CN112625056B - Synthetic method of benzoborazole - Google Patents

Synthetic method of benzoborazole Download PDF

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CN112625056B
CN112625056B CN202011587986.9A CN202011587986A CN112625056B CN 112625056 B CN112625056 B CN 112625056B CN 202011587986 A CN202011587986 A CN 202011587986A CN 112625056 B CN112625056 B CN 112625056B
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CN112625056A (en
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李欢
赵婧
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Wenzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of benzoborazole. The compounds shown in the formulas (A) and (B) and the reaction solvent are simple and easy to obtain as raw materials for preparing the benzoborazole by adopting the method; the reaction steps are simple, and the product can be obtained only by one step; the reaction atom economy is high, and the reaction condition is mild; the reaction is suitable for large-scale preparation.

Description

Synthetic method of benzoborazole
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of benzoborazole.
Background
Benzoborazole is a five-membered cyclic arylboronic acid half-ester. Compounds Tavaborole, crisabarole containing the structure of benzoborazole have been approved by the FDA for the treatment of onychomycosis and atopic dermatitis, respectively; the compound SCYX-7158/AN5568 is being used in clinical trials for the treatment of African trypanosomiasis. Such compounds are found to have specific carbohydrate binding properties under physiological conditions. The compounds have been studied extensively in pharmacy and found to possess a variety of biological activities, such as antibacterial, antifungal, antiviral, anti-inflammatory, antiprotozoal, and the like.
At present, a plurality of methods for synthesizing the benzoborazole compound can be summarized into three types. The first is the addition reaction of nucleophilic reagent and o-formyl aryl boric acid, and the nucleophilic reagent includes sodium borohydride, organic zinc reagent, indole, nitro alkane, amine, carbonyl compound, alpha, beta-unsaturated carbonyl compound, allyl nitrile, cyano silane, isonitrile, etc. And the second method is to introduce boric acid/ester group at the ortho position of the aromatic ring carbon unit by means of metallization-boronization or transition metal catalyzed boronization, and then cyclize to obtain the benzoborazole. The third type is an intramolecular oxy-alkene addition reaction of an ortho-alkenyl substituted aryl boronic acid. However, these reactions require the use of relatively complicated arylboron compounds, expensive transition metal catalysts, severe operating conditions or cumbersome operating procedures.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method of benzoborazole.
The technical scheme adopted by the invention is as follows: a synthetic method of benzoborazole is characterized in that a compound shown in the following formula (A) and a compound shown in the following formula (B) are subjected to dehydration condensation reaction in an organic solvent under the condition of a strong acid catalyst to prepare a compound shown in the following formula (C), wherein the reaction formula is as follows:
Figure BDA0002867722930000011
wherein:
R 1 is alkyl or alkoxyHydroxy or halogen;
R 2 is aryl, alkyl, ester group or hydrogen, wherein the aryl is phenyl or phenyl with substituent groups, and the substituent groups on the aryl are alkyl, alkoxy, halogen, cyano, nitro, ester group or alkynyl;
R 3 is aryl, alkyl, ester group or hydrogen, wherein the aryl is phenyl or phenyl with substituent groups, and the substituent groups on the aryl are alkyl, alkoxy, halogen, cyano, nitro, ester group or alkynyl;
the organic solvent is one or more of trichloromethane, dichloromethane, dichloroethane and carbon tetrachloride.
Preferably, the strong acid catalyst is one or more of trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid monohydrate, and a solid acid catalyst.
Preferably, the strong acid catalyst is trifluoroacetic acid, and the molar ratio of the compound represented by the formula (a) to the trifluoroacetic acid is 1.2 to 1.
Preferably, the strong acid catalyst is trifluoromethanesulfonic acid, and the molar ratio of the compound represented by formula (a) to trifluoromethanesulfonic acid is 1.01 to 1:1.
Preferably, the strong acid catalyst is p-toluenesulfonic acid monohydrate, and the molar ratio of the compound represented by the formula (a) to the hydrated p-toluenesulfonic acid monohydrate is 1.
Preferably, the organic solvent is chloroform.
Preferably, the molar concentration of the compound represented by the formula (A) in the solvent is 0.1mol/L.
Preferably, the molar concentration of the compound represented by the formula (B) in the solvent is 0.12 to 0.2mol/L.
Preferably, the reaction temperature is from room temperature to 50 ℃.
The invention has the following beneficial effects: the compounds shown in the formulas (A) and (B) and the reaction solvent are simple and easy to obtain as raw materials for preparing the benzoborazole by adopting the method; the reaction steps are simple, and the product can be obtained only by one step; the reaction atom economy is high, and the reaction condition is mild; the reaction is suitable for large-scale preparation.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1:
Figure BDA0002867722930000021
Figure BDA0002867722930000022
Figure BDA0002867722930000031
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the formula and paraformaldehyde 2 (18mg, 0.6 mmol) are sequentially added into a Schlenk tube, nitrogen is protected, a solvent (5 mL) is added, the corresponding amount of the catalyst in the table 1 is added under stirring, then a seal is formed, and the reaction is stirred at room temperature. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3a in the yield shown in table 1.
1 H NMR(400MHz,DMSO-d6):δ9.16(s,1H),6.83(d,J＝1.7Hz,1H),6.63(d,J＝1.8Hz,1H),4.85(s,2H),3.79(s,3H),3.78(s,3H). 13 C NMR(125MHz,DMSO-d6):δ160.84,154.47,134.05,104.91,101.28,67.87,55.46,55.21.
Example 2:
Figure BDA0002867722930000032
the method comprises the following steps:
a stirring magneton, the compound 1b (106mg, 0.5 mmol) of the above formula, and paraformaldehyde 2 (18mg, 0.6 mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoroacetic acid (111. Mu.L, 1.5 mmol) under stirring, sealing, and stirring at room temperature for reaction for 17 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3b (74mg, 66%).
The second method comprises the following steps:
a stirring magneton, the compound 1b (106mg, 0.5 mmol) of the above formula, paraformaldehyde 2 (18mg, 0.6 mmol), p-toluenesulfonic acid monohydrate (48mg, 0.25mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by sealing and stirring at room temperature for reaction for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3b (36mg, 32%).
The third method comprises the following steps:
a stirring magneton, the compound 1b (106mg, 0.5 mmol) of the above formula, and paraformaldehyde 2 (18mg, 0.5 mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (6.6. Mu.L, 0.075 mmol) under stirring, sealing, and stirring at room temperature for reaction for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3b (47mg, 42%).
