Synthesis method and application of chiral 3, 4-disubstituted pyrrolidone compound

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a synthesis method and application of a chiral 3, 4-disubstituted pyrrolidone compound. The synthesis method comprises the following steps: mixing a # imgabs0 # hydrogen source, a catalyst and a solvent, and reacting to obtain a chiral 3, 4-disubstituted pyrrolidone compound; wherein R1 and R2 are respectively and independently substituted or unsubstituted aryl or alkyl; the substitution is selected from halogen or C1-C10 alkyl. According to the synthetic method provided by the invention, the yield exceeds 92%, for example, the yield gt; the enantioselectivity ee is not less than 95%, and the diastereoselectivity drgt is not less than 95%; 20: 1.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method and application of chiral 3,4-disubstituted pyrrolidone compounds. Background Art

[0002] Chiral 3,4-disubstituted pyrrolidone molecular skeletons are widely present in bioactive molecules, drugs, and natural product fragments, and they often exhibit important physiological activities. Therefore, the synthesis of chiral 3,4-disubstituted pyrrolidone compounds is of great significance in the fields of medicinal chemistry and synthetic chemistry. It is recorded in the prior art that a gold-catalyzed cycloisomerization of N-alkenyl β-ketoamide synthesized a 3,4-disubstituted pyrrolidone compound with moderate stereoselectivity. This transformation requires the preparation of chiral N-alkenyl amide as a substrate through a palladium-catalyzed dynamic kinetic asymmetric resolution process, and the reaction conditions are relatively harsh. A series of chiral cis-3.4 functionalized hydroxypyrrolidones were synthesized by continuous organic small molecule-catalyzed aldol condensation reaction, reductive amination and cyclization. In addition, chiral 3,4-disubstituted pyrrolidone compounds can also be synthesized from optically pure oxirane amino esters. However, these existing methods generally have shortcomings such as limited substrate range, low efficiency, poor step economy, and harsh reaction conditions. It is still a great challenge to develop simple and effective strategies to construct chiral substituted pyrrolidones.

[0003] The patent (CN111793017A) synthesizes a series of chiral 3,4-disubstituted pyrrolidone compounds by combining single asymmetric transfer hydrogenation with dynamic kinetic resolution strategy, which has high conversion rate and excellent stereoselectivity. However, this method only achieves the formal reduction of a carbon-carbon double bond, and the synthesis of some of its substrates still requires the use of palladium carbon / hydrogen, and the use of hydrogen requires high-pressure equipment, harsh reaction conditions, and high risk. Therefore, it is very necessary to develop a new method for synthesizing chiral 3,4-disubstituted pyrrolidone compounds, which does not require the use of hydrogen and has mild reaction conditions. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a synthesis method and application of chiral 3,4-disubstituted pyrrolidone compounds. The synthesis method of the present invention has mild conditions and simple operation, and the target compound is obtained with high yield and high stereoselectivity, and the substrate has a wide range of application and the product has high application value.

[0005] The present invention provides a method combining double asymmetric transfer hydrogenation and dynamic kinetic splitting strategy, realizing asymmetric reduction of formal carbon-oxygen double bonds and carbon-carbon double bonds, and constructing chiral 3,4-disubstituted pyrrolidone compounds in one pot. Compared with the asymmetric hydrogenation reaction using hydrogen as the hydrogen source, the asymmetric transfer hydrogenation of the present invention avoids the use of hydrogen, does not require special equipment that withstands high pressure, the hydrogen source is cheap and easy to obtain, the reaction conditions are milder, the operation is simpler, and the danger is greatly reduced. At present, there is no report on the method of synthesizing chiral 3,4-disubstituted pyrrolidone compounds by double asymmetric transfer hydrogenation method.

[0006] The first aspect of the present invention provides a method for synthesizing chiral 3,4-disubstituted pyrrolidone compounds.

[0007] Specifically, a method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound comprises the following steps:

[0008] A hydrogen source, a catalyst and a solvent are mixed and reacted to obtain the chiral 3,4-disubstituted pyrrolidone compound;

[0009] Among them, R 1 , R 2 are independently substituted or unsubstituted aryl or alkyl;

[0010] The substitution is selected from halogen or C1-C10 alkyl.

[0011] Preferably, R 1 , R 2 Each is independently a substituted or unsubstituted C6-C30 aryl group or C1-C8 alkyl group.

[0012] Preferably, the halogen comprises F, Cl or Br.

[0013] Preferably, the alkyl group includes methyl, ethyl, propyl or butyl.

