CN1176074C - Multi-substitutent beta-monofluoropyrrole compounds and preparing process thereof - Google Patents

Multi-substitutent beta-monofluoropyrrole compounds and preparing process thereof Download PDF

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CN1176074C
CN1176074C CNB021116415A CN02111641A CN1176074C CN 1176074 C CN1176074 C CN 1176074C CN B021116415 A CNB021116415 A CN B021116415A CN 02111641 A CN02111641 A CN 02111641A CN 1176074 C CN1176074 C CN 1176074C
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CN1381445A (en
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朱士正
王彦利
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The present invention relates to a polysubstituted beta-monofluoro pyrrole compound, and a new, convenient and high-efficiency preparing method thereof. The structural formula of the compound is disclosed in the right formula, wherein R<1> or R<2> represents C<1-5> alkyl, alpha-naphthyl or beta-naphthyl, 2-furyl, benzyl(-CH2Ph) and substituted or unsubstituted phenyl ZAr-; Z represents H, C<1 to 4> alkyl; X or W, and Y represent OR and NRR'. In the substituted group, X represents halogen, and W represents OR, NH2, NHR, NHCOR, NRR' or NO2, wherein R or R' represents C<1 to 4> alkyl. Under the catalytic action of metal, the compound is synthesized by using easily-obtained raw materials by three-step reaction. The compound of the present invention has certain potential physiological activity, and thus, an effective synthetic method is provided for selecting prodrug.

Description

Polysubstituted β-single fluoro azoles and preparation method thereof
Technical field
The present invention relates to the polysubstituted β of a class-single fluoro azoles, and a kind of novel, easy, the preparation method efficiently of this compounds.This method is under metal catalytic, is set out by the raw material that is easy to get, and three-step reaction is synthetic to have the method for various substituted radical β-single fluoro azoles.Compound of the present invention has some potential physiologically actives, for the screening of prodrug provides a kind of very effectively synthetic method.
Background technology
Pyrrole ring is one of the most important basic structural unit of organic molecule (Johes, R.A.; Bean, G.P.The Chemistry of Pyrroles Academic Press, London, 1977.Schofield, K.Hetero-Aromatic Nitrogen Compounds, Pyrrole and Pyridines.Butterworths, London, 1967).Pyrrole ring not only can participate in the number of chemical reaction, and its structure also extensively is present in various natural products (Sundberg, R.J.In Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W., Scriven, E.F.V., Eds.; Pergamon Press:Oxford, New York, Toronto, Sydney, Peris, Frankfurt, 1996; Vol.2, pp119.F ü rstner, A.Synlett 1999,1523), synthetic drugs (Gribble, G.W.In Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W., Scriven, E.F.V., Eds.; Pergamon Press:Oxford, New York, Toronto, Sydney, Peris, Frankfurt, 1996; Vol.2, pp207), the physiologically active molecule, as (Katritzky, A.R. in microbiotic and the alkaloid; Rees, C.In Comprehensive Heterocyclic Chemistry II; Bird, C.W.; Cheeseman, G.W.H., Eds.; Pergamon Press:Oxford; 1996; Vol.2, pp370).Polypyrrole also can be used as electro-conductive material (MacDiarmid, A.G.Synth.Met.1997,84,27-34).Wherein 1,2,4,5-four substituted azoles are owing to show outstanding physiologically active, as germ resistance, and antiviral property, anti-inflammatory, multiple physiologically active such as oxidation-resistance and attract tremendous attention (Braun, R.U.; Zeitier, K.; M ü ller, T.J.J.Org.Lett.2001,3 (21), 3297-3300).
Recently studies show that at the key position of molecule and introduce fluorine atom with physiologically active, often can change and significantly strengthen its physiologically active, can strengthen result of treatment and pharmacologically active (Kirk, the K.L.InBiochemistry of the Elements Series of medicine especially; Frieden, E., Ed.; Plenum Press:New York, 1991; Vol.9B.).So the fluoro pyrroles has caused chemist and medicine scholar's extensive interest.The fluoro pyrroles also often be used to synthetic polypyrrole and agricultural and medical aspect compound (Handbookof Conducting Polymers, Skotheim, T.A., the Ed. of potential use are arranged; Mercel Dekker, New York, 1986.Audebert, P.; Bidan, G.Synth.Met.1986,15,89-22.Ofer, D.; Crooks, R.M.; Wrighton., M.S.J Am.Chem.Soc.1990,112,7869-7879.Ho-Hoang, A.; Favche, F.; Lemaire, M.New J.Chem.1992,16,1017-1018).For example the porphyrin by the fluoro pyrrole derivatives is designed with the diagnosis and phototherapy reagent (Ando, the A. that do cancer; Shinada, T.; Kinishita, S.; Arimura, N.; Koyama, M.; Nagai, T.; Miki, T.; Kumadaski, I.; Sato, H.Chem.Pharm.Bull.1990,38,2175-2178).