1 H NMR(400MHz,DMSO-d6):δ9.12(s,1H),7.09(s,1H),4.97(s,2H),3.84(s,3H),3.82(s,3H),3.77(s,3H). 13 C NMR(125MHz,DMSO-d6):δ153.67,147.19,143.37,138.04,108.35,67.90,60.55,59.97,56.06.
Example 3:
Figure BDA0002867722930000041
the method comprises the following steps:
a stirring magneton, the compound 1c (166mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by addition of trifluoroacetic acid (297. Mu.L, 4 mmol) under stirring, sealing, and reaction was stirred at room temperature for 22 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3c (62mg, 35%).
The second method comprises the following steps:
a stirring magneton, the compound 1c (166mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (18. Mu.L, 0.2 mmol) under stirring, sealing, and reacting at room temperature for 36 hours with stirring. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3c (71mg, 40%).
1 H NMR(400MHz,DMSO-d6):δ9.01(s,1H),7.22(s,1H),7.17(s,1H),4.88(s,2H),3.81(s,3H),2.20(s,3H). 13 C NMR(125MHz,DMSO-d6):δ156.99,146.20,129.56,123.22,110.75,69.67,55.30,16.83.
Example 4:
Figure BDA0002867722930000042
the method comprises the following steps:
a stirring magneton, the compound 1d (114mg, 0.5 mmol) of the above formula, and paraformaldehyde 2 (18mg, 0.6 mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoroacetic acid (186. Mu.L, 2.5 mmol) under stirring, sealing, and reaction was stirred at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 3d (58mg, 48%).
The second method comprises the following steps:
a stirring magneton, the compound 1d (228mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (31. Mu.L, 0.35 mmol) under stirring, sealing, and reaction was stirred at room temperature for 72 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3d (54mg, 22%).
1 H NMR(400MHz,DMSO-d6):δ9.15(s,1H),7.47-7.45(m,2H),7.41-7.38(m,2H),7.35-7.31(m,3H),7.13(dd,J＝8.2,1.9Hz,1H),5.12(s,2H),4.92(s,2H). 13 C NMR(125MHz,DMSO-d6):δ157.77,146.31,137.34,128.51,127.84,127.65,122.44,118.91,115.05,69.71,69.48.
Example 5:
Figure BDA0002867722930000051
the method comprises the following steps:
a stirring magneton, the compound 1e of the above formula (106mg, 0.7 mmol), and paraformaldehyde 2 (25mg, 0.84mmol) were sequentially added to a Schlenk tube, and chloroform (7 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (3.1. Mu.L, 0.035 mmol) under stirring, followed by sealing, heating at 40 ℃ and stirring for 18 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give said compound of formula 3e (38mg, 33%).
The second method comprises the following steps:
a stirring magneton, the compound 1e (76mg, 0.5 mmol) of the above formula, paraformaldehyde 2 (18mg, 0.6 mmol), p-toluenesulfonic acid monohydrate (48mg, 0.25mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by sealing and stirring at room temperature for reaction for 18 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3e (32mg, 39%).
1 H NMR(400MHz,DMSO-d6):δ9.13(s,1H),7.31(d,J＝8.3Hz,1H),7.26(d,J＝2.4Hz,1H),7.05(dd,J＝8.3,2.4Hz,1H),4.92(s,2H),3.77(s,3H). 13 C NMR(125MHz,DMSO-d6):δ158.71,146.07,122.39,118.14,113.88,69.73,55.26.
Example 6:
Figure BDA0002867722930000061
the method comprises the following steps:
a stirring magneton, the compound 1f (170mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) under stirring, sealing, and heating and stirring at 40 ℃ for reaction for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3f (39mg, 21%).
The second method comprises the following steps:
a stirring magneton, the compound 1f of the above formula (170mg, 1mmol), paraformaldehyde 2 (36mg, 1.2mmol) and p-toluenesulfonic acid monohydrate (95mg, 0.5 mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by sealing and stirring at room temperature for reaction for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3f (50mg, 27%).
1 H NMR(400MHz,DMSO-d6):δ9.34(s,1H),7.02(dd,J＝7.5,1.4Hz,1H),6.98(dd,J＝11.5,1.4Hz,1H),4.89(s,2H),3.83(s,3H). 13 C NMR(125MHz,DMSO-d6):δ163.17(d,J＝241.5Hz),154.82(d,J＝9.8Hz),137.25(d,J＝0.9Hz),107.28(d,J＝20.3Hz),101.30(d,J＝27.7Hz),67.88,55.74.
Example 7:
Figure BDA0002867722930000062
a stirring magneton, 1g (85mg, 0.5 mmol) of the compound of the above formula, and paraformaldehyde 2 (18mg, 0.6 mmol) were sequentially charged into a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (18. Mu.L, 0.2 mmol) under stirring, sealing, and heating and stirring at 40 ℃ for reaction for 72 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give 3g (50mg, 55%) of the compound of the formula.
1 H NMR(400MHz,DMSO-d6):δ9.19(s,1H),7.44(d,J＝8.7Hz,1H),7.28(d,J＝11.3Hz,1H),4.91(s,2H),3.86(s,3H). 13 C NMR(125MHz,DMSO-d6):δ153.98(d,J＝248.1Hz),146.79(d,J＝3.3Hz),146.77(d,J＝15.2Hz),114.33(d,J＝2.2Hz),109.14(d,J＝19.3Hz),69.35(d,J＝2.4Hz),55.89.
Example 8:
Figure BDA0002867722930000071
a stirring magneton, the compound of the formula 1h (170mg, 1mmol), and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, under nitrogen protection, chloroform (10 mL) was added, trifluoromethanesulfonic acid (18. Mu.L, 0.2 mmol) was added under stirring, and then the mixture was sealed and heated at 40 ℃ with stirring for reaction for 48 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula (139mg, 77%) for 3 h.
1 H NMR(400MHz,DMSO-d6):δ9.26(s,1H),7.33-7.29(m,1H),7.16(d,J＝8.1Hz,1H),4.94(s,2H),3.84(s,3H). 13 C NMR(125MHz,DMSO-d6):δ152.49(d,J＝249.9Hz),146.67(d,J＝7.6Hz),145.88(d,J＝11.7Hz),118.37,117.87(d,J＝4.0Hz),69.46,56.65.
Example 9:
Figure BDA0002867722930000072
the method comprises the following steps:
a stirring magneton, the compound 1i (83mg, 0.5 mmol) of the above formula, and paraformaldehyde 2 (18mg, 0.6 mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (2.2. Mu.L, 0.025 mmol) under stirring, sealing, and stirring at room temperature for reaction for 8 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3i (39mg, 43%).
