Method for synthesizing pyridino-cyclic alcohol chiral compound through asymmetric catalytic hydrogenation

Abstract

The invention discloses a method for synthesizing a pyridocyclic alcohol chiral compound through asymmetric catalytic hydrogenation, which comprises the following step: in an organic solvent, carrying out asymmetric hydrogenation reduction reaction on a pyridocyclic ketone compound in the presence of a ruthenium catalyst, formic acid and organic alkali to form the pyridocyclic alcohol chiral compound. The chemical purity of the pyridino-cyclic alcohol chiral compound prepared by the method reaches 99% or above, the optical purity can reach 99% or above at most, the yield can reach 99% or above at most, and the method is high in raw material utilization rate, simple and easy to implement and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of chiral compound preparation, and particularly relates to a method for asymmetric catalytic hydrogenation synthesis of chiral pyrido-cycloalcohol compounds. Background Art

[0002] In the fields of organic chemistry and materials science, chiral compounds exhibit great application potential due to their unique physical and chemical properties, especially in asymmetric catalysis, drug development, and the preparation of functional materials. Among them, chiral pyrido-cycloalcohol compounds, as a precursor part of an important class of chiral nitrogen-phosphorus ligands, the chiral characteristics in their structures not only endow these compounds with unique biological activities but also make them key components for constructing highly efficient catalysts. Chiral nitrogen-phosphorus ligands, as a class of hetero-bidentate ligands with large structural tunability, can significantly enhance the catalytic activity of metal complexes by flexibly adjusting their substituents, ligand sites, and coordination configurations, thus having broad application prospects in the fields of asymmetric synthesis, drug synthesis, etc.

[0003] However, the efficient and high-purity preparation of chiral pyrido-cycloalcohol compounds is a major challenge in the field of chemical synthesis. Traditional preparation methods are often cumbersome, have low yields, and it is difficult to ensure both the chemical purity and optical purity of the products simultaneously, which greatly limits the popularization and use of such compounds in high-end application fields. Especially in asymmetric hydrogenation reactions, how to select appropriate hydrogen sources, catalysts, and ligand systems to achieve the efficient and high-purity preparation of chiral alcohols derived from pyridine groups, and ensure that the chemical purity and optical purity of the products meet the standards of industrial applications, remains a technical problem to be solved urgently. Summary of the Invention

[0004] To solve the above technical problems, the present invention provides a method for asymmetric catalytic hydrogenation synthesis of chiral pyrido-cycloalcohol compounds.

[0005] The present invention is achieved through the following technical solutions:

[0006] The present invention provides a method for asymmetric catalytic hydrogenation synthesis of chiral pyrido-cycloalcohol compounds, comprising the following steps:

[0007] In an organic solvent, the compound shown in Formula I undergoes an asymmetric hydrogenation reduction reaction in the presence of a ruthenium catalyst, formic acid, and an organic base to form the compound shown in Formula II, and the reaction formula is as follows:

[0008]

[0009] Wherein, R 1 、R 2 and R 3Each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, nitro, amino, alkyl, alkoxy, cycloalkyl, heterocyclic group, acyl group-containing group, sulfonyl group-containing group, aryl, heteroaryl; n is 1, 2 or 3;

[0010] The ruthenium catalyst is selected from the compounds represented by the following formula:

[0011]

[0012] In the present invention, formic acid and an organic base are used as hydrogen sources, and chiral pyrido-fused cycloalcohol compounds with high chemical purity and high optical purity are obtained by hydrogenation under the catalysis of a ruthenium metal catalyst.

[0013] Furthermore, the compound represented by Formula I is selected from one of the following structures:

[0014]

[0015] Furthermore, the compound represented by Formula I is a pyrido-fused cycloketone compound, and it can be 2-phenyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one.

[0016] Furthermore, the organic solvent is selected from one or more of toluene, tetrahydrofuran, ethyl acetate, dichloromethane, methyl tert-butyl ether and methanol, and preferably ethyl acetate.

[0017] Furthermore, the organic base is selected from one or more of triethylamine, potassium formate, sodium formate, diethylamine, N-methylmorpholine, tetramethylethylenediamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, potassium acetate, sodium acetate and ammonium formate, and preferably 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

[0018] Furthermore, the molar ratio of formic acid to the organic base is (1 - 3):1, and preferably 5:3.

