A chiral spirodihydroindane ligand and its preparation method and application

Abstract

The present invention provides a chiral spirodihydroindane ligand and a preparation method and application thereof. The chiral spirodihydroindane ligand has a compound of formula A or an acceptable salt thereof: wherein R1 is selected from one of hydrogen, alkyl, alkoxy, aryl, and heteroaryl, and R2 is selected from one of alkyl, alkoxy, aryl, and heteroaryl. The chiral spirodihydroindane ligand of the present invention has high selectivity and high yield, and has wide substrate applicability.

Description

Technical Field

[0001] The invention relates to the technical field of spirocyclic ligands, and in particular to a chiral spirodihydroindane ligand and a preparation method and application thereof. Background Art

[0002] In organisms, bioactive enzymes, proteins, nucleic acids and cell surface receptors usually have chirality. When bioactive substances interact and recognize with receptors, the chemical reactions in the organisms combine with specific chiral small molecules in an enantioselective manner. Based on the organic matter contained in organisms, they have the characteristics of chiral recognition. If this feature is used reasonably, many difficult diseases can be solved. (S)-configuration ibuprofen is a non-steroidal, highly effective antipyretic and analgesic, while (R)-configuration ibuprofen (Lbuprofen) is completely inactive and only increases the metabolic burden in the body.

[0003] At present, chiral compounds are mainly obtained through the following three ways: racemate resolution, asymmetric synthesis induced by chiral substrates, and asymmetric catalytic synthesis. Among them, racemate resolution can only obtain a single isomer at most 50%, which limits the efficiency of preparing chiral compounds. Substrate-induced asymmetric synthesis is to synthesize chiral compounds through the chiral units originally in the substrate, using the chiral induction effect. Although this method can obtain optically pure chiral molecules, stoichiometric optically pure compounds are required in the reaction, and some chiral auxiliary groups cannot be recycled, resulting in waste. Asymmetric catalysis is the process of using a chiral catalyst to convert a potential chiral substrate into an optically active product with a specific configuration.

[0004] In asymmetric catalytic reactions, chiral ligands play a vital role in chiral control and catalytic efficiency. Chiral ligands control the chiral environment around the metal, thereby affecting the optical activity of the product. The chiral control and catalytic activity of the ligand are mainly affected by the following factors: the rigidity of the ligand skeleton, the spatial structure of the ligand skeleton and the electronic properties of the coordinating atoms, among which the skeleton structure of the ligand has a very important influence. Although there are many chiral ligands, only a few ligands have high versatility and applicability in forming catalysts with metals. 1,1'-Spirodihydroindane ligands are a variety of ligands developed based on the spirodihydroindane skeleton, including monophosphines, bisphosphines, phosphine-oxazoline ligands, phosphine-nitrogen ligands, bisoxazoline ligands, phosphine-amino-pyridines and chiral phosphonic acids, etc., with C2 symmetry, as well as strong rigidity, high stability, and easy modification. Zhou Qilin et al. derived and synthesized the chiral phosphoramidite ligand SIPHOS based on chiral 1,1'-spirodihydroindane-7,7'-diphenol (SPINOL), and achieved excellent enantioselectivity in the Rh-catalyzed asymmetric hydrogenation reduction of α-dehydroamino acid esters and aromatic enamides, which has a greater catalytic advantage on some substrates than the traditional BINOL-derived ligands. Subsequently, a series of organometallic ligands based on the spirodihydroindane skeleton were developed to catalyze asymmetric hydrogenation reactions, asymmetric carbon-carbon bonds and carbon-heterobond bonding reactions.

[0005] However, in the bonding reactions of asymmetric carbon-carbon bonds and carbon-hetero bonds, since the bond energy of the CH bond is very high and the electronegativity of carbon and hydrogen are very close, the polarity of the CH bond is very small. These factors make it inert. Selective catalytic activation of the CH bond and construction of other carbon-containing chemical bonds under mild conditions poses dual challenges of thermodynamics and kinetics, which is a bottleneck problem restricting major breakthroughs in molecular synthesis and preparation.

