CN115181062A - Preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester - Google Patents
Preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester Download PDFInfo
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- CN115181062A CN115181062A CN202210710436.4A CN202210710436A CN115181062A CN 115181062 A CN115181062 A CN 115181062A CN 202210710436 A CN202210710436 A CN 202210710436A CN 115181062 A CN115181062 A CN 115181062A
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- Prior art keywords
- methyl
- methylpyridine
- chloro
- carboxylic acid
- ethyl ester
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- XWPSWOKQWBNRDW-UHFFFAOYSA-N methyl 6-chloro-3-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=NC(Cl)=CC=C1C XWPSWOKQWBNRDW-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- TZGLJGUBXFTQIU-UHFFFAOYSA-N ethyl 3-methyl-1-oxidopyridin-1-ium-2-carboxylate Chemical compound CCOC(=O)C1=C(C)C=CC=[N+]1[O-] TZGLJGUBXFTQIU-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000002156 mixing Methods 0.000 claims abstract description 33
- VKKVFRWNHZHHQU-UHFFFAOYSA-N ethyl 3-methylpyridine-2-carboxylate Chemical compound CCOC(=O)C1=NC=CC=C1C VKKVFRWNHZHHQU-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 28
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 24
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000012320 chlorinating reagent Substances 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 239000012074 organic phase Substances 0.000 description 42
- 239000000243 solution Substances 0.000 description 42
- 238000003756 stirring Methods 0.000 description 38
- 238000001914 filtration Methods 0.000 description 25
- 238000002390 rotary evaporation Methods 0.000 description 21
- 239000011259 mixed solution Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 238000001816 cooling Methods 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 15
- 230000008025 crystallization Effects 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000004949 mass spectrometry Methods 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 239000005457 ice water Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- CCQFKEITVOTHIW-UHFFFAOYSA-N methyl 3-methylpyridine-2-carboxylate Chemical compound COC(=O)C1=NC=CC=C1C CCQFKEITVOTHIW-UHFFFAOYSA-N 0.000 description 7
- 238000005086 pumping Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 101150109738 Ptger4 gene Proteins 0.000 description 6
- 239000002464 receptor antagonist Substances 0.000 description 6
- 229940044551 receptor antagonist Drugs 0.000 description 6
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 229940111134 coxibs Drugs 0.000 description 4
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000010979 pH adjustment Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- LMHIBYREWJHKNZ-UHFFFAOYSA-N 3-methylpyridine-2-carboxylic acid Chemical compound CC1=CC=CN=C1C(O)=O LMHIBYREWJHKNZ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- -1 PGU and TxA 2) Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. The invention provides a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, which comprises the following steps: mixing 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent, and carrying out oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide; and mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent, and carrying out chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. The preparation method provided by the invention can be used for preparing 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, and the preparation raw materials are easy to obtain, the operation is simple, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
Background
Arthritis generally refers to an inflammatory disease occurring in joints and their surrounding tissues of the human body, and arthritis is a major cause of disability. Drugs for treating arthritis generally include NSAIDs (non-steroidal anti-inflammatory drugs) or COX-2 inhibitors, but the use of NSAIDs or COX-2 inhibitors may cause side effects and may adversely affect the cardiovascular system. Thus, patients with poor cardiovascular conditions (e.g., hypertension) are unable to use NSAIDs or COX-2 inhibitors.
The research shows that the prostaglandin E 2 (PGE 2 ) EP4 of the receptor subtype is the major receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis. Selective EP4 receptor antagonists are useful in the treatment of arthritis. The selective EP4 receptor antagonists have the structural formula
Since selective EP4 receptor antagonists do not interfere with the biosynthesis of prostaglandins (e.g., PGU and TxA 2), selective EP4 receptor antagonists do not have the cardiovascular side effects of NSAIDs and COX-2 inhibitors.
6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester (C) 8 H 8 ClNO 2 ) Is an intermediate for the synthesis of selective EP4 receptor antagonists. However, there are few reports on the synthesis method of methyl 3-methyl-6-chloropyridate.
