CN117682980B - Preparation method of 2-acetyl tetrahydropyridine - Google Patents
Preparation method of 2-acetyl tetrahydropyridine Download PDFInfo
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- CN117682980B CN117682980B CN202410146674.6A CN202410146674A CN117682980B CN 117682980 B CN117682980 B CN 117682980B CN 202410146674 A CN202410146674 A CN 202410146674A CN 117682980 B CN117682980 B CN 117682980B
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- tetrahydropyridine
- picolinic acid
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- HRAOWRVFLSYJKN-UHFFFAOYSA-N 6-acetyl-1,2,3,4-tetrahydropyridine Chemical compound CC(=O)C1=CCCCN1 HRAOWRVFLSYJKN-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims abstract description 50
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 41
- -1 amine hydrochloride Chemical class 0.000 claims abstract description 21
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 19
- 230000009467 reduction Effects 0.000 claims abstract description 19
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 15
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 238000006722 reduction reaction Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- XNAVFKFQASKYMW-UHFFFAOYSA-N C(O)[ClH]CO Chemical compound C(O)[ClH]CO XNAVFKFQASKYMW-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 5
- 150000002466 imines Chemical class 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 abstract description 4
- 150000001408 amides Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 235000013599 spices Nutrition 0.000 abstract description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 238000001514 detection method Methods 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 238000004817 gas chromatography Methods 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000010779 crude oil Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GNZWXNKZMHJXNU-UHFFFAOYSA-N 6-acetyl-2,3,4,5-tetrahydropyridine Chemical compound CC(=O)C1=NCCCC1 GNZWXNKZMHJXNU-UHFFFAOYSA-N 0.000 description 4
- 101100047644 Arabidopsis thaliana ATHX gene Proteins 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- ZGKNRILGBQAZDJ-UHFFFAOYSA-N 1-(3,4-dihydro-2h-pyridin-1-yl)ethanone Chemical compound CC(=O)N1CCCC=C1 ZGKNRILGBQAZDJ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 241000482268 Zea mays subsp. mays Species 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000021168 barbecue Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of 2-acetyl tetrahydropyridine, belonging to the technical field of essence and spice. The preparation method of the 2-acetyl tetrahydropyridine provided by the invention comprises the following steps: 2-picolinic acid and dimethylol amine hydrochloride undergo a condensation reaction to synthesize an intermediate I; synthesizing an intermediate II by hydrogenation reduction of the intermediate I; carrying out Grignard reaction on the intermediate II and a methyl Grignard reagent to obtain 2-acetyl tetrahydropyridine; the structural formulas of the intermediate I and the intermediate II are shown as follows:、 . The Weinreb amide is constructed by controlling the condensation reaction of 2-picolinic acid and dimethylhydroxylamine hydrochloride; then the hydrogenation reduction pyridine ring stays in imine by controlling the reaction time, temperature and pressure, so as to avoid excessive reduction; finally, the 2-acetyl tetrahydropyridine is obtained through the Grignard reaction which is stopped at the acetyl. The whole process is simple, the reaction condition is mild, the selectivity is good, the product yield is high, and the industrial production is easy.
Description
Technical Field
The invention belongs to the technical field of essence and spice, and particularly relates to a preparation method of 2-acetyl tetrahydropyridine.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
2-Acetyl tetrahydropyridine (ATHP for short) is a volatile small molecular heterocyclic compound, is considered to be one of characteristic aroma compounds of grains, and has characteristic aroma of bread barbecue, crust and popcorn. The compound comprises two components of 2-acetyl-3, 4,5, 6-tetrahydropyridine and 2-acetyl-1, 4,5, 6-tetrahydropyridine, wherein the two components are tautomers, the boiling points of the two components are 205 ℃ and 269 ℃, and the structural formulas of the two components are as follows:
At present, a plurality of preparation methods of ATHP are adopted, and the preparation methods mainly have the problems of complicated process, harsh conditions, low yield, poor safety and the like due to the use of dangerous reagents or toxic reagents (LDA, sodium azide, hydrocyanic acid and the like). Patent CN109503469A discloses a preparation method of 2-acetyl pyridine, which takes 2-picolinic acid as a raw material, obtains a compound II through acyl chlorination reaction, obtains a compound III through condensation of the compound II and dialkyl malonate, and obtains the 2-acetyl pyridine through hydrolysis reaction of the compound III. However, the compound obtained by this preparation method is not ATHP, which is only an acetyl group and does not give ATHP by hydrogenation reduction.