The second method comprises the following steps:
a stirring magneton, the compound 1i (83mg, 0.5 mmol) of the above formula, paraformaldehyde 2 (18mg, 0.6 mmol), p-toluenesulfonic acid monohydrate (48mg, 0.25mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by sealing and stirring at room temperature for reaction for 8 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3i (30mg, 34%).
1 H NMR(400MHz,DMSO-d6):δ9.10(s,1H),7.08(d,J＝2.1Hz,1H),6.86(d,J＝1.8Hz,1H),4.88(s,2H),3.75(s,3H),2.19(s,3H). 13 C NMR(125MHz,DMSO-d6):δ159.10,145.12,132.21,118.69,111.23,69.08,55.22,17.51.
Example 10:
Figure BDA0002867722930000081
a stirring magneton, the compound 1j (105mg, 0.7 mmol) of the above formula, and paraformaldehyde 2 (25mg, 0.84mmol) were sequentially added to a Schlenk tube, and chloroform (7 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (6.2. Mu.L, 0.07 mmol) under stirring, sealing, and heating and stirring at 50 ℃ for reaction for 72 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3j (40mg, 35%).
1 H NMR(400MHz,DMSO-d6):δ9.06(s,1H),7.34(s,1H),7.07(s,1H),4.90(s,2H),2.31(s,3H),2.18(s,3H). 13 C NMR(125MHz,DMSO-d6):δ150.07,136.14,132.37,130.56,128.18,69.25,20.95,17.35.
Example 11:
Figure BDA0002867722930000082
a Schlenk tube was charged with a stirring magneton, compound 1k (170mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) in this order, under nitrogen protection, chloroform (10 mL) was added, further trifluoromethanesulfonic acid (35. Mu.L, 0.4 mmol) was added under stirring, and then the mixture was sealed and stirred at 40 ℃ for reaction for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3k (113mg, 62%).
1 H NMR(400MHz,DMSO-d6):δ9.31(s,1H),7.10-7.01(m,2H),4.92(s,2H),3.80(s,3H). 13 C NMR(125MHz,DMSO-d6):δ157.58(d,J＝240.0Hz),150.09(d,J＝1.8Hz),143.18(d,J＝8.7Hz),114.58(d,J＝7.4Hz),114.27(d,J＝25.0Hz),67.99,55.73.
Example 12:
Figure BDA0002867722930000083
a stirring magneton, 1L (186mg, 1mmol) of the compound of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (35. Mu.L, 0.4 mmol) under stirring, sealing, and reacting by heating at 40 ℃ for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 3l (130mg, 66%).
1 H NMR(400MHz,DMSO-d6):δ9.18(s,1H),7.30(d,J＝8.4Hz,1H),7.07(d,J＝8.5Hz,1H),4.91(s,1H),3.82(s,1H). 13 C NMR(125MHz,DMSO-d6):δ152.61,143.46,128.89,126.89,114.31,67.53,55.58.
Example 13:
Figure BDA0002867722930000091
a stirring magneton, the compound 1m (138mg, 1mmol) of the above formula, and paraformaldehyde 2 (36mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen protection, and trifluoroacetic acid (297. Mu.L, 4 mmol) was further added under stirring, followed by sealing and reaction with heating at 40 ℃ for 20 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 3m (37mg, 25%).
1 H NMR(500MHz,DMSO-d6):δ9.60(s,1H),9.11(s,1H),7.18-7.17(m,2H),6.87-6.83(m,1H),4.89(s,2H). 13 C NMR(125MHz,DMSO-d6):δ151.72,140.14,128.85,121.42,116.88,68.42.
Example 14:
Figure BDA0002867722930000092
the method comprises the following steps:
a Schlenk tube was charged with a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) and, under nitrogen protection, chloroform (7 mL) was added thereto, and further, the compound 4a of the above formula (47. Mu.L, 0.84 mmol) and trifluoroacetic acid (208. Mu.L, 2.8 mmol) were added thereto under stirring, followed by sealing and stirring at room temperature for 53 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5a (91mg, 63%).
The second method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4a of the above formula (67. Mu.L, 1.2 mmol), trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) and stirred under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5a (103mg, 49%).
1 H NMR(400MHz,CDCl 3 -d1):δ6.79(d,J＝1.8Hz,1H),6.55(d,J＝1.9Hz,1H),6.25(s,1H),5.34(q,J＝6.5Hz,1H),3.83(s,3H),3.82(s,3H),1.55(d,J＝6.5Hz,3H). 13 C NMR(125MHz,CDCl 3 -d1):δ161.11,154.72,138.69,103.76,102.04,77.32,55.44,54.98,21.06.
Example 15:
Figure BDA0002867722930000101
the method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4b (64. Mu.L, 0.6 mmol) of the above formula and trifluoroacetic acid (186. Mu.L, 2.5 mmol) were added under stirring, followed by sealing and stirring at room temperature for 18 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5b (94mg, 75%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4b (64. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (4.4. Mu.L, 0.05 mmol) were added under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5b (62mg, 47%).
1 H NMR(400MHz,DMSO-d6):δ9.04(s,1H),6.79(d,J＝1.8Hz,1H),6.61(d,J＝1.9Hz,1H),5.10(dd,J＝9.8,2.2Hz,1H),3.78(s,3H),3.77(s,3H),1.95-1.81(m,2H),1.20-1.14(m,1H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H). 13 C NMR(125MHz,DMSO-d6):δ160.76,154.60,137.54,104.83,101.47,77.59,55.39,55.35,44.24,24.79,23.85,21.95.
Example 16:
Figure BDA0002867722930000102
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and chloroform (10 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4c of the above formula (109. Mu.L, 1.2 mmol), trifluoroacetic acid (446. Mu.L, 6 mmol) were added with stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5c (216mg, 92%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4c (55. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (6.6. Mu.L, 0.075 mmol) were added under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5c (84mg, 71%).
1 H NMR(400MHz,DMSO-d6):δ9.05(s,1H),6.79(d,J＝1.9Hz,1H),6.61(d,J＝1.9Hz,1H),5.03(d,J＝2.2Hz,1H),3.78(s,3H),3.77(s,3H),2.46-2.38(m,1H),1.09(d,J＝6.9Hz,3H),0.35(d,J＝6.8Hz,3H). 13 C NMR(125MHz,DMSO-d6):δ160.75,154.72,135.88,104.72,101.34,83.09,55.35,55.29,29.66,20.35,13.82.
Example 17:
Figure BDA0002867722930000111
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 4d of the above formula (180mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, and trifluoroacetic acid (297. Mu.L, 4 mmol) was further added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5d (124mg, 41%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4d (90mg, 0.6 mmol) of the above formula were sequentially added into a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) under stirring, sealing, and reaction with stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5d (48mg, 32%).
