Recovery method of edoxaban intermediate resolving agent R-phenylethylamine

Abstract

The invention discloses a method for recovering an edoxaban intermediate resolving agent R-phenylethylamine, which comprises the following steps: S1, adding an organic solvent A into a mother solution containing free R-phenylethylamine salt, cooling to 5-15 DEG C, adding inorganic acid to adjust the pH value to acidity, heating to 25-30 DEG C, and collecting a water phase; s2, cooling the water phase to 5-15 DEG C, adding inorganic alkali to adjust the pH to be alkaline, heating to 25-30 DEG C, adding an organic solvent B, and collecting an organic phase; and carrying out reduced pressure desolventizing distillation under the vacuum of-0.09 to-0.1 MPa at the temperature of less than or equal to 50 DEG C until no fraction exists, heating to 50-110 DEG C, carrying out reduced pressure distillation, and collecting the fraction with the top temperature of 80-100 DEG C, thereby obtaining the (R)-(+)-phenylethylamine. According to the method, the mother liquor is subjected to acid adjustment, solvent extraction, water phase alkali adjustment, solvent extraction and reduced pressure distillation and concentration, so that the yield and the recovery purity of the product can be improved, and the method is stable in process, easy to operate, short in time consumption and low in cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical manufacturing intermediates, and more specifically, to a method for recovering the resolving agent R-phenethylamine of edoxaban intermediate. Background Art

[0002] Edoxaban tosylate tablets are an anticoagulant factor Xa inhibitor, mainly used for preventing venous thrombosis, treating acute deep vein thrombosis, reducing the risk of myocardial infarction, relieving pain and swelling, and for rehabilitation after hip replacement surgery, etc.

[0003] From the structure of edoxaban, this molecule contains 3 chiral centers. Therefore, compound 1 is the key intermediate for synthesizing edoxaban, and its molecular formula is: C 14 H 27 N 3 O 3 , and the structural formula: 1

[0004]

[0005] Currently, the industrial synthesis method of compound 1 mainly uses racemic 3-cyclohexene-1-carboxylic acid as the starting material, which is resolved by R-phenethylamine to obtain (1S)-3-cyclohexene-1-carboxylic acid, followed by epoxidation, ring opening, and deprotection to obtain intermediate 1. The specific route is as follows:

[0006]

[0007]

[0008] Currently, there is no relevant research reporting the recovery and recycling of the resolving agent R-phenethylamine in this process route.

[0009] CN103242169A provides a method for recycling and reusing the chiral amine resolving reagent in the preparation of optically active γ-lactone spices, realizing the circular economy of the resolving agent resources. However, the recovery rates of the chiral reagents R-phenethylamine and S-phenethylamine recovered by vacuum distillation in this patent are 50% - 75%, only a preliminary recovery is carried out.

[0010] CN104086439A reports the recovery steps of the resolving agent R-phenethylamine for pregabalin intermediate, including adjusting the pH of the free mother liquor to alkaline, extracting with an organic solvent, collecting the organic layer and concentrating it under reduced pressure, and distilling to obtain the fraction of R-phenethylamine, reducing wastewater discharge and lowering production costs, but the yield is average.

[0011] CN107573248A discloses a method for recovering the resolving agent R-phenylethylamine in the preparation of R-lipoic acid. By controlling the temperature at 20°C to 25°C, adding an inorganic base to adjust the pH to 10 to 14, collecting the organic layer, removing the solvent, and collecting the fraction within 187°C to 189°C. However, the temperature in this process is too high, resulting in relatively high energy consumption in the process.

[0012] CN113087630A discloses a method for recovering the resolving agent R-phenylethylamine in the preparation of perindopril intermediate. By controlling the temperature at 30°C to 40°C, dropwise adding an inorganic base to adjust the pH to alkaline, controlling the temperature ≤ 50°C, distilling off the solvent, then performing acid salting and crystallization, and then adjusting to alkaline, collecting the organic layer, removing the solvent, and collecting the fraction by vacuum distillation. This method has cumbersome steps, low purity of R-phenylethylamine, and cumbersome process operations.

