Method for preparing amine salt of single-configuration tropine acid and resolution method of tropine acid

Abstract

The invention discloses a method for preparing single-configuration tropine acid amine salt from (+ / -)-tropine acid and a resolution method of a tropine acid enantiomer, and relates to the technical field of compound separation. The resolution step comprises the following steps: adding racemic tropine acid and a resolving agent into a solvent, heating and refluxing to completely dissolve the solid, and clarifying the solution; cooling the solution until a solid is separated out, and filtering to obtain S or R configuration tropine acid amine salt; dissociating the obtained S-or R-configuration tropine acid amine salt in an alkaline solution to recover the resolving agent; and acidifying and dissociating the solution to obtain the S or R configuration tropine acid. The tropine acid resolution method is simple in preparation process, mild in reaction condition, low in equipment condition requirement, short in reaction time, high in yield and easy in post-treatment, and the resolving agent can be recycled.

Description

Technical Field

[0001] The invention relates to the technical field of compound separation, in particular to a method for preparing a single-configuration tropic acid amine salt and a method for splitting tropic acid. Background Art

[0002] The property that an object and its mirror image cannot be completely overlapped is called chirality. A pair of stereoisomers that are the object and the mirror image of each other but cannot be overlapped are called enantiomers. They are a class of compounds with the same physical and chemical properties but usually different physiological activities. Drugs with chiral factors in their active molecular structures can be called chiral drugs. Chiral drugs can be divided into racemic chiral drugs and single enantiomer chiral drugs. According to incomplete statistics, 40% of chemically synthesized drugs on the market are chiral drugs, most of which are racemic compounds, while chiral drugs administered as single enantiomers account for only 12%. A large number of studies and clinical practices have shown that the two enantiomers of chiral drugs often have different biological activities and pharmacological and toxicological effects. Taking racemic chiral drugs is potentially dangerous, so restricting the production of chiral drug racemates and developing single enantiomer drugs have become established policies of medical management decision-making departments and the pharmaceutical industry in various countries. The Technical Guidelines for Quality Control Research of Chiral Drugs clearly mentions that different stereoisomers of chiral drugs may have differences in efficacy, pharmacokinetics and toxicology, and requires that when conducting pharmacological and toxicological studies on chiral drugs, each stereoisomer of the drug should be obtained separately, and necessary comparative studies should be conducted to determine the drug to be further developed. In the production process of raw materials, it is required that the optical purity of all chiral raw materials and reagents should be controlled, and each reaction intermediate after the introduction of the chiral center should also be combined with the reaction mechanism to effectively separate and control the stereoisomer impurities that may be produced.

[0003] 3-Hydroxy-2-phenylpropionic acid (Tropic acid), as an important pharmaceutical intermediate, is an important intermediate of the basic drugs anisodamine, tropicamide, and atropine. Atropine is a type of post-hoclic anticholinergic drug with a wide range of pharmacological effects. Its enantiomers have significant differences in pharmacological effects. L-atropine (-) has a strong efficacy, but is more toxic than dextroatropine (+). Tropicic acid is an intermediate of atropine. When producing atropine, the process is to first split tropic acid to obtain optically pure tropic acid, and then synthesize it.

[0004]

[0005] In the prior art, there are mainly the following methods for obtaining optically pure tropic acid on a large scale:

[0006] 1. In 1972, the University of Tokyo in Japan published the following synthesis method (Chem. Pharm. Bull. 1972, 20 (6), 1282-1286.). This route uses L-phenylalanine as a raw material and treats it with sodium nitrite in trifluoroacetic acid to directly obtain optically active S-tropic acid, but the yield is only 24.2%, and the optical purity of the product is low.

