A method for the synthesis of chiral β-hydroxy carboxylic acid esters catalyzed by ruthenium complexes

Abstract

The present invention provides a method for synthesizing chiral β-hydroxycarboxylic acid esters. Using β-ketoesters as raw materials, ruthenium complexes modified with chiral tridentate PNN ligands as catalysts, and alcohols as solvents, a homogeneous catalytic system is employed to carry out a hydrogenation reaction to obtain chiral β-hydroxycarboxylic acid esters in high yields (>99%) and high ee values ((>99%). This reaction has high activity, mild reaction conditions, and inexpensive and readily available starting materials, and thus has high industrial application value.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a synthesis method for preparing chiral β-hydroxycarboxylic acid esters by asymmetric hydrogenation of β-ketoesters catalyzed by ruthenium complexes. Background Art

[0002] The asymmetric hydrogenation of transition metals to synthesize chiral secondary alcohols has great industrial application prospects, because such catalysts exhibit high reaction activity and enantioselective or diastereoselective properties in the hydrogenation of ketone compounds [(a) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659. (b) Kumobayashi, H.; Miura, T.; Sayo, N.; Saito, T.; Zhang, X. Synlett 2001, 1055. (c) Zhang, L.; Tang, Y.; Han, Z.; Ding, K. Angew. Chem. Int. Ed. 2019, 58, 4973. (d) Xie, J.; Liu, X.; Xie, J.; Wang, L.; Zhou, Q. Angew. Chem., Int. Ed. 2011, 50, 7329.]. Chiral β-hydroxycarboxylic acid esters are important organic synthesis intermediates and can be used to synthesize the chiral drug Baclofen [(e) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry, 2003, 14, 581.]. So far, there are mainly two methods to obtain chiral β-hydroxycarboxylic acid esters. One is to obtain the corresponding chiral β-borated carboxylic acid esters by asymmetric hydrogenation of rhodium-catalyzed β-borated-α,β-unsaturated carboxylic acid esters and then hydrolyze them to obtain β-hydroxycarboxylic acid esters [(f) Liu, G.; Li, A.; Qin, X.; Han, Z.; Dong, X.; Zhang, X. Adv. Synth. Catal. 2019, 361, 2844.], and the other is to prepare chiral β-hydroxycarboxylic acid esters by asymmetric hydrogenation of β-ketoesters [(g) Yamamura, T.; Nakane, S.; Nomura, Y.; Tanaka, S.; Kitamura, M. Tetrahedron 2016, 72, 3781. (h) Berthod, M.; Saluzzo, C.; Mignani, G.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 639.]. Nevertheless, it is still of great research significance to explore new catalytic systems to improve the catalytic reaction activity.

[0003] For the above purposes, we have achieved a method for obtaining chiral β-hydroxycarboxylic acid esters through asymmetric hydrogenation using a ruthenium complex modified with a tridentate PNN chiral ligand as a catalyst and β-ketoesters as raw materials, and successfully obtained the corresponding β-hydroxycarboxylic acid esters in high yields (up to 99%) and high ee values (up to 99%). Summary of the Invention

[0004] The object of the present invention is to provide a method for synthesizing chiral β-hydroxycarboxylic acid ester compounds, which provides an efficient hydrogenation catalytic system and has the advantages of simple operation, easily available raw materials, and high reaction activity, greatly reducing the reaction cost and having high industrial application value.

[0005] Specifically, the present invention provides a method for synthesizing chiral β-hydroxycarboxylic acid ester compounds, which uses β-ketoesters and hydrogen as raw materials, a chiral ruthenium complex as a catalyst, and undergoes a hydrogenation reaction under the conditions of an alcohol solvent and a base additive to produce chiral β-hydroxycarboxylic acid esters in high yields and high ee values. The specific steps are as follows:

[0006] In a glove box, add the ruthenium complex and the base additive to a reaction flask, then add a solution of β-ketoester, place it in a high-pressure reaction kettle, displace with hydrogen 3 times, fill with hydrogen to 3-5 MPa, react at 20-60 °C for 1-24 hours, cool to room temperature, slowly release hydrogen, remove the solvent, and separate the residue by column chromatography to obtain chiral β-hydroxycarboxylic acid esters.

