Method for preparing (2S,3AS,7AS)-octahydro-1H-indole-2-carboxylic acid
The method addresses the inefficiencies of existing synthesis methods by using hydrogenation with a recyclable ruthenium catalyst and (R)-(+)-α-methylbenzylamine, achieving high chiral purity and yield for (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid suitable for industrial applications.
Patent Information
- Application Number
- JP2025562110
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-04-25
- Filing Date
- 2024-04-22
- Publication Date
- 2026-04-30
AI Technical Summary
Existing methods for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid are unsatisfactory in terms of purity, yield, cost, and recyclability of the hydrogenation catalyst, making them inefficient for industrial applications.
A method involving hydrogenation of (2S)-indoline-2-carboxylic acid in an aqueous solvent with a metal catalyst, such as ruthenium on carbon, and alkali at controlled temperatures and pressures, followed by recovery and recycling of the catalyst, along with the use of (R)-(+)-α-methylbenzylamine for stereospecific synthesis.
The method achieves high chiral purity and yield with reduced catalyst costs through efficient recovery and recycling, making it suitable for industrial-scale production.
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Abstract
Description
Technical Field
[0004]
[0001] The present invention relates to a method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid, and more particularly, to an improved method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A) with high chiral purity, high yield, and high industrial applicability.
Background Art
[0002] (2S,3aS,7aS)-Octahydro-1H-indole-2-carboxylic acid of the compound of formula (A) is an important intermediate compound that forms the core structure of antihypertensive drugs such as perindopril and its salts, as well as antiviral drugs such as odalasvir and its salts.
Chemical Formula
[0003] Compound (A) exists as eight stereoisomers, and the (2S,3aS,7aS)-isomer is the most important in the activity of these drugs. Various attempts for the synthesis of this isomer using chemical decomposition and enzymatic decomposition have been reported.
[0004] U.S. Patent No. 4,935,525 to Michel Vincent, Bagneux et al. discloses the preparation of the compound of formula (A) shown in Scheme 1 below.
Chemical Formula
[0005] This method involves the preparation of the ethyl ester of indole-2-carboxylic acid. The ethyl ester of indole-2-carboxylic acid is hydrogenated with tin hydrochloric acid to form (R,S)-ethoxycarbonylindoline, and the S-isomer is separated using α-methylbenzylamine. The (S)-ethoxycarbonyl is then hydrogenated with platinum, nickel, palladium, or rhodium, particularly 5% rhodium, to form compound (A). The desired (2S,3aS,7aS)-isomer is separated from the (2S,3aR,7aR)-isomer by crystallization from lower aliphatic alcohols, acetonitrile, dioxane, and ethyl acetate, either individually, in combination with each other, or in combination with water. However, the above method does not provide details regarding the purity of the (S,S,S)-stereoisomer.
[0006] The cited reference "Efficient access to N-protected derivatives of (R,R,R)-and(S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution" in "Tetrahedron: Asymmetry," Volume 18, Issue 19, September 27, 2007, pp. 2358-2364, by Carlos Cativiela et al., discloses the hydrogenation of indoline-2-carboxylic acid in acetic acid in the presence of PtO2, as shown in Scheme 2 below. [ka]
[0007] In the hydrogenation reaction, the solvent is evaporated and the resulting residue is crystallized first from ethanol, and then from a dioxane-water mixture, to obtain a racemic white solid. The reported time for the completion of the reaction is 24 hours. The N-Boc protected benzyl ester of this chiral compound is further subjected to HPLC degradation on a chiral column.
[0008] Chen Weiren et al.'s PCT application, International Publication No. 2007062865, discloses the catalytic hydrogenation of ethyl(S)-indoline-2-carboxylate hydrochloride using Pd / C in ethanol. The reaction mixture is hydrogenated at 60°C and 50 bar with stirring until hydrogen is consumed. After filtering the catalyst, the filtrate is hydrolyzed with sodium hydroxide. After workup, (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid is isolated and obtained as a white powder in 40% yield.
[0009] U.S. Patent No. 7,666,896 by Rajendra Narayanrao Kankan et al. discloses a method for preparing (2S,3aS,7aS)-octahydroindole-2-carboxylic acid by hydrogenation of (S)-indoline-2-carboxylic acid in an alkaline solvent at a pressure of 5 to 20 bar in the presence of rhodium / alumina at 50°C.