[0007]

[0008] 2. In 2005, the Delft University of Technology in the Netherlands announced an enzymatic kinetic resolution method for tropic acid (Tetrahedron: Asymmetry 16 (2005) 3892–3896.). This route uses (±)-tropic acid as a raw material, and obtains (±)-tropic acid butyl ester by treating with n-butanol. R-tropic acid can be obtained with a yield of 47% by subsequent enzyme treatment, and S-tropic acid butyl ester can be obtained with a yield of 43%. The optical purity of R-tropic acid obtained by this method is still not high, and its ee value is 90%. In addition, due to the use of the relatively expensive lipase CAL-B, the production cost is high, which is not conducive to industrial scale-up production.

[0009]

[0010] 3. In 2014, Saitama University in Japan announced the following splitting method (Tetrahedron 70 (2014)

[0011] 7923–7928.). This route uses (±)-tropic acid as a raw material and treats it with (1R,2S)-2-amino-1,2-diphenylethanol in 50% isopropanol to obtain an amine salt formed by S-tropic acid and (1R,2S)-2-amino-1,2-diphenylethanol with a yield of 61% and an ee value of 90%. This method still obtains an amine salt of S-tropic acid, but does not obtain relatively pure S-tropic acid. In addition, this method is very sensitive to the composition of the solvent. For example, if pure isopropanol is used as the solvent, the ee value of the product is reduced to 52%, which is not conducive to industrial scale-up production.

[0012]

[0013] The above disclosed methods indicate that there is still no widely known suitable method for obtaining single enantiomers of tropic acid with high optical purity on a large scale. Summary of the invention

[0014] The object of the present invention is to provide a method for preparing tropic acid of R or S configuration which is easy to realize industrially and conveniently and can be obtained on a large scale with high optical purity. Compared with the intermediate amine salt obtained by separation in the prior art, the enantiomeric excess (ee%) of the intermediate amine salt is higher, the optical purity is better, the product ee% is high and the yield is good. Compared with the existing public synthetic route, the preparation process is simple, the reaction conditions are mild, the requirements for equipment conditions are not high, the reaction time is short, the yield is high, the post-treatment is easy, the method is economical and environmentally friendly, and the method is suitable for large-scale industrial production and has good industrial prospects.

[0015] According to the splitting method published by Saitama University in Japan, the splitting agent (1R,2S)-2-amino-1,2-diphenylethanol is first used to form an amine salt with S-tropic acid, and then the amine salt is dissociated into S-tropic acid to achieve the splitting effect. Among them, the preparation of single-configuration tropic acid amine salt is particularly critical. If the purity and yield of single-configuration tropic acid amine salt can be stably controlled, it will be convenient to obtain high-purity, high-yield single-configuration tropic acid.

[0016] Based on the above problems, the present invention provides a method for preparing (±)-tropic acid into a single-configuration tropic acid amine salt, comprising the following contents:

[0017] (±)-Tropic acid and a chiral resolving agent are heated in a solvent until they are dissolved, cooled and stirred to precipitate solid A first, and then the solid and liquid are separated;

[0018] Collecting solid A, to obtain one of (S)-tropic acid amine salt and (R)-tropic acid amine salt;

[0019] The liquid was collected and stirred at room temperature to precipitate solid B again. Solid B was collected to obtain a single-configuration tropic acid amine salt having a different configuration from solid A.

[0020] Wherein, the chiral resolving agent is selected from one of the following:

[0021]

[0022] The configuration of the solid A precipitated first is determined by the type of chiral resolving agent used.

[0023] By using the chiral resolving agent, not only can a single-configuration amine salt with high purity and high yield be obtained, but also the S and R configuration amine salts can be separated and obtained by a single feed, with good stability and simple process.

[0024] Wherein, the solvent is selected from anhydrous ethanol, isopropanol, n-butanol, tert-butanol, 95% ethanol, 75% ethanol or a mixture thereof. In some specific embodiments of the present invention, when 95% ethanol, anhydrous ethanol, n-propanol or n-butanol is used as the solvent, an amine salt with a high ee value can be obtained more stably and with a better yield.

