Process for preparation of (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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480036411.8 (22) Application Date 2024.04.22 (30) Priority Data 202321029703 2023.04.25 IN (85) PCT International Application Entering National Phase Date 2025.11.28 (86) PCT International Application Application Data PCT / IN2024 / 050422 2024.04.22 (87) PCT International Application Publication Data WO2024 / 224414 EN 2024.10.31 (71) Applicant: Arti Pharmaceutical Laboratories Ltd. Address: Vapi, India (72) Inventors: P.H. Desai, N.J. Salvi, B.S. Patrawell, M.R. Kulkarni (74) Patent Agency: Shanghai Huacheng Intellectual Property Agency Co., Ltd. 31300 Patent Attorney: Du Juan (51) Int.Cl. C07D 209 / 42 (2006.01) C07C 29 / 136 (2006.01) A61K 31 / 404 (2006.01) B01J 23 / 46 (2006.01) C07D 263 / 44 (2006.01) (54) Invention Title: Method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (57) Abstract: This invention relates to a method for preparing a compound of formula (A). A method for the stereospecific synthesis of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid as shown in formula (A) comprises 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). Furthermore, the present invention also includes a method for synthesizing the compound shown in formula (I) by resolving the indoline-2-carboxylic acid shown in formula (II). The method of the present invention provides the compound shown in formula (A) with higher chiral purity and higher yield, without generating a large amount of undesirable byproducts. The method of the present invention is cost-effective due to the recyclability and reusability of the catalyst and resolving agent (R)-(+)-α-methylbenzylamine, and its higher efficiency. Claims 3 pages, Description 11 pages, CN 121219263 A 2025.12.26 CN 1 21 21 92 63 A 1. A method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid of formula (A), comprising the following steps: hydrogenating the compound of formula (I) in an aqueous medium at a predetermined temperature and a predetermined pressure in the presence of a metal catalyst and a base to form the compound of 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 further comprises recovering and reusing the metal catalyst used in the process. 9. The method according to claim 1, wherein preparing the compound of formula (I) by resolving indoline-2-carboxylic acid of formula (II) comprises the following steps: a. adding the compound of formula (II) to a solution of (R)-(+)-α-methylbenzylamine in a predetermined solvent having a predetermined water content; b. heating the reaction mixture at a predetermined temperature; c. gradually cooling the reactants to a predetermined temperature; d. separating the (R)-α-methylbenzylamine salt of the (S)-isomer of formula (I-SA) by filtration; e. reacting the compound of formula (I-SA) with a predetermined acid or base in an aqueous medium to form the compound of formula (I); f. separating and racemicizing the (R)-isomer to form the compound of formula (II); and g. recovering the resolving agent (R)-α-methylbenzylamine. 10. The method of claim 9, wherein the process of adding the compound of formula (II) to the (R)-(+)-α-methylbenzylamine solution in step (a) is performed using a predetermined solvent selected from ethanol and isopropanol. 11. The method of claim 10, wherein the predetermined solvent is isopropanol with a water content of 4-6%. 12. The method of 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 of claim 9, wherein the gradual cooling of the reactants in step (c) is carried out at a predetermined temperature of 30-35°C, and stirring is performed.14. The method according to claim 9, wherein the predetermined acid in step (e) is selected from HCl, H2SO4 and acetic acid; and 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 separating and racemicizing the (R)-isomer to form the compound represented by formula (II) comprises the following steps: i. distilling the filtrate obtained in step (d); ii. adding water to the filtrate obtained in step (i); iii. adjusting the pH of the reaction mixture to a predetermined pH of 3.5-4.5 using an acid selected from HCl, H2SO4, and acetic acid; iv. separating the (R)-isomer by filtration; v. adding the (R)-isomer to water and a base selected from metal hydroxides, carbonates, and ammonia; vi. heating with stirring to a temperature of 135-175 °C for a predetermined time of 3-10 hours; vii. gradually cooling the reaction mixture to a temperature of 30-35 °C and adjusting the pH to 3.5-4.5 using an acid selected from HCl, H2SO4, and acetic acid; and viii. separating the compound represented by formula (II) by filtration. 16. The method according to claim 9, wherein separating and racemicizing the (R)-isomer to form the compound represented by formula (II) comprises the following steps: i. distilling the filtrate obtained in step (d); ii. adding water to the filtrate obtained in step (i); iii. adjusting the pH of the reaction mixture to a predetermined value of 10-12 using a base selected from metal hydroxides, carbonates, and ammonia; iv. separating (R)-α-methylbenzylamine by extraction with a suitable solvent; v. adjusting the pH of the reaction mixture to 3.5-4.5 using an acid selected from HCl, H2SO4, and acetic acid; vi. separating the (R)-isomer by filtration; vii. adding the (R)-isomer to water and a base selected from metal hydroxides, carbonates, and ammonia; viii. heating to a temperature of 135-175 °C with stirring for 3-10 hours; ix. gradually cooling the reaction mixture to 30-35 °C. The temperature was set at ℃, and the pH was adjusted to 3.5–4.5 using an acid selected from HCl, H2SO4, and acetic acid; and x. The compound shown in formula (II) was separated by filtration.17. The method according to claims 1 and 9, wherein recovering the resolving agent (R)-α-methylbenzylamine comprises the following steps: i. adjusting the pH of the filtrate obtained in steps (e) and (iv) by separating and racemicizing the (R)-isomer to form the compound represented by formula (II) to a predetermined pH of 10-12 using a base selected from metal hydroxides, carbonates, and ammonia; ii. adding a suitable organic solvent to the reaction mixture obtained in the above steps and stirring; iii. separating the layers by distilling the organic layer under vacuum; and iv. separating pure (R)-α-methylbenzylamine by distilling the resulting material. 18. The method according to claims 1 and 9, wherein recovering the resolving agent (R)-α-methylbenzylamine comprises the following steps: i. distilling the organic layer under vacuum; and ii. separating pure (R)-α-methylbenzylamine by distilling the resulting material. Claims 3 / 3 Page 4 CN 121219263 A Method for preparing (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid 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 Art

