CN115611802B - Synthetic method of 3-acetyl-2-chloropyridine - Google Patents
Synthetic method of 3-acetyl-2-chloropyridine Download PDFInfo
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- CN115611802B CN115611802B CN202211532679.XA CN202211532679A CN115611802B CN 115611802 B CN115611802 B CN 115611802B CN 202211532679 A CN202211532679 A CN 202211532679A CN 115611802 B CN115611802 B CN 115611802B
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- WIWIOUAFBHZLNQ-UHFFFAOYSA-N 1-(2-chloropyridin-3-yl)ethanone Chemical compound CC(=O)C1=CC=CN=C1Cl WIWIOUAFBHZLNQ-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- -1 2-chloronicotinic acid lithium salt Chemical compound 0.000 claims abstract description 41
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 33
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims abstract description 26
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000007259 addition reaction Methods 0.000 claims abstract description 13
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000001308 synthesis method Methods 0.000 claims abstract description 7
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims abstract description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims abstract description 6
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims abstract description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 86
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- 238000010438 heat treatment Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000012535 impurity Substances 0.000 claims description 19
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
- 239000007788 liquid Substances 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000011261 inert gas Substances 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000005070 sampling Methods 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 24
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 6
- 229910003002 lithium salt Inorganic materials 0.000 abstract description 4
- 159000000002 lithium salts Chemical class 0.000 abstract description 4
- 238000001816 cooling Methods 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 10
- 230000002572 peristaltic effect Effects 0.000 description 10
- 238000004321 preservation Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 7
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 239000008399 tap water Substances 0.000 description 6
- 235000020679 tap water Nutrition 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- 239000012267 brine Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 3
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000004795 grignard reagents Chemical class 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 3
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- MYGAJZBZLONIBZ-UHFFFAOYSA-N methyl 2-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1Cl MYGAJZBZLONIBZ-UHFFFAOYSA-N 0.000 description 2
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- OXAIIPJGBIWVIM-UHFFFAOYSA-M potassium;2-chloropyridine-3-carboxylate Chemical compound [K+].[O-]C(=O)C1=CC=CN=C1Cl OXAIIPJGBIWVIM-UHFFFAOYSA-M 0.000 description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 2
- MGWQFMQXJGUBRB-UHFFFAOYSA-M sodium 2-chloropyridine-3-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CN=C1Cl MGWQFMQXJGUBRB-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- AZFMFGIMDGBJRR-UHFFFAOYSA-N 1-(1-oxidopyridin-1-ium-3-yl)ethanone Chemical compound CC(=O)C1=CC=C[N+]([O-])=C1 AZFMFGIMDGBJRR-UHFFFAOYSA-N 0.000 description 1
- FVMGQROBOUHKQO-UHFFFAOYSA-N 1-(2-chloropyridin-3-yl)ethanol Chemical compound CC(O)C1=CC=CN=C1Cl FVMGQROBOUHKQO-UHFFFAOYSA-N 0.000 description 1
- WVPQLRNAQVXWAV-UHFFFAOYSA-N 2-(2-chloropyridin-3-yl)propan-2-ol Chemical compound CC(C)(O)C1=CC=CN=C1Cl WVPQLRNAQVXWAV-UHFFFAOYSA-N 0.000 description 1
- CJGGKSPGRJHZNP-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyrazine Chemical compound C1=CN=C2NN=NC2=N1 CJGGKSPGRJHZNP-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the field of organic synthesis, and relates to a synthetic method of 3-acetyl-2-chloropyridine. The method comprises the following steps: taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate and/or a lithium salt. The synthesis method has the advantages of high reaction yield, high product purity, mild reaction conditions, safe and easy operation of reaction, simple treatment after reaction, suitability for large-scale production and obvious industrial value.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of a drug intermediate, and more particularly relates to a synthetic method of 3-acetyl-2-chloropyridine.