[0025] In order to ensure that tropic acid reacts to the maximum extent, the molar ratio of the chiral resolving agent to (±)-tropic acid is greater than 0.6:1. In some specific embodiments of the present invention, the molar ratio of the chiral resolving agent to (±)-tropic acid is 0.6-1.2:1, preferably 1.0:1, which can achieve a higher yield of single-configuration amine salts. Specifically, the molar ratio of the chiral resolving agent to (±)-tropic acid can be 0.6:1, 0.8:1, 1.0:1, 1.2:1.

[0026] In the above process steps, after dissolving, a single-configuration amine salt is obtained by cooling and crystallizing. For example, the cooling and stirring temperature can be selected from 20 to 40° C. In some specific embodiments of the present invention, room temperature is selected.

[0027] The room temperature mentioned in the present invention refers to 25±5°C.

[0028] In the present invention, the amount of solvent used should be such that the solid can be completely dissolved during the reflux process.

[0029] Based on the preparation method of the above amine salt, the present invention also provides a method for chiral separation of (±)-tropic acid, comprising the following contents:

[0030] A1: Using the aforementioned method, (±)-tropic acid is prepared into a single-configuration tropic acid amine salt;

[0031] A2: The single-configuration tropic acid amine salt obtained in step A1 is reacted under the action of a base, and the solid-liquid separation is performed;

[0032] A3: Collect the liquid of A2, add acid to make the solution pH <2, react to precipitate solid, collect the solid to obtain the single-configuration tropic acid after separation.

[0033] Furthermore, step A2 may include a step of recrystallizing the single-configuration tropic acid amine salt. The recrystallized single-configuration tropic acid amine salt is reacted under the action of a base to separate the solid from the liquid.

[0034] Recrystallization further improves the purity of the amine salt.

[0035] The solvent for recrystallization can be selected from one or more of anhydrous ethanol, 95% ethanol, n-propanol, and n-butanol, preferably 95% ethanol. The temperature can be from room temperature to the reflux temperature of the solvent.

[0036] Since A1 obtains a single-configuration amine salt with high ee value and high yield, after being treated with alkali and acid, the single-configuration tropic acid obtained also has a high ee value and high yield.

[0037] Wherein, the base in A2 is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0038] In the present invention, the alkali is added in the form of an alkali aqueous solution with a mass concentration of 1% to 50%.

[0039] In some specific embodiments of the present invention, the aqueous alkali solution is selected from 2-30% NaOH, 2-30% KOH, which can ensure a stable high yield and high ee value, especially 10% NaOH, 10% KOH.

[0040] In A3, the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and trifluoroacetic acid. The acid concentration is selected from 1% to 50%.

[0041] In some specific embodiments of the present invention, the acid is selected from hydrochloric acid, hydrobromic acid or sulfuric acid with a concentration of 30-40%, which can ensure a high yield while ensuring a high ee value.

[0042] The concentration of hydrochloric acid in the present invention is a mass percentage. The concentrated hydrochloric acid used in the present invention is selected from commercially available concentrated hydrochloric acid, and the concentration is 36-38%.

[0043] The invention adopts a left-handed amino compound as a chiral splitting agent, performs a reaction in a non-toxic solvent such as an alcohol or water solvent, splits (±)-tropic acid, and obtains intermediates (S)-tropic acid amine salt and (R)-tropic acid amine salt with high ee% value by utilizing the different solubility of the intermediates in the reaction solvent. During the reaction, the intermediate (R)-tropic acid amine salt or (S)-tropic acid amine salt is dissolved in an aqueous solution of an alkaline compound to realize the recovery of the left-handed amino compound solid; and concentrated acid is added to the remaining filtrate and the pH is adjusted to be less than 1 to obtain (R)-tropic acid and (S)-tropic acid products with high ee% value.

[0044] The invention solves the problem that the existing process for obtaining optically pure tropic acid cannot achieve large-scale production due to low ee% value of the split product, low yield and harsh process conditions, overcomes the disadvantage that the reagents used in the existing process are expensive (such as lipase CAL-B, etc.), and avoids the use of toxic reagents.

