CN101508714A - Fragrant acid ester derivative of 5-fluorine-2'-deoxidized uridine and synthesis thereof - Google Patents
Fragrant acid ester derivative of 5-fluorine-2'-deoxidized uridine and synthesis thereof Download PDFInfo
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Abstract
The invention discloses an aromatic acid ester derivative of 5-fluoro-2'-deoxyuridine and a synthesis method thereof. The synthesis method comprises the following steps: adding the 5-fluoro-2'-deoxyuridine with the concentration of 1.0-40mg/ml and an acyl donor to a non-aqueous medium, wherein, mol ratio of the 5-fluoro-2'-deoxyuridine to the acyl donor is 1:1.1-30; adding enzyme at a ratio of 0.1-10:1 based on the weight of the 5-fluoro-2'-deoxyuridine; performing an acylation reaction at the temperature of 20-60 DEG C and the normal pressure, and at an oscillation speed of 100-300rpm; and separating to obtain the aromatic acid ester derivative of 5-fluoro-2'-deoxyuridine. The method helps synthesize various aromatic acid ester derivatives of 5-fluoro-2'-deoxyuridine with novel structures and potential pharmaceutical value. The method has the advantages of mild condition, environmental protection, high regioselectivity of the reaction, simple and controllable reaction process, easy product separation and the like.
Description
Technical field
The present invention relates to 5-fluoro-2 '-the aryl esters derivative and the enzyme catalysis preparation method thereof of deoxyuridine.
Background technology
5-fluoro-2 '-deoxyuridine is a class fluoro deoxynucleoside, is widely used in the various cancers of clinical treatment.But clinically, this anti-tumor agent comprising salmosin also shows various toxic side effect, as cause biliary tract inflammation of hepatitis and sclerotic type etc. (Grem J.L.Invest.New Drugs, 2000,18:299-313).Be similar to other nucleoside medicine, 5-fluoro-2 '-the membrane permeation power of deoxyuridine is relatively poor, is difficult for being absorbed, and oral administration biaavailability is lower; And unstable in vivo, easily by the nucleoside phosphorylase metabolism for the 5 FU 5 fluorouracil of low antitumour activity (its antitumour activity than 5-fluoro-2 '-low 5000 times of deoxyuridine).
Although 5-fluoro-2 '-deoxyuridine has above-mentioned shortcoming as clinical application, yet discovers that it is carried out chemically modified can significantly improve its oral administration biaavailability, reduce its toxic side effect.Absorb better as lipotropy nucleoside prodrugs stomach.Nishizawa etc. synthesized a series of 5-fluoro-2 '-the lipid acid diester deriv of deoxyuridine, mouse is carried out oral test, the anti-tumor activity of finding various diester derivs is all than parental generation chemical combination object height (Nishizawa Y., Casida J.E.Biochem.Pharmacol., 1965,14:1605-1619).Studies show that utilize the prodrug principle of design can not only strengthen effectively 5-fluoro-2 '-oral absorption of deoxyuridine, but also can prevent the fracture of its glycosidic link.Amidon etc. synthesized a series of 5-fluoro-2 '-the amino acid ester prodrug of deoxyuridine, find 5 '-L-Isoleucine ester prodrugs has high chemistry and enzymolysis stability; And various amino acid ester prodrugs all can strengthen effectively 5-fluoro-2 '-stability of deoxyuridine glycosidic link; 5 '-L-Isoleucine and 5 '-the membrane permeation force rate 5-fluoro-2 of L-L-valine ester prodrug '-deoxyuridine is high 8 and 11 times respectively, so greatly strengthened its oral administration biaavailability (Vig B.S., Lorenzi P.J., Mittal S., et al.Pharm.Res., 2003,20:1381-1388; Landowski C.P, Song X.Q., Lorenzi P.L., et al.Pharm.Res., 2005,22:1510-1518).
5-fluoro-2 '-two hydroxyls that reactive behavior is similar contained on the sugar ring of deoxyuridine.When adopting general chemical process direct esterification, regioselectivity is low, easily produces a large amount of by products, the product separation difficulty; Be the synthetic acylate of determining the position, need encircle specific hydroxyl to sugar and protect and go operation such as protection, many, the complex process of reactions steps; This method adopts basic catalyst simultaneously, easily produces alkali waste, to environment cause severe contamination (Xia Z.P, Wiebe L.I., Miller G.G., et al.Arch.Pharm., 1999,332:286-294).Undoubtedly, utilizing enzyme process regioselectivity acidylate is an alternative route with prospect.