[0014] Preferably, the chiral 3,4-disubstituted pyrrolidone compound has the structural formula Among them, R 1 , R 2 are each independently a substituted or unsubstituted aryl or alkyl.

[0015] Preferably, the catalyst is at least one of a ruthenium catalyst, an iridium catalyst or a rhodium catalyst.

[0016] Preferably, the catalyst is selected from at least one of the following catalysts:

[0017] Cat-1, Cat-2, Cat-3, Cat-4, and Cat-5 are numbers given to different catalysts, Ts stands for p-toluenesulfonyl, and Ph stands for phenyl.

[0018] Preferably, the hydrogen source is selected from at least one of formic acid / triethylamine azeotropic mixture, formic acid / triethylenediamine azeotropic mixture, formic acid, potassium formate, sodium formate or isopropanol.

[0019] Further preferably, the hydrogen source is formic acid / triethylamine azeotropic mixture (ie, HCOOH / Et3N, volume ratio of 3-5:2).

[0020] Preferably, the solvent is an aprotic solvent or a protic solvent.

[0021] Preferably, the aprotic solvent is selected from at least one of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene and acetonitrile.

[0022] Preferably, the protic solvent is selected from at least one of water, methanol, ethanol, trifluoroethanol, isopropanol, hexafluoroisopropanol, and tert-butanol.

[0023] Preferably, the reaction temperature is 20-100°C, more preferably 30-90°C.

[0024] Preferably, the reaction time is 1 minute to 48 hours, more preferably 10-24 hours.

[0025] Preferably, the catalyst and The molar ratio is 1:(10-1000), and more preferably 1:(100-1000).

[0026] Preferably, the The molar ratio of hydrogen to the hydrogen source is 1:(2-100), more preferably 1:(2-10)

[0027] The reaction equation of the synthesis method of the present invention is as follows:

[0028]

[0029] The second aspect of the present invention provides a method for synthesizing chiral 3,4-disubstituted pyrrolidone compounds for use in the field of drug synthesis. Compared with the prior art, the beneficial effects of the present invention are as follows: the synthesis method provided by the present invention has a yield of more than 92%, for example, a yield>95%, an enantioselectivity ee≥95%, and a diastereoselectivity dr>20:1. Therefore, the present invention provides a method for synthesizing chiral 3,4-disubstituted pyrrolidone compounds with high efficiency, high yield, high enantioselectivity and high diastereoselectivity. DETAILED DESCRIPTION

[0030] In order to make the technical scheme of the present invention more clearly understood by those skilled in the art, the following embodiments are listed for illustration. It should be pointed out that the following embodiments do not limit the protection scope of the present invention.

[0031] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods. The technical means for confirming the structure of the compound are all general technical means known to those skilled in the art, such as nuclear magnetic resonance technology. The technical means for confirming the chiral optical properties are all general technical means known to those skilled in the art, such as high performance liquid chromatography.

[0032] In the following examples, Bn represents

[0033] Example 1

[0034] A method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound comprises the following steps:

[0035] Accurately weigh the above substrate 1a (28 mg, 0.1 mmol), catalyst Cat-1 (i.e. Cat-1) 0.7 mg, add 1 mL of isopropanol (IPA), 50 μL of HCOOH / Et3N (volume ratio 5:2), place in a 10 mL reaction tube equipped with a stirrer, and reflux at 90 ° C (reflux means reflux) for 12 hours. After the reaction is completed, silica gel is added to the reaction solution and spin-dried, and purified by column chromatography to obtain 22.0 mg of a white solid product (compound 1b) after purification.

[0037] The NMR characterization results of compound 1b are as follows: 1 H NMR (400MHz, CDCl3) δ7.41–7.31(m,3H),7.28–7.25(m,2H),7.21–7.14(m,3H),6.89–6.79(m,2H),4.68(d,J=14.4Hz,1H),4.49(dd,J=7.0,2.9Hz,1H ),4.20(d,J=14.5Hz,1H),3.92(d,J=3.0Hz,1H),3.12–3.05(m,2H),2.95( dd,J=10.3,2.8Hz,1H),2.73-2.65(m,1H),2.20(dd,J=14.0,11.2Hz,1H). 13C NMR (101MHz, CDCl3) δ174.20,139.63,135.86,129.08,128.87,128.62,128.41,127.95,126.14,71.97,46.84,46.81,39.73,31.87.

[0038] The enantioselectivity ee value corresponding to the synthesis method of this embodiment is: 99%; the diastereoselectivity dr value is: >20:1 (HPLC conditions: Daicel AD-H column, n-hexane / isopropanol volume ratio = 90:10, flow rate = 1.0 mL / min, detection wavelength = 210 nm, temperature = 31°C).