[0013] Therefore, there is still no relevant report on the recovery of the resolving agent for edoxaban intermediate for reference at present.

[0014] In view of this, the present application is specifically proposed. Summary of the Invention

[0015] The problem existing in the prior art is that there is currently a lack of a method for recovering the resolving agent R-phenylethylamine for edoxaban intermediate. To solve the above problems, the present invention provides a method for recovering the resolving agent R-phenylethylamine for edoxaban intermediate. Through a series of methods such as acid adjustment, solvent extraction, re-adjusting the water phase to alkaline, solvent extraction, and vacuum distillation concentration, the yield and recovery purity of the product can be improved, and the process is stable, easy to operate, time-consuming is short, and the cost is low.

[0016] The present invention is achieved through the following technical solutions:

[0017] A method for recovering the resolving agent R-phenylethylamine for edoxaban intermediate, comprising the following steps:

[0018] S1. Add organic solvent A to the mother liquor containing free R-phenylethylamine, then cool down by 5 - 15°C, add inorganic acid to adjust the pH to acidic, heat up to 25 - 30°C, collect the aqueous phase, and extract the organic layer with deionized water twice, and combine the aqueous phases;

[0019] S2. Cool the aqueous phase to 5 - 15°C, add inorganic base to adjust the pH to alkaline, heat up to 25 - 30°C, then add organic solvent B, collect the organic phase, and extract twice with organic solvent B in total and combine the organic layers; Under vacuum of -0.09 to -0.1 MPa and temperature control ≤ 50°C, perform vacuum distillation until there is no distillate, then heat up to 50 - 110°C for vacuum distillation, and collect the fraction with the top temperature of 80 - 100°C to obtain (R)-(+)-phenylethylamine.

[0020] The racemate 3-cyclohexene-1-carboxylic acid is obtained as a salt product and a crystallization mother liquor after being resolved by R-phenylethylamine and recrystallized. After acidification, liberation, and desolvation treatment of the salt product, the target product intermediate (1S)-3-cyclohexene-1-carboxylic acid and the remaining salt mother liquor are obtained. Both the salt mother liquor and the crystallization mother liquor contain the R-phenylethylamine salt of (1R)-3-cyclohexene-1-carboxylic acid and a large amount of free R-phenylethylamine to be recovered, refined, and recycled. The process route is as follows:

[0021]

[0022] Through a series of methods such as acid adjustment, solvent extraction, re-alkali adjustment in the aqueous phase, solvent extraction, and vacuum distillation concentration of the mother liquor, the present invention can improve the yield and recovery purity of the product, and the process is stable, easy to operate, time-consuming, and low-cost.

[0023] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the crystallization mother liquor obtained after the racemate 3-cyclohexene-1-carboxylic acid is resolved by R-phenylethylamine and recrystallized.

[0024] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the filtrate obtained after adding acid to the crystallization mother liquor, cooling for crystallization, and filtering (1R)-3-cyclohexene-1-carboxylic acid.

[0025] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the salt mother liquor obtained after acidification and recrystallization of the salt product obtained after the racemate 3-cyclohexene-1-carboxylic acid is resolved by R-phenylethylamine and recrystallized.

[0026] In a specific embodiment, in step S1, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydroiodic acid, and hydrobromic acid.

[0027] In a specific embodiment, in step S1, the inorganic acid adjusts the pH to 2-4.

[0028] In a specific embodiment, in step S1, the organic solvent A is selected from one or more of toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, ethyl acetate, and methyl tert-butyl ether, and a mixed solvent in any proportion.

[0029] In a specific embodiment, in step S2, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0030] In a specific embodiment, in step S2, the inorganic base adjusts the pH to 9-11.

