CN102311299A - Method for synthesizing chiral secondary alcohol through asymmetric hydrogenation reaction - Google Patents

Abstract

The invention discloses a method for synthesizing chiral secondary alcohol by asymmetric hydrogenation reaction. In the present invention, the catalyst precursor is prepared by reacting phenyl ruthenium dichloride, chiral bridged bisphosphine ligand (Rax)-BuP and chiral diamine (R, R)-DPEN, using latent chiral ketone and hydrogen as the reaction Using potassium tert-butoxide as an auxiliary agent, a chiral secondary alcohol can be synthesized in one step through asymmetric hydrogenation reaction in a low-carbon alcohol solvent. The conversion rate of reactants is up to 99wt%, and the enantioselectivity of products is up to 92%.

Description

Method for Synthesizing Chiral Secondary Alcohols by Asymmetric Hydrogenation

technical field

The invention relates to a method for synthesizing chiral secondary alcohols by asymmetric hydrogenation reaction.

Background technique

Chiral secondary alcohols are important intermediates for the synthesis of optically active drugs, and the catalytic asymmetric hydrogenation of latent chiral ketones is one of the most effective methods to obtain chiral secondary alcohols. In the asymmetric hydrogenation method for the synthesis of chiral secondary alcohols, the key to obtain catalytic activity and enantioselectivity is the chiral ligand. Patent (EP-A-071826) discloses atropisomeric binaphthyl-type bisphosphine ligands (BINAP, Tol-BINAP, Xylyl-BINAP, H8-BINAP) with a _C2 axis of symmetry, and chiral diamines DPEN or DAIPEN , a catalyst precursor prepared with ruthenium, in the asymmetric hydrogenation reaction of latent chiral ketones, gave a higher yield and enantioselective product chiral alcohol; in 1995, Noyori et al. reported Ru-BINAP derivatives-chiral In the asymmetric hydrogenation reaction of hypochiral ketones without other functional groups, the ternary system composed of neutral diamine-KOH can quantitatively convert the reactant, and the enantioselectivity of the product is higher, (T.Ohkuma, H Ooka, T. Ikariya, R. Noyori, J. Am. Chem. Soc., 1995, 117, 2675). In 2009, Zhang et al. reported that the biphenyl bisphosphine ligand C ₃ ^* -Tunephos/diamine-Ru(II) catalyst precursor shown in formula I showed excellent activity in the asymmetric hydrogenation reaction of latent chiral ketones and enantioselectivity (W. Li, X. Sun, L. Zhou, G. Hou, S. Yu, X. Zhang, J. Org. Chem. 2009, 74, 1397.).

Formula I _C 3 ^* -Tunephos

Atropisomeric binaphthyl-type bisphosphine ligands, biphenyl-type bisphosphine ligands, and bipyridine-type bisphosphine ligands with a _C2 axis of symmetry, when the phosphorus atom contains a 3,5-dimethylbenzene substituent When , the ruthenium catalytic precursor composed of chiral diamine with larger steric hindrance shows relatively high catalytic activity and enantioselectivity in the asymmetric hydrogenation reaction of latent chiral ketones. However, in these existing asymmetric hydrogenation reaction methods, there are obvious deficiencies: the slight changes in the stereostructure and steric electronic effect of the chiral bisphosphine ligand usually lead to significant changes in the activity and enantioselectivity of the ruthenium catalytic precursor. reduce.

Contents of the invention

The object of the present invention is to provide a method for asymmetric hydrogenation of latent chiral ketones to synthesize chiral secondary alcohols.

The present invention is realized through the following measures:

In the present invention, the catalyst precursor is prepared by reacting phenyl ruthenium dichloride, chiral bridged bisphosphine ligand (Rax)-BuP and chiral diamine (R, R)-DPEN, using latent chiral ketone and hydrogen as the reaction Using potassium tert-butoxide as an auxiliary agent, in a low-carbon alcohol solvent, a chiral secondary alcohol can be synthesized in one step through asymmetric hydrogenation reaction.