β-fluoro azoles synthetic has three kinds of methods commonly used.First kind is Schiemann reaction, and promptly the reaction of tetrafluoride boron pyrroles β-diazonium salt obtains β-fluoro pyrroles (Onda, H. with 17% productive rate under the illumination effect; Toi, H.; Aoyama, Y.; Ogoshi, H.Tetrahedron Lett.1985,26,4221-4224).Reaction formula is as follows:
Figure C0211164100051
Second kind is by α, α-two fluoro-γ-(drawing electron group)-replacement ketone compounds under the ammoniacal liquor effect at first cyclisation obtain the pyrrolin compound, handle obtaining β-single fluoro azole compounds then with potassium hydroxide aqueous solution.(Qiu，Z.M.；Burton，D.J.Tetrahedron?Lett.1994，35(25)，4319-4322)。Reaction formula is as follows:
The third is to obtain [2+3] cycloaddition product by the N-tertiary butyl-2-carbalkoxy ethylenimine and chlorotrifluoroethylene under heating condition.Handle the cycloaddition product with the alkali sodium methylate and obtain 3,4-two fluoro azole compounds.(Leroy，J.；Wakselman，C.Tetrahedron?Lett.1994，35，8605-8608)。Reaction formula is as follows:
Very obviously above three kinds of methods respectively have its deficiency and limitation.1. the first method productive rate is very low, has only 17%; 2. the cyclisation precursor is difficult to preparation in the second method, and uses the highly basic potassium hydroxide aqueous solution, and substituting group is had bigger restriction; 3. the third method needs 200 ℃ of heating in closed reactor, the operational danger height, and the preparation difficulty of ethylenimine is higher.From aforesaid method, directly fluoridize the general condition harshness, productive rate is low, and the substitution in ring base is had bigger restriction, and suitable fluorine-containing precursor preparation method is fewer.So synthetic effective means that still lacks for polysubstituted β-fluoro pyrroles.Therefore be necessary very much to develop a kind of efficiently, neutral, gentle synthetic polysubstituted β-fluoro pyrroles's method.
The intramolecularly N-H key insertion reaction of metal carbene is to make up nitrogenous heterocyclic effective ways (ModernCatalytic Methods for Organic Synthesis with Diazo Compounds Doyle, M.P.; McKervey, M.A.; Ye, T.Eds.John Wiley ﹠amp; Sons, Inc.:New York, 1997.pp436).Penta azacyclo can be synthesized easily, six-membered heterocycle, azetidinone, and the condensed ring system that links to each other with beta-lactam.Because this type of good reaction selectivity, the productive rate height now has been applied to suitability for industrialized production.As Merck company in the industry of microbiotic (+)-Thienamycin is synthetic, just with Rh 2(OAc) 4The metal carbene that catalytic α-diazonium-beta-ketoester produced to the insertion reaction of intramolecular acid amides N-H key as committed step (Heck, J.V.; Christensen, B.G.Tetrahedron Lett.1981,22,5027-5030).
Summary of the invention
The object of the invention provides the polysubstituted β of a class-single fluoro azoles.
Another purpose of the present invention provides the synthetic method of such azoles.Realized catalytic γ in the present invention by Rh (II), γ-two fluoro-α-diazonium-beta-ketoester optionally intramolecularly N-H key insertion reaction for the committed step high productivity has prepared a series of polysubstituted β-fluoro azoles.
The invention provides polysubstituted β-single fluoro azoles that a class has following structural formula:
R wherein 1Or R 2=C 1-5Alkyl, α-or betanaphthyl, 2-furyl, benzyl (CH 2Ph), replace or unsubstituted phenyl ZAr-Z=H, C 1-4Alkyl, X or W.Y＝OR，NRR`。
In the above-described substituting group, X is a halogen, as F, Cl, Br, I; W is OR, NH 2, NHCOR, NHR, NRR` or NO 2R or R` are C 1-4Alkyl, R can be identical or inequality with R`.
Another purpose of the present invention provides the synthetic method of such azoles.
Typical reaction formula is as follows in the method for the present invention:
Figure C0211164100071
Above-mentioned polysubstituted β of the present invention-single fluoro azoles can prepare by following method:
In organic solvent and under 0 ℃-30 ℃, imines R 2CH=NHR 1, XCF 2COCH 2COY, zinc powder and CuX, its mol ratio is respectively 1～1.1: 1～1.1: 2.0-3.0: 0.3-1.0, the recommendation ratio is 1.1: 1.0: 2.0: 0.3, reacted 2-48 hour.The saturated aqueous ammonium chloride acidifying is used in the reaction back, removes by filter excessive metal and metal-salt, through ethyl acetate extraction, after washing, drying, the evaporation, obtains α through recrystallization or column chromatography purification again, α-two fluoro ketone compounds R 2CH (NHR 1) CF 2COCH 2COY.Can add a certain amount of molecular sieve during reaction, to improve productive rate, as 4 molecular sieves.XCF 2COCH 2The ratio of COY and molecular sieve is that 1 mmole restrains than 0-1, and the recommendation ratio is that 1 mmole restrains than 0.1-1.R wherein 1, R 2, Y as previously mentioned; X is a halogen.