1 H NMR(400MHz,DMSO-d6):δ9.16(s,1H),7.35-7.31(m,2H),7.29-7.24(m,3H),6.81(d,J＝1.8Hz,1H),6.62(d,J＝1.8Hz,1H),5.23(dd,J＝6.1,1.7Hz,1H),4.50(d,J＝12.3Hz,1H),4.45(d,J＝12.3Hz,1H),4.00(dd,J＝10.7,1.8Hz,1H),3.78(s,3H),3.76(s,3H),3.42(dd,J＝10.7,6.1Hz,1H). 13 C NMR(125MHz,DMSO-d6):δ161.20,154.81,138.60,133.27,128.27,127.49,127.43,105.04,101.43,78.97,72.35,71.81,55.47,55.36.
Example 18:
Figure BDA0002867722930000121
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and chloroform (10 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4e of the above formula (219. Mu.L, 1.2 mmol), trifluoroacetic acid (297. Mu.L, 4 mmol) were added to the tube under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5e (186mg, 59%).
The second method comprises the following steps:
into a Schlenk tube were sequentially added a stirring magneton, the compound 1a of the above formula (91mg, 0.5 mmol), under nitrogen protection, chloroform (5 mL) and the compound 4e of the above formula (109. Mu.L, 0.6 mmol), trifluoromethanesulfonic acid (6.6. Mu.L, 0.075 mmol) under stirring, followed by sealing and stirring at room temperature for reaction for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give said compound of formula 5e (52mg, 33%).
1 H NMR(400MHz,DMSO-d6):δ9.07(s,1H),6.79(d,J＝1.9Hz,1H),6.61(d,J＝1.9Hz,1H),5.39-5.36(m,2H),5.05(dd,J＝8.2,2.5Hz,1H),3.78(s,3H),3.77(s,3H),2.15-2.08(m,1H),2.01-1.90(m,5H),1.26-1.21(m,6H),0.84(t,J＝6.8Hz,3H). 13 C NMR(125MHz,DMSO-d6):δ160.84,154.66,136.75,130.32,129.66,104.85,101.41,78.40,55.38,55.31,34.56,32.05,30.89,28.75,27.92,22.04,13.95.
Example 19:
Figure BDA0002867722930000122
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and chloroform (10 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4f of the above formula (158. Mu.L, 1.2 mmol) and trifluoroacetic acid (297. Mu.L, 4 mmol) were added to the tube under stirring, followed by sealing and stirring at room temperature for 12 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5f (186mg, 67%).
The second method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (91mg, 0.5 mmol), and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4f of the above formula (79. Mu.L, 0.6 mmol) and trifluoromethanesulfonic acid (6.6. Mu.L, 0.075 mmol) were added under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5f (65mg, 47%).
1 H NMR(400MHz,DMSO-d6):δ9.07(s,1H),6.80(d,J＝1.9Hz,1H),6.61(d,J＝1.9Hz,1H),5.35-5.31(m,2H),5.07(dd,J＝8.0,2.3Hz,1H),3.78(s,3H),3.77(s,3H),2.13-2.07(m,2H),2.00-1.92(m,4H),0.90(t,J＝7.5Hz,3H). 13 C NMR(125MHz,DMSO-d6):δ160.86,154.67,136.63,131.72,128.63,104.85,101.41,78.48,55.39,55.31,34.60,22.52,20.04,14.24.
Example 20:
Figure BDA0002867722930000131
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and then 4g (123. Mu.L, 1.2 mmol) of the compound of the above formula and trifluoroacetic acid (22. Mu.L, 0.3 mmol) were added under stirring, followed by sealing and stirring at room temperature for 72 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give 5g (125mg, 47%) of the compound of the formula.
1 H NMR(400MHz,DMSO-d6):δ9.57(s,1H),6.85(d,J＝1.9Hz,1H),6.66(d,J＝1.9Hz,1H),5.48(s,1H),4.19-4.07(m,2H),3.79(s,3H),3.77(s,3H),1.18(t,J＝7.1Hz,3H). 13 C NMR(125MHz,DMSO-d6):δ169.96,161.75,154.97,131.77,105.27,101.77,77.46,60.86,55.59,55.49,14.08.
Example 21:
Figure BDA0002867722930000132
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), protected with nitrogen, chloroform (10 mL) was added to the Schlenk tube, and the compound of the above formula (133. Mu.L, 1.2 mmol) trifluoroacetic acid (743. Mu.L, 10 mmol) was added with stirring, followed by sealing and stirring at room temperature for reaction for 33 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula (5 h) (234mg, 89%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound of the above formula was added under stirring for 4 hours (67. Mu.L, 0.6 mmol) and trifluoromethanesulfonic acid (4.4. Mu.L, 0.05 mmol), followed by sealing and stirring at room temperature for 48 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula (xxvii) 5h (84mg, 63%).
1 H NMR(400MHz,DMSO-d6):δ9.87(s,1H),6.89(d,J＝1.9Hz,1H),6.73(d,J＝1.9Hz,1H),5.72(q,J＝5.7Hz,1H),3.81(s,6H). 13 C NMR(125MHz,DMSO-d6):δ162.52,156.01,126.96,124.49(q,J＝280.0Hz),105.82,102.31,75.80(q,J＝32.8Hz),55.67,55.60.
Example 22:
Figure BDA0002867722930000141
the method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4i (61. Mu.L, 0.6 mmol) of the above formula and trifluoroacetic acid (186. Mu.L, 2.5 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for reaction for 44 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5i (69mg, 51%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4i (61. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5i (58mg, 51%).
1 H NMR(400MHz,DMSO-d6):δ9.28(s,1H),7.31-7.25(m,3H),7.18-7.13(m,2H),6.89(d，J＝2.0Hz,1H),6.59(d,J＝2.0Hz,1H),6.04(s,1H),3.79(s,3H),3.59(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.27,154.88,140.87,136.62,128.11,127.70,127.12,104.93,101.87,80.53,55.47,55.31.
Example 23:
Figure BDA0002867722930000142
a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) and chloroform (7 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4j of the above formula (99. Mu.L, 0.84 mmol) and trifluoroacetic acid (260. Mu.L, 3.5 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for reaction for 42 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 5j (84mg, 42%).
1 H NMR(400MHz,DMSO-d6):δ9.24(s,1H),7.09(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,2H),6.88(d,J＝1.8Hz,1H),6.58(d,J＝1.8Hz,1H),5.99(s,1H),3.79(s,3H),3.59(s,3H),2.26(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.19,154.85,137.94,136.79,136.70,128.66,127.03,104.83,101.80,80.37,55.44,55.27,20.81.