[0039] Example 2

[0040] A method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound comprises the following steps:

[0041] Accurately weigh the above substrate 2a (28 mg, 0.1 mmol), catalyst Cat-2 (i.e. Cat-2) 0.7 mg, add 1 mL of isopropanol (IPA), 50 μL of HCOOH / Et3N (5:2), place in a 10 mL reaction tube equipped with a stirrer, react at 80 ° C for 10 hours. After the reaction is completed, solid precipitates, filter, wash and purify with petroleum ether to obtain 27 mg of a white solid product (compound 2b).

[0043] The NMR characterization results of compound 2b are as follows: 1 H NMR (400MHz, CDCl3) δ7.54–7.29(m,3H),7.28–7.25(m,2H),6.99(d,J=7.7Hz,2H),6.8 0–6.64(m,2H),4.69(d,J=14.4Hz,1H),4.49–4.41(m,1H),4.19(d,J=14.4Hz,1H),3.1 5(d,J=2.4Hz,1H),3.08(dd,J=10.3,6.0Hz,1H),3.01(dd,J=14.0,4.5Hz,1H),2.93(d d,J=10.3,2.6Hz,1H),2.71–2.62(m,1H),2.28(s,3H),2.12(dd,J=14.0,11.3Hz,1H). 13C NMR (101MHz, CDCl3) δ174.07,136.42,135.87,135.65,129.10,128.95,128.86,128.62,127.93,72.01,46.84,46.75,39.76,31.37,20.97.

[0044] The enantioselectivity ee value corresponding to the synthesis method of this embodiment is: 99%; the diastereoselectivity dr value is: >20:1 (HPLC conditions: Daicel AD-H column, n-hexane / isopropanol volume ratio = 90:10, flow rate = 1.0 mL / min, detection wavelength = 210 nm, temperature = 31°C).

[0045] Example 3

[0046] A method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound comprises the following steps:

[0047] Accurately weigh the above substrate 3a (29 mg, 0.1 mmol), catalyst Cat-2 (i.e., Cat-2) 0.7 mg, add 1 mL of isopropanol (IPA), 50 μL of HCOOH / Et3N (5:2), place in a 10 mL reaction tube equipped with a stirrer, react at 90 ° C for 12 hours. After the reaction is completed, solid precipitates, filter, wash and purify with petroleum ether to obtain 27 mg of a white solid product (compound 3b).

[0049] The NMR characterization results of compound 3b are as follows: 1 H NMR (400MHz, CDCl3) δ7.42–7.31(m,3H),7.32-7.26(m,2H),7.12-7.05(m,2H),7.00-6.96(m,1H),6.56(d,1H),4.65(d, 1H), 4.51 (s, 1H), 4.27 (d, J = 14.4Hz, 1H), 3.15-3.07 (m, 2H), 3.01 (d, 1H), 2.74-2.66 (m, 1H), 2.27 (s, 1H), 2.23 (s, 3H). 13 CNMR(101MHz,CDCl3)δ174.46,137.74,136.40,135.84,130.39,129.79,128.8 9,128.67,127.98,126.31,125.82,72.03,47.04,46.97,37.78,29.10,19.31.

[0050] The enantioselectivity ee value corresponding to the synthesis method of this embodiment is: 99%; the diastereoselectivity dr value is: >20:1 (HPLC conditions: Daicel AD-H column, n-hexane / isopropanol volume ratio = 90:10, flow rate = 1.0 mL / min, detection wavelength = 210 nm, temperature = 31°C).

[0051] Example 4

[0052] A method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound comprises the following steps:

[0053] Accurately weigh the above substrate 4a (36 mg, 0.1 mmol), catalyst Cat-1 (i.e. Cat-1) 0.7 mg, add 1 mL of isopropanol (IPA), 50 μL of HCOOH / Et3N (volume ratio 5:2), place in a 10 mL reaction tube equipped with a stirrer, react at 90 ° C for 12 hours. After the reaction is completed, solid precipitates, filter, wash and purify with petroleum ether to obtain 35 mg of a white solid product (compound 4b).

