CN112159389A - Preparation method of difluoro-ketone carbonyl substituted nitrile compound - Google Patents

Preparation method of difluoro-ketone carbonyl substituted nitrile compound Download PDF

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CN112159389A
CN112159389A CN202011182396.8A CN202011182396A CN112159389A CN 112159389 A CN112159389 A CN 112159389A CN 202011182396 A CN202011182396 A CN 202011182396A CN 112159389 A CN112159389 A CN 112159389A
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吴范宏
郑程
吴晶晶
吴平杰
付晓艺
叶斌斌
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Shanghai Institute of Technology
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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    • B01J31/16Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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    • C07C253/00Preparation of carboxylic acid nitriles
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    • C07C253/00Preparation of carboxylic acid nitriles
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00Carboxylic acid nitriles
    • C07C255/01Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
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Abstract

The invention relates to a preparation method of difluoro ketone carbonyl substituted nitrile compounds, which comprises the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound, which is shown as the following formula:
Figure DDA0002750536170000011
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle. Compared with the prior art, the method has the advantages of high efficiency, short reaction time, high yield and the like, has better industrial production prospect, and the prepared difluoro ketone carbonyl substituted nitrile compound has good physiological activity and better application potential in the fields of medicines and pesticides.

Description

Preparation method of difluoro-ketone carbonyl substituted nitrile compound
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of a difluoro ketone carbonyl substituted nitrile compound.
Background
After the fluorine atom or the fluorine-containing group is introduced into the organic compound molecule, the physical property, the chemical property and the physiological property (such as lipophilicity, metabolic stability, binding capacity with target protein, cell membrane penetrability and bioavailability) of the organic compound are obviously improved compared with the parent molecule. It is well known that cyano groups are readily converted to other functional groups and have wide utility in the field of synthetic methodology. Therefore, the use of low toxicity cyanide-containing compounds to accomplish the cyanated difluorination of alkynes has attracted the attention of chemists.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for preparing the difluoroketone carbonyl substituted nitrile compound, which has the advantages of high efficiency, short reaction time, high yield, better industrial production prospect, good physiological activity and better application potential in the fields of medicines and pesticides.
The purpose of the invention can be realized by the following technical scheme:
a method for preparing difluoro ketone carbonyl substituted nitrile compounds comprises the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound shown as the following formula:
Figure BDA0002750536160000011
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle.
Further, when R is1When the substituted phenyl is substituted, the substituent in the substituted phenyl is selected from one or more of phenyl, hydrogen, fluorine, bromine, chlorine, C1-C4 alkyl, nitro, methoxy or trifluoromethyl.
Further, when R is2When the substituent is substituted phenyl, the substituent is selected from any one or more of hydrogen, fluorine, bromine, chlorine, nitro, methoxy, C1-C4 alkyl, trifluoromethyl, benzyl, ester group, nitrile group or phenyl.
Further, the catalyst comprises Cu (CH)3CN)4PF6