[0010] Methods known in the art for preparing the compound of formula (A) are unsatisfactory in terms of the cost, recyclability, and reuse of the hydrogenation catalyst.
[0011] Therefore, an improved method for preparing the compound of formula (A) is needed that yields a high-purity final product without substantial amounts of undesirable by-products. A method for preparing the compound of formula (A) with higher yield, industrial scalability, and cost-effectiveness is also needed. [Overview of the project]
[0012] The present invention describes a method for preparing the compound of formula (A). More specifically, one aspect of the present invention relates to the stereospecific synthesis of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A), and another aspect of the present invention relates to the synthesis of the compound of formula (I) by decomposition of indoline-2-carboxylic acid of formula (II). [ka]
[0013] A method for the stereospecific synthesis of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A) involves hydrogenating the compound of formula (I) in an aqueous solvent in the presence of a metal catalyst and an alkali to form the compound of formula (A).
[0014] A method for synthesizing the compound of formula (I) by decomposing the indoline-2-carboxylic acid of formula (II) comprises several steps. This method includes 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; isolating the (S)-isomer (R)-α-methylbenzylamine salt of formula (I-SA) by filtration; reacting the compound of formula (I-SA) with a predetermined acid or alkali to form the compound of formula (I) in an aqueous solvent, followed by isolating the (R)-isomer and racemizing it to form the compound of formula (II); and recovering the decomposition agent (R)-α-methylbenzylamine. [Modes for carrying out the invention]
[0015] Any reference in this specification to “one embodiment” or “embodiment” means that certain features, structures, characteristics, or functions described in relation to an embodiment are included in at least one embodiment of the present invention. The phrase “in one embodiment” appearing in various parts of this specification does not necessarily refer to the same embodiment.
[0016] In this specification, references to “preferred embodiments” mean specific features, structures, properties, or functions that are described in detail, thereby omitting known configurations and functions for the sake of clarity in describing the invention.
[0017] The above description of specific embodiments of the present invention is presented for illustrative and explanatory purposes only. They are not intended to be exhaustive or to limit the invention to the exact forms disclosed, and of course, many modifications and variations are possible considering the teachings above.
[0018] The inventors of the present invention have developed a method for preparing a compound of formula (A) that provides a higher yield of the compound (A) and is efficient in the recovery and reuse of the catalyst in the method. This method has a higher chiral purity and is cost-effective even in larger-scale production.
[0019] In one aspect, the present invention relates to the stereospecific synthesis of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A).
Chemical formula
[0020] The stereospecific synthesis of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A) includes the following. Hydrogenating (2S)-indoline-2-carboxylic acid of formula (I) in an aqueous solvent at a predetermined temperature and a predetermined pressure in the presence of a metal catalyst and an alkali to form a compound of formula (A).
Chemical formula
[0021] In this embodiment of the present invention, the alkali used for the hydrogenation in step (a) is selected from hydroxides, carbonates, and bicarbonates of alkali metals or alkaline earth metals. The metal catalyst used for the hydrogenation in step (a) is ruthenium supported on carbon. The hydrogenation is carried out at a predetermined temperature of 60 - 140°C, preferably 70 - 110°C, under a predetermined hydrogen pressure of 15 - 30 kg, preferably 20 - 25 kg.
[0022] In preferred embodiments, hydrogenation is carried out in a wet catalyst addition of 1-10%, preferably using 5% carbon-supported ruthenium. The alkali used for hydrogenation is preferably selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. More preferably, the alkali used is selected from sodium hydroxide and sodium bicarbonate.
[0023] Furthermore, in a preferred embodiment, the recovery and recycling of the ruthenium catalyst used in the preparation of the compound of formula (A) is described. After the reaction is complete, the reaction mass is filtered and the catalyst is recovered under nitrogen. The recovered catalyst is washed with water, and the recycled catalyst is used as a new catalyst in the next batch.
[0024] This method is performed with optimal efficiency, leading to the efficient recovery and recycling of over 90% of the catalyst used.