[0055] The NMR characterization results of compound 4b are as follows: 1 H NMR(400MHz, CDCl3)δ7.49–7.30(m,3H),7.30–7.17(m,4H),6.81–6.44(m,2H), 4.73(d,J=14.4Hz,1H),4.45(dd,J=7.1,2.4Hz,1H),4.12(d,J=14.4Hz,1H),3.6 0(d,J=2.7Hz,1H),3.09(dd,J=10.3,6.0Hz,1H),2.99(dd,J=14.0,4.7Hz,1H), 2.88(dd,J=10.3,2.6Hz,1H),2.67-2.58(m,1H),2.12(dd,J=14.0,11.0Hz,1H). 13 CNMR (101MHz, CDCl3) δ173.86,138.50,135.77,131.47,130.79,128.93,128.70,128.04,120.02,71.84,46.79,46.43,39.59,31.28.

[0056] The enantioselectivity ee value corresponding to the synthesis method of this embodiment is: 99%; the diastereoselectivity dr value is: >20:1 (HPLC conditions: Daicel AD-H column, n-hexane / isopropanol volume ratio = 90:10, flow rate = 1.0 mL / min, detection wavelength = 210 nm, temperature = 31°C).

[0057] Comparative Examples 1-3:

[0058] The reaction equations involved in Comparative Examples 1-3 are as follows:

[0059]

[0060] The ligands corresponding to Comparative Examples 1-3 are:

[0061]

[0062] Three common hydrogenation catalytic systems (Ir / f-Amphox, Ir / f-Amphol and Ir / f-Ampha catalytic systems, with the metal precursor being [Ir(COD)Cl]2) were selected, potassium tert-butoxide ( t BuOK) was used as the base and isopropanol (IPA) was used as the solvent. The reaction was carried out at room temperature (RT) for 24 h under 40 atm of hydrogen. S / C = 100 means that the ratio of the molar amount of the catalyst to the molar amount of the substrate 1a is 1:100.

[0063] The yield, enantioselectivity ee, and diastereoselectivity dr results corresponding to Comparative Examples 1-3 are shown in Table 1.

[0064] Table 1 Comparative Examples 1-3 Reaction Results

[0065] Ligand Yield (%) Enantioselectivity ee (%) Diastereoselective dr Comparative Example 1 L1 >99 40 6:1 Comparative Example 2 L2 >99 5 16:1 Comparative Example 3 L3 >99 11 3:1

[0066] It can be seen from Table 1 and the effects of the embodiments of the present invention that when the three catalytic systems used in Comparative Examples 1-3 use hydrogen as the hydrogen source, their reaction yields are all >99%, but their ee values ​​are all ≤40%, which is poorer than the reaction system of the present invention.

[0067] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the present invention. Although the present invention has been described with reference to the preferred embodiments of the present invention, it should be understood by those skilled in the art that various changes can be made in form and details without departing from the spirit and scope of the present invention, which are all deemed to be within the protection scope of the present invention.

Claims

1. A method for synthesizing a chiral 3,4-disubstituted pyrrolidone compound, characterized in that: The following steps are involved: A hydrogen source, a catalyst and a solvent are mixed and reacted to obtain the chiral 3,4-disubstituted pyrrolidone compound; Among them, R 1 , R 2 are independently substituted or unsubstituted aryl or alkyl; The substitution is selected from halogen or C1-C10 alkyl.

2. The synthesis method according to claim 1, characterized in that R 1 , R 2 Each is independently a substituted or unsubstituted C6-C30 aryl group or C1-C8 alkyl group.

3. The synthesis method according to claim 1, characterized in that The halogen includes F, Cl or Br.

4. The synthesis method according to claim 1, characterized in that The structural formula of the chiral 3,4-disubstituted pyrrolidone compound is Among them, R 1 , R 2 are each independently a substituted or unsubstituted aryl or alkyl.

5. The synthesis method according to claim 1, characterized in that The catalyst is at least one of a ruthenium catalyst, an iridium catalyst or a rhodium catalyst.

6. The synthesis method according to claim 1 or 5, characterized in that: The catalyst is selected from at least one of the following catalysts:

7. The synthesis method according to claim 1, characterized in that The hydrogen source is selected from at least one of formic acid / triethylamine azeotropic mixture, formic acid / triethylenediamine azeotropic mixture, formic acid, potassium formate, sodium formate or isopropanol.

8. The synthesis method according to claim 1, characterized in that The formic acid / triethylamine azeotropic mixture or formic acid / triethylenediamine mixture.

9. The synthesis method according to any one of claims 1 to 5, characterized in that The reaction temperature is 20-100°C; and / or, the reaction time is 1 minute to 48 hours; and / or, the catalyst and The molar ratio is 1: (10-1000) and / or, The molar ratio to the hydrogen source is 1:(2-100).

10. Application of the synthesis method according to any one of claims 1 to 9 in the field of drug synthesis.

Images