Disclosure of Invention
In view of the above, the present invention provides a preparation method of methyl 6-chloro-3-methyl-2-pyridinecarboxylate, which can prepare methyl 6-chloro-3-methyl-2-pyridinecarboxylate for synthesizing selective EP4 receptor antagonist.
In order to solve the technical problems, the invention provides a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, which comprises the following steps:
mixing 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent, and carrying out oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
and mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent for chlorination reaction to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
Preferably, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester to the m-chloroperoxybenzoic acid is 1 (2-7).
Preferably, the volume ratio of the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester to the first organic solvent is 1g (8-15) mL.
Preferably, the temperature of the oxidation reaction is 20-40 ℃ and the time is 10-20 h.
Preferably, the temperature of the chlorination reaction is 20-40 ℃ and the time is 8-15 h.
Preferably, the chlorinating agent comprises phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride.
Preferably, the catalyst comprises N, N-dimethylformamide, palladium trichloride, ferric chloride or aluminium chloride.
Preferably, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the chlorinating agent is 1 (3-7);
the molar ratio of the catalyst to the chlorinating agent is 1 (1-5).
Preferably, the volume ratio of the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the second organic solvent is 1g (8-15) mL.
Preferably, the first organic solvent and the second organic solvent independently comprise dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran.
The invention provides a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, which comprises the following steps: mixing 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent, and carrying out oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide; and mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent, and carrying out chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. According to the preparation method provided by the invention, the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester can be prepared, and the prepared 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester has high yield and purity; the yield of the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester prepared by the preparation method provided by the invention is more than 63%, and the purity is more than 96%. The preparation method provided by the invention has the advantages of easily available preparation raw materials, simple operation and suitability for industrial production.
Detailed Description
The invention provides a preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester, which comprises the following steps:
mixing 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent for oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
and mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent, and carrying out chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
In the present invention, all the raw materials are commercially available products well known to those skilled in the art, unless otherwise specified.
The 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent are mixed for oxidation reaction to obtain the 3-methylpyridine-2-carboxylic acid ethyl ester oxide. In the present invention, the mixing preferably comprises the steps of:
dissolving 3-methylpyridine-2-carboxylic acid ethyl ester in a first organic solvent to obtain a 3-methylpyridine-2-carboxylic acid ethyl ester solution;
and (3) firstly mixing the 3-methylpyridine-2-carboxylic acid ethyl ester solution and m-chloroperoxybenzoic acid to obtain a solution to be reacted.
The invention dissolves 3-methylpyridine-2-carboxylic acid ethyl ester in a first organic solvent to obtain a 3-methylpyridine-2-carboxylic acid ethyl ester solution. In the present invention, the ethyl 3-methylpyridine-2-carboxylate is purchased from Annaiji chemical industry. In the present invention, the first organic solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran, and more preferably dichloromethane, acetone or acetonitrile. In the present invention, the ratio of the mass of the ethyl 3-methylpyridine-2-carboxylate to the volume of the first organic solvent is preferably 1g (8 to 15) mL, more preferably 1g (9 to 12) mL. In the present invention, the temperature of the dissolution is preferably-1 to 1 ℃, more preferably 0 ℃. The invention can be dissolved at low temperature to avoid violent reaction and explosion. The invention has no special requirements on the dissolving mode as long as the dissolving can be completely carried out.
After the 3-methylpyridine-2-carboxylic acid ethyl ester solution is obtained, the 3-methylpyridine-2-carboxylic acid ethyl ester solution and m-chloroperoxybenzoic acid are firstly mixed to obtain a solution to be reacted. In the present invention, the molar ratio of the ethyl 3-methylpyridine-2-carboxylate to m-chloroperoxybenzoic acid is preferably 1 (2 to 7), more preferably 1 (3 to 6.5). In the present invention, the first mixing is preferably performed under stirring conditions, and the rotation speed of the stirring is preferably 800 to 1000r/min, and more preferably 850 to 950r/min; the stirring time is preferably 10 to 20min, more preferably 15 to 18min.