Example 24:
Figure BDA0002867722930000151
the method comprises the following steps:
a Schlenk tube was charged with a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) in this order, protected with nitrogen, and then chloroform (7 mL) was added, followed by charging, with stirring, the compound 4k of the above formula (90. Mu.L, 0.84 mmol) and trifluoroacetic acid (260. Mu.L, 3.5 mmol) in this order, followed by sealing and stirring at room temperature for reaction for 40 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5k (114mg, 51%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4k (65. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5k (56mg, 35%).
1 H NMR(400MHz,DMSO-d6):δ9.31(s,1H),7.21-7.16(m,2H),7.14-7.08(m,2H),6.88(d,J＝2.0Hz,1H),6.60(d,J＝2.0Hz,1H),6.05(s,1H),3.79(s,3H),3.60(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.67(d,J＝242.7Hz),161.34,154.34,137.12(d,J＝2.9Hz),136.42,129.06(d,J＝8.3Hz),114.88(d,J＝21.4Hz),104.96,101.92,79.69,55.49,55.35.
Example 25:
Figure BDA0002867722930000161
a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) and 4L of the compound of the above formula (118mg, 0.84mmol) were sequentially added to a Schlenk tube, and chloroform (7 mL) was added under nitrogen, followed by addition of trifluoroacetic acid (260. Mu.L, 3.5 mmol) under stirring, sealing and stirring at room temperature for reaction for 40 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give 5l (183mg, 86%) of the compound of the formula.
1 H NMR(400MHz,DMSO-d6):δ9.35(s,1H),7.36(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,2H),6.89(d,J＝1.9Hz,1H),6.60(d,J＝1.9Hz,1H),6.05(s,1H),3.79(s,3H),3.61(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.38,154.80,139.87,136.21,132.21,128.94,128.15,105.00,101.90,79.62,55.47,55.33.
Example 26:
Figure BDA0002867722930000162
a stirring magneton, the compound 1a of the above formula (91mg, 0.5 mmol), and the compound 4m of the above formula (111mg, 0.6 mmol) were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoroacetic acid (149. Mu.L, 2 mmol) under stirring, sealing, and reaction with stirring at room temperature for 42 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 5m (100mg, 58%).
1 H NMR(400MHz,CDCl 3 -d1):δ7.42(d,J＝8.4Hz,2H),7.11(d,J＝8.4Hz,2H),6.82(d,J＝1.9Hz,1H),6.50(d,J＝1.9Hz,1H),6.08(s,1H),5.74(s,1H),3.83(s,3H),3.62(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.36,154.78,140.28,136.14,131.07,129.29,120.74,104.99,101.89,79.66,55.48,55.34.
Example 27:
Figure BDA0002867722930000171
the first method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and nitrogen atmosphere were sequentially added to a Schlenk tube, chloroform (10 mL) was added, and the compound 4n of the above formula (164. Mu.L, 1.2 mmol) and trifluoroacetic acid (297. Mu.L, 4 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5n (230mg, 68%).
A second method:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4n (82. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (18. Mu.L, 0.2 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 10 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5n (122mg, 72%).
1 H NMR(400MHz,DMSO-d6):δ9.44(s,1H),7.68(d,J＝8.2Hz,2H),7.41(d,J＝8.1Hz,2H),6.91(d,J＝1.9Hz,1H),6.61(d,J＝1.9Hz,1H),6.16(s,1H),3.80(s,3H),3.62(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.59,154.91,145.51,136.08,128.50(q,J＝31.5Hz),127.93,125.10(q,J＝3.7Hz),124.43(q,J＝270.4Hz),105.15,101.97,79.79,55.48,55.31.
Example 28:
Figure BDA0002867722930000172
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) and the compound 4o of the above formula (138mg, 0.84mmol) were sequentially added to a Schlenk tube, and chloroform (7 mL) was added under nitrogen, and trifluoroacetic acid (104. Mu.L, 1.4 mmol) was further added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5o (67mg, 29%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4o (98mg, 0.6 mmol) of the above formula are sequentially added into a Schlenk tube, chloroform (5 mL) is added under the protection of nitrogen, trifluoromethanesulfonic acid (8.8. Mu.L, 0.1 mmol) is added under stirring, and then the mixture is sealed and stirred at room temperature for reaction for 25 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5o (54mg, 33%).
1 H NMR(400MHz,DMSO-d6):δ9.37(s,1H),7.90(d,J＝8.3Hz,2H),7.33(d,J＝8.3Hz,2H),6.90(d,J＝2.0Hz,1H),6.60(d,J＝2.0Hz,1H),6.12(s,1H),3.83(s,3H),3.80(s,3H),3.60(s,3H). 13 C NMR(125MHz,DMSO-d6):δ166.15,161.42,154.82,146.07,136.12,129.12,129.06,127.40,105.06,101.93,79.86,55.48,55.31,52.11.
Example 29:
Figure BDA0002867722930000181
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 4p of the above formula (157mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, followed by addition of trifluoroacetic acid (446. Mu.L, 6 mmol) under stirring, sealing, and reaction at room temperature for 60 hours with stirring. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5p (251mg, 85%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4p (79mg, 0.6 mmol) of the above formula were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (17.6. Mu.L, 0.2 mmol) under stirring, sealing, and reacting at room temperature for 25 hours with stirring. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5p (75mg, 50%).
1 H NMR(400MHz,DMSO-d6):δ9.46(s,1H),7.78(d,J＝8.3Hz,2H),7.38(d,J＝8.3Hz,2H),6.90(d,J＝1.9Hz,1H),6.60(d,J＝1.9Hz,1H),6.14(s,1H),3.79(s,3H),3.61(s,3H). 13 C NMR(126MHz,DMSO-d6):δ161.55,154.80,146.28,135.79,132.20,128.06,118.87,110.56,105.19,101.98,79.61,55.51,55.37.
Example 30:
Figure BDA0002867722930000191
the method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4q (91mg, 0.6 mmol) of the above formula were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoroacetic acid (371. Mu.L, 5 mmol) under stirring, sealing and reaction with stirring at room temperature for 48 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5q (120mg, 76%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4q (91mg, 0.6 mmol) of the above formula were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by adding trifluoromethanesulfonic acid (27. Mu.L, 0.3 mmol) under stirring, sealing, and reacting at room temperature for 26 hours with stirring. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5q (132mg, 84%).