[0019] Furthermore, the molar ratio of the compound represented by Formula I to the ruthenium catalyst is (10 - 1000):1, preferably (190 - 210):1, and more preferably 200:1.

[0020] Furthermore, the molar ratio of the compound represented by Formula I to formic acid is 1:(1 - 30), preferably 1:(2 - 5), and more preferably 1:3.

[0021] Furthermore, the molar ratio of the compound represented by Formula I to the organic solvent is 1:(1 - 20), preferably 1:(2 - 5), and more preferably 1:3.

[0022] Furthermore, the temperature of the asymmetric hydrogenation reduction reaction is 5-45 °C, preferably 25-30 °C.

[0023] Specifically, first mix and stir formic acid and an organic base, then add a ruthenium catalyst and the compound shown in Formula I, and finally add an organic solvent; alternatively, first add the compound shown in Formula I to an organic solvent, then add formic acid and an organic base, and finally add a ruthenium catalyst.

[0024] Advantages of the present invention:

[0025] The present invention provides a method for asymmetric catalytic hydrogenation synthesis of pyridine-fused cyclic alcohol chiral compounds, which can asymmetrically hydrogenate pyridine-fused cyclic ketone compounds into pyridine-fused cyclic alcohol chiral compounds. The chemical purity of the pyridine-fused cyclic alcohol chiral compounds prepared by the present invention reaches more than 99%, the optical purity can reach up to more than 99% at most, and the yield can reach up to more than 99% at most. This method has high raw material utilization rate, and the preparation method is simple and easy to implement, and is suitable for industrial scale-up production. Description of the Drawings

[0026] Figure 1 It is a chiral analysis and test result diagram of (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol prepared in Example 1. Detailed Embodiments

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0028] The present invention provides a method for asymmetric catalytic hydrogenation synthesis of pyridine-fused cyclic alcohol chiral compounds, comprising the following steps:

[0029] In an organic solvent, the compound shown in Formula I undergoes an asymmetric hydrogenation reduction reaction in the presence of a ruthenium catalyst, formic acid, and an organic base to form the compound shown in Formula II, and the reaction formula is as follows:

[0030]

[0031] Wherein, R 1 , R 2 and R 3Each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by one or more substituents selected from halogen, cyano, nitro, amino, alkyl, alkoxy, cycloalkyl, heterocyclic group, acyl-containing group, sulfonyl-containing group, aryl, heteroaryl; n is 1, 2 or 3;

[0032] The ruthenium catalyst is selected from the compounds shown by the following formula:

[0033]

[0034] The present invention has developed a series of catalysts formed by ruthenium and ligands, and this catalyst is used for the asymmetric catalytic hydrogenation of the compound shown by formula I, so that the compound shown by formula I has a high conversion rate and good reduction selectivity.

[0035] In the specific embodiment, the compound shown by formula I is selected from one of the following structures:

[0036]

[0037] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and can implement it, but the examples given are not intended to limit the present invention. Unless otherwise stated, the percentages and parts used herein are weight percentages and weight parts.

[0038] The experimental methods used in the following examples are all conventional methods unless otherwise specified, and the materials, reagents, etc. used can be obtained from commercial channels unless otherwise specified.

[0039] Example 1

[0040] A method for the asymmetric catalytic hydrogenation synthesis of (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol, comprising the following steps:

[0041] (1) Synthesis of the catalyst:

[0042] N-[(1S,2S)-2-amino-1,2-diphenylethyl]-2,3,4,5,6-pentafluorobenzenesulfinamide (82.98 g, 0.136 mol, 1.0 eq), dichloro-bis(4-methylisopropylphenyl)ruthenium(II) (120 g, 0.271 mol, 2.0 eq), and triethylamine (54.9 g, 0.542 mol, 4.0 eq) were successively added to the reaction flask, and then 1500 mL of isopropanol was added, and the mixture was refluxed and stirred at 80 °C for 4 h. After the reaction was completed by TLC, the solvent was evaporated under reduced pressure to obtain a solid, and the catalyst Ⅳ was obtained by recrystallization with ethanol. The obtained recrystallized product was dried in an oven to obtain 186.3 g of a yellow solid powder with a yield of 89%. The 1H NMR data of catalyst Ⅳ are as follows:

[0043] 1 H NMR(400MHz,Chloroform-d)δ7.05–6.43(m,10H),6.19(d,J=5.7Hz,1H),5.94(d,J=5.9Hz,1H),5.79(dd,J=11.2,5.9Hz,2H),3.77(t,J=12.9Hz,1H),3.51(dd,J=28.2,11.7Hz,2H),3.22(p,J=6.9Hz,1H),2.41(s,3H),1.46(d,J=6.9Hz,3H),1.41(d,J=6.9Hz,3H).

