CN105859622B - The method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazolone derivatives - Google Patents
The method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazolone derivatives Download PDFInfo
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Abstract
A kind of method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazoline ketone compounds, using the chiral diphosphine complex of palladium as catalyst, under the conditions of 50-100 DEG C, hydrogen atmosphere, 800-1400psi, in organic solvent, synthesis of chiral fluoro pyrazolone derivatives；The mass ratio of the material example of substrate and catalyst is 25/l-100/l, and the hydrogenation of fluoro pyrazoles alcohol can obtain corresponding chiral pyrazol quinoline ketones derivant, and enantiomeric excess can reach 96%.Operation of the present invention is simple and practical, and raw material is easy to get, and enantioselectivity is good, and yield is high, and reaction has the features such as green, Atom economy, environmentally friendly.
Description
Technical field
The invention belongs to organic synthesis fields, are related to a kind of method of synthesis of chiral fluoro pyrazolone derivatives, tool
Body is related to a kind of method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazolone derivatives.
Technical background
Chiral fluoro pyrazolone and its derivative are a kind of heterocyclic compounds with extensive physiology and pharmacological activity,
With very high researching value and application prospect.This kind of compound has a variety of potential pharmaceutical activity, such as: anticancer, anti-inflammatory, town
The characteristics such as quiet, sleeping and anti-alzheimer's disease.Medicine is caused to the structure and bioactivity research of this kind of compound for many years
The attention of educational circles.
Other than as drug, chiral fluoro pyrazolone and its derivative are also used as chiral auxiliaries and chiral reagent to exist
It is obtained in Synthetic Organic Chemistry and successfully applies (document: a) E.Gould, T.Lebl, A.M.Z.Slawin, M.Reid,
A.D.Smith,Tetrahedron 2010,66,8992；b)G.Ma,J.Deng,M.P.Sibi,
Angew.Chem.Int.Ed.2014,53,11818.)。
In view of the importance of fluoro pyrazolone and its derivative in drug and synthesis chemical field, and the choosing of mapping at present
The method of such compound of the synthesis of selecting property is still fewer, and therefore, we attempt to realize the equal of fluoro pyrazoles alcohol derivatives
Phase asymmetric hydrogenation.
Summary of the invention
The object of the present invention is to provide a kind of high enantioselectivities of palladium chtalyst asymmetric hydrogenation fluoro pyrazoles alcohol derivatives
The method of synthesis of chiral pyrazolone derivative, operation of the present invention is simple and practical, and raw material is easy to get, and enantioselectivity is good, and yield is high,
And reaction has green Atom economy, advantages of environment protection.
To achieve the above object, technical scheme is as follows:
A kind of method of palladium chtalyst asymmetric hydrogenation fluoro pyrazoles alcohol derivatives synthesis of chiral pyrazolone derivative, with
The chiral diphosphine complex of palladium is as catalyst, under the conditions of 50-100 DEG C, hydrogen atmosphere, 800-1400psi, in organic solvent
In, synthesis of chiral fluoro pyrazolone derivatives；
The structural formula of reactant fluoro pyrazoles alcohol derivatives are as follows:
The structural formula of product chirality fluoro pyrazolone derivatives are as follows:
Wherein, Ar is phenyl or the phenyl containing substituent group, and the substituent group on phenyl is-CF3、-Me、-MeO、-COOMe、-
One of COOEt ,-F ,-Cl or-Br or two kinds, substituent group number are 1~5, and substituent group is identical or different；
The R is H, C1-C20Alkyl；
The RfFor fluorine-containing C1-C20Alkyl, molecular formula CnF2n+1, n=1-20 integer；
" * " indicates chiral centre or asymmetric center.
The organic solvent is selected from ethyl acetate, methylene chloride, trifluoroethanol, toluene, one of tetrahydrofuran or two
Kind or more mixing；
The dosage of the organic solvent is that every mM of reactant is added 8-16 milliliters；
Catalyst the mass ratio of the material example of substrate and catalyst in hydrogenation synthetic reaction system is 25/1-100/l；
Reaction time is 20-48 hours.
