Preparation method of 2-piperidone derivative

Abstract

The invention discloses a preparation method of a 2-piperidone derivative, which comprises the following steps: reacting brominated difluoroacetamide, arylboronic acid, bis (triphenylphosphine) nickel dichloride, 3, 4, 7, 8-tetramethyl-1, 10-phenanthroline, formic acid, acetic anhydride and sodium carbonate at 90 DEG C for 16 hours, and after the reaction is completed, performing post-treatment to obtain the 2-piperidone derivative. According to the preparation method, bromo-difluoroacetamide and arylboronic acid are used as reactants, formic acid is used as a carbonyl source, reaction conditions are mild, operation is easy, the tolerance range of substrate functional groups is wide, and reaction efficiency is high. Various 2-piperidone derivatives can be synthesized according to actual needs, and the practicability of the method is widened while the operation is convenient.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-piperidone derivatives. BACKGROUND

[0002] As a privileged structural unit in the field of organic synthesis and medicinal chemistry, lactams are a class of core scaffolds with important pharmaceutical value and widely exist in various natural products, bioactive molecules and drugs. However, compared with β-lactams and γ-lactams, there are relatively few drug molecules containing δ-lactam structures. From the perspective of organic chemistry and medicinal chemistry, functional modification of organic molecules can endow them with structural diversity and complexity, which is of great significance for their application in drug design and research. Introducing fluorine atoms into molecules is an effective modification method, because fluorine has high reactivity and unique properties such as small atomic radius, high electronegativity and strong carbon-fluorine bond energy. The presence of fluorine atoms usually has a significant impact on the physical, chemical and biological properties of molecules. In particular, gem-difluoro groups have attracted widespread attention from researchers due to their wide application in the pesticide and pharmaceutical industries. Under this background, the introduction of gem-difluoro groups into δ-lactam structures is expected to expand the synthetic application of this kind of scaffold, which has important value in drug research and development and biological research.

[0003] In addition, as a key synthetic building block in organic chemistry, carbonyl-containing compounds are widely used to construct complex drug molecules due to their high reactivity and diverse transformation ability. Therefore, the preparation of carbonyl-containing compounds has always been the focus of continuous attention from academia and industry. In recent decades, transition metal-catalyzed carbonylation reactions have become an economical and efficient synthetic tool due to their application in the synthesis of carbonyl-containing compounds. Generally, the transition metals commonly used in carbonylation reactions mainly focus on palladium, rhodium and iridium, which is due to their high catalytic efficiency and reactivity. However, these metals are expensive, and some reactions also require the use of more expensive ligands, which limits their application in industrial production and fine chemical synthesis. Therefore, low-cost and abundant metals such as nickel become an ideal alternative. However, the application of nickel catalysts in carbonylation reactions is relatively rare, and the reason is that nickel has a high affinity for carbon monoxide (CO), which easily leads to catalyst deactivation. In order to overcome this shortcoming, researchers have developed a series of nickel-catalyzed radical carbonylation reactions, which can use low-pressure CO gas or CO substitutes as the source of carbonyl groups. Therefore, considering the development prospects of nickel-catalyzed carbonylation reactions and the important biological activity of 2-piperidone, developing simple and efficient carbonylation reactions to synthesize 2-piperidone derivatives has a very broad development prospect.

[0004] Based on this, we developed nickel-catalyzed carbonylation cyclization reaction to synthesize 2-piperidone derivatives. The reaction starts from simple and readily available bromo difluoroacetamide and aryl boronic acid compound, with formic acid as the source of carbonyl, to synthesize a variety of 2-piperidone derivatives. The reaction opens up a new synthetic route for nickel-catalyzed carbonylation to construct 2-piperidone derivatives. SUMMARY

[0005] The application provides a preparation method of 2-piperidone derivatives, which has simple steps, cheap and readily available reaction raw materials, can be compatible with various functional groups, and has good reaction applicability. The aryl boronic acid is used as the raw material and the promoter, and the formic acid is used as the source of carbonyl, thereby providing a new direction for the synthesis of 2-piperidone derivatives.