In the present invention, the m-chloroperoxybenzoic acid is an oxidizing agent, and the m-chloroperoxybenzoic acid is an organic reagent having both oxidizing and acidic properties.
In the present invention, the temperature of the oxidation reaction is preferably 20 to 40 ℃, more preferably 15 to 30 ℃; the heating rate for heating to the temperature required by the oxidation reaction is preferably 2-10 ℃/min, more preferably 4-6 ℃/min; the time for the oxidation reaction is preferably 10 to 20 hours, more preferably 13 to 17 hours.
In the invention, the structural formula of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide is shown as a formula a:
in the present invention, it is preferable that the oxidation reaction further comprises:
adjusting the pH value of the system after the oxidation reaction to 6.5-7.5;
extracting the solution after the pH value is adjusted, and taking an organic phase;
and dehydrating the organic phase, and then sequentially filtering and rotary evaporating to obtain the 3-methylpyridine-2-carboxylic acid ethyl ester oxide.
The invention adjusts the pH value of the system after the oxidation reaction to be 6.5-7.5. In the present invention, the pH of the solution after the pH adjustment is preferably 7 to 7.3. In the present invention, the pH adjustor for adjusting pH preferably includes an aqueous sodium bicarbonate solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution or an aqueous sodium hydroxide solution; the mass concentration of the pH adjuster is preferably 10 to 20%, and more preferably 15 to 18%. The amount of the pH regulator used in the present invention is not particularly limited as long as the desired pH can be achieved. In the present invention, the pH is preferably adjusted by stirring, and the stirring time is preferably 20 to 40min, more preferably 25 to 30min. The invention has no special requirement on the rotating speed of the stirring, and can adopt any rotating speed.
After the pH value is adjusted, the solution after the pH value is adjusted is extracted, and an organic phase is taken. In the present invention, the extractant for extraction preferably includes ethyl acetate. In the present invention, the volume ratio of the solution after the pH adjustment to the extractant is preferably 1 (0.8 to 2), more preferably 1 (1 to 1.5). The extraction method is not particularly limited, and the conventional method in the field can be adopted.
After the organic phase is obtained, the organic phase is dehydrated and then sequentially filtered and rotary evaporated to obtain the 3-methylpyridine-2-carboxylic acid ethyl ester oxide. In the present invention, the dehydrating solvent for dehydration preferably contains anhydrous sodium sulfate. In the present invention, the ratio of the mass of the anhydrous sodium sulfate to the volume of the organic phase is preferably (0.07 to 0.3) g:1mL, and more preferably (0.071 to 0.12) g:1mL. In the present invention, the filtration removes the dehydrating agent. The present invention has no special requirements for the filtration, and can be carried out by adopting a conventional mode in the field. In the present invention, the temperature of the rotary evaporation is preferably 40 to 50 ℃, more preferably 45 to 48 ℃. In the present invention, the volume ratio of the liquid after rotary evaporation to the organic phase after dehydration is preferably (0.2 to 0.5): 1, more preferably (0.2 to 0.5): 1. The invention has no special requirement on the rotary evaporation time as long as the volume ratio of the liquid after rotary evaporation to the organic phase after dehydration can be satisfied.
In the present invention, the ethyl 3-methylpyridine-2-carboxylate oxide is a yellow solution.
After the 3-methylpyridine-2-carboxylic acid ethyl ester oxide is obtained, the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent are mixed for chlorination reaction to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the present invention, the mixing preferably comprises the steps of:
premixing a second organic solvent, a chlorinating agent and a catalyst to obtain a mixed solution;
and secondly, mixing the mixed solution with 3-methylpyridine-2-carboxylic acid ethyl ester oxide to obtain a reaction solution to be subjected to chlorination reaction.
