A preparation process of (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol

Abstract

The present invention provides a kind of (1R, 2R) 2-amino-1-(4-nitrophenyl) 1,3-propylene glycol preparation process, the substrate of the reduction process is (2S, 3R) 2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid, after esterification reaction, (1R, 2R) 2-amino-1-(4-nitrophenyl) 1,3-propylene glycol is obtained through reduction reaction under sodium borohydride-Lewis acid conditions. The preparation process obtains the final product by a two-step method, and the first step esterification reaction optimizes the reagents in the reaction process and controls the addition amount so that the molar yield of the final product (2S, 3R) 2-amino-3-hydroxy-3-(4-nitrobenzene) ethyl propionate of the esterification reaction can reach 98%, thereby avoiding the generation of by-product methyl ester, and the second step reduction reaction improves the molar yield of refined left alcohol by adding Lewis acid, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chloramphenicol intermediate preparation, and in particular to a preparation process of (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. Background Art

[0002] Currently, in the process of enzymatically synthesizing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (refined left-handed amino compound, also known as refined left-hand alcohol), (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionic acid is used as the starting material. The carboxylic acid can be directly reduced by borane, but this method has low yield and high industrial production risk. Another method is to prepare (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol by esterification followed by reduction, but the existing method has low yield and impurity control is difficult to meet downstream demand.

[0003] There are two main reduction processes for (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid: Figure 1 As shown, one is a direct reduction method. In 2019, Hunan Pilot Biotechnology Co., Ltd. applied for a patent number CN201910172579.2, entitled "A method for preparing chloramphenicol." Using (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid as the starting material, borane-reduced carboxylic acid is directly prepared in situ using a sodium borohydride-sulfuric acid system. Although the direct reduction method in this patent can save one step, the sulfuric acid addition process is highly dangerous, the generated borane is highly toxic, and the overall process yield is low. The crude product still needs to be purified, which is not conducive to industrial production.

[0004] Secondly, if Figure 1The indirect reduction method shown here typically prepares (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate first, followed by reduction to obtain the purified left-handed amino compound. This is the mainstream process in industrial production. In 2012, Pengfei Xu et al. prepared methyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate, which was then reduced with sodium borohydride and purified by column chromatography to obtain the purified left-handed amino compound in a crude yield of 90% (Chin. J. Chem., 2013, 31, 149-153). In 2023, Juan Lin et al. obtained (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid ethyl ester under sulfuric acid-ethanol conditions, and reduced it with potassium borohydride (1.3 eq.) to obtain a crude product with a yield of 89% (Catal. Sci. Technol., 2023, 13, 684-693). However, the indirect reduction method currently published has the problem that the methyl ester intermediate is not easy to store and the separation step is cumbersome, which also leads to the inability to produce on a large scale. Although the ethyl ester intermediate is relatively stable and suitable for the indirect reduction process, the amount of potassium borohydride used in the current process is large (1.3 eq), which is expensive compared with sodium borohydride; sodium borohydride (58% yield, Nature. 1955, 175, 346) or lithium triethylborohydride (69% yield, Gazzetta Chimica Italiana. 1996, 126, 173-8.) is used alone, and there is also the problem of low yield in the reduction step.

[0005] Therefore, in view of the current status of the preparation of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol by existing processes, it is of great significance to develop a reduction process that is low-cost, can be produced on a large scale, and does not require repeated purification. Summary of the Invention

[0006] In view of the problems of high reaction cost, complicated purification steps and impossibility of large-scale production in the current indirect reduction process for preparing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, the present invention provides a process for preparing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

[0007] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0008] A process for preparing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. The substrate of the reduction process is (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionic acid (Compound I). After esterification, the product is reduced under sodium borohydride-Lewis acid conditions to obtain (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (Compound III). The specific reaction formula is as follows:

[0009]

[0010] Furthermore, the esterification reaction is specifically as follows: (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid is added to ethanol, and then a catalyst is added dropwise to carry out an esterification reaction. After the reaction is complete, the mixture is concentrated, neutralized, filtered, recrystallized and dried to obtain (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid ethyl ester (Compound II).

