A process for the preparation of (S)-4-(methylsulfonyl)butan-2-ol

Abstract

The application discloses a preparation method of (S)-4-(methyl sulfone) butane-2-ol, which comprises the following steps: firstly, oxidizing the sulfur in compound I to obtain compound II; secondly, reducing the carbonyl in compound II into a chiral alcohol to obtain compound III, which is the final product; or firstly, reducing the carbonyl in compound I into a chiral alcohol to obtain compound IV; and thirdly, oxidizing the sulfur in compound IV to obtain compound III, which is the final product.

Description

Technical Field

[0001] This invention relates to a method for preparing sulfone chiral alcohols, and particularly to a method for preparing (S)-4-(methyl sulfone)butane-2-ol. Background Technology

[0002] (S)-4-(methyl sulfone)butane-2-ol and its related derivatives have wide applications in medicinal chemistry and organic synthesis and are an important class of pharmaceutical intermediates. However, there are currently no reports on the synthesis of (S)-4-(methyl sulfone)butane-2-ol and its derivatives. Therefore, it is necessary to develop a preparation method that is easy to operate, has good chiral selectivity, is easy to control, and has a suitable overall yield. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for synthesizing (S)-4-(methyl sulfone)butane-2-ol, which has readily available raw materials, convenient operation, good chiral selectivity, controllable reaction process, and high overall yield.

[0004] To solve the above-mentioned technical problems, the preparation method of (S)-4-(methyl sulfone)butane-2-ol provided by the present invention can be carried out according to method one or method two;

[0005] Method 1 includes the following steps:

[0006] Step a1. Dissolve compound I in the reaction solution. Under vacuum and inert gas protection, lower the temperature of the reaction system to 2-15°C, add the oxidant, and continue stirring until the reaction is complete. Extract with an extractant and combine the organic phases to concentrate and obtain compound II.

[0007] Step a2. Dissolve compound II in buffer solution, add enzyme at a certain temperature, and continue stirring until the reaction is complete. Then add enzyme inactivating agent to the reaction system, continue stirring for a period of time, filter, extract the filtrate with extractant, combine the organic phases and concentrate to obtain compound III.

[0008] The reaction formula is as follows:

[0009]

[0010] Method 2 includes the following steps:

[0011] Step b1. Dissolve compound I in buffer solution, add enzyme at a certain temperature, stir continuously until the reaction is complete, add enzyme inactivating agent to the reaction system, stir for a period of time, filter, extract the filtrate with extractant, combine organic phases and concentrate to obtain compound IV;

[0012] Step b2. Dissolve compound IV in the reaction solution. Under vacuum and inert gas protection, lower the temperature of the reaction system to 2-15°C and add the oxidant. Continue stirring until the reaction is complete. Extract the filtrate with an extractant. Combine the organic phases and concentrate. Replace the extractant with n-heptane and concentrate again to obtain compound III.

[0013] The reaction formula is as follows:

[0014]

[0015] This invention provides a method for synthesizing (S)-4-(methyl sulfone)butane-2-ol. The method involves first oxidizing sulfur in the raw material to obtain a compound of formula II, then reducing the carbonyl group in formula II to a chiral alcohol. Alternatively, the carbonyl group in the raw material can be reduced to obtain a compound of formula IV, and then the sulfur in formula IV can be oxidized to obtain a compound of formula III, i.e., the final product. The method provided by this invention has a simple preparation process, good chiral selectivity, and high product yield. It should be noted that although sulfur oxidation has been disclosed in prior patents, the oxidation reaction is hindered in the presence of carbonyl or hydroxyl groups, resulting in a low yield of the sulfur-oxidized product. However, using the raw materials, reaction solvent, and preparation conditions selected in this application, the yield of compound II in method one can reach 78.85%, and the yield of compound III in method two can reach 70%. The good sulfur oxidation effect enables the synthetic route of this invention to be realized, and the yield of the final product is relatively high. Preferably, in steps a1 and b2, the reaction solution is a mixture of acetone and water, with a volume ratio of acetone to water of 7:(2-4). In step a1, if the volume ratio of acetone to water in the reaction solution is higher or lower than this range, it will affect the yield of compound II.

[0016] Preferably, in steps a1 and b2, the oxidant is potassium peroxymonosulfonate.

[0017] Preferably, in steps a1 and b2, the vacuum level is -0.05 to -0.2 MPa, more preferably -0.1 MPa, and the inert gas is nitrogen.