[0006] A preparation method of 2-piperidone derivatives comprises the following steps: reacting a nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid, acetic anhydride, sodium carbonate, bromo difluoroacetamide and aryl boronic acid at 60-90 DEG C for 12-20 hours, and after the reaction is completed, post-treatment to obtain the 2-piperidone derivatives.

[0007] The structure of the bromo difluoroacetamide is shown in formula (II):

[0008]

[0009] The structure of the aryl boronic acid is shown in formula (III):

[0010] Ar'-B(OH)2 (III);

[0011] The structure of the 2-piperidone derivatives is shown in formula (I):

[0012]

[0013] In formula (I)-(III), Ar is a substituted or unsubstituted phenyl, the substituents on the phenyl are C1-C4 alkyl, C1-C4 alkoxy or halogen, Ar' is a naphthyl, a substituted or unsubstituted phenyl, the substituents on the phenyl are C1-C4 alkyl, C1-C4 alkoxy, C1-C4 acyl, trifluoromethyl or halogen.

[0014] The molar ratio of the nickel catalyst, 3,4,7,8-tetramethyl-1,10-phenanthroline and sodium carbonate is 0.1:0.1:1.5.

[0015] The positions of the substituents on Ar are para or meta; the positions of the substituents on Ar' are para.

[0016] The reaction formula is as follows:

[0017]

[0018] In the present application, the optional post-treatment process includes filtration, silica gel mixing, and final purification by column chromatography to obtain the corresponding 2-piperidone derivative. The purification by column chromatography is a common technique in the art.

[0019] As a preferred embodiment, Ar is a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group, a tert-butyl group, a methoxy group, F, Cl or Br. Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, and the substituent on the phenyl group is a methyl group, a methoxy group, an acetyl group or F. In this case, the bromodifluoroacetamide and the aryl boronic acid are readily available, and the reaction has a high yield.

[0020] The aryl boronic acid used to prepare the 2-piperidone derivative is inexpensive and widely available in nature. As a preferred embodiment, the molar ratio of the bromodifluoroacetamide: aryl boronic acid: nickel catalyst is 1:1-2:0.05-0.1. As a further preferred embodiment, the molar ratio of the bromodifluoroacetamide: aryl boronic acid: nickel catalyst is 1:1.5:0.1.

[0021] As a preferred embodiment, the reaction time is 16 hours. A long reaction time increases the cost of the reaction, and on the contrary, it is difficult to ensure the completion of the reaction.

[0022] As a preferred embodiment, the reaction is carried out in acetonitrile. The amount of acetonitrile used is sufficient to dissolve the starting material. For example, for 0.2 mmol of bromodifluoroacetamide, the amount of acetonitrile used is about 1-2 mL.

[0023] As a preferred embodiment, the nickel catalyst is bis(triphenylphosphine)nickel dichloride. Among the various nickel catalysts, bis(triphenylphosphine)nickel dichloride is inexpensive, and the use of bis(triphenylphosphine)nickel dichloride as a catalyst has a high reaction efficiency.

[0024] As a further preferred embodiment, the 2-piperidone derivative is one of the compounds represented by formula (I-1) to formula (I-5):

[0025]

[0026] In the above preparation method, the aryl boronic acid, formic acid, acetic anhydride, bis(triphenylphosphine)nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline and sodium carbonate are generally commercially available products, and can be easily obtained from the market.

[0027] Compared with the prior art, the present application has the following advantages:

[0028] The method has the advantages of simple preparation process, easy operation, simple post-treatment, cheap and easily available starting material, wide functional group tolerance of substrates and high reaction efficiency. Various 2-piperidone derivatives can be synthesized according to actual needs, and the method has high practicability. DETAILED DESCRIPTION

[0029] The application is further described below in combination with specific examples.