[0045] During the acid addition process, when the pH is <2, a white solid product begins to precipitate (single-configuration tropic acid). Under the premise of ensuring product quality, in order to ensure efficient and more complete precipitation of the product, the pH of the system is usually adjusted to <1.

[0046] The pH test can be carried out by conventional methods, for example, using pH test paper, pH meter, etc.

[0047] The process of the present invention can also be used to recycle the chiral resolving agent, which includes: collecting the solid after solid-liquid separation of A2 to obtain the chiral resolving agent. The recycling of the resolving agent further reduces the process cost.

[0048] The beneficial effects of the present invention are:

[0049] 1. The splitting method of the present invention overcomes the disadvantages of low splitting efficiency of obtaining optically pure tropic acid in the existing process technology, such as low ee% value, low yield, harsh process conditions, inability to achieve scale and expensive reagents (such as lipase CAL-B, etc.), and the synthesis method has simple steps, low cost, and avoids the use of toxic reagents.

[0050] 2. The present invention adopts refined amino compounds as chiral splitting agents, operates in alcohol and water solvents, and realizes the splitting of tropic acid on a scale of 100 grams. R-tropic acid and S-tropic acid with good optical purity can be obtained respectively in a single salt-forming-desalting process. The splitting efficiency is high, the process price is low, the operation is simple, and the process time required is short, which greatly improves the splitting efficiency.

[0051] 3. The present invention realizes the reuse of the resolution agent. The resolution agent recovered during the desalting process is subjected to a secondary salt-desalting process to obtain R-tropic acid and S-tropic acid with good optical purity, and the resolution cost is further reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 HPLC spectrum of commercially available (±)-tropic acid

[0053] Figure 2 HPLC spectrum of commercially available (S)-tropic acid

[0054] Figure 3 HPLC spectrum of (S)-tropic acid obtained in Example 1

[0055] Figure 4 HPLC spectrum of (R)-tropic acid obtained in Example 1 DETAILED DESCRIPTION

[0056] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described here are only a part of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention.

[0057] The general reaction formula of tropic acid splitting of the present invention is as follows:

[0058] Example 1

[0059]

[0060] 1. Preparation of single-configuration tropic acid amine salt

[0061] 10.0 g of (±)-tropic acid (brand: adamas) and 13.2 g (1.0 eq.) of (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol were added to 50 mL of 95% ethanol, heated under reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 1 hour, filtered to obtain a white solid, dried at 45°C, and collected to obtain 11.0 g of a crude white solid (S)-tropic acid amine salt, with a yield of 48% and an ee value of 96%. The yellow filtrate obtained by filtration was continued to be stirred at room temperature, and a white solid began to precipitate after 6 hours. The stirring was continued for 10 hours, filtered to obtain a white solid, dried at 45°C, and collected to obtain 9.8 g of a white solid (R)-tropic acid amine salt, with a yield of 43% and an ee value of 93%.

[0062] 2. Recrystallization of single-configuration tropic acid amine salt

[0063] Add 25 mL of 95% ethanol to 11 g of crude (S)-tropic acid amine salt, heat under reflux to dissolve, then stop heating, cool and stir to precipitate solid, continue stirring for 1 hour after cooling to 25 ° C, filter to obtain a white solid, dry at 45 ° C, collect 10.6 g of white solid (S)-tropic acid amine salt, the recrystallization yield is 96%, and the ee value is> 99%;

[0064] 3. Amine salt dissociates to form tropic acid

[0065] 20 mL of 10% NaOH (aq.) was added to the obtained 9.8 g (S)-tropic acid amine salt and 9.8 g (R)-tropic acid amine salt, respectively. The mixture was stirred at room temperature for 1 h and filtered to obtain a white solid, namely (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol. 3.6 g of (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol was recovered after treatment with (S)-tropic acid amine salt, and 3.0 g of (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol was recovered after treatment with (R)-tropic acid amine salt. 4 ml of concentrated hydrochloric acid was added to the two filtrates at 25° C. to adjust the pH of the filtrate to <1 (the pH test paper showed dark red), and a white solid was precipitated. After stirring at 25° C. for 1 hour, the mixture was filtered, dried, and collected to obtain a white solid. 2.8 g of (S)-tropic acid was collected, with a yield of 65% and an ee value of >99%; 2.4 g of (R)-tropic acid was collected, with a yield of 56% and an ee value of 93%.

