CN117946000A - Synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylic acid methyl ester - Google Patents
Synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylic acid methyl ester Download PDFInfo
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- DYVBKZSTFRYZKE-UHFFFAOYSA-N methyl 1-methyl-2-oxoquinoline-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=CC(=O)N(C)C2=C1 DYVBKZSTFRYZKE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 230000029936 alkylation Effects 0.000 claims abstract 2
- 238000005804 alkylation reaction Methods 0.000 claims abstract 2
- 230000032050 esterification Effects 0.000 claims abstract 2
- 238000005886 esterification reaction Methods 0.000 claims abstract 2
- 230000003647 oxidation Effects 0.000 claims abstract 2
- 238000007254 oxidation reaction Methods 0.000 claims abstract 2
- 230000008707 rearrangement Effects 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003208 petroleum Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- HBHLDFROPPTEDU-UHFFFAOYSA-N 4-bromo-1-methylquinolin-2-one Chemical compound C1=CC=C2C(Br)=CC(=O)N(C)C2=C1 HBHLDFROPPTEDU-UHFFFAOYSA-N 0.000 claims description 15
- TVKJUZLWHSECDN-UHFFFAOYSA-N 4-bromo-1-oxidoquinolin-1-ium Chemical compound C1=CC=C2[N+]([O-])=CC=C(Br)C2=C1 TVKJUZLWHSECDN-UHFFFAOYSA-N 0.000 claims description 15
- SUXIPCHEUMEUSV-UHFFFAOYSA-N 4-bromoquinoline Chemical compound C1=CC=C2C(Br)=CC=NC2=C1 SUXIPCHEUMEUSV-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WIVIYVYDZYAUMB-UHFFFAOYSA-N 4-bromo-1h-quinolin-2-one Chemical compound C1=CC=C2C(Br)=CC(=O)NC2=C1 WIVIYVYDZYAUMB-UHFFFAOYSA-N 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 239000005457 ice water Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 125000006267 biphenyl group Chemical group 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- IBZUISWMZGLPKG-UHFFFAOYSA-N phosphoric acid azide Chemical compound [N-]=[N+]=[N-].OP(O)(O)=O IBZUISWMZGLPKG-UHFFFAOYSA-N 0.000 claims description 5
- PMZDQRJGMBOQBF-UHFFFAOYSA-N quinolin-4-ol Chemical compound C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000005086 pumping Methods 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000004809 thin layer chromatography Methods 0.000 description 15
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 12
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 6
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 229910020667 PBr3 Inorganic materials 0.000 description 4
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 230000032798 delamination Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- -1 class of aromatic organic compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and relates to a synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester. The synthesis method comprises the following steps: the quinoline-4-alcohol is used as a raw material, and the 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester is prepared through five steps of reactions of substitution, oxidation, rearrangement, alkylation and esterification, so that a synthesis method with low raw material cost, high yield and safe operation is provided for the compound.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester.
Background
Quinoline derivatives are a class of aromatic organic compounds containing pyridine rings and benzene rings, and have a variety of applications, including use as catalysts for organic synthesis reactions and intermediates for pharmaceutical synthesis (J.Med. Chem.2001, 2374-2377). 1-methyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylic acid methyl ester is an important pharmaceutical intermediate and has wide application prospect in the field of medicines. The invention provides a new synthesis method with low raw materials and simple operation for 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester and provides thinking for accelerating industrial production thereof by improving the synthesis route and synthesis conditions.