[0025] In another aspect, the present invention relates to the synthesis of the compound of formula (I) by decomposing the indoline-2-carboxylic acid of formula (II). [ka]
[0026] In one embodiment, the synthesis of the compound of formula (I) by decomposing the indoline-2-carboxylic acid of formula (II) includes the following steps. a. Adding the compound of formula (II) to solution (R)-(+)-α-methylbenzylamine in a predetermined solvent having a predetermined water content. [ka] b. Heat the reaction mixture to a predetermined temperature. c. Gradually cool the reaction mixture to a predetermined temperature. d. Isolate the (S)-isomer (R)-α-methylbenzylamine salt of formula (I-SA) by filtration. [ka] e. Reacting a compound of formula (I-SA) with a predetermined acid or alkali to form a compound of formula (I) in an aqueous solvent. [ka] f. Isolation and racemization of the (R)-isomer to form the compound of formula (II), and [ka] g. Recovery of the decomposition agent (R)-α-methylbenzylamine.
[0027] A schematic diagram of the synthesis of the compound of formula (I) by decomposing the indoline-2-carboxylic acid of formula (II) of the present invention is shown below. [ka]
[0028] In one embodiment of the present invention, the predetermined solvent used in step (a) is selected from ethanol and isopropyl alcohol, and preferably the solvent used is isopropyl alcohol having a predetermined water content of 4 to 6%.
[0029] In one embodiment of the present invention, the heating of the reaction mixture in step (b) is carried out at a predetermined temperature of 50 to 90°C, preferably 55 to 80°C, and more preferably 65 to 70°C.
[0030] In one embodiment of the present invention, in step (c), the reaction mass is gradually cooled from 50-55°C to a predetermined temperature of 30-35°C and stirred.
[0031] In one embodiment of the present invention, the reaction of the compound of formula (I-SA) with a predetermined acid in step (e) is selected from HCl, H2SO4, and acetic acid, or the predetermined alkali is selected from metal hydroxides, carbonates, and ammonia, forming the compound of formula (I) in an aqueous solvent.
[0032] The isolation and racemization of the (R)-isomer to form the compound of formula (II) in step (f) is carried out by two routes.
[0033] In one embodiment, in route 1, the isolation and racemization of the (R)-isomer for forming the compound of formula (II) is carried out by 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 3.5-4.5 using a predetermined acid selected from HCl, H2SO4, and acetic acid. iv. Isolate the (R)-isomer by filtration. v. Adding the (R)-isomer to water and a predetermined alkali selected from metal hydroxides, carbonates, and ammonia. vi. Heat to a predetermined temperature of 135-175°C for a predetermined time of 3-10 hours while stirring. vii. Gradually cool the reaction mixture 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 viii. Isolate the compound of formula (II) by filtration.
[0034] In another embodiment, in route 2, the isolation and racemization of the (R)-isomer to form the compound of formula (II) is carried out by 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 10-12 using a predetermined alkali selected from metal hydroxides, carbonates, and ammonia. iv. Isolate (R)-α-methylbenzylamine by extraction using a suitable solvent. v. Adjust the pH of the reaction mixture to 3.5-4.5 using a predetermined acid selected from HCl, H2SO4, and acetic acid. vi. Isolate the (R)-isomer by filtration. vii. Adding the (R)-isomer to water and a predetermined alkali selected from metal hydroxides, carbonates, and ammonia. viii. Heat to a predetermined temperature of 135-175°C for a predetermined time of 3-10 hours while stirring. ix. Gradually cool the reaction mixture 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 x. Isolate the compound of formula (II) by filtration.
[0035] This method includes the recovery of the decomposition agent (R)-α-methylbenzylamine in step (g) via two routes.
[0036] In Route 1, the recovery of the decomposition agent (R)-α-methylbenzylamine is carried out by the following steps. i. Adjust the pH of the filtrate obtained in step (e) and step (iv) of the (R)-isomer isolation and racemization route 1 for forming the compound of formula (II) to 10-12 using a predetermined alkali selected from metal hydroxides, carbonates, and ammonia. ii. Add an appropriate organic solvent to the reaction mixture obtained in the above step and stir. iii. Separate the layers and distill the organic layer under vacuum, and iv. Isolate pure (R)-α-methylbenzylamine by distillation of the obtained mass.
[0037] In route 2, the recovery of the decomposition agent (R)-α-methylbenzylamine is carried out by the following steps. i. Distilling organic layers under vacuum, and ii. Isolate pure (R)-α-methylbenzylamine by distillation of the obtained mass. [Examples]
[0038] These and other embodiments will become apparent to those skilled in the art and others, given the following detailed descriptions of some embodiments. However, it should be understood that this summary and detailed description are merely illustrative of some examples of various embodiments and are not intended to limit the claimed invention. The following examples illustrate, but do not limit, the invention.
