Process for the preparation of (1r,2r)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol
By combining a small amount of catalyst with potassium borohydride in the preparation of (1R,2R)-2-amino-1-(4-(methanesulfonyl)phenyl)propane-1,3-diol, and controlling the temperature, the safety risks and high costs caused by the large amount of potassium borohydride used in the prior art are solved, thus improving both safety and economy.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- HEADING NANJING PHARMTECH CO LTD
- Filing Date
- 2026-04-16
- Publication Date
- 2026-07-14
AI Technical Summary
Existing methods for preparing (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol (D-ol) require the use of an equivalent excess of potassium borohydride, resulting in high exothermic activity in the early stages of the reaction, high safety risks, and limitations on production batch scale.
A small amount of catalyst, such as TMSCl or Ca(OTf)2, is combined with potassium borohydride to carry out the reduction reaction, with the reaction temperature controlled within the range of 0~45℃, preferably 30~35℃.
It significantly reduces the amount of reducing agent used, reduces hydrogen production, improves process safety, and lowers production costs, which is in line with the concept of green chemistry.
Smart Images
Figure CN122380992A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to an improved method for preparing (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol (D-alcohol). Background Technology
[0002] (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol (D-ol for short) is one of the important intermediates in the synthesis of florfenicol. Florfenicol, also known as florfenicol, is a third-generation amide antibacterial veterinary drug developed by Schering-Plough in 1980. In its drug structure, florfenicol replaces the hydroxyl group on the methylene group of the original florfenicol with a fluorine atom, avoiding the loss of activity due to acetylation of the hydroxyl group by bacterial acetyltransferases. Furthermore, florfenicol also shows good efficacy against some chloramphenicol- and florfenicol-resistant bacteria, exhibiting a very broad antibacterial spectrum. Currently, florfenicol is widely used as a veterinary antibiotic for the prevention and treatment of respiratory diseases in poultry caused by Actinobacillus and Haemophilus, as well as digestive system diseases in poultry caused by Escherichia coli and Pasteurella. Therefore, the efficient preparation of D-ol is of significant research importance. Its structural formula is as follows:
[0003]
[0004] The current mainstream processes for preparing D-ols are as follows:
[0005] D-ethyl ester and methanol are added to a reaction vessel, and the temperature is lowered to below 10°C. 1.3 equivalents of potassium borohydride are then added in batches, with the temperature controlled below 10°C. After the addition is complete, the temperature is slowly raised to 40-50°C for reduction. The reaction is stopped after 2 hours, and the product is concentrated to obtain D-ol. Although this method is widely used in current industrial production, its main problem is that an excess of potassium borohydride is required for complete reaction. Therefore, the system releases a large amount of heat in the early stages of the reaction, necessitating cooling with a refrigerant below -10°C. Furthermore, potassium borohydride decomposes to produce a large amount of hydrogen gas, posing a significant safety risk to production and limiting the batch size of production. Summary of the Invention
[0006] In view of the problems existing in the current production process, the present invention provides an improved method for preparing (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol (i.e., D-alcohol).
[0007] The method of the present invention includes the following synthetic route:
[0008]
[0009] Specifically, the method of the present invention includes the following steps:
[0010] (1) Add the raw material D-ester to an organic solvent, add the catalyst, and stir;
[0011] (2) A reducing agent is added in batches at a temperature of 0~45℃ to carry out a reduction reaction to obtain D-alcohol;
[0012] The catalyst is selected from at least one of TMSCl, AlCl3, LiCl, LiBr, CaCl2, CaBr2, CoCl2, NiCl2, Ca(OAc)2, Ca(OTf)2, ZnCl2, and CuCl2.
[0013] In one embodiment of the method of the present invention, the raw material D-ester is selected from at least one of D-methyl ester, D-ethyl ester, and D-isopropyl ester; the organic solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran, and diethylene glycol dimethyl ether.