[0011] Furthermore, the reaction reagent is selected from one of sulfuric acid, thionyl chloride, phosphoric acid or p-toluenesulfonic acid, the amount of the reaction reagent is 1.1-2 equivalents, and the temperature of the reaction system of the esterification reaction is controlled at 60-70° C. during the process of dropwise addition of the reaction reagent;

[0012] Preferably, the reaction reagent is thionyl chloride, and the amount of thionyl chloride used is 1.5 equivalents;

[0013] The catalyst added in the esterification reaction is DMF, and the temperature of the reaction system of the esterification reaction is controlled at 70° C. during the process of dropwise addition of the reaction reagents;

[0014] More preferably, the amount of thionyl chloride used is 1.0 equivalent and the amount of DMF used is 0.01 equivalent.

[0015] Furthermore, the recrystallization temperature is 40-70° C., the reagent added in the recrystallization process is ethanol, and the amount of ethanol is 4 to 10 times by weight; the pH value after neutralization is 7-11;

[0016] Preferably, the recrystallization temperature is 60° C., the amount of ethanol used is 5 times by weight, and the pH value after neutralization is 8-9.

[0017] Furthermore, the (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl)propionic acid ethyl ester obtained after drying is added to a solvent, and then a reducing agent is added to carry out a reduction reaction. After the reaction, the product is acid quenched, concentrated, decolorized, neutralized, crystallized, pulped and dried to obtain (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

[0018] Furthermore, during the reduction reaction, a Lewis acid is added to the reaction system as a reduction enhancer, wherein the Lewis acid is one of FeCl3, NiCl2, AlCl3, BF3, CaCl2, CeCl3, NdCl3, CoCl2, CuCl2, ZnCl2, ZrCl4, BOPregaent, NbCl5, Cu(OTf)2, Sc(OTf)3 or Zn(OTf)2, and the amount of the Lewis acid is 0.2-0.7 equivalents.

[0019] Furthermore, the Lewis acid is one of FeCl3, CaCl2 or ZnCl2, and the amount of the Lewis acid is 0.2 equivalents.

[0020] Furthermore, the solvent is selected from one of toluene, chlorobenzene, tetrahydrofuran, methanol, ethanol, isopropanol, water or methyl tert-ether, and the amount of the solvent is 7-15 times by weight; the reducing agent is one of LiBH4, NaBH4, KBH4, LiAlH4, Red-A1, DiBAL-H or BH3, and the amount of the reducing agent is 1.2-1.5 equivalents; the reaction temperature during the reduction reaction is -15-5°C.

[0021] Furthermore, the amount of the solvent is 10 times the mass ratio, and the solvent is ethanol; the reducing agent is one of LiBH4 or NaBH4, and the amount of the reducing agent is 1.2 equivalents; the reaction temperature during the reduction reaction is -10 to -2°C.

[0022] Furthermore, the order of adding reagents in the reduction reaction is: solvent-ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate-Lewis acid-reducing agent.

[0023] The present invention has the following beneficial effects:

[0024] 1. The present invention provides a preparation process for (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. During the esterification reaction, by optimizing the reaction reagents and the amount of catalyst added during the reaction, the molar yield of the final product of the esterification reaction, ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate, can reach 98%, thereby avoiding the influence of the by-product methyl ester on the subsequent reduction reaction and avoiding the tedious separation operation.

[0025] 2. The present invention provides a preparation process for (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. During the reduction reaction, by adding a Lewis acid and controlling the amount of the Lewis acid added, the reduction of ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate is more complete, thereby improving the molar yield of (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol.

[0026] 3. The preparation process of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol provided by the present invention has high safety performance and convenient operation, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Schematic diagram of the existing process for preparing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol;

[0028] Figure 2 Schematic diagram of the esterification process in the process for preparing (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol of the present invention;

[0029] Figure 3 Schematic diagram of the reduction process in the process for preparing (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol of the present invention;

[0030] Figure 4 This is the NMR mass spectrum of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol prepared in Example 4;

[0031] Figure 5 This is the mass spectrum of (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol prepared in Example 4;

[0032] Figure 6 Example 7 is the liquid phase spectrum of the reaction liquid at the end of the reaction of Example 7;

[0033] Figure 7 This is the liquid phase spectrum of the product after the reduction reaction is completed in Example 7. DETAILED DESCRIPTION

[0034] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments.