[0007]

[0008] R, R 1 are each independently selected from hydrogen, C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkane groups, cycloalkyl groups with C 3 -C 12 (preferably C 3 -C 8 , more preferably C 3 -C 6 ) in the ring, phenyl and substituted phenyl, benzyl and substituted benzyl; the substituents of the phenyl and benzyl groups are each independently selected from C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkane groups, C 1 -C 40(Preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkoxy, halogen, nitro, ester group or cyano group; R, R 1 are the same or different groups.

[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 methanol.

[0010] The ruthenium complex has the following general structural formula:

[0011]

[0012] In the formula:

[0013] Two Ars are phenyl groups, and the aromatic rings of 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl groups have C 6 -C 60 (Preferably C 6 -C 30 , more preferably C 6 -C 24 ) aromatic groups; The substituents are C 1 -C 40 (Preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkyl, C 1 -C 40 (Preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkoxy, halogen, nitro, ester group or cyano group;

[0014] R 1 、R 2 are the same or different groups, and are respectively hydrogen, C 1 -C 40 (Preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkyl, and the number of carbon atoms in the aromatic ring is C 6 -C 60 (Preferably C 6 -C 30 , more preferably C 6 -C24 ) an aromatic group (the aromatic group is phenyl, a 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl group, and the substituent is C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkyl, C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkoxy, halogen, nitro, ester group or cyano group, etc.) or an aromatic ring containing one or more N, S, O, P heteroatoms and having a carbon number of C 3 -C 60 aromatic group (the aromatic group is phenyl, a 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted or 2,4,6-trisubstituted aryl group, and the substituent is C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkyl, C 1 -C 40 (preferably C 1 -C 30 , more preferably C 1 -C 6 ) alkoxy, halogen, nitro, ester group or cyano group, etc.) (preferably C 3 -C 30 , more preferably C 3 -C 24 );

[0015] R 1 , R 2 can jointly form a cyclic group as shown below with the N atom, where n is a natural number from 1 to 6 (preferably from 1 to 5, more preferably from 3 to 5).

[0016]

[0017] The ruthenium complex is preferably Ru-Ib.

[0018]

[0019] The reaction medium is at least one or more of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide. Methanol is preferred.

[0020] The base additive is selected from i Pr 2 NEt, i PrNMe 2 , NEt 3 , DMAP, KOH, NaOH, Na 2 CO 3 , Cs 2 CO 3 , K 2 CO 3 , NaHCO 3 , t BuOK, t BuONa, t BuOLi, MeONa or K 3 PO 4 one or more of them; BuOK is preferred. t BuOK.

[0021] The molar ratio of the β-ketoester to the base additive is 10 - 1000:1 (preferably 10 - 500:1, more preferably 10 - 100:1).

[0022] The molar ratio of the β-ketoester to the ruthenium complex is 100 - 50000:1 (preferably 100 - 5000:1, more preferably 100 - 1000:1).

[0023] The reaction temperature is 20 - 80 °C (preferably 20 - 60 °C, more preferably 20 - 40 °C).

[0024] The reaction time is 12 - 24 h (preferably 12 - 20 h, more preferably 12 - 16 h)

[0025] Under this homogeneous catalytic system, the hydrogenation reaction of the present invention gives chiral β-hydroxycarboxylic esters in high yield (>99%) and high ee value (>99%). BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The specification drawings forming a part of the present invention are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. Hereinafter, the embodiments of the present invention will be described in detail with reference to the drawings, where:

[0027] Figure 11H NMR spectrum of methyl (R)-3-hydroxy-3-phenylpropionate II-A prepared in Example 1 Detailed Description of the Invention

[0028] The present invention will be further described below in conjunction with specific embodiments. The products in the embodiments are all known products. 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 without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0029] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those 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 the conventional manner in the art or according to 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 only for demonstration purposes. The nuclear magnetic resonance in the embodiments of the present invention is measured by a Bruker 400 or 700M nuclear magnetic resonance spectrometer.

