CN101215290A - Method for synthesizing 11H-naphthol[1',2',5,6]pyran[2,3,d]pyridin-11(10H)-one compounds - Google Patents
Method for synthesizing 11H-naphthol[1',2',5,6]pyran[2,3,d]pyridin-11(10H)-one compounds Download PDFInfo
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- CN101215290A CN101215290A CNA2007103042720A CN200710304272A CN101215290A CN 101215290 A CN101215290 A CN 101215290A CN A2007103042720 A CNA2007103042720 A CN A2007103042720A CN 200710304272 A CN200710304272 A CN 200710304272A CN 101215290 A CN101215290 A CN 101215290A
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Abstract
The invention relates to a synthesis of 11H-naphthol and [1', 2':5, 6] pyran [2, 3-d] pyrimidine -11(10H) ketone heterocyclic compound. The general formula is that R is substituent on naphthalene ring, which can be aryl, alkyl, halogen, nitro, nitroso or alkoxy, and the kind, number and position on naphthalene ring of substituent are not limited. R1 is H or any substituent, R2 and R3 are alkyl, cycloalkyl or aryl, and wherein any one can be H. Catalyst can be Louis acids, protonic acids or alkalis, wherein anhydrous zinc chloride, anhydrous aluminium trichloride, copper chloride, cuprous chloride, hydrochloric acid, sulfuric acid, pyridine, piperidine, sodium carbonate, sodium-hydroxide or potassium hydroxide, and sodium alcoholate or potassium are more superior. The reaction is carried out through promoting by microwave, and the purification adopts the methods of recrystallization or column chromatography separation. The invention has wider raw material diversity, simple technology, mild reaction condition and extensive reaction application range, which can synthesize various 11H-naphthol and [1', 2':5, 6] pyran [2, 3-d] pyrimidine -11(10H) ketone heterocyclic compound.
Description
Technical field
The present invention relates to the also synthetic method of [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone heterogeneous ring compound of a kind of 11H-naphthols.
Background technology
Pyrans hepyramine class fused ring compound be a class have a good physiologically active contain oxygen, nitrogen heterocyclic, as antitumour activity [Academy, Section B:Biological, Geological andChemical Science, 1983,83B (19): 241-9.], antitumor [Egyptian Journal ofPharmaceutical Sciences, 2003,44 (2): 155-176; Acta PharmaceuticaHungarica, 2001,71 (3): 261-269.] activity, its polynary fused ring compound often has better pharmaceutical characteristic [Pharmazie, 1992,47:486-487; Journal of SaudiChemical Society, 2006,9 (3): 575-596.].Has important researching value at field of medicaments.
The synthetic rare report of pyrans hepyramine fused ring compound can be with adjacent amino-nitrile and anhydride reaction [Journal of Saudi Chemical Society, 2006,9 (3): 575-596.], severe reaction conditions needs to use sulfuric acid to be solvent, contaminate environment; The aminopyrimidinone of use and α are also arranged, beta-unsaturated carbonyl compound prepared in reaction [Egyptian Journal of Chemistry, 2004,47 (1): 63-74.], but the intermediate aminopyrimidinone is difficult to preparation, and price is higher.In addition, the neither 11H-naphthols that is suitable for spirane structure of these synthetic methods [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone compounds synthetic also.Therefore, the present invention relates to the also method of [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-polynary fused ring compound of ketone of a kind of synthetic easily naphthols.
Summary of the invention
The present invention relates to also [1 ', 2 ': 5,6] pyrans [2 of a kind of 11H-naphthols, 3-d] pyrimidine-11 (10H)-ketone (English name 11H-naphtho[1 ', 2 ': 5,6] pyrano[2,3-d]-microwave synthesis method of pyrimidin-11 (10H)-one) heterogeneous ring compound.This method is under catalyst action, adopts adjacent amino pyrans prussiate and ketone to react under microwave radiation, directly generates target compound.Reaction expression is:
Wherein R is the substituting group on the naphthalene nucleus, can be aryl, alkyl, and halogen, nitro, nitroso-group or alkoxyl group, this substituent kind, quantity and the position on naphthalene nucleus are not limit.R
1Be H or any substituting group.R
2, R
3Be alkyl, cycloalkyl or aryl, one of them can be H.