[0035] Example 1

[0036] like Figure 2 The schematic diagram of the esterification process is shown in FIG. 3 , and the specific reaction operation is as follows:

[0037] At room temperature, 23 kg of anhydrous ethanol was first added to a 50 L reactor. 5.00 kg of (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionic acid was weighed and added to the reactor. After stirring, 2.6 kg of thionyl chloride was added dropwise to the reactor. The temperature in the reactor was kept below 70°C during the addition process, and the addition time was controlled within 2-3 hours. After the addition was complete, 24 g of DMF was slowly added and the temperature was raised to reflux and maintained. After the control was qualified, vacuum distillation was initiated until no liquid flowed out. The temperature was then lowered to 20-40°C, and 12.5 kg of methyl tert-butyl ether was added. The pH was controlled at 8-11 while stirring. The mixture was kept at this temperature for 2 hours, centrifuged, and slurried. The crude product was recrystallized from ethanol to obtain a wet product, which was then dried under vacuum. The molar yield of ethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionate was measured to be 98%.

[0038] Example 2

[0039] Esterification reaction (thionyl chloride (1.5 eq)): 23 kg of anhydrous ethanol was added to a 50 L reactor at room temperature. 5.00 kg of (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionic acid was weighed and added to the reactor. After stirring, 3.94 kg of thionyl chloride was added dropwise to the reactor. The reactor temperature was kept below 70°C during the addition process, and the addition time was controlled within 2-3 hours. After the addition was complete, the temperature was raised to reflux and maintained. After the control was qualified, vacuum distillation was initiated until no liquid flowed out. The temperature was then lowered to 20-40°C, and 12.5 kg of methyl tert-butyl ether was added. The pH was controlled at 8-11 while stirring. The reaction mixture was kept at this temperature for 2 hours, centrifuged, and slurried. The crude product was recrystallized from ethanol to obtain a wet product, which was then dried under vacuum. The molar yield of ethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionate was determined to be 96%.

[0040] Example 3

[0041] Esterification reaction (thionyl chloride (2.0 eq)): 23 kg of anhydrous ethanol was added to a 50 L reactor at room temperature. 5.00 kg of (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionic acid was weighed and added to the reactor. After stirring, 5.25 kg of thionyl chloride was added dropwise to the reactor. The reactor temperature was kept below 70°C during the addition, and the addition time was controlled within 2-3 hours. After the addition was complete, the temperature was raised to reflux and maintained. After the control was qualified, vacuum distillation was initiated until no liquid flowed out. The temperature was then lowered to 20-40°C, and 12.5 kg of methyl tert-butyl ether was added. The pH was controlled at 8-11 while stirring. The reaction mixture was kept at this temperature for 2 hours, centrifuged, and slurried. The crude product was recrystallized from ethanol to obtain a wet product, which was then dried under vacuum. The molar yield of ethyl (2S,3R)-2-amino-3-hydroxy-3-(4-nitrobenzene)propionate was determined to be 92%.

[0042] Example 4

[0043] Esterification reaction operation:

[0044] At room temperature, 23 kg of anhydrous ethanol was first added to a 50 L reactor. 5.00 kg of (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid was weighed and added to the reactor. After stirring, 3.94 kg of thionyl chloride was added dropwise to the reactor. The temperature in the reactor was controlled to be <50°C during the addition process, and the addition time was controlled to be 2-3 hours. After the addition was completed, the temperature was raised to reflux and maintained. After the control was qualified, vacuum distillation was started until no liquid flowed out. The temperature was then lowered to 20-40°C, and 12.5 kg of methyl tert-butyl ether was added. The pH was controlled to 8-11 under stirring. The reaction mixture was kept warm for 2 hours, centrifuged, and slurried. The crude product was recrystallized from ethanol to obtain a wet product, which was then dried under vacuum. The molar yield of ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate was measured to be 72%.

