CN104817525A - Fluorine-containing 2,3-dihydrobenzofuran-3-alcoholic compound and preparation method thereof - Google Patents
Fluorine-containing 2,3-dihydrobenzofuran-3-alcoholic compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical chemistry and fluorine chemistry and specifically discloses novel fluorine-containing 2,3-dihydrobenzofuran-3-alcohol and its preparation method. The specific preparation method is as follows: in a dry organic solvent, triphenyl phosphine difluoroacetate is used as a difluoromethylation reagent, and 2'-hydroxy chalcone with different substituent groups is transferred to a 2,2-difluoro-3-styryl-2,3-dihydrobenzofuran-3-alcoholic compound by one step. The fluorine-containing 2,3-dihydrobenzofuran alcohol is a compound with a wide range of application and especially has potential application value in the aspect of medicine.
Description
Technical field
The present invention relates to pharmaceutical chemistry technology and fluorine chemistry field, disclose a kind of novel fluorine 2,3-Dihydrobenzofuranes-3-alcohol and preparation method thereof specifically.
Background technology
2,3-Dihydrobenzofuranes-3-alcohol be the important natural product skeleton of a class (
j. Med. Chem.
2011,
54, 3506;
j. Nat. Prod. 2012,
75, 1500;
j. Am. Chem. Soc. 2014,
136, 2659) and pharmaceutical chemicals skeleton (as anticarcinogen Silvestrol:
j. Med. Chem.
2012,
55, 558;
j. Med. Chem. 2012,
55, 8859;
org. Lett. 2013,
15, 1406), develop the new compound containing 2,3-Dihydrobenzofuranes-3-ol skeleton and there is important medical practical value; The synthesis of this compounds generally need comparatively special raw material and metal catalyst (
j. Am. Chem. Soc. 2006,
128, 16504;
j. Am. Chem. Soc. 2009,
131, 2786;
angew. Chem. Int. Ed. 2012,
51, 971), therefore develop new nonmetal catalyzed method and prepare 2,3-Dihydrobenzofuranes-3-ol skeleton compound there is certain practical significance.
Fluorine (F)-as the highest element of electronegativity, be introduced in organic molecule, its physics, chemistry and biological physiology performance can be changed; It is determined by its special physiologically active that organic fluoride-containing compound is applied to pharmacy field; First, the radius of F is suitable with the radius of H, OH, and after H or OH in molecule is replaced by F, whole molecular volume and steric configuration change are not quite; Secondly, introduce the lipotropy that fluorine can strengthen organic molecule, fluorochemicals is strengthened the penetrativity of film, tissue in vivo, improve its absorption in vivo and transmission speed; Again, carbon-fluorine bond high stability, makes it be difficult to leave away with the form of ion or free radical, can cause the restraining effect to pathways metabolism in physiologically active; Therefore introduce in natural radioactivity molecule or pharmaceutical activity molecule fluorine be design new drug important method (
chem. Rev. 2014,
114, 2432;
chem. Eur. J. 2014,
20, 16830); In fluorochemicals, containing difluoromethyl compound more and more come into one's own (
synthesis 2014,
46, 842).The bioisostere of difluoromethyl in hydroxyl, the hydroxyl in replaceable drug molecule and do not affect the pharmacological action of medicine; And utilize the strong lipotropy of difluoromethyl, the absorption of medicine can be promoted to reduce the consumption of medicine; Recently some medicine as: Desflurane (narcotic,
drugs.
1995,
50, 742), Pantoprazole (gastric acid secretion inhibitor,
drugs. 2003,
63, 101) and N-(difluoromethyl) pyridin-2 (1H)-one-substituted acetic acids (enzyme inhibitors,
bioorg. Med. Chem. Lett. 2010,
20, 2168) all contain difluoromethyl group.
Difluoromethyl is introduced in 2,3-Dihydrobenzofuranes-3-ol skeleton compound, in conjunction with the advantage of two class groups, can will has important practical value in new drug design synthesis.
Summary of the invention
Object of the present invention is intended to expansion 2, the scope of 3-Dihydrobenzofuranes-3-alcohol, develops a kind of novel fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds, another object of the present invention is to provide above-mentioned fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compound preparation methods.
Fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds of the present invention, is characterized in that it is the compound with following chemical structure of general formula:
In chemical general formula:
R
1for the substituted radical of phenyl ring, such as: the alkyl of H, halogen, methoxyl group, C1 ~ C6.