[0014] Preferably, the volume of the organic solvent used is 4 to 8 times the mass of the raw material D-ester; more preferably, it is 5 times the volume (ml / g); preferably, the organic solvent is methanol.
[0015] In one embodiment of the method of the present invention, the catalyst is selected from TMSCl and Ca(OTf)2. Considering various factors, the use of these two catalysts achieves better technical results.
[0016] Preferably, the amount of catalyst used is 0.05 ~ 0.5 eq, more preferably 0.1 eq. In the method of the present invention, the amount of catalyst used is very small, which significantly reduces the amount of catalyst used compared with the prior art, and greatly reduces material costs.
[0017] In one embodiment of the method of the present invention, the reducing agent is selected from at least one of potassium borohydride and sodium borohydride;
[0018] Preferably, the reducing agent is potassium borohydride. Experiments have shown that, in many cases, using potassium borohydride as a reducing agent results in a significantly better reaction than sodium borohydride. Therefore, potassium borohydride has a greater advantage in terms of the conversion rate of the reaction raw materials.
[0019] Preferably, the amount of potassium borohydride used is 0.6~1.3 eq; more preferably 0.6 eq;
[0020] Preferably, the reaction temperature is 0~45℃, more preferably 30~35℃. The method of the present invention can be carried out within a mild temperature range, avoiding the use of low and high temperatures, reducing energy consumption, and lowering production costs.
[0021] Beneficial effects of the present invention
[0022] This invention achieves unexpected technical effects by complexing a small amount of catalyst with a reducing agent. The method of this invention significantly improves the activity of the reducing agent and greatly reduces the amount of reducing agent used. On the one hand, this method reduces the amount of hydrogen generated during the reaction process, improving process safety; on the other hand, it significantly reduces the amount of reducing agent used, lowers production costs, and reduces emissions of waste gas, wastewater, and solid waste, aligning with the principles of industrialized production and green chemistry. Attached Figure Description
[0023] Figure 1 This is the central control HPLC chromatogram of the reaction step in Example 1.
[0024] Figure 2 It is the D-ol obtained in Example 1. 1 H NMR spectrum.
[0025] Figure 3 This is the central control HPLC chromatogram of the reaction step in Example 2.
[0026] Figure 4 This is the central control HPLC chromatogram of the reaction step in Example 3.
[0027] Figure 5 This is the central control HPLC chromatogram of the reaction step in Example 4.
[0028] Figure 6 This is the central control HPLC chromatogram of the reaction step in Example 5.
[0029] Figure 7 This is the central control HPLC chromatogram of the reaction step in Example 6.
[0030] Figure 8 This is the central control HPLC chromatogram of the reaction step in Example 7.
[0031] Figure 9 This is the central control HPLC chromatogram of the reaction step in Example 8.
[0032] Figure 10 This is the central control HPLC chromatogram of the reaction step in Example 9.
[0033] Figure 11 This is the central control HPLC chromatogram of the reaction step in Example 10.
[0034] Figure 12 This is the central control HPLC chromatogram of the reaction step in Example 11. Detailed Implementation
[0035] The following embodiments are provided to aid in understanding the present invention. However, it should be understood that these embodiments are for illustrative purposes only and do not constitute any limitation. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of the present invention.
[0036] It should be noted that this invention makes further improvements based on existing mature raw materials and processes, achieving unexpected technical effects. Therefore, the peak positions (retention times) of the raw materials and reaction products in high-performance liquid chromatography (HPLC) are well known. By analyzing the peak positions and the area percentages of the raw materials and reaction products using HPLC, the conversion rate of the raw materials and the approximate yield of the reaction products can be determined, thereby verifying the reaction effect of the method of this invention after the addition of a catalyst. In the following examples, the reaction effect was determined by HPLC. The retention time of the target product, D-ol, was approximately 3.8 min.
[0037] Example 1
[0038] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of trimethylchlorosilane (TMSCl, 0.38 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After addition, the reaction was maintained at 35–40 °C for 2 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 1 The peak area percentage of D-ol was 96.38%.