[0045] Example 5

[0046] Esterification reaction operation:

[0047] At room temperature, 23 kg of anhydrous ethanol was first added to a 50 L reactor; 5.00 kg of (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid was stirred evenly, and then 3.8 kg of p-toluenesulfonic acid was added dropwise, and the temperature in the reactor was controlled to be less than 70°C during the addition process; the addition time was controlled to be 2-3 hours; after the addition was completed, the temperature was raised to reflux and kept warm; after the intermediate control was qualified, the temperature was lowered to room temperature, 12.5 kg of methyl tert-butyl ether was added, and the pH value was 8-11 under stirring; the reaction mixture was kept warm for 2 hours under stirring, centrifuged, and slurried. The crude product was recrystallized from ethanol to obtain a wet product, which was dried in vacuo. The molar yield of ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate was measured to be 92%.

[0048] Example 6

[0049] Esterification reaction (sulfuric acid) 23 kg of anhydrous ethanol was first added to a 50 L reactor at room temperature; 5.00 kg of (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid was stirred evenly and then 2.28 kg of concentrated sulfuric acid was added dropwise, and the temperature in the reactor was controlled to be <70°C during the addition process; the addition time was controlled to be 2-3 hours; after the addition was completed, the temperature was raised to reflux and kept warm; after the intermediate control was qualified, the temperature was lowered to room temperature, 12.5 kg of methyl tert-butyl ether was added, and the pH value was 8-11 under stirring; the mixture was kept warm for 2 hours under stirring, centrifuged, and slurried. The crude product was recrystallized in ethanol to obtain a wet product, which was vacuum dried. The molar yield of (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid ethyl ester was measured to be 92%.

[0050] The reaction conditions of the esterification reactions of Examples 1-6 are summarized in Table 1 below:

[0051]

[0052] Example 7

[0053] like Figure 3 The reduction process schematic diagram is shown, and the specific reaction operation is as follows:

[0054] At room temperature, 30 kg of anhydrous ethanol was added to a 50 L reactor, 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate was added, the temperature was lowered to -5 to 0 ° C, 0.42 kg of calcium chloride was added, and the mixture was stirred for 0.5 hours. 0.68 kg of sodium borohydride solid was added in batches at 0-5 ° C, and the mixture was stirred at 0-5 ° C for 1 hour. The raw material residue was sampled and tested to be <0.5%, which was qualified in the control. The liquid phase spectrum of the reaction liquid was as follows: Figure 6 As shown; 9.56Kg of sulfuric acid was added dropwise to quench the reaction, and the internal temperature was controlled at 0-30°C during the addition process (a large amount of hydrogen was produced). After the addition was completed, the mixture was stirred for 1h; ethanol and water were distilled under reduced pressure, the temperature was controlled at ≤60°C, 15Kg of process water was added, 0.19Kg of activated carbon was added, and the mixture was stirred for 0.5h. The pH was adjusted to 9-10, the product was precipitated, and the mixture was kept warm at 35-40°C for 1h. The crude product was filtered, and the filter cake was slurried with 3.81Kg of process water to obtain a refined product, which was dried at 50-60°C to obtain refined left alcohol. Its nuclear magnetic spectrum was detected as follows Figure 4 As shown, the specific nuclear magnetic detection data are 1H NMR (600MHz, DMSO-d6) δ (ppm) = 8.19 (d, J = 9.0Hz, 2H), 7.60 (d, J = 9.0Hz, 2H), 5.53 (s, 1H), 4.69 (d, J = 4.2Hz, 1H), 4.66 (s, 1H), 3.36 (dd, J = 10.2, 5.4Hz, 1H), 3.19 (dd, J = 10.2, 6.0Hz, 1H), 2.73 (t, J = 5.4Hz, 1H), 2.51-2.49 (m, 2H). Its mass spectrum is as shown Figure 5 As shown, the mass spectrum results are: MS (ESI) m / z = 213.00 [M+H] + .mp.: 161.3-162.9, specific rotation: -29.5° (1MHCl, c=1%, 20°C), ignition residue: 0.02%, its liquid phase spectrum is as follows Figure 7 The detection showed that the molar yield of refined left alcohol was 85%.

