CN102993088A - 4-hydroxy-2-pyridone preparation method - Google Patents
4-hydroxy-2-pyridone preparation method Download PDFInfo
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Abstract
The invention relates to a 4-hydroxy-2-pyridone preparation method. The method includes stirring and heating ethyl cyanoacetate and trimethyl orthoacetate for reaction, cooling the ethyl cyanoacetate and the trimethyl orthoacetate, and subjecting the ethyl cyanoacetate and the trimethyl orthoacetate to recrystallization to obtain 2-cyano-3-methoxy-2-ethyl crotonate; dissolving obtained substances and N, N-dimethylformamide dimethyl acetal in dimethylbenzene for reflux reaction to obtain 2-cyano-3-methoxy-5-(dimethylamino)-2, 4-pentadienoic acid ethyl ester; stirring the obtained compound in glacial acetic acid for reflux reaction to obtain 4-methoxy-2-pyridone-3-carboxylate ethyl ester; and mixing the 4-methoxy-2-pyridone-3-carboxylate ethyl ester, hydrobromic acid and a solvent for reflux reaction to obtain 4-hydroxy-2-pyridone. According to the method, starting raw materials are easy to obtain, costs are low, the yield is high, the reaction operation is simple, the reaction line is short, industrial production is easy to achieve, and the method has good application prospects.
Description
Technical field
The invention belongs to alkaloidal preparation field, particularly the preparation method of a kind of 4-hydroxyl-2-pyridone.
Background technology
4-hydroxyl-2-pyridine compounds is to extract to separate a class new type natural alkaloid that obtains from the fermented liquid of the endophytes such as plant and animal, also be the important pharmaceutical intermediate of a class such as (the Jessen HJ such as antifungal drug Ciclopirox Olamine, antitumour drug Gimeracil simultaneously, Gademann is alkaloids:Structures and synthetic approaches.Nat.Prod.Rep. K.4-Hydroxy-2-pyridone, 2010,27:1168-1185; Tang Yumin, Li Jing, the progress of the holy seal of Zhao .4-hydroxyl-2-pyridinone natural alkaloid. organic chemistry, 2011,31:9-21; Zhao Shengyin, Huang Jing, journey is built, Liu Baoshuo, the progress of synthesis of Chen Chen .4-hydroxyl-2-pyridine compounds. organic chemistry, 2012,32:9-21.).Bioactivity research shows that 4-hydroxyl-2-pyridine compounds has the multiple biological activitys such as antimycotic, antibiotic, antiviral and antitumor, and its study on the synthesis is one of study hotspot of natural product chemistry and Synthetic Organic Chemistry always.
The synthetic method of 4-hydroxyl-2-pyridone mainly contains following two kinds: the first take pyridine as raw material through H
2O
2Oxidation, nitrated, generate 4-benzyloxy-N-pyridine oxide with benzylalcohol reaction, and by transposition under the aceticanhydride effect and the synthetic 4-hydroxyl of Pd/C catalytic hydrogenation debenzylation-2-pyridine compounds (Lin Zhigang, Wen Ren, Zhang Jiange, the research of the flat .1-amino of Miu Yu-gamma-carbolines derivative synthesizing process. Chinese pharmaceutical chemistry magazine, 2003,13:267-269; Cook PD, Day, RT, Robins RK.An improved synthesis of3-deazacytosine, 3-deazauracil, 3-deazacytidine, and3-deazauridine.J.Heterocyclic Chem.1977,14 (8): 1295-1298), method two obtains 2-(1-methoxy-ethylene base) propane dinitrile take propane dinitrile and trimethyl orthoacetate as raw material through condensation, then with N, the condensation of dinethylformamide dimethyl acetal, cyclization obtains 4-methoxyl group-3-cyano group-2-pyridone in acetic acid at last, then through 5-position chloro, demethoxylation and decyanation obtain 5-chloro-4-hydroxyl-2-pyridone (Mttelbach M in HBr solution at last, Kastner G, Junek H.Syntheses with nitriles.LXXI.Synthesis of4-hydroxynicotinic acid from butadienedicarbonitriles.Arch Pharm, 1985,318:81-86.Yano S, Ohno T, Ogawa K.Convenient and practical synthesis of 5-chloro-4-hydroxy-2 (1H)-pyridinone.Heterocycles, 1993, the report that preparation 4-hydroxyl-2-pyridone 36:145-148), is not yet arranged for the method document.Above-mentioned two kinds of synthetic methods are found relatively method (1) is although reaction is classical, simple to operate, raw material is easy to get, and step is longer, and total recovery is lower, and the three wastes are more, and production cost is higher; Method (2) route is shorter, but because the propane dinitrile price is more expensive.Because shortcomings such as aforesaid method exist that reaction scheme is long, yield is low and the reaction conditions time is long, cost is relatively high in scale operation.