In summary, there is an urgent need to develop a new preparation method of 2-acetyl tetrahydropyridine with high safety, high product yield, strong operability and easy industrialization.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a preparation method of 2-acetyl tetrahydropyridine, which has the advantages of easily available raw materials, high product yield, strong operability and easy industrialization.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
In a first aspect of the present invention, there is provided a process for the preparation of 2-acetyl tetrahydropyridine, comprising the steps of:
2-picolinic acid and dimethylol amine hydrochloride undergo a condensation reaction to synthesize an intermediate I;
synthesizing an intermediate II by hydrogenation reduction of the intermediate I;
carrying out Grignard reaction on the intermediate II and a methyl Grignard reagent to obtain 2-acetyl tetrahydropyridine;
the structural formulas of the intermediate I and the intermediate II are shown as follows:
；/>。
the equation for the above reaction is as follows:
The Weinreb amide (intermediate I) is constructed through condensation reaction; then, by controlling the reaction time, temperature and pressure, the imine is ensured to stay in the hydrogenation reduction of the pyridine ring, and excessive reduction is avoided; finally, the 2-acetyl tetrahydropyridine is obtained by the Grignard reaction and the Grignard reaction is controlled to stay in the acetyl. The whole process is simple, the reaction condition is mild, the selectivity is good, the product yield and purity are high, and the industrial production is easy.
In some embodiments of the invention, the condensation reaction specifically comprises the steps of:
N, N' -Carbonyl Diimidazole (CDI), dimethylhydroxylamine hydrochloride (chemical name: N, O-dimethylhydroxylamine hydrochloride) and triethylamine are sequentially added into a 2-picolinic acid organic solution, and condensation reaction is carried out at normal temperature, so as to obtain an intermediate I.
In some embodiments of the invention, the solvent of the organic solution of 2-picolinic acid is selected from one of tetrahydrofuran, dichloromethane, dichloroethane, methyl tert-butyl ether or 2-methyltetrahydrofuran, preferably dichloromethane.
In some embodiments of the invention, the mass ratio of 2-picolinic acid to organic solvent in the 2-picolinic acid organic solution is from 0.2 to 0.3:1.
In some embodiments of the invention, the mass ratio of 2-picolinic acid, N' -carbonyldiimidazole, dimethylhydroxylamine hydrochloride and triethylamine is 1-3:5:1-3:1-3.
In some embodiments of the invention, after adding N, N' -carbonyl diimidazole to the 2-picolinic acid organic solution, stirring at room temperature to react for 1-2h, then sequentially adding dimethylol amine hydrochloride and triethylamine, and continuing to keep the temperature and reacting until the reaction stops.
In some embodiments of the invention, after the reaction is stopped, the filtrate is filtered and collected, the filtrate is washed once with saturated ammonium chloride solution, saturated sodium bicarbonate solution and deionized water, the collected organic phases are dried over anhydrous magnesium sulfate, and the filtrate is dried under negative pressure to obtain an oil of intermediate I. The obtained intermediate I can be directly used for the next hydrogenation reduction reaction without purification.
In some embodiments of the invention, the hydrogenation reduction comprises the steps of:
Adding a catalyst into the alcohol solution containing the intermediate I, and carrying out hydrogenation reduction reaction in a hydrogen atmosphere to obtain an intermediate II after the reaction is finished.
In some embodiments of the invention, the alcohol is selected from one of methanol, ethanol or isopropanol.
In some embodiments of the invention, the mass ratio of intermediate I to alcohol in the alcohol solution containing intermediate I is 0.3-0.4:1.
In some embodiments of the invention, the catalyst is palladium on carbon. Through verification, the piperidine group is obtained by hydrogenation reduction of ruthenium carbon, raney nickel cannot be subjected to hydrogenation reduction, and only palladium carbon is used as a catalyst to control hydrogenation reduction of pyridine ring to stay in imine, so that over reduction is avoided.
In some embodiments of the invention, the mass ratio of intermediate I to catalyst is 9-11:1.