[0066] When (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (i.e., the compound represented by formula (II)) is used as a chiral resolution agent, similar to the above steps, the white solid that is preferentially precipitated after cooling is (R)-tropic acid amine salt. The filtrate is continuously stirred, and the precipitated solid is (S)-tropic acid amine salt.

[0067] The structure confirmation of the isolated (S)-tropic acid and (R)-tropic acid

[0068] The absolute configuration of the resolved product was confirmed by comparing the HPLC retention time with that of the commercial standard (S)-tropic acid.

[0069] Preparation of reference solution: Take commercially available (S)-tropic acid, accurately weigh it, and dilute it with mobile phase to make a solution containing approximately 0.2 mg of (S)-tropic acid per 1 ml, which serves as the reference solution.

[0070] Preparation of test solution: Take the (S)-tropic acid and (R)-tropic acid prepared above, weigh accurately, dilute with mobile phase to make solutions containing about 0.2 mg of (S)-tropic acid and (R)-tropic acid per 1 ml, respectively, as test solution

[0071] Mobile phase: n-hexane-isopropanol-ethanol = 78:12:10 (0.1% trifluoroacetic acid)

[0072] Stationary phase: cellulose-tris(4-methylbenzoate)

[0073] Detection conditions: detection wavelength was 205 nm, flow rate was 1.0 ml per minute, column temperature was 30 °C.

[0074] Sampling volume: 10 μl

[0075] The HPLC spectrum of the reference substance (S)-tropic acid is attached. Figure 2 The HPLC spectrum of (S)-tropic acid obtained in this embodiment is attached. Figure 3 The HPLC spectrum of (R)-tropic acid obtained in this embodiment is attached. Figure 4 .

[0076] Example 2

[0077] 100 g of (±)-tropic acid and 79 g (0.6 eq.) of (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol were added to 500 mL of 95% ethanol, heated under reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 1 hour, filtered to obtain a white solid (S)-tropic acid amine salt, dried at 45°C, and collected to obtain 92 g of a crude white solid (S)-tropic acid amine salt with an ee value of 93%; the yellow filtrate was concentrated to obtain 87 g of a yellow solid mixture of (R)-tropic acid amine salt (R) and tropic acid.

[0078] Add 250 mL of 95% ethanol to 92 g of crude (S)-tropic acid amine salt, heat to reflux and dissolve, then stop heating, cool and stir to precipitate solid, continue stirring for 1 hour after cooling to 25 ° C, filter to obtain a white solid, dry at 45 ° C, collect 91.5 g of white solid (S)-tropic acid amine salt, the recrystallization yield is 99%, and the ee value is> 99%;

[0079] 150 mL 10% NaOH (aq.) was added to (S)-tropic acid amine salt or (R)-tropic acid amine salt and tropic acid salt mixture respectively, stirred at room temperature for 1 hour and filtered to obtain a white solid, namely (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol. After treatment with (S)-tropic acid amine salt, 45 g of (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol was recovered; 30 ml of concentrated hydrochloric acid was added to the filtrate to adjust the pH of the filtrate to <1, and a white solid was precipitated. After stirring at 25°C for 1 hour, the white solid was filtered, dried and collected. 30 g of (S)-tropic acid was collected, with a total yield of 30% and an ee value of >99%; 35 g of (R)-tropic acid was collected, with a total yield of 35% and an ee value of 79%.