1 H NMR(400MHz,DMSO-d6):δ9.47(s,1H),8.18(d,J＝8.7Hz,2H),7.48(d,J＝8.7Hz,2H),6.92(d,J＝1.6Hz,1H),6.61(d,J＝1.7Hz,1H),6.21(s,1H),3.80(s,3H),3.62(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.57,154.78,148.27,147.08,135.71,128.32,123.41,105.20,101.98,79.29,55.51,55.38.
Example 31:
Figure BDA0002867722930000192
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 4r of the above formula (163mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, and trifluoroacetic acid (1114. Mu.L, 15 mmol) was further added under stirring, followed by sealing and stirring at room temperature for 18 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5r (93mg, 31%).
1 H NMR(400MHz,DMSO-d6):δ9.14(s,1H),7.27-7.23(m,1H),7.02(d,J＝8.0Hz,1H),6.87(d,J＝1.9Hz,1H),6.8-6.76(m,1H),6.60(d,J＝2.0Hz,1H),6.58(dd,J＝7.7,1.2Hz,1H),6.37(s,1H),3.83(s,3H),3.80(s,3H),3.58(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.14,157.55,154.77,135.97,129.22,128.62,127.10,120.26,111.49,104.83,101.74,74.49,55.76,55.46,55.34.
Example 32:
Figure BDA0002867722930000201
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and then the compound 4s of the above formula (126. Mu.L, 1.2 mmol) and trifluoroacetic acid (223. Mu.L, 3 mmol) were sequentially added thereto under stirring, followed by sealing and stirring at room temperature for 96 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 5s (190mg, 66%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 4s (63. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (6.6. Mu.L, 0.075 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 5s (71mg, 49%).
1 H NMR(400MHz,DMSO-d6):δ9.33(s,1H),7.35-7.30(m,1H),7.21-7.14(m,1H),7.10-7.07(m,1H),6.92-6.89(m,2H),6.62(d,J＝1.7Hz,1H),6.26(s,1H),3.80(s,3H),3.59(s,3H). 13 C NMR(125MHz,DMSO-d6):δ160.70(d,J＝245.5Hz),161.50,154.81,135.41,129.92(d,J＝8.3Hz),128.65(d,J＝3.8Hz),127.66(d,J＝12.7Hz),124.32(d,J＝3.1Hz),115.51(d,J＝21.7Hz),105.09,101.87,74.42(d,J＝3.3Hz),55.51,55.40.
Example 33:
Figure BDA0002867722930000202
the method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula and the compound 4t (91mg, 0.6 mmol) of the above formula were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by adding trifluoroacetic acid (297. Mu.L, 4 mmol) under stirring, sealing and reacting at room temperature for 24 hours with stirring. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5t (82mg, 52%).
The second method comprises the following steps:
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and the compound 4t (91mg, 0.6 mmol) of the above formula were sequentially added to a Schlenk tube, and chloroform (5 mL) was added under nitrogen protection, followed by addition of trifluoromethanesulfonic acid (27. Mu.L, 0.4 mmol) under stirring, sealing, and reaction with stirring at room temperature for 25 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5t (96mg, 61%).
1 H NMR(400MHz,DMSO-d6):δ9.55(s,1H),7.92(d,J＝7.9Hz,1H),7.61-7.50(m,2H),7.10(d,J＝6.9Hz,1H),6.89(d,J＝1.8Hz,1H),6.74(s,1H),6.59(d,J＝1.8Hz,1H),3.79(s,3H),3.57(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.65,154.48,149.38,135.49,133.77,133.08,129.06,127.92,124.21,105.32,101.86,74.42,55.53,55.30.
Example 34:
Figure BDA0002867722930000211
the method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (91mg, 0.5 mmol), and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4u of the above formula (79. Mu.L, 0.6 mmol) and trifluoroacetic acid (149. Mu.L, 2 mmol) were added to the tube under stirring, followed by sealing and stirring at room temperature for 42 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5u (141mg, 95%).
The second method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (91mg, 0.5 mmol), and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 4u of the above formula (79. Mu.L, 0.6 mmol) and trifluoromethanesulfonic acid (4.4. Mu.L, 0.05 mmol) were added under stirring, followed by sealing and stirring at room temperature for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give said compound of formula 5u (103mg, 67%).
1 H NMR(400MHz,DMSO-d6):δ9.16(s,1H),7.20-7.15(m,5H),6.82(d,J＝1.9Hz,1H),6.62(d,J＝1.9Hz,1H),5.11-5.09(m,2.6Hz,1H),3.78(s,6H),2.71-2.58(m,2H),2.42-2.35(m,2H). 13 C NMR(125MHz,DMSO-d6):δ160.92,154.70,141.96,136.53,128.42,128.34,125.78,104.94,101.51,78.41,55.43,55.37,36.33,31.00
Example 35:
Figure BDA0002867722930000221
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 4v of the above formula (187mg, 1mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, followed by trifluoroacetic acid (297. Mu.L, 4 mmol) with stirring, followed by sealing and stirring at room temperature for 42 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5v (91mg, 28%).
1 H NMR(400MHz,DMSO-d6):δ9.36(s,1H),7.92-7.85(m,2H),7.83-7.77(m,2H),7.52-7.46(m,2H),7.20(dd,J＝8.5,1.4Hz,1H),6.93(d,J＝1.9Hz,1H),6.60(d,J＝1.8Hz,1H),6.22(s,1H),3.81(s,3H),3.56(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.37,155.00,138.36,136.57,132.89,132.77,127.98,127.71,127.61,126.20,126.07,125.06,105.01,101.93,80.70,55.49,55.33.
Example 36:
Figure BDA0002867722930000222
a stirring magneton, the compound 1a of the above formula (127mg, 0.7 mmol) and the compound 4w of the above formula (131mg, 0.84mmol) were sequentially added to a Schlenk tube, and chloroform (7 mL) was added under nitrogen, followed by addition of trifluoroacetic acid (208. Mu.L, 4 mmol) under stirring, sealing, and reaction with stirring at room temperature for 60 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5w (51mg, 28%).
1 H NMR(400MHz,CDCl 3 ):δ8.42(d,J＝8.5Hz,1H),7.88(d,J＝8.1Hz,1H),7.79(d,J＝8.2Hz,1H),7.58(t,J＝7.4Hz,1H),7.51(t,J＝7.4Hz,1H),7.30(t,J＝7.7Hz,1H),7.00-6.95(m,2H),6.90(d,J＝1.7Hz,1H),6.59(d,J＝1.8Hz,1H),3.88(s,3H),3.58(s,3H). 13 C NMR(126MHz,DMSO):δ161.28,155.02,136.07,135.23,133.41,131.67,128.37,125.95,125.60,125.23,124.19,123.87,105.13,101.77,76.97,55.38,55.10.
