CN112876413B - Preparation and antiviral activity of 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative - Google Patents
Preparation and antiviral activity of 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
Abstract
The invention relates to a preparation method and antiviral activity of a 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative. A process for the preparation of a compound comprising the steps of: dissolving different isoquinoline-1 (2H) -ketone and different 2, 2-difluoro-2-bromoacetate or amide serving as raw materials in cyclohexane, adding a ligand and a palladium catalyst, reacting at 20-150 ℃ for 6-36 hours, separating and purifying a crude product after the reaction is finished, and obtaining the 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoroacetyl derivative. The method has the advantages that: the method has the advantages of simple and easily obtained raw materials, simple operation, high yield, wide substrate application range and easy purification of prepared products. The obtained compounds have good antiviral activity.
Description
(I) technical field
The invention relates to a preparation method and antiviral activity of a 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative.
(II) background of the invention
Isoquinoline-1 (2H) -ketone compounds are important organic structural units and widely exist in various natural products, drug molecules and medical intermediates with biological activity, so that 3-substituted and 4-substituted isoquinoline-1 (2H) -ketone derivatives, particularly researches on preparation methods of the compounds, are rapidly developed due to the rapidly developed hydrocarbon activation reaction in recent years. However, the research on 4-substituted isoquinoline-1 (2H) -ketone compounds mainly focuses on the direct introduction of a series of substituents such as halogen atoms, nitro groups, trifluoromethyl groups, aryl groups, alkynyl groups, thioether groups and the like through a one-step reaction and the introduction of other different groups through a plurality of steps, such as 4-substituted indole isoquinoline-1 (2H) -ketone compounds used for the research on Chemoattactrant receptor antagonists.
Although the previous work describes the synthesis of different 4-substituted isoquinolin-1 (2H) -one compounds, it does not specifically describe the synthesis of the 2- (isoquinolin-1 (2H) -one-4-yl) difluoroacetyl compounds mentioned in this patent, nor the antiviral activity of these compounds.
Disclosure of the invention
The invention aims to provide a preparation method and application of a 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative. The compound of the invention has good antiviral activity to tobacco mosaic virus.
The technical scheme of the invention is as follows:
a preparation method of 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivatives comprises the following steps: the method comprises the following steps of taking simple and easily obtained substituted isoquinoline-1 (2H) -ketone shown in a general formula 1 and a general formula 2 as initial raw materials, and carrying out coupling reaction under the mediation of potassium carbonate and a palladium catalyst to obtain the 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative shown in a general formula 3. The reaction equation is as follows:
the present invention is a compound of the following formula 3:
wherein R is 1 Is H,6-Cl,6-Br,7-Cl,6-CH 3 O;R 2 Is CH 3 、C 2 H 5 、CH(CH 3 ) 2 、CH 3 CHC 2 H 5 And R 4 R 5 C 6 H 3 ;R 3 Is C 2 H 5 O、morpholinyl、NHCH 2 CO 2 CH 3 ;R 4 Is H, 2-Cl,2-CH 3 、2-F、3-CH 3 O、3-Cl、3-CH 3 、4-CH 3 O、4-Cl、4-F、4-CH 3 、4-NH 2 ;R 5 Is H, 3-CH 3 。
The compound of the general formula 3 has the function of resisting tobacco mosaic virus. The compound of the invention has good inhibitory activity to tobacco mosaic virus under the dosage of 500 mg/L.
Detailed Description
The essential features of the invention can be seen from the following examples, which should not be construed as limiting the invention in any way.
