CN117069662A - Synthesis method of 4, 6-dichloro-2- (difluoromethyl) pyrimidine - Google Patents
Synthesis method of 4, 6-dichloro-2- (difluoromethyl) pyrimidine Download PDFInfo
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- CN117069662A CN117069662A CN202311336625.0A CN202311336625A CN117069662A CN 117069662 A CN117069662 A CN 117069662A CN 202311336625 A CN202311336625 A CN 202311336625A CN 117069662 A CN117069662 A CN 117069662A
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- difluoromethyl
- pyrimidine
- potassium
- sodium
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- KHLZCSAFJCIVRL-UHFFFAOYSA-N 4,6-dichloro-2-(difluoromethyl)pyrimidine Chemical compound FC(F)c1nc(Cl)cc(Cl)n1 KHLZCSAFJCIVRL-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- XPQIEWVNVRVIHS-UHFFFAOYSA-N 2-(difluoromethyl)-4-hydroxy-1h-pyrimidin-6-one Chemical compound OC1=CC(O)=NC(C(F)F)=N1 XPQIEWVNVRVIHS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 claims abstract description 12
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 238000010791 quenching Methods 0.000 claims description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- 230000000171 quenching effect Effects 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- 238000004321 preservation Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- -1 alkali metal alkoxide Chemical class 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- SRBPHIMDSSPBIL-UHFFFAOYSA-N [K].C(C(C)C)O Chemical compound [K].C(C(C)C)O SRBPHIMDSSPBIL-UHFFFAOYSA-N 0.000 claims description 2
- SPUCFJYSOOULRC-UHFFFAOYSA-N [Na].CC(C)CO Chemical compound [Na].CC(C)CO SPUCFJYSOOULRC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- MKNZKCSKEUHUPM-UHFFFAOYSA-N potassium;butan-1-ol Chemical compound [K+].CCCCO MKNZKCSKEUHUPM-UHFFFAOYSA-N 0.000 claims description 2
- AWDMDDKZURRKFG-UHFFFAOYSA-N potassium;propan-1-olate Chemical compound [K+].CCC[O-] AWDMDDKZURRKFG-UHFFFAOYSA-N 0.000 claims description 2
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 claims description 2
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000006467 substitution reaction Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 230000003321 amplification Effects 0.000 abstract 1
- 238000003199 nucleic acid amplification method Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical class ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 description 1
- HIMKWMSBWDZYRB-UHFFFAOYSA-N 4,6-dichloropyrimidine-2-carbaldehyde Chemical compound ClC1=CC(Cl)=NC(C=O)=N1 HIMKWMSBWDZYRB-UHFFFAOYSA-N 0.000 description 1
- 229940127379 Kallikrein Inhibitors Drugs 0.000 description 1
- 102000003827 Plasma Kallikrein Human genes 0.000 description 1
- 108090000113 Plasma Kallikrein Proteins 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000007039 two-step reaction Methods 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
-
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
Abstract
The application discloses a method for synthesizing 4, 6-dichloro-2- (difluoromethyl) pyrimidine, which synthesizes a 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine intermediate through ethyl difluoroacetate and malonamide, and then obtains a final product 4, 6-dichloro-2- (difluoromethyl) pyrimidine through selective substitution reaction. The starting materials ethyl difluoroacetate and malonamide used in the application are cheap and easily available chemical raw materials, the used reagents and organic alkali are cheap and easily available chemical reagents, the reaction is carried out by two steps of reactions, the reaction is mild, the total yield is high, the amplification production has no special requirement on equipment, and the operation is convenient. The post-treatment is simple, and the generated waste water and waste liquid are less, thereby being beneficial to environmental protection.
Description
Technical Field
The application belongs to the technical field of organic chemical synthesis, and particularly relates to a method for synthesizing a heterocyclic compound, in particular to a method for synthesizing 4, 6-dichloro-2- (difluoromethyl) pyrimidine.
Background
4, 6-dichloro-2- (difluoromethyl) pyrimidine is a 4,6-dichloropyrimidine derivative, the CAS registration number of which is 1816289-02-7, has important roles in medicine research and development and chemical production, and can be applied to the synthesis of plasma kallikrein inhibitors.
PCT patent publication No. WO2022/197758A1, at 2022, month 09, 22, discloses a method for synthesizing 4, 6-dichloro-2- (difluoromethyl) pyrimidine from 4,6-dichloropyrimidine-2-carbaldehyde as a raw material and diethylaminosulfur trifluoride as a fluoro reagent, wherein the method comprises the following steps:
；
the synthesis path has high raw material cost, harsh requirements on production equipment, low synthesis efficiency, low separation and purification efficiency by using the preparation thin layer chromatography, and difficult mass production.
Therefore, it is a current research direction to find a synthetic route capable of mass-producing 4, 6-dichloro-2- (difluoromethyl) pyrimidine.
