Synthesis method of alpha-fluoropyridine acetate compound containing propargyl

Abstract

The invention discloses a synthesis method of a chiral propargyl-containing alpha-fluoro-substituted pyridine acetate compound, which comprises the following steps: in an organic solvent, under the catalysis of a nickel / copper bimetallic system and in the presence of alkali, carrying out asymmetric propargylation reaction on an alpha-fluoro-substituted pyridine acetate compound I and a propargyl alcohol ester compound II to obtain the chiral propargyl-containing alpha-fluoro-substituted pyridine acetate compound with high yield. The chiral propargyl-containing alpha-fluoro-substituted pyridine acetate compound III is obtained through high enantiomer and diastereomer selectivity, and has good functional group tolerance; the nickel catalytic system is composed of metal nickel and a chiral ligand, and the chiral ligand has a structure as shown in a formula IV; the copper catalyst system is composed of a copper salt and a chiral ligand, and the chiral ligand has a structure as shown in a formula V.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds. Background Art

[0002] Fluorine atoms are widely used in organic chemistry due to their unique electronic properties and stability. Their introduction can significantly change the physical properties, reactivity and biological activity of molecules. α-Fluorine-substituted pyridine acetate, as a fluorine-containing pyridine derivative, may play an important role in regulating enzyme activity and receptor binding in organisms. The pyridine ring itself has good biological activity, and the introduction of fluorine atoms at its α position may enhance the compound's ability to bind to specific receptors, thereby enhancing its potential as a drug candidate molecule. Therefore, the study of its derivatization has important academic and application value.

[0003] In recent years, transition metal-catalyzed asymmetric propargylation has become an important tool for constructing new complex molecules, with advantages such as high step economy and high reaction efficiency. Through the combination of chiral ligands and metals, multiple chiral centers can be precisely controlled in a single-step reaction, achieving efficient asymmetric construction of the core skeleton of natural products.

[0004] Therefore, the transition metal-catalyzed asymmetric propargylation reaction for the derivatization of α-fluoro-substituted pyridine acetates not only has the potential for high efficiency and selectivity, but also has important application value and methodological significance. However, the realization of this reaction still faces certain challenges. Summary of the invention

[0005] In order to overcome the shortcomings of the prior art, one of the purposes of the present invention is to provide a method for synthesizing a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound. The present invention uses commonly used metal nickel and copper salts as metal precursors and commercially available chiral ligands to form a catalytic system to achieve the synthesis of a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound.

[0006] The technical solution of the present invention is as follows:

[0007] A method for synthesizing a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound comprises the following steps:

[0008] In an organic solvent, an α-fluorine-substituted pyridine acetate compound I and a propargyl alcohol ester compound II are subjected to an asymmetric propargylation reaction under the catalysis of a nickel / copper bimetallic system in the presence of a base to obtain a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound III; the nickel catalyst system is composed of metallic nickel and a chiral ligand, and the chiral ligand has a structure shown in formula IV; the copper catalyst system is composed of a copper salt and a chiral ligand, and the chiral ligand has a structure shown in formula V.

[0009]

[0010] Wherein in compound I, R1 is methyl, cyano, methoxy, trifluoromethyl, etc.;

[0011] In compound II, R2 is C1-C4 alkyl, phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalene-2-yl, etc.; R3 is methyl, phenyl, 4-methylthiophenyl, 4-methoxyphenyl, thiophene-2-yl, etc.; R4 is methoxycarbonyl, tert-butyloxycarbonyl, benzoyl, etc.;

[0012] In compound III, substituent R1 is the same as R1 in compound I; substituent R2 is the same as R2 in compound II, and substituent R3 is the same as R3 in compound II;

[0013] In compound IV, substituent R6 is phenyl, naphth-1-yl, tert-butyl, cyclohexyl, furan-2-yl, etc.; R7 is tert-butyl, phenyl, cyclohexyl, 4-trifluoromethylphenyl, etc.;

[0014] In compound V, the substituent R8 is phenyl, methyl, ethyl, isopropyl or the like.

[0015] Preferably according to the present invention, the solvent is 1,4-dioxane, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, dichloromethane or tetrahydrofuran; the solvent concentration is 0.02-0.2 mol / L; and the solvent is anhydrous.

[0016] Preferably according to the present invention, the copper catalyst is a copper catalyst in which a copper salt and a chiral ligand V are in situ complexed, and the copper salt is copper tetrafluoroborate tetraacetonitrile; the molar ratio of the copper catalyst to the α-fluoro-substituted pyridine acetate compound I is 0.01-0.2:1; and the molar ratio of the copper salt in the copper catalyst to the chiral ligand V is 1:1.