Summary of the invention
Technical problem to be solved by this invention provides the preparation method of a kind of 4-hydroxyl-2-pyridone, and it is reported first that this inventive method obtains 4-hydroxyl-2-pyridone by 4-hydroxyl-2-pyridone-3-carboxylic acid, ethyl ester decarboxylation; The method starting raw material is easy to get, and cost is low, and yield is higher, and operation is simple, and reaction scheme is short, is easy to suitability for industrialized production, has a good application prospect.
The preparation method of a kind of 4-hydroxyl of the present invention-2-pyridone comprises:
(1) with ethyl cyanoacetate and trimethyl orthoacetate, be heated with stirring to 130 ~ 135 ℃, stirring reaction 4 ~ 5h is cooled to room temperature, recrystallization gets 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester, and wherein the molar ratio of ethyl cyanoacetate and trimethyl orthoacetate is 1:1 ~ 2;
(2) with 2-cyano group-3-methoxyl group 2-butylene acetoacetic ester and N, the dinethylformamide dimethyl acetal is dissolved in the dimethylbenzene, heated and stirred back flow reaction 4 ~ 5h, separating-purifying, get 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester, wherein the molar ratio of 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester and DMF dimethyl acetal is 1:1 ~ 2;
(3) with compound 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester is stirring and refluxing reaction 3 ~ 5h in Glacial acetic acid, separating-purifying, obtain 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester, compound 2-cyano group-3-methoxyl group-5-(dimethylamino)-2 wherein, the weight and volume ratio of 4-pentadienoic acid ethyl ester and Glacial acetic acid is 1 gram: 1 ~ 10 milliliter;
(4) compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester, Hydrogen bromide and reaction solvent are mixed, stirring and refluxing, separating-purifying, obtain 4-hydroxyl-2-pyridone, wherein the volume ratio of Hydrogen bromide and reaction solvent is 1:1 ~ 100, and 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester and hydrobromic weight and volume ratio are 1 gram: 1 ~ 5 milliliter.
The chemical structural formula of prepared 4-hydroxyl-2-pyridone is:
The method of separating-purifying is in the described step (3): pressure reducing and steaming acetic acid, resistates adds water, stirs the lower NaHCO of adding
3Transfer pH to 8-9, with reactant CH
2Cl
2Extract 2 times, saturated nacl aqueous solution washing 2 times, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent obtains red solid, uses re-crystallizing in ethyl acetate.
Reaction solvent is water or Glacial acetic acid in the described step (4).
Hydrobromic mass percentage concentration is 48% in the described step (4).
The stirring and refluxing time is 1 ~ 24h in the described step (4).
Separating-purifying in the described step (4) is: concentrating under reduced pressure, and resistates adds water, and stir the lower NaOH of adding and transfer pH to 8 ~ 9, suction filtration, filtrate transfers pH to 3-4 to separate out white solid with 4N hydrochloric acid, uses at last ethyl alcohol recrystallization.
