CN106866567B - The synthetic method of fluoro Oxazolidinone derivative - Google Patents

The synthetic method of fluoro Oxazolidinone derivative Download PDF

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CN106866567B
CN106866567B CN201710128901.2A CN201710128901A CN106866567B CN 106866567 B CN106866567 B CN 106866567B CN 201710128901 A CN201710128901 A CN 201710128901A CN 106866567 B CN106866567 B CN 106866567B
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oxazolidine
ketone
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nmr
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CN106866567A (en
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陆红健
阳斌
李子博
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D263/44—Two oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention discloses the synthetic methods of a kind of fluoro Oxazolidinone derivative.This method provides directly prepare various fluorinated oxazolidine -2- ketone, oxazolidine -2,4- diketone and 1, the method for 3- oxazines alkane -2- ketone in a mild condition.Simultaneously because high price fluorination reagent derives from fluorine anion, therefore this method can be applied to Radiofluorinated Oxazolidinone derivative preparation.The present invention is fluorinated cyclization strategies by intramolecular and has carried out fluorination oxazolidine -2- ketone, and fluorination oxazolidine -2,4- diketone is effectively synthesized with fluorination 1,3- oxazines alkane -2- ketone.The reaction has extensive substrate spectrum, the tolerance of a variety of functional groups, and can be used in constructing biologically active molecular structure.

Description

The synthetic method of fluoro Oxazolidinone derivative
Technical field
The present invention relates to synthesizing activity small organic molecule fields, and in particular to the conjunction of a kind of fluoro Oxazolidinone derivative At method.
Background technique
Compound containing alkene structures carries out intramolecular fluoro cyclization can construct the tool including C-F key with a step There is the cyclic structure of multiple new keys, may be used as the universal architecture unit of the building fluorine-containing bioactive compound of aliphatic.? It the use of the fluoro cyclisation of electrophilic fluorination reagent is one of most important method in reported synthetic method.However, electrophilic fluorination Reagent is usually prepared by fluorine gas, and preparation cost is high, and which has limited it in industry and laboratory, is especially existed18F radioactivity mark Application in note.Recently, in the research of fluoro cyclization, hypervalent iodine reagent has obtained extensive concern as Fluorine source, because Unique reactivity is shown for them, and can readily be obtained from cheap fluoride.Alkane is used in these reactions The alkene and styrene derivative that base replaces are as effective nucleopilic reagent, and the substrate with electron-deficient double bond carries out fluoro ring The reaction of change has no document report.Oxazolidine -2- keto analog effectively can treat bacterium infection and the disease that causes simultaneously. For example, N- aryl-oxazolidine -2- ketone is considered as the last line of defense for fighting gram-positive bacterium pathogen, these diseases Substance produces resistance to the antibiotic including methicillin and vancomycin.
Summary of the invention
The purpose of the present invention is be applied to silver catalytic cyclization/1,2- (miscellaneous) aryl migration/fluorine using high price fluorine iodine compound Change cascade reaction, to efficiently and compactly synthesize various fluorination Oxazolidinone derivatives.
In order to achieve the above objectives, present invention provide the technical scheme that
A kind of fluoro Oxazolidinone derivative, structural formula are as follows:
Specifically:
The synthetic method of the fluoro Oxazolidinone derivative specifically includes following:
Fluorine cyclization synthesizing fluoro oxazole is carried out using styrene or acrylamide derivative and high price fluorine iodine reagent Alkane ketone compounds
By substrate 2, the desired amount of compound 1 (1.5 equivalent), AgSbF6Or AgBF4(0.1 equivalent) and DCM, which are introduced, to be added Into reaction flask.And stir mixture at a temperature of 20-60 DEG C, pass through the progress of TLC monitoring reaction.Knot is reacted when observing Reaction mixture is concentrated to dryness by beam, extracts isolated Oxazolidinone derivative 3 by column chromatography.
Synthetic product includes:
Synthetic reaction has:
Further, the high price fluorine iodine reagent is the skeleton structure and derivative including compound 1.