In organic solvent and under 0 ℃-30 ℃, molecular formula is R 2CH (NHR 1) CF 2COCH 2The α of COY, α-two fluoro ketone compounds, replacement or the benzene that does not replace or naphthalene sulfonyl nitrine Z-ArSO 2N 3And alkali reaction, its mol ratio is respectively 1.0: 0.8-1.2: 0.8-3.0, more alkali is to reaction also not influence.Reacted 1-6 hour.Reaction after filtration, recrystallization or column chromatography purification can obtain α-diazonium carbonyl compound R 2CH (NHR 1) CF 2COC (N 2) COY.R wherein 1, R 2, Y as previously mentioned; X is a halogen; Z is H, OR, NH 2, NHR, NRR`, NO 2,, NHCOR, N COOR; R or R` as previously mentioned, described alkali is organic amine compound or the monovalence metal inorganic alkali that contains lone-pair electron on the nitrogen-atoms.The organic amine compound that contains lone-pair electron on the described nitrogen-atoms is benzyl lauryl amine, triethylamine, Tributylamine, trioctylamine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene (DBU), 4-(N, the N-dimethyl)-pyridine or 1,4-diazacyclo [2.2.2] octane etc., described monovalence metal inorganic alkali can be the carbonate or the supercarbonate of monovalence metal, as salt of wormwood (K 2CO 3), yellow soda ash (Na 2CO 3), cesium carbonate (Cs 2CO 3), saleratus (KHCO 3), sodium bicarbonate (NaHCO 3) etc.
In organic solvent and under 80 ℃-110 ℃, molecular formula is R 2CH (NHR 1) CF 2COC (N 2) α-diazonium carbonyl compound of COY and organic rhodium catalyst reaction generated polysubstituted β-single fluoro azoles in 8-16 hour.The mol ratio of α-diazonium carbonyl compound and organic rhodium catalyst is 1.0: 0.001-0.1, the recommendation ratio is 1.0: 0.002-0.005.Remove by filter rhodium catalyst, evaporation removes and desolvates, and recrystallization can obtain polysubstituted β-single fluoro azoles.R wherein 1, R 2, Y as previously mentioned; Catalyst system therefor is acetic acid rhodium Rh 2(OAc) 4, butanic acid rhodium Rh 2(OOCC 3H 7) 4, uncle's rhodium butyrate Rh 2(OOC (CH 3) 3) 4, caproic acid rhodium Rh 2(OOCC 5H 11) 4, trifluoracetic acid rhodium Rh 2(OOCCF 3) 4, perfluorobutyric acid rhodium Rh 2(OOCC 3F 7) 4Deng.
Used organic solvent can be tetrahydrofuran (THF), ether, sherwood oil, N among the present invention, dinethylformamide, toluene, dimethylbenzene, dimethyl sulfoxide (DMSO), methylene dichloride or chloroform etc.Organic solvent is recommended as toluene or dimethylbenzene when α-diazonium carbonyl compound and catalyst reaction.
Above-mentioned reaction is looked the difference of substrate and reaction times difference slightly, and result's productive rate preferably generates corresponding polysubstituted β-single fluoro azoles, and three step overall yields are 67-82%, looks the difference of substrate and reaction yield difference slightly.
The inventive method operation is easy, and productive rate is higher.Find that in addition reaction metal and catalyzer that zinc and cuprous halide etc. are commonly used also play good effect through simple processing.And rhodium catalyst can reclaim, and recycling is suitable for suitability for industrialized production.This reaction raw materials is easy to get and has variable very widely kind, so this reaction can be synthesized a large amount of azoles that contains different substituents group at short notice.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Embodiment 1
4,4-two fluoro-3-oxos-5-phenyl-5-anilino-Valeric acid ethylester synthetic.