[0039] Post-processing: The reaction was quenched with acetic acid, followed by concentration under reduced pressure to remove methanol. 100 ml of ethyl acetate and 20 ml of water were added, and the mixture was stirred until dissolved and clarified. After standing and separating into layers, the aqueous phase was extracted once with 50 ml of ethyl acetate. The organic phases were combined, desolventized under reduced pressure, and then 30 ml of methyl tert-butyl ether (MTBE) was added. The mixture was stirred at room temperature for 1 hour, filtered, and dried to obtain 7.8 g of D-alcohol, with a yield of 91.7%. 1 The H NMR spectrum can be seen Figure 2 .
[0040] Example 2
[0041] In a 250 ml reaction flask, diethylene glycol dimethyl ether (Diglyme, 60 ml, 6V) and sodium borohydride (0.93 g, 0.7 eq) were added sequentially. Stirring was started, and the temperature was maintained at 10–20 °C. Aluminum trichloride (AlCl3) (0.46 g, 0.1 eq) was added, followed by the addition of D-ethyl ester (10 g, 1.0 eq) in portions. After the addition was complete, the temperature was raised to 35–40 °C and the reaction was carried out for 6 hours. The reaction was then stopped, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 3The peak area percentage of D-ol was 95.63%.
[0042] Example 3
[0043] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl ester (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of calcium trifluoromethanesulfonate (Ca(OTf)2, 1.18 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 3 hours. The reaction was then terminated, and samples were taken for HPLC analysis. (See chromatogram for details.) Figure 4 The peak area percentage of D-ol was 96.75%.
[0044] Post-processing: Acetic acid was added to quench the reaction, and then methanol was removed by concentration under reduced pressure. 100 ml of ethyl acetate and 20 ml of water were added, stirred to dissolve and clarify, and allowed to stand for separation. The aqueous phase was extracted once with 50 ml of ethyl acetate. The organic phases were combined, desolventized under reduced pressure, and then 30 ml of MTBE was added and stirred at room temperature for 1 h. After filtration and drying, 7.96 g of D-alcohol was obtained, with a yield of 93.2%.
[0045] Example 4
[0046] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of zinc chloride (ZnCl2, 0.47 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 8 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 5 The peak area percentage of D-ol was 20.66%.
[0047] Example 5
[0048] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of lithium chloride (LiCl, 0.15 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 16 h. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 6 The peak area percentage of D-ol was 27.58%.
[0049] Example 6
[0050] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of nickel chloride (NiCl, 0.45 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 6 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 7 The peak area percentage of D-ol was 75.75%.
[0051] Example 7
[0052] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of copper chloride (CuCl2, 0.46 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 3 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 8 The peak area percentage of D-ol was 47.10%.
[0053] Example 8
[0054] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of calcium chloride (CaCl2, 0.39 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 16 h. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 9 The peak area percentage of D-ol was 85.90%.
[0055] Example 9
[0056] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of cobalt chloride (CoCl2, 0.45 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 6 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 10 The peak area percentage of D-ol was 20.04%.
[0057] Example 10
[0058] In a 250 ml reaction flask, ethylene glycol (60 ml, 6V) and D-ethyl ester (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of TMSCl (0.38 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 8 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 11 The peak area percentage of D-ol was 57.02%.
[0059] Example 11
[0060] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-ethyl acetate (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of calcium acetate (Ca(OAc)₂, 0.55 g, 0.1 eq). The temperature was raised to 25–30 °C, and potassium borohydride (1.32 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 35–40 °C for 2 hours. The reaction was then terminated, and samples were taken for HPLC analysis. The chromatogram is shown below. Figure 12 The peak area percentage of D-ol was 88.63%.
[0061] Example 12
[0062] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-methyl ester (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of TMSCl (0.4 g, 0.1 eq). The temperature was raised to 20–25 °C, and potassium borohydride (1.4 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 30–35 °C for 6 hours, at which point the reaction was terminated. HPLC analysis showed that the peak area percentage of D-ol was 96.21%.