Our initial experiment is used to the fluorine iodine compound 1 of air and moisture stabilization as Fluorine source (table 1), recently quilt Research for styrene and the ionic fluoro cyclization of alkyl substituted olefine derivative.Compound 1 using fluoride with Prepared by the analog that its chloro or OTs replace, so that it is applicable to carrier-free addition18The Radiofluorinated reaction of F- is ground Study carefully.As shown in table 1, from unsaturated urethane, (2)s can obtain fluorinated oxazolidine -2- ketone.It is sieved by condition Choosing, it has been found that use AgSbF6As catalyst, raw material 2a can obtain fluorination N- aryl-oxazole with 79% separation yield Alkane -2- ketone (3a).Use other metallic catalysts, such as AgBF4, AgOTf and AgF2Product (the item of low yield can only be obtained Mesh 3-6), and there is the reactivity (entry 7) that will be greatly reduced raw material in a small amount of water.When the additional fluorine anion of addition When, product 3a (entry 8) is not observed in the presence of AgOTf.Ag catalyst is not added, or molecular sieve is only added, does not all have Have to form required product 3a.
The screening of 1. reaction condition of table
After obtaining optimum reaction condition, we start to be studied (table 2) to the application range of reaction substrate.We are first It first attempts to change the aryl substituent on N atom, it is found that it is good the reaction all has electron rich aryl and electron-deficient aryl Functional group's tolerance (3a-f) can obtain N- aryl-oxazolidine -2- ketone with medium to good yield.Functional group on phenyl Such as halogen (3c, e), the functional groups such as ester group (3d) and methoxyl group (3a, f) can be compatible with reaction well.In addition, alkyl-substituted Substrate (3g-1) shows good reactivity in the method, can obtain target product with the yield of 66-78%.Then, Influence we have also investigated aromatics migrating group (3j-t) to reaction.Research is found on phenyl ring with electron substituent group and suction Aryl migration (3j-p) can effectively occur for electron substituent group.Although the migration performance of 9H- carbazole is poor (3t), other miscellaneous Aryl such as thienyl and furyl (3q-s) are the effective mobilities being used as in the fluoro cyclisation induced by high price fluorine iodine reagent for the first time Group.It has been investigated that the substituent R in substrate2Influence to reaction is smaller (3u-v).In addition to terminal olefin, internal olefin (Z) -2w is also used as substrate, obtains target product (3w) with medium yield.Using alkyl-substituted alkene as substrate, energy Fluorination oxazolidine -2- ketone (3x) is accessed, has no that alkyl migrates.In addition to the product of available 5 member ring, the party can also be passed through Method smoothly prepares 6 cyclic products (3y), is the key structure in a kind of novel antiretroviral and anti-bacterial drug.
The derivative of 2. styrene of tablea
We have found that the acrylamide that phenyl replaces can also be obtained under improved reaction condition using the catalyst system Corresponding product.We have carried out simple research to the substrate spectrum of acrylamide, and the results are shown in Table 3, spreads out with styrene Biology is similar, has electrophilic or electron-donating group on phenyl ring and heterocycle is all good migrating group, finally with medium Yield obtains product oxazolidine -2,4- diketone (3 ').Use of acrylamide as the high price fluorine iodine reagent mediation of nucleopilic reagent Document report is had no before fluoro cyclisation, this is also the special character of this method.
The reaction of 3. acrylamide derivative of table
The utility model has the advantages that
The present invention is fluorinated cyclization strategies by intramolecular and has carried out fluorination oxazolidine -2- ketone, is fluorinated oxazolidine -2,4- diketone With being effectively synthesized for fluorination 1,3- oxazines alkane -2- ketone.The reaction have extensive substrate spectrum, the tolerance of a variety of functional groups, And it can be used in constructing biologically active molecular structure.
Specific embodiment
The present invention is further explained in the light of specific embodiments.
Fluorine cyclization synthesizing fluoro oxazole is carried out using styrene or acrylamide derivative and high price fluorine iodine reagent Alkane ketone compounds
By substrate 2, the desired amount of compound 1 (1.5 equivalent), AgSbF6Or AgBF4(0.1 equivalent) and DCM, which are introduced, to be added Into reaction flask.And stir mixture at 20-60 DEG C, pass through the progress of TLC monitoring reaction.When observing that reaction terminates, Reaction mixture is concentrated to dryness, isolated Oxazolidinone derivative 3 is extracted by column chromatography.