Disclosure of Invention
The invention aims to provide a synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester, which can be used as a medical intermediate, and has the advantages of low raw materials, simple process and high yield.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
A compound which is 1-methyl-2-oxo-1, 2-dihydro-4-quinolinecarboxylic acid methyl ester having a molecular structure shown in formula 1:
the invention also provides a synthesis method of the compound, which takes quinoline-4-alcohol (compound A) as a raw material, and synthesizes the compound through five steps of reactions, wherein the synthesis route is shown in the following formula 2:
The synthesis method comprises the following steps:
S1, dissolving quinoline-4-alcohol (compound A) in N, N-Dimethylformamide (DMF) solution, and adding phosphorus tribromide (PBr 3) in portions at proper temperature for reaction for 60 minutes. Adding the reaction solution into ice water, adding potassium carbonate to quench the reaction, extracting with methyl tert-butyl ether (MTBE), collecting an organic phase, concentrating and drying to obtain a product 4-bromoquinoline (compound B);
S2, dissolving 4-bromoquinoline (compound B) in Dichloromethane (DCM), adding m-chloroperoxybenzoic acid (m-CPBA), stirring at normal temperature, and reacting overnight. Adding aqueous potassium carbonate solution, layering, extracting organic phase, extracting aqueous phase with DCM, collecting organic phase and drying to obtain 4-bromoquinoline 1-oxide (compound C);
s3, dissolving 4-bromoquinoline 1-oxide (compound C) in DCM, dissolving sodium hydroxide in water, mixing and stirring, slowly dropwise adding benzoyl chloride (BzCl) in an ice-water bath environment, and stirring for 30 minutes. Concentrating DCM, beating with water and filtering to give the product 4-bromoquinolin-2-one (compound D);
S4, dissolving 4-bromoquinoline-2-ketone (compound D) in DMF solution of sodium hydride, stirring at room temperature until no bubble exists, slowly adding methyl iodide, and stirring at room temperature for reaction. Slowly quenching with ammonium chloride aqueous solution, adding water and filtering, washing filter residue with water, extracting filtrate with MTBE, collecting organic phase, concentrating and drying to obtain product 4-bromo-1-methylquinolin-2 (1H) -one (compound E);
S5, adding 4-bromo-1-methylquinolin-2 (1H) -one (compound E), triethylamine, methanol and diphenyl azide phosphate palladium chloride into a reaction kettle, sealing the container, introducing stirring, pumping air in the kettle by a vacuum pump, introducing carbon monoxide (CO), enabling the air pressure to reach 10KPa, closing a vent valve, heating to 100 ℃, and reacting overnight. The reaction solution was concentrated and dried, water was added, decolorized with activated carbon, extracted with DCM, the organic phase concentrated, and the solid was slurried with ethyl acetate and dried to give the product methyl 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylate (compound F).
Preferably, in step S1, the molar ratio of quinolin-4-ol to PBr3 is 1:1.05 and the reaction temperature is 20 ℃.
Preferably, in step S2, the molar ratio of 4-bromoquinoline to m-CPBA is 1:1.2, and the reaction temperature is 20-30 ℃.
Preferably, in step S3, the molar ratio of 4-bromoquinoline 1-oxide to BzCl is 1:1.2, and the reaction temperature is 0 ℃.
Preferably, in the step S4, the molar ratio of the 4-bromoquinolin-2-one, the sodium hydride and the methyl iodide is 1:1.2:1.2, and the reaction temperature is 20 to 30 ℃.
Preferably, in the step S5, the molar ratio of the 4-bromo-1-methylquinolin-2 (1H) -one to the triethylamine is 1:2, and the gas pressure in the reaction vessel is 10KPa and the temperature is 100 ℃.
The invention has the beneficial effects that: the invention provides a novel synthesis method for a medical intermediate 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester, which takes quinoline-4-alcohol (compound A) as a raw material, and most experiments synthesize 1-methyl-2-oxo-1, 2-dihydro-quinoline-4-carboxylic acid methyl ester (compound F) under normal temperature conditions.
Drawings
FIG. 1 is a 1H-NMR chart of Compound E;
FIG. 2 is a 1H-NMR chart of compound F.
Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the invention is provided. These embodiments are provided only for illustrating and not limiting the scope or practice of the invention, which is defined by the appended claims and includes obvious variations or modifications made thereon.
Example 1
Synthesis of S1, 4-bromoquinoline (compound B):
10g (0.069 mol) of quinolin-4-ol were weighed out, added to 50mL of DMF, the temperature was controlled below 20℃and 19.5g (0.072 mol) of PBr3 was added in portions and the reaction was stirred for 60 minutes. The reaction was checked for completion by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was added to ice water, quenched with potassium carbonate, extracted three times with 15mL of MTBE, the organic phase was collected and concentrated using a rotary evaporator to give 10.95g of 4-bromoquinoline (compound B) in a yield of 76.3%.
Synthesis of S2, 4-bromoquinoline 1-oxide (Compound C):
7.5g (0.036 mol) of 4-bromoquinoline was weighed out, added to 75mLDCM, dissolved by stirring, added with 9.7g (0.045 mol) of m-CPBA, and stirred at room temperature overnight. The completion of the reaction was detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), an aqueous potassium carbonate solution was added for delamination, and the organic phase was extracted, collected and dried to give 6.31g of 4-bromoquinoline 1-oxide (compound C) in a yield of 78.2%.
