A method for synthesizing and applying (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride

Abstract

The application belongs to the technical field of chemical industry, and discloses a synthesis method and application of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride, wherein trichloroisocyanuric acid is used as an oxidant, and silica gel loaded 2,2,6,6-tetramethylpiperidine oxide is added as a novel supported catalyst; the supported catalyst is removed and recovered through filtration to obtain an oxidation product IM1; then, sodium triacetoxyborohydride is used as a reducing agent to reduce a trans chiral ketone carbonyl to obtain a trans amino acid product IM2 which cannot be obtained through a fermentation method; finally, the target product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride is synthesized through a one-step synthesis method under a heating reaction condition in a methanol system. The product prepared through the method has high purity, low raw material cost, simple operation, and is suitable for industrial production and can meet the needs of the future medical and other fields.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical industry, and particularly relates to a synthesis method and application of (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride. BACKGROUND

[0002] (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester and its derivatives are very important intermediates of medicines, pesticides and other chemical additives; have been widely used in food and medicine fields, and particularly in the research and development of polypeptide drugs in recent years, more and more non-natural chiral amino acids are used, and the existing technologies for non-natural chiral D-hydroxy proline are obtained by multi-step reaction to realize the inversion of the hydroxyl configuration, which leads to difficult purification, high raw material cost and difficulty in large-scale production. Therefore, it is more and more urgent to develop a process with cheap raw materials and suitable for large-scale production.

[0003] Through retrieval, the following two published documents related to the patent application of the application are found:

[0004] 1. The method of Chinese patent publication CN116514864A and the method, specifically relate to a preparation method of (2S, 4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsiloxy)-2-methyl pyrrolidine-2-carboxylic acid. The preparation of the (2S, 4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsiloxy)-2-methyl pyrrolidine-2-carboxylic acid is carried out by taking Boc-L-trans-hydroxyproline as a starting material, and then performing methyl esterification reaction, TBS protection reaction, methylation reaction and de-methyl esterification reaction, so that the finished product is obtained. The preparation method of the (2S, 4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsiloxy)-2-methyl pyrrolidine-2-carboxylic acid provided by the application is a brand-new preparation method, which has the advantages of safety, environmental protection and easy scale-up production.

[0005] 2. Chinese patent publication CN116396202A specifically relates to a preparation method of (2S, 4S)-4-fluoropyrrolidine-2-carboxylic acid. The preparation of the (2S, 4S)-4-fluoropyrrolidine-2-carboxylic acid is carried out by taking (2S, 4R)-N-Boc-4-hydroxy-proline as a starting material, and then performing methyl esterification reaction, DeoxoFluor fluorination reaction, TFA Boc protection group removal and LiOH methyl ester removal reaction, so that the finished product is obtained. The preparation method of the (2S, 4S)-4-fluoropyrrolidine-2-carboxylic acid provided by the application is a brand-new preparation method, which has the advantages of safety, environmental protection and easy scale-up production.

[0006] 3、The Journal of Organic Chemistry, 2005, vol. 70, # 16, p. 6447- 6453 reported a process of chiral inversion of similar compound configuration using Mitsunobu reaction leading to purification difficulty. The present application uses sodium triacetoxyborohydride as reducing agent to realize chiral asymmetric trans-reduction of ketone carbonyl group through the guidance of carboxylic acid group. This method realizes high selective chiral reduction in the molecule for the first time. The raw material is cheap and the experimental operation is obviously superior to the experimental process in the literature, which is suitable for industrial scale-up.

[0007] Through comparison, the technical development in the above three patent publications does not use the process of immobilized catalyst and trans-chiral reduction, thus being essentially different from the present application. SUMMARY

[0008] The present application aims to overcome the deficiencies in the prior art and provide a synthesis method and application of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride.

[0009] The technical solution adopted by the present application to solve its technical problems is as follows:

[0010] A synthesis method of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride, which uses trichloroisocyanuric acid as an oxidant, adds silica gel loaded 2,2,6,6-tetramethylpiperidine oxide as a new type of supported catalyst, removes and recovers the supported catalyst by filtration to obtain an oxidation product IM1; then uses sodium triacetoxyborohydride as a reducing agent to trans-chirally reduce the ketone carbonyl group to obtain a trans-amino acid product IM2 that cannot be obtained by fermentation; and finally synthesizes the target product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride in one step through heating reaction conditions of thionyl chloride in a methanol system.

[0011] Further, the preparation method of the silica gel loaded 2,2,6,6-tetramethylpiperidine oxide comprises the following steps:

[0012] Anhydrous methanol is added to 3-aminopropyl functionalized silica gel, followed by the addition of 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl free radical, and stirring is continued at room temperature for 1 h, then sodium cyanoborohydride is added, and the reaction is continuously stirred for 3 days; the reaction system is filtered to remove and recover the supported catalyst, the solid is washed with methanol, water and methanol three times, and then dried under vacuum at 40-45 DEG C to obtain the silica gel loaded catalyst 2,2,6,6-tetramethylpiperidine oxide.