Synthetic product includes:
The yield of specific each product, identification are as follows
Prepare the fluoro- 3- of 5- benzyl -5- (4- methoxyphenyl) oxazolidine -2- ketone (3a)
3.27(m,2H)ppm.19F NMR(376MHz,CDCl3)δ-92.52ppm.13C NMR(101MHz,CDCl3)δ156.96, 152.32 (d, J=1.7Hz), 132.23 (d, J=4.2Hz), 130.37,130.20,128.95,128.03,120.68, 114.49,112.31 (d, J=233.1Hz), 55.58,54.10 (d, J=30.6Hz), 42.03 (d, J=29.1Hz) ppm.IR (KBr)ν3005,2990,1771,1515,1456,1339,1275,1360,1080,828,764,750,704.HRMS(ESI) m/z calcd.for C17H16FNNaO3 +(M+Na+):324.1006,Found:324.1002.
5- benzyl -5- fluoro- 3- (p-methylphenyl) oxazolidine -2- ketone (3b)
2.31(s,3H)ppm.19F NMR(376MHz,CDCl3)δ-92.40ppm.13C NMR(101MHz,CDCl3)δ152.13, (134.70,132.25 d, J=4.3Hz), 130.42,129.86,129.04,128.11,118.69,112.31 (d, J= 233.1Hz), 53.77 (d, J=30.7Hz), 42.15 (d, J=29.1Hz), 20.90ppm.IR (KBr) ν 3033,3006, 2986,2921,2851,1774,1517,1468,1404,1335,1275,1261,1080,976,810,764,750, 702.HRMS(ESI)m/z calcd.for C17H16FNNaO2 +(M+Na+):308.1057,Found:308.1045.
5- benzyl -3- (4- chlorphenyl) -5- fluorine oxazolidine -2- ketone (3c)
MHz,CDCl3)δ-92.42ppm.13C NMR(101MHz,CDCl3) δ 151.90,135.81,132.00 (d, J=4.2Hz), (130.39,130.18,129.36,129.08,128.20,119.66,112.24 d, J=233.9Hz), 53.51 (d, J= 30.8Hz), 42.03 (d, J=28.9Hz) ppm.IR (KBr) ν 3005,2986,1771,1496,1338,1275,1261, 1094,1080,978,826,764,750,704.HRMS(ESI)m/z calcd.for C16H14ClFNO2 +(M+H+): 306.0692,Found:306.0688.
4- (the fluoro- 2- oxo oxazolidine -3- base of 5- benzyl -5-) methyl benzoate (3d)
=10.9Hz, 1H), 3.90 (s, 3H), 3.49-3.30 (m, 2H) ppm.19F NMR(376MHz,CDCl3)δ-92.28ppm.13C NMR(101MHz,CDCl3) δ 166.44,151.72,141.16,131.93 (d, J=4.2Hz), 131.01,130.41, (129.14,128.27,126.24,117.51,112.27 d, J=234.1Hz), 53.36 (d, J=30.8Hz), 52.27, 42.06 (d, J=28.9Hz) ppm.IR (KBr) ν 3033,3004,2951,2920,2849,1778,1717,1608,1517, 1497,1281,1187,1112,980,853,767,748,703.HRMS(ESI)m/z calcd.for C18H16FNNaO4 +(M+ Na+):352.0956,Found:352.0956.
5- benzyl -3- (3- bromophenyl) -5- fluorine oxazolidine -2- ketone (3e)
13C NMR(101MHz,CDCl3) δ 151.73,138.48,131.95 (d, J=4.3Hz), 130.62,130.39,129.11, (128.23,127.83,123.08,121.27,116.89,112.26 d, J=234.0Hz), 53.39 (d, J=30.8Hz), 42.00 (d, J=28.8Hz) ppm.IR (KBr) ν 3004,2990,2920,2849,1779,1593,1482,1339,1275, 1261,1080,992,938,764,750,700.HRMS(ESI)m/z calcd.for C16H14BrFNO2 +(M+H+): 350.0186,Found:350.0184.