[0055] Example 8

[0056] Reduction reaction operation:

[0057] Add 30 kg of anhydrous ethanol to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5 to 0 ° C, add 0.514 kg of zinc chloride, stir for 0.5 hours, add 0.68 kg of sodium borohydride solid in batches at 0-5 ° C, stir and react at 0-5 ° C for 1 hour, take samples to test the raw material residue <0.5%, qualified in the control; add 9.56 kg of sulfuric acid dropwise to quench The reaction was quenched, and the internal temperature was controlled at 0-30°C during the addition process (a large amount of hydrogen was produced), and the mixture was stirred for 1 hour after the addition was completed; ethanol and water were distilled under reduced pressure, and the temperature was controlled at ≤60°C. 15 kg of process water was added, 0.19 kg of activated carbon was added, and the mixture was stirred for 0.5 hours. The pH was adjusted to 9-10, and the product was precipitated. The mixture was kept warm at 35-40°C for 1 hour, and the crude product was filtered. The filter cake was slurried with 3.81 kg of process water to obtain a refined product, which was dried at 50-60°C to obtain refined left alcohol with a molar yield of 78%.

[0058] Example 9

[0059] Reduction reaction operation:

[0060] Add 30 kg of anhydrous ethanol to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5 to 0 ° C, add 0.612 kg of ferric chloride, stir for 0.5 hours, add 0.68 kg of sodium borohydride solid in batches at 0-5 ° C, stir and react at 0-5 ° C for 1 hour, take samples to test the raw material residue <0.5%, qualified in the control; add 9.56 kg of sulfuric acid dropwise to quench The reaction was quenched, and the internal temperature was controlled at 0-30°C during the addition process (a large amount of hydrogen was produced), and the mixture was stirred for 1 hour after the addition was completed; ethanol and water were distilled under reduced pressure, and the temperature was controlled at ≤60°C. 15 kg of process water was added, 0.19 kg of activated carbon was added, and the mixture was stirred for 0.5 hours. The pH was adjusted to 9-10, and the product was precipitated. The mixture was kept warm at 35-40°C for 1 hour, and the crude product was filtered. The filter cake was slurried with 3.81 kg of process water to obtain a refined product, which was dried at 50-60°C to obtain refined left alcohol with a molar yield of 65%.

[0061] Comparative Example 1

[0062] Reduction reaction (CaCl2 replaced with I2): Add 30 kg of anhydrous ethanol to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S,3R)-2-amino-3-yl-3-(4-nitrobenzene)propionate, cool to -5-0°C, add 0.956 kg of elemental iodine, stir for 0.5 hours, add 0.68 kg of solid sodium borohydride in batches at 0-5°C, stir at 0-5°C for 1 hour, sample and test for residual raw material <0.5%, passing the control; add 9.5 kg of sulfuric acid dropwise. 56Kg quench the reaction, control the internal temperature at 0-30℃ during the addition process (produce a large amount of hydrogen), add sodium thiosulfate solution after the addition is completed and stir for 1h; distill ethanol and water under reduced pressure, control the temperature ≤60℃, add 15Kg of process water, add 0.19Kg of activated carbon, stir for 0.5h, adjust the pH to 9-10, precipitate the product, keep warm at 35-40℃ for 1h, filter the crude product, and slurry the filter cake with 3.81Kg of process water to obtain a refined product, which is dried at 50-60℃ with a molar yield of 35%.

[0063] Comparative Example 2

[0064] Reduction reaction (reduce the amount of calcium chloride to 0.1eq): add 30kg of anhydrous ethanol to a 50L reactor at room temperature, add 3.81kg of ethyl (2S,3R)-2-amino-3-yl-3-(4-nitrobenzene)propionate, cool to -5-0°C, add 0.21kg of calcium chloride, stir for 0.5hr, add 0.68kg of sodium borohydride solid in batches at 0-5°C, stir and react at 0-5°C for 1h, take samples for detection, and the raw material residue is >0.5%, which fails the in-process control.

