A method for synthesizing diphenyl-2-pyridylmethane derivatives

Abstract

The present invention provides a method for synthesizing a diphenyl-2-pyridylmethane derivative. Compound D, butylboric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1 are mixed and stirred, reacted, and separated and purified to obtain a diphenyl-2-pyridylmethane derivative E, whose chemical reaction formula is: wherein R1 and R2 are independently selected from one of hydrogen, alkyl, alkoxy, aryl and heteroaryl. The present invention has high selectivity and high yield, high reaction catalytic efficiency, low catalyst dosage, simple post-processing, and no by-products are generated in the system.

Description

Technical Field

[0001] The invention relates to the technical field of carbocyclic compound synthesis, and in particular to a method for synthesizing diphenyl-2-pyridylmethane derivatives. Background Art

[0002] Chiral compounds, as precursors, intermediates or final products of medicines, pesticides, fragrances and functional materials, play an extremely important role in fine chemical production. Researching methods to obtain single enantiomer compounds remains one of the top priorities for contemporary chemists. Carbon heteroatom bonds (CX) are ubiquitous in biological molecules in nature. They are one of the most active parts in the molecular structure of organic compounds and one of the basic skeleton raw materials for synthesizing these enantiomeric products. Therefore, constructing CX bonds is a hot topic for organic chemists.

[0003] Transition metal-catalyzed CH bond insertion reactions are not only highly efficient and economical, but also provide a simple method for us to construct various complex molecules from simple and readily available raw materials. In the past few decades, more and more transition metal catalysts have been developed and successfully applied to the activation of various CH bonds, providing a new and effective method for the construction of CX bonds.

[0004] However, there are currently few effective methods for CH bond activation, and its activity and selectivity are difficult to regulate. Therefore, the development of various transition metal catalysts for efficient CH bond activation is an important challenge currently faced. The main obstacle in Pd-catalyzed CH bond activation reactions is the need for a ligand that binds to Pd to control its chemical, regio- and stereo-selectivity for inserting into the CH bond.

[0005] Therefore, it is necessary to develop a Pd-catalyzed asymmetric C—H activation / C—C coupling reaction with high yield and selectivity to discriminate chiral C—H bonds via metal insertion. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing diphenyl-2-pyridylmethane derivatives by a palladium-catalyzed carbon-hydrogen activation reaction, which solves the problems of low yield and low selectivity in the prior art.

[0007] The present invention provides a method for synthesizing a diphenyl-2-pyridylmethane derivative. Compound D, butylboric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1 are mixed and stirred to react, and a diphenyl-2-pyridylmethane derivative E is obtained through separation and purification. The chemical reaction formula is:

[0008]

[0009] Wherein, R1 and R2 are independently selected from one of hydrogen, alkyl, alkoxy, aryl and heteroaryl.

[0010] Further, the catalyst is Pd(OAc)2, and the ligand is

[0011] Wherein, R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

[0012] Furthermore, the oxidant is benzodiquinone, and the additive is silver oxide.

[0013] Furthermore, the organic solvent 1 is tetrahydrofuran.

[0014] Furthermore, the molar ratio of the compound D: butylboric acid: catalyst: ligand: oxidant: additive is 1:1:0.1:0.2:0.5:1.0.

[0015] Furthermore, the reaction temperature is 50-60°C and the reaction time is 20-24h.

[0016] Furthermore, the preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst, and an organic base, a 7-carboxyl-1,1'-spirodihydroindane compound represented by formula B reacts with a compound represented by formula C to prepare a compound represented by formula A, and the reaction formula is as follows:

[0017]

[0018] Wherein, R is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

[0019] Furthermore, the acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.

[0020] Further, the molar ratio of the 7-carboxy-1,1'-spirodihydroindane compound represented by formula B: the compound represented by formula C: the acylating agent: the organic base is 0.9-1:1-1.1:1.3-1.5:3;

[0021] In terms of mol / L, the ratio of the 7-carboxy-1,1'-spirodihydroindane compound shown in formula A to the catalyst is 1:0.01.