5- benzyl -3- (3,5- Dimethoxyphenyl) -5- fluorine oxazolidine -2- ketone (3f)
ppm.13C NMR(101MHz,CDCl3) δ 161.37,151.87,139.05,132.15 (d, J=4.3Hz), 130.40, (129.05,128.14,112.18 d, J=233.2Hz), 97.21,96.67,55.63,53.77 (d, J=30.7Hz), 42.08 (d, J=29.1Hz) ppm.IR (KBr) ν 3005,2984,1771,1596,1456,1275,1261,1205,1156,1012, 764,750,704.HRMS(ESI)m/z calcd.for C18H18FNNaO4 +(M+Na+):354.1112Found:354.1112
5- benzyl -3- cyclopenta -5- fluorine oxazolidine -2- ketone (3g)
1.36–1.24(m,1H)ppm.19F NMR(376MHz,CDCl3)δ-93.00ppm.13CNMR(101MHz,CDCl3)δ154.64, 132.54 (d, J=4.3Hz), 130.29,128.83,127.85,113.11 (d, J=232.5Hz), 54.47,49.57 (d, J =30.4Hz), 42.20 (d, J=29.6Hz), 29.37,28.68,23.89,23.81ppm.IR (KBr) ν 3005,2989, 1771,1456,1275,1260,1040,908,765,704.HRMS(ESI)m/z calcd.for C15H18FNNaO2 +(M+Na+):286.1214,Found:286.1214.
The fluoro- 3- of 5- benzyl -5- (thiene-3-yl methyl) oxazolidine -2- ketone (3h)
=3.3Hz, 1H), 4.57 (s, 2H), 3.54,3.43 (ABq, J=10.8Hz, 1H), 3.46,3.37 (ABq, J=10.8Hz, 1H),3.32–3.17(m,2H)ppm.19F NMR(376MHz,CDCl3)δ-93.09ppm.13C NMR(101MHz,CDCl3)δ (154.74,137.07,132.29 d, J=4.7Hz), 130.33,128.86,127.88,127.20,127.12,126.22, 113.10 (d, J=233.9Hz), 52.03 (d, J=30.3Hz), 42.38,42.07 (d, J=29.4Hz) ppm.IR (KBr) ν 3005,2989,1776,1473,1275,1261,1029,897,765,750,703.HRMS(ESI)m/z calcd.forC15H15FNO2S+(M+H+):292.0802,Found:292.0807.
2- (the fluoro- 2- oxo oxazolidine -3- base of 5- benzyl -5-) -3- phenylpropionate (3i)
2H), 3.35-3.04 (m, 3H), 2.95-2.81 (m, 1H), [1.23 (t, J=7.1Hz), 1.18 (t, J=7.1Hz), (3H)] ppm.19F NMR(376MHz,CDCl3)δ-92.12,-94.35ppm.13C NMR(101MHz,CDCl3)δ169.95,169.81, 155.15 (d, J=1.5Hz), 154.92 (d, J=1.4Hz), 135.71,135.63,132.33 (d, J=3.2Hz), 132.31 (d, J=4.7Hz), 130.38,130.30,128.92,128.89,128.85,128.81,128.69,128.54,127.89, (127.85,127.36,127.29,113.42 d, J=234.4Hz), 113.38 (d, J=234.5Hz), 61.92,61.83, 56.63,56.54,50.60 (d, J=29.6Hz), 50.48 (d, J=30.7Hz), 42.18 (d, J=28.9Hz), 42.06 (d, ), J=29.5Hz 35.48,35.18,14.14ppm.IR (KBr) ν 3005,2989,1779,1738,1456,1275,1261, 1031,897,765,750,703.HRMS(ESI)m/z calcd.for C21H22FNNaO4 +(M+Na+):394.1425, Found:394.1425.
5- ([1,1'- xenyl] -4- ylmethyl) the fluoro- 3- of -5- (4- methoxyphenyl) oxazolidine -2- ketone (3j)
NMR(376MHz,CDCl3)δ-92.48ppm.13C NMR(101MHz,CDCl3)δ157.01,152.33,140.99,140.53, 131.20 (d, J=4.1Hz), 130.81,130.24,128.95,127.67,127.63,127.17,120.70,114.54, 112.32 (d, J=233.2Hz), 55.62,54.20 (d, J=30.6Hz), 41.75 (d, J=29.2Hz) ppm.IR (KBr) ν 3006,2919,2849,1765,1748,1520,1470,1275,1259,1158,824,764,750,692.HRMS(ESI)m/ z calcd.for C23H21FNO3 +(M+H+):378.1500,Found:378.1495.
