A method for asymmetric synthesis of cyclobutane derivatives

Abstract

The present invention provides a method for asymmetric synthesis of cyclobutane derivatives. Compound 2 and PhBpin are used as substrates, and are mixed with a catalyst, a ligand, an additive, an oxidant, a base, water, and a solvent for reaction to generate a target compound 1. The reaction formula is as follows: wherein R 1 The present invention forms a chiral complex by using a chiral α-amino spirocyclic ligand and a Pd(II) center, thereby achieving high yield and high enantioselectivity and providing a new approach to the asymmetric synthesis of cyclobutane derivatives.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric synthesis, in particular to a method for asymmetric synthesis of cyclobutane derivatives. Background Art

[0002] Cyclobutane skeleton structures are widely present in natural and synthetic drug molecules. Many of these compounds have significant anticancer and antibacterial biological activities, such as Ivosidenib for the treatment of acute myeloid leukemia, Lobaplatin, Carboplatin, Dicycloplatin for the treatment of small cell lung cancer, solid tumors or non-small cell lung cancer, Flucilovine F18 for the treatment of prostate cancer, and natural drugs such as (-)-grandisol, (β)-bourbonene, Atlanticone D, etc. At the same time, due to the tension of cyclobutane itself, it can undergo unique ring-opening or ring-expansion reactions under relatively mild conditions, which has promoted the development of a variety of synthetic methods. Therefore, cyclobutane derivatives have high research value both in organic synthesis and in the field of biology.

[0003] Since cyclobutane structures are widely present in biologically active natural products and drugs, their enantioselective synthesis has always received close attention, but the chiral all-carbon quaternary carbon centers present in related molecules are often difficult to construct efficiently. At present, the synthesis of cyclobutane is mainly achieved through two strategies to construct chiral centers: one is enantioselective cyclization reactions, involving cycloaddition, cyclization and ring expansion reactions; the other is enantioselective functionalization of chiral cyclobutane or cyclobutene intermediates, such as α-position functionalization, desymmetrization, carbon-hydrogen bond activation, etc. Carbon-hydrogen bond activation is currently a hot topic of research. However, there are currently few effective methods for carbon-hydrogen bond activation, and its activity and selectivity are difficult to regulate.

[0004] Therefore, developing various transition metal catalysts to efficiently activate CH bonds 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 of inserting into the CH bond, thereby obtaining a highly selective, high-yield, simple, and functional group-compatible asymmetric synthesis of cyclobutane derivatives. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a method for asymmetric synthesis of cyclobutane derivatives, which solves the problems of low selectivity and low yield in the prior art.

[0006] The purpose of the present invention is to provide a method for asymmetric synthesis of cyclobutane derivatives, using compound 2 and PhBpin as substrates, mixed with a catalyst, a ligand, an additive, an oxidant, a base, water, and a solvent for reaction to generate a target compound 1, and the reaction formula is as follows:

[0007]

[0008] Among them, R 1 One selected from alkyl, alkoxy, aromatic and heteroaryl.

[0009] Furthermore, R 1 It is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl and benzyl.

[0010] Furthermore, the catalyst is Pd(OAc) 2 .

[0011] Furthermore, the oxidant is 1,4-benzoquinone and the additive is Ag. 2 CO 3 .

[0012] Further, the base is Na 2 CO 3 , K 2 CO 3 In one of the above methods, the solvent is tert-amyl alcohol.

[0013] Furthermore, in molar ratio, compound 2:PhBpin:catalyst:ligand:additive:oxidant:base:water=1:2:0.1:0.15:2.5:0.5:2:5; in mol / L, compound 2:solvent=1:5.

[0014] Furthermore, the chemical structure of the ligand is shown in Formula 3:

[0015]

[0016] Among them, R 2 It is one of an alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group.

[0017] Furthermore, the preparation method of the ligand is to react a 7-carboxy-1,1'-spirodihydroindane compound shown in Formula 4 with a compound of Formula 5 in the presence of an organic solvent, an acylating agent, a catalyst, and an organic base to prepare a compound shown in Formula 3, and the reaction formula is as follows:

[0018]

[0019] Among them, R 2It is one of an alkyl group, an alkoxy group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group.