The catalyst by palladium metal precursor and chiral diphosphine ligand in organic solvent, nitrogen or argon gas protection
Under, after being stirred at room temperature 30 minutes to 1 hour, excessive organic solvent vacuum is taken away, catalyst is made；
The metal precursor of palladium is trifluoracetic acid palladium (Pd (OCOCF3)2), chiral diphosphine ligand is (S)-MeO-Biphep,
(S)-SynPhos, (S)-SegPhos, (S)-BINAP, (S, S ', R, R ')-TangPhos, and (1S, 1S ', 2R, 2R ')-
One of DuanPhos；
L1:(S)-BINAP
L2:(S)-MeO-Biphep
L3:(S)-SynPhos
L4:(1S,1S’,2R,2R’)-DuanPhos
L5:(S,S’,R,R’)-TangPhos
L6:(S)-SegPhos。
The organic solvent used in catalyst for preparing is acetone, ethyl acetate, methylene chloride, trifluoroethanol, first
Benzene, one or more of tetrahydrofuran；
In catalyst preparation system: the molar ratio of trifluoracetic acid palladium and chiral diphosphine ligand is 1/1.1-1/1.5, trifluoro
The mass percent that palladium acetate and chiral diphosphine ligand amount to is 1-5%, remaining is organic solvent.
The R is H, C1-C20Alkyl；
The RfFor fluorine-containing C1-C20Alkyl, molecular formula CnF2n+1, n=1-20 integer.
Bronsted acid is added in reaction process, bronsted acid is selected from trifluoroacetic acid, p-methyl benzenesulfonic acid monohydrate, benzene
The molar ratio of formic acid, one of L- camphorsulfonic acid, D- camphorsulfonic acid, bronsted acid additional amount and reactant is 0.5:1-2:
1, after reaction, extra acid is washed off with alkaline salt solution again in reaction system, and alkaline salt solution is selected from sodium carbonate liquor, carbonic acid
Hydrogen sodium solution, sodium hydroxide solution.
Catalyst is the complex of trifluoracetic acid palladium and (S)-MeO-Biphep or (R, R ', S, S ')-TangPhos, and Ar is
Phenyl, Rf CF3Or C2F5, R is hydrogen or C1-C20Alkyl, Hydrogen Vapor Pressure 1200psi, solvent be methylene chloride or trifluoro second
When alcohol, as a result most preferably, enantiomeric excess can reach 96%.
The invention has the following advantages that
1. reactivity and enantioselectivity are high, fully reacting, generation product is single-minded, and nucleus magnetic hydrogen spectrum does not detect secondary anti-
It answers, convenient separation, high enantiomeric excess sterling can be obtained.
2. a plurality of types of chiral fluoro pyrazolone derivatives, such as aryl, 4- alkyl or H on the position 2- can be obtained
Equal substituted substrate can have very high enantioselectivity and cis-selectivity.
3. catalyst preparation is convenient, operation is simple and practical.
4. comparing prior synthesizing method, a large amount of chiral fluoro pyrazoles are just can be obtained using a small amount of chiral catalyst in the method
Quinoline ketones derivant realizes chiral increment, and substrate spectrum is more extensive.
5. operation of the present invention is simple and practical, raw material is easy to get, and enantioselectivity is good, and yield is high, and reacts with green, atom
Economy, it is environmentally friendly the features such as.
Specific embodiment
The present invention is described in detail below by embodiment；But the present invention is not limited to following embodiments.
Embodiment 1: the optimization of condition
In a reaction flask full of nitrogen, trifluoracetic acid palladium (0.006 mM, 2.0 milligrams) and chiral diphosphine is added
Ligand (0.0066 mM), adds the acetone that 1mL newly distills, and is stirred at room temperature 30-60 minutes, then takes out solvent in vacuo
It walks.In glove box, the above-mentioned catalyst prepared is transferred to another Fluoride for Raw Material that is equipped with for pyrazoles alcohol derivatives with needle tubing
(wherein, Ar is phenyl, R H, R to 1afFor CF3) (0.3 mM) reaction flask in, share 2mL methylene chloride and/or three
Fluoroethanol adds bronsted acid (0.3 mM).Reaction flask is put into the autoclave of a stainless steel, is passed through hydrogen
1200psi reacts 24-48 hours at room temperature.Saturation Na is added in slow release hydrogen, system2CO3Aqueous solution stirs 10 minutes, and
After adopt and be extracted with dichloromethane three times, merge organic phase and drying, remove directly column chromatography (elution after solvent with Rotary Evaporators
The volume ratio of agent petroleum ether and methylene chloride is the isolated pure product of 1:1-1:2).
Reaction equation:
Chiral diphosphine ligand are as follows:
In formula
L1:(S)-BINAP
L2:(S)-MeO-Biphep
L3:(S)-SynPhos
L4:(1S,1S’,2R,2R’)-DuanPhos
L5:(S,S’,R,R’)-TangPhos
Yield is separation yield, and the enantiomeric excess of product is measured with Chiral liquid chromatography, is shown in Table 1.