Summary of the invention
The objective of the invention is to overcome female medicine 5-fluoro-2 '-deoxyuridine many deficiencies clinically, provide a class 5-fluoro-2 '-the aryl esters derivative of deoxyuridine.
Another object of the present invention is to problem, propose the method for the synthetic above-claimed cpd of enzyme catalysis at the prior art existence.
The present invention is an acry radical donor with aromatic acid vinyl acetate, acetoxime ester or acid anhydrides, utilize enzyme catalysis 5-fluoro-2 '-deoxyuridine carries out acylation reaction, synthetic compound shown in general formula (I), (II), (III).By select different enzymes can synthesize 5-fluoro-2 '-deoxyuridine 3 '-ester, 5 '-ester and 3 ', 5 '-diester deriv.
Purpose of the present invention is achieved through the following technical solutions:
5-fluoro-2 '-structure such as the general formula (I) of deoxyuridine aryl esters derivative, (II), (III) shown in:
Wherein, n=1,2,3 or 4; M=2,3 or 4.
5-fluoro-2 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that:
Adding 5-fluoro-2 in non-aqueous media '-deoxyuridine and acry radical donor, acry radical donor and 5-fluoro-2 '-mol ratio of deoxyuridine is 1.1-30:1, the add-on of non-aqueous media be make 5-fluoro-2 '-concentration of deoxyuridine is 1.0-40mg/mL, by 5-fluoro-2 '-mass ratio of deoxyuridine and enzyme is that 0.1-10:1 adds enzyme, in temperature is that 20-60 ℃, hunting speed are to carry out acylation reaction under 100-300rpm, the normal pressure, separation and purification obtain 5-fluoro-2 '-deoxyuridine aryl esters derivative;
Described enzyme is one or more in lipase, the proteolytic enzyme; Described lipase derives from antarctic candida (Candida antarctica), the thermophilic hyphomycete of cotton shape (Thermomyces lanuginosus), rice black root Mucor (Rhizomucor miehe), cloth gram Hall Salmonella (Burkholderia cepacia), pseudomonas fluorescens (Pseudomonas fluorescens), aspergillus niger (Aspergillus niger), rice black wool mould (Mucor miehei) or Pancreas Sus domestica; Described proteolytic enzyme derives from subtilis (Bacillussubtilis) or Bacillus licheniformis (Bacillus licheniformis);
Described acry radical donor is aromatic acid vinyl acetate, acetoxime ester or acid anhydrides;
Described non-aqueous media is the mixed system of organic solvent, ionic liquid, organic solvent mixed system, organic solvent and ionic liquid; Described organic solvent is an aprotic organic solvent; Described ionic liquid is for containing the low anionic ionic liquid of nucleophilicity; Described organic solvent mixed system is that two kinds in the aprotic organic solvent are that 1-19:1 mixing gets according to volume ratio; The mixed system of described organic solvent and ionic liquid is the mixture that contains low anionic ionic liquid of nucleophilicity and aprotic organic solvent, and wherein ionic liquid volume content in mixed system is 2-95%.
For further realizing the object of the invention, described aprotic organic solvent is preferably dimethyl sulfoxide (DMSO), N, dinethylformamide, pyridine, acetonitrile, acetone, tetrahydrofuran (THF), diox, ethyl acetate, isopropyl ether, toluene, dimethylbenzene, ethylbenzene, normal hexane, normal heptane, octane, positive nonane or hexanaphthene.
The negatively charged ion of described ionic liquid is preferably tetrafluoroborate ion, hexafluorophosphoricacid acid ions or two (trifluoromethyl sulphonyl) imines ion or amino acid ion.
Described hunting speed is preferably 150-250rpm; Described temperature of reaction is preferably 40-60 ℃.
Described separation purification method is for after reacting end, and filtration is dezymotized, vacuum concentration, uses methyl alcohol, ethanol or ethyl acetate crystallization again, perhaps obtains target product through silica gel column chromatography.