[0030] Examples 1-15

[0031] According to the raw material ratio in Table 1, bromo difluoroacetamide (II), aryl boronic acid (III), pre-reaction product of bis (triphenylphosphine) nickel dichloride, 3,4,7,8-tetramethyl-1,10-phenanthroline, formic acid and acetic anhydride, sodium carbonate, acetonitrile (2 mL) were added in a 15 mL sealed tube, and then stirred uniformly. The reaction was carried out according to the reaction conditions in Table 2. After the reaction was completed, filtration, silica gel sample mixing and column chromatography purification were carried out to obtain the corresponding 2-piperidone derivative (I). The reaction process is shown in the following formula:

[0032]

[0033] Table 1: Raw material addition amount of examples 1-15

[0034]

[0035] Table 2

[0036]

[0037] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, tBu is tert-butyl, and CF3 is trifluoromethyl.

[0038] The structure confirmation data of the compounds prepared in examples 1-5 are as follows:

[0039] The nuclear magnetic resonance (H NMR and C NMR) detection data of the 2-piperidone derivative (I-1) prepared in example 1 are as follows: 1 H NMR and 13 C NMR) detection data:

[0040]

[0041] 1H NMR (400 MHz, CDC13) δ 8.01 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.31 (dd, J = 10.0, 8.8 Hz, 3H), 3.98 - 3.90 (m, 1H), 3.66 - 3.61 (m, 1H), 3.56 (d, J = 15.9 Hz, 1H), 3.22 - 3.08 (m, 2H), 2.30 - 2.25 (m, 1H), 2.08 - 1.97 (m, 1H).

[0042] 13 C NMR (101 MHz, CDC13) δ 196.9, 161.1 (t, J = 30.1 Hz), 141.0, 136.3, 133.7, 129.4, 128.8, 128.0, 127.7, 125.6, 113.6 (dd, J = 248.9, 244.9 Hz), 50.1, 37.4 (t, J = 20.7 Hz), 35.3, 25.0 (d, J = 7.5 Hz).

[0043] The 2-piperidone derivative (I-2) prepared from Example 2 was detected by nuclear magnetic resonance (H NMR and C NMR) to have the following data: 1 H NMR and 13 C NMR) detection data:

[0044]

[0045] 1 H NMR (400 MHz, CDC13) δ 8.01 (d, J = 7.3 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.31 (dd, J = 10.0, 8.8 Hz, 3H), 3.98 - 3.90 (m, 1H), 3.66 - 3.61 (m, 1H), 3.56 (d, J = 15.9 Hz, 1H), 3.22 - 3.08 (m, 2H), 2.30 - 2.25 (m, 1H), 2.08 - 1.97 (m, 1H).

[0046] 13C NMR (101 MHz, CDC13) δ 196.6, 161.2 (t, J = 30.0 Hz), 144.6, 141.0, 133.9, 129.4, 129.4, 129.1, 128.2, 127.7, 125.6, 113.6 (dd, J = 249.0, 244.9 Hz), 50.1, 37.4 J (t, J = 20.8 Hz), 35.2, 24.9 (d, J = 7.5 Hz). 21.7.

[0047] The nuclear magnetic resonance (1H NMR and 1 H NMR and 13 C NMR) detection data of the 2-piperidone derivative (I-3) prepared from Example 3 are as follows:

[0048]

[0049] 1 H NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 12.2, 8.4 Hz, 2H), 7.66 - 7.57 (m, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.32 (dd, J = 8.6, 7.3 Hz, 3H), 4.00 - 3.92 (m, 1H), 3.72 - 3.63 (m, 2H), 3.33 (dd, J = 17.8, 10.0 Hz, 1H), 3.25 - 3.11 (m, 1H), 2.34 - 2.29 (m, 1H), 2.12 - 2.01 (m, 1H).