[0063] Example 13
[0064] In a 250 ml reaction flask, methanol (50 ml, 5V) and D-isopropyl ester (10 g, 1.0 eq) were added sequentially. Stirring was started, followed by the addition of TMSCl (0.36 g, 0.1 eq). The temperature was raised to 20–25 °C, and potassium borohydride (1.3 g, 0.7 eq) was added in portions, maintaining the temperature T < 40 °C throughout the addition process. After the addition was complete, the reaction was maintained at 30–35 °C for 6 hours, at which point the reaction was terminated. HPLC analysis showed that the peak area percentage of D-alcohol was 92.51%.
[0065] Example 14
[0066] The following section uses D-ethyl ester as an example to investigate the effects of TMSCl dosage, KBH4 dosage, reaction time, and reaction temperature on the amount of reaction product and the remaining amount of raw materials, with methanol as the organic solvent. Specific data are shown in Table 1.
[0067] Table 1
[0068] Serial Number solvent TMSCl dosage <![CDATA[Dosage of KBH4]]> Time (h) Temperature (°C) D-ol Remaining D-ethyl ester 1 methanol 0.05eq 0.7eq 2 30~45 92.06% 3.16% 2 methanol 0.1eq 0.7eq 2 30~35 96.5% 0.09% 3 methanol 0.3eq 0.7eq 2 30~35 95% 1.25% 4 methanol 0.5eq 0.7eq 2 30~35 93.85% 2.62% 5 methanol 0.1eq 0.6eq 2 30~35 95.5% 1.75% 6 methanol 0.1eq 0.8eq 2 30~35 96.1% 0.35% 7 methanol 0.1eq 0.9eq 2 30~35 96.8% 0.12% 8 methanol 0.1eq 1.0eq 2 30~35 98.4% 0.10% 9 methanol 0.1eq 0.8eq 16 15~20 75.5% 20.3% 10 methanol 0.1eq 0.8eq 16 5~10 9% 81.8%
[0069] As shown in Table 1, a high conversion rate can be obtained by adding the catalyst TMSCl at a mild temperature of 30~35℃ without the need for an excessive amount of reducing agent (KBH4).
[0070] In conjunction with the preceding embodiments, this invention significantly improves the activity of the reducing agent by adding a small amount of catalyst, greatly reducing the amount of reducing agent required and achieving unexpected technical effects. The method of this invention can reduce the amount of hydrogen produced during the reaction process, improve process safety, and is a method suitable for industrial production.
Claims
1. A method for preparing (1R,2R)-2-amino-1-(4-(methylsulfonyl)phenyl)propane-1,3-diol, the synthetic route of which is as follows: The method includes the following steps: (1) Add the raw material D-ester to an organic solvent, add the catalyst, and stir; (2) A reducing agent is added in batches at a temperature of 0~45℃ to carry out a reduction reaction, yielding D alcohol; in, The catalyst is selected from at least one of TMSCl, Ca(OAc)2, and Ca(OTf)2.
2. The method according to claim 1, characterized in that, The raw material D-ester is selected from at least one of D-methyl ester, D-ethyl ester, and D-isopropyl ester; the organic solvent is selected from methanol.
3. The method according to claim 1, characterized in that, The amount of organic solvent used is 4 to 8 times the volume of the raw material D-ester.
4. The method according to claim 1, characterized in that, The organic solvent is methanol.
5. The method according to claim 1, characterized in that, The amount of catalyst used is 0.05 ~ 0.5 eq, based on the raw material D-ester.
6. The method according to claim 1, characterized in that, The reducing agent is selected from at least one of potassium borohydride and sodium borohydride.
7. The method according to claim 1, characterized in that, The reducing agent is potassium borohydride.
8. The method according to claim 1, characterized in that, The amount of potassium borohydride used is 0.6~1.3 eq, based on the raw material D-ester.
9. The method according to claim 1, characterized in that, The reduction reaction is carried out at a temperature of 30~35℃.