The second organic solvent, the chlorinating agent and the catalyst are premixed to obtain a mixed solution. In the present invention, the second organic solvent preferably includes dichloromethane, chloroform, acetone, acetonitrile or tetrahydrofuran, and more preferably dichloromethane, chloroform or acetone. In the present invention, the chlorinating agent preferably comprises phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride, more preferably iron trichloride, thionyl chloride or carbon tetrachloride. In the present invention, the catalyst preferably comprises N, N-dimethylformamide, palladium trichloride, iron chloride or aluminum chloride, more preferably iron chloride or aluminum chloride. The invention can be carried out only under the action of the catalyst. In the present invention, the molar ratio of the catalyst to the chlorinating agent is preferably 1 (1 to 5), more preferably 1 (1.2 to 3.3).
In the present invention, the premixing is preferably carried out under the condition of ice bath with stirring; the rotating speed of the stirring is preferably 800-1000 r/min, and more preferably 850-950 r/min; the stirring time is preferably 20 to 40min, more preferably 25 to 30min.
After the mixed solution is obtained, the mixed solution and the 3-methylpyridine-2-carboxylic acid ethyl ester oxide are mixed for the second time to obtain a reaction solution to be subjected to chlorination reaction. In the present invention, the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the chlorinating agent is preferably 1 (3 to 7), and more preferably 1 (4 to 6). In the present invention, the ratio of the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the volume of the second organic solvent is preferably 1g (8 to 15) mL, and more preferably 1g (10 to 12) mL. The second mixing mode is not particularly required, and the second mixing mode can be mixed uniformly.
In the present invention, the temperature of the chlorination reaction is preferably 20 to 40 ℃, more preferably 30 to 35 ℃; the time of the chlorination reaction is preferably 8 to 18 hours, and more preferably 10 to 15 hours. The invention preferably quenches the chlorination reaction by mixing the chlorination reaction product with an ice water mixture. In the present invention, the volume ratio of the chlorination reaction product to the ice-water mixture is preferably 0.8 to 1.2, more preferably 1.
In the present invention, it is preferable that the chlorination reaction further comprises:
adjusting the pH value of the product after quenching reaction to 7.5-8.5;
extracting the system with the adjusted pH value to obtain an organic phase;
dehydrating the organic phase, and then sequentially filtering and rotary evaporating to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester;
and (3) recrystallizing and drying the crude product of the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in sequence to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The invention adjusts the pH value of the product after quenching reaction to 7.5-8.5. In the present invention, the pH value of the system after adjusting the pH value is preferably 8 to 8.3. In the present invention, the pH adjustor for adjusting pH preferably includes an aqueous solution of sodium carbonate, an aqueous solution of potassium carbonate, an aqueous solution of sodium hydrogencarbonate or aqueous solution of sodium hydroxide; the mass concentration of the pH adjuster is preferably 10 to 20%, and more preferably 15 to 18%. The amount of the pH regulator used in the present invention is not particularly limited as long as the desired pH can be achieved. In the present invention, the pH adjustment is preferably accompanied by stirring, and the stirring time is preferably 0.8 to 1.2 hours, more preferably 1 hour. The stirring speed is not particularly limited, and any rotating speed can be adopted.
The invention makes the 6-chlorine-3-methyl-2-pyridine carboxylic acid methyl ester separated out in alkaline environment after adjusting the pH value.
After the pH value is adjusted, the system for adjusting the pH value is extracted to obtain an organic phase. In the present invention, the extractant for extraction preferably includes ethyl acetate. In the present invention, the volume ratio of the system after the pH adjustment to the extractant is preferably 1 (1 to 5), and more preferably 1 (2 to 4). The extraction mode is not particularly limited in the invention, and the conventional mode in the field can be adopted.
After an organic phase is obtained, the organic phase is dehydrated, and then is sequentially filtered and steamed in a rotary mode to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the present invention, the dehydrating reagent for dehydration preferably comprises anhydrous sodium sulfate. In the present invention, the ratio of the mass of the anhydrous sodium sulfate to the volume of the organic phase is preferably (0.1 to 0.3) g:1mL, more preferably (0.1 to 0.15) g:1mL. In the present invention, the filtration removes the dehydrating agent. The present invention has no special requirements for the filtration, and can be carried out by adopting a conventional mode in the field. In the present invention, the rotary evaporation is used to remove the extractant; the rotary evaporation temperature is preferably 40-50 ℃, and more preferably 45-48 ℃. The invention has no special requirement on the rotary evaporation time as long as the extractant can be removed.