In some embodiments of the invention, the hydrogenation reduction reaction is carried out at a reaction pressure of 0.08 to 0.1 MPa and a reaction temperature of 40 to 45 ℃. The reaction time is from 30 to 35 h, preferably from 30 to 32 h. The invention adopts palladium carbon as a catalyst, and ensures that the palladium carbon stays in imine during the hydrogenation reduction of pyridine rings by controlling the reaction pressure, time and temperature, thereby avoiding excessive reduction.
In some embodiments of the invention, after the reaction is completed, the catalyst is filtered off and the filtrate is freed of organic solvent to give intermediate II as an oil. The obtained intermediate II can be directly used for the next Grignard reaction without purification.
In some embodiments of the invention, the grignard reaction comprises the steps of:
And (3) adding a methyl Grignard reagent into the intermediate II organic solution, and carrying out Grignard reaction in a protective atmosphere to obtain the 2-acetyl tetrahydropyridine after the reaction is finished.
Specifically, adding the intermediate II into an organic solvent to obtain an intermediate II organic solution, cooling the intermediate II organic solution in a cold bath after nitrogen is completely added, adding a methyl Grignard reagent when the temperature is reduced to the reaction temperature, and carrying out heat preservation reaction.
In some embodiments of the invention, the solvent of the intermediate II organic solution is selected from one of tetrahydrofuran, dichloromethane, dichloroethane, methyl tert-butyl ether or 2-methyltetrahydrofuran, preferably tetrahydrofuran.
In some embodiments of the invention, the mass ratio of intermediate II to organic solvent in the intermediate II organic solution is 0.1-0.2:1.
In some embodiments of the invention, the methyl grignard reagent is selected from one of methyl magnesium bromide or methyl magnesium iodide. Preferably, the concentration of the methyl Grignard reagent is 2-4 mol/L.
In some embodiments of the invention, the ratio of the intermediate II to the methyl Grignard reagent is 120-160:380-450 g/mL.
In some embodiments of the invention, the Grignard reaction is carried out at a reaction temperature of-10 to 0 ℃. The reaction time is 4-5 h.
In some embodiments of the invention, after the Grignard reaction is finished, adding a saturated ammonium chloride solution into the reaction system for quenching, standing for separating liquid, collecting an organic phase, extracting an aqueous phase with methylene dichloride, combining the organic phases, drying with anhydrous magnesium sulfate, filtering, and evaporating the organic solvent under negative pressure to obtain a crude product oily substance of the 2-acetyl tetrahydropyridine. The crude oil can be further rectified and purified to obtain a pure 2-acetyl tetrahydropyridine product.
The beneficial effects of the invention are as follows:
The invention provides a preparation method of 2-acetyl tetrahydropyridine, which comprises the following steps: 2-picolinic acid and dimethylol amine hydrochloride undergo a condensation reaction to synthesize an intermediate I; synthesizing an intermediate II by hydrogenation reduction of the intermediate I; and carrying out Grignard reaction on the intermediate II and a methyl Grignard reagent to obtain the 2-acetyl tetrahydropyridine. The Weinreb amide is constructed by controlling the condensation reaction of 2-picolinic acid and dimethylhydroxylamine hydrochloride; then the hydrogenation reduction pyridine ring stays in imine by controlling the reaction time, temperature and pressure, so as to avoid excessive reduction; finally, the 2-acetyl tetrahydropyridine is obtained through the Grignard reaction which is stopped at the acetyl. The whole process is simple, the reaction condition is mild, the selectivity is good, the product yield and purity are high, and the industrial production is easy.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a gas chromatograph of a combination of 2-acetyltetrahydropyridine obtained in example 3 of the present invention;
FIG. 2 is a gas chromatograph of 2-acetyl-3, 4,5, 6-tetrahydropyridine (5.938 min) in 2-acetyl-tetrahydropyridine obtained in example 3 of the present invention, wherein A is the mass spectrum of 2-acetyl-3, 4,5, 6-tetrahydropyridine obtained by the test, B is the mass spectrum of 2-acetyl-3, 4,5, 6-tetrahydropyridine matched with the mass spectrum in the database, and the molecular weight of the two figures is greater than 200 (i.e. the abscissa is after 200) without peaks;
FIG. 3 is a gas chromatograph of 2-acetyl-1, 4,5, 6-tetrahydropyridine (6.919 min) in 2-acetyl-tetrahydropyridine obtained in example 3 of the present invention, wherein A is the mass spectrum of 2-acetyl-1, 4,5, 6-tetrahydropyridine obtained by the test, B is the mass spectrum of 2-acetyl-1, 4,5, 6-tetrahydropyridine matched with the mass spectrum in the database, and the molecular weight of the two figures is greater than 200 (i.e. the abscissa is after 200) without peaks;
FIG. 4 is an H-spectrum of 2-acetyltetrahydropyridine obtained in example 3 of the present invention;
FIG. 5 is a graph showing the C-spectrum of 2-acetyltetrahydropyridine obtained in example 3 of the present invention;
FIG. 6 is a gas-mass-flow diagram of the oil of intermediate I obtained in example 1 of the present invention;
FIG. 7 is a mass spectrum of the intermediate I oil obtained in example 1 of the present invention, wherein the mass spectrum has a molecular weight of more than 200 (i.e., the abscissa is after 200) and no peak;
FIG. 8 is a gas chromatogram of the pure 2-acetyltetrahydropyridine obtained in example 1 of the present invention, showing no peak at an abscissa (i.e., retention time) of more than 12 min.
