CN112250616B - Preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester - Google Patents
Preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester Download PDFInfo
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Abstract
The invention discloses a preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, which comprises the following steps: dissolving 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester in a solvent, adding an alkali, and reacting to obtain 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester. According to the preparation method of the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, the used raw materials of the 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester, the lithium bromide, the lithium carbonate and the like are wide in source, cheap and easily available, and the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester can be quickly and efficiently obtained by only one-step reaction.
Description
Technical Field
The invention relates to the field of organic synthesis, and in particular relates to a preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester.
Background
4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (I) is an important intermediate, can be used for carrying out 1, 4-conjugate addition reaction with boron reagent, zinc reagent, aluminum reagent and the like, and is an important raw material for synthesizing chiral piperidone. The compound I has wide application in the synthesis of molecules containing piperidine alkaloids and drugs, and has wide market prospect.
The synthesis processes reported for tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate (I) are the following:
chem. commun.2005,1711-1713 reported a process for preparing I from 4-methoxypyridine (II) reduced with potassium tris (isopropoxy) borohydride, reacted with BOC-anhydride, demethylated under acidic conditions to give I in 41% overall yield, the formula:
reagents and conditions: a) k (i-PrO)3BH,THF,i-PrOH；b)(Boc)2O；c)10％HCl,41％for3 steps.
The potassium tri (isopropoxy) borohydride used in the method has high activity, and the potassium tri (isopropoxy) borohydride is prepared in situ from triisopropyl borate and potassium hydride when in use. Potassium hydride has high activity, releases heat and hydrogen when heated or contacted with moisture and acids, causes combustion and explosion, and has high danger when being used in large quantities. Therefore, this method is not suitable for large-scale preparation of I.
J.am. chem. soc.2011,133,14566-14569 reports a process for preparing I from N-tert-butoxycarbonyl-4-piperidone (III) by oxidation with oxygen over a palladium catalyst, of the formula:
reagents and conditions: 5 mol% Pd (CF)3CO2)2,O2,DMSO,80℃,48h,72％.
In the method, oxygen (O) is used2) As an oxidant, oxygen is potentially explosive in contact with organic matter. The palladium trifluoroacetate catalyst used in the reaction is high in price, the reaction time is long (48 hours are needed), and the product needs to be purified by column chromatography. Therefore, this method is not suitable for large-scale preparation of I.
Chinese patent publication No. CN106631992A discloses a process for preparing I from N-tert-butoxycarbonyl-4-piperidone (III). In the process, N-tert-butyloxycarbonyl-4-piperidone (III) reacts with elemental halogen under an alkaline condition to obtain 3-hydroxy-4, 4-dimethoxy-piperidine-1-carboxylic acid tert-butyl ester (IV), the IV is subjected to hydroxy activation and elimination to obtain 4, 4-dimethoxy-3, 4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (V), and the V is deprotected to obtain I, wherein the reaction formula is as follows:
reagents and conditions: a) i is2,KOH,MeOH,60％；b)i.(CF3SO2)2O,pyridine,CH2Cl2；ii.NaOMe,toluene,50℃,90％；c)p-TsOH,acetone,40％.
Although the reaction conditions of the process for preparing I from III are mild, the process requires 4 steps of reaction for preparing I, the total yield is low and only reaches 22%, and the process is not suitable for large-scale production.
Disclosure of Invention
Therefore, the technical problem to be solved by the present invention is to overcome the defects of long preparation route, low yield, difficult product separation and purification or use of high-risk raw material reagents in the prior art for 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, so as to provide a preparation method for 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, wherein the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester can be rapidly and efficiently obtained through one-step reaction.
In order to solve the technical problem, the invention provides a preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, which comprises the following steps:
dissolving 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester (VI) in a solvent, adding alkali, and reacting to obtain 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (I);
the reaction formula is as follows:
preferably, the reaction temperature is 60-180 ℃, and the reaction time is 0.5-1 h.
Preferably, the reaction temperature is 80-110 ℃, and the reaction time is 0.5-1 h.
Preferably, the molar ratio of the 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester and the base is from 1:0.1 to 1: 8.
Preferably, the molar ratio of the 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester and the base is from 1:1 to 1: 3.
Preferably, the base is at least one of lithium bromide, lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, and the solvent is at least one of N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DME) or N-methylpyrrolidone (NMP).
Preferably, the base is at least one of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), and the solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, 1, 4-dioxane, or acetonitrile.
The technical scheme of the invention has the following advantages:
1. according to the preparation method of the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, the used raw materials of the 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester, the lithium bromide, the lithium carbonate and the like are wide in source, cheap and easily available, and the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester can be quickly and efficiently obtained by only one-step reaction.