Synthesis of S3, 4-bromoquinolin-2-one (Compound D):
6.05g (0.027 mol) of 4-bromoquinoline 1-oxide (compound C) was weighed into 75mLDCM and dissolved, 2.43g of sodium hydroxide was weighed into 25mL of water and dissolved, and the two solutions were mixed and stirred, 4.5g (0.032 mol) of BzCl was slowly added dropwise in an ice water bath, and stirred for 30 minutes. The reaction was complete as detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), concentrated DCM, slurried with water and filtered to give 5.14g of 4-bromoquinolin-2-one (compound D) in 84.9% yield.
Synthesis of S4, 4-bromo-1-methylquinolin-2 (1H) -one (Compound E):
4.93g (0.022 mol) of 4-bromoquinolin-2-one (compound D) was weighed out, added to a DMF solution of NaH and stirred for dissolution until no bubbles were formed, 3.7g (0.026 mol) of methyl iodide was slowly added and the reaction was stirred at room temperature. The reaction was checked for completion using thin layer chromatography (petroleum ether: ethyl acetate=1:1), slowly quenched with aqueous ammonium chloride, added water and filtered, the filtrate extracted with 15mLMTBE, the organic phase was collected, concentrated and dried to give 3.64g of 4-bromo-1-methylquinolin-2 (1H) -one (compound E) in 69.5% yield.
Synthesis of S5, 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylic acid methyl ester (Compound F):
3.57g (0.015 mol) of 4-bromo-1-methylquinolin-2 (1H) -one (compound E), 3.04g (0.03 mol) of triethylamine, 0.036g of diphenyl azide phosphate palladium chloride and 50mL of methanol are weighed and added into a high-temperature and high-pressure reaction kettle, the container is closed, the stirring is carried out, air in the kettle is pumped by a vacuum pump, sufficient carbon monoxide gas is introduced to enable the air pressure to reach 10KPa, a vent valve is closed, the temperature is raised to 100 ℃, and the reaction is carried out overnight. The reaction completion was detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was concentrated and dried, 25mL of water was added, decolorized with 0.4g of activated carbon, extracted with 15mLDCM, the organic phase was collected and concentrated, the solid was slurried with petroleum ether, and dried to give 2.79g of methyl 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylate (compound F) in 85.7% yield.
Example 2
Synthesis of S1, 4-bromoquinoline (compound B):
100g (0.69 mol) of quinolin-4-ol were weighed out, added to 50mL of DMF, the temperature was controlled below 20℃and 195g (0.72 mol) of PBr3 were added in portions and the reaction was stirred for 60 minutes. The reaction was completely detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was added to ice water, quenched with potassium carbonate, extracted three times with 150mLMTBE, and the organic phase was collected and concentrated by rotary evaporator to obtain 111.12g of 4-bromoquinoline (compound B) in 77.4% yield.
Synthesis of S2, 4-bromoquinoline 1-oxide (Compound C):
75g (0.36 mol) of 4-bromoquinoline was weighed out, added to 750mLDCM, dissolved by stirring, 97g (0.45 mol) of m-CPBA was added, and stirred at room temperature overnight. The completion of the reaction was detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), an aqueous potassium carbonate solution was added for delamination, and the organic phase was extracted, collected and dried to yield 63.8g of 4-bromoquinoline 1-oxide (compound C) in a yield of 79.1%.
Synthesis of S3, 4-bromoquinolin-2-one (Compound D):
60g (0.27 mol) of 4-bromoquinoline 1-oxide (compound C) was weighed, added to 750mLDCM and dissolved, 24.3g of sodium hydroxide was weighed, added to 250mL of water and dissolved, and the two solutions were mixed and stirred, 45g (0.32 mol) of BzCl was slowly added dropwise in an ice water bath, and stirred for 30 minutes. The reaction was checked for completion using thin layer chromatography (petroleum ether: ethyl acetate=1:1), DCM was concentrated, slurried with water and filtered to give 51.72g of 4-bromoquinolin-2-one (compound D) in 85.5% yield.