Background
3-acetyl-2-chloropyridine (CAS: 55676-21-6) is an important organic synthesis intermediate and a drug intermediate, can be used for synthesizing azaquinolinone anticancer drugs (US 2012258982) and synthesizing triazolopyridine and triazolopyrazine anticancer drugs (WO 2011079804). The synthesis route of 3-acetyl-2-chloropyridine has three main routes.
In the first route, 2-chloronicotinic acid or derivatives thereof are used as raw materials.
2-Chloronicotinic acid or its derivatives (esters, weinreb amides, nitriles) can be subjected to addition reaction with organometallic reagents (magnesium, lithium, tin) to give 3-acetyl-2-chloropyridine.
In 2010, and in WO2011079804, cambodia medicine (shanghai) limited, 2-chloronicotinic acid was reacted with 2.5 equivalents of methylmagnesium bromide and treated to give 3-acetyl-2-chloropyridine in 77% yield. The inventor finds that a large amount of methane gas is discharged in the reaction during pilot plant test, so that great potential safety hazard exists, a byproduct 2- (2' -chloropyridin-3-yl) propan-2-ol (dimethyl impurity) is generated, the purification is not easy, the defects of long feeding time, long construction period, small batch, large energy waste and the like exist, and the route is not suitable for industrial production. Methyl 2-chloronicotinate can also react with methylmagnesium bromide to produce 3-acetyl-2-chloropyridine with a yield of 66% (Journal of Heterocyclic Chemistry, 1999, 36, 445-452), but methyl 2-chloronicotinate is also expensive and not suitable for scale-up production.
In 2012, hoffmann La Roche company, switzerland reported in patent WO2012136684, weinreb amide of 2-chloronicotinic acid reacted with 2.5 equivalents of methyl magnesium chloride, and 3-acetyl-2-chloropyridine was obtained by post-treatment and column chromatography purification with a yield of 72%. In the synthesis of Weinreb amide, an expensive condensing agent BOP is used, the reaction time is long, and the intermediate also needs silica gel column chromatography purification before the next addition reaction with methyl magnesium chloride can be carried out. This route is not suitable for scale-up production.
In 2017, lee Jae In university of mad girl, korea reported In patent KR101766414 that the yield could be increased to 90% by reacting Weinreb amide of 2-chloronicotinic acid with methyllithium instead of grignard reagent. However, the price of methyl lithium is several times that of the Grignard reagent, and the production cost is high, so that the method is not suitable for large-scale production.
Lee Jae In also reports (Bull. Korean chem. Soc. 2013, 34, 1253-1256) that the yield can be increased to 91% by reacting Weinreb amide with methyl magnesium chloride, instead of Weinreb amide, with an ester of 2-chloronicotinic acid with 2-hydroxypyridine. However, the ester molecular weight of 2-hydroxypyridine is large, the atom economy of the route is not high, and the raw materials for synthesizing the ester are expensive, the production cost is high, and the method is not suitable for large-scale production.
In 2010, mcNab Hamish and Gaywood Alexander P. of Edinburgh university, UK (Organic and Biomolecular Chemistry, 2010, 8, 5166-5173), 2-chloronicotinonitrile was reacted with 4.27 equivalents of methyl magnesium chloride to give 3-acetyl-2-chloropyridine in 65% yield after work-up. 2-chloronicotinonitrile is relatively expensive and requires the use of an excess of the Grignard reagent, which is not suitable for scale-up.
In addition to reacting with magnesium and lithium reagents, 3-acetyl-2-chloropyridine can also be synthesized by reacting nicotinoyl chloride with tetramethyltin. In 1997, U.S. Syntex Inc. reported in patent US5688795 that 2-chloronicotinyl chloride reacted with tetramethyltin under the catalysis of bis (benzonitrile) palladium (II) dichloride and purified by silica gel column chromatography to give 3-acetyl-2-chloropyridine with a yield of 54%. The yield is not high, the raw material of tetramethyl tin is not easy to obtain, the cost is high, an expensive metal palladium catalyst is also needed, and the method is not suitable for industrial production.