With activated zinc powder (0.131g, 2.0mmol) and CuCl (0.030g 0.3mmol) stirred under the room temperature 0.5 hour in tetrahydrofuran (THF) (2mL).Drip 4-bromo-4 at 0 ℃ then, (0.245g is 1.0mmol) with N-phenyl phenyl aldehyde imines (0.199g, tetrahydrofuran solution 1.1mmol) (1mL) for 4-two fluoro-3-oxo-ethyl butyrates, rise to 30 ℃ of reactions 2.5 hours after dropwising, TLC and fluorine spectrum show that reaction finishes.Add saturated ammonium chloride solution (5mL) in reaction solution, suction filtration is removed excessive zinc powder, and solid is washed (5mL * 2) twice with ethyl acetate.Tell organic layer, water layer ethyl acetate extraction (10mL * 3).Merge organic layer, wash (15mL) successively with water, saturated common salt washing (25mL), anhydrous sodium sulfate drying.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (3: 1/V: be that eluent obtains adduct 4 V), 4-two fluoro-3-oxos-5-phenyl-5-anilino-Valeric acid ethylester (0.295g, 0.85mmol), productive rate: 85.0%.Light yellow solid, fusing point 74-75 ℃.
1HNMR(CDCl 3)δ＝12.20(s，O-H，0.54H)，6.63-7.45(m，10H)，5.48(s，0.54H)，5.08-5.20(m，1H，5-H)，4.50(s，1H，N-H)，4.22(q，2H，J＝7.1Hz)，3.59(s，0.92H)，1.30(t，3H，J＝7.1Hz).
19FNMR(CDCl 3)δ＝-107.5(dd， 2J F-F＝264.0Hz， 3J H-F＝7.9Hz，0.46F)，-120.0(dd， 2J F-F＝264.0Hz， 3J H-F＝19.5Hz，0.46F)，-110.3(dd， 2J F-F＝259.0Hz， 3J H-F＝9.1Hz，0.54F)，-119.0(dd， 2J F-F＝259.0Hz， 3J H-F＝15.0Hz，0.54F).
IR(neat)cm -1：ν＝3383，1765，1707，1663，1372-1118.
m/z(EI)347(M +，5)，227(M +-HOEt，14)，182(Ph(PhNH)CH +，100).
HRMS calculated value: C 19H 19NF 2O 3: 347.13330. measured value: 347.13283.
Embodiment 2
4,4-two fluoro-3-oxo-5-(2-furyl)-5-anilino-Valeric acid ethylesters synthetic.
With activated zinc powder (0.131g, 2.0mmol) and CuCl (0.030g 0.3mmol) stirred under the room temperature 0.5 hour in tetrahydrofuran (THF) (2mL).Drip 4-bromo-4 at 0 ℃ then, (0.245g is 1.0mmol) with N-benzofurane aldimine (0.188g, tetrahydrofuran solution 1.1mmol) (1mL) for 4-two fluoro-3-oxo-ethyl butyrates, rise to 30 ℃ of reactions 6 hours after dropwising, TLC and fluorine spectrum show that reaction finishes.Add saturated ammonium chloride solution (5mL) in reaction solution, suction filtration is removed excessive zinc powder, and solid is washed (5mL * 2) twice with ethyl acetate.Tell organic layer, water layer ethyl acetate extraction (10mL * 3).Merge organic layer, wash (15mL) successively with water, saturated common salt washing (25mL), anhydrous sodium sulfate drying.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (V: V, 8: 1 to 3: 1) for eluent obtains adduct 4,4-two fluoro-3-oxo-5-(2-furyl)-5-anilino-Valeric acid ethylesters (0.253g, 0.75mmol), productive rate: 75.0%.Light yellow liquid.
1HNMR(CDCl 3)δ＝12.10(s，O-H，0.52H)，7.40-7.42(m，1H)，7.15-7.25(m，2H)，6.71-6.85(m，3H)，6.33-6.37(m，2H)，5.55(s，0.52)，5.20-5.32(m，1H)，4.14-4.30(m，2H)，3.77(s，0.96H)，1.23and?1.30(t，3H，J＝7.1Hz).
19F?NMR(CDCl 3)δ＝-108.0(dd， 2J F-F＝263.3Hz， 3J H-F＝7.8Hz，0.48F)，-119.6(dd， 2J F-F＝263.3Hz， 3J H-F＝18.5Hz，0.48F)，-112.9(d， 2J F-F＝257.2Hz，0.52F)，-127.6(dd， 2J F-F＝257.2Hz， 3J H-F＝24.4Hz，0.52F).
IR(neat)cm -1：ν＝3383，1755，1371-1144.
m/z(EI)337(M +，4.31)，392(M +-OEt，0.75)，222(M +-COCH 2CO 2Et，0.64)，172(M +-CF 2COCH 2CO 2Et，100.00).
HRMS calculated value: C 17H 17NF 2O 4: 337.11223. measured value: 337.11240.
Embodiment 3
4,4-two fluoro-3-oxos-5-phenyl-5-benzamido group-Valeric acid ethylester synthetic.