[0013] Further, the ratio of 3-aminopropyl functionalized silica gel: anhydrous methanol: 4-oxo-2, 2, 6, 6-tetramethylpiperidine-1-oxyl radical: sodium cyanoborohydride is 20:60:3.40:1.26 g:ml: g: g;

[0014] Alternatively, 25 ml of methanol, water, and methanol are used for each 20 g of 3-aminopropyl functionalized silica gel.

[0015] Further, the ratio of trichloroisocyanuric acid: 2, 2, 6, 6-tetramethylpiperidine oxide is 442.5:2 g: g.

[0016] Further, the specific steps are as follows:

[0017] (1) Preparation of IM1

[0018]

[0019] Anhydrous ethyl acetate, SM (Chinese name: N-Boc-cis-4-hydroxy-D-proline), silica gel supported 2, 2, 6, 6-tetramethylpiperidine oxide, and trichloroisocyanuric acid are added to a stirred reactor, which is cooled to 0-5°C, and then trichloroisocyanuric acid is added in batches. After stirring at this temperature for 2 h, the reaction is completed. After filtering out the catalyst from the reaction system, the reaction is quenched with a 10% sodium thiosulfate solution, and then the organic phase is separated by liquid-liquid extraction. The organic phase is dried with sodium sulfate, and then concentrated at 35-40°C to obtain IM1.

[0020] In the above process, the ratio of ethyl acetate: SM: silica gel supported 2, 2, 6, 6-tetramethylpiperidine oxide: trichloroisocyanuric acid: 10% sodium thiosulfate solution: sodium sulfate is 2400:400:2:442.5:1000:150 mL: g: g: g: mL: g.

[0021] (2) Preparation of IM2

[0022]

[0023] Anhydrous dichloromethane, IM1, anhydrous acetic acid, and sodium triacetoxyborohydride are added to a stirred reactor that has been sufficiently replaced with N2, and then the mixture is reacted at room temperature for 30 h. After adding saturated sodium chloride solution, the organic phase is obtained by liquid-liquid extraction, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain crude IM2.

[0024] In the above process, the ratio of dichloromethane: IM1: anhydrous acetic acid: sodium triacetoxyborohydride: saturated sodium chloride solution is 900:60:18.8:89:200 mL: g: g: g: mL.

[0025] (3) Preparation of (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride

[0026]

[0027] In a stirred reactor with N2 sufficient replacement, anhydrous methanol, IM2, thionyl chloride is added, and the reaction is refluxed at 70 DEG C, and the crude product after concentration under reduced pressure is slurried with ethyl acetate at room temperature for 2h, and the end product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride is obtained by filtration;

[0028] Wherein, the ratio of anhydrous methanol: IM2: thionyl chloride: ethyl acetate is 300:60:37:120 mL:g:g:mL.

[0029] The application of the synthetic method as described above in the preparation of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride.

[0030] The advantages and positive effects obtained by the application are:

[0031] 1、The method uses cheap and readily available trichloroisocyanuric acid (TCCA) as an oxidant, and adds silica gel loaded 2,2,6,6-tetramethylpiperidine oxide (SilicaCAT-TEMPO) (0.005% / w) as a new type of supported catalyst, and after removing and recovering the catalyst by filtration, the oxidation product IM1 can be obtained in high yield; then, using sodium triacetoxyborohydride as a reducing agent, the trans-keto carbonyl group is reduced, and the trans-amino acid product IM2 cannot be obtained by fermentation method, the catalyst can be recycled and reused, greatly reducing the production cost; finally, the target product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride is synthesized in one step by heating reaction of thionyl chloride in a methanol system. The product prepared by the method has high purity, low raw material cost, simple operation, is suitable for industrial production, and can meet the needs of future medical and other fields.

[0032] 2、The first step of the method uses a self-prepared silica gel loaded catalyst SilicaCAT-TEMPO, which can improve the catalytic efficiency and purification efficiency, and the catalyst can be recycled and reused, greatly reducing the synthesis cost.

[0033] 3、The second step of the method of the present application uses sodium triacetoxyborohydride as a reducing agent, and the chiral asymmetric trans-reduction of the ketone carbonyl group is realized through the guiding effect of the carboxyl group. This method realizes the chiral reduction with high selectivity in such molecules for the first time, avoids the purification difficulties caused by the configuration inversion reaction of Mitsunobu, and is suitable for industrial scale-up. The possible catalytic mechanism of the reaction is as follows: first, the free carboxyl group replaces one acetate anion in sodium triacetoxyborohydride, so that the reducing agent and the carboxylic acid are in the same plane, and then the hydride ion attacks the ketone carbonyl group, thereby producing the target compound mainly in the trans form.

[0034]

[0035] 4、The last step of the method of the present application realizes the removal of the protecting group and the methylation of the carboxylic acid by one-pot method, and the target compound with high yield can be obtained by directly concentrating the reaction mixture and then beating with a small amount of ethyl acetate.