Further, the ligand comprises 2,2':6', 2' -Terpyrdine (alpha, alpha-Terpyridine).
Further, the radical initiator includes Lauroyl Peroxide (LPO); the solvent comprises CH3OH。
Further, the molar ratio of the compound of formula (1), the compound of formula (2), the compound of formula (3), the catalyst, the ligand and the radical initiator is 0.3:0.45:0.6:0.03:0.06: 0.75.
Further, the reaction temperature is 65-70 ℃, preferably 70 ℃ and the reaction time is 4-6h, preferably 5 h.
Further, the extraction is carried out by adopting an extraction liquid, the extraction liquid comprises ethyl acetate and water in a volume ratio of (0.8-1):1, the volume ratio of the extraction liquid to the reaction liquid is 1: (1-1.5), and the extraction times are 3-4 times.
Further, the separation is carried out in a chromatographic column by using an eluent, wherein the eluent is n-hexane and ethyl acetate with the volume ratio of (30-500) to 1, preferably (30-50) to 1, and the elution time is 2-5 h.
Compared with the prior art, the preparation method has the advantages of short reaction time, lower reaction temperature, high yield and the like, and has better industrial production prospect: the difluoro ketone carbonyl substituted nitrile compound prepared by the invention has a brand new structure, has good physiological activity and can be used as a universal building block for various organic synthesis reactions.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
This example synthesized (E) -4, 4-difluoro-5-oxo-2, 5-diphenylpent-2-enenitrile
Figure BDA0002750536160000031
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, which were weighed in advance, were charged into the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, firstly decompressing and carrying out rotary distillation to remove the methanol, after the rotary distillation, using petroleum ether: column chromatography with methanol (60-20):1 eluent gave 70.5mg (83% yield) of pale yellow oily liquid.
1H NMR(500MHz,CDCl3):7.83(d,J=10.0Hz,2H),7.61(t,J=7.5Hz, 1H),7.45–7.39(m,3H),7.35-7.29(m,4H),6.89(t,J=12.5Hz,1H).
13C NMR(125MHz,CDCl3):186.27(t,2'JC-F=30.0Hz),135.41(t,2JC-F= 26.9Hz),134.81,131.04,130.60,130.43,129.80(t,3'JC-F=3.1Hz),128.77,128.70, 126.67,124.57(t,3JC-F=7.5Hz),117.47,113.91(t,1JC-F=251.3Hz).
19F NMR(376MHz,CDCl3):-90.76(d,J=15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]=for C17H11F2NO:306.0701,found: 306.0702.
Example 2
This example synthesized (E) -4, 4-difluoro-5- (4-methoxyphenyl) -5-oxo-2-phenylpent-2-enenitrile
Figure BDA0002750536160000032
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; under the protection of nitrogen, 2-difluoro-2-iodo-1- (4-methoxyphenyl) ethan-1-one (0.0936g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, which were weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid, 63.9mg, and yield was 68%.
1H NMR(500MHz,CDCl3):7.85(d,J=10.0Hz,2H),7.41-7.37(m,1H), 7.35–7.32(m,4H),6.91-6.85(m,3H),3.87(s,3H).
13C NMR(125MHz,CDCl3):184.73(t,2'JC-F=29.4Hz),164.87,135.71(t, 2JC-F=26.9Hz),132.49(t,3'JC-F=2.5Hz),130.53,130.47,128.76,128.63,124.19 (t,3JC-F=7.5Hz),123.82,117.60,114.19(t,1JC-F=251.3Hz),114.12,55.64.
19F NMR(376MHz,CDCl3):-90.84(d,J=15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]=for C18H13F2NO2:336.0807,found: 336.0809.
Example 3
This example synthesized (E) -4, 4-difluoro-5- (4-fluorophenyl) -5-oxo-2-phenylpent-2-enenitrile
Figure BDA0002750536160000041
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-1- (4-fluorophenyl) -2-iodoethan-1-one (0.0900g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, previously weighed, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid (64.2 mg, yield 71%).
(E)-4,4-difluoro-5-(4-fluorophenyl)-5-oxo-2-phenylpent-2-enenitrile, purified by flash column chromatography on silica gel(PE/EA=30/1),light yellow oily liquid,64.2mg,71%yield.
1H NMR(500MHz,CDCl3):7.88(dd,J=5.0Hz,2H),7.41(t,J=7.5Hz, 1H),7.35–7.30(m,4H),7.11(t,J=7.5Hz,2H),6.88(t,J=12.5Hz,1H).