[0031] In a specific embodiment, in step S2, the organic solvent B is selected as a low-boiling solvent, which is a mixed solvent of one or more of dichloromethane, ethyl acetate, and methyl tert-butyl ether in any proportion.

[0032] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0033] 1. The method for recovering the edoxaban intermediate resolving agent R-phenylethylamine provided by the embodiment of the present invention, through a series of methods such as acid adjustment of the mother liquor, solvent extraction, re-alkali adjustment of the aqueous phase, solvent extraction, and vacuum distillation concentration, the recovered (R)-(+)-phenylethylamine has a colorless and transparent appearance, the yield is stably above 90%, the GC purity ≥ 99%, and the specific rotation is greater than or equal to 36°, which can meet the standard of fresh (R)-(+)-phenylethylamine;

[0034] 2. The method for recovering the edoxaban intermediate resolving agent R-phenylethylamine provided by the embodiment of the present invention has a simple way to recover (R)-(+)-phenylethylamine, is easy to operate, has mild conditions, is stable in the production process, takes a short time, and has low costs;

[0035] 3. The method for recovering the edoxaban intermediate resolving agent R-phenylethylamine provided by the embodiment of the present invention can recover both the organic solvent A and the organic solvent B used, reducing the generation of waste liquid and environmental pollution, and conforming to the concept of green and sustainable chemical processes. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can be obtained based on these drawings without creative efforts.

[0037] Figure 1 It is a flowchart of the method for recovering the edoxaban intermediate resolving agent R-phenylethylamine provided by the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0038] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0039] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is obvious to those of ordinary skill in the art that the present invention does not have to employ these specific details. In other embodiments, well-known materials or methods have not been specifically described to avoid obscuring the present invention.

[0040] Throughout the specification, references to "an embodiment", "embodiments", "an example" or "examples" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Thus, the phrases "an embodiment", "embodiments", "an example" or "examples" that appear throughout the specification do not necessarily all refer to the same embodiment or example. In addition, the particular features, structures, or characteristics may be combined in any suitable combination and / or sub-combination in one or more embodiments or examples. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0041] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundary of a particular range. The ranges defined in this way can include the end values or not include the end values, and can be combined arbitrarily, that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60-120 and 80-110 are listed for a specific parameter, it is understood that ranges of 60-110 and 80-120 are also contemplated. In addition, if the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, then the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise specified, the numerical range "a-b" represents an abbreviated representation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" have been fully listed herein, and "0-5" is only an abbreviated representation of these numerical combinations. In addition, when it is stated that a certain parameter is an integer ≥2, it is equivalent to disclosing that the parameter is, for example, the integers 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc. If there is no special instruction, all steps of this application can be carried out in sequence or randomly, and preferably in sequence. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) carried out in sequence, or may include steps (b) and (a) carried out in sequence. For example, it is mentioned that the method may further include step (c), which means that step (c) can be added to the method in any order. For example, the method may include steps (a), (b), and (c), or may include steps (a), (c), and (b), or may include steps (c), (a), and (b), etc.

[0042] Currently, in the recovery process of R-phenethylamine, there are problems such as low yield, high energy consumption, and cumbersome steps. At the same time, there is a lack of a method for recovering R-phenethylamine, the resolving agent for edoxaban intermediates. To solve the above problems,

[0043] As Figure 1 shown, the present invention provides a method for recovering the resolving agent R-phenylethylamine of edoxaban intermediate, comprising the following steps:

[0044] S1. Add organic solvent A to the mother liquor containing free R-phenylethylamine, then cool down by 5 - 15 °C, adjust the pH to acidic with inorganic acid, heat up to 25 - 30 °C, collect the aqueous phase, extract the organic layer with deionized water twice, and combine the aqueous phases;

[0045] S2. Cool the aqueous phase to 5 - 15 °C, adjust the pH to basic with inorganic base, after heating up to 25 - 30 °C, add organic solvent B, collect the organic phase, where organic solvent B is added in total twice and the organic layers are combined; under vacuum of -0.09 to -0.1 MPa and temperature control ≤ 50 °C, distill under reduced pressure until there is no distillate, then heat up to 50 - 110 °C and distill under reduced pressure, collect the fraction with the top temperature of 80 - 100 °C to obtain (R)-(+)-phenylethylamine.