Disclosure of Invention
In order to solve the problems, the application provides a synthesis method of 4, 6-dichloro-2- (difluoromethyl) pyrimidine, which has the advantages of low cost, high yield, high quality, suitability for industrial mass production and the like.
Specifically, the application provides the following technical scheme:
a synthetic method of 4, 6-dichloro-2- (difluoromethyl) pyrimidine comprises the following steps:
1) Mixing a solvent, malonamide and an alcohol solution of alkali metal alkoxide, introducing nitrogen, controlling the temperature to be 25-35 ℃, adding ethyl difluoroacetate into the system, gradually heating the system to be 75-80 ℃ after the completion of the reaction, carrying out heat preservation reaction for 10-15 hours, cooling the system after the system is completely converted, filtering, and drying to obtain an intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine;
2) Adding the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine into phosphorus oxychloride at 20-40 ℃, stirring and controlling the temperature to 20-40 ℃, adding organic base into the system, then slowly heating the system to 98-105 ℃, keeping the temperature for 2-5 hours, completely converting the system, cooling to room temperature, quenching with cold water at 0-5 ℃, controlling the temperature in the quenching process to 0-30 ℃, extracting and washing the water phase after the quenching is finished, merging and concentrating the post-treatment solvent of the obtained product, and rectifying the obtained oily substance under reduced pressure to obtain the target product 4, 6-dichloro-2- (difluoromethyl) pyrimidine.
In one embodiment of the application, the molar ratio of the malonamide to the alkali metal alkoxide is 1:1-1:3; illustratively, 1:1,1:1.5,1:2,1:2.5,1:3.
In one embodiment of the present application, the molar ratio of phosphorus oxychloride to 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine is 2:1 to 8:1, preferably 2:1 to 5:1, and illustratively 2:1,3:1,4:1,5:1,6:1,7:1,8:1.
In one embodiment of the present application, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
In one embodiment of the present application, the alkali metal alkoxide is selected from one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, potassium n-propoxide, potassium isopropoxide, sodium n-butoxide, sodium isobutanol, sodium t-butoxide, potassium n-butoxide, potassium isobutanol, and potassium t-butoxide.
In one embodiment of the present application, the alcohol in the alcohol solution in step 1) is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol.
In one embodiment of the application, the alcohol of the alcohol solution in step 1) is the same alcohol as the solvent.
In one embodiment of the present application, the organic base in step 2) is selected from one or more of triethylamine, N-diisopropylethylamine, pyridine, diethylamine and piperazine.
In one embodiment of the present application, the post-treatment solvent in step 2) is selected from one or more of n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, ethyl acetate and dichloromethane.
In one embodiment of the present application, both step 1) and step 2) are performed under stirring.
In one embodiment of the application, the aqueous phase is extracted with n-hexane after the end of the quench in step 2).
The application has the beneficial effects that:
according to the application, the 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine intermediate is synthesized by using ethyl difluoroacetate and malonamide, then the final product 4, 6-dichloro-2- (difluoromethyl) pyrimidine is obtained through a selective substitution reaction, the ethyl difluoroacetate and the malonamide which are adopted as starting materials are cheap and easily available chemical raw materials, the reagents and the organic base which are used are cheap and easily available chemical reagents, the reaction is subjected to two-step reaction and one-step rectification purification, the reaction process is mild, the total yield is high, the total yield is stabilized to be more than 75%, the adopted reagents and the organic base are both cheap and easily available chemical reagents, the amplified production has no special requirements on equipment, the operation is convenient, the post treatment is simple, the generated waste water and waste liquid are less, and the environmental protection is facilitated.
Drawings
FIG. 1 is a chart showing nuclear magnetic resonance hydrogen spectra of intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine.
FIG. 2 is a chart showing nuclear magnetic resonance hydrogen spectrum of the target product 4, 6-dichloro-2- (difluoromethyl) pyrimidine.
Detailed Description
The technical scheme of the application will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the application. All techniques implemented based on the above description of the application are intended to be included within the scope of the application.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1
Methanol (500 mL,10 Vol), malonamide (50 g,0.49 mol) and a methanol solution of sodium methoxide (181 mL,0.98 mol) are sequentially added into a 1L four-mouth bottle under stirring, nitrogen is replaced three times, ethyl difluoroacetate (60.8 g,0.49 mol) is dropwise added into the system at the temperature of 25 ℃, after the dropwise addition, the system is gradually heated to 75 ℃, the system is subjected to heat preservation reaction 10 h to confirm complete conversion, the system is cooled and filtered, and the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine is obtained after drying, wherein the weight is 69.2 g, and the yield is 87.2%.
