A process for the preparation of 2-ester piperidines

Abstract

The present application relates to a kind of preparation methods of 2-ester piperidine.This method will pyridine-2-carboxylic acid and alcohol condensation, again with halogenated hydrocarbon form quaternary ammonium salt, then, in the hydrogen environment in organic solvent, under the catalysis of iridium complex formed by iridium metal catalyst and chiral bisphosphine ligand, asymmetric hydrogenation is carried out to obtain 2-ester piperidine (I).The method has mild reaction condition, excellent enantioselectivity, high chemical yield, has potential industrial application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing 2-ester piperidine. Background Technology

[0002] Chiral piperidines are valuable and ubiquitous structural skeletons found in abundant natural alkaloids, synthetic bioactive compounds, and pharmaceuticals, playing a significant role in the chemical and pharmaceutical industries. While numerous methods have been developed to obtain them, the asymmetric hydrogenation of substituted pyridines is the most direct, atom-economical, and efficient approach.

[0003] Existing reports on the synthesis of chiral piperidines using asymmetric hydrogenation methods almost all involve the asymmetric hydrogenation of aryl-substituted pyridinium salts, such as the asymmetric hydrogenation of 2-aryl pyridinium salts reported by Zhou Yonggui's research group (Angew. Chem. Int. Ed. 2012, 51, 10181-10184) and the asymmetric hydrogenation of 2-aryl pyridinium salts reported by Zhang Xumu's research group (Angew. Chem. Int. Ed. 2014, 53, 12761-12764). Currently, there are no reports on the asymmetric hydrogenation of pyridinium salts with ester substituents on the pyridinium ring. Therefore, developing an asymmetric hydrogenation method for ester-substituted pyridinium salts is of great significance. Summary of the Invention

[0004] Therefore, it is necessary to provide a method for preparing 2-ester piperidine.

[0005] To achieve the above objectives, the present invention provides a technical solution:

[0006] A method for preparing 2-ester piperidine includes the following steps:

[0007] (1) Pyridine-2-carboxylic acid is placed in an organic solvent, and an alcohol, a condensing agent and a base are added to undergo a condensation reaction to obtain 2-ester pyridine;

[0008] (2) 2-ester pyridine is placed in an organic solvent and a halogenated product (halogenated alkanes, halogenated aromatics, such as iodomethane, bromoethane, iodoethane, benzyl bromide, benzyl chloride, 1-bromopropane, 1-bromobutane) is added to react and 2-ester pyridine quaternary ammonium salt is obtained.

[0009] (3) The 2-ester pyridine quaternary ammonium salt is asymmetrically hydrogenated in an organic solvent under the catalysis of an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, with the addition of a halogen-containing additive, to obtain 2-ester piperidine in a hydrogen environment.

[0010]

[0011] The structural formula of the pyridine-2-carboxylic acid is as follows: The structural formula of the 2-ester pyridine is as follows: The structural formula of the 2-ester pyridine quaternary ammonium salt is as follows: The structural formula of the 2-ester piperidine is as follows: R1 is any one of C1-C5 alkyl, aralkyl, aryl, or substituted aryl; R2 is any one of hydrogen, alkyl, aralkyl, aryl, or substituted aryl; and X is any one of chloride ion, bromide ion, or iodide ion.

[0012] Preferably, in step 3, the catalyst comprises at least one of methoxy(cyclooctadiene)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, bis(cyclooctene)iridium chloride dimer, bis(1,5-cyclooctadiene iridium tetratetra[3,5-bis(trifluoromethyl)phenyl]boronic acid, and (1,5-cyclooctadiene)(pyrimidine)(tricyclohexylphosphine)iridium hexafluorophosphate.

[0013] Preferably, in step 3, the chiral bisphosphine ligand comprises at least one of (S,S)-f-Binaphane, (R,R)-Me-DUPHOS, (R,R)-QuinoxP*, (S,S)-Et-DUPHOS, (S)-SegPhos, (R)-SynPhos, (R)-(-)-DTBM-SegPhos, (S)-MeO-BIPHEP, (R,R)-BDPP, and CTH-(R)-P-Phos, and the chemical structural formula of the chiral bisphosphine ligand is as follows:

[0014]

[0015] Preferably, in step 3, the halogenated additive used is an elemental halogen or a halogenated anionic salt.

[0016] Preferably, in step 3, the molar ratio of the 2-ester pyridine quaternary ammonium salt, the iridium metal catalyst, the chiral bisphosphine ligand, and the halogen-containing additive is 1:(0.001~0.1):(0.002~0.1):(0.1~1).

[0017] Preferably, in step 3, the reaction pressure of hydrogen in the asymmetric hydrogenation reaction is 10–80 atm.