A method for the synthesis of chiral secondary alcohols by asymmetric hydrogenation, characterized in that the method comprises the following processes in sequence:

The preparation process of catalyst precursor: under nitrogen protection, phenyl ruthenium dichloride and chiral bridged bisphosphine ligand (Rax)-BuP as shown in formula II, in N, N-dimethylformamide solvent Mix in medium, react at 80-120°C; after cooling to room temperature, add chiral diamine (R, R)-DPEN shown in formula III, react at room temperature; distill the solvent under reduced pressure, add dichloromethane to dissolve the solid, Concentrate the solution, add hexane to the concentrated solution to produce a brownish-yellow precipitate, filter, and distill the solvent from the filtrate under reduced pressure to obtain a khaki-yellow solid that is a ruthenium catalyst precursor;

Formula II(R _ax )-BuP Formula III(R,R)-DPEN

Asymmetric hydrogenation reaction process: under the protection of nitrogen, dissolve the ruthenium catalyst precursor and potassium tert-butoxide in low-carbon alcohol, then add the reactant hypochiral ketone, in a hydrogen atmosphere, pressure 1-5MPa, temperature 18- 28°C, stirred and reacted for 18-64 hours; the product was concentrated under reduced pressure after flash column chromatography to obtain the product chiral secondary alcohol.

The reaction product conversion rate of the present invention is up to 99% by weight, and the product enantioselectivity is up to 92%.

Reaction of the present invention represents with formula IV:

Formula IV R=H, -Br, -CH ₃ -, or-OCH ₃

For the synthesis method of chiral bridged bisphosphine ligand (Rax)-BuP, see literature (L. Qiu, A.S.C.Chan, et al J. Am. Chem. Soc., 2006, 128(17), 5955). Chiral diamine (R,R)-DPEN is a commercial reagent.

The molar ratio of phenyl ruthenium dichloride, chiral bridged bisphosphine ligand and chiral diamine is 0.5:1.1:1.1˜0.45:1:1.

The reactant latent chiral ketone is selected from p-bromoacetophenone, p-methylacetophenone, p-methoxyacetophenone, meta-bromoacetophenone, meta-methylacetophenone, meta-methylacetophenone One of oxyacetophenone, ortho-bromoacetophenone, ortho-methylacetophenone and ortho-methoxyacetophenone.

The number of moles of latent chiral ketones per liter of low-carbon alcohol is 2.0-5.0.

The low-carbon alcohol is selected from one of methanol, isopropanol and n-butanol.

The molar ratio of the ruthenium catalyst precursor to the latent chiral ketone is 1:5000˜1:500.

The molar ratio of potassium tert-butoxide to latent chiral ketone is 1:110-1:11.

The present invention has the following advantages: the ruthenium catalyst precursor prepared by reacting chiral bridged bisphosphine ligand with chiral diamine and phenyl ruthenium dichloride is not afraid of oxidation in air and can be weighed in air; Substance chiral ketone is cheap and easy to obtain; after a one-step asymmetric hydrogenation reaction, under 1-5MPa hydrogen pressure, stirring reaction at 18-28°C for a certain period of time, chiral phenylethyl alcohol or substituted phenylethyl alcohol can be efficiently synthesized after simple post-treatment.

Detailed ways

In order to better understand the present invention, it is illustrated by examples.

Example 1:

Add phenyl ruthenium dichloride (〔RuCl ₂ beneze〕 ₂ ) (0.05 mmol, 25 mg) into a 100 mL Schlenk bottle, bridge chiral bisphosphine ligand (Rax)-BuP (0.105 mmol, 64.3 mg), N, N- Dimethylformamide 6mL, under the protection of nitrogen, 100 ℃, stirred reaction. After the solution was cooled to room temperature, chiral diamine (R, R)-DPEN (0.105 mmol, 23 mg) was added, the reaction was continued to stir at this temperature, the solvent was distilled off under reduced pressure, dichloromethane was added to dissolve the solid, and the solution was concentrated , Add hexane to the concentrated solution to produce a brownish yellow precipitate, filter, and distill the solvent from the filtrate under reduced pressure to obtain a khaki solid as a ruthenium catalyst precursor. ³¹ pNMR (CDCl ₃ , 202 MHz) δ=47.5 ppm(s) of the ruthenium catalyst precursor.