The conditional filtering of 1. asymmetric hydrogenation fluoro pyrazoles alcohol derivatives of table
Note:[1]Reaction 48 hours.
Embodiment 2: the disubstituted fluoro pyrazoles alcohol derivatives of palladium chtalyst asymmetric hydrogenation
In a reaction flask full of nitrogen, trifluoracetic acid palladium (0.006 mM, 2.0 milligrams) and chiral diphosphine is added
Ligand (0.0066 mM), adds the acetone that 1mL newly distills, and is stirred at room temperature 30-60 minutes, then takes out solvent in vacuo
It walks.In glove box, the above-mentioned catalyst prepared is transferred to another Fluoride for Raw Material that is equipped with for pyrazoles alcohols derivative with syringe
In the reaction flask of object (0.3 mM), 2mL methylene chloride or trifluoroethanol are shared, adds bronsted acid (0.3 milli
Mole).Reaction flask is put into the autoclave of a stainless steel, is passed through hydrogen 1200psi, is reacted 24-48 hours at 60 DEG C.Slowly
Saturation Na is added in On The Drug Release hydrogen, system2CO3Aqueous solution stirs 10 minutes, then adopts and is extracted with dichloromethane three times, is associated with
Machine phase and drying, directly (volume ratio of eluent petroleum ether and methylene chloride is column chromatography after removing solvent with Rotary Evaporators
1:1-1:2) isolated pure product, reaction equation are as follows:
The disubstituted fluoro pyrazoles alcohol derivatives of 2. asymmetric hydrogenation of table
Note:[1]Pd(OCOCF3)2(4mol%), (S)-MeO-Biphep (4.2mol%), 1b (0.2mmol), H2
(1200psi),TFA(0.2mmol)；[2]Pd(OCOCF3)2(4mol%), and (S, S ', R, R ')-TangPhos (5.2mol%), 1i
or 1j(0.2mmol),H2(1200psi),L-CSA(0.2mmol),TFE(2mL),100℃,48h。
Embodiment 3: palladium chtalyst asymmetric hydrogenation three replaces fluoro pyrazoles alcohol derivatives
In a reaction flask full of nitrogen, trifluoracetic acid palladium (0.008 mM, 2.7 milligrams) and chiral ligand is added
(0.0104 mM) adds the acetone that 1mL newly distills, is stirred at room temperature 30-60 minutes, then takes solvent in vacuo away.?
In glove box, the above-mentioned catalyst prepared is transferred to another Fluoride for Raw Material that is equipped with for pyrazoles alcohol derivatives (0.2 milli with needle tubing
Mole) reaction flask in, share 2mL methylene chloride and/or trifluoroethanol, add bronsted acid (0.2 mM).
Reaction flask is put into the autoclave of a stainless steel, is passed through hydrogen 1200psi, is reacted 24-48 hours at 100 DEG C.Slowly release
Saturation Na is added in hydrogen release gas, system2CO3Aqueous solution stirs 10min, then adopts and is extracted with dichloromethane three times, merges organic phase simultaneously
It is dry, with Rotary Evaporators remove after solvent directly column chromatography (volume ratio of eluent petroleum ether and methylene chloride is 1:1-1:
2) isolated pure product, reaction equation are as follows:
3. asymmetric hydrogenation three of table replaces fluoro pyrazoles alcohol derivatives
(S)-2-Phenyl-5-(trifluoromethyl)pyrazolidin-3-one(2a):Pale yellow
solid；Mp=104-105 DEG C, yield 94%, 96%ee, [α]20 D=+20.0 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.77 (d, J=8.1Hz, 2H), 7.36 (t, J=7.9Hz, 2H), 7.16 (t, J=7.4Hz, 1H),
5.15 (d, J=7.3Hz, 1H), 4.13-4.02 (m, 1H), 3.18 (dd, J=17.5,9.7Hz, 1H), 2.84 (dd, J=
17.6,3.1Hz,1H)；13C NMR(100MHz,CDCl3)δ167.5,137.8,128.9,125.4(q,JC-F=278Hz),
125.2,118.9,53.9(q,JC-F=32Hz), 33.7；19F NMR(377MHz,CDCl3)δ-78.4(s,3F)；HRMS
Calculated For C10H10F3N2O[M+H]+231.0745,found:231.0740；HPLC(AD-H,elute:
Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=6.2min (maj), t2=
7.5min.