Example 37:
Figure BDA0002867722930000231
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 4x of the above formula (156mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, followed by addition of trifluoroacetic acid (297. Mu.L, 4 mmol) under stirring, sealing, and the reaction was stirred at room temperature for 12 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 5x (11mg, 4%).
1 H NMR(400MHz,DMSO-d6):δ7.41(d,J＝8.0Hz,2H),7.17(d,J＝8.1Hz,2H),6.89(d,J＝1.4Hz,1H),6.60(d,J＝1.3Hz,1H),6.06(s,1H),4.17(s,1H),3.79(s,3H),3.60(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.38,154.83,141.70,136.21,131.61,127.41,121.08,105.01,101.92,83.51,80.74,79.96,55.50,55.36.
Example 38:
Figure BDA0002867722930000232
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6a (73. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (18. Mu.L, 0.2 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7a (77mg, 70%).
1 H NMR(400MHz,DMSO-d6):δ8.94(s,1H),6.77(d,J＝1.9Hz,1H),6.61(d,J＝1.8Hz,1H),3.80(s,3H),3.77(s,3H),1.45(s,6H). 13 C NMR(125MHz,DMSO-d6):δ160.77,154.43,141.52,104.95,101.76,82.30,55.46,55.40,27.67.
Example 39:
Figure BDA0002867722930000233
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), under nitrogen protection, chloroform (10 mL) were added to a Schlenk tube, and the compound 6b of the above formula (90. Mu.L, 1 mmol), trifluoromethanesulfonic acid (35. Mu.L, 0.4 mmol) were added to the tube, followed by sealing and stirring at room temperature for 15 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7b (143mg, 61%).
1 H NMR(400MHz,DMSO-d6):δ9.06(s,1H),6.74(d,J＝2.0Hz,1H),6.65(d,J＝2.0Hz,1H),3.87(s,3H),3.77(s,3H),2.74-2.65(m,2H),2.2-2.17(m,2H),2.07-1.99(m,2H). 13 C NMR(125MHz,DMSO-d6):δ160.87,155.34,138.36,104.61,101.81,85.71,55.61,55.43,33.24,13.32.
Example 40:
Figure BDA0002867722930000241
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6c of the above formula (106. Mu.L, 1.2 mmol) and trifluoromethanesulfonic acid (88. Mu.L, 1 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 11 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give said compound of formula 7c (227mg, 92%).
1 H NMR(400MHz,DMSO-d6):δ8.94(s,1H),6.76(d,J＝2.0Hz,1H),6.62(d,J＝1.9Hz,1H),3.79(s,3H),3.77(s,3H),2.32-2.22(m,2H),1.89-1.78(m,4H),1.51-1.44(m,2H). 13 C NMR(125MHz,DMSO-d6):δ160.88,154.63,138.04,104.78,101.76,92.54,78.25,55.42,37.77,24.54.
Example 41:
Figure BDA0002867722930000242
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6d (62. Mu.L, 0.6 mmol) of the above formula and trifluoromethanesulfonic acid (15. Mu.L, 0.175 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 24 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7d (123mg, 94%).
1 H NMR(400MHz,DMSO-d6):δ8.95(s,1H),6.77(d,J＝1.9Hz,1H),6.60(d,J＝1.9Hz,1H),3.79(s,3H),3.76(s,3H),2.20-2.15(m,2H),1.76-1.56(m,5H),1.26-1.23(m,3H). 13 C NMR(125MHz,DMSO-d6):δ160.61,154.67,141.57,105.00,101.80,83.73,55.44,55.37,35.24,25.01,22.33.
Example 42:
Figure BDA0002867722930000251
the first method comprises the following steps:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6e of the above formula (108. Mu.L, 1.2 mmol) and trifluoroacetic acid (1500. Mu.L, 20 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 72 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7e (149mg, 56%).
A second method:
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6e of the above formula (108. Mu.L, 1.2 mmol) and trifluoromethanesulfonic acid (44. Mu.L, 0.5 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7e (118mg, 44%).
1 H NMR(400MHz,DMSO-d6):δ9.56(s,1H),6.83(d,J＝1.8Hz,1H),6.65(d,J＝1.8Hz,1H),3.79(s,3H),3.76(s,3H),3.56(s,3H),1.63(s,3H). 13 C NMR(125MHz,DMSO-d6):δ171.50,161.54,154.74,136.38,105.28,102.10,83.35,55.74,55.53,52.36,22.97.
Example 43:
Figure BDA0002867722930000252
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 6f of the above formula (130. Mu.L, 1.2 mmol) and trifluoromethanesulfonic acid (88. Mu.L, 1 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 36 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7f (260mg, 93%).
1 H NMR(400MHz,DMSO-d6):δ9.07(s,1H),6.75(d,J＝2.0Hz,1H),6.61(d,J＝2.0Hz,1H),3.80(s,3H),3.77(s,3H),3.42(s,3H),2.91(d,J＝14.2Hz,1H),2.76(d,J＝14.2Hz,1H),1.51(s,3H). 13 C NMR(125MHz,DMSO-d6):δ169.86,160.96,154.37,139.12,104.93,101.69,81.89,55.58,55.40,50.97,43.51,26.46.
Example 44:
Figure BDA0002867722930000261
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and then 6g (168. Mu.L, 1.2 mmol) of the compound of the above formula and trifluoromethanesulfonic acid (106. Mu.L, 1.2 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 22 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of the formula 7g (312mg, 92%).
1 H NMR(400MHz,DMSO-d6):δ10.03(s,1H),7.59-7.55(m,2H),7.41-7.35(m,3H),6.94(d,J＝1.9Hz,1H),6.75(d,J＝2.1Hz,1H),3.82(s,3H),3.74(s,3H). 13 C NMR(125MHz,DMSO-d6):δ162.61,155.89,136.12,131.03,128.78,128.24,126.99,125.16(q,J＝283.6Hz),106.24,103.21,86.67(q,J＝30.3Hz),55.75,55.62.
Example 45:
Figure BDA0002867722930000262
a Schlenk tube was charged with a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) in this order, protected with nitrogen, and chloroform (10 mL) was added, followed by charging the compound of the above formula (170. Mu.L, 1.2 mmol) and trifluoromethanesulfonic acid (44. Mu.L, 0.5 mmol) in this order with stirring, followed by sealing and stirring at room temperature for 12 hours. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7h (282mg, 86%).
