A method for synthesizing chiral pyridine-2,6-diol

Abstract

The present invention provides a method for synthesizing chiral pyridine-2,6-diol. Using 2,6-diacylpyridine as the raw material, a complex formed in-situ by metal iridium and a PNN ligand with a phenyl skeleton is used as the catalyst, ethanol as the solvent, and sodium tert-butoxide as the base additive. Under this homogeneous catalytic system, a hydrogenation reaction occurs to obtain chiral pyridine-2,6-diol with a high yield (>99%) and high ee value (>99%) and de value (>99%). This reaction has high activity, mild reaction conditions, the starting materials are cheap and easily available, and using ethanol as the solvent is clean and environmentally friendly, having high industrial application value.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a synthetic method for preparing chiral pyridine-2,6-diol compounds by asymmetric hydrogenation of 2,6-diacylpyridine catalyzed by iridium. Background Art

[0002] The asymmetric hydrogenation of unsaturated double bonds is the simplest and most effective method for converting prochiral compounds into chiral compounds. Before the development of homogeneous catalytic hydrogenation of platinum group metals and chiral ligands, the enantioselective hydrogenation of double bonds was achieved by introducing chiral auxiliaries into substrates or by heterogeneous hydrogenation on chiral supports. However, the efficiency of these relatively old methods is very low in terms of enantioselectivity induction and turnover numbers (TONs). In the 1960s, the rhodium-catalyzed systems of Wilkinson and Schrock / Osborn achieved transition metal-catalyzed homogeneous hydrogenation reactions, in which enantioselectivity was more effective [(a) J.A. Osborn, G. Wilkinson and J.F. Young, Chem. Commun., 1965, 17. (b) J.A. Osborn, F.H. Jardine, J.F. Young and G. Wilkinson, J. Chem. Soc. A, 1966, 1711–1732. (c) R.R. Schrock and J.A. Osborn, J. Am. Chem. Soc., 1976, 98, 2143–2147. (d) R.R. Schrock and J.A. Osborn, J. Am. Chem. Soc., 1976, 98, 4450–4455.]. Subsequently, Monsanto successfully applied Rh-catalyzed asymmetric hydrogenation in the production processes of L-Dopa and Takasago's menthol. Since then, the enantioselective hydrogenation strategy of unsaturated double bonds has become one of the most effective tools for synthesizing chiral molecules [(e) W.S. Knowles, Angew. Chem., Int. Ed., 2002, 41, 1998–2007. (f) R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008–2022.].

[0003] Chiral pyridine-2,6-diol, as an important intermediate, can be used to synthesize P,N,P ligands with C2 symmetry. Such ligands are of great significance in asymmetric reactions [(g) Q. Jiang, D. V. Plew, S. Murtuza, X. Zhang. Tetrahedron Lett., 1996, 37, 797–800.]. However, due to the coordination of the nitrogen atom in 2,6-diacylpyridine compounds, the reaction activity of the asymmetric reduction of such compounds is low and the enantioselectivity is poor. So far, only a few catalysts can be used to catalyze the asymmetric reduction of 2,6-diacylpyridine [(h) D. Bailey, D. O’Hap, U. Dyer, R. B. Lamont. Tetrahedron: asymmetry, 1993, 4, 1255–1258. (i) T. Ohkuma, M. Koizumi, M. Yoshida, R. Noyori. Org. Lett., 2000, 2, 1749–1751.]. Therefore, it is of great significance to develop new catalysts for the catalytic asymmetric hydrogenation of 2,6-diacylpyridine to prepare chiral pyridine-2,6-diol. Summary of the Invention

[0004] The object of the present invention is to provide a method for synthesizing chiral pyridine-2,6-diol compounds. This method provides an efficient hydrogenation catalytic system. Potassium tert-butoxide is used as an alkali additive in the reaction system. The operation is simple, the raw materials are easily available, the reaction activity is high, the reaction cost is greatly reduced, and it has high industrial application value.

