Method for preparing (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid

Abstract

The invention relates to a method for preparing a compound shown in a formula (A). The method for stereospecifically synthesizing (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid as shown in a formula (A) comprises the step of hydrogenating a compound as shown in a formula (I) in an aqueous medium in the presence of a metal catalyst and alkali to form the compound as shown in the formula (A). In addition, the invention also comprises a method for synthesizing the compound as shown in the formula (I) by resolving the indoline-2-carboxylic acid as shown in the formula (II). The method of the present invention provides a compound represented by formula (A) with higher chiral purity and higher yield, and does not produce large amounts of undesired by-products. The catalyst and the resolving agent (R)-(+)-alpha-methylbenzylamine can be recycled and reused, and the efficiency is higher, so that the method disclosed by the invention has cost benefit.

Description

Technical Field

[0001] This invention relates to a method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid, and more specifically to an improved method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid as shown in formula (A), which has high chiral purity, high yield and high industrial applicability. Background Technology

[0002] The compound (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A) is an important key intermediate compound that constitutes the core structure of antihypertensive drugs such as perindopril and its salts, as well as antiviral drugs such as odatavir and its salts.

[0003]

[0004] Compound (A) exists in eight stereoisomers, among which the (2S, 3aS, 7aS)-isomer is crucial to the activity of these drugs. Various attempts to synthesize this isomer via chemical and enzymatic resolution have been reported in the literature.

[0005] Michel Vincent, Bagneux, et al.’s U.S. patent application US 4,935,525 discloses the preparation of the compound shown in formula (A) as shown in Scheme 1 below.

[0006]

[0007] Option 1

[0008] This method relates to the preparation of ethyl indole-2-carboxylate. Ethyl indole-2-carboxylate is hydrogenated with tin-hydrochloric acid to yield (R,S)-ethoxycarbonylindoline, and the S-isomer is separated using α-methylbenzylamine. The (S)-ethoxycarbonyl group is then hydrogenated with platinum, nickel, palladium, or rhodium (especially 5% rhodium) to yield compound (A). The desired (2S,3aS,7aS)-isomer is separated from the (2S,3aR,7aR)-isomer by crystallization from lower fatty alcohols, acetonitrile, dioxane, and ethyl acetate (which may be used alone, mixed with each other, or mixed with water). However, the above method does not provide any details regarding the purity of the (S,S,S)-stereoisomer.

[0009] Cited references Efficient access to N-protected derivatives of (R,R, R)-and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution"The hydrogenation of indoline-2-carboxylic acid in acetic acid in the presence of PtO2 was disclosed by Carlos Cativila et al. in Tetrahedron: Asymmetry, Vol. 18, No. 19, pp. 2358-2364 on September 27, 2007, as shown in Scheme 2 below."

[0010]

[0011] Option 2

[0012] In the hydrogenation reaction, the solvent was evaporated to dryness, and the resulting residue was first crystallized from ethanol, and then from a dioxane-water mixture, to give a racemic white solid. The reported reaction completion time was 24 hours. The N-Boc protected benzyl ester of this chiral compound was further resolved by HPLC on a chiral column.

[0013] Chen Weiren et al.'s PCT application WO2007062865 discloses a catalytic hydrogenation of (S)-indoline-2-carboxylic acid ethyl ester hydrochloride in ethanol using Pd / C. The reaction mixture was hydrogenated under stirring at 60 °C and 50 bar until hydrogen was exhausted. After filtering off the catalyst, the filtrate was hydrolyzed with sodium hydroxide. After post-treatment, (2S,3aS,7aS)-octahydro-1H-indoline-2-carboxylic acid was isolated as a white powder in 40% yield.

[0014] US Patent 7,666,896 by Rajendra Narayanrao Kankan et al. discloses a method for preparing (2S,3aS,7aS)-octahydro-indole-2-carboxylic acid, which involves hydrogenating (S)-indoline-2-carboxylic acid in an alkaline medium at 50°C and 5-20 bar in the presence of rhodium / alumina.

[0015] The existing methods for preparing the compound shown in formula (A) have not achieved ideal results in terms of cost, recyclability and reusability of hydrogenation catalysts.