Example 1:
n-methylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.6 mmol), xantphos (9 mol%), tetrakis (triphenylphosphine) palladium (2 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 28 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3a. The yield thereof was found to be 51%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J=9.0Hz,1H),7.79(d,J=8.1Hz,1H),7.68(t,J=7.7Hz,1H),7.59-7.49(m,2H),4.31(q,J=7.1Hz,2H),3.66(s,3H),1.28(t,J=7.1Hz,3H)。
Example 2:
N-Ethylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.2 mmol), xantphos (15 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added sequentially to a pressure resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3b. The yield thereof was found to be 45%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.47(dd,J=8.1,1.0Hz,1H),7.79(d,J=8.0Hz,1H),7.67(t,J=7.7Hz,1H),7.58-7.47(m,2H),4.30(q,J=7.1Hz,2H),4.10(q,J=7.2Hz,2H),1.40(t,J=7.2Hz,3H),1.26(t,J=7.1Hz,3H)。
Example 3:
n-isopropylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3c. The yield thereof was found to be 80%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.50(d,J=8.1Hz,1H),7.81(d,J=8.2Hz,1H),7.73-7.65(m,1H),7.55(dd,J=13.9,5.8Hz,2H),5.41-5.35(m,1H),4.32(q,J=7.1Hz,2H),1.43(d,J=6.9Hz,6H),1.29(t,J=7.1Hz,3H)。
Example 4:
n-phenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.6 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3d. The yield thereof was found to be 89%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J=8.1Hz,1H),7.86(d,J=8.2Hz,1H),7.74(t,J=7.6Hz,1H),7.66(s,1H),7.63-7.50(m,1H),7.46(t,J=6.8Hz,1H),4.34(t,J=10.6Hz,1H),1.30(t,J=6.3Hz,1H)。
Example 5:
6-methoxy-N-isopropylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (3.0 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 150 ℃ for 20 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3e. The yield thereof was found to be 68%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.40(d,J=9.0Hz,1H),7.56(s,1H),7.21(s,1H),7.09(dd,J=9.0,2.4Hz,1H),5.36(m,,1H),4.32(q,J=7.1Hz,2H),3.91(s,3H),1.42(d,J=6.9Hz,6H),1.29(t,J=7.1Hz,3H)。
Example 6:
6-chloro-N-isopropylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3f. The yield thereof was found to be 78%. Yellow solid. Melting point 113.2-115.3 ℃. 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J=8.6Hz,1H),7.84(s,1H),7.59(s,1H),7.48(d,J=8.6Hz,1H),5.41-5.27(m,1H),4.36(q,J=7.1Hz,2H),1.43(d,J=6.8Hz,6H),1.33(t,J=7.1Hz,3H).
Example 7:
6-bromo-N-isopropylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.5 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3g. The yield thereof was found to be 71%. Yellow solid. Melting point 118.6-119.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.31(d,J=8.6Hz,1H),7.98(s,1H),7.61(d,J=8.6Hz,1H),7.55(s,1H),5.36-5.27(m,1H),4.33(q,J=7.1Hz,2H),1.39(d,J=6.8Hz,6H),1.30(t,J=7.1Hz,3H).
Example 8:
7-chloro-N-isopropylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.6 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product for 3h. The yield thereof was found to be 57%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.46(d,J=1.6Hz,1H),7.78(d,J=8.7Hz,1H),7.62(dd,J=8.7,1.7Hz,1H),7.54(s,1H),5.41-5.29(m,1H),4.32(q,J=7.1Hz,2H),1.42(d,J=6.8Hz,6H),1.29(t,J=7.1Hz,3H).
Example 9:
n-sec-butylisoquinolin-1 (2H) -one (0) was sequentially added to the pressure-resistant reaction tube at room temperature.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL). The reaction mixture was then reacted at 130 ℃ for 15 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3i. The yield thereof was found to be 80%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.49(d,J=8.0Hz,1H),7.81(d,J=8.1Hz,1H),7.68(t,J=7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.48(s,1H),5.28-5.08(m,1H),4.30(q,J=7.1Hz,3H),1.89-1.65(m,3H),1.37(dd,J=16.7,7.1Hz,4H),1.28(dd,J=16.2,9.1Hz,4H),0.89(t,J=7.3Hz,4H).