[0005] Specifically, the present invention provides a method for synthesizing chiral pyridine-2,6-diol compounds. Using 2,6-diacylpyridine and hydrogen as raw materials, a complex formed in situ by metal iridium and an aryl backbone PNN ligand in a reaction medium is used as a catalyst. Under the action of an alkali additive, a hydrogenation reaction occurs, and chiral pyridine-2,6-diol is generated with high yield, high ee and de values. The specific steps are as follows:

[0006] In a glove box, metal iridium and an aryl backbone PNN ligand are vigorously stirred in ethanol at a molar ratio of 1:1.1 - 1:2.2 for 0.5 - 1 hour. Subsequently, an ethanol solution of 2,6-diacylpyridine is added thereto, and then an alkali additive is added. Finally, it is placed in a reaction kettle, purged with hydrogen 3 times, filled with hydrogen to 3 - 5 MPa, and reacted at 20 - 60 °C for 1 - 24 hours. After cooling to room temperature, the hydrogen is slowly released, the solvent is removed, and the residue is separated by column chromatography to obtain pyridine-2,6-diol.

[0007]

[0008] R is selected from hydrogen, C1-C40 (preferably a C1-C 30 , more preferably a C1-C6) alkane group, a cycloalkyl group with 3 to C 12 (preferably a C3-C8, more preferably a C3-C6) cycloalkyl group, phenyl and substituted phenyl, benzyl and substituted benzyl, etc.; the substituents of the phenyl and benzyl groups are each independently selected from C1-C 40 (preferably a C1-C 30 , more preferably a C1-C6) alkane group, a C1-C 40 (preferably a C1-C 30 , more preferably a C1-C6) alkoxy group, halogen, nitro, ester group or cyano group, one or more of them.

[0009] The reaction medium is selected from at least one of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide. Preferably ethanol.

[0010] The base additive is selected from one or more of KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, i Pr2NEt, i PrNMe2, NEt3, t BuOK, t BuONa, t BuOLi, MeONa, MeOK or K3PO4. Preferably t BuOK.

[0011] The complex formed in-situ by the iridium metal and the PNN ligand of the aryl skeleton is used as a catalyst, and the general structural formula of the PNN ligand is as follows:

[0012]

[0013] In the formula:

[0014] Ar is an aromatic group with 6 to C carbon atoms in the aromatic ring such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, 2,4,6-trisubstituted aryl, etc. 60 (preferably a C6-C 30 , more preferably a C6-C 24 ) aromatic group; the substituents are C1-C 40 (preferably a C1-C 30 , more preferably a C1-C6) alkane group, a C1-C 40 (preferably a C1-C 30 , more preferably a C1-C6) alkoxy group, halogen, nitro, ester group or cyano group, one or more of them. ;

[0015] R 1 and R 2 are the same or different groups, being hydrogen, C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkyl; the aromatic ring has a carbon number of C6-C 60 (preferably C6-C 30 , more preferably C6-C 24 ) aromatic group, and the aromatic ring having one or more N, S, O, P heteroatoms has a carbon number of C3-C 60 aromatic group (preferably C3-C 30 , more preferably C3-C 24 ).

[0016] R 1 and R 2 can together with the N atom form a cyclic group as shown below, where n is a natural number from 1 to 6 (preferably from 1 to 5, more preferably from 3 to 5).

[0017]

[0018] For the chiral phenylphosphine-1,2-diphenylethylenediamine ligand, the above cycloalkyl and cycloalkyl-derived groups are preferably the six-membered piperidine ring L-1a.

[0019]

[0020] The molar ratio of the substrate to the catalyst is 100 - 50000:1

[0021] The molar ratio of the substrate to the base additive is 10 - 10000:1

[0022] The catalytic reaction conditions are as follows:

[0023] Temperature: room temperature - 100 °C, preferably 20 °C;

[0024] Pressure: 3 MPa;

[0025] Time: 0.1 - 24 hours, preferably 12 hours.

[0026] The present invention has the following advantages:

[0027] 1. The starting materials are readily available

[0028] 2. The reaction conditions are mild, the reaction activity is high, the enantioselectivity is high, and the product yield is high.