The present invention has following advantage compared with prior art:
(1) adopt biological catalyst efficiently---enzyme catalysis 5-fluoro-2 '-deoxyuridine aryl esters derivative is synthetic.Enzymatic reaction has high selectivity, and by select different enzymes can synthesize 5-fluoro-2 '-deoxyuridine 3 '-ester, 5 '-ester and 3 ', 5 '-diester deriv, therefore overcome traditional chemical method selectivity low, easily generate by product, need protection and shortcoming such as deprotection operation and productive rate be low;
(2) the present invention need not radical protection and deprotection operation, and reaction process is simple and easy to control, and product is easily separated;
(3) the present invention is to be that 20-60 ℃, hunting speed are under 100-300rpm, the condition of normal pressure in temperature, utilize enzyme catalysis prepare 5-fluoro-2 '-the aryl esters derivative of deoxyuridine, reaction conditions gentleness, environmental friendliness.
Embodiment
For understanding the present invention better, the present invention is described in further detail below in conjunction with embodiment, but the scope of protection of present invention is not limited to the scope that embodiment represents.
Embodiment 1:5-fluoro-2 '-deoxyuridine 3 '-phenylacetate synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), toluylic acid vinyl acetate (1.64mmol), 30mL tetrahydrofuran (THF) add in the sealing tool plug triangular flask, then add 200mg and derive from the immobilized lipase that cloth restrains Hall Salmonella (Burkholderia cepacia), place vibration in 50 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 134mg, yield is 90%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 3 '-Rf value and the nuclear magnetic data of phenylacetate on TLC is as follows: Rf=0.31 (PE/EA=1/1);
1H NMR (DMSO-d
6) δ: 2.27 (apparent d, 2H, H
2 '), 3.64 (s, 2H, H
2 "), 3.74 (s, 2H, H
5 '), 4.02 (s, 1H, H
4 '), 5.26 (s, 1H, H
3 '), 5.33 (br s, 1H, OH), 6.17 (t, J=7.2Hz, 1H, H
1 '), 7.25-7.35 (m, 5H, H
o, H
p, H
m), 8.21 (d, J=7.2Hz, 1H, H
6), 11.88 (d, J=4.0Hz, 1H, H
3);
13C NMR (DMSO-d
6) δ: 36.9 (C
2 '), 40.1 (C
2 "), 61.3 (C
5 '), 75.2 (C
3 '), 84.4 (C
4 '), 84.9 (C
1 '), 124.3,124.6 (C
6), 126.9 (C
p), 128.4 (C
m), 129.4 (C
o), 134.1 (C
i), 139.0,141.3 (C
5), 149.1 (C
2), 156.9,157.1 (C
4), 170.9 (C
1 ").Nuclear magnetic data shows that this compound is described target product.
Embodiment 2:5-fluoro-2 '-deoxyuridine 5 '-(3-phenylpropionic acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 3-phenylpropionic acid acetoxime ester (1.64mmol), 4mL normal hexane/pyridine (1/6, volume ratio) adds in the sealing tool plug triangular flask, then add 100mg subtilis (Bacillus subtilis) proteolytic enzyme, place vibration in 60 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 133mg, yield is 86%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 5 '-Rf value and the nuclear magnetic data of (3-phenylpropionic acid) ester on TLC is as follows: Rf=0.33 (PE/EA=1/2);
1H NMR (DMSO-d
6) δ: 2.11-2.24 (m, 2H, H
2 '), 2.68 (t, J=7.6Hz, 2H, H
2 "), 2.87 (t, J=7.6Hz, 2H, H
3 "), 3.93 (br s, 1H, H
3 '), 4.20-4.25 (m, 3H, H
4 ', H
5 '), 5.34 (br s, 1H, OH), 6.15 (t, 1H, H
1 '), 7.19-7.90 (m, 5H, H
o, H
m, H
p), 7.91 (d, J=7.2Hz, 1H, H
6), 11.89 (d, J=4.8Hz, 1H, H
3);
13C NMR (DMSO-d
6) δ: 30.2 (C
2 "), 35.0 (C
3 "), 38.7 (C
2 '), 63.8 (C
5 '), 70.0 (C
3 '), 83.9 (C
4 '), 84.6 (C
1 '), 124.6,124.9 (C
6), 126.1 (C
p), 128.2,128.4 (C
m, C
o), 139.0,141.3 (C
5), 140.4 (C
i), 149.0 (C
2), 156.9,157.2 (C
4), 172.1 (C
1 ").Nuclear magnetic data shows that this compound is described target product.