[0022] Furthermore, the reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

[0023] In one embodiment of the present invention, the preparation method of the 7-carboxyl-1,1'-spirodihydroindane compound represented by formula B comprises:

[0024] Using 1,1'-spirodihydroindane-7,7'-diol as a starting material, the product is obtained through methylation reaction, first sulfonation reaction, first substitution reaction, demethylation reaction, second sulfonation reaction, second substitution reaction, and hydrolysis reaction; the reaction process is as follows:

[0025]

[0026] Specifically, the process comprises the following steps: (1) adding 1,1'-spirodihydroindane-7,7'-diol into an organic solvent 1 to generate a compound 2 under the action of a methylating agent and a first base;

[0027] (2) Compound 2 is mixed with organic solvent 2, and a first sulfonation reagent and a second base are added to generate compound 3;

[0028] (3) Compound 3 is added to organic solvent 3, and in the presence of CO, a first catalyst, a first reaction substrate, and a third base are added to perform a first substitution reaction to generate compound 4;

[0029] (4) Compound 4 is added to organic solvent 4, and demethylation reaction occurs under the action of a demethylating agent to generate compound 5;

[0030] (5) Compound 5 is added to an organic solvent 5, and a second sulfonation reagent and a fourth base are added to generate compound 6;

[0031] (6) Compound 6 is added to organic solvent 6, and in the presence of nitrogen, a second catalyst and a second reaction substrate are added to carry out a second substitution reaction to generate compound 7;

[0032] (7) Compound 7 is added to an organic solvent 7 and hydrolyzed in the presence of a fifth base to generate a 7-carboxy-1,1'-spirodihydroindane compound represented by formula B.

[0033] Preferably, in step (1), the organic solvent 1 is tetrahydrofuran, the methylating agent is methyl iodide, and the first base is sodium hydride; the reaction temperature is 0-10° C., and the reaction time is 6-12 h;

[0034] In step (2), the organic solvent 2 is dichloromethane, the first sulfonating agent is trifluoromethanesulfonic anhydride, and the second base is pyridine; the reaction temperature is 0-10° C., and the reaction time is 6-12 h;

[0035] In step (3), the organic solvent 3 is acetonitrile and methanol; the third base is triethylamine; the first catalyst is PdCl2 (dppf); the first reaction substrate is methanol; the reaction temperature is 80°C, and the reaction time is 16-24h;

[0036] In step (4), the organic solvent 4 is DCM, the demethylating agent is BBr3, the reaction temperature is -20-10°C, and the reaction time is 6-8h;

[0037] In step (5), the organic solvent 5 is dichloromethane, the second sulfonating agent is trifluoromethanesulfonic anhydride, the fourth base is pyridine, the reaction temperature is -0-10°C, and the reaction time is 6-12h;

[0038] In step (6), the organic solvent 6 is methanol; the second catalyst is PdCl2(dppf); the second reaction substrate is HCOONa;

[0039] In step (7), the organic solvent 7 is DMSO; the fifth base is potassium hydroxide; the reaction temperature is 150° C., and the reaction time is 16-24 hours.

[0040] Preferably, in step (1), in a molar ratio, 1,1'-spirodihydroindane-7,7'-diol:methylating agent:first base=2:1:1;

[0041] In step (2), in terms of molar ratio, compound 2: first sulfonation reagent: second base = 10:13:15;

[0042] In step (3), in terms of molar ratio, compound 3: first catalyst: first reaction substrate: third base = 10:0.5:100:30;

[0043] In step (4), the molar ratio of compound 4 to first demethylating agent is 1:3;

[0044] In step (5), in terms of molar ratio, compound 5: second sulfonation reagent: fourth base = 10:13:15;

[0045] In step (6), in terms of molar ratio, compound 6: second catalyst, second reaction substrate = 10:0.5:30;

[0046] In step (7), the molar ratio of compound 7 to fifth base is 1:10.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] 1. The present invention uses palladium acetate and a chiral spirocyclic ligand as catalysts for the first time to catalyze the CC bond coupling reaction of substituted diphenyl-2-pyridylmethane and butylboronic acid, and synthesizes a series of diphenyl-2-pyridylmethane derivatives with excellent enantioselectivity and high yield, providing more options for the development of organic synthesis and biomedicine;

[0049] 2. The chiral spirocyclic ligand synthesized for the first time in the present invention has high reaction catalytic efficiency, low catalyst dosage, simple post-treatment, and no by-products are generated in the system.

[0050] 3. The present invention is easy to operate, has mild reaction conditions, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0051] The technical solution of the present invention is further described below in conjunction with embodiments.