In addition to the synthesis of 3-acetyl-2-chloropyridine by reaction with an organometallic reagent as described above, 3-acetyl-2-chloropyridine can also be synthesized by acylation, decarboxylation of nicotinoyl chloride with diethyl malonate. In 2007, memory Pharmaceuticals corporation reported in US patent No. 5, 20070078147 that 2-chloronicotinic acid and oxalyl chloride reacted to form 2-chloronicotinoyl chloride with a yield of 98%; reacting 2-chloronicotinoyl chloride with diethyl malonate under the catalysis of anhydrous magnesium chloride to generate 2- (2-chloronicotinoyl) diethyl malonate with the yield of 85%; the diethyl 2- (2-chloronicotinyl) malonate is decarboxylated in wet DMSO at 130 ℃, and the product is obtained by silica gel column chromatography purification, with the yield of 52%. The total yield of the three-step reaction is 43.3 percent and is not high.
And in the second route, 3-acetylpyridine is used as a raw material.
In 2010, mcNab Hamish and Gaywood Alexander P. of Edinburgh university, UK (Organic and Biomolecular Chemistry, 2010, 8, 5166-5173), 3-acetylpyridine was oxidized with 30% hydrogen peroxide to produce 3-acetylpyridine N-oxide, which was then reacted with phosphorus oxychloride at 100 ℃ for 1 hour, followed by post-treatment to obtain 3-acetyl-2-chloropyridine, with a total yield of 33% in the two steps. The total yield is not high, the price of the raw material 3-acetylpyridine is expensive, the production cost is high, and the large-scale production is not available.
And the third route is to use 2-chloropyridine as a raw material.
In 2011, the university of kansasa in the united states is reported in patent WO2011005759, newly prepared LDA is used as alkali, 2-chloropyridine and acetaldehyde are subjected to addition reaction, after post-treatment and silica gel column chromatography purification, 1- (2-chloropyridine-3-yl) ethanol is obtained, then chromium trioxide is used for oxidation to obtain a crude acetyl-2-chloropyridine product, and the pure product is obtained after silica gel column chromatography purification. The total yield of the two-step reaction is 51.8%. The total yield is not high, low temperature of minus 78 ℃ is required, silica gel column chromatography is also required for purification, and the method is not suitable for industrial production.
In summary, the existing processes present more or less drawbacks: or the raw material cost is high, the total yield is low, the reaction production period is long, or column chromatography purification and other operation steps which are not suitable for amplification are required, and the like, so that the method is not suitable for industrial production. In order to provide a large amount of cheap 3-acetyl-2-chloropyridine products and provide guarantee for the development of subsequent medicaments, a new method for synthesizing the compound is very necessary to be developed.
Disclosure of Invention
Aiming at the defects that the existing process is not suitable for industrial production due to high cost, low yield, long reaction production period or the need of column chromatography purification. The invention develops a synthesis method which has the advantages of cheap and easily obtained raw materials, safe and easily operated reaction, mild reaction conditions, simple post-reaction treatment, higher yield, suitability for large-scale production and obvious industrial value.
In order to achieve the above object, the present invention provides a method for synthesizing 3-acetyl-2-chloropyridine, the method comprising:
taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate and/or a lithium salt.
According to a preferred embodiment of the present invention, the step of generating the lithium 2-chloronicotinate comprises: and (2) taking water as a solvent, and contacting the 2-chloronicotinic acid with a lithium-containing compound for reaction to obtain the 2-chloronicotinic acid lithium salt.
Further, the molar ratio of the 2-chloronicotinic acid to the lithium-containing compound is 0.9 to 1.0:1.
further, the reaction temperature for producing the lithium 2-chloronicotinate is 40 to 50 ℃.
According to the invention, the lithium salt is preferably lithium carbonate.