[0016] Therefore, an improved method for preparing the compound shown in formula (A) is needed to obtain a high-purity final product without generating a large amount of undesirable byproducts. Furthermore, a method for preparing the compound shown in formula (A) with higher yield, industrial scalability, and cost-effectiveness is also needed. Summary of the Invention

[0017] This invention describes a method for preparing the compound shown in formula (A). More specifically, one aspect of the invention relates to the stereospecific synthesis of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A), and another aspect of the invention relates to the synthesis of the compound shown in formula (I) by resolving indoline-2-carboxylic acid shown in formula (II).

[0018]

[0019] The stereospecific synthesis method of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A) includes: hydrogenating the compound shown in formula (I) in an aqueous medium in the presence of a metal catalyst and a base to form the compound shown in formula (A).

[0020] The method for synthesizing the compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) comprises several steps. The method includes the following steps: adding the compound of formula (II) to a solution of (R)-(+)-α-methylbenzylamine in a solvent; heating the reaction mixture; gradually cooling the reaction mixture; separating the (R)-α-methylbenzylamine salt of the (S)-isomer of formula (I-SA) by filtration; reacting the compound of formula (I-SA) with a predetermined acid or base in an aqueous medium to form the compound of formula (I); then separating and racemicizing the (R)-isomer to form the compound of formula (II); and recovering the resolving agent (R)-α-methylbenzylamine. Detailed Implementation

[0021] The term "one embodiment" or "implementation" as used in this specification refers to a specific feature, structure, characteristic, or function associated with that embodiment that is included in at least one embodiment of the invention. The phrase "in one embodiment" appearing in various places throughout the specification does not necessarily refer to the same embodiment.

[0022] The term "preferred embodiment" as used in this specification refers to describing a specific feature, structure, characteristic, or function in detail by omitting known structures and functions, so as to clearly illustrate the present invention.

[0023] The above description of specific embodiments of the present invention is for illustrative and descriptive purposes only. These descriptions are not intended to be exhaustive or to limit the invention to the precise forms disclosed; various modifications and variations based on the above teachings are clearly feasible.

[0024] The inventors of this invention have developed a method for preparing the compound shown in formula (A), which provides a higher yield of compound (A) and allows for efficient recovery and reuse of the catalyst in the process. This method is cost-effective and achieves higher chiral purity even in larger-scale production.

[0025] In one aspect, the present invention relates to the stereospecific synthesis of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A).

[0026]

[0027] The stereospecific synthesis of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A) includes:

[0028] In the presence of a metal catalyst and a base, at a predetermined temperature and pressure, the (2S)-indoline-2-carboxylic acid of formula (I) is hydrogenated in an aqueous medium to form the compound of formula (A).

[0029]

[0030] Option 3

[0031] In this embodiment of the invention, the base used for hydrogenation in step (a) is selected from hydroxides, carbonates, and bicarbonates of alkali metals or alkaline earth metals. The metal catalyst used for hydrogenation in step (a) is ruthenium on carbon. Hydrogenation is carried out at a predetermined temperature of 60-140 °C, preferably 70-110 °C, and a predetermined hydrogen pressure of 15-30 kg, preferably 20-25 kg.

[0032] In a preferred embodiment, hydrogenation is carried out with a catalyst loading of 1-10% (wet weight), preferably using 5% ruthenium supported on carbon during the hydrogenation process. The base used for hydrogenation is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. More preferably, the base used is selected from sodium hydroxide and sodium bicarbonate.

[0033] Furthermore, in a preferred embodiment, the recovery and recycling of the ruthenium catalyst used in the method for preparing the compound shown in formula (A) is described. After the reaction is complete, the reactants are filtered, and the catalyst is recovered under nitrogen. The recovered catalyst is washed with water, and the recycled catalyst can be used as fresh catalyst for the next batch.

[0034] This method is implemented with optimal efficiency, thereby achieving effective recovery and recycling of >90% of the catalyst used.

[0035] In another aspect, the present invention relates to the synthesis of the compound shown in formula (I) by resolving indoline-2-carboxylic acid as shown in formula (II).