13C NMR(125MHz,CDCl3):184.84(t,2'JC-F=30.0Hz),167.64,165.58, 135.06(t,2JC-F=26.9Hz),132.78(dt,J=10.0Hz,3.1Hz),130.63,130.43, 128.72,127.43,124.74(t,3JC-F=8.1Hz),117.39,116.16(d,1'JC-F=21.3Hz), 113.94(t,1JC-F=250.6Hz).
19F NMR(376MHz,CDCl3):-90.62(d,J=11.3Hz,2F),-100.85(m,1F).
HRMS(ESI-TOF)calculated[M+Na]=for C17H10F3NO:324.0607,found: 324.0608.
Example 4
This example synthesized (E) -4, 4-difluoro-5-oxo-2-phenyl-5- (thiophen-2-yl) pent-2-enenitrile
Figure BDA0002750536160000051
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; under the protection of nitrogen, 2-difluoro-2-iodo-1- (thiophen-2-yl) ethan-1-one (0.0864g, 0.3mmol), phenylacetylene (0.0460g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol were weighed in advance, and added to the above 10mL standard reaction tube with a liquid charger; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain a pale yellow oily liquid (71.2 mg, yield 82%).
1H NMR(500MHz,CDCl3):7.84(s,1H),7.79(d,J=5.0Hz,1H),7.42– 7.34(m,5H),7.35(t,J=5.0Hz,1H),6.83(t,J=12.5Hz,1H).
13C NMR(125MHz,CDCl3):179.73(t,2'JC-F=30.6Hz),137.28,137.19, 135.94(t,3'JC-F=4.4Hz),134.85(t,2JC-F=26.3Hz),130.57,130.46,128.88, 128.76(t,4'JC-F=2.5Hz),128.69,124.91(t,3JC-F=7.5Hz),117.47,113.69(t,1JC-F=251.3Hz).
19F NMR(376MHz,CDCl3):-92.22(d,J=15.0Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]=for C15H9F2NOS:312.0265,found: 312.0267.
Example 5
This example synthesized (E) -4, 4-difluoro-5-oxo-5-phenyl-2- (p-tolyl) pent-2-enenitrile
Figure BDA0002750536160000061
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), p-tolylacetylene (0.0523g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain 58.0mg of a pale yellow oily liquid with a yield of 65%.
1H NMR(500MHz,CDCl3):7.84(d,J=5.0Hz,2H),7.61(t,J=7.5Hz, 1H),7.43(t,J=7.5Hz,2H),7.21(d,J=5.0Hz,2H),7.13(d,J=10.0Hz,2H), 6.84(t,J=12.5Hz,1H),2.35(s,3H).
13C NMR(125MHz,CDCl3):186.32(t,2'JC-F=29.4Hz),141.09,134.74, 134.59(t,2JC-F=26.9Hz),131.13,129.79(t,3'JC-F=2.5Hz),129.36,128.77, 128.73,127.58 124.67(t,3JC-F=8.1Hz),117.63,113.95(t,1JC-F=250.0Hz), 21.38.
19F NMR(376MHz,CDCl3):-90.73(d,J=11.3Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]=for C18H13F2NO:320.0857,found: 320.0861.
Example 6
This example synthesized (E) -2- (4-ethylphenyl) -4, 4-difluoro-5-oxo-5-phenylpent-2-enenitrile
Figure BDA0002750536160000071
The preparation method comprises the following steps:
respectively weighing and adding the copper tetracyanamide hexafluorophosphate (0.0112g, 0.03mmol), the alpha, alpha-terpyridine (0.0140 g, 0.06mmol) and the dilauroyl peroxide (0.2290g, 0.75mmol) into a 10mL standard reaction tube, vacuumizing and backfilling with nitrogen for three times; 2, 2-difluoro-2-iodo-1-phenylethane-1-one (0.0846g, 0.3mmol), p-ethylphenylacetylene (0.0586g, 0.45mmol), trimethylsilyl cyanide (0.0595g, 0.6mmol) and 1.5mL of methanol, weighed in advance, were added to the above 10mL standard reaction tube with a liquid charger under nitrogen protection; after the feeding is finished, sealing the mixture by using a sealing film, placing the mixture in an oil bath kettle, gradually raising the temperature to 70 ℃, keeping the temperature and stirring the mixture for about 5 hours, and monitoring the reaction completion by TLC. After the reaction, methanol was removed by rotary evaporation under reduced pressure, and after the rotary evaporation, the product was purified by silica gel (PE/EA: 30/1) column chromatography to obtain 68.2mg of a pale yellow oily liquid with a yield of 73%.
1H NMR(500MHz,CDCl3):7.81(d,J=5.0Hz,2H),7.60(t,J=7.5Hz, 1H),7.42(t,J=7.5Hz,2H),7.22(d,J=5.0Hz,2H),7.15(d,J=5.0Hz,2H), 6.84(t,J=12.5Hz,1H),2.64(q,J=8.3Hz,2H),1.23(t,J=7.5Hz,3H).
13C NMR(125MHz,CDCl3):186.30(t,2'JC-F=29.4Hz),147.34,134.70, 134.62(t,2JC-F=26.9Hz),131.16,129.71(t,3'JC-F=2.5Hz),128.88,128.70, 128.19,127.75,124.67(t,3JC-F=8.1Hz),117.63,113.89(t,1JC-F=250.0Hz), 28.70,15.25.
19F NMR(376MHz,CDCl3):-90.56(d,J=11.3Hz,2F).
HRMS(ESI-TOF)calculated[M+Na]=for C19H15F2NO:334.1014,found: 334.1016。