Example 10:
6-methoxy-N-sec-butylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (4 mol%) and cyclohexane (1.0 mL) were added sequentially to a pressure resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3j. The yield thereof was found to be 80%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 ) δ 8.40 (d, J =9.0hz, 1h), 7.48 (s, 1H), 7.21 (s, 1H), 7.10 (dd, J =9.0,2.3hz, 1h), 5.27-5.06 (m, 1H), 4.31 (q, J =7.1hz, 2h), 3.91 (s, 3H), 1.88-1.64 (m, 3H), 1.39 (d, J =6.9hz, 4h), 1.28 (t, J =7.1hz, 3h), 0.89 (t, J =7.4hz, 3h), example 11:
6-chloro-N-sec-butylisoquinolin-1 (2H) -one (0.2 mmol), difluoro (E) were added sequentially to a pressure-resistant reaction tube at room temperatureEthyl bromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (20 mol%) and cyclohexane (1.0 mL). The reaction mixture was then reacted at 20 ℃ for 36 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3k. The yield thereof was found to be 75%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.41(d,J=8.7Hz,1H),7.83(s,1H),7.56-7.41(m,2H),5.26-5.03(m,1H),4.33(q,J=7.1Hz,3H),1.87-1.66(m,2H),1.39(d,J=6.8Hz,3H),1.30(q,J=6.9Hz,3H),0.88(t,J=7.4Hz,3H).
Example 12:
6-bromo-N-sec-butylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (13 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3l. The yield thereof was found to be 72%. Yellow solid. Melting point 109.7-111.3 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.47(d,J=2.1Hz,1H),7.79(d,J=8.8Hz,1H),7.63(dd,J=8.8,2.0Hz,1H),7.48(s,1H),5.51-4.72(m,1H),4.32(q,J=7.1Hz,2H),1.86-1.71(m,2H),1.41(d,J=6.8Hz,3H),1.28(t,J=7.1Hz,3H),0.90(t,J=7.4Hz,3H).
Example 13:
7-chloro-N-sec-butylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), and potassium carbonate (0) were sequentially added to a pressure-resistant reaction tube at room temperature.4 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL). The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product of 3m. The yield thereof was found to be 63%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.34(d,J=8.6Hz,1H),8.01(s,1H),7.64(dd,J=8.6,1.7Hz,1H),7.50(s,1H),5.26-5.05(m,1H),4.35(q,J=7.1Hz,2H),1.85-1.70(m,2H),1.40(d,J=6.9Hz,4H),1.32(t,J=7.1Hz,4H),0.89(t,J=7.4Hz,4H).
Example 14:
n-p-chlorophenyl isoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3n. The yield thereof was found to be 93%. Yellow solid. Melting point 123.2-125.1 deg.C. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=8.1Hz,1H),7.85(d,J=8.1Hz,1H),7.74(t,J=7.7Hz,1H),7.63-7.56(m,2H),7.54-7.47(m,2H),7.43-7.38(m,2H),4.34(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).
Example 15:
at room temperature, in a pressure resistant reaction tube were added N-m-chlorophenyl isoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.6 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane in that order(1.0 mL). The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3o. The yield thereof was found to be 78%. Yellow solid. Melting point 115.6-116.9 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J=7.9Hz,1H),7.85(d,J=8.1Hz,1H),7.75(t,J=7.5Hz,1H),7.65-7.57(m,2H),7.53-7.43(m,3H),7.36(d,J=6.9Hz,1H),4.35(q,J=7.0Hz,2H),1.30(t,J=7.1Hz,3H).
Example 16:
n-m-methylphenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (5 mol%), tetrakis (triphenylphosphine) palladium (1 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 150 ℃ for 6 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3p. The yield thereof was found to be 63%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J=8.0Hz,1H),7.85(d,J=8.1Hz,1H),7.74(t,J=7.7Hz,1H),7.64(s,1H),7.59(t,J=7.6Hz,1H),7.42(t,J=7.7Hz,1H),7.30-7.21(m,3H),4.34(q,J=7.1Hz,2H),2.44(s,3H),1.30(t,J=7.1Hz,3H).