[0065] Comparative Example 3

[0066] Reduction reaction (reduce the amount of sodium borohydride to 1 eq): add 30 kg of anhydrous ethanol to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5-0°C, add 0.42 kg of calcium chloride, stir for 0.5 hr, add 0.57 kg of sodium borohydride solid in batches at 0-5°C, stir and react at 0-5°C for 1 hour, take samples for detection, and the raw material residue is >0.5%, which fails the in-process control.

[0067] Comparative Example 4

[0068] Reduction reaction (change reaction temperature 10-20 degrees Celsius): Add 30 kg of anhydrous ethanol to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S,3R)-2-amino-3-yl-3-(4-nitrobenzene)propionate, cool to 10-20°C, add 0.42 kg of calcium chloride, stir for 0.5 hours, add 0.68 kg of solid sodium borohydride in batches at 0-5°C, stir at 10-20°C for 1 hour, take samples to test the raw material residue <0.5%, control qualified; sulfuric acid 9.56Kg was added dropwise to quench the reaction, and the internal temperature was controlled at 0-30°C during the addition (a large amount of hydrogen was produced), and the addition was completed and stirred for 1h; ethanol and water were distilled under reduced pressure, and the temperature was controlled at ≤60°C, 15Kg of process water was added, 0.19Kg of activated carbon was added, and stirred for 0.5h, and the pH was adjusted to 9-10, and the product was precipitated, and kept warm at 35-40°C for 1h, and the crude product was filtered, and the filter cake was slurried with 3.81Kg of process water to obtain a refined product, which was dried at 50-60°C, with a molar yield of 65%.

[0069] Comparative Example 5

[0070] Reduction reaction (replacement of solvent): add 30 kg of anhydrous methanol to a 50 L reactor at room temperature, add 0.42 kg of calcium chloride, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5 to 0 ° C, stir for 0.5 hours, add 0.68 kg of sodium borohydride solid in batches at 0-5 ° C, stir and react at 0-5 ° C for 1 hour, take samples to detect the raw material residue > 0.5%, the control fails; extend the reaction time to 4 hours, take samples to detect the raw material The residue is less than 0.5%, and the central control is qualified; 4.31 kg of hydrochloric acid is added dropwise to quench the reaction, and the internal temperature is controlled at 0-30°C during the addition process (a large amount of hydrogen is produced), and the mixture is stirred for 1 hour after the addition is completed; ethanol and water are distilled under reduced pressure, and the temperature is controlled at ≤60°C. 15 kg of process water is added, 0.19 kg of activated carbon is added, and the mixture is stirred for 0.5 hours. The pH is adjusted to 9-10, and the product is precipitated. The mixture is kept warm at 35-40°C for 1 hour, and the crude product is filtered. The filter cake is slurried with 3.81 kg of process water to obtain a refined product, which is dried at 50-60°C with a molar yield of 60%.

[0071] Comparative Example 6

[0072] Reduction reaction (pH range): Add 30 kg of anhydrous tetrahydrofuran to a 50 L reactor at room temperature, add 0.42 kg of calcium chloride, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5 to 0 ° C, stir for 0.5 hours, add 0.68 kg of sodium borohydride solid in batches at 0-5 ° C, stir and react at 0-5 ° C for 1 hour, take samples to test the raw material residue > 0.5%, the control fails; extend the reaction time to 4 hours, sample and test the raw material The residue is less than 0.5%, and the central control is qualified; 4.31 kg of hydrochloric acid is added dropwise to quench the reaction, and the internal temperature is controlled at 0-30°C during the addition process (a large amount of hydrogen is produced), and the mixture is stirred for 1 hour after the addition is completed; ethanol and water are distilled under reduced pressure, and the temperature is controlled at ≤60°C. 15 kg of process water is added, 0.19 kg of activated carbon is added, and the mixture is stirred for 0.5 hours. The pH is adjusted to 11-13, and the product is precipitated. The mixture is kept warm at 35-40°C for 1 hour, and the crude product is filtered. The filter cake is slurried with 3.81 kg of process water to obtain a refined product, which is dried at 50-60°C with a molar yield of 33%.