R
2for aromatic group, such as phenyl ring, containing substituent phenyl ring, containing substituent furans, containing substituent thiophene.
The preparation method of fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds of the present invention, is characterized in that carrying out according to following step:
With different substituents 2 '-hydroxylated chalcone (formula I) and triphenylphosphine difluoroacetic acid salt (
chem. Commun. 2013,
49, 7513) and phase-transfer catalyst in dry organic solvent at 40 ~ 100 DEG C react 1 ~ 8 hour, boil off solvent, raffinate through silica gel column chromatography be separated obtain 2,2-bis-fluoro-3-styryl-2,3-Dihydrobenzofuranes-3-alcohol compound (formula II).
The mol ratio of described 2 '-hydroxylated chalcone and triphenylphosphine difluoroacetic acid salt and phase-transfer catalyst is 1: 1 ~ 3: 0 ~ 0.5.
Described organic solvent is: methylene dichloride, trichloromethane, tetracol phenixin, benzene, toluene, dimethylbenzene, p-Xylol, acetonitrile, tetrahydrofuran (THF), dimethyl formamide, N-Methyl pyrrolidone.
Described reaction solubility is that 0.1 ~ 1 mol/L(is as the criterion with 2 '-hydroxylated chalcone).
Described phase-transfer catalyst is: 4 bromide, tetraethylammonium bromide, Tetrabutyl amonium bromide, 18 hat six, 15 hats five.
The invention has the beneficial effects as follows and invented a kind of novel 2,2-bis-fluoro-3-styryl-2,3-Dihydrobenzofuranes-3-alcohol compounds, and obtain this compounds by easy method with good yield (the highest yield 75%).The compound of new synthesis, due to simultaneously containing 2,3-Dihydrobenzofuranes-3-ol skeleton and difluoromethyl group, therefore has potential using value at field of medicaments.
Embodiment
Contribute to understanding the present invention further by following example, but do not limit the present invention.
example 1: 2,2-bis-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol
At room temperature, 112.1 milligrams of (0.5 mmol) 2 '-hydroxylated chalcones and 356.3 milligrams of (1.0 mmol) triphenylphosphine difluoroacetic acid salt are added in 100 milliliters of round-bottomed bottles, add the dry acetonitrile of 2 mL again, then oil bath is heated to 60 DEG C of reactions 2 hours; After being distilled out by solvent, mixture, through silica gel column chromatography, is eluent by ethyl acetate/petroleum ether (volume ratio 1/20), obtains 102.1 milligram of 2,2-bis-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol, yield 75%.
1H NMR (400 MHz, CDCl
3) δ 2.92 (s, 1H), 6.39-6.44 (m, 1H), 6.92 (d,
J =16.0 Hz, 1H), 7.06 (d,
J =8.4 Hz, 1H), 7.17 (t,
J = 7.2 Hz, 1H), 7.30-7.42 (m, 5H), 7.44-7.47 (m, 2H);
13C NMR (100 MHz, CDCl
3) δ 154.8, 135.7, 132.7, 131.6, 130.5 (t,
J = 271.4 Hz), 128.7, 128.5, 127.8, 127.0, 125.2, 124.0, 111.1, 80.1-80.64 (m, 1C);
19F NMR (376 MHz, CDCl
3) δ-89.1（d,
J = 142.9 Hz, 1F），-82.8（d,
J = 142.9 Hz, 1F）；MS (ESI) m/z 275.2 [M+H]
+。
example 2: the fluoro-3-of 2,2-bis-(4-vinyl toluene base)-2,3-Dihydro-benzofuran-3-alcohol
At room temperature, 119.1 milligrams of (0.5 mmol) 1-(2-hydroxy phenyl)-3-p-methylphenyl acrylketone and 356.3 milligrams of (1.0 mmol) triphenylphosphine difluoroacetic acid salt are added in 100 milliliters of round-bottomed bottles, then add 39.6 milligrams (0.15 mmol) 18 and be preced with six, add the dry acetonitrile of 5 mL again, then oil bath is heated to 80 DEG C of reactions 3 hours; After being distilled out by solvent, mixture, through silica gel column chromatography, is eluent by ethyl acetate/petroleum ether (volume ratio 1/20), obtains 63.2 milligram of 2,2-bis-fluoro-3-(4-vinyltoluene base)-2,3-Dihydro-benzofuran-3-alcohol, yield 46%.
