Asymmetric synthesis method of chiral cyclopropane derivatives

Abstract

The present invention provides an asymmetric synthesis method of a chiral cyclopropane derivative. The method comprises dissolving compound 2 and an organic boron compound in a solvent, and obtaining a chiral cyclopropane derivative shown in formula 1 under the action of a catalyst, a ligand, an oxidant, an additive, and a base. The reaction equation is as follows: wherein R' is selected from one of an alkyl group, an alkoxy group, an aryl group, and a substituted aryl group, R is selected from one of an alkyl group, a cycloalkyl group, and a phenyl group, X is selected from a halogen, an alkoxy group, or an aryloxy group, and n is an integer of 1-3. When n is 2 or 3, X may be the same or different. The present invention has a very wide spectrum of substrate application range and functional group compatibility, high selectivity and high yield; and the method is simple, and is suitable for large-scale production and late modification of a series of drugs.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric synthesis, and in particular to an asymmetric synthesis method of chiral cyclopropane derivatives. Background Art

[0002] Asymmetric synthesis includes substrate-induced asymmetric synthesis and catalyst-induced asymmetric synthesis, and the most attractive and competitive one is chiral catalyst-induced asymmetric synthesis, which only requires a catalytic amount of chiral compounds to obtain new optically active substances. In particular, asymmetric catalytic reactions catalyzed by transition metal complexes are gaining more and more attention.

[0003] Cyclopropane derivatives are widely present in natural products and drug molecules and have good biological activities. For example, sponge extracts have antitumor activity, pyrethroid vinegar has insecticide activity, and coronatine has plant growth regulating activity. In the field of medicine, Imipenem is one of the most promising B2 lactam antibiotics developed in recent years. Although it has high antibiotic activity and strong execution of B2 lactam degradation, it is sensitive to renal metabolism in animals and humans, which can be inhibited by use with Cilastatin. Cilastatin is an inhibitor of hydrolases, and (+) 2,2-dimethylcyclopropanecarboxylic acid is an important intermediate in its synthesis.

[0004] Enantioselective CH bond modification methods are an important part of the asymmetric synthesis of chiral cyclopropane compounds. This method includes biomimetic methods, such as obtaining H atoms from cytochrome P450, and enzymatic processes; metal nitrile and metal carbene insertion methods; transition metal-mediated CH bond activation methods. There are two main methods for transition metal activation: one is desymmetric CH bond activation; the other is enantiotopic CH bond recognition of methylene by transition metal complexes. Transition metal-catalyzed CH bond activation is largely achieved through catalytic cycles, including palladium Pd(Ⅱ / 0), Pd(Ⅱ / Ⅳ), Pd(0 / Ⅱ), Pd(Ⅱ / Ⅱ), etc. Although these methods have greatly promoted asymmetric carbon-hydrogen bond functionalization, achieving high levels of enantioselectivity in these reactions remains a major challenge, mainly due to the lack of suitable ligand skeletons that can affect stereoinduction during CH cleavage. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides an asymmetric synthesis method for chiral cyclopropane derivatives, which solves the problem of low enantioselectivity caused by lack of a suitable ligand skeleton in the prior art.

[0006] In one aspect, the present invention provides an asymmetric synthesis method of a chiral cyclopropane derivative, comprising dissolving compound 2 and an organic boron compound in a solvent, and obtaining a chiral cyclopropane derivative shown in formula 1 under the action of a catalyst, a ligand, an oxidant, an additive, and a base. The reaction equation is as follows:

[0007]

[0008] Wherein, R' is selected from one of alkyl, alkoxy, aryl, substituted aryl, R is selected from one of alkyl, cycloalkyl, phenyl, X is selected from halogen, alkoxy or aryloxy, n is an integer of 1-3, when n is 2 or 3, X may be the same or different.

[0009] Furthermore, the organic boron compound is selected from one of phenylboronic acid pinacol ester, cyclohexene-1-boric acid pinacol ester, and butyl potassium trifluoroborate.

[0010] Furthermore, the catalyst is selected from Pd(OAc)2, the oxidant is selected from 1,4-benzoquinone, and the additive is Ag2CO3.