[0006] The traditional transition metal-catalyzed cross-coupling reaction has obvious disadvantages, such as the unavailability of transition metal catalysts and their high prices. The new direct CH activation also faces many challenges, such as the large amount of metal catalysts required, low selectivity and yield, and the strict requirements of the substrate for CH bond activation, which has great limitations. Therefore, there is an urgent need to develop a new chiral ligand catalyst with wide substrate applicability, high selectivity and high yield. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present invention provides a chiral spirodihydroindane ligand and a preparation method and application thereof, which solve the problems of low selectivity and low yield and stringent requirements on substrates in the prior art.

[0008] In one aspect, the present invention provides a chiral spirodihydroindane ligand having a compound of formula A or an acceptable salt thereof:

[0009]

[0010] Wherein, R1 is selected from one of hydrogen, alkyl, alkoxy, aryl and heteroaryl, and R2 is selected from one of alkyl, alkoxy, aryl and heteroaryl.

[0011] Furthermore, the chiral spirodihydroindane ligand has the following structural formula:

[0012]

[0013] Wherein, R2 is selected from one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

[0014] In another aspect, the present invention provides a method for preparing a chiral spirodihydroindane ligand, comprising the following steps: reacting a 7-carboxyl-1,1'-spirodihydroindane compound represented by formula B with a compound represented by formula C in the presence of an organic solvent, an acylating agent, a catalyst, and an organic base to prepare a compound represented by formula A, and the reaction formula is as follows:

[0015]

[0016] Wherein, R1 is selected from one of hydrogen, alkyl, alkoxy, aryl and heteroaryl, and R2 is selected from one of alkyl, alkoxy, aryl and heteroaryl.

[0017] Furthermore, the organic solvent is dichloromethane.

[0018] Furthermore, the acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine.

[0019] 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;

[0020] 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.

[0021] Furthermore, the reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

[0022] In another aspect, the present invention provides a transition metal catalyst comprising the chiral spirodihydroindane ligand.

[0023] In another aspect, the present invention provides a use of a chiral spirodihydroindane ligand in catalyzing an asymmetric reaction.

[0024] Furthermore, the chiral spirodihydroindane ligand forms a transition metal complex with palladium as a catalyst.

[0025] In one embodiment of the present invention, the preparation method of the 7-carboxyl-1,1'-spirodihydroindane compound represented by formula B comprises:

[0026] 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:

[0027]

[0028] 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;

[0029] (2) Compound 2 is mixed with organic solvent 2, and a first sulfonation reagent and a second base are added to generate compound 3;

[0030] (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;

[0031] (4) Compound 4 is added to organic solvent 4, and demethylation reaction occurs under the action of a demethylating agent to generate compound 5;

[0032] (5) Compound 5 is added to an organic solvent 5, and a second sulfonating reagent and a fourth base are added to generate compound 6;

[0033] (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;

[0034] (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.

[0035] Preferably, in step (1), the organic solvent 1 is tetrahydrofuran, the methylating agent is iodomethane, and the first base is sodium hydride; the reaction temperature is 0-10° C., and the reaction time is 6-12 h;

[0036] 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;

[0037] 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;

[0038] 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;

[0039] 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;

[0040] In step (6), the organic solvent 6 is methanol; the second catalyst is PdCl2(dppf); the second reaction substrate is HCOONa;

[0041] 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.

[0042] Preferably, in step (1), in a molar ratio, 1,1'-spirodihydroindane-7,7'-diol:methylating agent:first base=2:1:1;

[0043] In step (2), in terms of molar ratio, compound 2: first sulfonation reagent: second base = 10:13:15;

[0044] In step (3), in terms of molar ratio, compound 3: first catalyst: first reaction substrate: third base = 10:0.5:100:30;

[0045] In step (4), the molar ratio of compound 4 to first demethylating agent is 1:3;

[0046] In step (5), in terms of molar ratio, compound 5: second sulfonation reagent: fourth base = 10:13:15;

[0047] In step (6), in terms of molar ratio, compound 6: second catalyst, second reaction substrate = 10:0.5:30;

[0048] In step (7), the molar ratio of compound 7 to fifth base is 1:10.