According to a preferred embodiment of the present invention, the step of performing an addition reaction of the lithium 2-chloronicotinate with methyl magnesium bromide comprises:
(1) Under the protection of inert gas, stirring and mixing a first organic solvent and 2-chloronicotinic acid lithium salt, then dropwise adding methyl magnesium bromide, and naturally heating to the addition reaction temperature for reaction after dropwise adding is finished to obtain a reaction solution;
(2) And (3) under the protection of inert gas, dropwise adding the reaction liquid into low-temperature water, stirring for the first time, dropwise adding hydrochloric acid, heating to 20 to 25 ℃ after dropwise adding, stirring for the second time, standing for liquid separation, extracting the water phase by using a second organic solvent, combining organic phases, and concentrating to obtain the target product.
Further, in the step (1), the first organic solvent is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran.
Further, in the step (1), the molar ratio of the 2-chloronicotinic acid lithium salt to the methyl magnesium bromide is 1:1 to 1.5, preferably 1:1.1 to 1.3.
In the step (1), the dropping speed of the methylmagnesium bromide is 0.9 to 1.8kg/min per 1000kg of the reaction system.
Further, in the step (1), before dropping the methyl magnesium bromide, the temperature of the system is controlled to be below-4 ℃, and the temperature of the system is controlled not to exceed 0 ℃ in the dropping process.
Further, in the step (1), the addition reaction temperature is 12 to 18 ℃, and the reaction time is 0.5 to 1.5 hours.
Further, in the step (2), the temperature of the low-temperature water is 4 ℃ or lower.
Further, in the step (2), the mass of the low-temperature water is 0.3 to 0.5kg per 1kg of the reaction solution.
Further, in the step (2), the temperature of the system is controlled not to exceed 15 ℃ during the dropping process.
Further, in the step (2), the first time is 0.5 to 1.5 hours.
In the step (2), the molar addition amount of the hydrochloric acid is 1.8 to 2.0 times of the molar addition amount of the 2-chloronicotinic acid lithium salt.
Further, in the step (2), the second time is 1.5 to 2.5 hours.
Further, in the step (2), the second organic solvent is at least one selected from ethyl acetate, dichloromethane and methyl tert-butyl ether.
The inert gas in each step of the present invention may be nitrogen.
According to the invention, the time point for performing step (2) needs to be controlled, and specifically, the method and the standard for determining step (2) are as follows: and (3) detecting the reaction result by HPLC, wherein the 2-chloronicotinic acid in the system is less than 21 percent, and performing the step (2).
In the method of the present invention, the 2-chloronicotinic acid lithium salt generated by the reaction needs to be dried and then the subsequent addition reaction is performed, specifically, the 2-chloronicotinic acid lithium salt needs to be dried until the water content is less than 1%.
The synthesis method of the invention also comprises the rectification step: adding a 3-acetyl-2-chloropyridine crude product into a rectifying tower, starting heating, starting an oil pump to dry low-boiling-point substances, switching to a roots pump, gradually increasing the gas phase temperature until front fraction is evaporated, periodically sampling and detecting, switching to a main fraction collecting tank when the maximum impurity is less than 0.5%, periodically sampling and detecting, and stopping rectification when the impurity is more than 0.5% after a main peak to obtain a 3-acetyl-2-chloropyridine product.
The synthesis method of the invention has the following advantages:
(1) The reaction yield is high, the product purity is more than 99 percent, and the single impurity is less than 0.5 percent.
(2) By adding a low-cost lithium-containing compound such as lithium hydroxide monohydrate to form a lithium salt, 1 equivalent of methyl magnesium bromide can be saved, and the reaction economy is good.
(3) The method has the advantages of mild reaction conditions, safe reaction, easy operation, simple treatment after reaction (no need of column chromatography), suitability for large-scale production and obvious industrial value.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 is a nuclear magnetic spectrum of 3-acetyl-2-chloropyridine synthesized in example 1 of the present invention.
FIG. 2 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 1 of the present invention.