Detailed Description
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Unless otherwise specified, the reagents used in the examples below are all conventional products and are commercially available.
Example 1
Synthesis of 2-acetyl tetrahydropyridine
The reaction route is as follows:
The specific synthesis method is as follows:
(1) Synthesis of intermediate I
510-G dichloromethane, 123 g of 2-picolinic acid and 250-g CDI are sequentially added into a 1L reaction bottle, stirring is started, the reaction is carried out at 25-30 ℃ for 1-2 h, 117 g dimethylol hydrochloride and 116-g triethylamine are sequentially added, the heat-preserving reaction is continued for 3-4 h, the thin layer detection is carried out for 2-picolinic acid without residues, and the reaction is stopped.
The reaction solution is filtered, the filtrate is collected, the filtrate is washed once by saturated ammonium chloride solution, saturated sodium bicarbonate solution and deionized water, the collected organic phase is added to be dried by anhydrous magnesium sulfate, the filtrate is filtered, the organic solvent is evaporated to dryness under negative pressure, the oil of 149 g intermediate I is obtained, the yield is 89.7%, and the purity of the obtained intermediate I is more than 99% through gas chromatography detection.
The results of the gaseousness test of the oil of intermediate I are shown in FIG. 6 and FIG. 7, the final molecular weight of the product is determined as intermediate I through fragments, and the accuracy of the intermediate I is also demonstrated through subsequent verification of the synthesized product.
(2) Synthesis of intermediate II
Sequentially adding 448 g methanol, 14.9 g palladium carbon (dry basis), 149 g intermediate I and hydrogen for replacement into a 1L autoclave, controlling the pressure to be 0.08-0.1 MPa, heating to control the temperature to be 40-45 ℃, reacting for 30-32 h, filtering palladium carbon after the reaction is finished, and drying the organic solvent to obtain 145 g intermediate II oily substance, wherein the yield is 95%, and the purity of the obtained intermediate II is more than 99% through gas chromatography detection.
(3) Synthesis of 2-acetyl tetrahydropyridine
Sequentially adding 1160 g tetrahydrofuran and 145 g intermediate II into a 2L reaction bottle, cooling in a cold bath after adding nitrogen, adding 426 mL methyl magnesium bromide Grignard reagent (3 mol. L -1) when the temperature is reduced to-5 ℃, carrying out thermal insulation reaction for 4-5 h, adding saturated ammonium chloride solution for quenching, standing for separating liquid, collecting an organic phase, extracting a water phase with dichloromethane, mixing the organic phases, adding anhydrous magnesium sulfate for drying, filtering, and evaporating the organic solvent under negative pressure to obtain 96 g crude oil.
The crude oil is further rectified and purified to obtain 86.4 g of pure 2-acetyl tetrahydropyridine with the yield of 81 percent, and the purity of the obtained pure 2-acetyl tetrahydropyridine is more than 99 percent as shown in figure 8 and table 1 by gas chromatography detection.
