CN104817525B - The fluorine-containing alcohol compound of 2,3 Dihydrobenzofuranes 3 and preparation method - Google Patents
The fluorine-containing alcohol compound of 2,3 Dihydrobenzofuranes 3 and preparation method Download PDFInfo
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention relates to pharmaceutical chemistry technology and fluorine chemistry field, specifically discloses a kind of alcohol of 2,3 Dihydrobenzofuranes of novel fluorine 3 and preparation method thereof.Specific preparation method is as follows：In organic solvent is dried, it is difluoromethyl reagent using triphenylphosphine difluoroacetic acid salt, the step of 2 ' hydroxylated chalcone one with different substituents is converted into the alcohol compound of 2,2 difluoro, 32,3 Dihydrobenzofuranes of styryl 3.Of the present invention fluorine-containing 2,3 Dihydrobenzofuranes alcohol are the quite varied compounds of a kind of purposes, have potential using value particularly in terms of medicine.
Description
Technical field
The present invention relates to pharmaceutical chemistry technology and fluorine chemistry field, specifically discloses a kind of novel fluorine 2,3- bis-
Hydrogen benzofuran -3- alcohol and preparation method thereof.
Background technology
2,3- Dihydrobenzofuranes -3- alcohol is a kind of important natural products skeleton（J. Med. Chem. 2011, 54,
3506; J. Nat. Prod.2012, 75, 1500; J. Am. Chem. Soc.2014, 136, 2659）And medicineization
Product skeleton（Such as anticarcinogen Silvestrol:J. Med. Chem. 2012, 55, 558; J. Med. Chem.2012,55, 8859; Org. Lett.2013, 15, 1406）, develop the chemical combination of the new Dihydrobenzofuranes -3- ol skeletons Han 2,3-
Thing has important medical practical value；The synthesis of such compound generally requires more special raw material and metallic 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 prepare 2,3- Dihydrobenzofuranes-
3- ol skeleton compounds have certain practical significance.
Fluorine（F）- electronegativity highest element is used as, it is introduced into organic molecule, its physics, chemistry and life can be changed
Thing physiological property；Organic fluoride-containing compound, which is applied to pharmaceutical field, to be determined by its special physiologically active；First, the half of F
Footpath is suitable with H, OH radius, and whole molecular volume and spatial configuration change is little after the H in molecule or OH is replaced by F；Its
Secondary, the lipophilicity of organic molecule can be strengthened by introducing fluorine so that fluorochemical increases to the penetration capacity of film, tissue in vivo
By force, its absorption and transmission speed in vivo is improved；Again, carbon-fluorine bond high stability so that it be difficult with ion or
The form of free radical is left away, and the inhibitory action to metabolic pathway can be caused in terms of physiologically active；Therefore to natural activity molecule
Or it is the important method for designing new drug that fluorine is introduced in pharmaceutical activity molecule（Chem. Rev.2014, 114, 2432; Chem. Eur. J.2014, 20, 16830）；In fluorochemical, increasingly it is taken seriously containing difluoromethyl compound
（Synthesis2014, 46, 842）.Hydroxyl of the bioisostere of difluoromethyl in hydroxyl, replaceable drug molecule
Pharmacological action without influenceing medicine；And the strong lipophilicity of difluoromethyl is utilized, the absorption of medicine can be lifted to reduce medicine
Dosage；The nearest medicine of some is such as：Desflurane （Anesthetic,Drugs. 1995, 50, 742)、Pantoprazole
(acid secretion inhibitors,Drugs.2003, 63, 101) and N- (difluoromethyl) pyridin-2 (1H)-one-
Substituted acetic acids (enzyme inhibitor,Bioorg. Med. Chem. Lett.2010, 20, 2168) all
Contain difluoromethyl group.
Difluoromethyl is introduced in 2,3- Dihydrobenzofuranes -3- ol skeleton compounds, the excellent of two class groups can be combined
Point, by with important practical value in terms of new drug design synthesis.
The content of the invention
The purpose of the present invention is intended to expansion 2, the scope of 3- Dihydrobenzofuranes -3- alcohol, exploitation a kind of new fluorine-containing 2,
3- Dihydrobenzofuranes -3- alcohol compounds, it is a further object to provide above-mentioned fluorine-containing 2,3- dihydrobenzos furan
Mutter -3- alcohol compound preparation methods.