[0017] Preferably according to the present invention, the nickel catalyst is a nickel catalyst in which metallic nickel and a chiral ligand IV are in situ complexed, and the metallic nickel is bis(1,5-cyclooctadiene)nickel; the molar ratio of the nickel catalyst to the propargyl alcohol ester compound II is 0.01 to 0.1:1; and the molar ratio of the metallic nickel to the chiral ligand IV in the nickel catalyst is 1:1.

[0018] Preferably, according to the present invention, the molar ratio of the sodium formate to the α-fluoro-substituted pyridine acetate compound I is 0.1-5:1; the molar ratio of the compound of formula I to the compound of formula II is 1:0.5-3.

[0019] Preferably, according to the present invention, the metal catalyst is prepared according to the following method: under nitrogen protection, the metal and the chiral ligand are added to tetrahydrofuran, and stirred at room temperature for 20 to 40 minutes, and the obtained solution is the metal catalyst system.

[0020] Preferably according to the present invention, the propargylation reaction is carried out under an inert gas atmosphere, wherein the inert gas is nitrogen; the reaction temperature is 10 to 60° C.; and the reaction time is 24 to 72 hours.

[0021] According to the present invention, after the propargylation reaction of α-fluoro-substituted pyridine acetate compound I and propargyl alcohol ester compound II occurs, the product can be separated and characterized by a conventional separation and purification method. The specific post-reaction treatment steps are as follows: the reaction solution is filtered, spin-dried, and separated by silica gel column chromatography to obtain a chiral propargyl α-fluoro-substituted pyridine acetate compound III, the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the mixed solvent of ethyl acetate and petroleum ether in the mixed solvent is 0.05-0.5:1.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention uses α-fluorine-substituted pyridine acetate compounds I substituted with different substituents and propargyl alcohol ester compounds II substituted with different substituents as raw materials, combines the allenyl intermediate obtained by nickel catalysis with the enolate anion intermediate obtained by copper catalysis, and realizes the asymmetric propargylation reaction of α-fluorine-substituted pyridine acetate and propargyl alcohol ester by bimetallic catalysis. The present invention obtains a series of chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds with good yield, excellent diastereoselectivity and enantioselectivity under mild reaction conditions, and has the advantages of convenient operation, wide application range of substrates, cheap and easy-to-obtain catalysts, etc. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with specific implementation modes, but is not limited thereto.

[0025] Meanwhile, the experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents, materials and equipment described are all commercially available unless otherwise specified.

[0026] The yields described in the examples are molar yields.

[0027] The reaction route is as follows:

[0028] Example 1

[0029]

[0030] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetrafluoroborate copper tetraacetonitrile and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 1b (122.5 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 1a (50.7 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 1c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.125:1), and the yield was 83%.

[0031] The characterization data of the obtained product 1c are as follows:

[0032] White solid (>20:1dr, 99%ee)

[0033] 1 H NMR(400MHz, CDCl3)δ:8.62(d,J=4.3Hz,1H),7.46(td,J=7.8,1.6Hz,1H),7.18 –7.03(m,7H),5.07(dq,J=31.0,2.4Hz,1H),3.87(s,3H),1.86(d,J=2.4Hz,3H);

[0034] 13 C NMR(101MHz, CDCl3)δ:168.69,168.43,154.78,154.50,148.83,136.77,135.44,129.86, 127.75,127.40,123.44,120.62,120.52,99.97,98.00,76.16,53.31,44.55,44.35,3.87;

[0035] 19 F NMR(377MHz, CDCl3)δ:-175.28.

[0036] Example 2

[0037]

[0038] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetrafluoroborate copper tetraacetonitrile and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 2b (131.0 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 1a (50.7 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 2c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.11:1), and the yield was 81%.

[0039] The characterization data of the obtained product 2c are as follows:

[0040] White solid (12:1dr,>99%ee)

[0041] 1 H NMR(400MHz, CDCl3)δ:8.63(d,J=4.7Hz,1H),7.50(td,J=7.9,1.7Hz,1H),7.19–7.13(m,2H),7.02(t,J=9.0H z,2H),6.89(d,J=7.9Hz,2H),5.04(dq,J=31.1,2.4Hz,1H),3.88(s,3H),2.20(s,3H),1.86(d,J=2.4Hz,3H);

[0042] 13 C NMR(101MHz, CDCl3)δ:168.83,168.57,154.90,154.63,148.84,137.05,136.83,132.42,129.76, 128.54,123.45,120.75,120.65,100.07,98.10,80.21,76.38,53.34,44.20,44.01,21.12,3.93;

[0043] 19 F NMR(377MHz, CDCl3)δ:-175.22.