Embodiment 3:5-fluoro-2 '-deoxyuridine 3 '-(3-phenylpropionic acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 3-phenylpropionic acid vinyl acetate (8.2mmol), 30mL[C
4MIm] BF
4Add in the sealing tool plug triangular flask, then add the immobilized lipase that 50mg derives from cloth gram Hall Salmonella (Burkholderia cepacia), place vibration in 40 ℃, the constant temperature oscillator of 200rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, remove under filtration, extraction, the vacuum desolvate, after column chromatography purification gets product 139mg, yield is 90%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 3 '-Rf value and the nuclear magnetic data of (3-phenylpropionic acid) ester on TLC is as follows: Rf=0.36 (PE/EA=1/1);
1H NMR (DMSO-d
6) δ: 2.18-2.29 (m, 2H, H
2 '), 2.69 (t, J=7.6Hz, 2H, H
2 "), 2.88 (t, J=7.6Hz, 2H, H
3 "), 3.63 (br s, 2H, H
5 '), 3.95 (br s, 1H, H
4 '), 5.22 (t, J=2.4Hz, H
3 '), 5.34 (br s, 1H, OH), 6.15 (t, J=6.8Hz, 1H, H
1 '), 7.17-7.31 (m, 5H, H
o, H
m, H
p), 8.22 (d, J=7.2Hz, 1H, H
6), 11.89 (d, J=4.8Hz, 1H, H
3);
13C NMR (DMSO-d
6) δ: 30.2 (C
2 "), 35.0 (C
3 "), 36.9 (C
2 '), 61.3 (C
5 '), 74.8 (C
3 '), 84.4 (C
4 '), 84.9 (C
1 '), 124.3,124.6 (C
6), 126.2 (C
p), 128.3 (C
m), 128.4 (C
o), 139.0,141.2 (C
5), 140.3 (C
i), 149.1 (C
2), 156.9,157.1 (C
4), 171.9 (C
1 ").Nuclear magnetic data shows that this compound is described target product.
Embodiment 4:5-fluoro-2 '-deoxyuridine 3 ', 5 '-two (5-phenylvaleric acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 5-phenylvaleric acid vinyl acetate (3.28mmol), 15mL normal hexane/tetrahydrofuran (THF) (1/3, v/v) add in the sealing tool plug triangular flask, then add 200mg and derive from immobilized lipase of the thermophilic hyphomycete of cotton shape (Thermomyces lanuginosus) and the immobilized lipase that 200mg derives from cloth gram Hall Salmonella (Burkholderia cepacia), place vibration in 60 ℃, the constant temperature oscillator of 150rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 142mg, yield is 61%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 3 ', Rf value and the nuclear magnetic data of 5 '-two (5-phenylvaleric acid) ester on TLC is as follows: Rf=0.24 (PE/EA=2/1);
1H NMR (CDCl
3) δ: 1.67 (br s, 8H, H
3 ", H
4 "), 2.04-2.11 (m, 1H, H
2 '), 2.38 (apparent t, 4H, H
2 "), 2.45-2.50 (m, 1H, H
2 '), 2.63 (apparent d, 4H, H
5 "), 4.22 (apparent t, 1H, H
4 '), 4.26-4.43 (m, 2H, H
5 '), 5.16-5.18 (m, 1H, H
3 '), 6.28 (t, J=7.2Hz, 1H, H
1 '), 7.15-7.30 (m, 5H, H
o, H
m, H
p), 7.62 (d, J=6.4Hz, 1H, H
6), 9.64 (d, J=4.4Hz, 1H, H
3);
13C NMR (CDCl
3) δ: 25.0 (C
3 "), 31.4 (C
4 "), 34.5,34.7 (C
2 "), 36.1 (C
5 "), 38.5 (C
2 '), 64.3 (C
5 '), 74.3 (C
3 '), 83.3 (C
4 '), 85.9 (C
1 '), 123.6,123.9 (C
6), 126.5 (C
p), 129.0 (C
o, C
m), 139.0,140.2,142.5 (C
5, C
i), 149.5 (C
2), 157.2,157.5 (C
4), 173.4,173.7 (C
1 ').Nuclear magnetic data shows that this compound is described target product.