The fluoro- 5- of 5- (4- luorobenzyl) -3- (4- methoxyphenyl) oxazolidine -2- ketone (3k)
NMR(101MHz,CDCl3) δ 162.64 (d, J=246.9Hz), 157.06,152.23,132.03 (d, J=8.1Hz), 130.13,127.96 (t, J=3.7Hz), 120.72,115.93 (d, J=21.4Hz), 114.56,112.07 (dd, J= ), 233.0,1.2Hz 55.63,54.19 (d, J=30.6Hz), 41.32 (d, J=29.6Hz) ppm.IR (KBr) ν 3008, 2992,2920,2845,1771,1760,1512,1275,1258,1080,826,764,750.HRMS(ESI)m/z calcd.forC17H16F2NO3 +(M+H+):320.1093,Found:320.1091.
The fluoro- 5- of 5- (4- methoxy-benzyl) -3- (4- methoxyphenyl) oxazolidine -2- ketone (3l)
19F NMR(376MHz,CDCl3)δ-92.77ppm.13C NMR(101MHz,CDCl3)δ159.46,157.00,152.40, (131.46,130.31,124.19 d, J=4.6Hz), 120.69,114.55,114.43,112.49 (d, J=232.9Hz), 55.64,55.41,54.04 (d, J=30.6Hz), 41.23 (d, J=29.4Hz) ppm.IR (KBr) ν 3005,2984,1771, 1515,1456,1339,1275,1260,764,750.HRMS(ESI)m/z calcd.for C18H18FNNaO4 +(M+Na+): 354.1112,Found:354.1104.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- (4- (trifluoromethyl) benzyl) oxazolidine -2- ketone (3m)
2H)ppm.19F NMR(376MHz,CDCl3)δ-62.69,-92.86ppm.13CNMR(101MHz,CDCl3)δ157.18, 152.07 (d, J=1.7Hz), 136.22 (dd, J=3.2,1.3Hz), 130.84 (d, J=0.8Hz), 130.52 (q, J= 32.6Hz), 130.03,125.93 (q, J=3.7Hz), 124.10 (q, J=272.1Hz), 120.80,114.63,111.72 (d, J=233.4Hz), 55.66,54.46 (d, J=30.6Hz), 42.02 (d, J=29.5Hz) ppm.IR (KBr) ν 3005, 2990,1759,1275,1261,1159,1123,825,764,750.HRMS(ESI)m/z calcd.for C18H16F4NO3 +(M +H+):370.1061,Found:370.1065.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- (3- methoxy-benzyl) oxazolidine -2- ketone (3n)
2.36(s,3H)ppm.19F NMR(376MHz,CDCl3)δ-92.42ppm.13C NMR(101MHz,CDCl3)δ156.92, (152.36,138.66,132.12 d, J=4.1Hz), 131.13,130.24,128.81,128.78,127.35,120.64, 114.48,112.38 (d, J=233.1Hz), 55.60,54.06 (d, J=30.6Hz), 41.95 (d, J=29.0Hz), 21.49ppm.IR(KBr)ν3005,2989,1771,1515,1457,1339,1275,1260,1086,764,750, 706.HRMS(ESI)m/z calcd.forC18H18FNNaO3 +(M+Na+):338.1163,Found:338.1162.
The fluoro- 5- of 5- (2- methoxy-benzyl) -3- oxazolyl phenyl alkane -2- ketone (3o)
3H),3.54–3.37(m,2H)ppm.19F NMR(376MHz,CDCl3)δ-91.60ppm.13C NMR(101MHz,CDCl3)δ (157.56,152.26 d, J=2.0Hz), 137.48,132.80,129.48,129.31,124.70,121.27,120.72 (d, ), J=5.1Hz 118.49,112.77 (d, J=233.2Hz), 111.00,55.70,53.53 (d, J=30.4Hz), 34.98 (d, J=30.1Hz) ppm.IR (KBr) ν 3391,3004,2920,2849,1778,1646,1601,1503,1496,1468, 1406,1336,1248,752,696,669.HRMS(ESI)m/z calcd.for C17H16FNNaO3 +(M+Na+): 324.1006,Found:324.0998.