After the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is obtained, the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester is recrystallized and dried in sequence to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester. In the invention, the recrystallization is preferably carried out by dissolving crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in petroleum ether and then cooling for crystallization. In the present invention, the ratio of the mass of the crude methyl 6-chloro-3-methyl-2-pyridinecarboxylate to the volume of petroleum ether is preferably 1g (0.3 to 0.6) mL, more preferably 1g (0.4 to 0.5) mL. In the present invention, the drying is preferably a suction drying, and the suction drying preferably includes a water pump suction or an oil pump suction, and more preferably an oil pump suction.
In the present invention, methyl 6-chloro-3-methyl-2-pyridinecarboxylate is a yellow solid.
In the present invention, the reaction equation for synthesizing methyl 6-chloro-3-methyl-2-pyridinecarboxylate is shown in formula 1:
in order to further illustrate the present invention, the following embodiments are described in detail, but they should not be construed as limiting the scope of the present invention.
Example 1
Dissolving 12.0g of methyl 3-methylpyridine-2-carboxylate in 120mL of dichloromethane at 0 ℃ to obtain a 3-methylpyridine-2-carboxylate solution; stirring 3-methylpyridine-2-carboxylic acid ethyl ester solution and 88g of m-chloroperoxybenzoic acid for 15min at the temperature of 0 ℃ and the rotating speed of 800r/min, and then heating to 25 ℃ according to the heating rate of 6 ℃/min for oxidation reaction for 16h; adjusting the pH value of the system after the oxidation reaction to be 7 by using a sodium bicarbonate solution with the mass concentration of 20% (stirring for 30 min); extracting with 130mL ethyl acetate to obtain an organic phase; mixing 10g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on a filtrate obtained by filtering at 40 ℃ to obtain 9.5mL (8.49 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 10mL of LN, 50mL of dimethylformamide, 50mL of dichloromethane and 15mL of phosphorus trichloride for 30min under the ice-bath condition at the rotating speed of 800r/min to obtain a mixed solution; mixing the mixed solution with 5g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 30 ℃ for 10 hours, pouring the mixture into 50mL of ice-water mixture for quenching reaction, and then adjusting the pH value to 8 by using a sodium carbonate aqueous solution with the mass concentration of 10% (with stirring for 1 hour); extracting the solution with the adjusted pH value by using 150mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase with 20g of anhydrous sodium sulfate, filtering, and performing rotary evaporation on the filtered filtrate at 40 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 5mL of petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer, and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 168.3 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 185.7 (M + H) + 。
Example 2
6.0g of methyl 3-methylpyridine-2-carboxylate was dissolved in 60mL of chloroform at 0 ℃ to obtain a solution of ethyl 3-methylpyridine-2-carboxylate; stirring 3-methylpyridine-2-carboxylic acid ethyl ester solution and 45g of m-chloroperoxybenzoic acid for 15min at the temperature of 0 ℃ and the rotating speed of 900r/min, and then heating to 20 ℃ according to the heating rate of 6 ℃/min for oxidation reaction for 15h; adjusting the pH value of the system after the oxidation reaction to be 6.5 by using a sodium bicarbonate solution with the mass concentration of 10% (stirring for 30 min); extracting with 70mL ethyl acetate to obtain an organic phase; mixing 5g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on a filtrate obtained by filtering at 45 ℃ to obtain 4.7mL (4.92 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 3g of ferric chloride, 25mL of chloroform and 8mL of phosphorus pentachloride for 30min under the ice bath condition at the rotating speed of 900r/min to obtain a mixed solution; mixing the mixed solution with 2g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 35 ℃ for 12 hours, pouring the mixture into 30mL of ice-water mixture for quenching reaction, and then adjusting the pH value to 7.5 by using a sodium carbonate aqueous solution with the mass concentration of 10% (stirring for 1 hour); extracting the solution after the pH value is adjusted by using 80mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase by 10g of anhydrous sodium sulfate, filtering, and carrying out rotary evaporation on the filtrate obtained by filtering at 45 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 5mL of petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer, and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 168.2 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 186.1 (M + H) + 。
Example 3