1H NMR (400 MHz, CDCl3) δ2.35(s, 3H),3.00(s, 1H), 6.31-6.35 (dd, J = 16.0 Hz and J = 2.8 Hz, 1H), 6.85 (d, J = 16.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.11-7.16 (m, 3H), 7.32 (d, J = 8.0 Hz, 3H), 7.36-7.40 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 154.8, 138.4, 132.9, 132.5, 131.5, 130.5 (t, J = 271.6 Hz, 1C), 129.4, 128.4, 126.9, 125.3, 127.0, 125.3, 123.9, 123.0-123.1 (m, 1C), 111.0, 80.1-80.6 (m, 1C), 21.3; 19F NMR (376 MHz, CDCl3) δ-89.2（d, J = 142.9 Hz, 1F），-82.9（d, J = 142.5 Hz, 1F）; MS (ESI) m/z 289.4 [M+H]
+。
example 3: the fluoro-3-of 2,2-bis-(4-methoxyl-styrene)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is acetonitrile, and 60 DEG C of reaction times are 8 hours, obtains 90.5 milligram of 2,2-bis-fluoro-3-(4-methoxyl-styrene)-2,3-Dihydro-benzofuran-3-alcohol, yield 59%.
1H NMR (400 MHz, CDCl
3) δ3.14(s, 1H),3.80(s, 3H), 6.23-6.27 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H)6.79-6.87 (m, 3H), 7.01 (d,
J = 8.0 Hz, 1H), 7.13 (t,
J = 7.6 Hz, 1H), 7.31-7.39 (m, 4H);
13C NMR (100 MHz, CDCl
3) δ 159.8, 154.8, 132.1, 131.4, 130.6 (t,
J = 271.1 Hz, 1C), 128.5, 128.4, 128.3, 125.3, 123.9, 121.8, 121.7, 114.1, 111.0, 80.1-80.6 (m, 1C), 55.3;
19F NMR (376 MHz, CDCl
3) δ-89.2（d, J = 142.9 Hz, 1F），-82.9（d, J = 142.5 Hz, 1F）; MS (ESI) m/z 305.2 [M+H]
+。
example 4: the fluoro-3-of 2,2-bis-(4-fluorostyryl)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is dimethyl formamide, and 60 DEG C of reaction times are 1.5 hours, obtains 89.1 milligram of 2,2-bis-fluoro-3-(4-fluorostyryl)-2,3-Dihydro-benzofuran-3-alcohol, yield 61%.
1H NMR (400 MHz, CDCl
3) δ3.20(s, 1H), 6.27-6.32 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H), 6.84 (d,
J = 16.0 Hz, 1H), 7.00-7.04 (m, 3H), 7.11-7.15 (m, 1H), 7.30-7.32 (m, 1H), 7.36-7.40 (m, 3H);
13C NMR (100 MHz, CDCl
3) δ 164.0, 161.6, 154.7, 133.2, 131.9, 131.6, 131.5, 130.5 (t,
J = 272.1 Hz, 1C), 128.7, 128.6, 128.6, 128.2, 125.2, 124.0, 120.7, 116.3(t,
J = 259.2 Hz, 1C),
19F NMR (376 MHz, CDCl
3) δ-113.2（s，1F),-89.0（d,
J = 142.9 Hz, 1F），-82.8（d,
J = 142.5 Hz, 1F）; 116.0; MS (ESI) m/z 293.2 [M+H]
+。
example 5: the fluoro-3-of 2,2-bis-(4-chloro-styrene base)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is N-Methyl pyrrolidone, and 40 DEG C of reaction times are 4 hours, obtains 83.4 milligram of 2,2-bis-fluoro-3-(4-chloro-styrene base)-2,3-Dihydro-benzofuran-3-alcohol, yield 54%.