[0044] (2) Asymmetric catalytic hydrogenation reaction

[0045] The compound shown in formula I-1 (200 mg, 0.956 mmol) was added to 10.0 mL of ethyl acetate, then 3.0 mL of formic acid and 4.0 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) were added, and finally catalyst Ⅳ (3.5 mg, 0.005 mmol) was added. The reaction was stirred at room temperature for 10 h. After the reaction was completed as detected by TLC, sodium bicarbonate was added to neutralize the formic acid, and then extraction was carried out with EA. The organic phase was evaporated under reduced pressure to remove the solvent, and (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (the compound shown in formula Ⅱ-1) was obtained. The conversion rate of the raw material was over 97%, and the ee value (optical purity) was 99%. The 1H NMR data of the compound shown in formula Ⅱ-1 are as follows:

[0046] 1 H NMR(400MHz,Chloroform-d)δ8.00–7.92(m,1H),7.65–7.55(m,1H),7.49–7.36(m,2H),5.25(dd,J=7.4,6.1Hz,1H),3.36(s,0H),3.04(ddd,J=16.3,8.9,3.9Hz,0H),2.85(dt,J=15.7,7.8Hz,1H),2.58(dddd,J=13.2,8.2,7.4,3.9Hz,1H),2.07(dddd,J=13.4,8.9,7.3,6.1Hz,1H).

[0047] The (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol prepared in Example 1 was subjected to chiral analysis on a CHIRALCEL OD-H column under the conditions of iPrOH / n-Hexane = 10 / 90 and 1.0 mL / min. The test results are as Figure 1 shown, demonstrating that the (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol obtained after hydrogenation of the present invention has a single configuration and an optical purity of over 99%.

[0048] Example 2

[0049] A method for asymmetric catalytic hydrogenation synthesis of (7S)-6,7-dihydro-5H-7-hydroxy-cyclopenta[B]pyridine, comprising the following steps:

[0050]

[0051] Add the compound shown in formula I-2 (200 mg, 1.5 mmol) to 10.0 mL of ethyl acetate, then add 3.0 mL of formic acid and 4.0 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and finally add catalyst IV (5 mg, 0.007 mmol). Stir and react at room temperature for 10 h. After the reaction is completed as detected by TLC, add sodium bicarbonate to neutralize the formic acid, then extract with EA. Take the organic phase and evaporate the solvent under reduced pressure to obtain (7S)-6,7-dihydro-5H-7-hydroxy-cyclopenta[B]pyridine (the compound shown in formula II-2). The raw material conversion rate is over 98%, and the ee value is 99%. The nuclear magnetic resonance hydrogen spectrum data of the compound shown in formula II-2 are as follows:

[0052] 1 H NMR (400 MHz, Chloroform-d) δ 8.59 (dd, J = 3.5, 2.2 Hz, 1H), 7.81 (dd, J = 7.9, 2.2 Hz, 1H), 7.42 (dd, J = 7.7, 3.5 Hz, 1H), 5.16 (ddd, J = 5.3, 4.6, 3.7 Hz, 1H), 4.48 (d, J = 5.3 Hz, 1H), 2.96 (t, J = 5.8 Hz, 2H), 2.37 (dtd, J = 13.4, 5.8, 3.6 Hz, 1H), 2.21 (dtd, J = 13.5, 5.9, 4.6 Hz, 1H).