Fluorine-containing 2, the 3- Dihydrobenzofuranes -3- alcohol compounds of the present invention, it is characterised in that it is that have following chemistry
The compound of general structure：
In chemical general formula：
R1For the substituted radical of phenyl ring, such as：H, halogen, methoxyl group, C1~C6 alkyl.
R2For aromatic group, such as phenyl ring, the phenyl ring containing substituent, the furans containing substituent, the thiophene containing substituent.
The preparation method of fluorine-containing 2, the 3- Dihydrobenzofuranes -3- alcohol compounds of the present invention, it is characterised in that under
State step progress：
2 '-hydroxylated chalcone with different substituents（Formula I）With triphenylphosphine difluoroacetic acid salt（Chem. Commun.2013, 49, 7513）And reaction 1~8 is small at 40~100 DEG C in organic solvent is dried for phase transfer catalyst
When, solvent is boiled off, raffinate is through fluoro- 3- styryls -2, the 3- Dihydrobenzofuranes -3- alcohol of isolated 2, the 2- bis- of silica gel column chromatography
Class compound（Formula II）.
Described 2 '-hydroxylated chalcone is 1 with the mol ratio of triphenylphosphine difluoroacetic acid salt and phase transfer catalyst:
1~3:0~0.5.
The organic solvent is：Dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, dimethylbenzene, paraxylene, second
Nitrile, tetrahydrofuran, dimethylformamide, 1-METHYLPYRROLIDONE.
The reaction solubility is 0.1~1 mol/L（It is defined by 2 '-hydroxylated chalcone）.
The phase transfer catalyst is：4 bromide, tetraethylammonium bromide, TBAB, 18 hats six, ten
Five hats five.
The beneficial effects of the invention are as follows invented a kind of fluoro- 3- styryls -2,3- Dihydrobenzofuranes of new 2,2- bis- -
3- alcohol compounds, and by easy method with preferable yield（Highest yield 75%）Obtain such compound.Newly synthesize
Compound has due to containing 2,3- Dihydrobenzofuranes -3- ol skeletons and difluoromethyl group simultaneously in field of medicaments
Potential using value.
Embodiment
Contribute to further understand the present invention by following examples, but be not intended to limit the present invention.
Example 1：The fluoro- 3- styryls -2,3- Dihydro-benzofurans -3- alcohol of 2,2- bis-
At room temperature, by 112.1 milligrams of (0.5 mmol) 2 '-hydroxylated chalcones and 356.3 milligrams of (1.0 mmol) triphens
Base phosphine difluoroacetic acid salt is added into 100 milliliters of round-bottomed bottles, is added 2 mL and is dried acetonitrile, then oil bath heating to 60 DEG C of reactions
2 hours；After solvent is distilled out, mixture passes through silica gel column chromatography, uses ethyl acetate/petroleum ether（Volume ratio 1/20）For elution
Agent, obtain fluoro- 3- styryls -2, the 3- Dihydro-benzofuran -3- alcohol of 102.1 milligrams of 2,2- bis-, yield 75%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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, CDCl3) 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：Bis- fluoro- 3- of 2,2- (4- methyl styrenes base) -2,3- Dihydro-benzofuran -3- alcohol
At room temperature, by 119.1 milligrams of (0.5 mmol) 1- (2- hydroxy phenyls) -3- p-methylphenyls propenone and 356.3
Milligram (1.0 mmol) triphenylphosphine difluoroacetic acid salt is added into 100 milliliters of round-bottomed bottles, then adds 39.6 milligram (0.15
Mmol) 18 hat six, add 5 mL dry acetonitrile, then oil bath heating to 80 DEG C react 3 hours；After solvent is distilled out,
Mixture passes through silica gel column chromatography, uses ethyl acetate/petroleum ether（Volume ratio 1/20）For eluent, 63.2 milligrams of 2,2- bis- are obtained
Fluoro- 3- (4- vinyltoluenes 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 3：2,2- bis- fluoro- 3- (4- methoxyl-styrenes) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 1, solvent are acetonitrile, and 60 DEG C of reaction time are 8 hours, obtain 90.5 milligram 2,2-
Two fluoro- 3- (4- methoxyl-styrenes) -2,3- Dihydro-benzofuran -3- alcohol, yield 59%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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,
CDCl3) 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 4：2,2- bis- fluoro- 3- (4- fluorostyryls) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 1, solvent are dimethylformamide, and 60 DEG C of reaction time are 1.5 hours, are obtained
89.1 milligrams of 2,2-, bis- fluoro- 3- (4- fluorostyryls) -2,3- Dihydro-benzofuran -3- alcohol, yield 61%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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, CDCl3) 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：Bis- fluoro- 3- of 2,2- (4- chlorostyrenes base) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 1, solvent are 1-METHYLPYRROLIDONE, and 40 DEG C of reaction time are 4 hours, are obtained
83.4 milligrams of 2,2-, bis- fluoro- 3- (4- chlorostyrenes base) -2,3- Dihydro-benzofuran -3- alcohol, yield 54%.