[0080] Example 3

[0081] Recovered (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol was used for (±)-tropic acid resolution:

[0082] 5 g (±)-tropic acid (30.1 mmol) and 3.95 g (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol (18.6 mmol) were added to 25 mL 95% ethanol, heated under reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 2 hours, filtered to obtain a white solid (S)-tropic acid amine salt, dried at 45°C, collected 5.10 g solid, the yield was 45%, and the ee value was 97%.

[0083] Example 4

[0084] 2.5 kg of (±)-tropic acid and 1.9 kg (0.6 eq.) of (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol were added to 12.5 L of 95% ethanol, heated to reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 1 hour, filtered to obtain white solid (S)-tropic acid amine salt, dried at 45°C, collected to obtain 2.6 kg of white solid (S)-tropic acid amine salt crude product, with an ee value of 97%. 6.3 L of 95% ethanol was added to 2.6 kg of (S)-tropic acid amine salt crude product, heated to reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 1 hour, filtered to obtain white solid, dried at 45°C, collected to obtain 2.5 kg of white solid (S)-tropic acid amine salt, with a recrystallization yield of 98% and an ee value>99%;

[0085] Add 2.0L 10% NaOH (aq.) to (S)-tropic acid amine salt, stir at room temperature for 1h, and then filter to recover (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol; add 400ml concentrated hydrochloric acid to the filtrate to adjust the pH of the filtrate to <1, and precipitate a white solid. After stirring at 25°C for 1 hour, filter, dry, and collect to obtain 0.88kg of white solid (S)-tropic acid, with a total yield of 35% and an ee value of >99%.

[0086] Comparative Example 1

[0087]

[0088] 1.66 g (±)-tropic acid (10.0 mmol) and 2.13 g (1R, 2S)-2-amino-1,2-diphenylethanol (10.0 mmol) were added to 20 mL 50% isopropanol, heated under reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued stirring for 1 hour, filtered to obtain white solid (S)-tropic acid amine salt 2, dried at 45°C, collected 0.82 g solid, the yield was 22%, and the ee value was 98%.

[0089] To 0.82 g of (S)-tropic acid amine salt 2, add 1.8 mL of 10% NaOH (aq.), stir at room temperature for 1 h, filter, discard the filter cake, add 0.5 ml of concentrated hydrochloric acid to the filtrate to adjust the pH of the filtrate to <1, precipitate a white solid, stir at 25 ° C for 1 hour, filter, dry and collect to obtain 0.24 g of white solid (S)-tropic acid, with a yield of 65% and an ee value of 98%.

[0090] Comparative Example 2

[0091] 1 g (±)-tropic acid (6.02 mmol) and 0.73 g R (+)-α-phenylethylamine (6.02 mmol) were added to 10 mL of anhydrous ethanol, heated under reflux to dissolve, then the heating was stopped, cooled and stirred to precipitate a solid, cooled to 25°C and stirred for 1 hour, filtered to obtain a white solid (S)-tropic acid amine salt, dried at 45°C, and 0.52 g of solid was collected, with a yield of 30% and an ee value of 78%.

[0092] Comparative Example 3

[0093] 1 g (±)-Tropical acid (6.02 mmol) and 0.69 g L-proline (6.02 mmol) were added to 5 mL of anhydrous ethanol, heated under reflux to dissolve, then the heating was stopped, cooled and stirred to precipitate a solid, and the mixture was cooled to 25°C and stirred for 1 hour. The white solid (S)-tropic acid amine salt was filtered off and dried at 45°C to collect 1.56 g of solid, with a yield of 92% and an ee value of 8%.

[0094] Comparative Example 4

[0095] 1 g (±)-Tropic acid (6.02 mmol) and 1.94 g (–)-quinine (6.02 mmol) were added to 30 mL of anhydrous ethanol, heated to reflux to dissolve, then the heating was stopped, cooled and stirred to precipitate a solid, cooled to 25°C and stirred for 1 hour, filtered to obtain a white solid (S)-tropic acid amine salt, dried at 45°C, and collected to obtain 1.20 g of solid, with a yield of 40% and an ee value of 72%.