Claims (10)

1. A method for preparing difluoro ketone carbonyl substituted nitrile compounds is characterized by comprising the following steps: mixing a compound represented by the formula (1) with a catalyst, a ligand, a radical initiator and a solvent, and reacting the mixture in the presence of N2Reacting with a compound shown as a formula (2) and a compound shown as a formula (3) under protection until the reaction is complete, extracting and separating the obtained reaction liquid to obtain a compound shown as a formula (4), namely a difluoro ketone carbonyl substituted nitrile compound, which is shown as the following formula:
Figure FDA0002750536150000011
wherein: r1Is phenyl, substituted phenyl or heterocycle, R2Is phenyl, cyclohexenyl, substituted phenyl or heterocycle.
2. The method of claim 1, wherein R is the number of carbon atoms in the nitrile group1When the substituted phenyl is substituted, the substituent in the substituted phenyl is selected from one or more of phenyl, hydrogen, fluorine, bromine, chlorine, C1-C4 alkyl, nitro, methoxy or trifluoromethyl.
3. The method of claim 1, wherein R is the number of carbon atoms in the nitrile group2When substituted phenyl, the substituent is selected from hydrogen, fluorine, bromine,any one or more of chlorine, nitryl, methoxyl, C1-C4 alkyl, trifluoromethyl, benzyl, ester group, nitrile group or phenyl.
4. The method of claim 1, wherein the catalyst comprises Cu (CH)3CN)4PF6
5. The method as claimed in claim 1, wherein the ligand is 2,2':6',2 "-Terpyrdine.
6. The method of claim 1, wherein the radical initiator comprises lauroyl peroxide; the solvent comprises CH3OH。
7. The method for preparing difluoroketone carbonyl-substituted nitrile compounds as claimed in claim 1, wherein the molar ratio of the compound of formula (1), the compound of formula (2), the compound of formula (3), the catalyst, the ligand and the radical initiator is 0.3:0.45:0.6:0.03:0.06: 0.75.
8. The method for preparing difluoroketone carbonyl-substituted nitrile compounds as claimed in claim 1, wherein the reaction temperature is 65-70 ℃ and the reaction time is 4-6 h.
9. The method according to claim 1, wherein the extraction is performed by using an extraction solution, the extraction solution comprises ethyl acetate and water in a volume ratio of (0.8-1):1, the volume ratio of the extraction solution to the reaction solution is 1: (1-1.5), and the extraction times are 3-4 times.
10. The method for preparing difluoro-ketone carbonyl-substituted nitrile compound as claimed in claim 1, wherein the separation is performed by using an eluent for separation and purification in a chromatographic column, wherein the eluent comprises n-hexane and ethyl acetate in a volume ratio of (30-500):1, and the elution time is 2-5 h.
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Citations (2)

* Cited by examiner, † Cited by third party
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JPH06179646A (en) * 1992-12-15 1994-06-28 Tokuyama Soda Co Ltd Cyanoketone derivative
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