[0020] Further, the reaction includes at least one of the following conditions:

[0021] (1) The organic solvent is dichloromethane;

[0022] (2) the acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine;

[0023] (3) The molar ratio of the 7-carboxyl-1,1'-spirodihydroindane compound of Formula 4: the compound of Formula 5: the acylating agent: the organic base is 0.9-1:1-1.1:1.3-1.5:3; in terms of mol / L, the 7-carboxyl-1,1'-spirodihydroindane compound of Formula 4: the catalyst is 1:0.01;

[0024] (4) The reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

[0025] Furthermore, the reaction temperature is 60-70°C and the reaction time is 12-24h.

[0026] In one embodiment of the present invention, the preparation method of the 7-carboxyl-1,1'-spirodihydroindane compound shown in Formula 4 comprises:

[0027] 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:

[0028]

[0029] Specifically, the process comprises the following steps: (1) adding 1,1'-spirodihydroindane-7,7'-diol into an organic solvent 1 to generate a compound b under the action of a methylating agent and a first base;

[0030] (2) Compound b is mixed with organic solvent 2, and a first sulfonation reagent and a second base are added to generate compound c;

[0031] (3) Compound c 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 d;

[0032] (4) Compound d is added to organic solvent 4, and demethylation reaction occurs under the action of a demethylating agent to generate compound e;

[0033] (5) Compound e is added to organic solvent 5, and a second sulfonation reagent and a fourth base are added to generate compound f;

[0034] (6) Compound f 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 g;

[0035] (7) Compound g 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 of formula 4.

[0036] 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;

[0037] 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;

[0038] In step (3), the organic solvent 3 is acetonitrile and methanol; the third base is triethylamine; the first catalyst is PdCl 2 (dppf); the first reaction substrate is methanol; the reaction temperature is 80°C, and the reaction time is 16-24h;

[0039] In step (4), the organic solvent 4 is DCM and the demethylation agent is BBr 3 , the reaction temperature is -20-10°C, and the reaction time is 6-8h;

[0040] 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;

[0041] In step (6), the organic solvent 6 is methanol; the second catalyst is PdCl 2 (dppf); the second reaction substrate is HCOONa;

[0042] 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.

[0043] Preferably, in step (1), in a molar ratio, 1,1'-spirodihydroindane-7,7'-diol:methylating agent:first base=2:1:1;

[0044] In step (2), in terms of molar ratio, compound 2: first sulfonation reagent: second base = 10:13:15;

[0045] In step (3), in terms of molar ratio, compound 3: first catalyst: first reaction substrate: third base = 10:0.5:100:30;

[0046] In step (4), the molar ratio of compound 4 to first demethylating agent is 1:3;

[0047] In step (5), in terms of molar ratio, compound 5: second sulfonation reagent: fourth base = 10:13:15;

[0048] In step (6), in terms of molar ratio, compound 6: second catalyst, second reaction substrate = 10:0.5:30;

[0049] In step (7), the molar ratio of compound 7 to fifth base is 1:10.

[0050] The term "PhBpin" is phenylboronic acid pinacol ester, chemically known as 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane.

[0051] The term "Ar F " is a fluorine-substituted aryl group, including but not limited to fluorobenzene, fluorine-substituted benzophenone and fluorine-substituted diaryl sulfone, etc. In the embodiment of the present invention, Ar F Selected from 2,3,5,6-tetrafluorobenzonitrile group.

[0052] Compared with the prior art, the present invention has the following beneficial effects: the present invention realizes the enantioselectivity of the cross-coupling of the methylene CH bond in the cyclobutane derivative with the aromatic boric acid ester (phenylboronic acid pinacol ester). The chiral complex is formed by the chiral α-amino spirocyclic ligand and the Pd (II) center, achieving high yield and high enantioselectivity. This new chiral catalyst provides a new way for the asymmetric synthesis of cyclobutane derivatives. DETAILED DESCRIPTION

[0053] The technical solution of the present invention is further described below in conjunction with embodiments.