With activated zinc powder (0.131g, 2.0mmol) and CuCl (0.030g 0.3mmol) stirred under the room temperature 0.5 hour in tetrahydrofuran (THF) (2mL).Drip 4-bromo-4 at 0 ℃ then, (0.245g is 1.0mmol) with N-benzyl-phenyl aldehyde imines (0.215g, tetrahydrofuran solution 1.1mmol) (1mL) for 4-two fluoro-3-oxo-ethyl butyrates, rise to 30 ℃ of reactions 6 hours after dropwising, TLC and fluorine spectrum show that reaction finishes.Add saturated ammonium chloride solution (5mL) in reaction solution, suction filtration is removed excessive zinc powder, and solid is washed (5mL * 2) twice with ethyl acetate.Tell organic layer, water layer ethyl acetate extraction (10mL * 3).Merge organic layer, wash (15mL) successively with water, saturated common salt washing (25mL), anhydrous sodium sulfate drying.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (V: V, 12: 1 to 5: 1) for eluent obtains adduct 4,4-two fluoro-3-oxos-5-phenyl-5-benzamido group-Valeric acid ethylester (0.245g, 0.68mmol), productive rate: 68.0%.Light yellow liquid.
1H?NMR(CDCl 3)δ＝11.95(s，0.37H，O-H)，7.14-7.39(m，10H)，5.37(s，0.37H)，4.13-4.22(m，3H，OCH 2CH 3?and?H-5)，3.64(s，1.26H)，3.45-3.71(m，2H)，1.96(br，1H，N-H)，1.23?and?1.25(t，3H，J＝7.2Hz).
19F?NMR(CDCl 3)δ＝-107.0(dd， 2J F-F＝257.5Hz， 3J H-F＝5.4Hz，0.63F)andδ-124.2(dd， 2J F-F＝257.5Hz， 3J H-F＝24.3Hz，0.63F)，-111.0(dd， 2J F-F＝259.4Hz， 3J H-F＝11.8Hz，0.37F)，-119.4(dd， 2J F-F＝259.4Hz， 3J H-F＝17.8Hz，0.37F).
IR(neat)cm -1：ν＝3338，1755，1733，1664，1369-1099.
m/z(EI)362(M +H，1.21)，316(M +-OEt，2.50)，274(M +-CH 2CO 2Et，0.50)，196(M +-CF 2COCH 2CO 2Et，100.00).
HRMS calculated value: C 20H 21NF 2O 3: 316.12193. measured value: 316.11842.
Embodiment 4
4,4-two fluoro-3-oxos-5-phenyl-5-anilino-2-diazonium-Valeric acid ethylester synthetic
Figure C0211164100111
4,4-two fluoro-3-oxos-5-phenyl-5-anilino-Valeric acid ethylester (0.240g, 0.69mmol) and p-toluene sulfonyt azide (0.134g 0.69mmol) is dissolved in toluene (5mL).Slowly drip under the condition of ice bath then triethylamine (0.1mL, 0.69mmol).Dropwise, rose to room temperature reaction 4 hours, the TLC demonstration reacts completely, and adds 10 milliliters of 30-60 ℃ of sherwood oils, stirs 10 minutes.Suction filtration is removed the para toluene sulfonamide solid, and solid is with sherwood oil and ethyl acetate (6: 1/V: V) wash (5mL * 2) twice.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (6: 1/V: be that eluent gets diazonium transfer product 4 V), 4-two fluoro-3-oxos-5-phenyl-5-anilino-2-diazonium-Valeric acid ethylester (0.227g, 0.61mmol), productive rate: 88.0%.White solid, fusing point 128-130 ℃
1H?NMR(CDCl 3)δ＝1.31(3H，t，J?7.2Hz)，4.33(2H，q，J?7.2Hz)，4.72(NH，d，J7.8Hz)，5.49(1H，d，d， 2J F-H20.4Hz， 2J F-H7.8Hz)，6.39-7.67(10H，m).
19FNMR(CDCl 3)δ＝-103.3(d， 2J F-F?259.4Hz，1F)，-115.6(d， 2J F-F259.4Hz， 2J F-H20.4Hz，1F).
MS(m/z％)：373(M +，3.40)，325(M +H-CO 2Et，12.13)，307(M +-HOEt-HF，4.56)，279(M +-1-CO 2Et-HF，22.78)，253(M +-C 6H 5NH +-N 2，12.68)，182(M +-CF 2COC(N 2)CO 2Et，100)，77(C 6H 5 +，48.17).
IR(KBr)：ν＝3342(NH，s)，2162(N≡N，s)，1720(CO 2Et，s)，1648(C＝O，s)，1122-1373(vs，C-F).
Ultimate analysis, calculated value: C, 61.13; N, 11.36; H, 4.56%. measured value: C, 61.38; N, 11.05; H, 4.60%.