1H NMR (400 MHz, CDCl
3) δ 3.45 (s, 1H), 6.32-6.37 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H), 6.84 (d,
J = 16.0 Hz, 1H), 7.01 (d,
J = 8.0 Hz, 1H), 7.11-7.15 (m, 1H),-7.28-7.40 (m, 6H);
13C NMR (100 MHz, CDCl
3) δ 154.7, 134.3, 134.1, 131.6,131.4, 130.5 (t,
J = 272.3 Hz, 1C), 128.9, 128.2, 125.3, 124.9, 124.0, 111.1,80.0-80.5 (m, 1C);
19F NMR (376 MHz, CDCl
3) δ-88.6（d,
J = 142.9 Hz, 1F），-82.5（d,
J = 142.5 Hz, 1F）; MS (ESI) m/z 309.1 [M+H]
+。
example 6: the fluoro-3-of 2,2-bis-(2-bromstyrol base)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 2 is synthesized, and catalyzer is Tetrabutyl amonium bromide, and solvent is tetrahydrofuran (THF), and 60 DEG C of reaction times are 2 hours, obtains 125.4 milligram of 2,2-bis-fluoro-3-(2-bromstyrol base)-2,3-Dihydro-benzofuran-3-alcohol, yield 71%.
1H NMR (400 MHz, CDCl
3) δ 3.20 (s, 1H), 6.29-6.34 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H), 7.02 (d,
J = 8.0 Hz, 1H), 7.12-7.16 (m, 2H),-7.24-7.30 (m, 2H), 7.35-7.41 (m, 2H), 7.52-7.58 (m, 2H);
13C NMR (100 MHz, CDCl
3) δ 135.9, 133.0, 131.7, 133.1, 131.6, 129.6 (t,
J = 270.9 Hz, 1C),128.0, 127.6, 127.5, 127.2, 127.1, 125.3, 124.1, 124.0, 111.0;
19F NMR (376 MHz, CDCl
3) δ -89.0（d,
J = 142.9 Hz, 1F），-82.5（d,
J = 142.9 Hz, 1F）； MS (ESI) m/z 309.1 [M+H]
+。
example 7: the fluoro-3-of 2,2-bis-(3-phenoxy group styryl)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is acetonitrile, and 60 DEG C of reaction times are 3 hours, obtains 62.3 milligram of 2,2-bis-fluoro-3-(3-phenoxy group styryl)-2,3-Dihydro-benzofuran-3-alcohol, yield 34%.
1H NMR (400 MHz, CDCl
3) δ 3.20 (s, 1H), 6.33-6.38 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H), 6.85 (d,
J = 16.0 Hz, 1H), 6.93-6.95 (m, 1H), 7.01-7.03 (m, 3H), 7.08-7.15 (m, 3H), 7.17-7.19 (m, 1H), 7.26-7.40 (m, 5H);
13C NMR (100 MHz, CDCl
3) δ 157.6, 157.1, 154.7, 137.6, 132.0, 131.6, 130.5 (t,
J = 271.7 Hz, 1C), 130.0, 129.8, 128.2, 125.3, 125.0, 124.9, 124.0, 123.5, 123.4, 122.0, 118.9, 118.8, 117.4, 111.1, 80.0-80.5 (m, 1C);
19F NMR (376 MHz, CDCl
3) δ-88.8（d,
J = 142.9 Hz, 1F），-82.7（d,
J = 142.9 Hz, 1F）; MS (ESI) m/z 309.1 [M+H]
+。
example 8: the fluoro-3-of 2,2-bis-(3-methyl-2-thiofuran ethylene base)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 2 is synthesized, and solvent is acetonitrile, and 60 DEG C of reaction times are 1 hour, obtains 64.8 milligram of 2,2-bis-fluoro-3-(3-methyl-2-thiofuran ethylene base)-2,3-Dihydro-benzofuran-3-alcohol, yield 44%.
1H NMR (400 MHz, CDCl
3) δ 2.26 (s, 3H), 6.09-6.14 (dd,
J = 16.0 Hzand
J = 2.8 Hz, 1H), 6.81 (d,
J = 5.2 Hz, 1H),-7.01-7.15 (m, 4H),-7.31-7.33 (m, 1H), 7.36-7.40 (m, 1H);
13C NMR (100 MHz, CDCl
3) δ 154.8, 154.7, 136.8, 134.4, 133.1, 131.6, 130.7, 130.4 (t,
J = 271.3 Hz, 1C), 128.4, 125.2, 124.2, 124.0, 122.5, 122.4, 111.0, 14.0;
19F NMR (376 MHz, CDCl
3) δ-89.7 (d,
J = 142.9 Hz, 1F)，-82.5（d,
J = 143.6 Hz, 1F）;MS (ESI) m/z 295.2 [M+H]
+。
example 9: the fluoro-3-of 2,2-bis-(2-(5-methyl-2-furans vinyl)-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is p-Xylol, and 60 DEG C of reaction times are 1 hour, obtains 39.1 milligram of 2,2-bis-fluoro-3-(2-(5-methyl-2-furans vinyl)-2,3-Dihydro-benzofuran-3-alcohol, yield 28%.