[0054] Example 1 Synthesis of ligand

[0055]

[0056] Under nitrogen protection, compound 4a (10 mmol), N,N-dimethylformamide (DMF, 100 μL) and dichloromethane (DCM, 10 mL) were added to the reaction flask, and oxalyl chloride (15 mmol) 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 and stirred for reaction for 2-3 hours. The mixture was concentrated to dryness to obtain the acyl chloride of 4a, and 10 mL of dichloromethane was added for later use. In another reaction flask, 5a (11 mmol), triethylamine (Et3 N, 30 mmol) and dichloromethane (30 mL), the acyl chloride solution of 4a obtained in the previous step was slowly added dropwise to 5a and triethylamine, stirred at room temperature for 3-4 hours, and the product 3a was obtained by quenching column chromatography in a yield of 95%.

[0057] The synthesis method of compound 4a comprises the following steps:

[0058]

[0059] Under nitrogen protection, compound a (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 b, with a yield of 77%.

[0060] Under nitrogen protection, compound b (10 mmol) and dichloromethane (100 mL) were added to the reaction flask, and pyridine (15 mmol) was added to the reaction system. Then, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2 Oin 60mL DCM), control the temperature at 0-10°C, react for 6-12 hours after the completion of the dropwise reaction, and obtain product c by quenching column chromatography with a yield of 91%.

[0061] Under nitrogen protection, compound c (10 mmol), methanol (100 mmol), acetonitrile (100 mL), and triethylamine (30 mmol) were added to the reaction flask. PdCl was then added to the system. 2 (dppf) (0.5 mmol), after addition, replace CO three times, pressurize to 2.5 MPa, react at 80°C for 16-24 hours, and obtain product d by quenching column chromatography. The yield is 80%.

[0062] Under nitrogen protection, compound d (10 mmol) and DCM (500 mL) were added to the reaction flask. Then BBr was added dropwise to the system. 3 (30 mmol), temperature controlled at -20°C-10°C. After addition, react for 6-8 hours, and the reaction solution is subjected to quench column chromatography to obtain compound e with a yield of 65%.

[0063] Under nitrogen protection, compound e (10 mmol) and dichloromethane (100 mL) were added to the reaction flask, and pyridine (15 mmol) was added to the reaction system. Then, a dichloromethane solution of trifluoromethanesulfonic anhydride (13 mmol Tf 2Oin 60mL DCM), control the temperature at 0-10°C, react for 6-12 hours after the completion of the dropwise addition, and obtain compound f by quenching column chromatography with a yield of 88%.

[0064] Under nitrogen protection, compound f (10 mmol), methanol (100 mmol) and HCOONa (30 mmol) were added to the reaction flask. PdCl was then added to the system. 2 (dppf) (0.5 mmol), after addition, replace nitrogen three times, react at 80°C for 16-24 hours, and obtain compound g by quenching column chromatography. The yield is 84%.

[0065] Under nitrogen protection, compound g (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 was completed, 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 4a with a yield of 80%.

[0066] Example 2 Synthesis of ligand

[0067]

[0068] Under nitrogen protection, compound 4b (9 mmol, same as in Example 1), N,N-dimethylformamide (DMF, 90 μL) and dichloromethane (DCM, 10 mL) were added to a reaction flask, and oxalyl chloride (13 mmol) 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 and stirred for reaction for 2-3 hours. The mixture was concentrated to dryness to obtain the acyl chloride of 4b, and 10 mL of dichloromethane was added for later use. In another reaction flask, 5b (10 mmol), triethylamine (Et 3 N, 30 mmol) and dichloromethane (30 mL), the acyl chloride solution of 4b obtained in the previous step was slowly added dropwise to 5b and triethylamine, stirred at room temperature for 3-4 hours, and the product 3b was obtained by quenching column chromatography in a yield of 91%.

[0069] Example 3 Synthesis of ligand

[0070]

[0071] Under nitrogen protection, compound 4c (10 mmol, same as in Example 1), N,N-dimethylformamide (DMF, 100 μL) and dichloromethane (DCM, 10 mL) were added to a reaction flask, and oxalyl chloride (15 mmol) 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 and reacted for 2-3 hours, and concentrated to dryness to obtain the acyl chloride of 4c. 10 mL of dichloromethane was added for later use. In another reaction flask, 5c (11 mmol), triethylamine (Et3 N, 30 mmol) and dichloromethane (30 mL), the acyl chloride solution of 4c obtained in the previous step was slowly added dropwise to 5c and triethylamine, stirred at room temperature for 3-4 hours, and the product 3c was obtained by quenching column chromatography in a yield of 93%.