[0096] Compared with the above comparative examples 1-4, the intermediate amine salt obtained by separation in the embodiment of the present invention has a higher enantiomeric excess (ee%), better optical purity, and a good product yield, and has the potential for large-scale production.

[0097] Embodiment 6-15

[0098]

[0099] 10g (±)-tropic acid (60.2mmol), 12.8g (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol (60.2mmol) were added to the solvent, heated to reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued to stir for 1 hour, filtered to obtain white solid (S)-tropic acid amine salt, dried at 45°C, collected and weighed. The effects of solvent type and solvent volume changes on product quality, yield and ee value are shown in Table 1:

[0100] Table 1 explores the effects of solvent type and solvent volume changes on product quality, yield and ee value

[0101]

[0102]

[0103] Conclusion: 95% ethanol, n-propanol, anhydrous ethanol and n-butanol can all produce products with high ee value.

[0104] Examples 16-18

[0105]

[0106] 10g (±)-tropic acid (60.2mmol), (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol were added to 95% ethanol, heated to reflux to dissolve, then stopped heating, cooled and stirred to precipitate solid, cooled to 25°C and continued to stir for 1 hour, filtered to obtain white solid (S)-tropic acid amine salt, dried at 45°C, collected and weighed. The effects of different (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol dosages on product yield and ee value are shown in Table 2:

[0107] Table 2 Exploration of the effect of changing the amount of (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol on product yield and ee value

[0108] Example (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol dosage Product Quality Yield ee value 16 12.8 g (1.0 equivalent. 60.2 mmol) 10.5g 46％ 96％ 17 10.5 g (0.8 equivalent. 49.5 mmol) 10.2g 43％ 95％ 18 7.9 g (0.6 eq. 37.2 mmol) 11.3g 48％ 96％

[0109] Conclusion: 0.6 to 1.0 equivalents of (1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol are suitable for the resolution of (±)-tropic acid.

[0110] Examples 19-25

[0111]

[0112] 10g (S)-tropic acid amine salt (96% ee, 26.4mmol) was added to the aqueous solution of alkali, stirred at 25℃ for 1 hour, and filtered to obtain a white solid; the corresponding concentrated hydrochloric acid was added to the filtrate to adjust the pH, stirred at 25℃ for 1 hour, filtered to obtain a white solid (S)-tropic acid, dried at 45℃, collected and weighed. The effects of the type of alkali solution and the volume of the alkali solution on the product quality, yield and ee value are shown in Table 3:

[0113] Table 3 explores the effects of alkali solution type and alkali solution volume change on product quality, yield and ee value

[0114] Example Alkali aqueous solution Alkaline solution volume Product Quality Yield ee value 19 2% NaOH 105.7mL 2.4g 55％ 96％ 20 5% NaOH 42.4mL 2.5g 57％ 96％ 21 10% NaOH 21.2mL 2.8g 63％ 96％ 22 30% NaOH 7.1mL 2.3g 52％ 95％ 23 10% KOH 29.7mL 2.7g 61％ 96％ 24 <![CDATA[10%Na2CO3]]> 56.0mL 0.8g 18％ 96％ 25 <![CDATA[10%K2CO3]]> 73.0mL 0.8g 18％ 96％

[0115] Conclusion: NaOH, KOH, etc. can obtain higher yields while ensuring high ee values, and are suitable dissociation agents.

[0116] Examples 26-31

[0117]

[0118] 10g (S)-tropic acid amine salt (96% ee, 26.4mmol) was added to 21.2mL 10% sodium hydroxide aqueous solution, stirred at 25℃ for 1 hour, and filtered to obtain a white solid; the corresponding acid aqueous solution was added to the filtrate to adjust the pH to 1, stirred at 25℃ for 1 hour, and filtered to obtain a white solid (S)-tropic acid, which was dried at 45℃ and collected and weighed. The effects of the type and volume of acid on the product quality, yield and ee value are shown in Table 4:

[0119] Table 4 explores the effects of alkali solution type and alkali solution volume change on product quality, yield and ee value