Add ruthenium catalyst precursor (0.0025mmol, 2.5mg), potassium tert-butoxide 0.114mmol, methanol 1mL to 100mL Schlenk bottle, stir and dissolve at room temperature, add acetophenone (2.5mmol, 0.29mL), transfer to 30mL high pressure with stirring Kettle, hydrogen atmosphere, 2MPa, 20 ℃ stirring reaction for 20 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 46wt% as measured by gas chromatography, and the product was 55% ee(S)-phenylethanol.

Example 2:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 1 mL of isopropanol, stirred and dissolved at room temperature, added acetophenone (2.5 mmol, 0.29 mL), transferred to a 30 mL stirred autoclave, hydrogen atmosphere, 2 MPa, 28 The reaction was stirred at °C for 18 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 75% ee(S)-phenethyl alcohol.

Example 3:

Ruthenium catalyst precursor and potassium butoxide as in Example 1, n-butanol 1mL, stirred and dissolved at room temperature, added acetophenone (2.5mmol, 0.29mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 1MPa, 20 The reaction was stirred at °C for 22 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 81% ee(S)-phenylethanol.

Example 4:

Ruthenium catalyst precursor and potassium tert-butoxide as in Example 1, n-butanol 2.2mL, stirred and dissolved at room temperature, added acetophenone (7.5mmol, 0.81mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 3MPa, The reaction was stirred at 20°C for 21 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 80% ee(S)-phenylethanol.

Example 5:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 3.5mL of n-butanol, stirred and dissolved at room temperature, added acetophenone (12.5mmol, 1.45mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 3MPa, The reaction was stirred at 20°C for 21 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 38wt% as measured by gas chromatography, and the product was 79% ee(S)-phenylethanol.

Embodiment 6:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 2 mL of n-butanol, stirred and dissolved at room temperature, added p-methylacetophenone (7.5 mmol, 1.0 mL), transferred to a 30 mL autoclave with stirring, hydrogen atmosphere, 3MPa, stirred and reacted at 20°C for 45 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 80% ee(S)-p-methylphenylethanol.

Embodiment 7:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 3 mL of n-butanol, stirred and dissolved at room temperature, added p-methoxyacetophenone (7.5 mmol, 1.13 g), transferred to a 30 mL stirred autoclave, and hydrogen atmosphere , 3MPa, stirred and reacted at 20°C for 40 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 81% ee(S)-p-methoxyphenylethanol.

Embodiment 8:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 3 mL of n-butanol, stirred and dissolved at room temperature, added p-bromoacetophenone (7.5 mmol, 1.49 g), transferred to a 30 mL stirred autoclave, hydrogen atmosphere, 3 MPa , 20°C and stirred for 41 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 69% ee(S)-p-bromophenylethanol.

Embodiment 9:

Ruthenium catalyst precursor and potassium tert-butoxide as in Example 1, n-butanol 2.5mL, stirred and dissolved at room temperature, added m-methylacetophenone (7.5mmol, 0.68mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere , 3MPa, stirred at 20°C for 64 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 84% ee(S)-m-methylphenylethanol.

Example 10:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 2.5mL of n-butanol, stirred and dissolved at room temperature, added m-bromoacetophenone (7.5mmol, 0.66mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 3MPa, stirred at 20°C for 22 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 76% ee(S)-m-bromophenylethanol.