[0029] 3. The catalyst is simple to prepare and highly efficient, and the whole process is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The accompanying drawings forming a part of this invention are used to provide a further understanding of the invention. The schematic embodiments and descriptions thereof of the invention are used to explain the invention and do not constitute an improper limitation of the invention. Hereinafter, the embodiments of the invention will be described in detail with reference to the drawings, wherein:

[0031] Figure 1 1H NMR spectrum of pyridine-2,6-diylbis(phenylmethanol) II-A prepared in Example 1;

[0032] Figure 2 13C NMR spectrum of pyridine-2,6-diylbis(phenylmethanol) II-A prepared in Example 1;

[0033] Figure 3 1H NMR spectrum of pyridine-2,6-diylbis(p-tolylmethanol) II-B prepared in Example 2;

[0034] Figure 4 13C NMR spectrum of pyridine-2,6-diylbis(p-tolylmethanol) II-B prepared in Example 2;

[0035] Figure 5 1H NMR spectrum of pyridine-2,6-diylbis(m-tolylmethanol) II-C prepared in Example 3;

[0036] Figure 6 13C NMR spectrum of pyridine-2,6-diylbis(m-tolylmethanol) II-C prepared in Example 3;

[0037] Figure 7 1H NMR spectrum of pyridine-2,6-diyldiethanol II-D prepared in Example 4;

[0038] Figure 8 13C NMR spectrum of pyridine-2,6-diyldiethanol II-D prepared in Example 4. Detailed Description of the Invention

[0039] The present invention will be further illustrated below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods in the following embodiments without specific conditions are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturers.

[0040] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to persons skilled in the art. The reagents or raw materials used in the present invention can be obtained through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in accordance with the conventional methods in the art or in accordance with the product instructions. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only. The nuclear magnetic resonance in the examples of the present invention was measured by a Bruker 400 nuclear magnetic resonance spectrometer.

[0041] Example 1 Chiral pyridine-2,6-diylbis(phenylmethanol) II-A was prepared from 2,6-dibenzoylpyridine I-A as a raw material.

[0042]

[0043] In a glove box, iridium metal (0.002 mmol) and ligand L-1a (0.0022 mmol) were vigorously stirred in ethanol at a molar ratio of 1:1.1 for 1 h. Subsequently, an ethanol solution (0.1 M) of 2,6-dibenzoylpyridine I-A (0.2 mmol) was added thereto, and t BuOK (0.02 mmol) was added. Subsequently, it was placed in a high-pressure reaction kettle, purged with hydrogen three times, and hydrogen was charged to 3 MPa, and the reaction was carried out at 20 °C for 12 hours. After the reaction was completed, hydrogen was slowly released, the solvent was removed, and the residue was separated by column chromatography to obtain chiral 2-pyridylphenylmethanol II-A with a yield of 99%, 99% ee and 99% de. The 1H NMR and 13C NMR spectra of pyridine-2,6-diylbis(phenylmethanol) II-A are as Figure 1 、 Figure 2 shown: 1 H NMR (400 MHz, CDCl3) δ 7.55–7.06 (m, 13H), 5.77 (s, 2H), 4.72 (s, 2H). 13 C NMR (101 MHz, CDCl3) δ 160.1, 142.8, 137.9, 128.6, 127.9, 127.0, 120.0, 75.4.

[0044] Example 2 In Example 1, I-A was replaced with I-B, and the rest was the same as in Example 1. The reaction gave chiral pyridine-2,6-diylbis(p-tolylmethanol) II-B with a yield of 99%, 99% ee and 99% de.

[0045]

[0046] The 1H NMR and 13C NMR spectra of pyridine-2,6-diylbis(p-tolylmethanol) II-B are asFigure 3 , Figure 4 as shown below: 1 HNMR(400MHz,CDCl3)δ7.53–7.04(m,8H),5.73(s,2H),4.72(s,2H),2.31(s,6H). 13 C NMR(101MHz,CDCl3)δ160.2,139.9,137.8,137.6,129.3,127.0 119.9,75.2,21.2.

[0047] Example 3 Replace I-A in Example 1 with I-C, and the rest is the same as in Example 1. The reaction gives chiral pyridine-2,6-diylbis(m-tolylmethanol) II-C in 99% yield, 99% ee and 99% de.