FIG. 3 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 2 of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
Example 1
Synthesis of lithium 2-chloronicotinate:
325kg of tap water was charged into a 1000L reactor, and 171.8kg (1 eq.) of lithium hydroxide monohydrate was added thereto with stirring. And (3) opening cold brine, quickly adding 600kg of 2-chloronicotinic acid into the reaction kettle, controlling the temperature to be 40-50 ℃ for reaction for 2h, controlling the temperature to be 40 ℃ for discharging, cooling to be below 20 ℃, performing suction filtration, and drying in an oven until the water content is less than 1%, thus obtaining 660kg of the product 2-chloronicotinic acid lithium salt with the yield of 98%.
Synthesis of acetyl-2-chloropyridine:
200kg of tetrahydrofuran is added into a 2000L reaction kettle, stirring is started, 100kg of 2-chloronicotinic acid lithium salt is added, then 250kg of tetrahydrofuran is added, air is replaced by nitrogen once (the nitrogen can be replaced when the pressure in the kettle is less than-0.08 MPa), an emptying valve is opened, and the temperature is reduced to be below-4 ℃ under the protection of nitrogen. 300kg (1.2 eq.) of methyl magnesium bromide is added dropwise by using a peristaltic pump, the dropping speed is controlled (the former 20 percent is 0.6kg/min, the later 80 percent is 0.8 kg/min), and the dropping temperature is not more than 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, the 2-chloronicotinic acid is remained 19.9 percent, the content of the dimethyl impurity is 1.3 percent, and the content of the product is 78.5 percent. Adding 350kg of water into another 3000L reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into the reaction kettle of 2000L, wherein the dropwise adding temperature is not more than 10 ℃. After the dripping is finished, stirring for 1h. Then 182L of hydrochloric acid of 6mol/L is added dropwise, and the dropping temperature is not more than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 200L of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. Then, the product is rectified under reduced pressure to obtain 73.5kg, and the yield is as follows: 73.8%, GC purity: 99.5 percent. FIG. 1 is a nuclear magnetic spectrum of 3-acetyl-2-chloropyridine synthesized in example 1. FIG. 2 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 1.
The rectification method comprises the following steps: adding the crude product of 3-acetyl-2-chloropyridine into the rectifying tower, heating, pumping to dry the low-boiling-point substances, distilling off the fraction when the liquid phase temperature rises to about 80 ℃, and when the liquid phase temperature rises to 120 ℃, distilling off no obvious fraction when the gas phase temperature rises to 80 ℃. Switching to a Roots pump, gradually increasing the gas phase temperature to about 130 deg.C, gradually increasing the liquid phase temperature to about 140 deg.C, evaporating the front fraction, sampling and detecting once every 20 minutes until the maximum impurity is less than 0.5%, switching to a main fraction collection tank (gradually decreasing the gas phase temperature to 116 deg.C, decreasing the liquid phase temperature to 124 deg.C), and separately placing the front fraction. GC monitoring is carried out every 1h, impurities are gradually increased after the main peak, and rectification is stopped when the impurities after the main peak are more than 0.5 percent.
Example 2
Synthesis of lithium 2-chloronicotinate: the same as in example 1.
Synthesis of acetyl-2-chloropyridine:
adding 20kg of 2-methyltetrahydrofuran into a 200L reaction kettle, starting stirring, adding 10kg of 2-chloronicotinic acid lithium salt, then adding 25kg of 2-methyltetrahydrofuran, replacing air once by nitrogen (the nitrogen can be replaced when the pressure in the kettle is less than-0.08 MPa), opening an air release valve, and cooling to below-4 ℃ under the protection of nitrogen. 30kg (1.2 eq.) of a tetrahydrofuran solution of methylmagnesium bromide is added dropwise by using a peristaltic pump, the dropping speed is controlled (0.5 kg/min), and the dropping temperature is controlled not to exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, the 2-chloronicotinic acid remains 19.8 percent, the content of the dimethyl impurity is 1.5 percent, and the content of the product is 78.3 percent. Adding 35kg of water into another 300L reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into a 200L reaction kettle, wherein the dropwise adding temperature is not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18L of 6mol/L hydrochloric acid is added dropwise, and the dropping temperature is not more than 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20L of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then 6.7kg of product is obtained by adopting the method of the embodiment 1 to carry out vacuum rectification, and the yield is as follows: 69.3%, GC purity: 99.2 percent. FIG. 3 is a GC diagram of 3-acetyl-2-chloropyridine synthesized in example 2.