[0018] Preferably, in step 3, the third organic solvent includes at least one of tetrahydrofuran, ethyl acetate, methanol, dioxane, acetone, methyl acetate, and toluene.

[0019] Preferably, in step 3, when there are two types of the third organic solvent, the volume ratio of the two solvents is 1:(0.1 to 0.9).

[0020] Preferably, in step 3, the reaction temperature range of the asymmetric hydrogenation reaction is –40 to 20°C.

[0021] Preferably, in step 3, the reaction time range of the asymmetric hydrogenation reaction is 12 to 72 hours.

[0022] The beneficial effects of this invention are:

[0023] This invention involves the asymmetric hydrogenation of 2-ester-pyridine quaternary ammonium salt in an organic solvent under hydrogen atmosphere via the addition of a haloalkane, catalyzed by an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, to yield 2-ester-piperidine (I). This invention offers advantages such as mild reaction conditions, excellent enantioselectivity, mild operation, high chemical yield, and high optical purity, making it suitable for scale-up applications and possessing potential industrial value. Attached Figure Description

[0024] Figure 1 The hydrogen spectrum of compound (Ia);

[0025] Figure 2 This is the carbon spectrum of compound (Ia).

[0026] Figure 3 The hydrogen spectrum of compound (Ib);

[0027] Figure 4 This is the carbon spectrum of compound (Ib). Detailed Implementation

[0028] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0029] In the embodiments, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0030] A method for preparing 2-ester piperidine includes the following steps:

[0031] (1) Pyridine-2-carboxylic acid is placed in an organic solvent, and an alcohol, a condensing agent and a base are added to undergo a condensation reaction to obtain 2-ester pyridine;

[0032] (2) 2-ester pyridine is placed in an organic solvent and a halogenated product (halogenated alkanes, halogenated aromatics, such as iodomethane, bromoethane, iodoethane, benzyl bromide, benzyl chloride, 1-bromopropane, 1-bromobutane) is added to react and 2-ester pyridine quaternary ammonium salt is obtained.

[0033] (3) The 2-ester pyridine quaternary ammonium salt is asymmetrically hydrogenated in an organic solvent under the catalysis of an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, with the addition of a halogen-containing additive, to obtain 2-ester piperidine in a hydrogen environment.

[0034]

[0035] The structural formula of the pyridine-2-carboxylic acid is as follows: The structural formula of the 2-ester pyridine is as follows: The structural formula of the 2-ester pyridine quaternary ammonium salt is as follows: The structural formula of the 2-ester piperidine is as follows:

[0036] R1 is any one of C1-C5 alkyl, aralkyl, aryl, or substituted aryl; R2 is any one of hydrogen, alkyl, aralkyl, aryl, or substituted aryl; and X is any one of chloride ion, bromide ion, or iodide ion.

[0037] In some embodiments, in step 1, the alcohol is at least one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclopentylethanol, cyclohexylethanol, benzyl alcohol, and substituted benzyl alcohol. Preferably, the alcohol is benzyl alcohol.

[0038] In some embodiments, in step 1, the condensing agent is at least one selected from N,N'-dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, and 1-hydroxy-7-azabenzotriazole. Preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0039] In some embodiments, in step 1, the first organic solvent is at least one selected from dichloromethane, tetrahydrofuran, acetonitrile, acetone, and ethyl acetate. Preferably, the solvent is dichloromethane.

[0040] In some embodiments, in step 1, the base is at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and 4-dimethylaminopyridine. Preferably, the base is 4-dimethylaminopyridine.

[0041] In some embodiments, in step 2, the haloalkane is at least one selected from iodomethane, bromoethane, benzyl bromide, benzyl chloride, 1-bromopropane, and 1-bromobutane.

[0042] In some embodiments, in step 2, the second organic solvent used is at least one selected from methanol, acetone, ethyl acetate, dichloromethane, and diethyl ether. Preferably, the second solvent is acetone.

[0043] In some embodiments, in step 3, the catalyst comprises at least one of methoxy(cyclooctadiene)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, bis(cyclooctene)iridium chloride dimer, bis(1,5-cyclooctadiene iridium tetratetra[3,5-bis(trifluoromethyl)phenyl]boronic acid, and (1,5-cyclooctadiene)(pyrimidine)(tricyclohexylphosphine)iridium hexafluorophosphate. Preferably, the catalyst is 1,5-cyclooctadiene iridium chloride dimer.

[0044] In some embodiments, in step 3, the chiral bisphosphine ligand includes at least one of (S,S)-f-Binaphane, (R,R)-Me-DUPHOS, (R,R)-QuinoxP*, (S,S)-Et-DUPHOS, (S)-SegPhos, (R)-SynPhos, (R)-(-)-DTBM-SegPhos, (S)-MeO-BIPHEP, (R,R)-BDPP, and CTH-(R)-P-Phos, and the chemical structural formula of the chiral bisphosphine ligand is as follows:

[0045]

[0046] Preferably, in step 3, the chiral ligand is the chiral bisphosphine ligand (R,R)-BDPP, which has excellent enantioselectivity.