Phosphorus oxychloride (113.5 g,0.74 mol) is added into a 1L four-mouth bottle under stirring, 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine (60 g,0.37 mol) is added in batches at the temperature of 20 ℃, N-diisopropylethylamine (95.64 g,0.74 mol) is dropwise added into the system at the temperature of 20 ℃ under stirring, the system is slowly heated to 98 ℃, the system is subjected to heat preservation reaction for 2 h, the conversion is confirmed to be complete, the reaction system is cooled to room temperature and then is dripped into a 2L three-mouth bottle filled with cold water (600 mL,10 Vol) at the temperature of 0 ℃ for quenching, the water phase is washed by N-hexane (300 mL ×3, 5V×3) after the quenching is finished, then the obtained N-hexane solution is combined and concentrated, the obtained oily matter is subjected to rectification under reduced pressure after the concentration, and 60-80 ℃ fractions are collected to obtain the 4, 6-dichloro-2- (difluoromethyl) pyrimidine 55. 55.3 g, the purity of which is 75.1 percent.
FIG. 1 is a chart showing nuclear magnetic resonance hydrogen spectra of intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine prepared in example 1.
FIG. 2 is a chart showing nuclear magnetic resonance hydrogen spectra of the target product 4, 6-dichloro-2- (difluoromethyl) pyrimidine prepared in example 1.
The nuclear magnetic resonance apparatus is provided by Bruker BioSpin GmbH company, the test solvents are heavy water and deuterated chloroform respectively, and the test temperature is room temperature.
Example 2
Ethanol (1000 mL,10 Vol), malonamide (100 g,0.98 mol) and sodium ethoxide ethanol solution (363 mL,1.96 mol) are sequentially added into a 3L four-mouth bottle under stirring, nitrogen is replaced for three times, ethyl difluoroacetate (243 g,1.96 mol) is dropwise added into the system at the temperature of 35 ℃, the system is gradually heated to 80 ℃ after the dropwise addition is finished, the system is subjected to heat preservation reaction 16 h, the system is subjected to confirmation of complete conversion, the system is cooled and filtered, and the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine 144 g is obtained after drying, and the yield is 90.7%.
Phosphorus oxychloride (472.9 g,3.08 mol) is added into a 1L four-mouth bottle under stirring, 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine (100 g,0.62 mol) is added in batches at the temperature of 40 ℃, stirring is kept after the addition, triethylamine (125 g,1.24 mol) is dropwise added into the system at the temperature of 40 ℃, the system is slowly heated to 105 ℃, the system is subjected to heat preservation reaction for 5h, the conversion is confirmed to be complete, the reaction system is dripped into a 2L three-mouth bottle filled with 5 ℃ cold water (1000 mL,10 Vol) for quenching after the temperature is reduced to the room temperature, the quenching process is controlled to 30 ℃, water phase is extracted and washed by normal hexane (500 mL X3, 5V X3) after the quenching is finished, then the obtained normal hexane solution is combined and concentrated, the obtained oily matter after the concentration is concentrated is subjected to reduced pressure rectification, and the fraction at the temperature of 60-80 ℃ is collected to obtain the 4, 6-dichloro-2- (difluoromethyl) pyrimidine with the purity of 93. 93.5 g, 99.9%, and the yield of 76.2%.
Example 3
Methanol (1000 ml,10 Vol), malonamide (100 g,0.98 mol) and a methanol solution of potassium methoxide (803 ml,1.96 mol) are sequentially added into a 3L four-mouth bottle under stirring, nitrogen is replaced for three times, ethyl difluoroacetate (243 g,1.96 mol) is dropwise added into the system at the temperature of 30 ℃, after the dropwise addition, the system is gradually heated to 78 ℃, the system is subjected to heat preservation reaction 16 h to confirm complete conversion, the system is cooled and filtered, and the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine is obtained after drying, 140 g, and the yield is 88.2%.
Phosphorus oxychloride (472.9 g,3.08 mol) is added into a 1L four-mouth bottle under stirring, 4, 6-dihydroxyl-2- (difluoromethyl) pyrimidine (100 g,0.62 mol) is added in batches at the temperature of 30 ℃, stirring is kept after the addition, triethylamine (125 g,1.24 mol) is dropwise added into the system at the temperature of 30+/-10 ℃, the system is slowly heated to 100 ℃, the system is subjected to heat preservation reaction for 5 hours to confirm complete conversion, the reaction system is dripped into a 2L three-mouth bottle filled with cold water (1000 mL,10 Vol) at the temperature of 3 ℃ to quench the reaction system, the quenching process is controlled at the temperature of 15 ℃, water phase is extracted by normal hexane (500 mL multiplied by 3, 5V multiplied by 3) after the quenching process is finished, then the obtained normal hexane solution is combined and concentrated, the obtained oily matter is subjected to reduced pressure rectification after the concentration is finished, and the fraction at the temperature of 60-80 ℃ is collected to obtain the 4, 6-dichloro-2- (difluoromethyl) pyrimidine 95.1 g, the purity is 99.8%, and the yield is 77.5%.