[0036]

[0037] In one embodiment, the synthesis of the compound shown in formula (I) by resolving indoline-2-carboxylic acid as shown in formula (II) includes the following steps:

[0038] a. Add the compound of formula (II) to a solution of (R)-(+)-α-methylbenzylamine in a predetermined solvent having a predetermined water content;

[0039]

[0040] b. Heat the reaction mixture at a predetermined temperature;

[0041] c. Gradually cool the reactants to the predetermined temperature;

[0042] d. Separation of the (R)-α-methylbenzylamine salt of the (S)-isomer shown in formula (I-SA) by filtration;

[0043]

[0044] e. React the compound of formula (I-SA) with a predetermined acid or base in an aqueous medium to form the compound of formula (I);

[0045]

[0046] f. Separation and racemization of the (R)-isomer to form the compound represented by formula (II); and

[0047]

[0048] g. Recovery of the resolving agent (R)-α-methylbenzylamine.

[0049] The present invention provides a schematic diagram of the synthesis of the compound shown in formula (I) by resolving indoline-2-carboxylic acid as shown in formula (II).

[0050]

[0051] Option 4

[0052] In one embodiment of the present invention, the predetermined solvent used in step (a) is selected from ethanol and isopropanol, and preferably isopropanol with a predetermined water content of 4-6%.

[0053] In one embodiment of the invention, the heating of the reaction mixture in step (b) is carried out at a predetermined temperature of 50-90 °C, preferably 55-80 °C, more preferably 65-70 °C.

[0054] In one embodiment of the present invention, in step (c), the reactants are gradually cooled from 50-55°C to a predetermined temperature of 30-35°C and stirred.

[0055] In one embodiment of the invention, in step (e), the compound represented by formula (I-SA) is reacted with a predetermined acid selected from HCl, H2SO4 and acetic acid or a predetermined base selected from metal hydroxides, carbonates and ammonia in an aqueous medium to form the compound represented by formula (I).

[0056] In step (f), the separation and racemization of the (R)-isomer to form the compound represented by formula (II) is carried out via two routes.

[0057] In one embodiment, in route 1, the isolation and racemization of the (R)-isomer to form the compound represented by formula (II) is carried out by the following steps:

[0058] i. Distill the filtrate obtained in step (d);

[0059] ii. Add water to the filtrate obtained in step (i);

[0060] iii. Adjust the pH of the reaction mixture to 3.5-4.5 using a predetermined acid selected from HCl, H2SO4 and acetic acid;

[0061] iv. Separation of (R)-isomers by filtration;

[0062] v. Add the (R)-isomer to water and a predetermined base selected from metal hydroxides, carbonates and ammonia;

[0063] vi. Heat to a predetermined temperature of 135-175 °C with stirring for a predetermined time of 3-10 hours;

[0064] vii. Gradually cool the reactants to a predetermined temperature of 30-35 °C, and adjust the pH to 3.5-4.5 using a predetermined acid selected from HCl, H₂SO₄, and acetic acid; and

[0065] viii. Separate the compound shown in formula (II) by filtration.

[0066] In another embodiment, in route 2, the separation and racemization of the (R)-isomer to form the compound represented by formula (II) is carried out by the following steps:

[0067] i. Distill the filtrate obtained in step (d);

[0068] ii. Add water to the filtrate obtained in step (i);

[0069] iii. Adjust the pH of the reaction mixture to 10-12 using a predetermined base selected from metal hydroxides, carbonates, and ammonia;

[0070] iv. Separation of (R)-α-methylbenzylamine by extraction with a suitable solvent;

[0071] v. Adjust the pH of the reaction mixture to 3.5-4.5 using a predetermined acid selected from HCl, H2SO4 and acetic acid;

[0072] vi. To separate (R)-isomers by filtration;

[0073] vii. Add the (R)-isomer to water and a predetermined base selected from metal hydroxides, carbonates and ammonia;

[0074] viii. Heat to a predetermined temperature of 135-175 °C with stirring for a predetermined time of 3-10 hours;

[0075] ix. Gradually cool the reactants to a predetermined temperature of 30-35 °C, and adjust the pH to 3.5-4.5 using a predetermined acid selected from HCl, H₂SO₄, and acetic acid; and

[0076] x. Separate the compound shown in formula (II) by filtration.