[0018] Preferably, in step a1, the extractant is dichloromethane; and in steps a2, b1, and b2, the extractant is ethyl acetate.

[0019] Preferably, in steps a2 and b1, the buffer solution is a phosphate solution with a pH of 6.0-7.5.

[0020] Preferably, in steps a2 and b1, the enzyme added is KRED-G03 (an SDR family oxidoreductase derived from the wild-type ketone reductase of Lactobacillus kef iri, with NCBI accession number WP_054768785.1), and the enzyme inactivation agent is acetonitrile.

[0021] Preferably, in steps a2 and b1, the reaction temperature is 25-35℃.

[0022] Preferably, in steps a2 and b1, after adding acetonitrile, stirring is continued for 0.5-1.5 hours.

[0023] Through extensive and in-depth research and numerous screening experiments, the inventors of this application have unexpectedly developed a method for synthesizing (S)-4-(methyl sulfone)butane-2-ol for the first time. The raw materials of this invention are readily available, the preparation process is simple, and the product exhibits good chiral selectivity and high yield. Detailed Implementation

[0024] The technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0025] Example 1 Method 1

[0026] Compound I (2.0 g, 16.92 mmol) was dissolved in acetone (42 mL) and water (18 mL). The mixture was kept under vacuum (-0.1 MPa) with N2 protection, cooled to 10 °C, and Oxone (26 g, 2.5 eq.) was added. The mixture was stirred for 17 hours, and GC showed complete consumption of the starting material. The reaction solution was quenched with 2% sodium sulfite solution and extracted three times with dichloromethane (30 mL). The organic phase was concentrated to give compound II (42.0 g, 13.34 mmol) in 78.85% yield.

[0027] Compound II (10.00 g, 66.7 mmol) was dissolved in buffer (500 mL), and then the enzyme was added at 30 °C. After the addition was complete, the mixture was stirred at 30 °C for 20 hours. HPLC showed that the reaction was complete. Acetonitrile (10 V) was added to the reaction system, and the mixture was stirred at 30 °C for 1 hour. The mixture was then filtered through diatomaceous earth to obtain the filtrate. The filtrate was extracted three times with ethyl acetate (15 V), and the organic phases were combined and concentrated to obtain compound III, the target product (381.1 g, 53.4 mmol), with a yield of 80.0% and a chiral purity of 100%.

[0028] The NMR results are as follows: δ 4.68 (s, 1H), 3.69 (m, 1H), 3.08-3.35 (m, 2H), 2.95 (s, 3H), 1.66-1.77 (m, 2H), 1.08 (d, 2H).

[0029] Method one-to-one ratio

[0030] Compound I (1.0 g, 8.46 mmol) was dissolved in ethanol (21 mL) and water (9 mL), and the mixture was kept under vacuum (-0.1 MPa) with N2 protection. The mixture was cooled to 10 °C, and Oxone (13 g, 2.5 eq.) was added. The mixture was stirred for 17 hours, and GC showed that the starting material was completely consumed. The reaction solution was quenched with 2% sodium sulfite solution and extracted three times with dichloromethane (20 mL). The organic phase was concentrated to give compound II (0.4 g, 2.63 mmol) in 31.4% yield.

[0031] Method 1:1 ratio 2

[0032] Compound I (1.0 g, 8.46 mmol) was dissolved in acetonitrile (42 mL) and water (18 mL). The mixture was placed under vacuum (-0.1 MPa) N2 protection, cooled to 10 °C, and Oxone (13 g, 2.5 eq.) was added. The mixture was stirred for 17 hours, and GC showed complete consumption of the starting material. The reaction solution was quenched with 2% sodium sulfite solution and extracted three times with ethyl acetate (20 mL). The organic phase was concentrated to give compound II (0.4 g, 2.63 mmol) in 31.4% yield.

[0033] Method 1:1 ratio 3

[0034] Compound I (1.0 g, 8.46 mmol) was dissolved in water (50 ml), and the mixture was kept under vacuum (-0.1 MPa) with N2 protection. The mixture was cooled to 10 °C, and Oxone (13 g, 2.5 eq.) was added. The mixture was stirred for 17 hours, and GC showed that the starting material was completely consumed. No post-treatment was performed, and the target product II was not obtained.

[0035] As can be seen from Comparative Examples 1 to 3, the choice of reaction solvent has a significant impact on the yield of compound II during the preparation of compound II from compound I.