Example 17:
n-m-methoxyphenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.3 mmol), potassium carbonate (0.4 mmol), xantphos (16 mol%), tetrakis (triphenylphosphine) palladium (25 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 29 hours.Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing by using mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3q. The yield thereof was found to be 69%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J=8.0Hz,1H),7.85(d,J=8.2Hz,1H),7.74(t,J=7.7Hz,1H),7.64(s,1H),7.59(t,J=7.6Hz,1H),7.43(t,J=7.9Hz,1H),7.12-6.95(m,3H),4.34(q,J=7.1Hz,2H),3.86(s,3H),1.30(t,J=7.1Hz,3H).
Example 18:
n-o-fluorophenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (15 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3q. The yield thereof was found to be 61%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J=8.0Hz,1H),7.87(d,J=8.2Hz,1H),7.75(t,J=7.7Hz,1H),7.60(t,J=7.6Hz,1H),7.55(s,1H),7.53-7.41(m,2H),7.36-7.24(m,3H),4.34(q,J=7.0Hz,2H),1.30(t,J=7.1Hz,3H).
Example 19:
n-p-fluorophenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.1 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. Then the reaction mixture is reacted for 20 hours at 100 DEG (2. The reaction is stopped, the crude product is obtained by concentration under reduced pressure, finally petroleum ether and acetic acid are usedWashing with mixed eluent of ethyl ester, and performing flash column chromatography to obtain the target product 3s. The yield thereof was found to be 91%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=8.0Hz,1H),7.85(d,J=8.2Hz,1H),7.74(t,J=7.7Hz,1H),7.64-7.55(m,2H),7.49-7.40(m,2H),7.22(t,J=8.5Hz,2H),4.34(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).
Example 20:
n-o-chlorophenyl isoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.6 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain target product 3t. The yield thereof was found to be 65%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.45(d,J=7.5Hz,1H),7.81(d,J=8.1Hz,1H),7.69(t,J=7.1Hz,1H),7.56-7.49(m,2H),7.44-7.35(m,4H),4.26(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).
Example 21:
n-o-methylphenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 24 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3u. The yield thereof was found to be 54%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.53(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.75(t,J=7.7Hz,1H),7.59(t,J=7.6Hz,1H),7.50(s,1H),7.44-7.34(m,3H),7.27(d,J=8.1Hz,2H),4.33(q,J=7.0Hz,2H),2.18(s,3H),1.29(t,J=7.0Hz,3H).
Example 22:
N-p-Methylphenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.2 mmol), potassium carbonate (0.4 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3v. The yield thereof was found to be 89%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.58(d,J=7.5Hz,1H),7.91(d,J=8.2Hz,1H),7.78(t,J=7.1Hz,1H),7.69(s,1H),7.63(t,J=7.6Hz,1H),7.38(s,4H),4.39(q,J=7.1Hz,2H),2.49(s,3H),1.35(t,J=7.1Hz,3H).
Example 23:
n-p-methoxyphenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (18 mol%), tetrakis (triphenylphosphine) palladium (20 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 80 ℃ for 30 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3w. The yield thereof was found to be 93%. Yellow solid. Melting point 117.6-118.7 deg.C. 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J=8.0Hz,1H),7.85(d,J=8.2Hz,1H),7.72(t,J=7.6Hz,1H),7.62(s,1H),7.57(t,J=7.6Hz,1H),7.35(d,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),4.34(q,J=7.1Hz,2H),3.87(s,3H),1.30(t,J=7.1Hz,3H).
Example 24:
n-p-cyanophenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (10 mol%), tetrakis (triphenylphosphine) palladium (5 mol%) and cyclohexane (1.0 mL) were successively added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 110 ℃ for 24 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3x. The yield thereof was found to be 95%. Yellow solid. Melting point 125.3-125.9 deg.C. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=8.0Hz,1H),7.91-7.80(m,3H),7.77(t,J=7.6Hz,1H),7.71-7.56(m,4H),4.35(q,J=7.0Hz,2H),1.30(t,J=7.1Hz,3H).
Example 25:
n-p-aminophenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (11 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3y. The yield thereof was found to be 95%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J=8.0Hz,1H),7.85(d,J=8.1Hz,1H),7.75(t,J=7.7Hz,1H),7.68-7.58(m,2H),7.55-7.43(m,3H),7.36(d,J=7.0Hz,1H),4.35(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).