[0039] Example 1 Preparation of 1-acetylindoline-2-carboxylic acid 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 batches over approximately 60 minutes. The mixture was stirred at 45°C for 45 minutes. The reaction mixture was then cooled to 15-20°C, acetic anhydride (95.01 g m) was slowly added, and the mixture was stirred at 15-20°C for 1-2 hours. An aqueous HCl solution was prepared separately by mixing concentrated HCl (100 ml) with water (700 ml) at 5-10°C, and the reaction mixture was quenched in this aqueous HCl solution. 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 obtain 1-acetylindoline-2-carboxylic acid (112 gm, yield 88%).
[0040] Example 2 Preparation of 1-acetylindoline-2-carboxylic acid 1 gm of 5% wet Pd / C was added to a mixture of 1-acetylindoline-2-carboxylic acid (100 gm) isolated in Example 1 and acetic acid (750 ml). The reaction mixture was stirred at 30-35°C for 10-15 minutes. Hydrogen gas pressure (8 kg) was added, and the mixture was heated to 70-72°C and stirred for 2-3 hours. The mixture was filtered through a high-flow bed and washed with acetic acid (100 ml). The solvent was removed from the filtrate at 75-80°C under vacuum. The mixture was cooled to 55-60°C and water (100 ml) was added. The mixture was stirred at 55-60°C for 30 minutes and then cooled to 30-35°C. The mixture was filtered and dried by suction. The resulting wet solid was suspended in ethyl acetate (200 ml) and the temperature was raised to 55-60°C. The reaction mixture was stirred for 30 minutes and then cooled to 30-35°C. The reaction mixture was further cooled to 5-10°C and stirred for 60 minutes. The reaction mixture was filtered, washed with ethyl acetate (50 ml), and dried by vacuum. The solid was further dried under vacuum at 50-55°C for 8 hours to obtain 1-acetylindoline-2-carboxylic acid (88 gm, 88%).
[0041] Example 3 Preparation of indoline-2-carboxylic acid 100 gm of 1-acetylindoline-2-carboxylic acid obtained in Example 2 was added to 250 ml of concentrated HCl at 30-35°C, and the mixture was stirred for 15-16 hours. The pH was adjusted to 3.8-4.1 using an aqueous sodium hydroxide solution, and the mixture was stirred at 10-15°C for 60 minutes. The slurry was filtered, washed with water (50 ml x 2), and dried by vacuum. The solid was further dried under vacuum at 50-55°C for 8 hours to obtain indoline-2-carboxylic acid (75.7 gm, 95.2%).
[0042] Example 4 Preparation of (2S)-indoline-2-carboxylic acid (I) a. Preparation of (R)-(+)-α-methylbenzylamine salt (I-SA) of (2S)-indoline-2-carboxylic acid: (R)-(+)-α-methylbenzylamine (RAMBA) (371.1 gm) was added to a mixture of IPA (5000 ml) and water (200 ml) at 30-35°C. 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 gm) prepared in Example 3 was added to the reaction mixture lot by lot at 65-70°C for approximately 60-75 minutes. 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). The resulting filtrate 1 was stored for the recovery of other isomers. The (R)-(+)-α-methylbenzylamine salt of (2S)-indoline-2-carboxylic acid was vacuum-dried and then dried under vacuum for 5-6 hours. (Dry weight 250 g / m²).
[0043] b.1. Preparation of (2S)-indoline-2-carboxylic acid (I): (2S)-indoline-2-carboxylic acid (R)-(+)-α-methylbenzylamine salt (250 gm) was added to water (750 ml) at 30-35°C. The pH was adjusted to 3.8-4.0 using concentrated HCl. The reaction mixture was stirred at 30-35°C for 60 minutes, and the slurry was filtered. The resulting filtrate 2 was stored for the recovery of the decomposing agent (R)-(+)-α-methylbenzylamine. The obtained (2S)-indoline-2-carboxylic acid (I) was washed with water (125 ml) and dried by vacuum. The solid was further dried under vacuum at 50-55°C for 8 hours to obtain indoline-2-carboxylic acid (135 gm, 27%).