Dissolving 7.20g of 3-methylpyridine-2-carboxylic acid methyl ester in 75mL of acetone at the temperature of 0 ℃ to obtain a 3-methylpyridine-2-carboxylic acid ethyl ester solution; stirring 3-methylpyridine-2-carboxylic acid ethyl ester solution and 53g of m-chloroperoxybenzoic acid for 15min at the temperature of 0 ℃ and the rotating speed of 850r/min, and then heating to 30 ℃ according to the heating rate of 4 ℃/min for oxidation reaction for 17h; adjusting the pH value of the system after the oxidation reaction to be 7.5 by using a sodium carbonate solution with the mass concentration of 10% (stirring for 30 min); extracting with 60mL ethyl acetate to obtain an organic phase; mixing 7g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on a filtrate obtained by filtering at 45 ℃ to obtain 5.6mL (5.01 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 3.5g of aluminum chloride, 30mL of acetone and 9mL of thionyl chloride for 30min at the rotating speed of 850r/min under the ice bath condition to obtain a mixed solution; mixing the mixed solution with 3g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 30 ℃ for 10 hours, pouring the mixture into 40mL of ice-water mixture for quenching reaction, and then adjusting the pH value to 8.5 by using a sodium bicarbonate aqueous solution with the mass concentration of 20% (with stirring for 1 hour); extracting the solution with the pH value adjusted by 90mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase by using 10g of anhydrous sodium sulfate, filtering, and performing rotary evaporation on the filtered filtrate at 45 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 3mL petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer, and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 167.8 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 185.2 (M + H) + 。
Example 4
Dissolving 8.5g of methyl 3-methylpyridine-2-carboxylate in 90mL of acetonitrile at 0 ℃ to obtain a solution of ethyl 3-methylpyridine-2-carboxylate; stirring 3-methylpyridine-2-carboxylic acid ethyl ester solution and 61g of m-chloroperoxybenzoic acid for 15min at the temperature of 0 ℃ and the rotating speed of 950r/min, and then heating to 40 ℃ according to the heating rate of 4 ℃/min for oxidation reaction for 13h; regulating (stirring for 30 min) the pH value of the system after the oxidation reaction to 6.5 by using a potassium carbonate solution with the mass concentration of 15%; extracting with 100mL ethyl acetate to obtain an organic phase; mixing 10g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on the filtered filtrate at 50 ℃ to obtain 6.6mL (5.89 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
7mLN, N-dimethylformamide, 35mL acetonitrile and 11mL carbon tetrachloride are stirred for 30min under the ice bath condition at the rotating speed of 950r/min to obtain a mixed solution; mixing the mixed solution with 3.5g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 35 ℃ for 18h, pouring the mixture into 50mL of ice-water mixture for quenching reaction, and adjusting the pH value to 8 by using a potassium carbonate aqueous solution with the mass concentration of 20% (with stirring for 1 h); extracting the solution with the adjusted pH value by using 150mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase by using 15g of anhydrous sodium sulfate, filtering, and carrying out rotary evaporation on the filtered filtrate at 50 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 5mL of petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 169.1 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 186.4 (M + H) + 。
Example 5
24.0g of methyl 3-methylpyridine-2-carboxylate is dissolved in 240mL of tetrahydrofuran at 0 ℃ to obtain a solution of ethyl 3-methylpyridine-2-carboxylate; stirring 3-methylpyridine-2-carboxylic ethyl ester solution and 175g of m-chloroperoxybenzoic acid at the temperature of 0 ℃ and the rotating speed of 1000r/min for 15min, and then heating to 30 ℃ according to the heating rate of 10 ℃/min for oxidation reaction for 20h; adjusting (stirring for 30 min) the pH value of the system after the oxidation reaction to 7 by using a sodium hydroxide solution with the mass concentration of 20%; extracting with 250mL ethyl acetate to obtain an organic phase; mixing 30g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on a filtrate obtained by filtering at 40 ℃ to obtain 19mL (16.97 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 20mLN, N-dimethylformamide, 100mL of tetrahydrofuran and 30mL of oxalyl chloride for 30min under the ice-bath condition at the rotating speed of 1000r/min to obtain a mixed solution; mixing the mixed solution with 10g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 30 ℃ for 10 hours, pouring the mixture into 100mL of ice-water mixture for quenching reaction, and adjusting the pH value to be 8 by using a 10% sodium hydroxide aqueous solution (with stirring for 1 hour); extracting the solution after the pH value is adjusted by using 250mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase by using 25g of anhydrous sodium sulfate, filtering, and performing rotary evaporation on the filtered filtrate at 40 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 20mL petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer, and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 168.5 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 186.3 (M + H) + 。