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

[0003]

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

[0005] US Patent Application US 4,935,525 by Michel Vincent, Bagneux, et al. discloses the preparation of the compound represented by formula (A), as shown in Scheme 1 below.

[0006]

[0007] Scheme 1

[0008] This method relates to the preparation of ethyl indole-2-carboxylate. Ethyl indole-2-carboxylate is hydrogenated with tin-hydrochloric acid to generate (R,S)-ethoxycarbonylindoline, and the S-isomer is separated using α-methylbenzylamine. The (S)-ethoxycarbonyl is then hydrogenated with platinum, nickel, palladium, or rhodium (especially 5% rhodium) to generate 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. Instructions 1 / 11 Page 5 CN 121219263 A

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

[0010]

[0011] Scheme 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 obtain a racemic white solid. The reported reaction completion time was 24 hours. The N-Boc protected benzyl ester of the chiral compound was further resolved by HPLC on a chiral column.

[0013] PCT application WO2007062865 by Chen Weiren et al. 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 the 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 separated to obtain a white powder in a yield of 40%.

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

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

[0016] Therefore, there is a need for an improved method for preparing the compound shown in formula (A) 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 needed. Summary of the Invention

[0017] The present 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 the indoline-2-carboxylic acid shown in formula (II). Specification 2 / 11 pages 6 CN 121219263 A

[0018]

[0019] The stereospecific synthesis method of the intermediate (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid shown in formula (A) comprises: 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 comprises 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 reactants; 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 Description

[0021] The term "one embodiment" or "embodiment" as used in this specification refers to a specific feature, structure, property, 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 in 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, property, or function in detail by omitting known structures and functions, so as to clearly illustrate the invention.

[0023] The above description of specific embodiments of the 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, and various modifications and variations based on the above teachings are obviously feasible.

[0024] The inventors of the present invention have developed a method for preparing the compound represented by formula (A), which provides a higher yield of compound (A) and allows for efficient recovery and reuse of the catalyst in the process. The 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) comprises:

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

[0029]

[0030] Scheme 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 on carbon during hydrogenation. 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 shown in formula (II).

[0036]

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

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

[0039]

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

[0041] c. gradually cooling the reactants to a predetermined temperature;

[0042] d. separating the (R)-α-methylbenzylamine salt of the (S)-isomer shown in formula (I-SA) by filtration; Specification 4 / 11 page 8 CN 121219263 A

[0043]

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

[0045]

[0046] f. Separate and racemate the (R)-isomer to form the compound shown in formula (II); and

[0047]

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

[0049] A schematic diagram of the synthesis of the compound shown in formula (I) by resolving the indoline-2-carboxylic acid shown in formula (II) is shown below. Specification 5 / 11 pages 9 CN 121219263 A

[0050]

[0051] Scheme 4

[0052] In one embodiment of the invention, the predetermined solvent used in step (a) is selected from ethanol and isopropanol, 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 present 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 separation and racemization of the (R)-isomer to form the compound represented by formula (II) is carried out by the following steps:

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

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

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

[0061] iv. separating the (R)-isomer by filtration;

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

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

[0064] vii. gradually cooling the reaction mixture to 30-35 °C. At a predetermined temperature of ℃, the pH value is adjusted to 3.5-4.5 using a predetermined acid selected from HCl, H2SO4 and acetic acid; and

[0065] viii. The compound shown in formula (II) is separated 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: Specification 6 / 11 pages 10 CN 121219263 A

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

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

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

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

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

[0072] vi. Separating the (R)-isomer by filtration;

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

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

[0075] ix. The reactants are gradually cooled to a predetermined temperature of 30-35 °C, and the pH is adjusted to 3.5-4.5 using a predetermined acid selected from HCl, H2SO4 and acetic acid; and

[0076] x. The compound represented by formula (II) is separated by filtration.

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

[0078] In route 1, the recovery of the resolving agent (R)-α-methylbenzylamine is carried out by the following steps:

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

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

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

[0082] iv. separating pure (R)-α-methylbenzylamine by distilling the resulting material.