Example 4
Methanol (1000 ml,10 Vol), malonamide (100 g,0.98 mol) and sodium methoxide methanol solution (363 ml,1.96 mol) are sequentially added into a 3L four-port bottle under stirring, nitrogen is replaced for three times, ethyl difluoroacetate (364.6 g,2.94 mol) is dropwise added into the system at the temperature of 35 ℃, after the dropwise addition, the system is gradually heated to 79 ℃, the temperature is kept for reaction 13 h, the system is confirmed to be completely converted after the reaction is completed, the system is cooled and filtered, and the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine is obtained after drying is 140 g, and the yield is 88.2%.
Phosphorus oxychloride (757 g,4.93 mol) is added into a 1L four-mouth bottle under stirring, 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine (100 g,0.62 mol) is added in batches at the temperature of 28 ℃, stirring is kept after the addition, pyridine (98.08 g,1.24 mol) is dropwise added into the system at the temperature of 28 ℃, the system is slowly heated to 102 ℃, the system is subjected to heat preservation reaction 5h to confirm complete conversion, the reaction system is dripped into a 2L three-mouth bottle filled with cold water (1000 mL,10 Vol) at the temperature of 2 ℃ to quench the room temperature, the quenching process is subjected to temperature control of 10 ℃, water phase is extracted with normal hexane (500 mL ×3, 5V ×3) after the quenching is finished, then the obtained normal hexane solution is combined and concentrated, the oily matter obtained after concentration is subjected to reduced pressure rectification, and the fraction at the temperature of 60-80 ℃ is collected to obtain the 4, 6-dichloro-2- (difluoromethyl) pyrimidine with the purity of 95. 95.75 g, and the yield of 99.8%.
The above description of exemplary embodiments of the application has been provided. However, the scope of the present application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, or the like, which are within the spirit and principles of the present application, should be made by those skilled in the art, and are intended to be included within the scope of the present application.
Claims (10)
1. A method for synthesizing 4, 6-dichloro-2- (difluoromethyl) pyrimidine, which is characterized by comprising the following steps:
1) Mixing a solvent, malonamide and an alcohol solution of alkali metal alkoxide, introducing nitrogen, controlling the temperature to be 25-35 ℃, adding ethyl difluoroacetate into the system, gradually heating the system to be 75-80 ℃ after the completion of the reaction, carrying out heat preservation reaction for 10-15 hours, cooling the system after the system is completely converted, filtering, and drying to obtain an intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine;
2) Adding the intermediate 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine into phosphorus oxychloride at 20-40 ℃, stirring and controlling the temperature to 20-40 ℃, adding organic base into the system, then slowly heating the system to 98-105 ℃, keeping the temperature for 2-5 hours, completely converting the system, cooling to room temperature, quenching with cold water at 0-5 ℃, controlling the temperature in the quenching process to 0-30 ℃, extracting and washing the water phase after the quenching is finished, merging and concentrating the post-treatment solvent of the obtained product, and rectifying the obtained oily substance under reduced pressure to obtain the target product 4, 6-dichloro-2- (difluoromethyl) pyrimidine.
2. The method of claim 1, wherein the molar ratio of malonamide to alkali metal alkoxide is 1:1 to 1:3.
3. The synthesis method according to claim 1, wherein the molar ratio of phosphorus oxychloride to 4, 6-dihydroxy-2- (difluoromethyl) pyrimidine is 2:1-8:1.
4. The synthetic method of claim 1, wherein the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol;
the alkali metal alkoxide is selected from one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, potassium n-propoxide, potassium isopropoxide, sodium n-butoxide, sodium isobutanol, sodium tert-butoxide, potassium n-butoxide, potassium isobutanol and potassium tert-butoxide.
5. The method of synthesis according to claim 1, wherein the alcohol in the alcohol solution in step 1) is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol.
6. The method according to claim 5, wherein the alcohol of the alcohol solution in step 1) and the solvent are the same alcohol.
7. The synthetic method of claim 1, wherein the organic base in step 2) is selected from one or more of triethylamine, N-diisopropylethylamine, pyridine, diethylamine, and piperazine.
8. The method of synthesis according to claim 1, wherein the post-treatment solvent in step 2) is selected from one or more of n-hexane, cyclohexane, n-heptane, methyl tert-butyl ether, ethyl acetate and dichloromethane.
9. The synthetic method according to any one of claims 1 to 8, wherein both of step 1) and step 2) are performed under stirring.
10. The synthesis according to any one of claims 1 to 8, wherein the aqueous phase is extracted with n-hexane after the end of the quenching in step 2).
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