[0036] Method 1:4

[0037] Compound I (1.0 g, 8.46 mmol) was dissolved in acetone (21 mL) and water (9 mL). The mixture was kept under vacuum (-0.1 MPa) with N2 protection, cooled to 10 °C, and Oxone (7.8 g, 1.5 eq.) was added. The mixture was stirred for 17 hours, and GC showed complete consumption of the starting material. The reaction solution was quenched with 2% sodium sulfite solution and extracted three times with ethyl acetate (20 mL). The organic phase was concentrated to give compound II (0.5 g, 3.33 mmol) in 39.3% yield.

[0038] Method 1:5

[0039] Compound I (1.0 g, 8.46 mmol) was dissolved in acetone (21 mL) and water (9 mL). The mixture was kept under vacuum (-0.1 MPa) with N2 protection, cooled to 10 °C, and Oxone (10.4 g, 2.0 eq.) was added. The mixture was stirred for 17 hours, and GC showed that the starting material was completely consumed. No post-treatment was performed, and the target product II was not obtained.

[0040] As can be seen from Comparative Examples 3 and 4, the amount of oxidant has a significant impact on the yield of compound II during the preparation of compound II from compound I.

[0041] Method 1:6

[0042] Compound I (0.24 g, 8.46 mmol) was dissolved in acetone (7 mL) and water (3 mL). Under vacuum (-0.1 MPa) N2 protection, at 20 °C, Oxone (3.07 g, 2.5 eq.) was added, and the mixture was stirred for 17 hours. GC showed that the starting material was completely consumed. The reaction purity was lower than that of the reaction at 10 °C. No post-treatment was performed, and the target product II was not obtained.

[0043] Method 1:7

[0044] Compound I (0.24 g, 8.46 mmol) was dissolved in acetone (7 mL) and water (3 mL). Under vacuum (-0.1 MPa) N2 protection, at 30 °C, Oxone (3.07 g, 2.5 eq.) was added, and the mixture was stirred for 17 hours. GC showed that the starting material was completely consumed. The reaction purity was lower than that of the reaction at 10 °C. No post-treatment was performed, and the target product II was not obtained.

[0045] As can be seen from Comparative Examples 6 and 7, the reaction temperature has a significant impact on the yield of Compound II during the preparation of Compound II from Compound I.

[0046] Example 2 Method 2

[0047] Compound I (100.00 g, 0.85 mol) was dissolved in buffer (500 mL), and then the enzyme was added at 30 °C. After the addition was complete, the mixture was stirred at 30 °C for 20 hours. HPLC showed that the reaction was complete. Acetonitrile (10 V) was added to the reaction system, and the mixture was stirred at 30 °C for 1 hour. The mixture was then filtered through diatomaceous earth to obtain the filtrate. The filtrate was extracted three times with ethyl acetate (15 V), and the combined organic phases were concentrated to give compound IV (281.37 g, 677 mmol), with a yield of 80.0% and a chiral purity of 100%.

[0048] Compound IV (0.5 g, 4.16 mmol) was dissolved in acetone (12 mL) and water (5 mL). The mixture was kept under vacuum (-0.1 MPa) N2 protection, cooled to 10 °C, and Oxone (6.5 g, 2.5 eq.) was added. The mixture was stirred for 19 hours, and GC showed complete consumption of the starting material. The reaction solution was quenched with 2% sodium sulfite solution and extracted three times with ethyl acetate (10 mL). The organic phase was concentrated, and ethyl acetate was replaced with n-heptane. The concentrate yielded compound III (3165 mg, 1.08 mmol) in 70% yield with 100% chiral purity.

[0049] Method 2 compared to Example 1

[0050] Compound IV (0.2 g, 1.7 mmol) was dissolved in acetonitrile (18 mL) and water (7 mL). Under vacuum (-0.1 MPa) N2 protection, Oxone (2.4 g, 2.5 eq.) was added at 0 °C and the mixture was stirred at 25 °C for 24 hours. GC showed that the starting material was completely consumed, but GC showed that the purity of the target product III was low. No post-treatment was performed, and no product was obtained.

[0051] Method 2 Comparative Example 2

[0052] Compound IV (0.2 g, 1.7 mmol) was dissolved in water (4 ml), and the mixture was subjected to a vacuum (-0.1 MPa) under N2 protection. NFSI (1.12 g, 2.5 eq.) was added, and the mixture was stirred at 25 degrees Celsius for 24 hours. GC showed that the starting material was completely consumed, but GC showed that the purity of the target product III was low. No post-treatment was performed, and no product was obtained.