(+)-2-o-Tolyl-5-(trifluoromethyl)pyrazolidin-3-one(2b):Pale yellow
solid；Mp=104-105 DEG C, yield 67%, 82%ee, [α]20 D=+18.4 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.34-7.25 (m, 4H), 5.17 (d, J=7.4Hz, 1H), 4.15 (d, J=7.1Hz, 1H), 3.23-
3.16(m,1H),2.89–2.83(m,1H),2.30(s,3H)；13C NMR(100MHz,CDCl3)δ167.3,135.4,135.3,
131.3,128.7,126.8,126.4,125.8(q,JC-F=277Hz), 54.4 (q, JC-F=32Hz), 32.3,18.2；19F
NMR(377MHz,CDCl3)δ-78.0(s,3F)；HRMS Calculated For C11H12F3N2O[M+H]+245.0902,
found:245.0896；HPLC (AD-H, elute:Hexanes/i-PrOH=80/20, detector:254nm, flow
rate:0.7mL/min),t1=8.0min (maj), t2=8.8min.
(+)-2-m-Tolyl-5-(trifluoromethyl)pyrazolidin-3-one(2c):Pale yellow
solid；Mp=89-90 DEG C, yield 93%, 95%ee, [α]20 D=+14.4 (c 0.50, CHCl3)；1H NMR(400MHz,
CDCl3) δ 7.57-7.50 (m, 2H), 7.26-7.20 (m, 1H), 6.97 (d, J=7.7Hz, 1H), 5.14 (br, 1H), 4.11-
4.01 (m, 1H), 3.15 (dd, J=17.5,9.7Hz, 1H), 2.82 (dd, J=17.5,3.1Hz, 1H), 2.35 (s, 3H)；13C
NMR(100MHz,CDCl3)δ167.5,138.9,137.7,128.7,126.1,125.5(q,JC-F=278Hz), 119.5,
116.2,53.8(q,JC-F=33Hz), 33.8,21.5；19F NMR(377MHz,CDCl3)δ-78.4(s,3F)；HRMS
Calculated For C11H12F3N2O[M+H]+245.0902,found:245.0896；HPLC(AD-H,elute:
Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=6.3min (maj), t2=
8.4min.
(+)-2-p-Tolyl-5-(trifluoromethyl)pyrazolidin-3-one(2d):Pale yellow
solid；Mp=140-141 DEG C, yield 93%, 96%ee, [α]20 D=+15.0 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.61 (d, J=8.6Hz, 2H), 7.14 (d, J=8.4Hz, 2H), 5.18 (d, J=6.6Hz, 1H),
4.04 (d, J=6.7Hz, 1H), 3.13 (dd, J=17.5,9.7Hz, 1H), 2.79 (dd, J=17.5,3.1Hz, 1H), 2.31
(s,3H)；13C NMR(100MHz,CDCl3)δ167.3,135.3,135.1,129.4,124.6(q,JC-F=278Hz),
119.1,53.9(q,JC-F=33Hz), 33.7,20.9；19F NMR(377MHz,CDCl3)δ-78.5(s,3F)；HRMS
Calculated For C11H12F3N2O[M+H]+245.0902,found:245.0896；HPLC(AD-H,elute:
Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=6.7min (maj), t2=
8.4min.
(+)-2-(4-Methoxyphenyl)-5-(trifluoromethyl)pyrazolidin-3-one
(2e):Pale yellow solid；Mp=122-123 DEG C, yield 94%, 95%ee, [α]20 D=+15.6 (c
0.50,CHCl3)；1H NMR(400MHz,CDCl3) δ 7.66 (d, J=9.1Hz, 2H), 6.90 (d, J=9.1Hz, 2H), 5.11
(d, J=7.6Hz, 1H), 4.13-4.07 (m, 1H), 3.80 (s, 3H), 3.19 (dd, J=17.5,9.7Hz, 1H), 2.85 (dd,
J=17.5,3.1Hz, 1H)；13C NMR(100MHz,CDCl3)δ167.0,157.2,131.0,123.9(q,JC-F=278Hz),
121.1,114.1,55.5,53.9(q,JC-F=33Hz), 33.5；19F NMR(377MHz,CDCl3)δ-78.4(s,3F)；HRMS
Calculated For C11H12F3N2O2[M+H]+261.0851,found:261.0845；HPLC(AD-H,elute:
Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=7.7min (maj), t2=
8.8min.