[0044] Example 3

[0045]

[0046] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetraacetonitrile copper tetrafluoroborate and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 3b (156.2 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 1a (50.7 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 3c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.11:1), and the yield was 69%.

[0047] The characterization data of the obtained product 3c are as follows:

[0048] White solid (15:1dr, 99%ee)

[0049] 1 H NMR(400MHz, CDCl3)δ:8.62(d,J=4.2Hz,1H),7.46(td,J=7.8,1.6Hz,1H),7.17–7.04( m,6H),5.05(dq,J=31.0,2.3Hz,1H),3.86(s,3H),1.85(d,J=2.4Hz,3H),1.19(s,9H);

[0050] 13 C NMR(101MHz, CDCl3)δ:168.81,168.55,154.84,154.57,150.20,148.76,136.67,132.26,129.47,124 .69,123.45,120.78,120.69,100.08,98.11,80.14,76.38,53.28,44.08,43.88,34.40,31.31,3.89;

[0051] 19 F NMR(377MHz, CDCl3)δ:-174.91.

[0052] Example 4

[0053]

[0054] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetraacetonitrile copper tetrafluoroborate and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 4b (169.9 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 1a (50.7 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 4c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.11:1), and the yield was 80%.

[0055] The characterization data of the obtained product 4c are as follows:

[0056] White solid (19:1dr, 99%ee)

[0057] 1 H NMR(400MHz, CDCl3)δ:8.61(d,J=4.7Hz,1H),7.51(td,J=7.8,1.7Hz,1H),7.22–7.12 (m,4H),7.03(d,J=7.6Hz,2H),5.13–5.00(m,1H),3.85(s,3H),1.85(d,J=2.4Hz,3H);

[0058] 13 C NMR(101MHz, CDCl3)δ:168.46,168.20,154.45,154.17,148.91,137.02,134.61,131.60,130 .91,123.64,121.60,120.66,120.56,99.72,97.75,80.79,75.66,53.39,43.86,43.67,3.84;

[0059] 19 F NMR(377MHz, CDCl3)δ:-175.54.

[0060] Example 5

[0061]

[0062] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetraacetonitrile copper tetrafluoroborate and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 5b (122.5 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 1a (50.7 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 5c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.125:1), and the yield was 54%.

[0063] The characterization data of the obtained product 5c are as follows:

[0064] Yellow liquid (19:1dr,>99%ee)

[0065] 1 H NMR (400MHz, CDCl3) δ: 8.65 (d, J = 4.7Hz, 1H), 7.77 (td, J = 7.8, 1.7Hz, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.4 4–7.38(m,2H),7.32–7.24(m,4H),4.26(dq,J=29.2,7.1Hz,1H),3.80(s,3H),1.12(d,J=7.1Hz,3H);

[0066] 13 C NMR(101MHz, CDCl3)δ:168.98,168.71,154.79,154.52,149.47,137.19,131.88,128.26,128.08,123.75,12 3.35,120.92,120.82,99.82,97.87,88.59,83.06,77.48,77.16,76.84,53.21,33.38,33.18,14.34,14.30;

[0067] 19 F NMR(377MHz, CDCl3)δ:-176.26.

[0068] Example 6

[0069]

[0070] Under nitrogen atmosphere, tetrahydrofuran solution of bis(1,5-cyclooctadiene)nickel and Josiphos SL-J002-1, tetraacetonitrile copper tetrafluoroborate and (S,S)-Ph-BPE were stirred at room temperature for 30 minutes. Pre-complexed nickel catalyst, 1b (122.5 mg, 0.6 mmol) were added to a 20 ml reaction bottle and stirred at room temperature for 10 minutes. Pre-complexed copper catalyst, sodium formate (61.2 mg, 0.9 mmol), 6a (59.8 mg, 0.3 mmol) were added to the reaction bottle in sequence and reacted at room temperature for 60 hours. The reaction solution was filtered and dried, and the target product 6c was separated by silica gel column chromatography. The eluent was ethyl acetate and petroleum ether (volume ratio was 0.3:1), and the yield was 71%.

[0071] The characterization data of the obtained product 6c are as follows:

[0072] Yellow liquid (18:1dr,99%ee)

[0073] 1 H NMR(400MHz, CDCl3)δ:8.40(d,J=5.5Hz,1H),7.20–7.04(m,5H),6.66-6.59(m,2H) ),5.05(dq,J=31.1,2.3Hz,1H),3.87(s,3H),3.61(s,3H),1.85(d,J=2.2Hz,3H);

[0074] 13 C NMR(101MHz, CDCl3)δ:168.64,168.38,166.33,156.49,156.22,150.01,135.48,129.89,127.77 ,127.39,110.14,106.48,106.37,99.90,97.93,80.25,76.19,55.21,53.33,44.38,44.19,3.87;

[0075] 19 F NMR(377MHz, CDCl3)δ:-174.57.