[0044] 2. Preparation of (2S)-indoline-2-carboxylic acid (I): (2S)-indoline-2-carboxylic acid (R)-(+)-α-methylbenzylamine salt (250 gm) was added to water (750 ml) at 30-35°C. The pH was adjusted to 10-12 using a 30% NaOH aqueous solution. MDC (500 ml) was added and the mixture was stirred for 15 minutes. The aqueous layer was separated, 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 obtained (2S)-indoline-2-carboxylic acid (I) was washed with water (125 ml) and dried by vacuum. The solid was further dried under vacuum at 50-55°C for 8 hours to obtain (2S)-indoline-2-carboxylic acid (130 gm, 26%).
[0045] c.1. Recovery of R-(+)-α-methylbenzylamine: The filtrate from Example 4.b.1 was taken and the pH was adjusted to 10-12 using a 30% sodium hydroxide aqueous solution. MDC (250 ml) was added and stirred for 15 minutes. The layers were separated. The aqueous layer was extracted again with MDC (250 ml). The mixed MDC layers were washed with water (200 ml). The organic layer was distilled to remove the solvent at a temperature below 50°C, and then R-(+)-α-methylbenzylamine was distilled under vacuum at NLT 650 mmHg at a temperature below 120°C.
[0046] 2. Recovery of R-(+)-α-methylbenzylamine: The organic layer of 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 at NLT 650 mmHg at a temperature below 120°C.
[0047] Example 5 Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) A sodium bicarbonate solution was prepared by adding sodium bicarbonate (51.5 g / m) to water (700 ml) and stirring to obtain a clear solution. (2S)-indoline-2-carboxylic acid(I) (100 g / m) obtained in Example 4.b.1 was added to the sodium bicarbonate solution prepared above, batch by batch at 30-35°C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reaction mixture. 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 reaction mixture was cooled to 30-35°C, the hydrogen pressure was released, and the mixture was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst was reused in the next batch.
[0048] 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 obtained 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 to 1.5 hours. The reaction mixture was filtered to remove inorganic substances and washed with methanol. The filtrate was distilled under vacuum at 50 to 55°C to obtain the residue. Acetone (700 ml) was added to the residue at 30 to 35°C and refluxed for 1 to 1.5 hours. The reaction mixture was cooled to 30 to 35°C, and then gradually cooled to 15 to 20°C. The mixture was stirred for 2 hours and filtered. The obtained solid was dried under vacuum at 55 to 60°C for 7 to 8 hours to obtain (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 gm, 82%). HPLC purity -99.2% Chiral purity: 98.5%
[0049] Example 6 Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) A sodium hydroxide solution was prepared by adding sodium hydroxide (24.53 g / m) to water (700 ml) and stirring to obtain a clear solution. To the sodium hydroxide solution prepared above, (2S)-indoline-2-carboxylic acid (I) (100 g / m) obtained in Example 4b) was added in batches at 30-35°C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reaction mixture. 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 reaction mixture was cooled to 30-35°C, the hydrogen pressure was released, and the mixture was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst will be reused in the next batch.
[0050] 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 obtained 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 to 1.5 hours. The reaction mixture was filtered to remove inorganic substances and washed with methanol. The filtrate was distilled under vacuum at 50 to 55°C to obtain the residue. Acetone (700 ml) was added to the residue at 30 to 35°C and refluxed for 1 to 1.5 hours. The reaction mixture was cooled to 30 to 35°C, and then gradually cooled to 15 to 20°C. The mixture was stirred for 2 hours and filtered. The obtained solid was dried under vacuum at 55 to 60°C for 7 to 8 hours to obtain (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (82.5 gms, 80%). HPLC purity -99.3% Chiral purity: 98.4%
[0051] Example 7 Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) A sodium hydroxide solution was prepared by adding sodium hydroxide (24.53 gm) to water (700 ml) and stirring to obtain a clear solution. To the sodium hydroxide solution prepared above, (2S)-indoline-2-carboxylic acid (I) (100 gm) obtained in Example 4b) was added in batches at 30-35°C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10 g) was added to the reaction mixture. 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 reaction mixture was cooled to 30-35°C, the hydrogen pressure was released, and the mixture was filtered. The catalyst separated by filtration was washed with water (100 ml) and stored under nitrogen. This catalyst will be reused in the next batch. The recovered catalyst weight was 9 gm.