[0077] The method includes recovering the resolving agent (R)-α-methylbenzylamine via two pathways in step (g).

[0078] In pathway 1, the resolving agent (R)-α-methylbenzylamine is recovered through the following steps:

[0079] i. Using a predetermined base selected from metal hydroxides, carbonates and ammonia, adjust the predetermined pH of the filtrate obtained in steps (e) and (iv) of route 1, by separating and racemicizing the (R)-isomer to form the compound shown in formula (II), to 10-12.

[0080] ii. Add a suitable organic solvent to the reaction mixture obtained in the above steps and stir;

[0081] iii. Separate the layers by distilling the organic layer under vacuum; and

[0082] iv. To separate pure (R)-α-methylbenzylamine from the distillation product.

[0083] In pathway 2, the resolving agent (R)-α-methylbenzylamine is recovered through the following steps:

[0084] i. Distillation of the organic layer under vacuum; and

[0085] ii. Pure (R)-α-methylbenzylamine is separated from the material obtained by distillation.

[0086] From the following detailed description of some embodiments, those skilled in the art and others will be able to clearly understand these and other embodiments. However, it should be understood that the content and specific embodiments of this invention are merely illustrative of some examples of various embodiments and are not intended to limit the claimed invention. The following examples are used to illustrate the invention but do not constitute a limitation thereof. Example

[0087] Example 1

[0088] Preparation of 1-acetylindoline-2-carboxylic acid

[0089] Triethylamine (74 ml) and 4-dimethylaminopyridine (1 g) were added to acetone (400 ml), and the mixture was stirred at 30-35 °C for 10 minutes. The temperature was raised to 40-45 °C, and indole-2-acetic acid was added in portions over approximately 60 minutes. The mixture was stirred at 45 °C for 45 minutes. The reactants were then cooled to 15-20 °C, and acetic anhydride (95.01 g) was slowly added, with stirring at 15-20 °C for 1-2 hours. The reactants were quenched in a separate HCl aqueous solution prepared by mixing concentrated HCl (100 ml) with water (700 ml) at 5-10 °C. The mixture was stirred for 30 minutes and filtered. The solid was washed with water (100 ml). The precipitate was dried under vacuum at 50-55 °C for 7-8 hours to give 1-acetylindoline-2-carboxylic acid (112 g, 88% yield).

[0090] Example 2

[0091] Preparation of 1-acetylindoline-2-carboxylic acid

[0092] Add 1 g of 5% wet Pd / C catalyst to the mixture of 1-acetylindoline-2-carboxylic acid (100 g) and acetic acid (750 ml) separated in Example 1. Stir the reaction mixture at 30-35 °C for 10-15 minutes. Apply hydrogen pressure (8 kg), heat the mixture to 70-72 °C, and stir for 2-3 hours. Filter the material through a Hyflow bed and wash with acetic acid (100 ml). Remove the solvent from the filtrate by vacuum distillation at 75-80 °C. Cool the material to 55-60 °C and add water (100 ml). Stir the material at 55-60 °C for 30 minutes and cool to 30-35 °C. Filter the material and dry it. Suspend the resulting wet solid in ethyl acetate (200 ml) and raise the temperature to 55-60 °C. Stir the reaction mixture for 30 minutes and cool to 30-35 °C. The reactants were further cooled to 5-10 °C and stirred for 60 minutes. The reactants were filtered, washed with ethyl acetate (50 ml), and dried. The solid was further dried under vacuum at 50-55 °C for 8 hours to give 1-acetylindoline-2-carboxylic acid (88 g, 88%).

[0093] Example 3

[0094] Preparation of indoline-2-carboxylic acid

[0095] At 30-35 °C, 100 g of 1-acetylindoline-2-carboxylic acid obtained in Example 2 was added to concentrated HCl (250 ml), and the mixture was stirred for 15-16 hours. The pH was adjusted to 3.8-4.1 with an aqueous sodium hydroxide solution, and the material was stirred at 10-15 °C for 60 minutes. The slurry was filtered, washed with water (50 ml × 2), and blotted dry. The solid was further vacuum dried at 50-55 °C for 8 hours to obtain indoline-2-carboxylic acid (75.7 g, 95.2%).