Example 3
Synthesis of lithium 2-chloronicotinate:
adding 200g of tap water into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, adding 50g of aqueous solution of 17.2g (1 eq.) of lithium hydroxide monohydrate, reacting for 2h, opening cold brine, cooling to below 20 ℃, performing suction filtration, and drying in an oven until the water content is less than 1%, thus obtaining 61g of the product 2-chloronicotinic acid lithium salt with the yield of 98%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an air release valve, and cooling to below-4 ℃ under the protection of nitrogen. 25g (1.0 eq.) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the addition rate (0.5 g/min) was controlled so that the addition temperature did not exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 28.6 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.5 percent, and the content of the product is 69.6 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring is carried out for 1h. Then, 15mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 6.1g of the product, and the yield is as follows: 63.1%, GC purity: 99.4 percent.
Example 4
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq.) of a tetrahydrofuran solution of methylmagnesium bromide is added dropwise by using a peristaltic pump, the dropping speed is controlled (0.5 g/min), and the dropping temperature is controlled not to exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. As a result of HPLC detection, 18.3% of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.6%, and the content of the product is 79.8%. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.2g of the product, the yield is as follows: 74.5%, GC purity: 99.5 percent.
Example 5
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 37.5g (1.5 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 49.3 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 3.5 percent, and the content of the product is 46.7 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring is carried out for 1h. Then 24mL of 6mol/L hydrochloric acid is added dropwise, and the dropping temperature is not higher than 10 ℃. After the dripping is finished, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.0g of the product, and the yield is as follows: 72.4%, GC purity: 99.1 percent.
Example 6
Synthesis of lithium 2-chloronicotinate: the same as in example 3.
Synthesis of acetyl-2-chloropyridine:
adding 20g of 2-methyltetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. HPLC detection reaction results show that 20.1% of 2-chloronicotinic acid remains, the content of the dimethyl impurity is 1.6%, and the content of the product is 77.9%. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.1g of the product, and the yield is as follows: 73.5%, GC purity: 99.5 percent.
Example 7
Synthesis of lithium 2-chloronicotinate:
adding 100g of tap water and 14g (0.5 eq.) of lithium carbonate into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, starting stirring, controlling the temperature to be 80 ℃, reacting for 2 hours, opening cold brine, cooling to below 20 ℃, performing suction filtration, and drying in an oven to obtain 55.8g of the product 2-chloronicotinic acid lithium salt, wherein the yield is 89.8%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 10g of 2-chloronicotinic acid lithium salt, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq.) of a tetrahydrofuran solution of methyl magnesium bromide is added dropwise by using a peristaltic pump, the dropping speed (0.5 g/min) is controlled, and the dropping temperature is 10 to 15 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. And (3) detecting the reaction result by HPLC (high performance liquid chromatography), wherein 19.2% of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 1.7%, the content of the product is 78.8%, and the reaction is stopped. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 7.1g of the product, and the yield is as follows: 73.7%, GC purity: 99.1 percent.
Comparative example 1
Synthesis of 2-chloronicotinic acid sodium salt:
adding 100g of tap water and 15.2g (1 eq.) of sodium hydroxide into a 300mL reaction kettle, adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, distilling under reduced pressure to dry, then adding 150g of methanol, cooling to below 20 ℃, carrying out suction filtration, and drying in an oven to obtain 60g of the product 2-chloronicotinate, wherein the yield is 87.7%.