[0011] Furthermore, the base is selected from one of NaHCO3 and Na2CO3, and the solvent is selected from one of tert-amyl alcohol and DMSO.

[0012] Furthermore, the chemical structure of the ligand is shown in Formula 3:

[0013]

[0014] Among them, R2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

[0015] 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:

[0016]

[0017] Among them, R2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

[0018] Further, the reaction includes at least one of the following conditions:

[0019] (1) The organic solvent is dichloromethane;

[0020] (2) the acylating agent is oxalyl chloride, the catalyst is N,N-dimethylformamide, and the organic base is triethylamine;

[0021] (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;

[0022] (4) The reaction time is 5-7 hours, and the reaction temperature is 0°C-room temperature.

[0023] Furthermore, the molar equivalent ratio of the compound 2: organic boron compound: catalyst: ligand: additive: oxidant: base is 1:1:0.05:0.1:0.75:0.25:2.

[0024] Furthermore, in terms of mol / L, the ratio of compound 2 to solvent is 1:2.5.

[0025] Furthermore, the reaction temperature is 35-45°C, and the reaction time is 6-10h.

[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 PdCl2 (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, the demethylating agent is BBr3, 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 PdCl2(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 technical principle of the present invention is as follows: In the prior art, electron-deficient amides are used as weakly coordinating directing groups on cyclopropane substrates and electron-deficient carbamates on ligands to achieve high enantioselectivity. However, the method is limited to the functionalization of relatively acidic cyclopropyl CH bonds, and is not applicable to C(sp) bonds with low reaction activity. 3 )-H bond enantioselective functionalization, this method is difficult to achieve. In order to solve this problem, it is necessary to design and synthesize new chiral ligands. The present invention realizes the enantioselective functionalization of the methylene C(sp) in the cyclopropanecarboxylic acid derivatives by ligands. 3 )-H bonds undergo cross-coupling with organoboron compounds.

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

[0052] (1) It has a very broad spectrum of substrate applicability and functional group compatibility;

[0053] (2) High selectivity and high yield;

[0054] (3) The method is simple and suitable for large-scale production and late-stage modification of serial drugs. DETAILED DESCRIPTION

[0055] The technical solution of the present invention is further described below in conjunction with embodiments.

[0056] Example 1 Synthesis of ligand

[0057]

[0058] Under nitrogen protection, compound 4a (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 acyl chloride of 4a, and 10mL of dichloromethane was added for standby use. Another reaction bottle was added with 5a (11mmol), triethylamine (Et3N, 30mmol) and dichloromethane (30mL), and 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 with a yield of 95%.

[0059] The synthesis method of compound 4a comprises the following steps:

[0060]

[0061] 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%.

[0062] Under nitrogen protection, compound b (10 mmol) and dichloromethane (100 mL) were added to a reaction flask, and pyridine (15 mmol) was added to the reaction system. Then, 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 product c with a yield of 91%.

[0063] Under nitrogen protection, compound c (10 mmol), methanol (100 mmol), acetonitrile (100 mL), and triethylamine (30 mmol) were added to the reaction bottle. 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 d with a yield of 80%.

[0064] Under nitrogen protection, compound d (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 e with a yield of 65%.

[0065] Under nitrogen protection, compound e (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 f with a yield of 88%.

[0066] Under nitrogen protection, compound f (10 mmol), methanol (100 mmol), and HCOONa (30 mmol) were added to the 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 g with a yield of 84%.

[0067] 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%.

[0068] Example 2 Synthesis of ligand

[0069]

[0070] Under nitrogen protection, compound 4b (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 acyl chloride of 4b, and 10mL of dichloromethane was added for standby use. Another reaction bottle was added with 5b (10mmol), triethylamine (Et3N, 27mmol) and dichloromethane (30mL), and 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 with a yield of 91%.

[0071] Example 3 Synthesis of ligand

[0072]

[0073] Under nitrogen protection, compound 4c (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 acyl chloride of 4c, and 10mL of dichloromethane was added for standby use. Another reaction bottle was added with 5c (11mmol), triethylamine (Et3N, 30mmol) and dichloromethane (30mL), and 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 with a yield of 93%.