[0052] Example 1 Synthesis of ligand

[0053]

[0054] Under nitrogen protection, compound B1 (10mmol), N,N-dimethylformamide (DMF, 100μL) and dichloromethane (DCM, 10mL) were added to the reaction bottle, and oxalyl chloride (15mmol) was added dropwise to the reaction system. The temperature was controlled at 0-10°C during the addition. After the addition was completed, the mixture was returned to room temperature, stirred for reaction for 2-3 hours, concentrated to dryness to obtain the acid chloride of B1, and 10mL of dichloromethane was added for standby use. In another reaction bottle, C1 (11mmol), triethylamine (Et3N, 30mmol) and dichloromethane (30mL) were added, and the acid chloride solution of B1 obtained in the previous step was slowly added dropwise to C1 and triethylamine, stirred at room temperature for 3-4 hours, and product A1 was obtained by quenching column chromatography with a yield of 95%;

[0055] Wherein, the preparation method of compound B1 is as follows:

[0056]

[0057] Under nitrogen protection, compound 1 (10 mmol) and tetrahydrofuran (200 mL) were added to a reaction bottle, and NaH (5 mmol) was added to the reaction system, and the temperature was controlled at 0-10° C. Then, a THF solution of iodomethane (5 mmol MeI in 60 mL THF) was added dropwise to the system, and the temperature was controlled at 0-10° C. The reaction was continued for 6-12 hours after the addition was completed, and the reaction solution was subjected to quenching column chromatography to obtain product 2, with a yield of 77%.

[0058] Under nitrogen protection, compound 2 (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf2O in 60 mL DCM) was added dropwise to the system, the temperature was controlled at 0-10°C, the reaction was continued for 6-12 hours, and the reaction solution was subjected to quenching column chromatography to obtain product 3 with a yield of 91%.

[0059] Under nitrogen protection, compound 3 (10 mmol), methanol (100 mmol), acetonitrile (100 mL), and triethylamine (30 mmol) were added to a reaction flask. PdCl2(dppf) (0.5 mmol) was then added to the system. After the addition was completed, CO was replaced three times, the pressure was increased to 2.5 MPa, and the reaction was carried out at 80°C for 16-24 hours. The reaction solution was subjected to quenching column chromatography to obtain product 4 with a yield of 80%.

[0060] Under nitrogen protection, compound 4 (10 mmol) and DCM (500 mL) were added to the reaction bottle. BBr3 (30 mmol) was then added dropwise to the system, and the temperature was controlled at -20°C to 10°C. After the addition, the reaction was continued for 6-8 hours, and the reaction solution was subjected to quenching column chromatography to obtain compound 5 with a yield of 65%.

[0061] Under nitrogen protection, compound 5 (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Subsequently, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf2O in 60 mL DCM) was added dropwise to the system, the temperature was controlled at 0-10°C, and the reaction was continued for 6-12 hours. The reaction solution was subjected to quenching column chromatography to obtain compound 6 with a yield of 88%.

[0062] Under nitrogen protection, compound 6 (10 mmol), methanol (100 mmol), and HCOONa (30 mmol) were added to a reaction flask. PdCl2(dppf) (0.5 mmol) was then added to the system. After the addition was completed, nitrogen was replaced three times, and the reaction was carried out at 80°C for 16-24 hours. The reaction solution was subjected to quenching column chromatography to obtain compound 7 with a yield of 84%.

[0063] Under nitrogen protection, compound 7 (10 mmol) and DMSO (500 mL) were added to the reaction flask. Then, 60% potassium hydroxide aqueous solution (100 mmol) was added to the system. After the addition, the temperature was raised to 150°C and the reaction was carried out for 16-24 hours. The reaction solution was subjected to quenching column chromatography to obtain product B1 with a yield of 80%.

[0064] Example 2 Synthesis of ligand

[0065]

[0066] Under nitrogen protection, compound B2 (9mmol), N,N-dimethylformamide (DMF, 90μL) and dichloromethane (DCM, 10mL) were added to the reaction bottle, and oxalyl chloride (13mmol) was added dropwise to the reaction system. The temperature was controlled at 0-10°C during the addition. After the addition, the mixture was returned to room temperature, stirred for reaction for 2-3 hours, concentrated to dryness to obtain the acid chloride of B2, and 10mL of dichloromethane was added for standby use. Another reaction bottle was added with C2 (10mmol), triethylamine (Et3N, 27mmol) and dichloromethane (30mL), and the acid chloride solution of B2 obtained in the previous step was slowly added dropwise to C2 and triethylamine, stirred at room temperature for 3-4 hours, and product A2 was obtained by quenching column chromatography with a yield of 91%.