[0052] The filtrate was placed in a clean, dry RBF 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 to 1.5 hours. The reaction mixture was filtered to remove inorganic substances and washed with methanol. The filtrate was distilled under vacuum at 50 to 55°C to obtain the residue. 1,4-dioxane (1000 ml) and water (200 ml) were added to the residue at 30 to 35°C and refluxed for 1 to 1.5 hours. The reaction mixture was cooled to 30 to 35°C, stirred for 2 hours, and filtered. The resulting solid was dried under vacuum at 55 to 60°C for 7 to 8 hours to obtain (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (84.5 gms, 82%). HPLC purity -99.9% Chiral purity: 98.8%
[0053] Example 8 Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) using the recovered catalyst. The catalyst was recovered and recycled into the next batch containing (2S)-indoline-2-carboxylic acid (100 gm). The recovered 5% Ru / C catalyst and a new 5% Ru / C catalyst (1 gm) were added and the process followed the method described in Example 5.
[0054] Similarly, a series of experiments were conducted using the recovered catalyst, and the results are summarized in the table below. [Table 1]
[0055] The catalyst was recycled 10 times, with 1% new catalyst added each time. The reaction proceeded smoothly without any reduction in catalytic efficiency, and the recovered catalyst was stored for one month before being used in the reaction. As shown in the table above, product formation was over 85%. Furthermore, a catalyst recycling study was conducted without adding new catalyst. The reaction proceeded smoothly using the recovered catalyst without the need for new catalyst replenishment. [Table 2]
[0056] Based on the above observations, it can be concluded that the catalyst is recyclable with or without the addition of new catalyst. More cycles were possible with or without the addition of new catalyst. Recycling significantly reduces catalyst costs, and each batch of catalyst consumption requires the addition of 10% new catalyst.
[0057] Example: 9 The effect of moisture content on yield and chiral purity The table below shows the effect of moisture content on yield and chiral purity. [Table 3]
[0058] In the context of the present invention, the method of the present invention provides a compound of formula (A) with higher chiral purity and higher yield, without substantially a large amount of undesirable by-products. Furthermore, the method of the present invention for preparing a compound of formula (A) is industrially and economically feasible for the recyclability and reuse of the catalyst and decomposition agent (R)-(+)-α-methylbenzylamine with higher efficiency.
[0059] Furthermore, in the method of the present invention, more than 90% of the catalyst is recovered and efficiently recycled as a new catalyst. This makes the method economically feasible because the recovery and recycling of the catalyst significantly reduces the cost of the catalyst.
[0060] The embodiments have been selected and described to best illustrate the principles of the present invention and its practical applications, thereby enabling those skilled in the art to best utilize the invention and various embodiments with various modifications suitable for specific intended uses.
[0061] Where circumstances may suggest or may be advantageous, various omissions and substitutions of equivalents are contemplated, but it is understood that these are intended to cover the application or implementation without departing from the scope of the invention.
Claims
1. A method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A), 【Chemistry 1】 The following steps, A method comprising hydrogenating a compound of formula (I) in an aqueous solvent at a predetermined temperature and pressure in the presence of a metal catalyst and an alkali to form a compound of formula (A). 【Chemistry 2】
2. The method according to claim 1, wherein the alkali used in hydrogenation in step (a) is selected from alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates.
3. The method according to claims 1 and 2, wherein the alkali used for hydrogenation in step (a) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and sodium bicarbonate, sodium carbonate, and potassium carbonate.
4. The method according to claim 1, wherein the hydrogenation method in step (a) is carried out under a predetermined hydrogen pressure of 15 to 30 kg.
5. The method according to claim 1, wherein the catalyst used in the hydrogenation method in step (a) is 1 to 15% carbon-supported ruthenium.
6. The method according to claim 1, wherein the amount of catalyst added in the hydrogenation method in step (a) is 1 to 10%.
7. The method according to claim 1, wherein the hydrogenation method in step (a) is carried out at a predetermined temperature of 60 to 140°C.
8. The method according to any one of claims 1 to 7, further comprising recovering and reusing the metal catalyst in the method.