[0072] Example 4

[0073]

[0074] Substrate 2a was added into a 10 mL sealed test tube (0.1 mmol, 1.0 equiv), Pd(OAc) 2 (0.1 equiv), PhBPin (2.0 equiv), the ligand prepared in Example 1 (0.15 equiv), Ag 2 CO 3 (2.5equiv), Na 2 CO 3 (2.0equiv), BQ(0.5equiv), H 2 O(5.0equiv), t AmylOH (0.5 mL). The reaction vessel was evacuated and backfilled with nitrogen. The reaction mixture was stirred and heated to 70°C for 15 h. Purification was performed to obtain the target product 1a. The yield of the target compound 1-1 was 92% and the ee value was 98%.

[0075] Example 5

[0076]

[0077] Substrate 2b was added into a 10 mL sealed test tube (0.1 mmol, 1.0 equiv), Pd(OAc) 2 (0.1equiv), PhBPin (2.0equiv), the ligand prepared in Example 2 (0.15equiv), Ag 2 CO 3 (2.5equiv), Na 2 CO 3 (2.0equiv), BQ(0.5equiv), H 2 O(5.0equiv), t AmylOH (0.5 mL). The reaction vessel was evacuated and backfilled with nitrogen. The reaction mixture was stirred and heated to 60°C for 24 h. Purification was performed to obtain the target product 1b. The yield of the target compound 1-1 was 94% and the ee value was 97%.

[0078] Comparative Example

[0079] Similar to Example 4, except that the chemical structure of the ligand used is as follows:

[0080]

[0081] After testing, the yield was 34% and the ee value was 23%.

[0082] 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 asymmetric synthesis of cyclobutane derivatives, characterized in that: Compound 2 and PhBpin are used as substrates, and are mixed with a catalyst, a ligand, an additive, an oxidant, a base, water, and a solvent to react to generate the target compound 1. The reaction formula is as follows: Wherein, R1 is selected from one of alkyl, alkoxy, aromatic and heteroaryl groups; Ar F is a fluorine-substituted aryl group; The catalyst is Pd(OAc)2; The oxidant is 1,4-benzoquinone, and the additive is Ag2CO3; The base is one of Na2CO3 and K2CO3, and the solvent is tert-amyl alcohol; The chemical structure of the ligand is shown in Formula 3: Wherein, R2 is an alkyl group.

2. The method for asymmetric synthesis of cyclobutane derivatives according to claim 1, characterized in that: R1 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, phenyl and benzyl.

3. The method for asymmetric synthesis of cyclobutane derivatives according to claim 1, characterized in that: In terms of molar ratio, compound 2:PhBpin:catalyst:ligand:additive:oxidant:base:water=1:2:0.1:0.15:2.5:0.5:2:5; in terms of mol / L, compound 2:solvent=1:

5.

4. The method for asymmetric synthesis of cyclobutane derivatives according to claim 1, characterized in that: The preparation method of the ligand is to react a 7-carboxyl-1,1'-spirodihydroindane compound shown in Formula 4 with a compound of Formula 5 in the presence of an organic solvent, an acylating agent, a catalyst, and an organic base to prepare a compound shown in Formula 3. The reaction formula is as follows: Wherein, R2 is an alkyl group.

5. The method for asymmetric synthesis of cyclobutane derivatives according to claim 4, characterized in that: The reaction comprises at least one of the following conditions: (1) The organic solvent is dichloromethane; (2) the acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine; (3) The molar ratio of the 7-carboxyl-1,1'-spirodihydroindane compound of Formula 4: the compound of Formula 5: the acylating agent: the organic base is 0.9-1:1-1.1:1.3-1.5:3; in terms of mol / L, the 7-carboxyl-1,1'-spirodihydroindane compound of Formula 4: the catalyst is 1:0.01; (4) The reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

6. The method for asymmetric synthesis of cyclobutane derivatives according to claim 1, characterized in that: The reaction temperature is 60-70°C and the reaction time is 12-24h.

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