Synthesis of S4, 4-bromo-1-methylquinolin-2 (1H) -one (Compound E):
49.5g (0.22 mol) of 4-bromoquinolin-2-one (compound D) was weighed, added to a DMF solution of NaH and dissolved by stirring until no bubbles were formed, 37g (0.26 mol) of methyl iodide was slowly added and the reaction was stirred at room temperature. The reaction was checked for completion by thin layer chromatography (petroleum ether: ethyl acetate=1:1), slowly quenched with aqueous ammonium chloride, added with water and filtered, the filtrate extracted with 150mLMTBE, the organic phase was collected, concentrated and dried to give 36.8g of 4-bromo-1-methylquinolin-2 (1H) -one (compound E) in 70.3% yield.
Synthesis of S5, 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylic acid methyl ester (Compound F):
36g (0.15 mol) of 4-bromo-1-methylquinolin-2 (1H) -one (compound E), 30.4g (0.3 mol) of triethylamine, 0.36g of diphenyl azide phosphate palladium chloride and 500mL of methanol are weighed, added into a high-temperature and high-pressure reaction kettle, a closed container is accessed and stirred, air in the kettle is pumped by a vacuum pump, sufficient carbon monoxide gas is introduced, the air pressure reaches 10KPa, a vent valve is closed, and the temperature is raised to 100 ℃ for reaction overnight. The reaction completion was detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was concentrated and dried, 250mL of water was added, 4g of activated carbon was decolorized, 150mLDCM was used for extraction, the organic phase was collected and concentrated, the solid was slurried with petroleum ether, and dried to give 28.41g of methyl 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylate (compound F) in a yield of 87.2%.
Example 3
Synthesis of S1, 4-bromoquinoline (compound B):
400g (2.75 mol) of quinolin-4-ol are weighed out, added to 2000ml of LDMF, the temperature is controlled below 20℃and 783g (2.89 mol) of PBr3 are added in portions and the reaction is stirred for 60 minutes. The reaction was completely detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was added to ice water, quenched with potassium carbonate, extracted three times with 500mLMTBE, and the organic phase was collected and concentrated using a rotary evaporator to give 446.86g of 4-bromoquinoline (compound B) in 78.1% yield.
Synthesis of S2, 4-bromoquinoline 1-oxide (Compound C):
317g (1.52 mol) of 4-bromoquinoline was weighed, added to 3000mLDCM, dissolved by stirring, 392.6g (1.82 mol) of m-CPBA was added, and stirred overnight at room temperature. The completion of the reaction was detected by thin layer chromatography (petroleum ether: ethyl acetate=1:1), an aqueous potassium carbonate solution was added for delamination, and the organic phase was extracted, collected and dried to give 271.8g of 4-bromoquinoline 1-oxide (compound C) in a yield of 79.8%.
Synthesis of S3, 4-bromoquinolin-2-one (Compound D):
241.8g (1.08 mol) of 4-bromoquinoline 1-oxide (compound C) was weighed, added to 3000mLDCM and dissolved, 97.15g of sodium hydroxide was weighed, added to 1000mL of water and dissolved, and the two solutions were mixed and stirred, 180g (1.29 mol) of BzCl was slowly added dropwise in an ice water bath, and stirred for 30 minutes. The reaction was checked for completion using thin layer chromatography (petroleum ether: ethyl acetate=1:1), DCM was concentrated, slurried with water and filtered to give 209.1g of 4-bromoquinolin-2-one (compound D) in 86.4% yield.
Synthesis of S4, 4-bromo-1-methylquinolin-2 (1H) -one (Compound E):
200g (0.89 mol) of 4-bromoquinolin-2-one (compound D) was weighed, added to a DMF solution of NaH and dissolved by stirring until no bubbles were formed, 152.1g (1.07 mol) of methyl iodide was slowly added and the mixture was reacted under stirring at room temperature. The reaction was checked for completion using thin layer chromatography (petroleum ether: ethyl acetate=1:1), slowly quenched with aqueous ammonium chloride, added water and filtered, the filtrate extracted with 500mL MTBE, the organic phase was collected, concentrated and dried to give 152.2g of 4-bromo-1-methylquinolin-2 (1H) -one (compound E) in 71.8% yield.