[0047] In some embodiments, the halogenated additive used in step 3 is an elemental halogen or a halogenated anionic salt. Preferably, the halogenated additive is potassium iodide.

[0048] In some embodiments, in step 3, the molar ratio of the 2-ester-pyridine quaternary ammonium salt, the iridium metal catalyst, the chiral bisphosphine ligand, and the halogen-containing additive is 1:(0.001-0.1):(0.002-0.1):(0.1-1). Preferably, the molar ratio of the 2-ester-pyridine quaternary ammonium salt, the iridium metal catalyst, the chiral bisphosphine ligand, and the halogen-containing additive is 1:(0.001-0.1):(0.002-0.1):(0.1-1).

[0049] In some embodiments, in step 3, the reaction pressure of hydrogen in the asymmetric hydrogenation reaction is 10–80 atm. Preferably, the reaction pressure of hydrogen in the asymmetric hydrogenation reaction is 60–80 atm.

[0050] In some embodiments, in step 3, the third organic solvent includes at least one selected from tetrahydrofuran, ethyl acetate, methanol, dioxane, acetone, methyl acetate, and toluene. Preferably, the organic solvent is methyl acetate.

[0051] In some embodiments, in step 3, when there are two types of the third organic solvent, the volume ratio of the two solvents is 1:(0.1 to 0.9).

[0052] In some embodiments, the reaction temperature range for the asymmetric hydrogenation reaction in step 3 is -40 to 20°C. More preferably, the reaction temperature range for the asymmetric hydrogenation reaction is -20 to 0°C.

[0053] In some embodiments, the reaction time for the asymmetric hydrogenation reaction in step 3 ranges from 12 to 72 hours. More preferably, the reaction time ranges from 48 to 72 hours.

[0054] Example 1

[0055] Preparation of compound (Ⅲa)

[0056]

[0057] Pyridinecarboxylic acid (Ⅳa) (500.0 mg, 4.1 mmol, 1.0 equiv.) was uniformly dispersed in DCM (15 mL). 4-DMAP (248.1 mg, 2.0 mmol, 0.5 equiv.) and EDCI (1.2 g, 6.1 mmol, 1.5 equiv.) were added sequentially at 0 °C, and the mixture was stirred for 15 min. Benzyl alcohol (0.47 mL, 4.5 mmol, 1.1 equiv.) was added, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC. Water was added, and the mixture was extracted with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (PE / EA = 100:1) to obtain the desired product Ⅲa (830.6 mg, 95% yield).

[0058] 1 H NMR (400MHz, Chloroform-d) δ8.76–8.74(m,1H),8.17–8.06(m,1H),7.87–7.72(m,1H),7.53–7.24(m,6H),5.45(s,2H).

[0059] 13 C NMR (100MHz, Chloroform-d) δ165.0,149.9,148.0,137.0,135.6,128.6,128.5,128.4,126.9,125.2,67.5.

[0060] Example 2

[0061] Preparation of compound (IIa)

[0062]

[0063] Benzyl 2-pyridinecarboxylate IIIa (213 mg, 1.0 mmol, 1.0 equiv.) was uniformly dispersed in acetone or methanol (10.0 mL), and benzyl bromide (142, 5 μL, 1.2 mmol, 1.2 equiv.) was added. The mixture was stirred at 0 °C for 12–96 h, and the reaction was monitored by TLC. Diethyl ether was added to the reaction solution, and a precipitate was formed. The precipitate was filtered, and the filter cake was washed with ethyl acetate to obtain a solid product, which was used directly in the next reaction. If no solid precipitate was obtained, the product was purified by rapid silica gel column chromatography (DCM / MeOH = 20:1) to obtain product IIa (368.9 mg, 96% yield).

[0064] Example 3

[0065] Preparation of compound (Ⅰa)

[0066]

[0067] 1,5-cyclooctadiene iridium chloride dimer (1.3 mg, 2.0 μmol, 2.0 mol%), (R,R)-BDPP (1.8 mg, 4.0 μmol, 4.0 mol%), and degassed methyl acetate (2 mL) were dissolved in a dry reaction flask and stirred for 15 min. Then, 2-methyl ester pyridinium salt (IIa) (30.8 mg, 0.1 mmol) and potassium iodide (16.6 mg, 0.1 mmol, 1.0 equiv.) were added to the reaction flask. The flask was placed in an autoclave, purged with hydrogen three times, and then hydrogen was introduced to 60 atm. The mixture was stirred at -20°C for 72 h. Hydrogen was slowly released, and after removing the solvent, the mixture was separated by silica gel column chromatography to obtain a transparent oil (I) (21.7 mg, 93% yield, 96% ee).