[0096] Example 4

[0097] Preparation of (2S)-indoline-2-carboxylic acid (I)

[0098] a. Preparation of (R)-(+)-α-methylbenzylamine salt (I-SA) of (2S)-indoline-2-carboxylic acid :

[0099] At 30-35 °C, (R)-(+)-α-methylbenzylamine (RAMBA) (371.1 g) was added to a mixture of IPA (5000 ml) and water (200 ml). The reaction mixture was stirred for 15 minutes. The temperature of the mixture was raised to 65-70 °C and stirred for 15 minutes. Indoline-2-carboxylic acid (500 g) prepared in Example 3 was added in portions to the above reactants over approximately 60-75 minutes at 65-70 °C. The reaction mixture was stirred at 65-70 °C for 60 minutes. The mixture was gradually cooled to 50-55 °C and stirred for 4 hours. The mixture was further cooled to 30-32 °C and stirred for 3 hours. The resulting slurry was filtered and washed with IPA (250 ml). Filtrate 1 was reserved for the recovery of other isomers. The (R)-(+)-α-methylbenzylamine salt of (2S)-indoline-2-carboxylic acid was dried by suction and further vacuum dried for 5-6 hours (dry weight 250g).

[0100] b.1. Preparation of (2S)-indoline-2-carboxylic acid (I) :

[0101] At 30-35 °C, (R)-(+)-α-methylbenzylamine salt (250 g) of (2S)-indoline-2-carboxylic acid was added to water (750 ml). The pH was adjusted to 3.8-4.0 with concentrated HCl. The reaction mixture was stirred at 30-35 °C for 60 minutes, and then the slurry was filtered. The resulting filtrate 2 was reserved as the resolving agent (R)-(+)-α-methylbenzylamine. The obtained (2S)-indoline-2-carboxylic acid (I) was washed with water (125 ml) and dried. The solid was further dried under vacuum at 50-55 °C for 8 hours to obtain indoline-2-carboxylic acid (135 g, 27%).

[0102] 2. Preparation of (2S)-indoline-2-carboxylic acid (I) :

[0103] At 30-35 °C, (R)-(+)-α-methylbenzylamine salt (250 g) of (2S)-indoline-2-carboxylic acid was added to water (750 ml). The pH was adjusted to 10-12 with 30% NaOH aqueous solution. MDC (500 ml) was added and stirred for 15 minutes. The aqueous layer was separated and cooled to 10-15 °C, and the pH was adjusted to 3.8-4.0. The reaction mixture was stirred at 30-35 °C for 60 minutes, and the slurry was filtered. The resulting (2S)-indoline-2-carboxylic acid (I) was washed with water (125 ml) and dried. The solid was further vacuum dried at 50-55 °C for 8 hours to obtain (2S)-indoline-2-carboxylic acid (130 g, 26%).

[0104] c.1. Recovery of R-(+)-α-methylbenzylamine :

[0105] Take the filtrate from Example 4.b.1 and adjust the pH to 10-12 with a 30% sodium hydroxide aqueous solution. Add MDC (250 ml) and stir for 15 minutes. Separate the layers. Extract the aqueous layer again with MDC (250 ml). Wash the combined MDC layers with water (200 ml). Distill the organic layer at a temperature below 50 °C to remove the solvent, and then distill R-(+)-α-methylbenzylamine under vacuum conditions below 120 °C and NLT 650 mm Hg.

[0106] 2. Recovery of R-(+)-α-methylbenzylamine :

[0107] The organic layer from Example 4.b.2 was distilled to remove the solvent at a temperature below 50 °C, and then R-(+)-α-methylbenzylamine was distilled under vacuum conditions below 120 °C and NLT 650 mmHg.

[0108] Example 5

[0109] Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A)

[0110] Sodium bicarbonate (51.5 g) was added to water (700 ml) and stirred to obtain a clear solution, thus preparing a sodium bicarbonate solution. (2S)-indoline-2-carboxylic acid (I) (100 g) obtained in Example 4.b.1 was added in portions to the prepared sodium bicarbonate solution at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reactants. A hydrogen pressure of 20-22 kg was applied at 30-35 °C. The temperature was raised to 80-85 °C, and the mixture was stirred for 4-6 hours. The reactants were cooled to 30-35 °C, the hydrogen pressure was released, and the mixture was filtered. The filtered catalyst was washed with water (100 ml) and stored under nitrogen. The catalyst can be reused in the next batch.