Synthesizing 3-acetyl-2-chloropyridine by using 2-chloronicotinate:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 11g of 2-chloronicotinate, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. According to the reaction result of HPLC detection, 38.8 percent of 2-chloronicotinic acid remains, the content of the dimethyl impurity is 3.2 percent, and the content of the product is 56.4 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After the dripping is finished, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 4.9g of product, the yield is as follows: 50.8%, GC purity: 98.1 percent.
Comparative example 2
Synthesis of 2-chloronicotinic acid sodium salt:
adding 100g of tap water and 20g of sodium carbonate (0.5 eq.) into a 300mL reaction kettle, quickly adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, opening cold brine, cooling to below 20 ℃, performing suction filtration, and drying in an oven to obtain 61.5g of the product 2-chloronicotinate, wherein the yield is 90%.
Synthesis of acetyl-2-chloropyridine:
adding 20g of tetrahydrofuran into a 200mL reaction kettle, starting stirring, adding 10g of 2-chloronicotinate, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 37.5g (1.5 eq.) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the addition rate (0.5 g/min) was controlled so that the addition temperature did not exceed 0 ℃. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. The reaction result is detected by HPLC, 32.1 percent of 2-chloronicotinic acid is remained, the content of the dimethyl impurity is 4.1 percent, and the content of the product is 63.2 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature not higher than 10 ℃. After the dripping is finished, stirring for 1h. Then 24mL of 6mol/L hydrochloric acid is added dropwise, and the dropping temperature is not higher than 10 ℃. After the dripping is finished, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no fractions below 80 ℃. And then the method of the embodiment 1 is adopted for reduced pressure rectification to obtain 4.8g of product, the yield is as follows: 55%, GC purity: 98.5 percent.
Comparative example 3
Synthesis of 2-chloronicotinic acid potassium salt:
adding 100g of tap water and 21.3g (1 eq.) of potassium hydroxide into a 300mL reaction kettle, adding 60g of 2-chloronicotinic acid into the reaction kettle, stirring, controlling the temperature to be 40-50 ℃, reacting for 2h, distilling under reduced pressure, adding 150g of methanol, cooling to below 20 ℃, filtering, and drying in an oven to obtain 66g of the 2-chloronicotinic acid potassium salt product with the yield of 88.6%.
Synthesizing 3-acetyl-2-chloropyridine by using 2-chloronicotinate:
adding 20g of tetrahydrofuran into a 200mL reaction bottle, starting stirring, adding 12g of 2-chloronicotinate, then adding 25g of tetrahydrofuran, replacing air once by nitrogen (replacing nitrogen when the pressure in the kettle is less than-0.08 MPa), opening an emptying valve, and cooling to below-4 ℃ under the protection of nitrogen. 30g (1.2 eq) of a tetrahydrofuran solution of methylmagnesium bromide was added dropwise by a peristaltic pump, and the dropping temperature was controlled so as not to exceed 0 ℃ at a rate of 0.5 g/min. Naturally heating to 15 ℃ after dripping, and reacting for 1h under the condition of heat preservation to obtain reaction liquid. According to the reaction result of HPLC detection, 49.3 percent of 2-chloronicotinic acid remains, the content of the dimethyl impurity is 3.5 percent, and the content of the product is 46.7 percent. Adding 35g of water into another 300mL reaction kettle, cooling to about 0 ℃ under the protection of nitrogen, and dropwise adding the reaction solution into 200mL reaction kettle at a temperature of not more than 10 ℃. After the dripping is finished, stirring for 1h. Then, 18mL of 6mol/L hydrochloric acid was added dropwise at a temperature not exceeding 10 ℃. After dripping, heating to 20-25 ℃, stirring for 2h, and standing for liquid separation. The aqueous phase is extracted once with 20mL of ethyl acetate, the organic phases are combined and concentrated to no distillate below 80 ℃. And then 3.8g of product is obtained by adopting the method of the embodiment 1 to carry out vacuum rectification, and the yield is as follows: 39.3%, GC purity: 98.2 percent.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (8)
1. A method for synthesizing 3-acetyl-2-chloropyridine, which is characterized by comprising the following steps:
taking 2-chloronicotinic acid as a raw material, reacting with a lithium-containing compound to generate 2-chloronicotinic acid lithium salt, drying the 2-chloronicotinic acid lithium salt, and then performing addition reaction with methyl magnesium bromide to generate 3-acetyl-2-chloropyridine; the lithium-containing compound is lithium hydroxide monohydrate;
the step of generating the lithium 2-chloronicotinate comprises the following steps: and (2) taking water as a solvent, and contacting the 2-chloronicotinic acid with a lithium-containing compound for reaction to obtain the 2-chloronicotinic acid lithium salt.