2. The preparation method of the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester provided by the invention has the advantages of short reaction time, mild conditions, simple and convenient operation, high yield, no need of column chromatography purification of the product, and suitability for large-scale production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 shows the preparation of tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate obtained in example 1 of the present invention1H NMR chart.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Example 1
Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (VI) (32.00g,0.115mol,1.0equiv.) was dissolved in 200mL DMF, LiBr (16.99g,0.196mol,1.7equiv.) and lithium carbonate (21.24g,0.288mol,2.5equiv.) were added, and the reaction was stirred at 90 ℃ for 0.5h and checked by TLC for completion. The reaction was allowed to cool to room temperature, poured into 2L of water, extracted with ethyl acetate (200mL x 2) and the organic phases combined. The organic phase was washed with saturated brine (300mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow oil, left to stand for a while to become a solid, slurried with n-heptane, filtered and dried to give a white solid, 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (15.09 g). Yield: 66.5 percent. The reaction formula involved in the process is:
as shown in figure 1 of the drawings, in which,1HNMR(400MHz,CDCl3)：δ(ppm)7.82(brs,1H),5.31(d,J＝8.32Hz,1H),3.98(t,J＝7.36Hz,1H),2.55(t,J＝7.36Hz,2H),1.54(s，9H)。
the successful preparation of tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate is verified by FIG. 1.
Example 2
Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (VI) (20.00g,0.072mol,1.0equiv.) was dissolved in 100mL NMP, LiBr (18.73g,0.216mol,3.0equiv.) was added, the reaction was carried out at 110 ℃ for 0.5h, and the reaction was complete by TLC. The reaction was allowed to cool to room temperature, poured into 1L of water, extracted with ethyl acetate (100mL x 2) and the organic phases combined. The organic phase was washed with saturated brine (200 mL. multidot.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a yellow oil, which was put into a refrigerator to precipitate a solid, which was slurried with n-heptane, filtered and dried to give a white solid, 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (6.80 g). Yield: 48.0 percent.
Example 3
Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (VI) (10.00g,0.036mol,1.0equiv.) was dissolved in 100mL of N, N-dimethylacetamide, sodium carbonate (15.24g,0.144mol,4.0equiv.) was added, the reaction was carried out at 80 ℃ for 1 hour, and the completion of the reaction was detected by TLC. The reaction was allowed to cool to room temperature, poured into 1L of water, extracted with ethyl acetate (100mL x 2) and the organic phases combined. The organic phase was washed with saturated brine (200mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 6: 1) to obtain 2.71g of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester as a white solid, with a yield of 38.3%.
Example 4
Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (VI) (10.00g,0.036mol,1.0equiv.) is dissolved in 80mL toluene, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU, 6.57g,0.043mol,1.2equiv.) is added and the reaction is completed by TLC at 80 ℃ for 1 h. The reaction is cooled to room temperature, 50mL of ethyl acetate is added, silica gel is filtered, the filtrate is decompressed and concentrated to obtain yellow oily matter, the yellow oily matter is put into a refrigerator to precipitate solid, n-heptane is used for pulping, and the white solid, namely the 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester, is obtained after filtration and drying, and 3.95g of the white solid is obtained. Yield: 55.7 percent.
Example 5
Tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (VI) (2.00g,7.19mmol,1.0equiv.) is dissolved in 40mL acetonitrile, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN, 2.32g,18.70mmol,2.6equiv.) is added, the reaction is carried out at 100 ℃ for 1h, and the reaction is detected by TLC to be complete. The reaction is cooled to room temperature, 50mL of n-heptane is added, silica gel is filtered, the filtrate is decompressed and concentrated to obtain yellow oily matter, the yellow oily matter is put into a refrigerator to precipitate solid, the n-heptane is pulped, and the white solid 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester is obtained after filtration and drying, wherein 0.73g of the white solid is obtained. Yield: 51.5 percent.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (4)
1. A preparation method of 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester is characterized by comprising the following steps:
dissolving 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester in a solvent, adding an alkali, reacting at 60-180 ℃ for 0.5-1H to obtain 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester;
the reaction formula is as follows:
the alkali is at least one of lithium bromide, lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate, and the solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone;
or, the base is at least one of 1, 8-diazabicyclo [5.4.0] undec-7-ene or 1, 5-diazabicyclo [4.3.0] non-5-ene, and the solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, toluene, xylene, 1, 4-dioxane, or acetonitrile.
2. The process for the preparation of tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate according to claim 1, characterized in that the reaction temperature is 80-110 ℃ and the reaction time is 0.5-1H.
3. The process for the preparation of tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate according to claim 1 or 2, characterized in that the molar ratio of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate and base is 1:0.1-1: 8.
4. The process for the preparation of tert-butyl 4-oxo-3, 4-dihydropyridine-1 (2H) -carboxylate according to claim 1 or 2, characterized in that the molar ratio of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate and base is 1:1 to 1: 3.
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| CN106631992A (en) * | 2017-01-05 | 2017-05-10 | 桑迪亚医药技术（上海）有限责任公司 | Synthesis method of 4-oxy-3,4-dihydro-2H-pyridine-1-tert-butyl formate |
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| Synthesis of Cyclic Enones via Direct Palladium-Catalyzed Aerobic;Tianning Diao，等;《J. Am. Chem. Soc》;20110818;第14566-14569页 * |
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