1H NMR (400 MHz, CDCl3) δ 3.45 (s, 1H), 6.32-6.37 (dd, J = 16.0 HzandJ = 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, CDCl3) 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, CDCl3) 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：Bis- fluoro- 3- of 2,2- (2- bromstyrols base) -2,3- Dihydro-benzofuran -3- alcohol
Similar with example 2 method synthesis, catalyst are TBAB, and solvent is tetrahydrofuran, during 60 DEG C of reactions
Between be 2 hours, obtain 125.4 milligrams of 2,2-, bis- fluoro- 3- (2- bromstyrols base) -2,3- Dihydro-benzofuran -3- alcohol, yield
71%。
1H NMR (400 MHz, CDCl3) δ 3.20 (s, 1H), 6.29-6.34 (dd, J = 16.0 HzandJ = 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, CDCl3) 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, CDCl3) 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：Bis- fluoro- 3- of 2,2- (3- phenoxy groups styryl) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 1, solvent are acetonitrile, and 60 DEG C of reaction time are 3 hours, obtain 62.3 milligram 2,2-
Two fluoro- 3- (3- phenoxy groups styryl) -2,3- Dihydro-benzofuran -3- alcohol, yield 34%.
1H NMR (400 MHz, CDCl3) δ 3.20 (s, 1H), 6.33-6.38 (dd, J = 16.0 HzandJ = 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, CDCl3) 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, CDCl3)
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：Bis- fluoro- 3- of 2,2- (3- methyl -2- thiofuran ethylenes base) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 2, solvent are acetonitrile, and 60 DEG C of reaction time are 1 hour, obtain 64.8 milligram 2,2-
Two fluoro- 3- (3- methyl -2- thiofuran ethylenes base) -2,3- Dihydro-benzofuran -3- alcohol, yield 44%.
1H NMR (400 MHz, CDCl3) δ 2.26 (s, 3H), 6.09-6.14 (dd, J = 16.0 HzandJ = 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, CDCl3) 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, CDCl3) 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：Bis- fluoro- 3- of 2,2- (2- (5- methyl -2- furans vinyl) -2,3- Dihydro-benzofuran -3- alcohol
The method synthesis similar with example 1, solvent are paraxylene, and 60 DEG C of reaction time are 1 hour, obtain 39.1 milligrams
2,2- bis- fluoro- 3- (2- (5- methyl -2- furans vinyl) -2,3- Dihydro-benzofuran -3- alcohol, yields 28%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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, CDCl3) 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：The fluoro- 3- styryls -2,3- Dihydro-benzofurans -3- alcohol of 2,2,5- tri-
Similar with example 1 method synthesis, solvent are acetonitrile, and 60 DEG C of reaction time are 2 hours, obtain 64.7 milligram 2,2,
Fluoro- 3- styryls -2, the 3- Dihydro-benzofuran -3- alcohol of 5- tri-, yield 44%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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,
CDCl3) 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：The fluoro- 3- styryls -2,3- Dihydro-benzofurans -3- alcohol of 2,2,6- tri-
The method synthesis similar with example 1, solvent are carbon tetrachloride, and 60 DEG C of reaction time are 2 hours, obtain 48.2 milligrams
2,2,6- tri- fluoro- 3- styryls -2,3- Dihydro-benzofuran -3- alcohol, yield 33%.