Example 26:
7-chloro-N-p-methoxyphenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.46 mmol), potassium carbonate (0.5 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 140 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3w. The yield thereof was found to be 70%. Yellow solid. Melting point 125.5-127.2 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.68(s,1H),8.02(d,J=8.8Hz,1H),7.87(dd,J=8.7,1.9Hz,1H),7.81(s,1H),7.54(d,J=8.7Hz,2H),7.23(d,J=8.7Hz,2H),4.54(q,J=7.1Hz,2H),4.07(s,3H),1.51(t,J=7.1Hz,3H).
Example 27:
n- (3, 4-dimethylphenyl) isoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3aa. The yield thereof was found to be 64%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.52(d,J=8.0Hz,1H),7.85(d,J=8.1Hz,1H),7.73(t,J=7.7Hz,1H),7.63(s,1H),7.57(t,J=7.6Hz,1H),7.31-7.24(m,1H),7.21(s,1H),7.16(d,J=7.9Hz,1H),4.34(q,J=7.1Hz,2H),2.33(s,6H),1.30(t,J=7.1Hz,3H).
Example 28:
at room temperature, 6-methoxy-N-p-chlorophenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.48 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3ab. The yield thereof was found to be 76%. Yellow solid. Melting point 118.5-119.3 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.25(d,J=9.0Hz,1H),7.42(s,1H),7.33(d,J=8.6Hz,2H),7.23(d,J=8.6Hz,2H),7.08(s,1H),6.97(dd,J=9.0,2.0Hz,1H),4.18(q,J=7.1Hz,2H),3.77(s,3H),1.14(t,J=7.1Hz,3H).
Example 29:
at room temperature, 6-chloro-N-p-methoxyphenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3ac. The yield thereof was found to be 67%. Yellow solid. Melting point 123.7-125.1 deg.C. 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J=8.5Hz,1H),7.87(s,1H),7.64(s,1H),7.51(d,J=8.3Hz,1H),7.33(d,J=8.4Hz,2H),7.02(d,J=8.4Hz,2H),4.36(q,J=6.9Hz,2H),3.86(s,3H),1.33(t,J=6.9Hz,3H)。
Example 30:
7-chloro-N-phenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (9 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain the target product 3ad. The yield thereof was found to be 87%. Yellow solid. Melting point 107.6-108.4 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.49(d,J=2.3Hz,1H),7.84(d,J=8.8Hz,1H),7.68(dd,J=8.8,2.3Hz,1H),7.63(s,1H),7.58-7.51(m,2H),7.51-7.40(m,3H),4.34(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H).
Example 31:
6-methoxy-N-phenylisoquinoline-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.6 mmol), xantphos (30 mol%), tetrakis (triphenylphosphine) palladium (10 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 110 ℃ for 28 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain the target product 3ae. The yield thereof was found to be 91%. Yellow solid. Melting point 113.2-114.9 deg.C. 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J=9.0Hz,1H),7.64(s,1H),7.57-7.49(m,2H),7.48-7.41(m,3H),7.26(s,1H),7.13(dd,J=9.0,2.4Hz,1H),4.34(q,J=7.1Hz,2H),3.93(s,3H),1.30(t,J=7.1Hz,3H).
Example 32:
6-chloro-N-phenylisoquinolin-1 (2H) -one (0.2 mmol), ethyl difluorobromoacetate (0.6 mmol), potassium carbonate (0.5 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 150 ℃ for 10 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain the target product 3af. The yield thereof was found to be 89%. Yellow solid. Melting point 107.9-109.3 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.45(d,J=8.6Hz,1H),7.89(s,1H),7.67(s,1H),7.57-7.53(m,3H),7.50-7.40(m,3H),4.37(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).