1H NMR (400 MHz, CDCl
3) δ 2.30 (s, 3H), 2.94 (s, 1H), 5.98-5.99 (m, 1H), 6.21-6.25 (m, 2H), 6.62 (d,
J = 15.6 Hz, 1H), 7.00 (d,
J = 8.0 Hz, 1H), 7.09-7.13 (m, 1H), 7.26-7.38 (m, 2H);
13C NMR (100 MHz, CDCl
3) δ 154.7, 153.0, 150.0, 131.4, 130.5 (t,
J = 271.8 Hz, 1C), 128.4, 125.2, 123.9, 120.9, 120.7 (d,
J = 5.0 Hz, 1C), 111.2, 111.0, 107.7, 80.0-80.5 (m, 1C),13.7; MS (ESI) m/z 279.2 [M + H]
+;
19F NMR (376 MHz, CDCl
3) δ-89.3 (d,
J = 142.5 Hz, 1F),-83.0 (d,
J = 142.5 Hz, 1F); IR (KBr) ν 3027, 2963, 2923, 2853, 1756, 1716, 1679, 1619, 1596, 1465, 1367, 1322, 1261, 1098, 1072, 1021, 932, 871, 799, 750, 617 cm
-1.
example 10: 2,2,5-tri-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is acetonitrile, and 60 DEG C of reaction times are 2 hours, obtains 64.7 milligram of 2,2,5-tri-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol, yield 44%.
1H NMR (400 MHz, CDCl
3) δ 3.28 (s, 1H), 6.33-6.38 (dd,
J = 8.0 Hzand
J = 2.8 Hz, 1H), 6.89 (d,
J = 16.0 Hz, 1H), 6.96-6.99 (dd,
J = 16.0 Hzand
J = 16.0 Hz, 1H),7.02-7.10 (m, 2H), 7.30-7.38 (m, 3H), 7.43-7.45 (m, 2H);
13C NMR (100 MHz, CDCl
3) δ 160.3, 157.9, 150.5, 135.4, 132.9, 130.7 (t,
J = 271.3 Hz, 1C), 129.7, 129.6, 128.9, 128.8, 128.6, 128.0, 127.0, 123.5, 123.4, 118.3, 118.1, 112.5, 112.3, 112.1, 112.0, 80.8, 80.6, 80.5, 80.3;
19F NMR (376 MHz, CDCl
3) δ -117.9(s, 1F),-88.3(d,
J = 141.8 Hz, 1F)，-82.7（d,
J = 142.1 Hz, 1F）; MS (ESI) m/z 293.2 [M+H]
+。
example 11: 2,2,6-tri-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol
The method similar with example 1 is synthesized, and solvent is tetracol phenixin, and 60 DEG C of reaction times are 2 hours, obtains 48.2 milligram of 2,2,6-tri-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol, yield 33%.
1H NMR (400 MHz, CDCl
3) δ 4.22 (s, 1H), 6.37-6.41 (dd,
J =
J = 16.0 Hzand 2.4 Hz, 1H), 6.74-6.77 (m, 1H),6.81-6.93 (m, 2H), 7.26-7.38 (m, 4H), 7.44 (d,
J = 32.0 Hz, 2H), 7.43-7.45 (m, 2H) ;
13C NMR (100 MHz, CDCl
3) δ 165.8, 163.3, 163.1, 155.7, 155.5, 135.7, 132.8, 130.8 (t,
J = 273.1 Hz, 1C), 128.8, 128.6, 127.2, 127.0, 126.7, 126.6, 126.5, 124.2, 124.1, 111.1, 110.9, 99.9, 99.6, 80.1, 79.8, 79.7, 79.6;
19F NMR (376 MHz, CDCl
3)δ-107.1（s, 1F),-88.3（d,
J = 141.4 Hz, 1F），-81.3（d,
J = 141.0 Hz, 1F）; MS (ESI) m/z 293.2 [M+H]
+。
example 12: bromo-2,2-bis-fluoro-3-styryl-2, the 3-Dihydro-benzofuran-3-alcohol of 5,7-bis-
The method similar with example 1 is synthesized, and solvent is dimethylbenzene, and 100 DEG C of reaction times are 1 hour, obtains 129.6 milligram of 5,7-bis-bromo-2,2-bis-fluoro-3-styryl-2,3-Dihydro-benzofuran-3-alcohol, yield 60%.