5- (3,5- dimethyl benzyl) -5- fluoro- 3- (4- methoxyphenyl) oxazolidine -2- ketone (3p)
(376MHz,CDCl3)δ-92.25ppm.13C NMR(101MHz,CDCl3)δ156.97,152.44,138.53,132.08(d,J =4.2Hz), 130.34,129.69,128.16,120.70,114.53,112.48 (d, J=233.0Hz), 55.64,54.10 (d, J=30.6Hz), 41.93 (d, J=28.9Hz), 21.38ppm.IR (KBr) ν 3005,2988,1771,1515,1457, 1339,1275,1260,1086,1067,764,750.HRMS(ESI)m/z calcd.for C19H20FNNaO3 +(M+Na+): 352.1319,Found:352.1314.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- (thiene-3-yl methyl) oxazolidine -2- ketone (3q)
NMR(376MHz,CDCl3)δ-92.91ppm.13C NMR(101MHz,CDCl3) δ 157.00,152.27,132.24 (d, J= 4.4Hz), 130.18,128.99,126.64,124.68,120.72,114.53,112.05 (d, J=232.9Hz), 55.62, 54.19 (d, J=30.5Hz), 36.79 (d, J=30.7Hz) ppm.IR (KBr) ν 2920,2849,1771,1646,1515, 1469,1338,1276,1255,1090,1060,830,764,750.HRMS(ESI)m/z calcd.for C15H15FNO3S+(M +H+):308.0751,Found:308.0742.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- (thiophene -2- ylmethyl) oxazolidine -2- ketone (3r)
19F NMR(376MHz,CDCl3)δ-93.23ppm.13C NMR(101MHz,CDCl3)δ157.10,152.14,133.14(d,J =5.2Hz), 130.17,128.56,127.47,126.20,120.82,114.59,111.68 (d, J=233.3Hz), 55.65,54.00 (d, J=30.4Hz), 36.57 (d, J=32.4Hz) ppm.IR (KBr) ν 3006,2920,2849,1775, 1646,1515,1469,1338,1275,1257,975,829,764,750.HRMS(ESI)m/z calcd.for C15H15FNO3S+(M+H+):308.0751,Found:308.0747.
The fluoro- 5- of 5- (furans -3- ylmethyl) -3- (4- methoxyphenyl) oxazolidine -2- ketone (3s)
(376MHz,CDCl3)δ-93.33ppm.13C NMR(101MHz,CDCl3)δ157.13,152.28,143.81,141.47, (130.28,120.79,116.06 d, J=4.9Hz), 114.63,112.10 (d, J=232.6Hz), 111.69,55.66, 54.28 (d, J=30.6Hz), 32.20 (d, J=31.7Hz) ppm.IR (KBr) ν 3392,3006,2920,2849,1771, 1646,1515,1469,1338,1251,1092,1024,874,749.HRMS(ESI)m/z calcd.for C15H15FNO4 +(M +H+):292.0980,Found:292.0967.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- ((9- phenyl -9H- carbazole -3- base) methyl) oxazolidine -2- ketone (3t)
10.9Hz,1H),3.76(s,3H),3.65–3.46(m,2H)ppm.19F NMR(376MHz,CDCl3)δ-92.29ppm.13C NMR(101MHz,CDCl3)δ156.91152.48,141.39,140.63,137.60,130.36,130.08,128.11, (127.79,127.20,126.48,123.87123.58 d, J=4.4Hz), 122.99,122.12,120.59,120.54, (120.29,114.50,112.82 d, J=232.9Hz), 110.31,110.09,55.63,54.03 (d, J=30.7Hz), 42.10 (d, J=29.1Hz) ppm.IR (KBr) ν 3055,3006,2955,2930,2835,1774,1597,1514,1503, 1458,1333,1251,1234,1151,977,937,828,763,749,698.HRMS(ESI)m/z calcd.forC29H23FN2NaO3 +(M+Na+):489.1585,Found:489.1583.
The fluoro- 3- of 5- benzyl -5- (4- methoxyphenyl) -4- methyl oxazolidine -2- ketone (3u)
(1H)], [3.80 (s), 3.78 (s), (3H)], 3.49-3.16 (m, 2H), [1.27 (d, J=6.7Hz), 1.03 (dd, J= 6.5,2.4Hz),(3H)]ppm.19F NMR(376MHz,CDCl3)δ-93.67,-111.55ppm.13C NMR(101MHz, CDCl3) δ 158.37,157.89,153.47 (d, J=1.4Hz), 152.40 (d, J=1.6Hz), 132.32,132.27, 130.58 (d, J=1.2Hz), 130.51,128.87,128.58,128.41,127.95,127.87,127.61,126.06, (124.52,114.74,114.65,114.52 d, J=232.8Hz), 113.64 (d, J=238.9Hz), 62.40 (d, J= 31.4Hz), 59.18 (d, J=25.7Hz), 55.60,55.58,41.87 (d, J=29.6Hz), 38.78 (d, J=26.4Hz), 14.78 (d, J=9.1Hz), 12.41 (d, J=12.0Hz) ppm.IR (KBr) ν 3000,2920,2849,1775,1646, 1515,1456,1396,1297,1250,1151,1038,989,962,831,750,702.HRMS(ESI)m/z calcd.for C18H18FNNaO3 +(M+Na+):338.1163Found:338.1163.
