperature for 1 hour. Then, 178.5g of ethyl 2-chloro-3-oxopentanoate was slowly added dropwise while stirring, and the temperature was controlled to 0 ℃ or lower. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for an additional 12 hours. Concentrating under reduced pressure, and adjusting pH of the concentrated substrate to 5-6 with concentrated hydrochloric acid. Filtration and washing of the filter cake with water 2 times followed by crystallization from isopropanol gave 138.8g of product in 87.6% yield.
C. Adding 800mL of ethanol into a 2L three-mouth reaction bottle under the protection of nitrogen, adding 103g of formamidine acetate, and cooling to 0 ℃. After 136g of sodium ethoxide was added to the reaction solution bottle, stirring was continued at that temperature for 1 hour, and then 178.5g of ethyl 2-chloro-3-oxopentanoate was added to the stirred system, and the temperature was controlled to be below 0 ℃. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for an additional 12 hours. Concentrating under reduced pressure, and adjusting pH of the concentrated substrate to 5-6 with concentrated hydrochloric acid. Filtration and washing of the filter cake with water 2 times followed by crystallization from isopropanol gave 132.4g of product in 83.5% yield.
Step two, under the protection of nitrogen, 232g of potassium fluoride, 600mL of sulfolane, 25g of phase transfer catalyst tetraphenylphosphonium bromide and 158.5g of 6-ethyl-5-chloro-4-hydroxypyrimidine are added into a 2L three-necked flask. The stirring was turned on and the temperature was slowly raised to 240 ℃. Stirring is continued for 24 hours at the temperature, then the temperature is reduced to 120 ℃, the solvent is distilled off under reduced pressure, the temperature is reduced to room temperature, 300ml of ethyl acetate is used for extraction, and 121.3g of product is obtained through concentration and crystallization, and the yield is 85.4%.
Step three, placing 142g of 6-ethyl-5-fluoro-4-hydroxypyrimidine into a 500ml single-neck flask, adding 256ml of phosphorus oxychloride and a small amount of catalyst DMF, heating to 90 ℃, stirring and reacting for 5 hours, after the reaction is completed, performing rotary evaporation to remove most of the solvent, then adding a proper amount of water, adjusting the pH to 5 with a saturated sodium carbonate solution, extracting for 3 times with 300ml of ethyl acetate, combining organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, and rectifying, separating and purifying the obtained crude product to obtain 144.8g of 6-ethyl-5-fluoro-4-chloropyrimidine, wherein the yield is 90.2%.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (9)
1. A preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine is characterized by comprising the following steps:
the synthesis path is as follows:
the preparation method comprises the following steps:
preparation of Q1, 6-ethyl-5-chloro-4-hydroxypyrimidine:
performing cyclization reaction on a reaction raw material A which is ethyl 2-chloro-3-oxopentanoate and a reaction raw material B which is formamidine acetate in a reaction solvent under the action of alkali at a reaction temperature for 10-24 hours; distilling, extracting and recrystallizing to obtain a product 6-ethyl-5-chloro-4-hydroxypyrimidine;
preparation of Q2, 6-ethyl-5-fluoro-4-hydroxypyrimidine:
reacting 6-ethyl-5-chloro-4-hydroxypyrimidine with potassium fluoride in a reaction solvent for 18-24 hours; the reaction temperature is 240-250 ℃, and 6-ethyl-5-fluoro-4-hydroxypyrimidine is obtained through distillation, extraction and recrystallization;
preparation of Q3, 6-ethyl-5-fluoro-4-chloropyrimidine:
carrying out chlorination reaction on 6-ethyl-5-fluoro-4-hydroxypyrimidine and a chlorinated reagent in a reaction solvent and a catalyst to generate 6-ethyl-5-fluoro-4-chloropyrimidine, wherein the chlorination reaction temperature is 80-90 ℃; the reaction time is 8-12 hours, and the 6-ethyl-5-fluoro-4-chloropyrimidine is obtained through the steps of extraction, drying and rectification.
2. The process for preparing 6-ethyl-5-fluoro-4-chloropyrimidine according to claim 1, characterized by: in the Q1, the reaction raw material A is 2-chloro-3-oxopentanoic acid methyl ester.
3. The process for producing 6-ethyl-5-fluoro-4-chloropyrimidine according to claim 1 or 2, characterized by: in the Q1, the reaction raw material B is formamidine hydrochloride.
4. The process for producing 6-ethyl-5-fluoro-4-chloropyrimidine according to claim 3, wherein: the reaction solvent is one of methanol, ethanol and isopropanol or a mixture of any proportion.
5. The process for preparing 6-ethyl-5-fluoro-4-chloropyrimidine according to claim 4, wherein: in the Q1, the base is sodium methoxide or sodium ethoxide.
6. The process according to claim 5 for preparing 6-ethyl-5-fluoro-4-chloropyrimidine, which comprises: in the Q1, the molar ratio of the alkali to the reaction raw material A is 2-4: 1.
7. The process according to claim 6 for the preparation of 6-ethyl-5-fluoro-4-chloropyrimidine, which comprises: in the Q2, the molar ratio of the potassium fluoride to the 6-ethyl-5-chloro-4-hydroxypyrimidine is 3-5: 1.
8. The process according to claim 7 for the preparation of 6-ethyl-5-fluoro-4-chloropyrimidine, which comprises: in the Q3, one of thionyl chloride, phosphorus oxychloride and triphosgene is used as a chlorinating reagent in the chlorination reaction.
9. The process for preparing 6-ethyl-5-fluoro-4-chloropyrimidine according to claim 8, characterized by: in the Q3, in the chlorination reaction, a catalyst is N, N-dimethylformamide or 4-N, N-dimethylpyridine.
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