(+)-2-(3-Chlorophenyl)-5-(trifluoromethyl)pyrazolidin-3-one(2f):Pale
yellow solid；Mp=115-116 DEG C, yield 89%, 95%ee, [α]20 D=+16.6 (c0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.83 (s, 1H), 7.73 (d, J=8.4Hz, 1H), 7.31-7.26 (m, 1H), 7.13 (d, J=
8.0Hz, 1H), 5.16 (d, J=7.4Hz, 1H), 4.16-4.10 (m, 1H), 3.22 (dd, J=17.5,9.7Hz, 1H), 2.87
(dd, J=17.5,3.1Hz, 1H)；13C NMR(100MHz,CDCl3)δ167.9,138.9,134.7,129.9,125.1,
124.5(q,JC-F=278Hz), 118.7,116.6,54.0 (q, JC-F=33Hz), 33.8；19F NMR(377MHz,CDCl3)δ-
78.4(s,3F)；HRMS Calculated For C10H9ClF3N2O[M+H]+265.0356,found:265.0350；HPLC
(AD-H, elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=
6.0min(maj),t2=7.1min.
(+)-2-(3,4-Dichlorophenyl)-5-(trifluoromethyl)pyrazolidin-3-one(2g):
Pale yellow solid；Mp=122-123 DEG C, yield 90%, 93%ee, [α]20 D=+5.8 (c 0.50, CHCl3)；1H
NMR(400MHz,CDCl3) δ 7.93 (d, J=2.5Hz, 1H), 7.70-7.67 (m, 1H), 7.39 (d, J=8.9Hz, 1H),
5.20 (d, J=7.3Hz, 1H), 4.17-4.10 (m, 1H), 3.21 (dd, J=17.7,9.6Hz, 1H), 2.85 (dd, J=
17.7,2.8Hz,1H)；13C NMR(100MHz,CDCl3)δ168.0,137.2,132.8,130.5,128.3,124.3(q,JC-F
=278Hz), 120.1,117.7,54.0 (q, JC-F=33Hz), 33.7；19F NMR(377MHz,CDCl3)δ-78.4(s,3F)；
HRMS Calculated For C10H8Cl2F3N2O[M+H]+298.9966,found:298.9960；HPLC(AD-H,elute:
Hexanes/i-PrOH=85/15, detector:254nm, flow rate:0.7mL/min), t1=9.1min (maj), t2=
10.1min.
(+)-2-(4-Fluorophenyl)-5-(trifluoromethyl)pyrazolidin-3-one(2h):Pale
yellow solid；Mp=111-112 DEG C, yield 93%, 94%ee, [α]20 D=+21.4 (c0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.77-7.73 (m, 2H), 7.07-7.02 (m, 2H), 5.16 (d, J=7.4Hz, 1H), 4.15-4.08
(m, 1H), 3.21 (dd, J=17.6,9.7Hz, 1H), 2.85 (dd, J=17.6,2.8Hz, 1H)；13C NMR(100MHz,
CDCl3)δ167.4,159.9(d,JC-F=245Hz), 133.9,123.6 (q, JC-F=275Hz), 120.8 (d, JC-F=
8.0Hz),115.6(d,JC-F=23Hz), 53.9 (q, JC-F=32Hz), 33.6；19F NMR(377MHz,CDCl3)δ-78.5
(s,3F),116.6(s,1F)；HRMS Calculated For C10H9F4N2O[M+H]+249.0651,found:249.0646；
HPLC (OJ-H, elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1
=6.9min (maj), t2=7.4min.