Embodiment 5
4,4-two fluoro-3-oxo-5-(2-furyl)-5-anilino-2-diazonium-Valeric acid ethylesters.
Figure C0211164100121
4,4-two fluoro-3-oxo-5-(2-furyl)-5-anilino-Valeric acid ethylesters (0.337g, 1.0mmol) and p-toluene sulfonyt azide (0.197g 1.0mmol) is dissolved in toluene (6mL).Slowly drip under the condition of ice bath then triethylamine (0.14mL, 1.0mmol).Dropwise, rose to room temperature reaction 5 hours, the TLC demonstration reacts completely, and adds 10 milliliters of 30-60 ℃ of sherwood oils, stirs 10 minutes.Suction filtration is removed the para toluene sulfonamide solid, and solid is with sherwood oil and ethyl acetate (6: 1/V: V) wash (5mL * 2) twice.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (7: 1/V: be that eluent gets diazonium transfer product 4 V), 4-two fluoro-3-oxo-5-(2-furyl)-5-anilino-2-diazonium-Valeric acid ethylesters (0.309g, 0.85mmol), productive rate: 85.0%.Light yellow solid, fusing point 96-98 ℃.
1H?NMR(CDCl 3)δ＝1.35(3H，t，J?7.1Hz)，4.36(2H，q，J?7.1Hz)，4.39(1H，s，br，NH)，5.66(1H，d，d， 2J HF19. 1J H-F7.3)，5.70(1H，d，d， 2J3.3Hz， 2J1.4Hz)，6.45(1H，d，J3.3Hz)，6.71-6.83(3H，m)，7.15-7.27(2H)，7.43(1H，d，J?1.4Hz).
19F?NMR(CDCl 3)δ＝-104.4(1F，d，d， 2J F-F259.4Hz， 2J F-H7.9Hz)，-114.8(1F，d，d， 2J F-F29.4Hz， 2J F-H16.9Hz)，
MS(m/z％)：363(M +，2.25)，335(M +-N 2，100)，242(M +-HF-CO 2Et-N 2，5.88)，
IR(KBr)：ν＝3331(NH，s)，2165(N≡N，s)，1723(CO 2Et，s)，1652(C＝O，s)，1082-1330(vs，C-F).
Ultimate analysis, calculated value: C, 56.20; N, 11.57; H, 4.13%. measured value: C, 56.26; N, 11.60; H, 4.22%.
Embodiment 6
4,4-two fluoro-3-oxos-5-phenyl-5-benzamido group-2-diazonium-Valeric acid ethylester.
4,4-two fluoro-3-oxos-5-phenyl-5-benzamido group-Valeric acid ethylester (0.361g, 1.0mmol) and p-toluene sulfonyt azide (0.197g 1.0mmol) is dissolved in toluene (6mL).Slowly drip under the condition of ice bath then triethylamine (0.14mL, 1.0mmol).Dropwise, rose to room temperature reaction 3 hours, the TLC demonstration reacts completely, and adds 10 milliliters of 30-60 ℃ of sherwood oils, stirs 10 minutes.Suction filtration is removed the para toluene sulfonamide solid, and solid is with sherwood oil and ethyl acetate (6: 1/V: V) wash (5mL * 2) twice.Rotary evaporation removes and desolvates, then column chromatography for separation.With sherwood oil and ethyl acetate (9: 1/V: be that eluent gets diazonium transfer product 4 V), 4-two fluoro-3-oxos-5-phenyl-5-benzamido group-2-diazonium-Valeric acid ethylester (0.333g, 0.86mmol), productive rate: 86.0%.Light yellow solid, fusing point 100-102 ℃
1H?NMR(CDCl 3)δ＝1.34(3H，t，J?7.2Hz)，3.54(1H，d，J?13.1Hz)，3.83(1H，d，J13.1Hz)，4.27(2H，q，J?7.2Hz)，4.53(1H，d，d， 2J F-H23.2Hz， 2J F-H5.6Hz)，7.23-7.46(10H，m).
19F?NMR(CDCl 3)δ＝-103.5(1F，d，d， 2J F-F259.4Hz， 2J F-H5.64Hz)，-117.2(1F，d，d， 2J F-F259.4Hz， 2J F-H21.9Hz).
MS(m/z％)：388(MH +，3.01)，259(M +-N 2，2.63)，339(M +-N 2-HF，2.76)，286(M +-N 2-CO 2Et，6.09)，196(M +-CF 2COC(N 2)CO 2Et，59.60)
IR(KBr)：ν＝3352(NH，s)，2151(N＝N，s)，1725(CO 2Et，s)，1668(C＝O，s)，1124-1374(vs，C-F)
Ultimate analysis, calculated value: C, 62.02; N, 10.85; H, 4.91%; Measured value: C, 62.30; N, 10.80; H, 4.98%.