[0053] Method 2 vs. Example 3

[0054] Compound IV (0.2 g, 1.7 mmol) was dissolved in dichloromethane (5 ml), and the mixture was protected under vacuum (-0.1 MPa) with N2. McPBA (1.2 g, 5 eq.) was added, and the mixture was stirred at 25 degrees Celsius for 24 hours. GC showed that the starting material was completely consumed, but GC showed that the purity of the target product III was low. No post-processing was performed, and no product was obtained.

[0055] Method 2 vs. Example 4

[0056] Compound IV (0.2 g, 1.7 mmol) was dissolved in acetonitrile (15 mL), and the mixture was kept under vacuum (-0.1 MPa) with N2 protection at 0 °C. Sodium tungstate (0.1 g, 0.1 eq.) and hydrogen peroxide (1 g, 5.0 eq.) were added, and the mixture was stirred at 25 °C for 24 hours. GC showed that the starting material was completely consumed, but GC showed that the purity of the target product III was low. No post-treatment was performed, and no product was obtained.

[0057] Method 2 vs. Example 5

[0058] Compound IV (0.6 g, 5 mmol) was dissolved in ethanol (28 mL) and water (9 mL). Under vacuum (-0.1 MPa) N2 protection, Oxone (7.2 g, 2.5 eq.) was added at 0 °C, and the mixture was stirred at 25 °C for 24 hours. GC showed that the starting material was completely consumed. The reaction solution was quenched with sodium sulfite solution, concentrated to remove ethanol, and extracted with ethyl acetate (300 mL). The concentrated organic phase yielded compound III (0.28 g, 2 mmol) in 40% yield.

[0059] As can be seen from Comparative Examples 1 to 5 of Method 2, the oxidation of sulfur is greatly affected by the solvent and the type of oxidant.

[0060] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing (S)-4-(methyl sulfone)butane-2-ol, characterized in that, Prepare according to method one or method two; Method 1 includes the following steps: Step a1. Dissolve compound I in the reaction solution. Under vacuum and inert gas protection, lower the temperature of the reaction system to 2-15°C, add the oxidant, and continue stirring until the reaction is complete. Extract with an extractant and combine the organic phases to concentrate and obtain compound II. Step a2. Dissolve compound II in buffer solution, add enzyme at a certain temperature, and continue stirring until the reaction is complete. Then add enzyme inactivating agent to the reaction system, continue stirring for a period of time, filter, extract the filtrate with extractant, combine the organic phases and concentrate to obtain compound III. The reaction formula is as follows: ； Method 2 includes the following steps: Step b1. Dissolve compound I in buffer solution, add enzyme at a certain temperature, stir continuously until the reaction is complete, add enzyme inactivating agent to the reaction system, stir for a period of time, filter, extract the filtrate with extractant, combine organic phases and concentrate to obtain compound IV; Step b2. Dissolve compound IV in the reaction solution. Under vacuum and inert gas protection, lower the temperature of the reaction system to 2-15°C and add the oxidant. Continue stirring until the reaction is complete. Extract the filtrate with an extractant. Combine the organic phases and concentrate. Replace the extractant with n-heptane and concentrate again to obtain compound III. The reaction formula is as follows: ； in: The reaction solutions in steps a1 and b2 are both mixtures of acetone and water, with a volume ratio of acetone to water of 7:(2-4). The oxidant in steps a1 and b2 is potassium peroxymonosulfonate, and the amount used is 2.5 equivalents; The enzymes used in steps a2 and b1 are both KRED-GO3.

2. The preparation method according to claim 1, characterized in that, In steps a1 and b2, the vacuum level is -0.05 to -0.2 MPa, and the inert gas is nitrogen.

3. The preparation method according to claim 1, characterized in that, In step a1, the extractant is dichloromethane; in steps a2, b1 and b2, the extractant is ethyl acetate.

4. The preparation method according to claim 1, characterized in that, In steps a2 and b1, the buffer solution is a phosphate buffer with a pH of 6-7.

5.

5. The preparation method according to claim 1, characterized in that, In steps a2 and b1, acetonitrile is used as the enzyme inactivating agent.

6. The preparation method according to claim 1, characterized in that, In steps a2 and b1, the reaction temperature is 25-35℃.

7. The preparation method according to claim 1, characterized in that, In steps a2 and b1, after adding acetonitrile, continue stirring for 0.5-1.5 hours.

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