Synthesis of S5, 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylic acid methyl ester (Compound F):
152.2g (0.64 mol) of 4-bromo-1-methylquinolin-2 (1H) -one (compound E), 129.52g (1.28 mol) of triethylamine, 1.5g of diphenyl azide phosphate palladium chloride and 2000mL of methanol are weighed and added into a high-temperature and high-pressure reaction kettle, the container is closed, the stirring is carried out, air in the kettle is pumped by using a vacuum pump, sufficient carbon monoxide gas is introduced, the air pressure reaches 10KPa, a vent valve is closed, the temperature is raised to 100 ℃, and the reaction is carried out overnight. The reaction was checked for completion by thin layer chromatography (petroleum ether: ethyl acetate=1:1), the reaction mixture was concentrated and dried, 1000mL of water was added, decolorized with 15g of activated carbon, extracted with 500mL of DCM, the organic phase was collected and concentrated, the solid was slurried with petroleum ether, and dried to give 123.4g of methyl 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylate (compound F) in 88.8% yield.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A synthesis method of 1-methyl-2-oxo-1, 2-dihydro-4-quinoline carboxylic acid methyl ester is characterized in that quinoline-4-alcohol is used as a raw material, and compounds are synthesized through five steps of reactions such as substitution, oxidation, rearrangement, alkylation and esterification, and the synthetic route is shown as the following formula:
The synthesis method comprises the following steps:
S1, adding quinoline-4-alcohol into N, N-dimethylformamide, controlling the temperature, adding PBr 3 in batches, pouring the reaction solution into ice water after the reaction is completed, adding potassium carbonate for quenching, extracting by using methyl tertiary butyl ether, merging organic phases, and concentrating to dryness to obtain a product 4-bromoquinoline;
S2, dissolving the 4-bromoquinoline obtained in the step S1 in DCM, stirring, adding m-CPBA, adding a potassium carbonate aqueous solution after the reaction is completed, layering, extracting an organic phase, extracting an aqueous phase with DCM, combining the organic phases and drying to obtain a product 4-bromoquinoline 1-oxide;
S3, adding the 4-bromoquinoline 1-oxide obtained in the step S2 into DCM, adding sodium hydroxide aqueous solution, mixing and stirring, adding BzCl into ice water bath, stirring until the reaction is completed, concentrating the DCM, pulping with water, and filtering to obtain a product 4-bromoquinoline-2-ketone;
S4, dissolving the 4-bromoquinolin-2-one obtained in the step S3 in a DMF solution of sodium hydride, stirring until no bubble exists, slowly adding methyl iodide, and reacting at normal temperature; after the reaction is finished, slowly quenching by using an ammonium chloride aqueous solution, adding enough water, filtering, washing filter residues by using water, extracting the filtrate by using MTBE for three times, combining organic phases, and concentrating to dryness to obtain a product of 4-bromo-1-methylquinolin-2 (1H) -one;
S5, adding the 4-bromo-1-methylquinolin-2 (1H) -one, triethylamine, methanol and diphenyl azide phosphate palladium chloride obtained in the step S4 into a reaction kettle, sealing the container, introducing into the container for stirring, pumping out air in the kettle by using a vacuum pump, introducing CO to adjust the air pressure, closing a vent valve, heating, and reacting overnight; after the reaction is finished, concentrating the system to dryness, adding water, decoloring with active carbon, extracting with DCM, concentrating the DCM, pulping the solid with petroleum ether, and drying to obtain the product of 1-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylic acid methyl ester.
2. The method of claim 1, wherein in step S1, the molar ratio of quinoline-4-ol to PBr 3 is 1:1.05 and the reaction temperature is 20 ℃.
3. The synthesis according to claim 1, wherein in step S2, the molar ratio of 4-bromoquinoline to m-CPBA is 1:1.2 and the reaction temperature is 20-30 ℃.
4. The synthesis according to claim 1, wherein in step S3, the molar ratio of 4-bromoquinoline 1-oxide to BzCl is 1:1.2 and the reaction temperature is 0 ℃.
5. The synthesis method according to claim 1, wherein in step S4, the molar ratio of 4-bromoquinolin-2-one, sodium hydride and methyl iodide is 1:1.2:1.2, and the reaction temperature is 20 to 30 ℃.
6. The synthesis method according to claim 1, wherein in the step S5, the molar ratio of 4-bromo-1-methylquinolin-2 (1H) -one to triethylamine is 1:2, the reaction is carried out at a gas pressure of 10KPa and a reaction temperature of 100 ℃.
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