Embodiment 7
1,4-phenylbenzene-3-hydroxyl-4-fluoro-2-minaline ethyl ester synthetic
Under 90 ℃ of conditions of oil bath, with diazonium compound 4, (0.373g, toluene solution 1.0mmol) (1.0mL) slowly are added drop-wise to and contain Rh 4-two fluoro-3-oxos-5-phenyl-5-anilino-2-diazonium-Valeric acid ethylester 2(OAc) 4(2mg in toluene solution 0.5mol%eq.) (4mL), dropwised in 20 minutes.Heat after 0.5 hour, being warming up to refluxes continues to react 12 hours, 19F NMR and TLC demonstration react completely.Filter, rotary evaporation removes and desolvates, then recrystallization, or column chromatography for separation, with normal hexane and ethyl acetate (5: 1/V: be that eluent gets pyrrole derivative 1 V), 4-phenylbenzene-3-hydroxyl-4-fluoro-2-minaline ethyl ester (0.309g, 0.95mmol), productive rate: 95.0%.White solid, fusing point 150-152 ℃.
1H?NMR(CDCl 3)δ＝1.00(3H，t，J?7.1Hz)，4.11(2H，q，J?7.1Hz)，7.15-7.32(10H，m)，8.37(1H，s).
19F?NMR(CDCl 3)δ＝-174.7(s).
MS(m/z％)：325(M +，51.9)，279(M +-HOEt，100.00)，252(M +-CO 2Et，3.83).
IR(KBr)：ν＝3335(OH，s)，1660(C＝O，s)，1135-1383(vs，C-F).
Ultimate analysis, calculated value: C, 70.15; N, 4.31; H, 4.92%. measured value: C, 70.26; N, 2.20; H, 4.91%.
Embodiment 8
Synthesizing of 1-phenyl-3-hydroxyl-4-fluoro-5-(2-furyl)-2-minaline ethyl ester.
Under 90 ℃ of conditions of oil bath, with diazonium compound 4, (0.363g, toluene solution 1.0mmol) (1.0mL) slowly are added drop-wise to and contain Rh 4-two fluoro-3-oxos-5-furyl-5-anilino-2-diazonium-Valeric acid ethylester 2(OAc) 4(2mg in toluene solution 0.5mol%eq.) (4mL), dropwised in 20 minutes.Heat after 0.5 hour, being warming up to refluxes continues to react 12 hours, 19F NMR and TLC demonstration react completely.Filter, rotary evaporation removes and desolvates, then recrystallization, or column chromatography for separation, with normal hexane and ethyl acetate (7: 1/V: V) be eluent get pyrrole derivative 1-phenyl-3-hydroxyl-4-fluoro-5-(2-furyl)-2-minaline ethyl ester (0.287g, 0.91mmol), productive rate: 91.0%.Light yellow solid, fusing point 84-86 ℃.
1H?NMR(CDCl 3)δ＝0.94(3H，t，J?7.2Hz)，4.06(2H，q，J?7.2Hz)，5.82(1H，d，J3.5Hz)，6.26(1H，m)，7.19-7.45(6H，m)，8.23(1H，s).
19F?NMR(CDCl 3)δ＝-174.7(s).
MS(m/z％)：315(M +，100.0)，269(M +-HOEt，100.0)，242(M +-CO 2Et，4.35).
IR(KBr)：ν＝3350(OH，s)，1663(C＝O，s)，1125-1324(vs，C-F).
Ultimate analysis, calculated value: C, 64.76; N, 4.44; H, 4.44%. measured value: C, 64.93; N, 4.43; H, 4.68%.
Embodiment 9
Synthesizing of 1-benzyl-3-hydroxyl-4-fluoro-5-phenyl-2-minaline ethyl ester.
Figure C0211164100151
Under 90 ℃ of conditions of oil bath, with diazonium compound 4, (0.387g, toluene solution 1.0mmol) (1.0mL) slowly are added drop-wise to and contain Rh 4-two fluoro-3-oxos-5-benzyl-5-anilino-2-diazonium-Valeric acid ethylester 2(OAc) 4(2mg in toluene solution 0.5mol%eq.) (4mL), dropwised in 20 minutes.Heat after 0.5 hour, being warming up to refluxes continues to react 8 hours, 19F NMR and TLC demonstration react completely.Filter, rotary evaporation removes and desolvates, then recrystallization, or column chromatography for separation, with normal hexane and ethyl acetate (7: 1/V: V) be eluent get pyrrole derivative 1-benzyl-3-hydroxyl-4-fluoro-5-phenyl-2-minaline ethyl ester (0.315g, 0.93mmol), productive rate: 93.0%.White solid, fusing point 122-127 ℃.