[0053] Example 3

[0054] A method for asymmetric catalytic hydrogenation synthesis of (S)-5,6,7,8-tetrahydroquinolin-8-ol, comprising the following steps:

[0055]

[0056] The compound shown in Formula I-3 (200 mg, 1.34 mmol) was added to 10.0 mL of ethyl acetate, then 3.0 mL of formic acid and 4.0 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added, and finally catalyst Ⅳ (5 mg, 0.007 mmol) was added. The reaction was stirred at room temperature for 10 h. After the reaction was completed as detected by TLC, sodium bicarbonate was added to neutralize the formic acid, and then extraction was carried out with EA. The organic phase was taken and the solvent was evaporated under reduced pressure to obtain (S)-5,6,7,8-tetrahydroquinolin-8-ol (the compound shown in Formula II-3). The conversion rate of the raw material was over 97%, and the ee value was 99%. The 1H NMR data of the compound shown in Formula II-3 are as follows:

[0057] 1 H NMR(400MHz,Chloroform-d)δ8.52(dd,J=3.5,2.2Hz,1H),7.62(dd,J=7.9,2.2Hz,1H),7.42(dd,J=7.9,3.5Hz,1H),5.04–4.73(m,1H),3.86(d,J=7.1Hz,1H),3.17–2.63(m,2H),2.24–1.67(m,4H).

[0058] Example 4

[0059] A method for asymmetric catalytic hydrogenation synthesis of (S)-2-phenyl-5,6,7,8-tetrahydroquinolin-8-ol, comprising the following steps:

[0060]

[0061] The compound shown in Formula I-4 (200 mg, 0.90 mmol) was added to 10.0 mL of ethyl acetate, then 3.0 mL of formic acid and 4.0 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were added, and finally catalyst Ⅳ (5 mg, 0.007 mmol) was added. The reaction was stirred at room temperature for 10 h. After the reaction was completed as detected by TLC, sodium bicarbonate was added to neutralize the formic acid, and then extraction was carried out with EA. The organic phase was taken and the solvent was evaporated under reduced pressure to obtain (S)-2-phenyl-5,6,7,8-tetrahydroquinolin-8-ol (the compound shown in Formula II-4). The conversion rate of the raw material was over 95%, and the ee value was 99%. The 1H NMR data of the compound shown in Formula II-4 are as follows:

[0062] 11H NMR (400 MHz, Chloroform-d) δ 7.89 - 7.80 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.44 - 7.33 (m, 3H), 4.94 (ddd, J = 7.0, 6.2, 3.9 Hz, 1H), 3.81 (d, J = 7.0 Hz, 1H), 2.95 - 2.79 (m, 2H), 2.12 (dddd, J = 13.4, 6.6, 5.5, 4.0 Hz, 1H), 2.02 - 1.82 (m, 3H).

[0063] Example 5

[0064] A method for the asymmetric catalytic hydrogenation synthesis of (S)-2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol, comprising the following steps:

[0065]

[0066] Add the compound shown in formula I-5 (200 mg, 0.90 mmol) to 10.0 mL of ethyl acetate, then add 3.0 mL of formic acid and 4.0 mL of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), and finally add catalyst IV (5 mg, 0.007 mmol). Stir and react at room temperature for 10 h. After detecting the completion of the reaction by TLC, add sodium bicarbonate to neutralize the formic acid, then extract with EA. Take the organic phase and evaporate the solvent under reduced pressure to obtain (S)-2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (the compound shown in formula II-5). The conversion rate of the raw material is over 96%, and the ee value is 99%. The nuclear magnetic resonance hydrogen spectrum data of the compound shown in formula II-5 are as follows:

[0067] 1 1H NMR (400 MHz, Chloroform-d) δ 7.89 - 7.81 (m, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.45 - 7.34 (m, 4H), 4.88 (ddd, J = 9.2, 8.2, 5.9 Hz, 1H), 4.04 (d, J = 9.1 Hz, 1H), 2.90 (ddd, J = 14.8, 8.8, 6.8 Hz, 1H), 2.78 (ddd, J = 14.7, 9.0, 6.7 Hz, 1H), 2.14 - 1.96 (m, 2H), 1.91 - 1.57 (m, 4H).

[0068] The ruthenium catalyst can be selected from the compounds shown by the following formula:

[0069]

[0070] The methods for synthesizing (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol in Examples 6-9 are substantially the same as in Example 1, except that catalyst IV is replaced with the above-mentioned catalysts III, V, VI, and VII.