(-)-5-(Perfluoroethyl)-2-phenylpyrazolidin-3-one(2i):Pale yellow
solid；Mp=120-121 DEG C, yield 95%, 94%ee, [α]20 D=-8.4 (c 0.50, CHCl3)；1H NMR(400MHz,
CDCl3) δ 7.77 (d, J=7.8Hz, 2H), 7.36 (t, J=8.0Hz, 2H), 7.16 (t, J=7.4Hz, 1H), 5.08 (d, J=
7.9Hz, 1H), 4.27-4.17 (m, 1H), 3.16 (dd, J=17.5,9.3Hz, 1H), 2.96 (dd, J=17.4,4.0Hz,
1H)；13C NMR(100MHz,CDCl3)δ167.7,137.80,128.9,125.2,118.7,52.8(dd,JC-F=29.0,
21.8Hz),33.3；19F NMR(377MHz,CDCl3) δ -81.7 (s, 3F) -121.6 (d, J=278Hz), -131.1 (d, J=
278Hz)；HRMS Calculated For C11H10F5N2O[M+H]+281.0713,found:281.0708；HPLC(AD-H,
Elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=5.6min, t2
=7.0min (maj)
(-)-5-(Perfluoroethyl)-2-(p-tolyl)pyrazolidin-3-one(2j):Pale yellow
solid；Mp=153-154 DEG C, yield 92%, 95%ee, [α]20 D=-5.8 (c 0.50, CHCl3)；1H NMR(400MHz,
CDCl3) δ 7.63 (d, J=8.5Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 5.06 (d, J=7.9Hz, 1H), 4.26-4.13
(m, 1H), 3.14 (dd, J=17.4,9.4Hz, 1H), 2.94 (dd, J=17.4,3.9Hz, 1H), 2.32 (s, 3H)；13C NMR
(100MHz,CDCl3) δ 167.4,135.3,135.0,129.4,118.8,52.8 (dd, J=29.0,21.8Hz), 33.2,
20.9；19F NMR(377MHz,CDCl3) δ -81.7 (s, 3F), -121.7 (d, J=278Hz, 1F), -131.0 (d, J=
278Hz,1F)；HRMS Calculated For C12H12F5N2O[M+H]+295.0870,found:295.0864；HPLC(OG-
H, elute:Hexanes/i-PrOH=90/10, detector:254nm, flow rate:0.7mL/min), t1=
14.8min,t2=17.1min (maj)
(-)-4-Methyl-2-phenyl-5-(trifluoromethyl)pyrazolidin-3-one(4a):Pale
yellow solid；Mp=84-85 DEG C, yield 92%, 89%ee, [α]20 D=-28.4 (c0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.79 (d, J=7.8Hz, 2H), 7.36 (t, J=8.0Hz, 2H), 7.15 (t, J=7.4Hz, 1H),
5.02 (d, J=8.8Hz, 1H), 3.77-3.67 (m, 1H), 3.00-2.90 (m, 1H), 1.46 (d, J=7.3Hz, 3H)；13C
NMR(100MHz,CDCl3)δ170.4,137.9,128.9,125.1,124.6(q,JC-F=277Hz), 118.7,61.6 (q,
JC-F=31Hz), 39.9,14.8；19F NMR(377MHz,CDCl3)δ-76.5(s,3F)；HRMS Calculated For
C11H12F3N2O[M+H]+245.0902,found:245.0896；HPLC (AD-H, elute:Hexanes/i-PrOH=70/30,
detector:254nm,flow rate:0.7mL/min),t1=5.5min, t2=6.2min (maj)
(+)-4-Methyl-2-(p-tolyl)-5-(trifluoromethyl)pyrazolidin-3-one(4b):
Pale yellow oil；Yield 97%, 88%ee, [α]20 D=+5.8 (c 0.50, CHCl3)；1H NMR(400MHz,
CDCl3) δ 7.66 (d, J=8.1Hz, 2H), 7.26-7.15 (m, 2H), 4.96 (d, J=8.8Hz, 1H), 3.75-3.68 (m,
1H), 3.00-2.92 (m, 1H), 2.33 (s, 3H), 1.45 (d, J=7.3Hz, 3H)；13C NMR(100MHz,CDCl3)δ
170.1,135.4,134.9,129.4,123.7(q,JC-F=278Hz), 118.8,61.6 (q, JC-F=31Hz), 39.8,
20.9,14.9；19F NMR(377MHz,CDCl3)δ-76.5(s,3F)；HRMS Calculated For C12H14F3N2O[M+H
]+259.1058,found:259.1053；HPLC (AD-H, elute:Hexanes/i-PrOH=70/30, detector:
254nm,flow rate:0.7mL/min),t1=6.0min, t2=6.9min (maj)
(+)-4-Ethyl-2-phenyl-5-(trifluoromethyl)pyrazolidin-3-one(4c):Pale
yellow solid；Mp=58-59 DEG C, yield 93%, 94%ee, [α]20 D=+0.4 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.78 (d, J=7.8Hz, 2H), 7.35 (t, J=8.0Hz, 2H), 7.14 (t, J=7.4Hz, 1H),
5.18 (d, J=7.5Hz, 1H), 3.76-3.71 (m, 1H), 2.76-2.73 (m, 1H), 1.96-1.94 (m, 1H), 1.79-1.75