Example 33:
n-p-chlorophenyl isoquinolin-1 (2H) -one (0.2 mmol), 2b (0.6 mmol), potassium carbonate (0.5 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3ag. The yield thereof was found to be 60%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=7.5Hz,1H),7.77-7.65(m,2H),7.59(t,J=7.5Hz,1H),7.54-7.45(m,3H),7.43-7.35(m,2H),3.99-3.50(m,8H).
Example 34:
sequentially adding the raw materials into a pressure-resistant reaction tube at room temperatureN-p-methoxyphenylisoquinolin-1 (2H) -one (0.2 mmol), 2b (0.8 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL). The reaction mixture was then reacted at 150 ℃ for 6 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product of 3ah. The yield thereof was found to be 67%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=8.0Hz,1H),7.76-7.69(m,2H),7.57(t,J=5.9Hz,1H),7.49(s,1H),7.36-7.29(m,2H),7.06-6.98(m,2H),3.87(s,3H),3.84-3.66(m,8H).
Example 35:
n-p-fluorophenylisoquinolin-1 (2H) -one (0.2 mmol), 2b (0.8 mmol), potassium carbonate (0.6 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure resistant reaction tube at room temperature. The reaction mixture was then reacted at 130 ℃ for 20 hours. Stopping reaction, concentrating under reduced pressure to obtain a crude product, washing with mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3ai. The yield thereof was found to be 57%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J=7.6Hz,1H),7.77-7.66(m,2H),7.62-7.56(m,1H),7.47(s,1H),7.43-7.38(m,2H),7.25-7.18(m,2H),3.87-3.70(m,8H)。
Example 36:
6-chloro-N-phenylisoquinolin-1 (2H) -one (0.2 mmol), 2b (0.8 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 130 ℃ for 10 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, and finallyThen flushing with mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain the target product 3aj. The yield thereof was found to be 63%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.45(d,J=8.7Hz,1H),7.65(s,1H),7.57-7.50(m,4H),7.50-7.44(m,1H),7.44-7.38(m,2H),3.79(m,8H).
Example 37:
6-chloro-N-p-methoxyphenylisoquinolin-1 (2H) -one (0.2 mmol), 2b (0.4 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3ak. The yield thereof was found to be 41%. White solid. Melting point 132.7-133.5 ℃. 1 H NMR(400MHz,CDCl 3 )δ8.43(d,J=8.7Hz,1H),7.65(s,1H),7.54-7.48(m,2H),7.35-7.28(m,2H),7.05-6.98(m,2H),3.86(s,3H),3.85-3.70(,4H).
Example 38:
n-p-methoxyphenylisoquinoline-1 (2H) -one (0.2 mmol), 2c (0.2 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were sequentially added to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping reaction, decompressing and concentrating to obtain a crude product, finally washing by using mixed eluent of petroleum ether and ethyl acetate, and carrying out flash column chromatography to obtain a target product 3al. The yield thereof was found to be 45%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J=8.0Hz,1H),7.86(d,J=8.2Hz,1H),7.74-7.68(m,1H),7.61(s,1H),7.55(t,J=7.6Hz,1H),7.33(d,J=8.9Hz,2H),7.14(s,1H),6.99(d,J=8.9Hz,2H),4.13(d,J=5.3Hz,2H),3.84(s,3H),3.74(s,3H)。
Example 39:
n-p-fluorophenylisoquinolin-1 (2H) -one (0.2 mmol), 2c (0.6 mmol), potassium carbonate (0.4 mmol), xantphos (20 mol%), tetrakis (triphenylphosphine) palladium (15 mol%) and cyclohexane (1.0 mL) were added in this order to a pressure-resistant reaction tube at room temperature. The reaction mixture was then reacted at 100 ℃ for 20 hours. Stopping the reaction, concentrating under reduced pressure to obtain a crude product, finally washing with a mixed eluent of petroleum ether and ethyl acetate, and performing flash column chromatography to obtain a target product 3am. The yield thereof was found to be 44%. A yellow liquid. 1 H NMR(400MHz,CDCl 3 )δ8.48(d,J=8.1Hz,1H),7.87(d,J=8.3Hz,1H),7.73(t,J=7.8Hz,1H),7.60(s,0H),7.56(t,J=7.6Hz,1H),7.45-7.37(m,2H),7.18(t,J=8.5Hz,1H),7.11(s,1H),4.14(d,J=5.3Hz,2H),3.75(s,3H).