[0068] 1 H NMR(400MHz,Chloroform-d)δ7.36-7.18(m,5H),3.78(d,J=13.6Hz,1H),3.73(s,3H),3.41(d,J=13.6Hz,1H),3.17(d d,J=7.6,4.4Hz,1H),2.96-2.91(m,1H),2.19-2.13(m,1H),1.90-1.77(m,2H),1.66-1.50(m,3H),1.42-1.32(m,1H).

[0069] 13C NMR (100MHz, Chloroform-d) δ174.5,138.3,129.3,128.2,127.1,64.5,60.7,51.6,50.2,29.7,25.4,22.6.

[0070] Example 4

[0071] Preparation of compound (Ⅰb)

[0072]

[0073] 1,5-cyclooctadiene iridium chloride dimer (1.3 mg, 2.0 μmol, 2.0 mol%), (R,R)-BDPP (1.8 mg, 4.0 μmol, 4.0 mol%), and degassed ethyl acetate (2 mL) were dissolved in a dry reaction flask and stirred for 15 min. Then, 2-benzyl ester pyridinium salt (IIa) (38.4 mg, 0.1 mmol) and potassium iodide (16.6 mg, 0.1 mmol, 1.0 equiv.) were added to the reaction flask. The flask was placed in an autoclave, purged with hydrogen three times, and then hydrogen was introduced to 80 atm. The mixture was stirred at –20°C for 72 h. Hydrogen was slowly released, and after removing the solvent, a transparent oil (Ib) (29.7 mg, 96% yield, 93% ee) was obtained by silica gel column chromatography.

[0074] 1 H NMR(400MHz,Chloroform-d)δ7.43-7.18(m,10H),5.18(s,2H),3.79(dd,J=13.2,2.0Hz,1H),3.42(d,J=13.2H z,1H),3.21(t,J=6.0Hz,1H),2.98-2.92(m,1H),2.25-2.11(m,1H),1.86-1.82(m,2H),1.69-1.47(m,3H),1.42

[0075] -1.33(m, 1H).

[0076] 13 C NMR (100MHz, Chloroform-d) δ173.8,138.4,136.1,129.3,128.7,128.5,128.4,128.2,127.1,66.2,64.2,60.6,50.2,29.7,25.4,22.5.

[0077] It should be noted that the specific parameters or reagents in the above embodiments are specific or preferred embodiments under the concept of the present invention, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

Claims

1. A process for the preparation of 2-ester-piperidines, characterized in that, The method comprises the steps of: (1) condensing pyridine-2-carboxylic acid in a first organic solvent with an alcohol, a condensing agent and a base to obtain 2-ester pyridine; (2) reacting the 2-ester pyridine with a halide in a second organic solvent to obtain a 2-ester pyridine quaternary ammonium salt; (3) catalyzing the 2-ester pyridine quaternary ammonium salt with an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, adding a halogen-containing additive, and performing asymmetric hydrogenation in a third organic solvent under a hydrogen atmosphere to obtain 2-ester piperidine; ； The pyridine-2-carboxylic acid has a structural formula of The 2-ester pyridine has a structural formula of The 2-ester pyridine quaternary ammonium salt has a structural formula of The 2-ester piperidine has a structural formula of ​ R1 is any one of C1-C5 alkyl, aralkyl, aryl, and substituted aryl, R2 is any one of hydrogen, alkyl, aralkyl, aryl, and substituted aryl, and X is any one of chloride, bromide, and iodide; In step 3, the catalyst is 1,5-cyclooctadiene iridium chloride dimer; In step 3, the chiral bisphosphine ligand is (R,R)-BDPP, and the chemical structural formula of the chiral bisphosphine ligand is as follows: 。 2. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the halogen-containing additive used is a halogen element or a halide salt.

3. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the molar ratio of the 2-ester pyridine quaternary ammonium salt, the iridium metal catalyst, the chiral bisphosphine ligand, and the halogen-containing additive is 1:(0.001-0.1):(0.002-0.1):(0.1-1).

4. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the reaction pressure of the hydrogen gas in the asymmetric hydrogenation reaction is 10-80 atm.

5. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the third organic solvent comprises at least one of tetrahydrofuran, ethyl acetate, methanol, dioxane, acetone, methyl acetate, and toluene.

6. The method for preparing 2-esterified piperidine according to claim 5, characterized in that, In step 3, when the third organic solvent is two solvents, the volume ratio of the two solvents is 1:(0.1-0.9).

7. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the reaction temperature range of the asymmetric hydrogenation reaction is -40-20°C.

8. The method for preparing 2-esterified piperidine according to claim 1, characterized in that, In step 3, the reaction time range of the asymmetric hydrogenation reaction is 12-72 h.

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