[0046] The racemate 3-cyclohexene-1-carboxylic acid is obtained through resolution with R-phenylethylamine and recrystallization to obtain the salt-forming fine product and the crystallization mother liquor. After the salt-forming fine product is acidified, freed, and desolvated, the target product intermediate (1S)-3-cyclohexene-1-carboxylic acid and the remaining salt-forming mother liquor are obtained. Both the salt-forming mother liquor and the crystallization mother liquor contain the R-phenylethylamine salt of (1R)-3-cyclohexene-1-carboxylic acid and a large amount of free R-phenylethylamine to be recovered, refined, and reused. The process route is as follows:

[0047]

[0048] The present invention can improve the product yield and the recovery purity of the product through a series of methods such as acid adjustment, solvent extraction, re-alkalization of the aqueous phase, solvent extraction, and concentration by vacuum distillation in the mother liquor, and the process is stable, easy to operate, time-consuming short, and low in cost.

[0049] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the crystallization mother liquor obtained after the racemate 3-cyclohexene-1-carboxylic acid is resolved with R-phenylethylamine and recrystallized.

[0050] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the filtrate obtained after the crystallization mother liquor is treated with acid, cooled for crystallization, and filtered to obtain (1R)-3-cyclohexene-1-carboxylic acid. As used in the present invention

[0051] In a specific embodiment, the mother liquor containing free R-phenylethylamine is the salt-forming mother liquor obtained after the salt-forming fine product obtained after the racemate 3-cyclohexene-1-carboxylic acid is resolved with R-phenylethylamine and recrystallized is acidified and recrystallized.

[0052] In a specific embodiment, in step S1, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydroiodic acid, and hydrobromic acid.

[0053] In a specific embodiment, in step S1, the inorganic acid adjusts the pH to 2-4.

[0054] In a specific embodiment, in step S1, the organic solvent A is selected from one or more of toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, ethyl acetate, and methyl tert-butyl ether, and a mixed solvent in any proportion.

[0055] In a specific embodiment, in step S2, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

[0056] In a specific embodiment, in step S2, the inorganic base adjusts the pH to 9-11.

[0057] In a specific embodiment, in step S2, the organic solvent B is selected from low-boiling solvents, one or more of dichloromethane, ethyl acetate, and methyl tert-butyl ether, and a mixed solvent in any proportion.

[0058] Example 1

[0059] The embodiment of the present invention provides a method for recovering the enantioseparation agent R-phenethylamine of edoxaban intermediate, comprising the following steps:

[0060] (1) Add 30 g of the concentrated solution of the mixed solution of the mother liquor after S1 free and the mother liquor of S2 shown in the process route, add 30 g of ethyl acetate, cool down to 10 °C, dropwise add 3N hydrochloric acid aqueous solution to adjust the pH = 2, slowly warm up to 24 °C, stir for 15 minutes, let it stand for layering, and collect the aqueous phase; at the same time, add 30 g of water to the organic layer and extract twice, and then collect the aqueous phase;

[0061] (2) Combine all the aqueous phases in step (1), cool down to 10 °C, dropwise add 15% sodium hydroxide aqueous solution to adjust the pH = 10, slowly warm up to 25 °C, add 30 g of ethyl acetate and stir for 15 minutes, let it stand for layering, and collect the organic phase; at the same time, stir the aqueous phase with 30 g of ethyl acetate for 15 minutes, let it stand for layering, and collect the organic phase;

[0062] (3) Combine all the organic phases in step (2), carry out vacuum distillation at -0.09 to -0.1 MPa and a temperature of 50 °C until there is no distillate, replace the receiving flask, and gradually increase the temperature of the external temperature to 110 °C, and receive the fraction with a top temperature of 85-95 °C to obtain 11.69 g of the target product (R)-(+)-phenethylamine, which is a colorless liquid, specific rotation: 38.6°, GC: 99.45%.