[0073] Comparative Example 7

[0074] Reduction reaction: Add 30 kg of anhydrous tetrahydrofuran to a 50 L reactor at room temperature, add 3.81 kg of ethyl (2S, 3R)-2-amino-3-yl-3-(4-nitrobenzene) propionate, cool to -5-0 ° C, stir for 0.5 hours, add 0.68 kg of sodium borohydride solid in batches at 0-5 ° C, stir and react at 0-5 ° C for 1 hour, take samples to detect the raw material residue> 0.5%, the control failed; extend the reaction time to 4 hours, take samples to detect the raw material residue< 0.5%, the control failed Control qualified; add 4.31Kg of hydrochloric acid to quench the reaction, control the internal temperature at 0-30℃ during the addition process (produce a large amount of hydrogen), and stir for 1h after the addition is completed; distill ethanol and water under reduced pressure, control the temperature ≤60℃, add 15Kg of process water, add 0.19Kg of activated carbon, stir for 0.5h, adjust the pH to 9-10, precipitate the product, keep warm at 35-40℃ for 1h, filter the crude product, and slurry the filter cake with 3.81Kg of process water to obtain a refined product, which is dried at 50-60℃ with a molar yield of 44%.

[0075] The reaction conditions of the reduction reactions of Examples 7-9 and Comparative Examples 1-7 are summarized in Table 1 below:

[0076]

Claims

1. A process for preparing (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, characterized in that: The substrate of the preparation process is (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrophenyl) propionic acid, which undergoes an esterification reaction and then a reduction reaction under sodium borohydride-Lewis acid conditions to obtain (1R, 2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol; The esterified product is added to a solvent, and then a reducing agent is added to carry out a reduction reaction. After the reaction, the product is acid quenched, concentrated, decolorized, neutralized to a pH of 9-10, crystallized, pulped, and dried to obtain (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol; The Lewis acid is one of FeCl3, CaCl2 or ZnCl2, and the amount of the Lewis acid is 0.2 equivalents; the amount of the solvent is 10 times the mass ratio, and the solvent is ethanol; the amount of the reducing agent NaBH4 is 1.2 equivalents, and the reaction temperature during the reduction reaction is 0 to 5°C.

2. The preparation process according to claim 1, wherein The esterification reaction specifically comprises: adding (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionic acid to ethanol, then dropwise adding a reaction reagent to carry out an esterification reaction. After the reaction is completed, the mixture is concentrated, neutralized, filtered, recrystallized, and dried to obtain ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate.

3. The preparation process according to claim 2, characterized in that The reaction reagent is selected from one of sulfuric acid, thionyl chloride, phosphoric acid or p-toluenesulfonic acid, and the amount of the reaction reagent is 1.1-2 equivalents. During the process of dropwise addition of the reaction reagent, the reaction system temperature of the esterification reaction is controlled at 60-70°C.

4. The preparation process according to claim 3, characterized in that The reaction reagent is thionyl chloride, and the amount of thionyl chloride used is 1.5 equivalents; A catalyst is added to the esterification reaction, wherein the catalyst is DMF. During the process of dropwise addition of the reaction reagents, the temperature of the reaction system of the esterification reaction is controlled at 70°C.

5. The preparation process according to claim 4, characterized in that: The dosage of the thionyl chloride is 1.0 equivalent and the dosage of DMF is 0.01 equivalent.

6. The preparation process according to claim 2, characterized in that The recrystallization temperature is 40-70° C., the reagent added in the recrystallization process is ethanol, and the amount of ethanol used is 4 to 10 times by weight; the pH value after neutralization is 7-11.

7. The preparation process according to claim 6, characterized in that The recrystallization temperature is 60° C., the amount of ethanol used is 5 times by weight, and the pH value after neutralization is 8-9.

8. The preparation process according to claim 1, wherein The order of adding reagents in the reduction reaction is: solvent→ethyl (2S, 3R)-2-amino-3-hydroxy-3-(4-nitrobenzene) propionate→Lewis acid→reducing agent.

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