1H?NMR(CDCl 3)δ＝1.16(3H，t，J?7.2Hz)，4.24(2H，q，J?7.2Hz)，5.32(2H，s)，6.26(2H，m)，7.20-7.39(8H，m)，8.27(1H，s).
19F?NMR(CDCl 3)δ＝-174.7(s).MS(m/z％)：315(M +，100.0)，269(M +-HOEt，100.0)，242(M +-CO 2Et，4.35).
IR(KBr)：ν＝3350(OH，s)，1663(C＝O，s)，1125-1324(vs，C-F).
Ultimate analysis, calculated value: C, 64.76; N, 4.44; H, 4.44%. measured value: C, 64.93; N, 4.43; H, 4.68%.

Claims (7)

1. polysubstituted β-single fluoro azoles is characterized in that having following structural formula:
Figure C021116410002C1
R wherein 1Or R 2=C 1-5Alkyl, α-, and betanaphthyl, the 2-furyl, benzyl replaces or unsubstituted phenyl ZAr-Z=H, C 1-4Alkyl, X or W, Y=OR, NRR`, wherein X is a halogen, W is OR, NH 2, NHR, NHCOR, NRR` or NO 2R or R` are C 1-4Alkyl.
2. the preparation method of polysubstituted according to claim 1 β-single fluoro azoles is characterized in that being made by following method:
1) in organic solvent, in the presence of the molecular sieve and under 0 ℃-30 ℃, imines R 2CH=NHR 1, XCF 2COCH 2COY, zinc powder and CuX reaction obtained molecular formula in 2-48 hour and are
R 2CH (NHR 1) CF 2COCH 2The α of COY, α-two fluoro ketone compounds, wherein imines, XCF 2COCH 2The mol ratio of COY, zinc powder and CuX is 1～1.1: 1～1.1: 2.0: 0.3-1.0, XCF 2COCH 2The ratio of COY and molecular sieve is that 1 mmole restrains than 0-1;
2) in organic solvent and under 0 ℃-30 ℃, molecular formula is R 2CH (NHR 1) CF 2COCH 2The α of COY, α-two fluoro ketone compounds is with the benzene or the naphthalene sulfonyl nitrine Z-ArSO that replace or do not replace 2N 3Be respectively 1.0 with the mol ratio of alkali: 0.8-1.2: 0.8-3.0, react 1-6 hour generation α-diazonium carbonyl compound R 2CH (NHR 1) CF 2COC (N 2) COY, described alkali is organic amine compound or the monovalence metal inorganic alkali that contains lone-pair electron on the nitrogen-atoms;
3) in organic solvent and under 80 ℃-110 ℃, molecular formula is R 2CH (NHR 1) CF 2COC (N 2) α-diazonium carbonyl compound of COY and the mol ratio of organic rhodium catalyst be 1.0: 0.001-0.1, react and generated polysubstituted β-single fluoro azoles in 8-16 hour; Above-mentioned R 1, R 2, Y, X and Z according to claim 1.
3. the preparation method as polysubstituted β-single fluoro azoles as described in the claim 2 is characterized in that described reaction 1) in, XCF 2COCH 2The ratio of COY and molecular sieve is that 1 mmole restrains than 0.1-1.
4. preparation method as polysubstituted β-single fluoro azoles as described in the claim 2, it is characterized in that described reaction 2) in, the organic amine compound that contains lone-pair electron on the described nitrogen-atoms is benzyl lauryl amine, triethylamine, Tributylamine, trioctylamine, pyridine, bipyridine, 1,8-diazacyclo [4.3.0]-5-nonene, 4-(N, the N-dimethyl)-and pyridine or 1,4-diazacyclo [2.2.2] octane.
5. the preparation method as polysubstituted β-single fluoro azoles as described in the claim 2 is characterized in that described reaction 2) in, described monovalence metal inorganic alkali is the carbonate or the supercarbonate of monovalence metal.
6. the preparation method as polysubstituted β-single fluoro azoles as described in the claim 2 is characterized in that described reaction 3) in, molecular formula is R 2CH (NHR 1) CF 2COC (N 2) α-diazonium carbonyl compound of COY and the mol ratio of catalyzer be 1.0: 0.002-0.005.
7. the preparation method as polysubstituted β-single fluoro azoles as described in the claim 2 is characterized in that described reaction 3) in, described organic rhodium catalyst is acetic acid rhodium Rh 2(OAc) 4, butanic acid rhodium Rh 2(OOCC 3H 7) 4, uncle's rhodium butyrate Rh 2(OOC (CH 3) 3) 4, caproic acid rhodium Rh 2(OOCC 5H 11) 4, trifluoracetic acid rhodium Rh 2(OOCCF 3) 4Or perfluorobutyric acid rhodium Rh 2(OOCC 3F 7) 4
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