[0048]

[0049] The 1H NMR and 13C NMR spectra of pyridine-2,6-diylbis(m-tolylmethanol) II-C are as shown in Figure 5 , Figure 6 as shown below: 1 HNMR(400MHz,CDCl3)δ7.55–7.06(m,11H),5.74(s,2H),4.67(s,2H),2.30(s,3H). 13 C NMR(101MHz,CDCl3)δ160.1,142.8,138.3,137.8,128.7,128.5,127.6,124.1,119.9,75.4,21.5.

[0050] Example 4 Replace I-A in Example 1 with I-D, and the rest is the same as in Example 1. The reaction gives pyridine-2,6-diylethanediol II-D in 99% yield, 99% ee and 99% de.

[0051]

[0052] The 1H NMR and 13C NMR spectra of pyridine-2,6-diylethanediol II-D are as shown in Figure 7 , Figure 8 as shown below: 1 H NMR(400MHz,CDCl3)δ7.71–7.20(m,3H),4.90(q,J=6.4Hz,2H),4.02(s 2H),1.51(d,J=6.4Hz,6H). 13 C NMR(101MHz,CDCl3)δ162.0,137.7,118.3,69.2,24.1.

[0053] The obtained product II-D can be used as a raw material for the synthesis of chiral phosphine ligands, which can be applied to the asymmetric transfer hydrogenation of ketone compounds (Q. Jiang, D. V. Plew, S. Murtuza, X. Zhang. Tetrahedron Lett., 1996, 37, 797–800).

[0054] The above-described embodiments merely represent the implementation manners of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing chiral pyridine-2,6-diol, characterized in that: Using 2,6-diacylpyridine and hydrogen as raw materials, in a reaction medium, a complex formed in situ by iridium metal and a phenyl-skeleton PNN ligand is used as a catalyst, and a base is used as an additive to carry out a hydrogenation reaction to produce chiral pyridine-2,6-diol; The PNN ligand of the phenyl skeleton is a six-membered piperidine ring L-1a; ； The 2,6-diacylpyridine compound has the following structure: ； Two of the Rs are each independently selected from hydrogen, a C1-C 40 linear or branched alkyl group, a cycloalkyl group having a ring number of C3-C 12 cycloalkyl group, phenyl group and substituted phenyl group, benzyl group and substituted benzyl group; the substituents on the substituted phenyl group or substituted benzyl group are each independently selected from a C1-C 40 alkyl group, a C1-C 40 alkoxy group, halogen, nitro group, ester group or cyano group; the base additive is t BuOK.

2. The synthesis method according to claim 1, characterized in that: The reaction medium is at least one of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide.

3. The synthesis method according to claim 1, characterized in that: The molar ratio of the 2,6-diacylpyridine to the catalyst is 100 - 50000:

1.

4. The synthesis method according to claim 3, characterized in that: The molar ratio of the 2,6-diacylpyridine to the catalyst is 100 - 5000:

1.

5. The synthesis method according to claim 4, characterized in that: The molar ratio of the 2,6-diacylpyridine to the catalyst is 100 - 1000:

1.

6. The synthesis method according to claim 1, characterized in that: The molar ratio of the 2,6-diacylpyridine to the base additive is 10 - 10000:

1.

7. The synthesis method according to claim 6, characterized in that: The molar ratio of the 2,6-diacylpyridine to the base additive is 10 - 1000:

1.

8. The synthesis method according to claim 7, characterized in that: The molar ratio of the 2,6-diacylpyridine to the base additive is 10 - 100:

1.

9. The synthesis method according to any one of claims 1-8, characterized in that: The specific method is as follows: Iridium metal and the PNN ligand of the phenyl skeleton are stirred in a reaction medium at a molar ratio of 1:1.1 - 1:2.2 for 0.5 - 1 hour, and then a reaction medium solution of 2,6-diacylpyridine is added thereto. A base additive is added, and it is placed in a high-pressure reaction kettle, purged with hydrogen, filled with hydrogen to 3 - 5 MPa, and reacted at 20 - 60 °C for 1 - 24 hours. After cooling to room temperature, the hydrogen is released, the solvent is removed, and chiral pyridine-2,6-diol is separated.

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