5- benzyl -4- ethyl -5- fluoro- 3- (4- methoxyphenyl) oxazolidine -2- ketone (3v)
49.4mg, 75%yield, dr=1.5:1.White solid, Mp 100-104 DEG C1H NMR(400MHz, CDCl3)δ7.44–7.29
0.85(m,3H)ppm.19F NMR(376MHz,CDCl3)δ-90.21,-111.31ppm.13C NMR(101MHz,CDCl3)δ (158.47,157.69,153.38,152.81,132.47 d, J=7.4Hz), 132.28,130.71,130.59 (d, J= 0.9Hz),129.06,128.89,128.56,128.22,127.93,127.61,126.32,124.19,114.68,114.66, 114.26 (d, J=232.6Hz), 113.92 (d, J=239.1Hz), 66.52 (d, J=29.5Hz), 63.72 (d, J= 24.9Hz), 55.59,55.56,43.27 (d, J=30.9Hz), 38.67 (d, J=26.4Hz), 21.56 (d, J=8.9Hz), 20.85 (d, J=10.7Hz), 9.95 (d, J=2.4Hz), 8.61ppm.IR (KBr) ν 3006,2986,2921,2851,1776, 1515,1456,1403,1275,1259,1125,1032,978,829,764,750,701.HRMS(ESI)m/z calcd.for C19H21FNO3 +(M+H+):330.1500,Found:330.1500.
The fluoro- 3- of 5- (4- methoxyphenyl) -5- (1- phenylethyl) oxazolidine -2- ketone (3w)
Hz,3H)ppm.19F NMR(376MHz,CDCl3)δ-97.07,-106.34ppm.13CNMR(101MHz,CDCl3)δ157.00, 156.95,152.54 (d, J=1.7Hz), 152.43,138.48 (d, J=4.7Hz), 138.33,130.27,130.22, (129.00,128.97,128.79,128.74 d, J=2.0Hz), 128.12,128.08,120.79,120.69,114.51, 114.49,113.87 (d, J=234.9Hz), 113.65 (d, J=237.8Hz), 55.63,54.49 (d, J=30.9Hz), 53.46 (d, J=31.1Hz), 46.50 (d, J=26.2Hz), 45.21 (d, J=27.6Hz), 14.98 (d, J=5.0Hz), 14.87 (d, J=3.9Hz) ppm.IR (KBr) ν 3005,2989,2918,2849,1773,1514,1463,1406,1337, 1275,1260,897,765,750.HRMS(ESI)m/z calcd.for C18H18FNNaO3 +(M+Na+):338.1163, Found:338.1165.
Own ring -2- the ketone (3x) of the fluoro- 3- of 6- benzyl -6- (4- methoxyphenyl) -1,3- oxygen azepine
18.4mg, 44%yield.Colorless oil.1H NMR(400MHz,CDCl3) δ 7.54 (d, J=8.1Hz, 2H), 7.38 (t, J=7.9
123.57,117.98,85.80 (d, J=174.2Hz), 77.19 (d, J=17.5Hz), 51.19 (d, J=5.2Hz), 21.00 (d, J=4.8Hz) ppm.IR (KBr) ν 3005,2989,2920,2851,1749,1460,1414,1322,1275,1261, 1119,897,763,750,706.HRMS(ESI)m/z calcd.for C11H12FNNaO2 +(M+Na+):232.0744, Found:232.0737.