[0076] The above are only some embodiments of the present invention, and do not limit the present invention in any form. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention are within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound, comprising the following steps: In an organic solvent, an α-fluorine-substituted pyridine acetate compound I and a propargyl alcohol ester compound II are subjected to an asymmetric propargylation reaction under the catalysis of a nickel / copper bimetallic system in the presence of a base to obtain a chiral propargyl-containing α-fluorine-substituted pyridine acetate compound III; the nickel catalyst system is composed of metallic nickel and a chiral ligand, and the chiral ligand has a structure shown in formula IV; the copper catalyst system is composed of a copper salt and a chiral ligand, and the chiral ligand has a structure shown in formula V. Wherein in compound I, R1 is methyl, cyano, methoxy, trifluoromethyl, etc.; In compound II, R2 is C1-C4 alkyl, phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalene-2-yl, etc.; R3 is methyl, phenyl, 4-methylthiophenyl, 4-methoxyphenyl, thiophene-2-yl, etc.; R4 is methoxycarbonyl, tert-butyloxycarbonyl, benzoyl, etc.; In compound III, substituent R1 is the same as R1 in compound I; substituent R2 is the same as R2 in compound II, and substituent R3 is the same as R3 in compound II; In compound IV, substituent R6 is phenyl, naphth-1-yl, tert-butyl, cyclohexyl, furan-2-yl, etc.; R7 is tert-butyl, phenyl, cyclohexyl, 4-trifluoromethylphenyl, etc.; In compound V, the substituent R8 is phenyl, methyl, ethyl, isopropyl or the like.

2. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: In compound I, R1 is methyl, cyano, methoxy, trifluoromethyl, etc.; in compound II, R2 is C1~C4 alkyl, phenyl, 4-methylphenyl, 4-chlorophenyl, naphthalen-2-yl, etc.; R3 is methyl, phenyl, 4-methylthiophenyl, 4-methoxyphenyl, thiophen-2-yl, etc.; R4 is methoxycarbonyl, tert-butoxycarbonyl, benzoyl, etc.; in compound III, the substituent R1 is the same as R1 in compound I; the substituent R2 is the same as R2 in compound II, and the substituent R3 is the same as R3 in compound II.

3. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The solvent is 1,4-dioxane, 2-methyltetrahydrofuran, ethyl acetate, N,N-dimethylacetamide, dichloromethane or tetrahydrofuran; the solvent concentration is 0.02-0.2 mol / L; and the solvent is treated with anhydrous solvent.

4. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The copper catalyst is a copper catalyst in which a copper salt and a chiral ligand V are in situ complexed, and the copper salt is copper tetrafluoroborate tetraacetonitrile; the molar ratio of the copper catalyst to the α-fluoro-substituted pyridine acetate compound I is 0.01-0.2:1; and the molar ratio of the copper salt in the copper catalyst to the chiral ligand V is 1:

1.

5. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The nickel catalyst is a nickel catalyst in which metal nickel and a chiral ligand IV are in situ complexed, and the metal nickel is bis(1,5-cyclooctadiene)nickel; the molar ratio of the nickel catalyst to the propargyl alcohol ester compound II is 0.01-0.1:1; and the molar ratio of the metal nickel to the chiral ligand IV in the nickel catalyst is 1:

1.

6. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The molar ratio of the sodium formate to the α-fluoro-substituted pyridine acetate compound I is 0.1-5:1; the molar ratio of the compound of formula I to the compound of formula II is 1:0.5-3.

7. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The metal catalyst is prepared according to the following method: under nitrogen protection, metal and chiral ligand are added into tetrahydrofuran, and stirred at room temperature for 20 to 40 minutes, and the obtained solution is a metal catalyst system.

8. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The propargylation reaction is carried out under an inert gas atmosphere, wherein the inert gas is nitrogen.

9. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: The temperature of the propargylation reaction is 10-60° C. and the reaction time is 24-72 hours.

10. The method for synthesizing chiral propargyl-containing α-fluorine-substituted pyridine acetate compounds according to claim 1, characterized in that: After the propargylation reaction of α-fluoro-substituted pyridine acetate compound I and propargyl alcohol ester compound II, the product can be separated and characterized by conventional separation and purification methods. The specific post-reaction treatment steps are as follows: the reaction solution is filtered, spin-dried, and separated by silica gel column chromatography to obtain chiral propargyl α-fluoro-substituted pyridine acetate compound III, the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of the mixed solvent of ethyl acetate and petroleum ether in the mixed solvent is 0.05-0.5:1.

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