Preparation process is:
(1) reinforced
With mol ratio is that the mixture of 1: 1～1: 500 adjacent amino pyrans prussiate and ketone adds in the reaction vessel, and the solvent that adds consumption and be 1～500 times of adjacent amino pyrans prussiate is as reaction medium.Reaction medium is, but is not limited to benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran (THF) and halogenated hydrocarbon neat solvent a kind of.Be liquid ketone down for normal temperature, except can using aforesaid reaction medium, self can be used as reaction medium.Adding consumption then is the catalyzer of 0.1～50 times of adjacent amino pyrans prussiate.Employed catalyzer is a kind of in Louis's acids, proton acids or the bases, wherein more excellent is, but is not limited to: Zinc Chloride Anhydrous, aluminum trichloride (anhydrous), cupric chloride, cuprous chloride, hydrochloric acid, sulfuric acid, pyridine, piperidines, yellow soda ash, sodium hydroxide (or potassium), sodium alkoxide (potassium).The addition sequence of adjacent amino-pyrazol prussiate, ketone, reaction medium and catalyzer can be changed arbitrarily.
(2) reaction
In the microwave synthesizer, reactant was reacted 10 seconds to 2 hours down at 60～200 ℃, with thin-layer chromatography (TLC) monitoring reaction progress, when the product amount no longer increases, stopped reaction.The developping agent of thin-layer chromatography is, but is not limited to ethyl acetate, sherwood oil, methyl alcohol, chloroform, methylene dichloride, acetone, tetrahydrofuran (THF), perhaps wherein both or three's mixed solution (each component ratio is: a kind of 1～99%).
(3) reaction solution is handled
Cooled reaction solution is scattered in 5 times of water below the volume of reaction solution, stir down with 5～90% sodium hydroxide or potassium hydroxide, aqueous sodium carbonate and be neutralized to alkalescence (PH=8～13), filter, filtrate is used ethyl acetate, perhaps a kind of organic solvent extraction in methylene dichloride, chloroform, the ether is 2-5 time, merges organic phase.With filter cake methyl alcohol, the perhaps a kind of organic solvent extracting in ethanol, acetone, tetrahydrofuran (THF), ethyl acetate, the acetonitrile, the organic phase that obtains after the extracting is mixed with the organic phase that above extraction obtains.Then with mixed liquid with but after being not limited to a kind of drying in anhydrous sodium sulphate, anhydrous calciumsulphate, anhydrous magnesium sulfate, the Calcium Chloride Powder Anhydrous siccative, rotation is steamed and is desolventized, and obtains solid mixture.The mixture that obtains is carried out recrystallization or column chromatography purification, promptly obtain pure target compound 11H-naphthols that productive rate (30%～99%) is higher than conventional heating means (10%～50%) also [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidine-11 (10H)-ketone, and the reaction times reduce to 10%～50% of conventional method.Recrystallization solvent can be, but be not limited to a kind of in methyl alcohol, ethanol, Virahol, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, chloroform, benzene, toluene, the oil of mirbane, or a kind of in ethyl acetate and sherwood oil mixed solution (volume ratio is 100: 1～1: 10), DMF and the alcohol mixeding liquid (volume ratio is 10: 1～1: 30).Adopt silicagel column or alumina column during column chromatography, developping agent is, but be not limited to a kind of in ethyl acetate/petroleum ether mixed solution (ratio is 1: 1～1: 3, volume ratio), methyl alcohol/chloroform mixed solution (ratio is 1: 10～1: 50, volume ratio), methylene dichloride, the acetone.
The present invention synthesizes also [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone compounds of multiple 11H-naphthols with simple technology.
Embodiment
Embodiment 1
In the container of 5mL, add DMF 3mL, pimelinketone 0.17g (0.17mmol), 2-amino-4-(3-nitrophenyl)-4H-naphtho-[2,1-b] pyrans-3-nitrile (1a) (0.51g, 0.15mmol), ZnCl
2(0.23g 1.6mmol), is heated to 160 ℃, insulation reaction 1h under this temperature in Biotage type microwave synthesizer, use the TLC monitoring reaction, when the product amount no longer increases, stopped reaction, allow behind the reaction solution naturally cooling, in the impouring 20mL water, the solid filtering of separating out.The solid of gained is scattered in the water once more, stirs down pH value to 12～13 with 20% sodium hydroxide solution regulator solution, suction filtration must thick product.Thick product separates with silica gel (200-300 order), and elutriant is the mixed solvent of ethyl acetate and sherwood oil (1: 2, volume ratio), obtain also [1 ', 2 ': 5,6] pyrans [2 of 11H-naphthols, 3-d] pyrimidine-11 (10H)-ketone (I), yield 54%, 275～278 ℃ of Mp.The reaction formula of compound 1a and pimelinketone is:
The spectral data of product (I) is: IR (KBr): 3187,2937,1659,1630,1527,1349, and 1227cm
-1.