[0111] The filtrate was washed with MDC (200 ml), and the pH of the aqueous layer was adjusted to 4.5 with dilute sulfuric acid. The resulting aqueous layer was washed with MDC (200 ml). The layers were separated, and the aqueous layer was concentrated under vacuum. Methanol (1000 ml) was added, and the hot mixture was stirred for 1–1.5 hours. The reaction mixture was filtered to remove inorganic matter and washed with methanol. The filtrate was vacuum distilled at 50–55 °C to obtain the residue. Acetone (700 ml) was added to the residue at 30–35 °C, and the mixture was refluxed for 1–1.5 hours. The reaction mixture was cooled to 30–35 °C, and then further gradually cooled to 15–20 °C. The mixture was stirred for 2 hours and filtered. The resulting solid was vacuum dried at 55–60 °C for 7–8 hours to give (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 g, 82%).

[0112] HPLC purity: 99.2%

[0113] Chiral purity: 98.5%

[0114] Example 6

[0115] Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A)

[0116] Sodium hydroxide (24.53 g) was added to water (700 ml) and stirred to obtain a clear solution, thus preparing a sodium hydroxide solution. (2S)-indoline-2-carboxylic acid (I) (100 g) obtained in Example 4b was added in portions to the prepared sodium hydroxide solution at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reactants. A hydrogen pressure of 20-22 kg was applied at 30-35 °C. The temperature was raised to 80-85 °C, and the mixture was stirred for 4 hours. The reactants were cooled to 30-35 °C, the hydrogen pressure was released, and the mixture was filtered. The filtered catalyst was washed with water (100 ml) and stored under nitrogen. This catalyst can be reused in the next batch.

[0117] The filtrate was washed with MDC (200 ml), and the pH of the aqueous layer was adjusted to 4.5 with dilute sulfuric acid. The resulting aqueous layer was washed with MDC (200 ml). The layers were separated, and the aqueous layer was concentrated under vacuum. Methanol (1000 ml) was added, and the hot mixture was stirred for 1–1.5 hours. The reaction mixture was filtered to remove inorganic matter and washed with methanol. The filtrate was vacuum distilled at 50–55 °C to obtain the residue. Acetone (700 ml) was added to the residue at 30–35 °C, and the mixture was refluxed for 1–1.5 hours. The reaction mixture was cooled to 30–35 °C, and then further gradually cooled to 15–20 °C. The mixture was stirred for 2 hours and filtered. The resulting solid was vacuum dried at 55–60 °C for 7–8 hours to give (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (82.5 g, 80%).

[0118] HPLC purity: 99.3%

[0119] Chiral purity: 98.4%

[0120] Example 7

[0121] Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A)

[0122] Sodium hydroxide (24.53 g) was added to water (700 ml) and stirred to obtain a clear solution, thus preparing a sodium hydroxide solution. (2S)-indoline-2-carboxylic acid (I) (100 g) obtained in Example 4b was added in portions to the prepared sodium hydroxide solution at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reactants. A hydrogen pressure of 20-22 kg was applied at 30-35 °C. The temperature was raised to 80-85 °C, and the mixture was stirred for 4-6 hours. The reactants were cooled to 30-35 °C, the hydrogen pressure was released, and the mixture was filtered. The filtered catalyst was washed with water (100 ml) and stored under nitrogen. This catalyst will be reused in the next batch. The recovered catalyst weighed 9 g.

[0123] The filtrate was placed in a clean, dry RBF container, and the pH was adjusted to 4.5 with dilute sulfuric acid. The resulting reaction mixture was concentrated under vacuum. Methanol (1000 ml) was added, and the hot mixture was stirred for 1–1.5 hours. The reaction mixture was filtered to remove inorganic matter and washed with methanol. The filtrate was vacuum distilled at 50–55 °C to obtain the residue. 1,4-dioxane (1000 ml) and water (200 ml) were added to the residue at 30–35 °C, and the mixture was refluxed for 1–1.5 hours. The reaction mixture was cooled to 30–35 °C, stirred for 2 hours, and filtered. The resulting solid was vacuum dried at 55–60 °C for 7–8 hours to give (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 g, 82%).