Example 40: antiviral activity
Selecting 3-5 leaf-period Saxismoke with uniform growth, mixing the medicament with virus juice of the same volume, inactivating for 30 minutes, performing friction inoculation with virus concentration of 20 microgram/ml, washing with running water after inoculation, repeating for 3 times, and setting 1 ‰ Tween 80 water solution as control. After 3 days, the number of virus plaques was counted and the results were calculated.
Inhibition (%) = [ (number of control scorched spots-number of treated scorched spots)/number of control scorched spots ]. Times.100%
Table 1: anti-tobacco mosaic virus test result (inhibition rate/%) (treatment dose 500 mg/L) of compound 3
A: isoquinolin-1 (2H) -ones.
Claims (8)
1. A process for preparing 2- (isoquinolin-1 (2H) -one-4-yl) difluoroacetyl derivatives features that the compounds of general formulas 1 and 2 are used as initial raw material and the reaction is carried out at Pd (Ph) 3 P) 4 、Xantphos、K 2 CO 3 Heating in cyclohexane in the presence of a solvent to perform a coupling reaction to obtain a 2- (isoquinoline-1 (2H) -ketone-4-yl) difluoro acetyl derivative shown as a general formula 3, wherein the reaction formula is as follows:
wherein R is 1 Is H,6-Cl,6-Br,7-Cl,6-CH 3 O;R 2 Is CH 3 ,C 2 H 5 ,CH(CH 3 ) 2 ,CH 3 CHC 2 H 5 Phenyl, substituted phenyl: the substituent of the substituted phenyl is 2-Cl,2-CH 3 ,2-F,3-CH 3 O,3-Cl,3-CH 3 ,4-CH 3 O,4-Cl,4-F,4-CH 3 ,4-NH 2 ,3,4-(CH 3 ) 2 ;R 3 Is C 2 H 5 O, morpholinyl, NHCH 2 CO 2 CH 3 。
2. The process for the preparation of 2- (isoquinolin-1 (2H) -on-4-yl) difluoroacetyl derivatives according to claim 1, characterized by comprising the following operating steps: the starting material was dissolved in cyclohexane and then Pd (Ph) was added 3 P) 4 、Xantphos、K 2 CO 3 Reacting for 6-36 hours at 20-150 ℃.
3. The process for producing a 2- (isoquinolin-1 (2H) -on-4-yl) difluoroacetyl derivative as claimed in claim 1, wherein the crude product is subjected to extraction, column chromatography separation and purification after the reaction is terminated.
4. The process for producing 2- (isoquinolin-1 (2H) -one-4-yl) difluoroacetyl derivatives as claimed in claim 1, wherein the general formula 1 is Pd (Ph) 3 P) 4 The molar ratio of the compounds is 1: 0.01-1: 0.2.
5. The process for preparing 2- (isoquinolin-1 (2H) -on-4-yl) difluoroacetyl derivatives as claimed in claim 1, characterized in that the molar ratio between the compounds of general formula 1 and Xantphos is from 1: 0.05 to 1: 0.30.
6. The process for preparing 2- (isoquinolin-1 (2H) -one-4-yl) difluoroacetyl derivatives as claimed in claim 1, wherein the general formulae 1 and K 2 CO 3 The molar ratio of the compounds is 1: 0.5-1: 3.0.
7. The process for producing a 2- (isoquinolin-1 (2H) -on-4-yl) difluoroacetyl derivative as claimed in claim 1, wherein the molar ratio of the compounds of the general formulae 1 and 2 is 1: 0.5 to 1: 4.0.
8. Use of a compound of formula 3 according to claim 1, characterized by its use against tobacco mosaic virus.
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CN111362933A (en) * | 2017-05-16 | 2020-07-03 | 南开大学 | α -amino acrylic acid microbicide and preparation method and application thereof |
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