(m, 1H), 1.08 (t, J=7.4Hz, 3H)；13C NMR(100MHz,CDCl3)δ170.0,137.9,128.8,125.1,124.7
(q,JC-F=278Hz), 119.0,58.5 (q, JC-F=31Hz), 46.3,23.1,11.1；19F NMR(377MHz,CDCl3)δ-
77.7(s,3F)；HRMS Calculated For C12H14F3N2O[M+H]+259.1058,found:259.1053；HPLC
(AD-H, elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=
5.5min,t2=6.4min (maj)
(+)-4-Ethyl-2-p-tolyl-5-(trifluoromethyl)pyrazolidin-3-one(4d):Pale
yellow solid；Mp=90-91 DEG C, yield 92%, 93%ee, [α]20 D=+2.0 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.66 (d, J=8.2Hz, 2H), 7.16 (d, J=8.1Hz, 2H), 5.06 (d, J=7.6Hz, 1H),
3.76–3.72(m,1H),2.79–2.76(m,1H),2.32(s,3H),2.01–1.90(m,1H),1.84–1.78(m,1H),
1.10 (t, J=7.3Hz, 3H)；13C NMR(100MHz,CDCl3)δ169.6,135.4,135.0,129.4,124.6(q,JC-F
=278Hz), 119.0,58.5 (q, JC-F=32Hz), 46.2,23.1,20.9,11.1；19F NMR(377MHz,CDCl3)δ-
77.7(s,3F)；HRMS Calculated For C13H16F3N2O[M+H]+273.1215,found:273.1209；HPLC
(OG-H, elute:Hexanes/i-PrOH=95/5, detector:254nm, flow rate:0.7mL/min), t1=
18.6min,t2=21.8min (maj)
(+)-4-Ethyl-2-m-tolyl-5-(trifluoromethyl)pyrazolidin-3-one(4e):Pale
yellow oil；Yield 90%, 92%ee, [α]20 D=+0.4 (c 0.50, CHCl3)；1H NMR(400MHz,CDCl3)δ
7.63-7.56 (m, 2H), 7.26-7.21 (m, 1H), 6.97 (d, J=7.6Hz, 1H), 5.06 (br, 1H), 3.75 (s, 1H),
2.80-2.75 (m, 1H), 2.36 (s, 3H), 2.00-1.91 (m, 1H), 1.83-1.76 (m, 1H), 1.10 (t, J=7.4Hz,
3H)；13C NMR(100MHz,CDCl3)δ169.8,138.8,137.8,128.7,126.0,124.9(q,JC-F=278Hz),
119.5,116.1,58.5(q,JC-F=31Hz), 46.3,23.1,21.5,11.1；19F NMR(377MHz,CDCl3)δ-77.7
(s,3F)；HRMS Calculated For C13H16F3N2O[M+H]+273.1215,found:273.1209；HPLC(AD-H,
Elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1=5.4min, t2
=6.9min (maj)
(+)-2-Phenyl-4-propyl-5-(trifluoromethyl)pyrazolidin-3-one(4f):Pale
yellow solid；Mp=96-70 DEG C, yield 85%, 93%ee, [α]20 D=+2.6 (c 0.50, CHCl3)；1H NMR
(400MHz,CDCl3) δ 7.80 (d, J=8.3Hz, 2H), 7.36 (t, J=7.9Hz, 2H), 7.15 (t, J=7.4Hz, 1H),
5.08 (br, 1H), 3.77-3.73 (m, 1H), 2.86 (d, J=3.1Hz, 1H), 1.93-1.74 (m, 1H), 1.56-1.54 (m,
1H), 1.55-1.50 (m, 2H), 1.00 (t, J=7.3Hz, 3H)；13C NMR(100MHz,CDCl3)δ170.2,137.9,
128.8,126.4(q,JC-F=278Hz), 125.1,118.9,58.9 (q, JC-F=32Hz), 44.7,31.9,20.1,13.6；19F NMR(377MHz,CDCl3)δ-77.8(s,3F)；HRMS Calculated For C13H16F3N2O[M+H]+273.1215,
found:273.1209；HPLC (AD-H, elute:Hexanes/i-PrOH=70/30, detector:254nm, flow
rate:0.7mL/min),t1=5.6min, t2=7.2min (maj)
(4S,5R)-4-Benzyl-2-phenyl-5-(trifluoromethyl)pyrazolidin-3-one(4g):
Pale yellow solid；Mp=117-118 DEG C, yield 94%, 95%ee, [α]20 D=+122.6 (c 0.50,
CHCl3)；1H NMR(400MHz,CDCl3) δ 7.71 (d, J=8.0Hz, 2H), 7.37-7.25 (m, 7H), 7.15 (t, J=
7.4Hz,1H),4.19(s,1H),3.76–3.73(m,1H),3.37–3.31(m,1H),3.23–3.19(m,1H),3.13-
3.08(m,1H)；13C NMR(100MHz,CDCl3)δ169.4,137.6,136.1,129.1,129.0,128.8,127.7,
125.3,125.2(q,JC-F=279Hz), 119.1,57.7 (q, JC-F=32Hz), 45.7,35.4；19F NMR(377MHz,
CDCl3)δ-77.5(s,3F)；HRMS Calculated For C17H16F3N2O[M+H]+321.1215,found:321.1209；
HPLC (AD-H, elute:Hexanes/i-PrOH=70/30, detector:254nm, flow rate:0.7mL/min), t1
=6.5min (maj), t2=7.1min.