1H NMR (400 MHz, CDCl
3) δ 3.22 (s, 1H), 6.31-6.35 (dd,
J = 16.0 Hzand
J = 2.4 Hz, 1H), 6.93 (d,
J = 16.0 Hz, 1H), 7.32-7.38 (m, 4H), 7.43-7.45 (m, 2H), 7.68 (d,
J = 2.0 Hz, 2H);
13C NMR (100 MHz, CDCl
3) δ 151.5, 136.8, 135.2, 133.7, 133.4, 131.2 (t,
J = 125.4 Hz, 1C), 128.8, 127.3, 127.2, 127.1, 122.7, 127.0, 122.6, 116.5, 104.8;
19F NMR (376 MHz, CDCl
3) δ-88.2（d,
J = 140.6 Hz, 1F），-82.2（d,
J = 140.6 Hz, 1F）；MS (ESI) m/z 432.8 [M]
+。
The present invention is not limited to the technology described in embodiment; its description is illustrative; and it is nonrestrictive; authority of the present invention limited by claim; can change according to the present invention based on the art personnel, technology related to the present invention that the method such as restructuring obtains, all within protection scope of the present invention.
Claims (7)
1. fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds, is characterized in that the chemical structure of general formula of described compound is:
In chemical general formula:
R
1for the substituted radical of phenyl ring, it is the alkyl of H, halogen, methoxyl group or C1 ~ C6;
R
2for aromatic group.
2. fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds as claimed in claim 1, is characterized in that: described aromatic group is phenyl ring, containing substituent phenyl ring, containing substituent furans or containing substituent thiophene.
3. the preparation method of fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds as claimed in claim 1, is characterized in that: carry out according to following step:
；
In dry organic solvent, at 40 ~ 100 DEG C, 1 ~ 8 hour is reacted with 2 '-hydroxylated chalcone of different substituents and triphenylphosphine difluoroacetic acid salt and phase-transfer catalyst, boil off solvent, raffinate is separated through silica gel column chromatography and obtains 2,2-bis-fluoro-3-styryl-2,3-Dihydrobenzofuranes-3-alcohol compound.
4. as claimed in claim 3 fluorine-containing 2, the preparation method of 3-Dihydrobenzofuranes-3-alcohol compound, is characterized in that: the mol ratio of described 2 '-hydroxylated chalcone and triphenylphosphine difluoroacetic acid salt and phase-transfer catalyst is 1: 1 ~ 3: 0 ~ 0.5.
5. as claimed in claim 3 fluorine-containing 2, the preparation method of 3-Dihydrobenzofuranes-3-alcohol compound, is characterized in that: described organic solvent is: methylene dichloride, trichloromethane, tetracol phenixin, benzene, toluene, dimethylbenzene, p-Xylol, acetonitrile, tetrahydrofuran (THF), dimethyl formamide or N-Methyl pyrrolidone.
6. the preparation method of fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds as claimed in claim 3, is characterized in that: the reaction solubility of described 2 '-hydroxylated chalcone is 0.1 ~ 1 mol/L.
7. the preparation method of fluorine-containing 2,3-Dihydrobenzofuranes-3-alcohol compounds as claimed in claim 3, is characterized in that described phase-transfer catalyst is: 4 bromide, tetraethylammonium bromide, Tetrabutyl amonium bromide, 18 hat six or 15 hats five.
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| CN109867645A (en) * | 2017-12-05 | 2019-06-11 | 中国医学科学院药物研究所 | A kind of synthetic method of 2,2- bis- fluoro- 2,3- dihydro substitution benzofuran compounds |
| CN109867645B (en) * | 2017-12-05 | 2021-09-14 | 中国医学科学院药物研究所 | Synthetic method of 2, 2-difluoro-2, 3-dihydro-substituted benzofuran compound |
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