[0063] Example 2

[0064] An embodiment of the present invention provides a method for recovering R-phenylethylamine, a resolving agent for edoxaban intermediates, comprising the following steps:

[0065] (1) Add 30 g of the concentrated solution of the mixed solution of the mother liquor after S1 free and the mother liquor of S2 shown in the process route to the reactor, add 30 g of dichloromethane, cool down to 10 °C, dropwise add 4N hydrochloric acid aqueous solution to adjust the pH = 3, slowly warm up to 30 °C, stir for 15 minutes, let it stand for liquid separation, and collect the aqueous phase; at the same time, add 30 g of water to the organic layer for extraction twice and then collect the aqueous phase;

[0066] (2) Combine all the aqueous phases in step (1), cool down to 10 °C, dropwise add 30% sodium carbonate aqueous solution to adjust the pH = 10, slowly warm up to 25 °C, add 30 g of dichloromethane, stir for 15 minutes, let it stand for liquid separation, and collect the organic phase. Stir the aqueous phase with 30 g of dichloromethane for 15 minutes, let it stand for liquid separation, and collect the organic phase;

[0067] (3) Combine all the organic phases in step (2), carry out vacuum distillation at -0.09 to -0.1 MPa and a temperature of 50 °C until there is no distillate, replace the receiving flask, gradually increase the external temperature to 110 °C, and receive the distillate with a top temperature of 85 - 95 °C to obtain 12.14 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid, specific rotation: 39.1°, GC: 99.37%.

[0068] Example 3

[0069] An embodiment of the present invention provides a method for recovering R-phenylethylamine, a resolving agent for edoxaban intermediates, comprising the following steps:

[0070] (1) Add 30 g of the concentrated solution of the mixed solution of the mother liquor after S1 free and the mother liquor of S2 shown in the process route to the reactor, add 30 g of toluene, cool down to 10 °C, dropwise add 3N phosphoric acid aqueous solution to adjust the pH = 2, slowly warm up to 30 °C, stir for 15 minutes, let it stand for liquid separation, and collect the aqueous phase. At the same time, add 30 g of water to the organic layer for extraction twice and then collect the aqueous phase;

[0071] (2) Combine all the aqueous phases in step (1), cool down to 10 °C, dropwise add 30% sodium carbonate aqueous solution to adjust the pH = 10, slowly warm up to 25 °C, add 30 g of dichloromethane, stir for 15 minutes, let it stand for liquid separation, and collect the organic phase. Stir the aqueous phase with 30 g of dichloromethane for 15 minutes, let it stand for liquid separation, and collect the organic phase.

[0072] (3) Combine all the organic phases in step (2), carry out vacuum distillation at -0.09 to -0.1 MPa and a temperature of 50 °C until there is no distillate, replace the receiving flask, gradually increase the external temperature to 110 °C, and receive the distillate with a top temperature of 85 - 95 °C to obtain 13.01 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid, specific rotation: 39.5°, GC: 99.44%.

[0073] Example 4

[0074] The embodiment of the present invention provides a method for recovering the resolving agent R-phenylethylamine of edoxaban intermediate, which comprises the following steps:

[0075] (1) Add 30 g of the concentrated solution of the mixed solution of the mother liquor after S1 free and the mother liquor of S2 shown in the process route to the reactor, add 30 g of xylene, cool down to 10 °C, dropwise add 3N hydrochloric acid aqueous solution to adjust the pH = 2, slowly heat up to 28 °C, stir for 15 minutes, stand for layering, collect the aqueous phase, and at the same time, add 30 g of water to the organic layer for extraction twice and then collect the aqueous phase.