Table 12 gas chromatography data for purity detection of pure acetyl tetrahydropyridine
Example 2
Synthesis of 2-acetyl tetrahydropyridine
The reaction route is as follows:
The specific synthesis method is as follows:
(1) Synthesis of intermediate I
510 G tetrahydrofuran, 123 g of 2-picolinic acid and 250 g CDI are sequentially added into a 1L reaction bottle, stirring is started, the reaction is carried out at 25-30 ℃ for 1-2 h, 117 g dimethylol hydrochloride and 116 g triethylamine are sequentially added, the thermal insulation reaction is continued for 3-4 h, the thin layer detection is carried out for 2-picolinic acid without residues, and the reaction is stopped.
The reaction solution is filtered, the filtrate is collected, the filtrate is washed once by saturated ammonium chloride solution, saturated sodium bicarbonate solution and deionized water, the collected organic phase is added to be dried by anhydrous magnesium sulfate, the filtrate is subjected to negative pressure evaporation to dry the organic solvent, 138 g of intermediate I oil is obtained, the yield is 83.1 percent, and the purity of the obtained intermediate I is more than 99 percent through gas chromatography detection.
(2) Synthesis of intermediate II
141 G ethanol, 13.8 g palladium carbon (dry basis), 138 g intermediate I and hydrogen are sequentially added into a 1L autoclave for replacement, the pressure is controlled to be 0.08-0.1 MPa, the temperature is controlled to be 40-45 ℃, the reaction is carried out for 30-32 hours, the palladium carbon is filtered after the reaction is finished, the organic solvent is removed to obtain 134 g intermediate II oily substance, the yield is 94.8%, and the purity of the obtained intermediate II is greater than 99% through gas chromatography detection.
(3) Synthesis of 2-acetyl tetrahydropyridine
Adding 1080 g tetrahydrofuran and 134 g intermediate II into a 2L reaction bottle in sequence, cooling the mixture in a cold bath after adding nitrogen, adding 394 mL methyl magnesium iodide Grignard reagent (3 mol. L -1) when the temperature is reduced to-5 ℃, carrying out heat preservation reaction for 4-5 h, adding saturated ammonium chloride solution for quenching, standing for separating liquid, collecting an organic phase, extracting a water phase by using dichloromethane, combining the organic phases, adding anhydrous magnesium sulfate for drying, filtering, and evaporating the organic solvent under negative pressure to obtain 84 g crude oil.
The crude oil is further rectified and purified to obtain 69.5g of pure 2-acetyl tetrahydropyridine with the yield of 70.5%, and the purity of the obtained pure 2-acetyl tetrahydropyridine is more than 99% through gas chromatography detection.
Example 3
Synthesis of 2-acetyl tetrahydropyridine
The reaction route is as follows:
The specific synthesis method is as follows:
(1) Synthesis of intermediate I
510-G dichloromethane, 123 g of 2-picolinic acid and 202-g CDI are sequentially added into a 1L reaction bottle, stirring is started, reaction is carried out at 25-30 ℃ for 1-2 h, 109-g dimethylol hydrochloride and 106-g triethylamine are sequentially added, heat preservation reaction is continued for 3-4 h, thin layer detection is carried out for 2-picolinic acid without residue, and the reaction is stopped.
The reaction solution is filtered, the filtrate is collected, the filtrate is washed once by saturated ammonium chloride solution, saturated sodium bicarbonate solution and deionized water, the collected organic phase is added to be dried by anhydrous magnesium sulfate, the filtrate is subjected to negative pressure evaporation to dry the organic solvent, the obtained intermediate I is 154.3 g oily substance, the yield is 92.9%, and the purity of the obtained intermediate I is more than 99% through gas chromatography detection.
(2) Synthesis of intermediate II
463 G methanol, 15.4 g palladium-carbon (dry basis), 154.3 g intermediate I and hydrogen are sequentially added into a 1L autoclave for replacement, the pressure is controlled to be 0.08-0.1 MPa, the temperature is controlled to be 40-45 ℃, the reaction is carried out for 30-32 hours, after the reaction is finished, the palladium-carbon is filtered, the organic solvent is removed, 150.2 g intermediate II oily matter is obtained, the yield is 95.1%, and the purity of the obtained intermediate II is greater than 99% through gas chromatography detection.