Embodiment 5:5-fluoro-2 '-deoxyuridine 5 '-(4-benzenebutanoic acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 4-benzenebutanoic acid vinyl acetate (6.15mmol), 40mL[C
4MIm] PF
6/ acetone (1/9, v/v) add in the sealing tool plug triangular flask, then add the proteolytic enzyme that 500mg derives from Bacillus licheniformis (Bacillus licheniformis), place vibration in 30 ℃, the constant temperature oscillator of 250rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 133mg, yield is 83%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 5 '-Rf value and the nuclear magnetic data of (4-benzenebutanoic acid) ester on TLC is as follows: Rf=0.12 (PE/EA=1/1);
1H NMR (DMSO-d
6) δ: 1.85 (apparent t, 2H, H
3 "), 2.16-2.26 (m, 2H, H
2 '), 2.34 (t, J=6.8Hz, 2H, H
2 "), 2.59 (t, J=7.2Hz, 2H, H
4 "), 3.94 (apparent d, 1H, H
4 '), 4.24 (apparent d, 3H, H
3 ', H
5 '), 5.35 (br s, 1H, OH), 6.14 (apparent d, 1H, H
1 '), 7.16-7.26 (m, 5H, H
o, H
m, H
p), 7.86 (d, J=6.8Hz, 1H, H
6), 11.76 (br s, 1H, H
3);
13C NMR (DMSO-d
6) δ: 26.3 (C
3 "), 32.8 (C
2 "), 34.3 (C
4 "), 38.7 (C
2 '), 63.8 (C
5 '), 70.0 (C
3 '), 83.9 (C
4 '), 84.6 (C
1 '), 124.6,124.9 (C
6), 125.9 (C
p), 128.3 (C
o, C
m), 139.0,141.4 (C
5, C
i), 149.0 (C
2), 156.9,157.2 (C
4), 172.6 (C
1 ").Nuclear magnetic data shows that this compound is described target product.
Embodiment 6:5-fluoro-2 '-deoxyuridine 3 '-(4-benzenebutanoic acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 4-benzenebutanoic acid acid anhydride (2.46mmol), 50mL cyclohexane/acetone (1/5, v/v) add in the sealing tool plug triangular flask, then add 300mg and derive from the lipase of pseudomonas fluorescens (Pseudomonas fluorescens), place vibration in 50 ℃, the constant temperature oscillator of 300rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 153mg, yield is 95%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 3 '-Rf value and the nuclear magnetic data of (4-benzenebutanoic acid) ester on TLC is as follows: Rf=0.36 (PE/EA=1/1);
1H NMR (DMSO-d
6) δ: 1.81-1.89 (m, 2H, H
3 "), 2.27-2.37 (m.4H, H
2 ', H
2 "), 2.60 (t, J=7.4Hz, H
4 "), 3.66 (apparent t, 2H, H
5 '), 4.01 (apparent d, 1H, H
4 '), 5.24 (apparent t, 1H, H
3 '), 5.34 (t, J=5.2Hz, 1H, OH), 6.17 (t, J=7.2Hz, 1H, H
1 '), 7.19-7.31 (m, 5H, H
o, H
m, H
p), 8.23 (d, J=7.2Hz, 1H, H
6), 11.90 (s, 1H, H
3);
13C NMR (DMSO-d
6) δ: 26.2 (C
3 "), 32.9 (C
2 "), 34.3 (C
4 "), 36.9 (C
2 '), 61.3 (C
5 '), 74.7 (C
3 '), 84.4 (C
4 '), 85.0 (C
1 '), 124.3,124.6 (C
6), 125.9 (C
p), 128.4 (C
o, C
m), 139.0,141.3 (C
5, C
i), 149.1 (C
2), 156.9,157.1 (C
4), 172.3 (C
1 ").Nuclear magnetic data shows that this compound is described target product.