[0076] (2) Combine all the aqueous phases in step (1), cool down to 10 °C, dropwise add 25% potassium carbonate aqueous solution to adjust the pH = 10, slowly heat up to 25 °C, add 30 g of dichloromethane, stir for 15 minutes, stand for layering, and collect the organic phase. Stir the aqueous phase with 30 g of dichloromethane for 15 minutes, stand for layering, and collect the organic phase.

[0077] (3) Combine all the organic phases in step (2), carry out vacuum distillation at -0.09 to -0.1 MPa and a temperature of 50 °C until there is no distillate, replace the receiving flask, increase the temperature in an external temperature gradient to 110 °C, and receive the fraction with a top temperature of 85 - 95 °C to obtain 12.60 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid, specific rotation: 36.9°, GC: 99.23%.

[0078] Example 5

[0079] The embodiment of the present invention provides a method for recovering the resolving agent R-phenylethylamine of edoxaban intermediate, which comprises the following steps:

[0080] (1) Add 30 g of the concentrated solution of the mixed solution of the mother liquor after S1 free and the mother liquor of S2 shown in the process route to the reactor, add 30 g of methyl tert-butyl ether, cool down to 11 °C, dropwise add 3N hydrochloric acid aqueous solution to adjust the pH = 2, slowly heat up to 26 °C, stir for 15 minutes, stand for layering, and collect the aqueous phase; at the same time, add 30 g of water to the organic layer for extraction twice and then collect the aqueous phase;

[0081] (2) Combine all the aqueous phases in step (1), cool down to 10 °C, dropwise add 25% potassium carbonate aqueous solution to adjust the pH = 10, slowly heat up to 25 °C, add 30 g of dichloromethane, stir for 15 minutes, stand for layering, and collect the organic phase. Stir the aqueous phase with 30 g of dichloromethane for 15 minutes, stand for layering, and collect the organic phase.

[0082] (3) Combine all the organic phases in step (2), and perform vacuum distillation at -0.09 to -0.1 MPa and 50 °C until no distillate is obtained. Replace the receiving flask, and increase the temperature in a gradient manner to 110 °C externally. Collect the distillate with a top temperature of 85 - 95 °C to obtain 12.41 of the target product (R)-(+)-phenylethylamine, which is a colorless liquid with a specific rotation of 37.4° and a GC purity of 99.2%.

[0083] Comparative Example 1

[0084] Refer to CN103242169A. Add 30 g of sodium hydroxide dissolved in 300 mL of water to a 1000 mL three-necked flask, and stir and add dropwise the concentrated solution of the mixed solution of the mother liquor after S1 free and the S2 mother liquor shown in the process route at 60 °C, and stir for 2 h. After cooling to room temperature, add 50% sulfuric acid dropwise to adjust the pH = 4. Extract and separate the organic layer, and then extract with ethyl acetate twice. Combine the organic layers, add 50 mL of methanol, and cool at -15 to -30 °C for 24 h to obtain 27.54 g of a white solid. Dissolve the solid in 100 g of water, and add 50% sulfuric acid to adjust the pH = 2. After the aqueous phase is extracted twice with ethyl acetate, combine the organic phases, and remove the solvent under reduced pressure to obtain 7 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid with a specific rotation of 37.7° and a GC purity of 98.2%. The recovery rate of this method is relatively low.

[0085] Comparative Example 2

[0086] Refer to CN104086439A. Add the concentrated solution of the mixed solution of the mother liquor after S1 free and the S2 mother liquor shown in the process route to a 1000 mL three-necked flask, heat up to 40 °C, add 30% aqueous sodium hydroxide solution dropwise to adjust the pH = 11, add 100 mL of dichloromethane, extract three times, collect the organic phase, and remove the solvent under reduced pressure at a controlled temperature of 40 °C for the organic phase to obtain 14.3 g of an oily substance. Continue to distill at 50 - 100 °C to obtain 9.11 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid with a specific rotation of 37.4° and a GC purity of 99.1%. The recovery rate of this method is relatively low.