1H NMR (400 MHz, CDCl3) 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, CDCl3) 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, CDCl3)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：The fluoro- 3- styryls -2,3- Dihydro-benzofurans -3- alcohol of the bromo- 2,2- bis- of 5,7- bis-
The method synthesis similar with example 1, solvent are dimethylbenzene, and 100 DEG C of reaction time are 1 hour, obtain 129.6 milligrams
5,7- bis- bromo- fluoro- 3- styryls -2, the 3- Dihydro-benzofuran -3- alcohol of 2,2- bis-, yield 60%.
1H NMR (400 MHz, CDCl3) δ 3.22 (s, 1H), 6.31-6.35 (dd, J = 16.0 HzandJ = 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, CDCl3) 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, CDCl3) 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 invention is not limited in the technology described in embodiment, its description be it is illustrative, and nonrestrictive,
The authority of the present invention is defined in the claims, and can be changed according to the present invention based on those skilled in the art, recombinated etc. just
The technology related to the present invention that method obtains, all within protection scope of the present invention.
Claims (4)
1. the preparation method of fluorine-containing 2,3- Dihydrobenzofuranes -3- alcohol compounds, it is characterised in that：Enter as steps described below
OK：
2 '-hydroxylated chalcone and triphenylphosphine difluoroacetic acid salt and phase transfer catalyst with different substituents are organic in drying
Reacted 1~8 hour at 40~100 DEG C in solvent, or 2 ' with different substituents-hydroxylated chalcone and triphenylphosphine difluoro
Acetate reacts 1~8 hour in organic solvent is dried at 40~100 DEG C；Solvent is boiled off, raffinate separates through silica gel column chromatography
Obtain the fluoro- 3- styryls -2,3- Dihydrobenzofuranes -3- alcohol compounds of 2,2- bis-；The organic solvent is：Four chlorinations
Carbon, paraxylene, acetonitrile, tetrahydrofuran, dimethylformamide or 1-METHYLPYRROLIDONE；The fluorine-containing 2,3- dihydrobenzos furan
Mutter -3- alcohol compounds, be fluoro- 3- styryls -2, the 3- Dihydro-benzofuran -3- alcohol of 2,2- bis-, fluoro- 3- (the 4- first of 2,2- bis-
Base styryl) -2,3- Dihydro-benzofuran -3- alcohol, 2,2- bis- fluoro- 3- (4- methoxyl-styrenes) -2,3- dihydros-benzene
And furan-3-ol, 2,2- bis- fluoro- 3- (4- fluorostyryls) -2,3- Dihydro-benzofuran -3- alcohol, fluoro- 3- (the 4- chlorine of 2,2- bis-
Styryl) -2,3- Dihydro-benzofuran -3- alcohol, bis- fluoro- 3- of 2,2- (2- bromstyrols base) -2,3- Dihydro-benzofurans -
3- alcohol, bis- fluoro- 3- of 2,2- (3- phenoxy groups styryl) -2,3- Dihydro-benzofuran -3- alcohol, bis- fluoro- 3- of 2,2- (3- methyl -
2- thiofuran ethylenes base) -2,3- Dihydro-benzofuran -3- alcohol, bis- fluoro- 3- of 2,2- (2- (5- methyl -2- furans vinyl) -2,3-
The fluoro- 3- styryls -2,3- Dihydro-benzofurans -3- alcohol of Dihydro-benzofuran -3- alcohol, 2,2,5- tri-, tri- fluoro- 3- of 2,2,6-
Styryl -2,3- Dihydro-benzofuran -3- alcohol or the fluoro- 3- styryls -2,3- dihydros-benzo furans of the bromo- 2,2- bis- of 5,7- bis-
Mutter -3- alcohol.
2. the preparation method of fluorine-containing 2,3- Dihydrobenzofuranes -3- alcohol compounds as claimed in claim 1, its feature exist
In：Described 2 '-hydroxylated chalcone is 1 with the mol ratio of triphenylphosphine difluoroacetic acid salt and phase transfer catalyst:1~3:0
~0.5.
3. the preparation method of fluorine-containing 2,3- Dihydrobenzofuranes -3- alcohol compounds as claimed in claim 1, its feature exist
In：The reaction solubility of the 2 '-hydroxylated chalcone is 0.1~1mol/L.
4. the preparation method of fluorine-containing 2,3- Dihydrobenzofuranes -3- alcohol compounds as claimed in claim 1, it is characterised in that
The phase transfer catalyst is：4 bromide, tetraethylammonium bromide, TBAB, 18 hats six or 15 hats five.
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