Embodiment 7:5-fluoro-2 '-deoxyuridine 3 '-(5-phenylvaleric acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 5-phenylvaleric acid vinyl acetate (2.05mmol), 20mL acetone add in the sealing tool plug triangular flask, then add 20mg and derive from the immobilized lipase that cloth restrains Hall Salmonella (Burkholderia cepacia), place vibration in 60 ℃, the constant temperature oscillator of 300rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 160mg, yield is 96%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 3 '-Rf value and the nuclear magnetic data of (5-phenylvaleric acid) ester on TLC is as follows: Rf=0.36 (PE/EA=1/1);
1H NMR (DMSO-d
6) δ: 1.57 (br s, 4H, H
3 ", H
4 "), 2.26-2.40 (m, 4H, H
2 ', H
2 "), 2.58 (t, J=7.2Hz, 2H, H
5 "), 3.65 (apparent d, 2H, H
5 '), 4.00 (br s, 1H, H
4 '), 5.24 (apparent d, 1H, H
3 '), 5.36 (t, J=4.8Hz, 1H, OH), 6.16 (t, J=4.8Hz, 1H, H
1 '), 7.15-7.29 (m, 5H, H
o, H
m, H
p), 8.22-8.25 (m, 1H, H
6), 11.91 (d, J=4.8Hz, 1H, H
3);
13C NMR (DMSO-d
6) δ: 23.9 (C
3 "), 30.3 (C
4 "), 33.3 (C
2 "), 34.8 (C
5 "), 37.0 (C
2 '), 61.3 (C
5 '), 74.7 (C
3 '), 84.5 (C
4 '), 85.0 (C
1 '), 124.3,124.7 (C
6), 125.7 (C
p), 128.3 (C
o, C
m), 139.0,141.3 (C
5), 141.9 (C
i), 149.1 (C
2), 156.9,157.2 (C
4), 172.5 (C
1 ').Nuclear magnetic data shows that this compound is described target product.
Embodiment 8:5-fluoro-2 '-deoxyuridine 5 '-(5-phenylvaleric acid) ester synthetic
With 5-fluoro-2 '-deoxyuridine (101mg, 0.41mmol), 5-phenylvaleric acid acetoxime ester (0.62mmol), 20mL[C
4MIm] BF
4/ tetrahydrofuran (THF) (1/19, v/v) add in the sealing tool plug triangular flask, then add 400mg and derive from the immobilized lipase of a meter black root Mucor (Rhizomucor miehe), place vibration in 25 ℃, the constant temperature oscillator of 300rpm under the normal pressure, utilize TLC monitoring reaction.After reaction finishes, filter, concentrated filtrate under the vacuum, after column chromatography purification gets product 123mg, yield is 74%, white powder, purity is greater than 99%.5-fluoro-2 '-deoxyuridine 5 '-Rf value and the nuclear magnetic data of (5-phenylvaleric acid) ester on TLC is as follows: Rf=0.12 (PE/EA=1/1);
1HNMR (DMSO-d
6) δ: 1.56-1.61 (m, 4H, H
3 ", H
4 "), 2.13-2.25 (m, 2H, H
2 '), 2.37 (t, J=5.6Hz, 2H, H
2 "), 2.57 (t, J=6.8Hz, 2H, H
5 "), 3.94 (apparent d, 1H, H
4 '), 4.24 (apparent d, 3H, H
5 ', H
3 '), 5.45 (br s, 1H, OH), 6.14-6.16 (m, 1H, H
1 '), 7.14-7.28 (m, 5H, H
o, H
m, H
p), 7.90 (d, J=7.2Hz, 1H, H
6), 11.89 (d, J=4.8Hz, 1H, H
3);
13C NMR (DMSO-d
6) δ: 24.1 (C
3 "), 30.3 (C
4 "), 33.3 (C
2 "), 34.8 (C
5 "), 38.8 (C
2 '), 63.7 (C
5 '), 70.0 (C
3 '), 83.9 (C
4 '), 84.6 (C
1 '), 124.5,124.8 (C
6), 125.7 (C
p), 128.3 (C
o, C
m), 139.0,141.3 (C
5), 141.9 (C
i), 149.0 (C
2), 156.9,157.2 (C
4), 172.7 (C
1 ').Nuclear magnetic data shows that this compound is described target product.
Simultaneously, experimental result show that the lipase that derives from antarctic candida (Candida antarctica), aspergillus niger (Aspergillus niger) or Pancreas Sus domestica all can the synthetic 5-fluoro-2 of efficient catalytic '-deoxyuridine 5 '-aryl esters.
From the foregoing description as can be seen, present method reaction conditions gentleness (20-60 ℃, 100-300rpm), under green bio catalyzer (enzyme) effect, by single step reaction can efficiently synthesize 5-fluoro-2 '-the various aryl esters derivatives of deoxyuridine.After the reaction; filtration can be removed enzyme; subsequent products separation and purification operation is simple, easy to operate, and yield reaches 70-92% behind the purifying, has overcome that traditional chemical method selectivity is low, protection/deprotection steps of needing time and effort consuming, has easily generated shortcomings such as by product and productive rate are low.