[0049] The technical principle of the present invention is:

[0050] The present invention introduces an N-acyl amino acid structure into a spirocyclic ring, and designs a novel spirocyclic ligand ((R)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7-carbonyl)-α-amino acid derivative with C2 symmetry. Studies have shown that the ligand and the cationic complex of palladium can highly selectively activate the CH bond, promote the formation of CC / CX (carbon-hetero) bonds, and obtain the desired target product with an enantioselectivity of more than 90%.

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] 1) The chiral spirodihydroindane ligand of the present invention has a low catalyst dosage and is highly selective and has a high yield.

[0053] 2) The chiral spirodihydroindane ligand of the present invention has a wide range of substrate applicability.

[0054] 3) The chiral spirodihydroindane ligand of the present invention is used to catalyze asymmetric reactions and can effectively inhibit side reactions.

[0055] 4) The synthesis route of the present invention is simple, the synthesis method is simple, and the synthesis cost is low. DETAILED DESCRIPTION

[0056] The technical solution of the present invention is further described below in conjunction with embodiments.

[0057] Example 1 Synthesis of ((R)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7-carbonyl)-L-alanine

[0058]

[0059] 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%;

[0060] Wherein, the preparation method of compound B1 is as follows:

[0061]

[0062] 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%.

[0063] 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%.

[0064] 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%.

[0065] 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%.

[0066] 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%.

[0067] 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%.

[0068] 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%.

[0069] Example 2 Synthesis of (S)-2-((R)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7-amide)butyric acid

[0070]

[0071] Under nitrogen protection, compound B2 (9mmol), N, N-dimethylformamide (DMF, 90μL) and dichloromethane (DCM, 10mL) were added to a 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 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 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%.

[0072] Example 3 Synthesis of ((R)-2,2',3,3'-tetrahydro-1,1'-spirobi[indene]-7-carbonyl)-L-phenylalanine

[0073]

[0074] 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℃ 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%.

[0075] Example 4 Synthesis of N-(4-cyano-2,3,5,6-tetrafluorophenyl)-2-(4-methoxybenzyl)-2,3,3-trimethylbutyramide

[0076]

[0077] 0.1 mmol of compound 2-1 (1.0 equiv), 0.2 mmol of potassium phenylborate (Ar-BF3K, 2 equiv), 0.01 mmol of palladium acetate (Pd(OAc)2, 0.1 equiv), 0.02 mmol of the ligand prepared in Example 1 (0.2 equiv), 0.2 mmol of silver carbonate (Ag2CO3, 2 equiv), 0.05 mmol of 1,4-benzoquinone (BQ., 0.5 equiv), 0.25 mmol of Na2CO3 (2.5 equiv), 0.5 mmol of H2O (5 equiv) and 0.5 mL of tert-amyl alcohol ( t AmylOH) in a nitrogen environment, mixed and stirred and heated to 50°C, reacted for 20 hours, filtered, washed, and concentrated to obtain the target compound 1-1.

[0078] After testing, the yield of the target compound 1-1 was 95% and the ee value was 99%.

[0079] 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 chiral spirodihydroindane ligand, characterized in that: A compound having formula A or an acceptable salt thereof: Wherein, R1 is selected from hydrogen, and R2 is selected from alkyl.

2. A chiral spirodihydroindane ligand according to claim 1, characterized in that: The structural formula of the chiral spirodihydroindane ligand is as follows: Wherein, R2 is selected from an alkyl group.

3. A method for preparing a chiral spirodihydroindane ligand according to claim 1 or 2, characterized in that: The following steps are involved: In the presence of an organic solvent, 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. The reaction formula is as follows: ， wherein R1 is selected from hydrogen, and R2 is selected from alkyl; The organic solvent is dichloromethane; The acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine; The molar ratio of the 7-carboxyl-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; In terms of mol / L, the ratio of 7-carboxyl-1,1'-spirodihydroindane compound represented by formula A to catalyst is 1:0.01; The reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

4. A transition metal catalyst, characterized in that: Contains the chiral spirodihydroindane ligand according to claim 1 or 2, and the transition metal catalyst is a palladium transition metal catalyst.

5. Use of the chiral spirodihydroindane ligand according to claim 1 or 2 in catalyzing an asymmetric reaction, wherein the asymmetric reaction is as follows: 。 6. The use according to claim 5, characterized in that: The chiral spirodihydroindane ligand forms a transition metal complex with palladium transition metal as a catalyst.

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