Example 11:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 2.5mL of n-butanol, stirred and dissolved at room temperature, added m-methoxyacetophenone (7.5mmol, 0.69mL), transferred to a 30mL autoclave with stirring, hydrogen Atmosphere, 3MPa, stirred and reacted at 20°C for 44 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 84% ee(S)-m-methoxyphenethyl alcohol.

Example 12:

The ruthenium catalyst precursor and potassium tert-butoxide are as in Example 1, 1 mL of n-butanol, stirred and dissolved at room temperature, added o-methyl acetophenone (2.5 mmol, 0.33 mL), transferred to a 30 mL stirred autoclave, hydrogen atmosphere, 5MPa, stirred at 20°C for 48 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 92% ee(S)-o-methylphenylethanol.

Example 13:

Ruthenium catalyst precursor and potassium tert-butoxide as in Example 1, n-butanol 1mL, stirring at room temperature to dissolve, adding o-bromoacetophenone (2.5mmol, 0.34mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere, 5MPa , 20°C and stirred for 48 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 89% ee(S)-o-bromophenylethanol.

Example 14:

Ruthenium catalyst precursor and potassium tert-butoxide as in Example 1, n-butanol 1mL, stirring at room temperature to dissolve, adding o-methoxyacetophenone (2.5mmol, 0.34mL), transferred to a 30mL autoclave with stirring, hydrogen atmosphere , 5MPa, stirred at 20°C for 48 hours. The hydrogen in the kettle was emptied, concentrated under reduced pressure after flash column chromatography, the reaction conversion rate was 99wt% as measured by gas chromatography, and the product was 58% ee(S)-o-methoxyphenethyl alcohol.

Claims (7)

1. a method for the synthesis of chiral secondary alcohols by asymmetric hydrogenation, characterized in that the method comprises the following processes successively: The preparation process of the catalyst precursor: under the protection of nitrogen, phenyl ruthenium dichloride and the chiral bridged bisphosphine ligand shown in formula II are mixed in N,N-dimethylformamide solvent, 80～ Reaction at 120°C; after cooling to room temperature, add chiral diamine as shown in formula III, and react at room temperature; distill the solvent under reduced pressure, add dichloromethane to dissolve the solid, concentrate the solution, add hexane to the concentrated solution to produce brown The yellow precipitate was filtered, and the filtrate was distilled off the solvent under reduced pressure to obtain a khaki solid as a ruthenium catalyst precursor; Formula II(R _ax )-BuP Formula III(R,R)-DPEN Asymmetric hydrogenation reaction process: under the protection of nitrogen, dissolve the ruthenium catalyst precursor and potassium tert-butoxide in low-carbon alcohol, then add the reactant hypochiral ketone, in a hydrogen atmosphere, pressure 1-5MPa, temperature 18- 28°C, stirred and reacted for 18-64 hours; the product was concentrated under reduced pressure after flash column chromatography to obtain the product chiral secondary alcohol. 2. The method according to claim 1, characterized in that the mol ratio between phenyl ruthenium dichloride, chiral bridged bisphosphine ligand and chiral diamine is 0.5: 1.1: 1.1～0.45: 1: 1. 3. The method as claimed in claim 1, wherein the latent chiral ketone is selected from para-bromoacetophenone, para-methylacetophenone, para-methoxyacetophenone, meta-bromoacetophenone , m-methyl acetophenone, m-methoxy acetophenone, ortho bromoacetophenone, ortho methyl acetophenone and ortho methoxy acetophenone. 4. The method according to claim 1, characterized in that the number of moles of latent chiral ketone per liter of lower alcohol is 2.0 to 5.0. 5. The method according to claim 1, characterized in that the lower alcohol is selected from the one in methyl alcohol, Virahol and n-butanol. 6. The method according to claim 1, characterized in that the molar ratio of the ruthenium catalyst precursor to the chiral ketone is 1:5000˜1:500. 7. The method according to claim 1, characterized in that the molar ratio of potassium tert-butoxide to latent chiral ketone is 1:110 to 1:11.