1H NMR (400MHz, DMSO-d
6): δ=8.12 (t, 1H, J=1.76Hz, ArH), 7.96 (m, 4H, J=1.76Hz, J=7.8Hz, ArH), 7.63 (d, 2H, J=7.8Hz, ArH), 7.58 (s, 1H, NH), and 7.43-7.52 (m, 4H, J=7.8Hz, ArH), 7.23 (s, 1H, NH), 5.76 (s, 1H, CH), 1.76 (m, 1H, CH
2), 1.66 (m, 4H, CH
2), 1.38 (m, 4H, CH
2), 1.22 (m, 1H, CH
2).
13C NMR (100MHz, DMSO-d
6): δ=165.5,154.8,148.8,147.7,147.6,134.1,130.8,130.6,129.9,129.6,128.6,127.4,125.0,123.3,121.9,121.1,117.0,116.9,81.6,67.1,36.3,36.0,34.3,24.7,21.1,20.7; ESI-MS:m/z=442.3[M+H
+] .Anal.Calcd.forC
26H
23N
3O
4: C, 70.73; H, 5.25; N, 9.52.Found:C, 70.45; H, 5.22; N, 9.61.
The molecule single crystal structure of compound (I) is a triclinic(crystalline)system, P
-1Spacer, unit cell parameters is: a=11.4633 (11) , b=12.6247 (12) , c=19.658 (2) , α=72.642 (8) °, β=89.045 (9) °, γ=68.340 (5) °.Its molecular structure is:
Embodiment 2
In the container of 5mL, add pimelinketone 3mL, and 2-amino-4-(4-nitrophenyl)-4H-naphtho-[2,1-b] pyrans-3-nitrile (1b) (0.51g, 0.15mmol), ZnCl
2(0.23g 1.6mmol), is heated to 165 ℃ in Biotage type microwave synthesizer, insulation reaction is 50 minutes under this temperature, uses the TLC monitoring reaction, when the product amount no longer increases, stopped reaction, allow reaction solution in device, cool off after, take out, in reaction solution impouring 30mL water, separate out solid, after the filtration, be scattered in the gained solid in the water once more, stir down pH value to 10～12 with 10% sodium hydroxide solution regulator solution, suction filtration must thick product.Thick product separates with silica gel (200-300 order), and elutriant is the mixed solvent of methyl alcohol/chloroform mixed solution (volume ratio is 50: 1), obtains 11H-naphthols also [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone (II), productive rate 65%, 274～276 ℃ of Mp.The reaction formula of compound 1b and pimelinketone is:
The spectral data of product (II) is: IR (KBr) v (cm
-1): 3183,2934,1663,1627,1517,1345,1230cm
-1.
1H NMR (400MHz, DMSO-d
6): δ=8.15 (m, 2H, ArH), 8.02 (m, 2H, ArH), 7.95 (d, 1H, ArH), 7.63 (s, 1H, NH), 7.47-7.56 (m, 5H, ArH), 7.27 (s, 1H, NH), 5.78 (s, 1H, CH), 1.70-1.80 (m, 5H, CH
2), 1.42 (m, 4H, CH
2), 1.27 (m, 1H, CH
2).
13C NMR (100MHz, DMSO-d
6): δ=165.4,154.8,154.2,147.5,145.6,130.8,130.6,129.6,128.7,127.4,125.0,123.7,123.2,117.0,116.9,81.3,67.0,36.3,36.1,34.6,24.7,21.2,20.8; MALDI-TOF (CCA): m/z=442.3[M+H
+] .Anal.Calcd.for C
23H
23N
3O
4: C, 70.73; H, 5.25; N, 9.52.Found:C, 70.55; H, 5.31; N, 9.59.
The molecule single crystal structure of compound (II) is a triclinic(crystalline)system, P
-1Spacer, unit cell parameters is: a=10.607 (4) , b=11.753 (6) , c=12.774 (6) , α=84.412 (14) °, β=69.673 (13) °, γ=78.047 (14) °.Its molecular structure is:
Claims (7)
1. the synthetic 11H-naphthols method of [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone compounds also, it is characterized in that: with amino pyrans prussiate of neighbour and reactive ketone, generate target compound, reaction expression is:
Wherein R is the substituting group on the naphthalene nucleus, can be aryl, alkyl, and halogen, nitro, nitroso-group or alkoxyl group, this substituent kind, quantity and the position on naphthalene nucleus are not limit; R
1Be H or any substituting group; R
2, R
3Be alkyl, cycloalkyl or aryl, one of them can be H.