[0030] Example 1 Preparation of ruthenium complex Ru-Ib from chiral PNN ligand and metal ruthenium precursor:

[0031]

[0032] Under a nitrogen atmosphere, the chiral PNN ligand L-1b (1.1 equiv., 0.22 mmol, 119.2 mg) and the THF solution (0.03 M, 7 mL) of the metal ruthenium precursor (PPh 3 ) 3 Ru(CO)(H)Cl (1.0 equiv., 0.2 mmol, 190.4 mg) were placed in an oil bath at 75 °C and stirred for 12 hours. After cooling to room temperature, the solvent was concentrated under reduced pressure to 1 mL, and n-hexane (10 mL) was added to precipitate a solid. The solid was collected by filtration and washed with a mixture of n-hexane and diethyl ether (v:v = 4:1, 20 mL) to obtain 131.9 mg of yellow solid Ru-Ib with a yield of 93%.

[0033] Example 2 Preparation of chiral methyl (R)-3-hydroxy-3-phenylpropionate II-A from methyl 3-oxo-3-phenylpropionate I-A.

[0034]

[0035] In a glove box, ruthenium complex Ru-Ib (0.001 mmol, 7.1 mg) and tBuOK (0.01 mmol, 11.2 mg) was added into the reaction flask, and then a methanol (0.5 M) solution of methyl 3-oxo-3-phenylpropionate I-A (1 mmol, 178.0 mg) was added. The molar ratio of the ruthenium complex Ru-Ib to t BuOK and methyl 3-oxo-3-phenylpropionate I-A was 1:10:100. Then it was placed in a high-pressure reactor, purged with hydrogen three times, filled with hydrogen to 3 MPa, and reacted at 20 °C for 12 hours. After the reaction was completed, the hydrogen was slowly released, the solvent was removed, and the residue was separated by column chromatography to obtain methyl (R)-3-hydroxy-3-phenylpropionate II-A with a yield of 99% and 99% ee.

[0036] The 1H NMR spectrum of methyl (R)-3-hydroxy-3-phenylpropionate II-A was as Figure 1 follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.38–7.25 (m, 5H), 5.12 (dd, J = 8.7, 2.9 Hz, 1H), 3.71 (s, 3H), 3.31 (s, 1H), 2.81–2.66 (m, 2H). II-A is a known compound [(h) Berthod, M.; Saluzzo, C.; Mignani, G.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 639.].

[0037] Example 3 The methanol in Example 2 was replaced with an equal volume of dichloromethane, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A with a yield of 99% and 90% ee.

[0038] Example 4 The ruthenium complex Ru-Ib in Example 2 was replaced with an equimolar amount of Ru-Ia, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A with a yield of 99% and 97% ee.

[0039]

[0040] Example 5 The ruthenium complex Ru-Ib in Example 2 was replaced with an equimolar amount of Ru-IIa, and the remaining procedures and conditions were the same as those in Example 2. The starting material methyl 3-oxo-3-phenylpropionate I-A remained, and no reaction product was detected.

[0041]

[0042] Example 6 The ruthenium complex Ru-Ib (0.001 mmol, 7.1 mg) in Example 2 was replaced with Ru-Ib (0.0001 mmol, 0.7 mg), and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A in 99% yield and 98% ee.

[0043] Example 7 The t BuOK (0.01 mmol, 11.2 mg) in Example 2 was replaced with t BuOK (0.001 mmol, 1.12 mg), and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A in 97% yield and 99% ee.

[0044] Example 8 The reaction temperature of 20 °C in Example 2 was replaced with 40 °C, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A in 99% yield and 99% ee.