1 H NMR(400MHz,DMSO-d6):δ9.66(s,1H),7.34-7.27(m,5H),6.89(d,J＝1.9Hz,1H),6.71(d,J＝1.9Hz,1H),3.81(s,3H),3.72(s,3H),3.63(s,3H). 13 C NMR(125MHz,DMSO-d6):δ170.72,161.91,155.34,139.37,134.90,127.84,127.65,127.26,105.70,102.66,87.87,55.70,55.58,52.63.
Example 46:
Figure BDA0002867722930000263
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol), and the compound 6i of the above formula (198mg, 1.2mmol) were sequentially added to a Schlenk tube, and chloroform (10 mL) was added under nitrogen, followed by addition of trifluoromethanesulfonic acid (44. Mu.L, 0.5 mmol) under stirring, sealing, and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give said compound of formula 7i (287mg, 86%).
1 H NMR(400MHz,DMSO-d6):δ9.44(s,1H),8.16(d,J＝8.9Hz,2H),7.61(d,J＝8.9Hz,2H),6.87(d,J＝1.9Hz,1H),6.62(d,J＝1.9Hz,1H),3.78(s,3H),3.70(s,3H),1.90(s,3H). 13 C NMR(125MHz,DMSO-d6):δ161.45,154.47,151.53,146.57,139.51,127.26,123.13,105.44,102.33,84.28,55.52,55.49,25.88.
Example 47:
Figure BDA0002867722930000271
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and chloroform (10 mL) were sequentially added to a Schlenk tube under nitrogen protection, and the compound 8a of the above formula (212. Mu.L, 1.5 mmol) and trifluoroacetic acid (371. Mu.L, 5 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 60 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 9a (186mg, 70%).
1 H NMR(400MHz,DMSO-d6):δ9.23(s,1H),6.80(d,J＝1.9Hz,1H),6.64(d,J＝1.9Hz,1H),5.38(dd,J＝9.7,2.8Hz,1H),3.80(s,3H),3.78(s,3H),3.63(s,3H),3.15(dd,J＝15.4,2.9Hz,1H),2.21(dd,J＝15.4,9.7Hz,1H). 13 C NMR(125MHz,DMSO-d6):δ171.01,161.33,154.62,135.32,105.08,101.59,75.72,55.50,55.47,51.51,40.24.
Example 48:
Figure BDA0002867722930000272
a stirring magneton, the compound 1a of the above formula (182mg, 1mmol) and nitrogen atmosphere were sequentially added to a Schlenk tube, chloroform (10 mL) was added, and the compound 8b of the above formula (246. Mu.L, 2 mmol) and trifluoromethanesulfonic acid (88. Mu.L, 1 mmol) were sequentially added under stirring, followed by sealing and stirring at room temperature for 48 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 7a (220mg, 99%).
1 H NMR(400MHz,DMSO-d6):δ8.94(s,1H),6.77(d,J＝1.9Hz,1H),6.61(d,J＝1.8Hz,1H),3.80(s,3H),3.77(s,3H),1.45(s,6H). 13 C NMR(125MHz,DMSO-d6):δ160.77,154.43,141.52,104.95,101.76,82.30,55.46,55.40,27.67.
Example 49:
Figure BDA0002867722930000281
a stirring magneton, the compound 1a (91mg, 0.5 mmol) of the above formula, and chloroform (5 mL) were added to a Schlenk tube in this order under nitrogen protection, and the compound 8a (85. Mu.L, 0.6 mmol) of the above formula, trifluoromethanesulfonic acid (88. Mu.L, 1 mmol), and water (9. Mu.L, 0.5 mmol) were added to the tube in this order under stirring, followed by sealing and stirring at room temperature for reaction for 34 hours. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography to give the compound of formula 9c (20mg, 16%).
1 H NMR(400MHz,DMSO-d6):δ9.20(s,1H),7.07(s,1H),6.90(s,1H),5.40(d,J＝9.5Hz,1H),3.80(s,3H),3.63(s,3H),3.17(dd,J＝15.5,2.1Hz,1H),2.34(s,3H),2.20(dd,J＝15.4,10Hz,1H). 13 C NMR(125MHz,DMSO-d6):δ171.06,153.65,139.93,139.38,122.71,113.94,75.82,55.33,51.63,40.10,21.44.

Claims (7)

1. A synthetic method of benzoborazole is characterized in that: in an organic solvent, under the condition of a strong acid catalyst, carrying out dehydration condensation reaction on a compound shown in the following formula (A) and a compound shown in the following formula (B) to obtain a compound shown in the following formula (C), wherein the reaction formula is as follows:
Figure DEST_PATH_IMAGE002
wherein:
r1 is alkoxy, hydroxyl, alkyl or halogen, at least one of the alkoxy, alkyl or hydroxyl is positioned at the meta position, R 2 And R 3 Are all H;
R 2 and R 3 When not all are H, wherein R 2 And R 3 The specific conditions are as follows:
R 2 is aryl, R 3 Is H, wherein aryl is phenyl or phenyl with substituent groups, and the substituent groups are alkyl, alkoxy, halogen, cyano, nitro and ester group;
or, R 2 Is aryl, R 3 Is alkyl and ester group, wherein aryl is phenyl or phenyl with substituent, and the substituent is alkyl, alkoxy, halogen, cyano, nitro and ester group;
or, R 2 Is alkyl, R 3 Is H, alkyl or ester group;
the organic solvent is trichloromethane;
the catalyst is trifluoromethanesulfonic acid, trifluoroacetic acid or p-toluenesulfonic acid monohydrate.
2. A method of synthesis of benzoborazole according to claim 1, characterized by: the strong acid catalyst is trifluoroacetic acid, and the molar ratio of the compound shown in the formula (A) to the trifluoroacetic acid is 1.
3. A process for the synthesis of benzoborazole according to claim 1, characterized in that: the strong acid catalyst is trifluoromethanesulfonic acid, and the molar ratio of the compound represented by the formula (A) to the trifluoromethanesulfonic acid is 1:0.01 to 1.
4. A method of synthesis of benzoborazole according to claim 1, characterized by: the strong acid catalyst is p-toluenesulfonic acid monohydrate, and the molar ratio of the compound shown in the formula (A) to the hydrated p-toluenesulfonic acid monohydrate is 1.5.
5. A method of synthesis of benzoborazole according to claim 1, characterized by: the molar concentration of the compound represented by the formula (A) in the solvent was 0.1mol/L.
6. A method of synthesis of benzoborazole according to claim 1, characterized by: the molar concentration of the compound represented by the formula (B) in the solvent is 0.12 to 0.2mol/L.
7. A process for the synthesis of benzoborazole according to claim 1, characterized in that: the reaction temperature is between room temperature and 50 DEG C o C。
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