2. a kind of synthetic 11H-naphthols as claimed in claim 1 also [1 ', 2 ': 5,6] pyrans [2,3-d] method of pyrimidine-11 (10H)-ketone compounds, it is characterized in that: reaction medium is, but be not limited to benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone, methyl-sulphoxide, N, dinethylformamide, N,N-dimethylacetamide, dioxane, tetrahydrofuran (THF) and halogenated hydrocarbon neat solvent a kind of; Be liquid carbonyl compound down for normal temperature, except can using aforesaid reaction medium, self also can be used as reaction medium.
3. a kind of synthetic 11H-naphthols as claimed in claim 1 is the method for [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone compounds also, and it is characterized in that: the ratio of the amount of substance of reactant 1,2 is 1: 1～1: 500.
4. a kind of synthetic 11H-naphthols as claimed in claim 1 also [1 ', 2 ': 5,6] pyrans [2,3-d] method of pyrimidine-11 (10H)-ketone compounds, it is characterized in that: catalyst for reaction can be a kind of in Louis's acids, proton acids or the bases, and wherein more excellent has: Zinc Chloride Anhydrous, aluminum trichloride (anhydrous), cupric chloride, cuprous chloride, hydrochloric acid, sulfuric acid, pyridine, piperidines, yellow soda ash, sodium hydroxide (or potassium), sodium alkoxide (potassium); Wherein, the consumption of lewis acid catalyst is, but is not limited to 1～1.5 times of amount of substance of reactant 1; The consumption of protonic acid or alkali catalyst be reactant 1 amount of substance 1%～100%.
5. a kind of synthetic 11H-naphthols as claimed in claim 1 also [1 ', 2 ': 5,6] pyrans [2,3-d] method of pyrimidine-11 (10H)-ketone compounds, it is characterized in that: the adjacent amino pyrans prussiate that participates in reaction can have different substituted radicals on pyranoid ring, comprise various electronics (nitro, halogen, carbonyl etc.) group and the electron donating groups (alkyl, alkoxyl group or amido) of drawing; Ketone can be aliphatic ketone, also can be aromatic ketone.
6. a kind of synthetic 11H-naphthols as claimed in claim 1 also [1 ', 2 ': 5,6] pyrans [2,3-d] method of pyrimidine-11 (10H)-ketone compounds, it is characterized in that: described reaction adopts microwave to promote synthetic method, in the microwave reaction device, reactant reacted 10 seconds to 2 hours down at 60～200 ℃, and the yield of product is 30-99%.
7. a kind of synthetic 11H-naphthols as claimed in claim 1 is the method for [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone compounds also, it is characterized in that the Separation ﹠ Purification method of product is:
(1) reactant is distributed in the less water, removes catalyzer, filter back gained solid organic solvent extracting, obtain extract with the alkali neutralization; Used organic solvent can be, but be not limited to methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ethyl acetate, acetonitrile;
(2) filtrate filtered is extracted, obtain extraction liquid; Extraction agent can be, but be not limited to ethyl acetate, methylene dichloride, chloroform, ether;
(3) with after extract and the extraction liquid merging, carry out drying; The siccative that uses is, but is not limited to anhydrous sodium sulphate, perhaps anhydrous calciumsulphate, anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous;
(4) with dried liquid concentration, obtain crude product, the thick product to gained carries out recrystallization or column chromatography purification then, promptly obtains also [1 ', 2 ': 5,6] pyrans [2,3-d] pyrimidines-11 (10H)-ketone of pure target compound 11H-naphthols; The recrystallization solvent of crude product can be, but be not limited to methyl alcohol, ethanol, Virahol, benzene, toluene, oil of mirbane, acetone, acetonitrile, tetrahydrofuran (THF), dioxane, ethyl acetate, methylene dichloride, chloroform; Elutriant used during column chromatography is, but (ratio is 1: 10～1: 100 to be not limited to methyl alcohol/chloroform mixed solution, volume ratio), (ratio is 50: 1～1: 5 to the ethyl acetate/petroleum ether mixed solution, volume ratio), a kind of in ethanol/methylene (ratio is 1: 10～1: 100, volume ratio), acetone, the ethyl acetate.
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| CNA2007103042720A CN101215290A (en) | 2007-12-26 | 2007-12-26 | Method for synthesizing 11H-naphthol[1',2',5,6]pyran[2,3,d]pyridin-11(10H)-one compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109153683A (en) * | 2015-12-29 | 2019-01-04 | 免疫目标公司 | 2H- chromene as NF- kB inhibitor simultaneously [2,3-D] pyrimidine -2,4 (3H)-diketone |
-
2007
- 2007-12-26 CN CNA2007103042720A patent/CN101215290A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109153683A (en) * | 2015-12-29 | 2019-01-04 | 免疫目标公司 | 2H- chromene as NF- kB inhibitor simultaneously [2,3-D] pyrimidine -2,4 (3H)-diketone |
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