[0083] In route 2, the recovery of the resolving agent (R)-α-methylbenzylamine is carried out by the following steps:

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

[0085] ii. separating pure (R)-α-methylbenzylamine by distilling the resulting material.

[0086] Given 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 only illustrate 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. Examples

[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 about 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, 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 reactants were 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 vacuum dried at 50-55°C for 7-8 hours to obtain 1-acetylindoline-2-carboxylic acid (112 g, yield 88%).

[0090] Example 2

[0091] Preparation instructions for 1-acetylindoline-2-carboxylic acid, page 7 / 11, CN 121219263 A

[0092] 1 g of 5% wet Pd / C catalyst was added to the mixture of 1-acetylindoline-2-carboxylic acid (100 g) and acetic acid (750 ml) separated in Example 1. The reaction mixture was stirred at 30-35°C for 10-15 minutes.Apply hydrogen pressure (8 kg) and heat the mixture to 70–72 °C, stirring 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. Further cool the reaction mixture to 5–10 °C and stir for 60 minutes. Filter the reaction mixture, wash with ethyl acetate (50 ml), and dry it. Further dry the solid 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] 1-acetylindoline-2-carboxylic acid (100g) obtained in Example 2 was added to concentrated HCl (250ml) at 30-35 °C, and the mixture was stirred for 15-16 hours. The pH value was adjusted to 3.8-4.1 with sodium hydroxide aqueous solution, and the material was stirred at 10-15 °C for 60 minutes. The slurry was filtered, washed with water (50ml×2), and dried. The solid was further vacuum dried at 50-55 °C for 8 hours to obtain indoline-2-carboxylic acid (75.7g, 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. The indoline-2-carboxylic acid (500 g) prepared in Example 3 was added in portions to the above reaction mixture over about 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 250 g).

[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 vacuum dried 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 obtained (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) using the instructions on page 8 / 11 of CN 121219263 A. 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, thereby preparing a sodium bicarbonate solution. The (2S)-indoline-2-carboxylic acid (I) (100 g) obtained in Example 4.b.1 was added in portions to the sodium bicarbonate solution prepared above 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, thereby preparing a sodium hydroxide solution. The (2S)-indoline-2-carboxylic acid (I) (100 g) obtained in Example 4b was added in portions to the sodium hydroxide solution prepared above 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 reaction mixture was 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.

[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) 9 / 11 pages 13 CN 121219263 A

[0122] Sodium hydroxide (24.53g) was added to water (700ml) and stirred to obtain a clear solution, thereby preparing a sodium hydroxide solution. The (2S)-indoline-2-carboxylic acid (I) (100g) obtained in Example 4b was added in portions to the sodium hydroxide solution prepared above at 30-35 °C. The reaction mixture was stirred for 30 minutes. 5% Ru / C (10g) was added to the reactants. A hydrogen pressure of 20-22kg was applied at 30-35 °C. Raise the temperature to 80-85 °C and stir the material for 4-6 hours. Cool the reaction material to 30-35 °C, release the hydrogen pressure, and filter the material. Wash the separated catalyst with water (100 ml) and store it under nitrogen. The catalyst will be reused in the next batch. The recovered catalyst weighs 9 g.

[0123] Place the filtrate in a clean, dry RBF and adjust the pH to 4.5 with dilute sulfuric acid. Concentrate the resulting reaction material under vacuum. Add methanol (1000 ml) and stir the hot mixture for 1-1.5 hours. Filter the reaction mixture to remove inorganic matter and wash with methanol. Vacuum distill the filtrate at 50-55 °C to obtain the residue. Add 1,4-dioxane (1000 ml) and water (200 ml) to the residue at 30-35 °C and reflux for 1-1.5 hours. Cool the reaction mixture to 30-35 °C, stir for 2 hours, and filter. The obtained solid was dried under vacuum at 55-60 °C for 7-8 hours to obtain (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] Preparation of (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (A) using recovered catalyst

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

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

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

[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 as described on page 14 of the specification (CN 121219263 A). The recovered catalyst was stored for one month and then reused in the reaction. As shown in the table above, the product formation rate was >85%. In addition, a catalyst recycling study was conducted without replenishing fresh catalyst. The reaction proceeded smoothly when the recovered catalyst was used without replenishing fresh catalyst.

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

[0134]

[0135] Based on the above observations, it can be concluded that the catalyst can be recycled regardless of whether fresh catalyst is replenished. More cycles can be performed regardless of whether fresh catalyst is added. Recycling greatly reduces the cost of the catalyst, and only 10% of the fresh catalyst loading needs to be replenished for each batch of catalyst consumption.

[0136] Example 9

[0137] Effect of Moisture Content on Yield and Chiral Purity

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

[0139]

[0140] In the context of the present invention, the method of the present invention provides higher chiral purity and higher yield of the compound represented by formula (A), without a large amount of undesirable byproducts. Furthermore, the method of the present invention 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 with higher efficiency.

[0141] In addition, in the method of the present invention, >90% of the catalyst is efficiently recovered and recycled as fresh catalyst. This makes the method economically feasible because 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. Specification 11 / 11 pages 15 CN 121219263 A.

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.