[0087] Comparative Example 3

[0088] Refer to CN113087630A. Add the concentrated solution of the mixed solution of the mother liquor after S1 free and the S2 mother liquor shown in Figure a to a 1000 mL three-necked flask, add 20% aqueous sodium hydroxide solution dropwise to adjust the pH = 10.5, add 150 mL of cyclohexane, heat up to 45 °C and stir for 15 min, let it stand and separate layers, and collect the organic phase. Add 150 mL of water to the organic phase, heat up to 45 °C and stir for 15 min, let it stand and separate layers, and collect the organic phase. Remove the solvent under reduced pressure at a controlled temperature of 45 °C to obtain 24.1 g of an oily substance.

[0089] Dissolve the oily substance in 200 mL of cyclohexane, cool it down to 0 - 10 °C, add dilute nitric acid dropwise to adjust the pH to 7, stir for 15 min, and then filter to obtain the filter cake.

[0090] Dissolve the filter cake in 200 mL of water, add 20% aqueous sodium hydroxide solution dropwise to adjust the pH to 10.5, add 150 mL of cyclohexane, heat it up to 45 °C, stir for 15 min, let it stand for liquid separation, collect the organic phase, control the temperature of the organic phase at 45 °C, remove the solvent under reduced pressure to obtain 13.4 g of oily substance. Then continue to distill at 50 - 100 °C to obtain 8.65 g of the target product (R)-(+)-phenylethylamine, which is a colorless liquid, specific rotation: 37.4°, GC: 93.2%. The recovery rate of this method is relatively low and the purity is also relatively low.

[0091] The specific embodiments described above have further elaborated on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. 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 recovering edoxaban intermediate resolving agent R-phenylethylamine, characterized in that: The steps include: S1. After adding organic solvent A to the mother liquor containing free R-phenylethylamine, the temperature was lowered by 5-15°C, the pH was adjusted to acidic by adding inorganic acid, the temperature was raised to 25-30°C, and the aqueous phase was collected; S2. The aqueous phase is cooled to 5-15°C, an inorganic base is added to adjust the pH to alkaline, and then the temperature is raised to 25-30°C, and an organic solvent B is added. The organic phase is collected and distilled under reduced pressure to obtain (R)-(+)-phenylethylamine.

2. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, The mother liquor containing free R-phenylethylamine is a crystallization mother liquor obtained by splitting and recrystallizing the racemic 3-cyclohexene-1-carboxylic acid with R-phenylethylamine.

3. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 2, characterized in that, The mother liquor containing free R-phenylethylamine is the filtrate obtained after the crystallization mother liquor is treated with acid, cooled, crystallized and filtered to obtain (1R)-3-cyclohexene-1-carboxylic acid.

4. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, The mother liquor containing free R-phenylethylamine is the mother liquor of the salt obtained by splitting and recrystallizing the racemic 3-cyclohexene-1-carboxylic acid with R-phenylethylamine, and then subjected to acidification, freeing and desolvation treatment.

5. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, In step S1, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydroiodic acid and hydrobromic acid.

6. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, In step S1, the pH is adjusted to 2-4 with an inorganic acid.

7. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, In step S1, the organic solvent A is selected from one or more mixed solvents of toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, ethyl acetate, and methyl tert-butyl ether in any proportion.

8. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, In step S2, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

9. A method for recovering edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that, In step S2, an inorganic base is used to adjust the pH to 9-11.

10. The method for recovering the edoxaban intermediate resolving agent R-phenylethylamine according to claim 1, characterized in that: In step S2, the organic solvent B is selected from a low boiling point solvent, a mixed solvent of one or more of dichloromethane, ethyl acetate, and methyl tert-butyl ether in any proportion.

Images