Claims (5)
1. a kind of method of palladium chtalyst asymmetric hydrogenation synthesis of chiral fluoro pyrazolone derivatives, it is characterised in that: with palladium
Chiral diphosphine complex as catalyst, under the conditions of 50-100 DEG C, hydrogen atmosphere, 800-1400psi, in organic solvent
In, synthesis of chiral fluoro pyrazolone derivatives；
The structural formula of reactant fluoro pyrazoles alcohol derivatives are as follows:
The structural formula of product chirality fluoro pyrazolone derivatives are as follows:
Wherein, Ar is phenyl or the phenyl containing substituent group, and the substituent group on phenyl is-CF3、-Me、-MeO、-COOMe、-
One of COOEt ,-F ,-Cl or-Br or two kinds, substituent group number are 1~5, and when substituent group number >=2, substituent group can be with
It is identical to can also be different；
The R is H, C1-C20Alkyl；
The RfFor fluorine-containing C1-C20Alkyl, molecular formula CnF2n+1, n=1-20 integer
Catalyst is the complex of trifluoracetic acid palladium and (S)-MeO-Biphep or (R, R ', S, S ')-TangPhos.
2. the method as described in claim 1, it is characterised in that:
The organic solvent is selected from acetone, ethyl acetate, methylene chloride, trifluoroethanol, toluene, one of tetrahydrofuran or two
Kind or more mixing；
The dosage of the organic solvent is that every mM of reactant is added 8-16 milliliters；
Catalyst the mass ratio of the material example of substrate and catalyst in hydrogenation synthetic reaction system is 25/1-100/l；
Reaction time is 20-48 hours.
3. the method as described in claim 1, it is characterised in that:
The catalyst by palladium metal precursor and chiral diphosphine ligand in organic solvent, nitrogen or argon gas protection under, room temperature
After stirring 30 minutes to 1 hour, excessive organic solvent vacuum is taken away, catalyst is made；
The metal precursor of palladium is trifluoracetic acid palladium (Pd (OCOCF3)2), chiral diphosphine ligand is (S)-MeO-Biphep, (S)-
SynPhos, (S)-SegPhos, (S)-BINAP, (S, S ', R, R ')-TangPhos, in (1S, 1S ', 2R, 2R ')-DuanPhos
One kind；
Described to prepare organic solvent used in catalyst be acetone, ethyl acetate, methylene chloride, trifluoroethanol, toluene, four
One or more of hydrogen furans；
The molar ratio of trifluoracetic acid palladium and chiral diphosphine ligand is 1:1.1-1.5, trifluoracetic acid palladium and chiral diphosphine ligand total amount
Mass percent in catalyst preparation reaction system is 1-5%, remaining is organic solvent.
4. the method as described in claim 1, it is characterised in that:
Bronsted acid is added in reaction process, bronsted acid is selected from trifluoroacetic acid, p-methyl benzenesulfonic acid monohydrate, benzene first
Acid, one of L- camphorsulfonic acid, D- camphorsulfonic acid, the molar ratio of bronsted acid additional amount and reactant are 0.5-2:1, instead
After answering, extra acid is washed off with alkaline salt solution again in reaction system, and alkaline salt solution is selected from sodium carbonate liquor, sodium bicarbonate
Solution, sodium hydroxide solution.
5. the method as described in claim 1, it is characterised in that:
The Ar is phenyl, RfFor CF3Or C2F5, R is hydrogen or C1-C20Alkyl, Hydrogen Vapor Pressure 1200psi, solvent is dichloro
Methane or trifluoroethanol.
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