9. The method according to claim 1, wherein the preparation of the compound of formula (I) by decomposing the indoline-2-carboxylic acid of formula (II) is performed in the following steps: a. Adding the compound of formula (II) to solution (R)-(+)-α-methylbenzylamine in a predetermined solvent having a predetermined water content. 【Transformation 3】 b. Heat the reaction mixture to a predetermined temperature. c. Gradually cool the reaction mixture to a predetermined temperature. d. Isolating the (S)-isomer (R)-α-methylbenzylamine salt of formula (I-SA) by filtration. 【Chemistry 4】 e. Reacting a compound of formula (I-SA) with a predetermined acid or alkali to form a compound of formula (I) in an aqueous solvent. 【Transformation 5】 f. Isolation and racemization of the (R)-isomer for forming the compound of formula (II), and 【Transformation 6】 g. Recovery of the decomposition agent (R)-α-methylbenzylamine, Methods that include...
10. The method according to claim 9, wherein the method of step (a) of adding the compound of formula (II) to the solution (R)-(+)-α-methylbenzylamine is carried out using a predetermined solvent selected from ethanol and isopropyl alcohol.
11. The method according to claim 10, wherein the predetermined solvent is isopropyl alcohol having a water content of 4 to 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 to 90°C.
13. The method according to claim 9, wherein the reaction mass in step (c) is gradually cooled at a predetermined temperature of 30 to 35°C and stirred.
14. The predetermined acid in step (e) is HCl, H ２ A predetermined alkali, selected from SO4 and acetic acid, is selected from metal hydroxides, carbonates, and ammonia to form a compound of formula (I) in an aqueous solvent. The method according to claim 9.
15. The isolation and racemization of the (R)-isomer for forming the compound of formula (II) is carried out in the following steps: i. Distill the filtrate obtained in step (d). ii. Add water to the filtrate obtained in step (i). iii. HCl, H ２ SO ４ And adjust the pH of the reaction mixture to 3.5 to 4.5 using an acid selected from acetic acid. iv. Isolate the (R)-isomer by filtration. v. Adding (R)-isomers to water and alkalis selected from metal hydroxides, carbonates, and ammonia. vi. Heat while stirring to a temperature of 135-175°C for a predetermined time of 3-10 hours. vii. Gradually cool the reaction mixture to a temperature of 30-35°C, and add HCl and H ２ SO ４ and adjusting the pH to 3.5-4.5 using an acid selected from acetic acid, viiii. Isolate the compound of formula (II) by filtration. The method according to claim 9, including the method described in claim 9.
16. The isolation and racemization of the (R)-isomer for forming the compound of formula (II) is carried out in 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 level of 10-12 using an alkali selected from metal hydroxides, carbonates, and ammonia. iv. Isolate (R)-α-methylbenzylamine by extraction with a suitable solvent. v. HCl, H ２ SO ４ and adjust the pH of the reaction mixture to 3.5 to 4.5 using an acid selected from acetic acid. vi. Isolate the (R)-isomer by filtration. vii. Adding (R)-isomers to water and alkalis selected from metal hydroxides, carbonates and ammonia, viiii. Heat to a temperature of 135-175°C for 3-10 hours while stirring. ix. Gradually cool the reaction mass to a temperature of 30 to 35 °C and adjust the pH to 3.5 to 4.5 using an acid selected from HCl, H ２ SO ４ and acetic acid, and x. Isolate the compound of formula (II) by filtration. The method according to claim 9, including the method described in claim 9.
17. The recovery of the decomposition agent (R)-α-methylbenzylamine is carried out in the following steps: i. Adjust the pH of the filtrate obtained in step (e) and step (iv) for the isolation and racemization of the (R)-isomer to form the compound of formula (II) to 10-12 using an alkali selected from metal hydroxides, carbonates, and ammonia. ii. Add an appropriate organic solvent to the reaction mixture obtained in the above step and stir. iii. Separating the layers and distilling the organic layer under vacuum, and iv. Isolate pure (R)-α-methylbenzylamine by distillation of the obtained mass. The method according to claims 1 and 9, including the method according to claims 1 and 9.
18. The recovery of the decomposition agent (R)-α-methylbenzylamine is carried out in the following steps: i. Distilling the organic layer under vacuum, and ii. Isolate pure (R)-α-methylbenzylamine by distillation of the obtained mass. The method according to claims 1 and 9, including the method according to claims 1 and 9.