The present invention is 4-hydroxyl-2-pyridone preparation method, because the considerations such as production cost factor, propane dinitrile is than the ethyl cyanoacetate price, we replace propane dinitrile and trimethyl orthoacetate condensation to obtain 2-cyano group-3-methoxyl group butene-2-carboxylic acid, ethyl ester with ethyl cyanoacetate, then obtain 2-cyano group-3-methoxyl group-5-(dimethylamino)-2 with the condensation of dimethyl formamide dimethyl acetal, 4-pentadienoic acid ethyl ester, cyclization obtains 4-methoxyl group-2-pyridone-3-ethyl formate in 80% aqueous acetic acid, at last in HBr demethylation and decarboxylation obtain 4-hydroxyl-2-pyridone (4-methoxyl group-2-pyridone-3-ethyl formate with reference to as Publication about Document synthesize, Kasum B, Prager RH.A classical approach to the synthesis ofperloline.AustJChem, 1983,36:1455-1467; Jessen HJ, Schumacher A, Shaw T, Pfaltz A, Gademann K.A unified approach for the stereoselective total synthesis of pyridone alkaloids and their neuritogenic activity.Angew.Chem Int.Ed., 2011,50:4222-4226), wherein obtaining 4-hydroxyl-2-pyridone by 4-hydroxyl-2-pyridone-3-carboxylic acid, ethyl ester decarboxylation is reported first.
Beneficial effect
(1) to obtain 4-hydroxyl-2-pyridone by 4-hydroxyl-2-pyridone-3-carboxylic acid, ethyl ester decarboxylation be reported first in the present invention;
(2) the inventive method starting raw material is easy to get, and cost is low, and yield is higher, and operation is simple, and reaction scheme is short, is easy to suitability for industrialized production, has a good application prospect.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
Embodiment 1
(1) 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester is synthetic
In eggplant-shape bottle, add ethyl cyanoacetate 10.7mL (0.1mol), trimethyl orthoacetate 12.7mL (0.1mol), be heated to 110 ℃ under stirring, again add trimethyl orthoacetate 2.5mL (0.02mmol) behind the stirring and refluxing reaction 2h, temperature rises to 135 ℃, the TLC monitoring is to reacting completely, and cooling directly adds 95% ethyl alcohol recrystallization and gets white solid 12.7g, yield 75%, m.p.132 ~ 135 ℃.
(2) 2-cyano group-5-(dimethylamino)-3-methoxyl group penta-2,4-diolefinic acid ethyl ester synthetic
Compound 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester 16.9g(0.1mol) and DMF dimethyl acetal 14.6mL(0.11mol) be dissolved in the 150mL dimethylbenzene heating reflux reaction 2h, the disappearance of TLC monitoring raw material point.The whole toluene that goes that reduces pressure gets oily liquids.Get yellow solid 2-cyano group-3-methoxyl group-5-(dimethylamino)-2 with ethyl alcohol recrystallization, 4-pentadienoic acid ethyl ester 15.5g, yield 69%, m.p.70 ~ 73 ℃.
1HNMR(400MHz,CDCl
3)δ:1.28~1.23(s,J=8.0Hz,3H,CH
3),2.93(s,3H,CH
3),3.15(s,3H,CH
3),3.96(s,3H,CH
3),4.14(q,J=8.0Hz,2H,CH
2),6.13(s,1H,CH=),7.46(d,J=12.5Hz,1H,CH=)。
(3) 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester is synthetic
Compound 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester 22.4g (0.1mol) is stirring and refluxing reaction 3h in 80% Glacial acetic acid 150mL, and pressure reducing and steaming acetic acid is finished in reaction, and resistates adds water 200mL, stirs the lower NaHCO of adding
3Transfer pH to 8-9, with reactant CH
2Cl
2Extract 2 times, saturated nacl aqueous solution washing 2 times, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent obtains red solid.Use re-crystallizing in ethyl acetate, obtain white solid 13.9g, yield 71%, m.p.150 ~ 152 ℃; IR υ 3116,2987,1720,1637,1546,1476,1440,1329,1255,1178,1133,1088,761cm
-1;
1HNMR (400MHz, CDCl
3) δ: 1.35 (t, J=7.1Hz, 3H, CH
3), 3.89 (s, 3H, OCH
3), 4.37 (q, J=7.1Hz, 2H, CH
2), 6.15 (d, J=7.4Hz, 1H, Ar-H), 7.48 (d, J=7.4Hz, 1H, Ar-H), 13.40 (brs, 1H, NH).