Claims (6)
1,5-fluoro-2 '-deoxyuridine aryl esters derivative, it is characterized in that: its structure such as general formula (I), (II), (III) shown in:
Wherein, n=1,2,3 or 4; M=2,3 or 4.
2, the described 5-fluoro-2 of claim 1 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that: adding 5-fluoro-2 in non-aqueous media '-deoxyuridine and acry radical donor, acry radical donor and 5-fluoro-2 '-mol ratio of deoxyuridine is 1.1-30: 1, the add-on of non-aqueous media be make 5-fluoro-2 '-concentration of deoxyuridine is 1.0-40mg/mL, by 5-fluoro-2 '-mass ratio of deoxyuridine and enzyme is that 0.1-10:1 adds enzyme, be 20-60 ℃ in temperature, hunting speed is 100-300rpm, carry out acylation reaction under the normal pressure, separation and purification obtain 5-fluoro-2 '-deoxyuridine aryl esters derivative;
Described enzyme is one or more in lipase, the proteolytic enzyme; Described lipase derives from antarctic candida, the thermophilic hyphomycete of cotton shape, rice black root Mucor, cloth gram Hall Salmonella, pseudomonas fluorescens, aspergillus niger, the mould or Pancreas Sus domestica of rice black wool; Described proteolytic enzyme derives from subtilis or Bacillus licheniformis;
Described acry radical donor is aromatic acid vinyl acetate, acetoxime ester or acid anhydrides;
Described non-aqueous media is the mixed system of organic solvent, ionic liquid, organic solvent mixed system, organic solvent and ionic liquid; Described organic solvent is an aprotic organic solvent; Described ionic liquid is for containing the low anionic ionic liquid of nucleophilicity; Described organic solvent mixed system is that two kinds in the aprotic organic solvent are that 1-19:1 mixing gets according to volume ratio; The mixed system of described organic solvent and ionic liquid is the mixture that contains low anionic ionic liquid of nucleophilicity and aprotic organic solvent, and wherein ionic liquid volume content in mixed system is 2-95%.
3,5-fluoro-2 according to claim 2 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that: described aprotic organic solvent is dimethyl sulfoxide (DMSO), N, dinethylformamide, pyridine, acetonitrile, acetone, tetrahydrofuran (THF), diox, ethyl acetate, isopropyl ether, toluene, dimethylbenzene, ethylbenzene, normal hexane, normal heptane, octane, positive nonane or hexanaphthene.
4,5-fluoro-2 according to claim 2 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that: the negatively charged ion of described ionic liquid is for containing tetrafluoroborate ion, hexafluorophosphoricacid acid ions or two (trifluoromethyl sulphonyl) imines ion or amino acid ion.
5,5-fluoro-2 according to claim 2 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that: described hunting speed is 150250rpm; Described temperature of reaction is 40-60 ℃.
6,5-fluoro-2 according to claim 2 '-synthetic method of deoxyuridine aryl esters derivative, it is characterized in that: described separation purification method is for after reacting end, filtration is dezymotized, vacuum concentration, use methyl alcohol, ethanol or ethyl acetate crystallization again, perhaps obtain target product through silica gel column chromatography.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105838600A (en) * | 2016-04-29 | 2016-08-10 | 浙江农林大学 | Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode |
| CN105838599A (en) * | 2016-04-29 | 2016-08-10 | 浙江农林大学 | Method for online synthesizing 5'-O-lauroyl uridine in lipozyme catalysis mode |
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2009
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105838600A (en) * | 2016-04-29 | 2016-08-10 | 浙江农林大学 | Method for online synthesizing 5'-O-palmitoyl uridine in lipozyme catalysis mode |
| CN105838599A (en) * | 2016-04-29 | 2016-08-10 | 浙江农林大学 | Method for online synthesizing 5'-O-lauroyl uridine in lipozyme catalysis mode |
| CN105838600B (en) * | 2016-04-29 | 2018-04-20 | 浙江农林大学 | A kind of method of 5 ' O palmityl uridines of lipase-catalyzed online synthesis |
| CN105838599B (en) * | 2016-04-29 | 2018-05-08 | 浙江农林大学 | A kind of method of 5 '-O- lauroyl uridines of lipase-catalyzed online synthesis |
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