Example 6
120g 3-methyl pyridine-2-carboxylic acid methyl ester is dissolved in 1200mL dichloromethane at 0 ℃ to obtain 3-methyl pyridine-2-carboxylic acid ethyl ester solution; stirring 3-methylpyridine-2-carboxylic ethyl ester solution and 880g of m-chloroperoxybenzoic acid at the temperature of 0 ℃ and the rotating speed of 900r/min for 15min, and then heating to 25 ℃ according to the heating rate of 3 ℃/min for oxidation reaction for 16h; adjusting the pH value of the system after the oxidation reaction to be 7 by using a sodium bicarbonate solution with the mass concentration of 20% (stirring for 30 min); extracting with 1300mL ethyl acetate to obtain an organic phase; mixing 130g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on the filtered filtrate at 40 ℃ to obtain 78.4mL (70.1 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 100mLN, N-dimethylformamide, 500mL dichloromethane and 150mL phosphorus trichloride for 30min under the ice bath condition at the rotating speed of 900r/min to obtain a mixed solution; mixing the mixed solution with 50g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 30 ℃ for 10 hours, pouring the mixture into 500mL of ice-water mixture for quenching reaction, and then adjusting the pH value to 8 by using a sodium carbonate aqueous solution with the mass concentration of 10% (stirring for 1 hour); extracting the solution after the pH value is adjusted by 1500mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase by using 200g of anhydrous sodium sulfate, filtering, and carrying out rotary evaporation on the filtered filtrate at 40 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 50mL of petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
The prepared ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate were examined by a liquid chromatography-mass spectrometer and the obtained purities are shown in table 1. Mass Spectrometry (M/z) of ethyl 3-methylpyridine-2-carboxylate oxide 168.2 (M + H) + (ii) a Mass Spectrometry (M/z) of methyl 6-chloro-3-methyl-2-pyridinecarboxylate 186.2 (M + H) + 。
From the mass spectrum results of examples 1 to 6, it was found that the substance produced by the production method provided by the present invention was methyl 6-chloro-3-methyl-2-pyridinecarboxylate.
Comparative example 1
The methyl 6-chloro-3-methyl-2-pyridinecarboxylate was prepared according to the method of example 1, except that acetic acid and hydrogen peroxide were used as the oxidizing agent, the specific steps were as follows:
mixing 5g of 3-methylpyridine-2-carboxylic acid methyl ester, 50g of acetic acid and 35g of hydrogen peroxide, and then carrying out oxidation reaction at 60 ℃ for 8h; adjusting the pH value of the system after the oxidation reaction to be 7 by using a sodium bicarbonate solution with the mass concentration of 20% (stirring for 30 min); extracting with 100mL ethyl acetate to obtain an organic phase; mixing 10g of anhydrous sodium sulfate and an organic phase, dehydrating, filtering, and performing rotary evaporation on the filtered filtrate at 40 ℃ to obtain 2.8mL (2.5 g) of 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
stirring 10mL of LN, 50mL of dimethylformamide, 50mL of dichloromethane and 15mL of phosphorus trichloride for 30min under the ice bath condition at the rotating speed of 900r/min to obtain a mixed solution; mixing the mixed solution with 5g of 3-methylpyridine-2-carboxylic acid ethyl ester oxide, performing chlorination reaction at 30 ℃ for 10 hours, pouring the mixture into 50mL of ice water mixture for quenching reaction, and then adjusting the pH value to 8 by using a sodium carbonate aqueous solution with the mass concentration of 10% (stirring for 1 hour); extracting the solution with the adjusted pH value by using 150mL of ethyl acetate to obtain an organic phase; dehydrating the organic phase with 20g of anhydrous sodium sulfate, filtering, and performing rotary evaporation on the filtered filtrate at 40 ℃ to obtain a crude product of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester; dissolving the crude 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester in 5mL of petroleum ether for cooling crystallization, and pumping the solid obtained by cooling crystallization by an oil pump to obtain the 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
Comparative example 2
Methyl 6-chloro-3-methyl-2-pyridinecarboxylate was prepared according to the method of example 1, except that no catalyst was added, i.e., no 10ml N, N-dimethylformamide was added during the chlorination reaction.