[0074] Example 4 N-(4-cyano-2,3,5,6-tetrafluorophenyl)-1-methyl-2-phenyl-2λ 3 -Synthesis of cyclopropane-1-carboxamide

[0075]

[0076] Under nitrogen conditions, 1mmol of compound 2-1, 1mmol of phenylboronic acid pinacol ester, 0.05mmol of palladium acetate (Pd(OAc)2), 0.1mmol of the ligand prepared in Example 1, 0.75mmol of Ag2CO3, 0.25mmol of 1,4-benzoquinone (BQ), 2mmol of NaHCO3 and 2.5ml of tert-amyl alcohol were mixed and reacted at 40°C for 8h to obtain the target product 1-1. After testing, the yield of the target product 1-1 was 95% and the ee value was 98%.

[0077] Example 5 1-(Benzyl)-N-(4-cyano-2,3,5,6-tetrafluorophenyl)-2-phenyl-2λ 3 -Synthesis of cyclopropane-1-carboxamide

[0078]

[0079] Under nitrogen conditions, 1mmol of compound 2-2, 1mmol of phenylboronic acid pinacol ester, 0.05mmol of palladium acetate (Pd(OAc)2), 0.1mmol of the ligand prepared in Example 1, 0.75mmol of Ag2CO3, 0.25mmol of 1,4-benzoquinone (BQ), 2mmol of NaHCO3 and 2.5ml of tert-amyl alcohol were mixed and reacted at 45°C for 6h to obtain the target product 1-2. After testing, the yield of the target product 1-2 was 94% and the ee value was 96%.

[0080] Example 6 2-butyl-N-(4-cyano-2,3,5,6-tetrafluorophenyl)-1-methoxy-2λ 3-Synthesis of cyclopropane-1-carboxamide

[0081]

[0082] Under nitrogen conditions, 1mmol of compound 2-3, 1mmol of potassium butyl trifluoroborate, 0.05mmol of palladium acetate (Pd(OAc)2), 0.1mmol of the ligand prepared in Example 1, 0.75mmol of Ag2CO3, 0.25mmol of 1,4-benzoquinone (BQ), 2mmol of NaHCO3 and 2.5ml of tert-amyl alcohol were mixed and reacted at 40°C for 10h to obtain the target product 1-3. After testing, the yield of the target product 1-3 was 90% and the ee value was 95%.

[0083] 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 chiral cyclopropane derivatives, characterized in that: The method comprises dissolving compound 2 and an organic boron compound in a solvent, and obtaining a chiral cyclopropane derivative shown in formula 1 under the action of a catalyst, a ligand, an oxidant, an additive, and a base. The reaction equation is as follows: ， wherein R' is selected from one of alkyl, alkoxy, aryl, and substituted aryl, R is selected from one of alkyl, cycloalkyl, and phenyl, wherein ArF is 4-cyano-2,3,5,6-tetrafluorophenyl; The organic boron compound is selected from one of phenylboronic acid pinacol ester, cyclohexene-1-boronic acid pinacol ester, and butyl potassium trifluoroborate; The catalyst is selected from Pd(OAc)2, the oxidant is selected from 1,4-benzoquinone, and the additive is Ag2CO3; The base is selected from one of NaHCO3 and Na2CO3, and the solvent is selected from one of tert-amyl alcohol and DMSO; The chemical structure of the ligand is shown in Formula 3: ， Among them, R2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

2. The asymmetric synthesis method of a chiral cyclopropane derivative 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: ， Among them, R2 is one of alkyl, alkoxy, phenyl, substituted phenyl, benzyl, and substituted benzyl.

3. The asymmetric synthesis method of a chiral cyclopropane derivative according to claim 2, 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.

4. The asymmetric synthesis method of a chiral cyclopropane derivative according to claim 1, characterized in that: The molar equivalent ratio of the compound 2: organic boron compound: catalyst: ligand: additive: oxidant: base is 1:1:0.05:0.1:0.75:0.25:

2.

5. The asymmetric synthesis method of a chiral cyclopropane derivative according to claim 1, characterized in that: In terms of mol / L, the ratio of compound 2 to solvent is 1:2.

5.

6. The asymmetric synthesis method of a chiral cyclopropane derivative according to claim 1, characterized in that: The reaction temperature is 35-45°C and the reaction time is 6-10h.

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