[0124] HPLC purity: 99.9%

[0125] Chiral purity: 98.8%

[0126] Example 8

[0127] (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) was prepared using a recycled catalyst.

[0128] The catalyst was recovered and recycled for use in the next batch containing (2S)-indoline-2-carboxylic acid (100 g). The recovered 5% Ru / C catalyst and fresh 5% Ru / C catalyst (1 g) were added, and the process was carried out according to the method described in Example 5.

[0129] Similarly, a series of experiments were conducted using the recycled catalyst, and the results are summarized in the table below.

[0130] Table 1: Catalyst recycling study with fresh catalyst replenishment

[0131]

[0132] The catalyst was recycled 10 times, with 1% fresh catalyst added each time. The reaction proceeded smoothly, and the catalyst efficiency did not decrease. The recovered catalyst was stored for one month and then used again in the reaction. As shown in the table above, the product formation rate was >85%. Furthermore, a catalyst recycling study was conducted without adding fresh catalyst. Using the recovered catalyst without adding fresh catalyst resulted in a smooth reaction.

[0133] Table 2: Catalyst recycling study without replenishment of fresh catalyst

[0134]

[0135] Based on the above observations, we can conclude that the catalyst can be recycled regardless of whether fresh catalyst is added. Furthermore, the number of cycles can be increased regardless of the addition of fresh catalyst. Recycling significantly reduces catalyst costs, requiring only 10% of the fresh catalyst load to be replenished per batch.

[0136] Example 9

[0137] Effect of moisture content on yield and chiral purity

[0138] The table below shows the effect of moisture content on yield and chiral purity:

[0139]

[0140] In the context of this invention, the method provides higher chiral purity and higher yield of the compound represented by formula (A), without a large amount of undesirable byproducts. Furthermore, the method for preparing the compound represented by formula (A) is industrially and economically feasible due to the recyclability and reusability of the catalyst and resolving agent (R)-(+)-α-methylbenzylamine, and its higher efficiency.

[0141] Furthermore, in the method of this invention, >90% of the catalyst is efficiently recovered and recycled as fresh catalyst. This makes the method economically feasible, as the recovery and recycling of the catalyst can significantly reduce catalyst costs.

[0142] The selected and described embodiments are intended to best explain the principles of the invention and its practical application, thereby enabling those skilled in the art to fully utilize the invention and its various embodiments, and to make various modifications according to specific uses.

[0143] It should be understood that, depending on the specific requirements or for ease of understanding, certain omissions or equivalent substitutions may be made to the content described, but these adjustments are all intended to cover the application or implementation of the present invention and do not depart from the protection scope of the present invention.

Claims

1. A method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid as shown in formula (A), Includes the following steps: In the presence of a metal catalyst and a base, at a predetermined temperature and pressure, the compound shown in formula (I) is hydrogenated in an aqueous medium to form the compound shown in formula (A). 。 2. The method according to claim 1, wherein, The base used for hydrogenation in step (a) is selected from hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals.

3. The method according to claims 1 and 2, wherein, The base used for hydrogenation in step (a) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, and potassium carbonate.

4. The method according to claim 1, wherein, The hydrogenation process in step (a) is carried out at a predetermined hydrogen pressure of 15-30 kg.

5. The method according to claim 1, wherein, The catalyst used in the hydrogenation process in step (a) is 1-15% ruthenium supported on carbon.

6. The method according to claim 1, wherein, The catalyst loading in the hydrogenation process in step (a) is 1-10%.

7. The method according to claim 1, wherein, The hydrogenation process in step (a) is carried out at a predetermined temperature of 60-140 °C.

8. The method according to any one of the preceding claims, wherein, The method also includes the recovery and reuse of the metal catalysts used in the process.