(3) Synthesis of 2-acetyl tetrahydropyridine
Adding 1200 g tetrahydrofuran and 150.2 g intermediate II into a 2L reaction bottle in sequence, emptying the mixture in a cold bath after adding nitrogen, cooling, adding 442 mL methyl magnesium bromide Grignard reagent (3 mol. L -1) when the temperature is reduced to-5 ℃, carrying out heat preservation reaction for 4-5 h, adding saturated ammonium chloride solution for quenching, standing for separating liquid, collecting an organic phase, extracting a water phase with dichloromethane, mixing the organic phase with anhydrous magnesium sulfate for drying, filtering, and evaporating the organic solvent under negative pressure to obtain 99.4 g crude oil.
The crude oil is further rectified and purified to obtain 89.5 g of pure 2-acetyl tetrahydropyridine with the yield of 81.1 percent, and the purity of the obtained pure 2-acetyl tetrahydropyridine is more than 99 percent through gas chromatography detection.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. The preparation method of the 2-acetyl tetrahydropyridine is characterized by comprising the following steps of:
2-picolinic acid and dimethylol amine hydrochloride undergo a condensation reaction to synthesize an intermediate I;
synthesizing an intermediate II by hydrogenation reduction of the intermediate I; the hydrogenation reduction comprises the following steps: adding a catalyst into the alcohol solution containing the intermediate I, and carrying out hydrogenation reduction reaction in a hydrogen atmosphere to obtain an intermediate II after the reaction is finished; in the alcohol solution containing the intermediate I, the mass ratio of the intermediate I to the alcohol is 0.3-0.4:1; the catalyst is palladium carbon; the mass ratio of the intermediate I to the catalyst is 9-11:1; the hydrogenation reduction reaction is carried out under the reaction pressure of 0.08-0.1MPa and the reaction temperature of 40-45 ℃ for 30-32 h;
carrying out Grignard reaction on the intermediate II and a methyl Grignard reagent to obtain 2-acetyl tetrahydropyridine;
the structural formula of the intermediate I is shown as follows:
the structural formula of the intermediate II is shown as follows:
2. the method for preparing 2-acetyl tetrahydropyridine according to claim 1, wherein the condensation reaction comprises the steps of:
And (3) adding N, N' -carbonyl diimidazole, dimethylol amine hydrochloride and triethylamine into the 2-picolinic acid organic solution in sequence, and carrying out condensation reaction at normal temperature to obtain an intermediate I after the reaction is finished.
3. The method for preparing 2-acetyl tetrahydropyridine according to claim 2, wherein the solvent of the 2-picolinic acid organic solution is selected from one of tetrahydrofuran, dichloromethane, dichloroethane, methyl tert-butyl ether or 2-methyltetrahydrofuran;
or, in the 2-picolinic acid organic solution, the mass ratio of the 2-picolinic acid to the organic solvent is 0.2-0.3:1;
The mass ratio of the 2-picolinic acid to the N, N' -carbonyl diimidazole to the dimethylol hydrochloride to the triethylamine is 1-3:5:1-3:1-3.
4. The method for preparing 2-acetyl tetrahydropyridine according to claim 2, wherein after adding N, N' -carbonyl diimidazole into the 2-picolinic acid organic solution, stirring at room temperature for reaction for 1-2 hours, adding dimethylol hydrochloride and triethylamine in sequence, and continuing the heat-preserving reaction until the reaction is stopped.
5. The method for preparing 2-acetyl tetrahydropyridine according to claim 1, wherein the alcohol is one selected from methanol, ethanol, and isopropanol.
6. The method for preparing 2-acetyl tetrahydropyridine according to claim 1, wherein the grignard reaction comprises the steps of:
And (3) adding a methyl Grignard reagent into the intermediate II organic solution, and carrying out Grignard reaction in a protective atmosphere to obtain the 2-acetyl tetrahydropyridine after the reaction is finished.
7. The method for preparing 2-acetyl tetrahydropyridine according to claim 6, wherein the solvent of the intermediate II organic solution is selected from one of tetrahydrofuran, dichloromethane, dichloroethane, methyl tert-butyl ether, or 2-methyl tetrahydrofuran;
Or, in the intermediate II organic solution, the mass ratio of the intermediate II to the organic solvent is 0.1-0.2:1;
or, the methyl Grignard reagent is selected from one of methyl magnesium bromide or methyl magnesium iodide; the dosage ratio of the intermediate II to the methyl Grignard reagent is 120-160:380-450g/mL.
8. The method for producing 2-acetyltetrahydropyridine according to claim 6, wherein the reaction temperature is-10 to 0 ℃.
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