[0071] The methods for synthesizing (7S)-6,7-dihydro-5H-7-hydroxy-cyclopenta[B]pyridine in Examples 10-13 are substantially the same as in Example 2, except that catalyst IV is replaced with the above-mentioned catalysts III, V, VI, and VII.

[0072] The methods for synthesizing (S)-5,6,7,8-tetrahydroquinolin-8-ol in Examples 14-17 are substantially the same as in Example 3, except that catalyst IV is replaced with the above-mentioned catalysts III, V, VI, and VII.

[0073] The methods for synthesizing (S)-2-phenyl-5,6,7,8-tetrahydroquinolin-8-ol in Examples 18-21 are substantially the same as in Example 16, except that catalyst IV is replaced with the above-mentioned catalysts III, V, VI, and VII.

[0074] The methods for synthesizing (S)-2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol in Examples 22-25 are substantially the same as in Example 5, except that catalyst IV is replaced with the above-mentioned catalysts III, V, VI, and VII.

[0075] The methods for synthesizing (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol in Examples 26-34 are substantially the same as in Example 1, except that DBU is replaced with triethylamine, potassium formate, sodium formate, diethylamine, N-methylmorpholine, tetramethylethylenediamine, potassium acetate, sodium acetate, ammonium formate.

[0076] The methods for synthesizing (S)-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol in Examples 35-40 are substantially the same as in Example 1, except that ethyl acetate is replaced with toluene, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, methanol.

[0077] The catalytic evaluation results of the catalysts in Examples 1-40 are shown in Table 1:

[0078] Table 1

[0079]

[0080]

[0081]

[0082] From the data of the above Examples 1 and 26-34, it can be seen that under the conditions of different organic bases, the effect of the hydrogenation reaction is the best under the condition of DBU, and the ee value of the product can reach 99%, and the yield (conversion rate) reaches more than 95%; from the data of Examples 1 and 35-40, it can be seen the influence of different solvents on the hydrogenation reaction. Among them, using ethyl acetate can make the ee value of the product reach 99% and the yield reach more than 95%.

[0083] Obviously, the above examples of the present invention are only examples for clearly explaining the present invention, rather than limitations on the implementation modes of the present invention. Those skilled in the art should understand that other different forms of changes or variations can be made on the basis of the above description. It is not necessary and impossible to enumerate all the implementation modes here. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing chiral pyridocyclic alcohol compounds by asymmetric catalytic hydrogenation, characterized in that: The following steps are involved: In an organic solvent, the compound represented by formula I is subjected to an asymmetric hydrogenation reduction reaction in the presence of a ruthenium catalyst, formic acid and an organic base to form a compound represented by formula II. The reaction formula is shown below: Among them, R 1 , R 2 and R 3 Each is independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halogen, cyano, nitro, amino, alkyl, alkoxy, cycloalkyl, heterocyclyl, acyl-containing group, sulfonyl-containing group, aryl or heteroaryl; n is 1, 2 or 3; The ruthenium catalyst is selected from the compounds shown in the following formula:

2. The method according to claim 1, characterized in that The compound represented by formula I is selected from one of the following structures:

3. The method according to claim 1, characterized in that The organic solvent is selected from one or more of toluene, tetrahydrofuran, ethyl acetate, dichloromethane, methyl tert-butyl ether and methanol.

4. The method according to claim 1, characterized in that The organic base is selected from one or more of triethylamine, potassium formate, sodium formate, diethylamine, N-methylmorpholine, tetramethylethylenediamine, 1,8-diazacyclo[5,4,0]undecene-7, potassium acetate, sodium acetate and ammonium formate.

5. The method according to claim 1, characterized in that The molar ratio of formic acid to organic base is (1-3):

1.

6. The method according to claim 1, characterized in that The molar ratio of the compound represented by formula I to the ruthenium catalyst is (10-1000):

1.

7. The method according to claim 1, characterized in that The molar ratio of the compound represented by formula I to formic acid is 1:(1-30).

8. The method according to claim 1, characterized in that The molar ratio of the compound represented by formula I to the organic solvent is 1:(1-20).

9. The method according to claim 1, characterized in that: The temperature of the asymmetric hydrogenation reduction reaction is 5-45°C.

10. The method according to claim 1, characterized in that The organic solvent is ethyl acetate, and the organic base is 1,8-diazacyclo[5,4,0]undecene-7.

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