(4) 4-hydroxyl-2-pyridone is synthetic
Compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester 20.0g (0.1mol) is at 48% Hydrogen bromide 40mL and water 160mL, stirring and refluxing reaction 6h, reaction is finished the lower NaOH of adding of stirring and is transferred pH to 8 ~ 9, suction filtration, and filtrate transfers pH to 3 ~ 4 to separate out white solid with 4N hydrochloric acid.Use ethyl alcohol recrystallization, obtain white solid 9.2g, yield 83%.m.p.270~272℃;IRυ3450,1620,1591,1491,1417,1264,1210,839,789cm
-1;
1HNMR(400MHz,DMSO-d
6)δ:5.49(d,J=5.4Hz,1H,Ar),5.77(q,J=5.8Hz,1H,Ar),7.18(d,J=7.1Hz,1H,Ar),10.46(s,1H,NH),10.92(s,1H,OH)。
Embodiment 2
(1) 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester is synthetic
In eggplant-shape bottle, add ethyl cyanoacetate 10.7mL (0.1mol), trimethyl orthoacetate 19.1mL (0.15mol), be heated to 110 ℃ under stirring, again add trimethyl orthoacetate 5.0mL (0.04mmol) behind the stirring and refluxing reaction 2h, temperature rises to 135 ℃, the TLC monitoring is to reacting completely, and cooling directly adds 95% ethyl alcohol recrystallization and gets white solid 13.7g, yield 81%, m.p.130 ~ 132 ℃.
(2) 2-cyano group-5-(dimethylamino)-3-methoxyl group penta-2,4-diolefinic acid ethyl ester synthetic
Compound 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester 16.9g(0.1mol) and N, N-METHYLFORMAMIDE dimethyl acetal 19.9mL(0.15mol) be dissolved in the 200mL dimethylbenzene heating reflux reaction 2h, the disappearance of TLC monitoring raw material point.The whole toluene that goes that reduces pressure gets oily liquids.Get yellow solid 2-cyano group-3-methoxyl group-5-(dimethylamino)-2 with ethyl alcohol recrystallization, 4-pentadienoic acid ethyl ester 14.1g, yield 63%.，m.p.70~73℃。
(3) 4-hydroxyl-2-pyridone is synthetic
Compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester 20.0g (0.1mol), 48% Hydrogen bromide 20mL and glacial acetic acid 150mL, stirring and refluxing reaction 12h, the complete 100mL that is evaporated to of reaction, stir the lower NaOH of adding and transfer pH to 8-9, suction filtration, filtrate transfers pH to 3 ~ 4 to separate out white solid with 4N hydrochloric acid.Use ethyl alcohol recrystallization, obtain white solid 8.7g, yield 78%, m.p.269 ~ 272 ℃.
Wherein the methoxyl group of the 4-among the embodiment-2-pyridone-3-carboxylic acid, ethyl ester synthesizes as described in Example 1.
Embodiment 3
Synthesizing of 4-hydroxyl-2-pyridone
Stirring and refluxing reaction 8h among compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester 20.0g (0.1mol), glacial acetic acid 50mL and the 48% Hydrogen bromide 20mL, the complete 100mL that is evaporated to of reaction, stir the lower NaOH of adding and transfer pH to 8-9, suction filtration, filtrate transfers pH to 3-4 to separate out white solid with 4N hydrochloric acid.Use ethyl alcohol recrystallization, obtain white solid 9.5g, yield 86%, m.p.270-272 ℃.
The wherein cyano group of the 2-among the embodiment-3-methoxyl group-2-butylene acetoacetic ester, 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester and 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester synthetic as described in Example 1.