5- (methyl fluoride) -5- methyl -3- oxazolyl phenyl alkane -2- ketone (3y)
2H)ppm.19F NMR(376MHz,CDCl3)δ-101.73ppm.13C NMR(101MHz,CDCl3)δ158.66,150.16, (135.14,133.39 d, J=4.9Hz), 130.60,128.74,127.69,127.23,114.75,113.29 (d, J= 226.8Hz), 55.63,44.73 (d, J=26.2Hz), 44.52 (d, J=4.5Hz), 28.43 (d, J=26.0Hz) ppm.IR (KBr)ν3005,2989,2916,1719,1512,1478,1426,1275,1260,1164,832,763,750,705.HRMS (ESI)m/z calcd.for C18H18FNNaO3 +(M+Na+):338.1163,Found:338.1157.
The fluoro- 3- of 5- benzyl -5- (4- chlorphenyl) oxazolidine -2,4- diketone (3 ' a)
MHz,CDCl3) δ 165.52 (d, J=24.3Hz), 150.78,130.62,129.79,129.68,129.59,129.18, (128.65,125.58,110.06 d, J=244.5Hz), 38.91 (d, J=28.2Hz) ppm.
5- benzyl -3- (4- chlorphenyl) -5- fluorine oxazolidine -2,4- diketone (3 ' b)
), Hz 150.40,135.56,130.58,129.82,129.60 (d, J=10.4Hz), 129.21,128.71,128.21, 126.70,110.09 (d, J=245.1Hz), 38.91 (d, J=28.1Hz) ppm.IR (KBr) ν 3005,2987,2922, 2847,1842,1765,1500,1426,1275,1260,825,764,750,699.HRMS(EI)m/z calcd.forC16H11ClFNO3 +:319.0406,Found:319.0406
3- (4- chlorphenyl) -5- (3,5- dimethyl benzyl) -5- fluorine oxazolidine -2,4- diketone (3 ' c)
(130.25,129.83,129.39 d, J=10.2Hz), 128.35,128.25,126.72,110.19 (d, J=245.0Hz), 38.79 (d, J=27.7Hz), 21.31ppm.
3- (4- chlorphenyl) -5- fluoro- 5- (4- luorobenzyl) oxazolidine -2,4- diketone (3 ' d)
=248.4Hz), 150.33,135.65,132.35 (d, J=8.2Hz), 129.91,128.17,126.56,125.37 (dd, J =10.3,3.4Hz), 116.25 (d, J=21.6Hz), 109.72 (dd, J=244.7,1.7Hz), 37.99 (d, J= 28.6Hz)ppm.
3- (4- chlorphenyl) -5- fluoro- 5- (4- methoxy-benzyl) oxazolidine -2,4- diketone (3 ' e)
MHz,CDCl3) δ 165.35 (d, J=24.5Hz), 159.83,150.50,135.51,131.71,129.81,128.26, (126.69,121.28 d, J=10.8Hz), 114.57,110.15 (d, J=245.3Hz), 55.43,37.98 (d, J= 28.1Hz)ppm.
3- (4- chlorphenyl) -5- fluoro- 5- (thiene-3-yl methyl) oxazolidine -2,4- diketone (3 ' f)
24.5Hz), 150.47,135.64,129.89,129.59 (d, J=10.9Hz), 128.91,128.23,127.17,126.76, 126.01,109.69 (d, J=245.4Hz), 33.52 (d, J=29.6Hz) ppm.IR (KBr) ν 3005,2989,1765, 1501,1457,1427,1275,1261,763,750,706.HRMS(EI)m/z calcd.for C14H9ClFNO3S+: 324.9970,Found:324.9969.
The above is only presently preferred embodiments of the present invention, is not intended to limit the present invention in any form, any ripe Professional and technical personnel is known, without departing from the scope of the present invention, according to the technical essence of the invention, to the above reality Any simple modifications, equivalent substitutions and improvements etc. made by example are applied, it is fallen within the scope of protection of the technical scheme of the present invention It is interior.

Claims (1)

1. a kind of preparation method of fluoro Oxazolidinone derivative, which is characterized in that the method be using styrene or Acrylamide derivative and high price fluorine iodine reagent carry out fluorine cyclization synthesizing fluoro Oxazolidinone derivative, specifically the bottom of by Object 2, compound 1, AgSbF6Or AgBF4It is added in reaction flask with DCM and stirs mixture at 20-60 DEG C, passed through Reaction mixture is concentrated to dryness by the progress of TLC monitoring reaction when observing that reaction terminates, and is passed through column chromatography and is extracted separation Obtain fluoro Oxazolidinone derivative 3；
Specific reaction equation is as follows:
Its synthetic product includes:
。
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