The purities of the ethyl 3-methylpyridine-2-carboxylate oxide and methyl 6-chloro-3-methyl-2-pyridinecarboxylate prepared in comparative example 1 and 2 were measured using a liquid chromatography-mass spectrometer, and the results are shown in table 1.
TABLE 1 yield and purity of the products prepared in examples 1-6
As can be seen from Table 1, the methyl 6-chloro-3-methyl-2-pyridinecarboxylate prepared by the preparation method provided by the present invention has high yield and purity.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (10)
1. A preparation method of 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester comprises the following steps:
mixing 3-methylpyridine-2-carboxylic acid ethyl ester, m-chloroperoxybenzoic acid and a first organic solvent, and carrying out oxidation reaction to obtain 3-methylpyridine-2-carboxylic acid ethyl ester oxide;
and mixing the 3-methylpyridine-2-carboxylic acid ethyl ester oxide, a chlorinating agent, a catalyst and a second organic solvent, and carrying out chlorination reaction to obtain 6-chloro-3-methyl-2-pyridinecarboxylic acid methyl ester.
2. The preparation method according to claim 1, wherein the molar ratio of the ethyl 3-methylpyridine-2-carboxylate to the m-chloroperoxybenzoic acid is 1 (2-7).
3. The preparation method according to claim 1, wherein the volume ratio of the mass of the ethyl 3-methylpyridine-2-carboxylate to the first organic solvent is 1g (8-15) mL.
4. The process according to any one of claims 1 to 3, wherein the oxidation reaction is carried out at a temperature of 20 to 40 ℃ for a time of 10 to 20 hours.
5. The preparation method according to claim 1, wherein the chlorination reaction is carried out at a temperature of 20-40 ℃ for 8-18 h.
6. The method according to claim 1, wherein the chlorinating agent comprises phosphorus trichloride, phosphorus pentachloride, thionyl chloride, carbon tetrachloride or oxalyl chloride.
7. The method of claim 1, wherein the catalyst comprises N, N-dimethylformamide, palladium trichloride, ferric chloride, or aluminum chloride.
8. The production process according to claim 1, 5 or 6, wherein the molar ratio of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the chlorinating agent is 1 (3-7);
the molar ratio of the catalyst to the chlorinating agent is 1 (1-5).
9. The method according to claim 1, wherein the volume ratio of the mass of the 3-methylpyridine-2-carboxylic acid ethyl ester oxide to the second organic solvent is 1g (8-15) mL.
10. The method of claim 1, wherein the first organic solvent and the second organic solvent independently comprise dichloromethane, chloroform, acetone, acetonitrile, or tetrahydrofuran.
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| CN111393361A (en) * | 2019-12-30 | 2020-07-10 | 浙江日出药业有限公司 | Safe and environment-friendly 2-chloronicotinic acid synthesis method |
| CN112279804A (en) * | 2020-11-20 | 2021-01-29 | 上海凌凯医药科技有限公司 | Method for preparing 2-chloro-4-neopentyl pyridine |
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