Embodiment 4
Synthesizing of 4-hydroxyl-2-pyridone
Stirring and refluxing reaction 12h among compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester 20.0g (0.1mol), 48% Hydrogen bromide 100mL and the water 100mL, concentrating under reduced pressure is finished in reaction, resistates adds water 200mL, stir the lower NaOH of adding and transfer pH to 8 ~ 9, suction filtration, filtrate transfers pH to 3 ~ 4 to separate out white solid with 4N hydrochloric acid, use ethyl alcohol recrystallization, obtain white solid 8.1g, yield 73%, m.p.268-270 ℃.
The wherein cyano group of the 2-among the embodiment-3-methoxyl group-2-butylene acetoacetic ester, 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester and 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester synthetic as described in Example 1.
Claims (6)
1. the preparation method of 4-hydroxyl-2-pyridone comprises:
(1) with ethyl cyanoacetate and trimethyl orthoacetate, be heated with stirring to 130 ~ 135 ℃, stirring reaction 4 ~ 5h is cooled to room temperature, recrystallization gets 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester, and wherein the molar ratio of ethyl cyanoacetate and trimethyl orthoacetate is 1:1 ~ 2;
(2) with 2-cyano group-3-methoxyl group 2-butylene acetoacetic ester and N, the dinethylformamide dimethyl acetal is dissolved in the dimethylbenzene, heated and stirred back flow reaction 4 ~ 5h, separating-purifying, get 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester, 2-cyano group-3-methoxyl group-2-butylene acetoacetic ester and N wherein, the molar ratio of N-METHYLFORMAMIDE dimethyl acetal is 1:1 ~ 2;
(3) with compound 2-cyano group-3-methoxyl group-5-(dimethylamino)-2,4-pentadienoic acid ethyl ester is stirring and refluxing reaction 3 ~ 5h in Glacial acetic acid, separating-purifying, obtain 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester, compound 2-cyano group-3-methoxyl group-5-(dimethylamino)-2 wherein, the weight and volume ratio of 4-pentadienoic acid ethyl ester and Glacial acetic acid is 1 gram: 1 ~ 10 milliliter;
(4) compound 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester, Hydrogen bromide and reaction solvent are mixed, stirring and refluxing, separating-purifying, obtain 4-hydroxyl-2-pyridone, wherein the volume ratio of Hydrogen bromide and reaction solvent is 1:1 ~ 100, and 4-methoxyl group-2-pyridone-3-carboxylic acid, ethyl ester and hydrobromic weight and volume ratio are 1 gram: 1 ~ 5 milliliter.
2. the preparation method of a kind of 4-hydroxyl according to claim 1-2-pyridone is characterized in that: the method for separating-purifying is in the described step (3): pressure reducing and steaming acetic acid, resistates adds water, stirs the lower NaHCO of adding
3Transfer pH to 8-9, with reactant CH
2Cl
2Extract 2 times, saturated nacl aqueous solution washing 2 times, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent obtains red solid, uses re-crystallizing in ethyl acetate.
3. the preparation method of a kind of 4-hydroxyl according to claim 1-2-pyridone is characterized in that: reaction solvent is water or Glacial acetic acid in the described step (4).
4. the preparation method of a kind of 4-hydroxyl according to claim 1-2-pyridone, it is characterized in that: hydrobromic mass percentage concentration is 48% in the described step (4).
5. the preparation method of a kind of 4-hydroxyl according to claim 1-2-pyridone is characterized in that: the stirring and refluxing time is 1 ~ 24h in the described step (4).
6. the preparation method of a kind of 4-hydroxyl according to claim 1-2-pyridone, it is characterized in that: the separating-purifying in the described step (4) is: concentrating under reduced pressure, resistates adds water, stir the lower NaOH of adding and transfer pH to 8 ~ 9, suction filtration, filtrate transfers pH to 3 ~ 4 to separate out white solid with 4N hydrochloric acid, uses at last ethyl alcohol recrystallization.
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| CN105037260A (en) * | 2015-07-09 | 2015-11-11 | 浙江科技学院 | 2-pyridone derivative and preparation method thereof |
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| CN108017577B (en) * | 2018-01-06 | 2019-03-01 | 怀化学院 | The process for catalytic synthesis of 2- pyridone |
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Application publication date: 20130327 |