[0050] 13 C NMR (101 MHz, CDC13) δ 196.8, 161.1 (t, J = 30.1 Hz), 141.0, 135.8, 133.6, 132.4, 130.0, 129.6, 129.4, 128.8, 128.7, 127.8, 127.7, 127.0, 125.6, 123.5, 113.7 (dd, J = 249.0, 245.1 Hz), 50.1, 37.5 (t, J = 20.7 Hz), 35.4, 25.0 (d, J = 7.6 Hz).

[0051] The nuclear magnetic resonance (1H NMR and 1 H NMR and 13 C NMR) detection data of the 2-piperidone derivative (I-3) prepared from Example 3 are as follows:

[0052]

[0053] , CDCl3)δ196.8,161.1(t,J=30.1Hz),141.0,135.8,133.6,132.4,130.0,129.6,129.4,128.8,128.7,127.8, 127.7, 127.0, 125.6, 123.5, 113.7 (dd, J = 249.0, 245.1Hz), 50.1, 37.5 (t, J = 20.7Hz), 35.4, 25.0 (d, J = 7.6Hz).

[0054] 19 F NMR(376MHz, CDCl3)δ-108.15(dd,J=278.7,18.6Hz),-110.13(d,J=278.7Hz).Mp135.1–135.6℃

[0055] Nuclear magnetic resonance (NMR) of the 2-piperidinone derivative (I-5) prepared in Example 5 1 H NMR and 13 The C NMR detection data are as follows:

[0056]

[0057] 1 H NMR (400 MHz, CDCl3) δ7.90 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.7 Hz,2H),3.96–3.88(m,1H),3.62–3.57(m,1H),3.51(d,J=15.8 Hz,1H),3.18–3.05(m,2H),2.43(s,3H),2.29–2.24(m,1H),2.06–1.95(m,1H). 13 CNMR(101 MHz, CDCl3)δ196.4,161.2(t,J=30.2 Hz),144.7,139.5,133.9,133.3,129.5,129.4,128.2,126.9,113.5(dd,J=249.1,244.9 Hz), 50.0, 37.4 (t, J = 20.7 Hz), 35.1, 24.9 (d, J = 7.6 Hz), 21.7.

Claims

1. A method for preparing a 2-piperidinone derivative, characterized in that, The process includes the following steps: reacting a nickel catalyst, ligand, formic acid, acetic anhydride, base, bromodifluoroacetamide, and arylboronic acid at 60–90 °C for 12–20 hours. After the reaction is complete, the product is post-treated to obtain the 2-piperidinone derivative. The structure of the bromodifluoroacetamide is shown in formula (II): The structure of the arylboronic acid is shown in formula (III): Ar'-B(OH)2 (III); The structure of the 2-piperidinone derivative is shown in formula (I): In formulas (I) to (III), Ar is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, or a halogen group, and Ar' is a naphthyl group, a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is a C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 acyl group, a trifluoromethyl group, or a halogen group.

2. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, Ar is a substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, tert-butyl, methoxy, F, chlorine or Br.

3. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, Ar' is a naphthyl, substituted or unsubstituted phenyl group, wherein the substituent on the phenyl group is methyl, methoxy, acetyl, trifluoromethyl or F.

4. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, In molar amounts, the ratio of bromodifluoroacetamide: arylboronic acid: formic acid: acetic anhydride: nickel catalyst: ligand: base is 1:1~2:10~15:10~15:0.05~0.1:0.05~0.1:1.5~2.

5. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The reaction uses acetonitrile as a solvent.

6. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The nickel catalyst is nickel di(triphenylphosphine)dichloride.

7. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The ligand is 3,4,7,8-tetramethyl-1,10-phenanthroline.

8. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The alkali mentioned is sodium carbonate.

9. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The formic acid and acetic anhydride are first pre-reacted to form the product formic acid and acetic anhydride, and then added to the reaction system for further reaction.

10. The method for preparing the 2-piperidinone derivative according to claim 1, characterized in that, The 2-piperidinone derivative is one of the compounds shown in formulas (I-1) to (I-5):

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