[0120] Example Acid solution Acid volume Product Quality Yield ee value 26 5% hydrochloric acid 38mL 0.5g 11％ 96％ 27 10% hydrochloric acid 19mL 1.5g 34％ 96％ 28 Concentrated hydrochloric acid 5mL 2.8g 63％ 96％ 29 33% Hydrobromic acid 13mL 2.8g 63％ 96％ 30 10% sulfuric acid 26mL 0.7g 16％ 96％ 31 30% sulfuric acid 8.6mL 2.6g 59％ 96％

[0121] Conclusion: Using 33% hydrobromic acid, concentrated hydrochloric acid, and 30% sulfuric acid can obtain higher yields while ensuring high ee values. Other concentrations or other acids cannot obtain better yields.

Claims

1. A method for preparing (±)-tropic acid into a single-configuration tropic acid amine salt, characterized in that: It includes the following: (±)-Tropic acid and a chiral resolving agent are heated in a solvent until they are dissolved, cooled and stirred to precipitate solid A first, and then the solid and liquid are separated; Collecting solid A, to obtain one of (S)-tropic acid amine salt and (R)-tropic acid amine salt; The liquid was collected and stirred at room temperature to precipitate solid B again. Solid B was collected to obtain a single-configuration tropic acid amine salt having a different configuration from solid A. Wherein, the chiral resolving agent is selected from one of the following: The configuration of the solid A precipitated first is determined by the type of chiral resolving agent used.

2. The method according to claim 1, characterized in that: The solvent is selected from anhydrous ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, 95% ethanol, 75% ethanol or a mixture thereof; preferably 95% ethanol, anhydrous ethanol, n-propanol, n-butanol.

3. The method according to claim 1, characterized in that The molar ratio of the chiral resolving agent to (±)-tropic acid is greater than 0.6:1; further, the molar ratio of the chiral resolving agent to (±)-tropic acid is selected from 0.6-1.2:

1.

4. The method according to claim 1, characterized in that: After dissolution, the temperature for cooling and stirring is selected from 20 to 40° C., and further selected from room temperature.

5. A chiral separation method for (±)-tropic acid, characterized in that: It includes the following: A1: using the method described in any one of claims 1 to 3 to prepare (±)-tropic acid into a single-configuration tropic acid amine salt; A2: The single-configuration tropic acid amine salt obtained in step A1 is reacted under the action of a base, and the solid-liquid separation is performed; A3: Collect the liquid of A2, add acid to make the solution pH <2, react to precipitate solid, collect the solid to obtain the single-configuration tropic acid after separation.

6. The method according to claim 5, characterized in that: The base in A2 is selected from any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; Furthermore, the alkali is added in the form of an alkali aqueous solution with a mass concentration of 1% to 50%.

7. The method according to claim 5, characterized in that The alkaline aqueous solution is selected from 2-30% NaOH, 2-30% KOH; preferably 10% NaOH, 10% KOH.

8. The method according to claim 5, characterized in that In A3, the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and trifluoroacetic acid; Furthermore, the acid concentration is selected from 1% to 50%.

9. A method for resolving tropic acid enantiomers according to claim 7, characterized in that: The acid is selected from hydrochloric acid, hydrobromic acid or sulfuric acid with a concentration of 30-40%.

10. The method according to claim 5, characterized in that: It also includes the recovery of the chiral resolving agent: collecting the solid after the solid-liquid separation of A2 to obtain the chiral resolving agent.

11. The method according to claim 5, characterized in that: A2 includes or does not include recrystallization of the single-configuration tropic acid amine salt; the recrystallized single-configuration tropic acid amine salt reacts under the action of a base to separate the solid from the liquid.

12. The method according to claim 11, characterized in that: The solvent for recrystallization can be selected from one or more of anhydrous ethanol, 95% ethanol, n-propanol, and n-butanol, preferably 95% ethanol; the temperature is selected from room temperature to solvent reflux temperature.

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