9. The method according to claim 1, wherein, The preparation of the compound shown in formula (I) by resolving indoline-2-carboxylic acid as shown in formula (II) includes the following steps: a. Add the compound of formula (II) to a solution of (R)-(+)-α-methylbenzylamine in a predetermined solvent having a predetermined water content; b. Heat the reaction mixture at a predetermined temperature; c. Gradually cool the reactants to the predetermined temperature; d. Separation of the (R)-α-methylbenzylamine salt of the (S)-isomer shown in formula (I-SA) by filtration; e. React the compound of formula (I-SA) with a predetermined acid or base in an aqueous medium to form the compound of formula (I); f. Separation and racemization of the (R)-isomer to form the compound represented by formula (II); and g. Recovery of the resolving agent (R)-α-methylbenzylamine.

10. The method according to claim 9, wherein, The process of adding the compound of formula (II) to the (R)-(+)-α-methylbenzylamine solution in step (a) is carried out using a predetermined solvent selected from ethanol and isopropanol.

11. The method according to claim 10, wherein, The predetermined solvent is isopropanol with a water content of 4-6%.

12. The method according to claim 9, wherein, The heating of the reaction mixture in step (b) is carried out at a predetermined temperature of 50-90°C.

13. The method according to claim 9, wherein, In step (c), the reactants are gradually cooled at a predetermined temperature of 30-35°C and stirred.

14. The method according to claim 9, wherein, The predetermined acid in step (e) is selected from HCl, H2SO4 and acetic acid; the predetermined base is selected from metal hydroxides, carbonates and ammonia, to form the compound of formula (I) in an aqueous medium.

15. The method according to claim 9, wherein, The process of isolating and racemicizing the (R)-isomer to form the compound represented by formula (II) includes the following steps: i. Distill the filtrate obtained in step (d); ii. Add water to the filtrate obtained in step (i); iii. Adjust the pH of the reaction mixture to a predetermined value of 3.5-4.5 using an acid selected from HCl, H2SO4 and acetic acid; iv. Separation of (R)-isomers by filtration; v. Add the (R)-isomer to water and a base selected from metal hydroxides, carbonates and ammonia; vi. Heat to a temperature of 135-175°C with stirring for a predetermined time of 3-10 hours; vii. Gradually cool the reactants to a temperature of 30-35 °C, and adjust the pH to 3.5-4.5 using an acid selected from HCl, H₂SO₄, and acetic acid; and viii. Separate the compound shown in formula (II) by filtration.

16. The method according to claim 9, wherein, The process of isolating and racemicizing the (R)-isomer to form the compound represented by formula (II) includes the following steps: i. Distill the filtrate obtained in step (d); ii. Add water to the filtrate obtained in step (i); iii. Adjust the pH of the reaction mixture to a predetermined value of 10-12 using a base selected from metal hydroxides, carbonates, and ammonia; iv. Separation of (R)-α-methylbenzylamine by extraction with a suitable solvent; v. Adjust the pH of the reaction mixture to 3.5–4.5 using an acid selected from HCl, H₂SO₄, and acetic acid; vi. To separate (R)-isomers by filtration; vii. Add the (R)-isomer to water and a base selected from metal hydroxides, carbonates and ammonia; viii. Heat to 135-175 ℃ with stirring for 3-10 hours; ix. Gradually cool the reactants to 30-35 °C, and adjust the pH to 3.5-4.5 using an acid selected from HCl, H₂SO₄, and acetic acid; and x. Separate the compound shown in formula (II) by filtration.

17. The method according to claims 1 and 9, wherein, The recovery of the resolving agent (R)-α-methylbenzylamine includes the following steps: i. Using a base selected from metal hydroxides, carbonates and ammonia, adjust the predetermined pH of the filtrate obtained in steps (e) and (iv) by separating and racemicizing the (R)-isomer to form the compound shown in formula (II) to 10-12; ii. Add a suitable organic solvent to the reaction mixture obtained in the above steps and stir; iii. Separate the layers by distilling the organic layer under vacuum; and iv. To separate pure (R)-α-methylbenzylamine from the distillation product.

18. The method according to claims 1 and 9, wherein, The recovery of the resolving agent (R)-α-methylbenzylamine includes the following steps: i. Distillation of the organic layer under vacuum; and ii. Pure (R)-α-methylbenzylamine is separated from the material obtained by distillation.

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