[0067] Example 3 Synthesis of ligand

[0068]

[0069] Under nitrogen protection, compound B3 (10mmol), N,N-dimethylformamide (DMF, 100μL) and dichloromethane (DCM, 10mL) were added to the reaction bottle, and oxalyl chloride (15mmol) was added dropwise to the reaction system. The temperature was controlled at 0-10°C during the addition. After the addition, the mixture was returned to room temperature, stirred for reaction for 2-3 hours, concentrated to dryness to obtain the acid chloride of B3, and 10mL of dichloromethane was added for standby use. Another reaction bottle was added with C3 (11mmol), triethylamine (Et3N, 30mmol) and dichloromethane (30mL), and the acid chloride solution of B3 obtained in the previous step was slowly added dropwise to C3 and triethylamine, stirred at room temperature for 3-4 hours, and product A3 was obtained by quenching column chromatography with a yield of 93%.

[0070] Example 4

[0071]

[0072] Under nitrogen protection, 0.25 mmol of compound D1, 0.25 mmol (1.0 eq) of butylboric acid, 25 μmol (10 mol%) of catalyst Pd(OAc)2, 50 μmol (20 mol%) of the ligand prepared in Example 1, 0.125 mmol (0.5 eq) of BQ (parabenzoquinone), 0.25 mmol (1.0 eq) of Ag2O, and 1 ml of tetrahydrofuran (THF) were added to the reaction vessel, and the mixture was reacted at 60°C for 20 h. The mixture was concentrated and filtered, and the target product E1 was purified. 1H NMR: δ0.88(3H,t,J=6.5Hz),1.25-1.37(2H,1.31(h,J=6.5Hz),1.31(h,J= 6.5Hz)),1.50-1.64(2H,1.57(tt,J=7.3,6.5Hz),1.57(tt,J=7.3,6.5Hz) ),2.18-2.30(6H,2.23(s),2.25(s)),2.61-2.73(2H,2.67(t,J=7.3Hz),2 .67(t,J=7.3Hz)),5.66(1H,s),6.98-7.34(9H,7.05(ddd,J=8.0,7.8,2.1H z),7.06(ddd,J=8.0,1.5,0.6Hz),7.08(dd,J=8.1,1.5Hz),7.09(ddd,J=8.0,7.8,1.5Hz),7.09(t,J=8.1Hz),7.09(dd,J=8.1,1.5Hz),7.17(ddd,J=8 .0,2.1,0.6Hz),7.21(ddd,J=7.4,5.1,1.5Hz),7.28(ddd,J=7.9,1.5,0.6 Hz)), 7.69 (1H, ddd, J = 7.9, 7.4, 1.9 Hz), 8.53 (1H, ddd, J = 5.1, 1.9, 0.6 Hz).

[0073] The reaction yield was found to be 93% and the enantioselective ee value was 90%.

[0074] Example 2

[0075]

[0076] Under nitrogen protection, 0.25 mmol of compound D2, 0.25 mmol (1.0 eq) of butylboric acid, 25 μmol (10 mol%) of Pd(OAc)2 catalyst, 50 μmol (20 mol%) of the ligand prepared in Example 2, 0.125 mmol (0.5 eq) of BQ, 0.25 mmol (1.0 eq) of Ag2O, and 1 ml of THF were added to the reaction vessel. The mixture was reacted at 50°C for 24 h. The mixture was concentrated and filtered, and the target product E2 was purified. 1H NMR: δ0.88(3H,t,J=6.5Hz),1.25-1.37(2H,1.31(h,J=6.5Hz),1.31(h,J=6.5Hz)), 1.49-1.63(2H,1.56(tt,J=7.3,6.5Hz), 1.56(tt,J=7.3,6. 5Hz)),2.61-2.73(2H,2.67(t,J=7.3Hz),2.67(t,J=7.3Hz)),5.68(1H,s),6.99-7.39(11H,7.05(ddd,J=7.8,1.6,0.6Hz),7.17(td,J=7.8,2.0 Hz), 7.19 (ddd, J=8.1, 7.8, 1.6Hz), 7.18 (ddd, J=8.1, 2.0, 0.6Hz), 7.20 (tt, J=7.7, 1.3Hz), 7.21 (ddd, J=7.4, 5.1, 1.5Hz), 7.28 (ddd, J=7.9, 1. 5,0.6Hz),7.28(dtd,J=7.6,1.3,0.5Hz),7.33(tdd,J=7.7,1.9,0.5Hz)),7.69(1H,ddd,J=7.9,7.4,1.9Hz),8.53(1H,ddd,J=5.1,1.9,0.6Hz).