2. The synthesis method according to claim 1, wherein the molar ratio of the 2-chloronicotinic acid to the lithium-containing compound is 0.9 to 1.0:1;
the reaction temperature for generating the 2-chloronicotinic acid lithium salt is 40 to 50 ℃.
3. The method of claim 1, wherein the step of performing an addition reaction of the lithium 2-chloronicotinate salt with the methyl magnesium bromide comprises:
(1) Under the protection of inert gas, stirring and mixing a first organic solvent and 2-chloronicotinic acid lithium salt, then dropwise adding methyl magnesium bromide, and naturally heating to the addition reaction temperature for reaction after dropwise adding to obtain a reaction solution;
(2) Under the protection of inert gas, dropwise adding the reaction liquid into low-temperature water, stirring for the first time, dropwise adding hydrochloric acid, heating to 20-25 ℃ after dropwise adding, stirring for the second time, standing for liquid separation, extracting the water phase with a second organic solvent, combining the organic phases, and concentrating to obtain the target product.
4. The synthetic method according to claim 3, wherein, in step (1),
the first organic solvent is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran;
the molar ratio of the 2-chloronicotinic acid lithium salt to the methyl magnesium bromide is 1:1 to 1.5;
the dropping speed of the methyl magnesium bromide is 0.9 to 1.8kg/min per 1000kg of reaction system;
before dropping methyl magnesium bromide, controlling the temperature of the system to be below-4 ℃, and controlling the temperature of the system to be not more than 0 ℃ in the dropping process;
the addition reaction temperature is 12 to 18 ℃, and the reaction time is 0.5 to 1.5h;
the inert gas is nitrogen.
5. The synthetic method according to claim 3, wherein, in the step (2),
the temperature of the low-temperature water is below 4 ℃;
the mass of the low-temperature water is 0.3 to 0.5kg relative to 1kg of the reaction liquid;
the temperature of the system is controlled not to exceed 15 ℃ in the dropping process;
the first time is 0.5 to 1.5h;
the molar addition amount of the hydrochloric acid is 1.8 to 2.0 times of the molar feeding amount of the 2-chloronicotinic acid lithium salt;
the second time is 1.5 to 2.5 hours;
the second organic solvent is selected from at least one of ethyl acetate, dichloromethane and methyl tert-butyl ether;
the inert gas is nitrogen.
6. The synthesis method according to claim 3, wherein the method and criteria for performing step (2) are judged as: and (3) detecting the reaction result by HPLC, wherein the 2-chloronicotinic acid in the system is less than 21 percent, and performing the step (2).
7. The method of any one of claims 1-6, wherein the drying results in a water content of the lithium 2-chloronicotinate of less than 1%.
8. A synthesis method according to any one of claims 1 to 6, wherein the method further comprises a rectification step: adding a 3-acetyl-2-chloropyridine crude product into a rectifying tower, starting heating, starting an oil pump to dry low-boiling-point substances, switching to a roots pump, gradually increasing the gas phase temperature until front fraction is evaporated, periodically sampling and detecting, switching to a main fraction collecting tank when the maximum impurity is less than 0.5%, periodically sampling and detecting, and stopping rectification when the impurity is more than 0.5% after a main peak to obtain a 3-acetyl-2-chloropyridine product.
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