[0045] Example 9 The reaction time of 12 h in Example 2 was replaced with 24 h, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave methyl (R)-3-hydroxy-3-phenylpropionate II-A in 99% yield and 99% ee.

[0046] Example 10 I-A in Example 2 was replaced with an equimolar amount of I-B, and the solvent methanol was replaced with an equal volume of ethanol, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave ethyl (R)-3-(4-chlorophenyl)-3-hydroxypropionate II-B in 99% yield and 99% ee. Product II-B is an intermediate for the synthesis of the chiral drug (R)-Baclofen [(e) Thakur, V.V.; Nikalje, M.D.; Sudalai, A. Tetrahedron: Asymmetry, 2003, 14, 581.].

[0047]

[0048] Example 11 The ruthenium complex Ru-Ib in Example 2 was replaced with an equimolar amount of Ru-IV, and the remaining procedures and conditions were the same as those in Example 2. The reaction gave ethyl (R)-3-(4-chlorophenyl)-3-hydroxypropionate II-B in 99% yield and 91% ee.

[0049]

[0050] The above-described embodiments merely represent the implementation modes of the present invention and are not intended 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 β-hydroxycarboxylic acid esters, characterized in that: using β-ketoesters and hydrogen as raw materials, a hydrogenation reaction occurs under a catalytic system with a ruthenium complex as a catalyst to produce β-hydroxycarboxylic acid esters; the general structural formula of the ruthenium complex is as follows: In the formula: two Ar are each phenyl; R 1 、R 2 are the same or different groups, each being a C 1 -C 6 alkyl group; The reaction medium is one or more of methanol, ethanol, isopropanol, dichloromethane, and dichloroethane; the reaction is carried out in the presence of a base additive selected from i Pr 2 NEt, i PrNMe 2 , NEt 3 , DMAP, KOH, NaOH, Na 2 CO 3 , Cs 2 CO 3 , K 2 CO 3 , NaHCO 3 , t BuOK, t BuONa, t BuOLi, MeONa or K 3 PO 4 and one or more of these.

2. The synthesis method according to claim 1, characterized in that: the β-ketoester compound has the following structure: R, R 3 are each independently selected from C 1 -C 40 alkane groups, cycloalkyl groups having C 3 -C 12 carbon atoms in the ring, phenyl and substituted phenyl, benzyl and substituted benzyl, or one or more of them; the substituents of the phenyl and benzyl are each independently selected from C 1 -C 40 alkane groups, C 1 -C 40 alkoxy groups, halogens, nitro groups or cyano groups, or one or more of them.

3. The synthesis method according to claim 1, characterized in that: the β-hydroxycarboxylic acid ester has the following structure: R, R 3 are each independently selected from C 1 -C 40 alkane groups, cycloalkyl groups with C 3 -C 12 carbon atoms in the ring, phenyl and substituted phenyl, benzyl and substituted benzyl, one or more than two of them; the substituents of the phenyl and benzyl are each independently selected from C 1 -C 40 alkane groups, C 1 -C 40 alkoxy groups, halogens, nitro groups or cyano groups, one or more than two of them.

4. The synthesis method according to claim 1, characterized in that: the ruthenium complex is Ru-Ib:

5. The synthesis method according to claim 1, characterized in that: the molar ratio of the β-ketoester to the base additive is 10 - 1000:1; the molar ratio of the β-ketoester to the catalyst ruthenium complex is 100 - 50000:

1.

6. The synthesis method according to claim 1, characterized in that: the reaction temperature is 20 - 80 °C.

7. According to the synthesis method according to any one of claims 1 - 6, characterized in that: the specific process of this method is: Add the ruthenium complex and the base additive into a reaction flask, then add a solution of β-ketoester, and place it in a high-pressure reaction kettle. Replace the atmosphere in the reaction kettle with hydrogen, fill hydrogen to 3 - 5 MPa, react at 20 - 60 °C for 1 - 24 hours, cool to room temperature and then release hydrogen, remove the solvent, and separate to obtain chiral β-hydroxycarboxylic acid esters.

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