[0077] The reaction yield was found to be 94% and the enantioselective ee value was 92%.

[0078] Example 3

[0079]

[0080] Under nitrogen protection, 0.25 mmol of compound D3, 0.25 mmol (1.0 eq) of butylboric acid, 25 μmol (10 mol%) of Pd(OAc)2, 50 μmol (20 mol%) of the ligand prepared in Example 3, 0.125 mmol (0.5 eq) of BQ, 0.25 mmol (1.0 eq) of Ag2O, and 1 ml of THF were added to the reaction vessel. The mixture was reacted at 60°C for 20 h. The mixture was concentrated and filtered, and the target product E3 was purified. 1H NMR: δ0.88(3H,t,J=6.5Hz),1.25-1.37(2H,1.31(h,J=6.5Hz),1.31(h,J=6.5 Hz)),1.44-1.57(2H,1.50(tt,J=7.4,6.5Hz),1.50(tt,J=7.4,6.5Hz)),2.51- 2.63(2H,2.57(t,J=7.4Hz),2.57(t,J=7.4Hz)),3.67-3.80(6H,3.72(s),3.75 (s)),5.67(1H,s),6.59-6.79(2H,6.65(dd,J=2.9,0.5Hz),6.72(dd,J=8.1,2. 9Hz)),6.81-7.06(4H,6.88(ddd,J=8.2,2.7,2.5Hz),6.90(td,J=2.7,0.5Hz), 6.99(ddd,J=7.9,2.7,2.5Hz),7.00(dd,J=8.1,0.5Hz)),7.14-7.34(3H,7.21( ddd,J=7.4,5.1,1.5Hz),7.22(ddd,J=8.2,7.9,0.5Hz),7.28(ddd,J=7.9,1.5, 0.6Hz)), 7.69 (1H,ddd,J=7.9,7.4,1.9Hz), 8.53(1H,ddd,J=5.1,1.9,0.6Hz).

[0081] The reaction yield was found to be 92% and the enantioselective ee value was 91%.

[0082] Comparative Example

[0083] Similar to Example 4, except that the ligand is replaced by a ligand in the following formula.

[0084]

[0085] The reaction yield was 45% and the enantioselective ee value was 46%.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing diphenyl-2-pyridylmethane derivatives, characterized in that: Compound D, butylboric acid, a catalyst, a ligand, an additive, an oxidant and an organic solvent 1 are mixed and stirred to react, and a diphenyl-2-pyridylmethane derivative E is obtained after separation and purification, and the chemical reaction formula thereof is: Wherein, R1 and R2 are independently selected from one of hydrogen, alkyl, alkoxy, aryl, and heteroaryl; The catalyst is Pd(OAc)2, and the ligand is Wherein, R is selected from alkyl or benzyl; The oxidant is p-benzoquinone, and the additive is silver oxide; The organic solvent 1 is tetrahydrofuran; The molar ratio of the compound D: butylboric acid: catalyst: ligand: oxidant: additive is 1:1:0.1:0.2:0.5:1.0; The reaction temperature is 50-60°C and the reaction time is 20-24h.

2. A method for synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 1, characterized in that: The preparation method of the ligand comprises the following steps: in the presence of an organic solvent 2, an acylating agent, a catalyst, and an organic base, a 7-carboxyl-1,1'-spirodihydroindane compound represented by formula B reacts with a compound represented by formula C to prepare a compound represented by formula A, and the reaction formula is as follows: Wherein, R is selected from an alkyl group or a benzyl group.

3. A method for synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 2, characterized in that: The acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, the organic base is triethylamine, and the organic solvent 2 is dichloromethane.

4. A method for synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 2, characterized in that: The molar ratio of the 7-carboxyl-1,1'-spirodihydroindane compound of formula B: the compound of formula C: the acylating agent: the organic base is 0.9-1:1-1.1:1.3-1.5:3; In terms of mol / L, the ratio of the 7-carboxy-1,1'-spirodihydroindane compound shown in formula A to the catalyst is 1:0.

01.

5. A method for synthesizing diphenyl-2-pyridylmethane derivatives as claimed in claim 2, characterized in that: The reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

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