[0036] 5、The purification of all the compounds synthesized by the method of the present application is realized by beating and recrystallization, avoiding the cumbersome purification method of column chromatography, which is also a highlight of the present application. This process greatly shortens the synthesis time and reduces the experimental cost. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 It is the nuclear magnetic resonance spectrum of the target product TM in the present application.

[0038] Figure 2 It is the high performance liquid chromatogram of the target product TM in the present application. DETAILED DESCRIPTION

[0039] The present application will be further described below in conjunction with examples, which are descriptive and not limiting, and cannot limit the protection scope of the present application.

[0040] The various experimental operations involved in the specific examples are all conventional techniques in the art, and the parts not specially noted in the text can be implemented by referring to various commonly used tool books, scientific and technical literature or related instructions, manuals, etc. before the application date of the present application.

[0041] A synthesis method of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride, which uses trichloroisocyanuric acid as an oxidant, adds silica gel loaded 2,2,6,6-tetramethylpiperidine oxide as a novel supported catalyst, removes and recovers the supported catalyst by filtration to obtain the oxidation product IM1; then uses sodium triacetoxyborohydride as a reducing agent to reduce the trans chiral ketone carbonyl to obtain the trans amino acid product IM2 which cannot be obtained by fermentation method; and finally synthesizes the target product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride in one step through a heating reaction condition of thionyl chloride in a methanol system.

[0042] Further, the preparation method of the silica gel loaded 2,2,6,6-tetramethylpiperidine oxide comprises the following steps:

[0043] Anhydrous methanol is added to 3-aminopropyl functionalized silica gel, then 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl radical is added, stirring at room temperature is continued for 1 h, sodium cyanoborohydride is then added, and the reaction continues to stir for 3 days; the reaction system is filtered to remove and recover the supported catalyst, the solid is washed with methanol, water and methanol three times, and then the silica gel loaded catalyst 2,2,6,6-tetramethylpiperidine oxide is obtained by drying under vacuum at 40-45°C.

[0044] Further, the ratio of 3-aminopropyl functionalized silica gel: anhydrous methanol: 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl radical: sodium cyanoborohydride is g: ml: g: g 20: 60: 3.40: 1.26.

[0045] Alternatively, 25 ml of methanol, water and methanol are used for washing per 20 g of 3-aminopropyl functionalized silica gel.

[0046] Further, the ratio of trichloroisocyanuric acid: 2,2,6,6-tetramethylpiperidine oxide is g: g 442.5: 2.

[0047] Further, the specific steps are as follows:

[0048] (1) Preparation of IM1

[0049]

[0050] In a stirred reactor, add anhydrous ethyl acetate, SM (Chinese name: N-Boc-cis-4-hydroxy-D-proline), silica gel supported 2,2,6,6-tetramethylpiperidine oxide, cool to 0-5°C, add trichloroisocyanuric acid in batches, stir the reaction at this temperature for 2h, and the reaction is completed; filter the catalyst from the reaction system, quench the reaction with 10% sodium thiosulfate solution, separate the liquid extract, dry the organic phase with sodium sulfate, and concentrate the organic phase at 35-40°C to obtain IM1;

[0051] Wherein, the ratio of ethyl acetate:SM:silica gel supported 2,2,6,6-tetramethylpiperidine oxide:trichloroisocyanuric acid:10% sodium thiosulfate solution:sodium sulfate is 2400:400:2:442.5:1000:150 mL:g:g:g:mL:g;

[0052] (2) Preparation of IM2

[0053]

[0054] In a stirred reactor, add anhydrous dichloromethane, IM1, anhydrous acetic acid, sodium triacetoxyborohydride, and react at room temperature for 30h; add saturated sodium chloride solution, separate the liquid extract to obtain the organic phase, dry with anhydrous sodium sulfate, filter and concentrate to obtain crude IM2;

[0055] Wherein, the ratio of dichloromethane:IM1:anhydrous acetic acid:sodium triacetoxyborohydride:saturated sodium chloride solution is 900:60:18.8:89:200 mL:g:g:g:mL;

[0056] (3) Preparation of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride

[0057]

[0058] In a stirred reactor, add anhydrous methanol, IM2, and thionyl chloride, and reflux at 70°C, then concentrate under reduced pressure, and then slurry the crude product with ethyl acetate at room temperature for 2h, and filter to obtain the final product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride;

[0059] Wherein, the ratio of anhydrous methanol:IM2:thionyl chloride:ethyl acetate is 300:60:37:120 mL:g:g:mL.

[0060] The synthetic method described above is applied in the preparation of (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride.

[0061] Specifically, the relevant preparation and detection are as follows:

[0062] route:

[0063]

[0064]

[0065] Example 1

[0066] Preparation of the catalyst (SilicaCAT-TEMPO):

[0067] 20 g of 3-aminopropyl-functionalized silica gel was placed in a 250 mL reaction flask, followed by 60 mL of anhydrous methanol, and then 3.40 g (20 mmol) of 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxo radical was added. The mixture was stirred at room temperature for 1 h, and then 1.26 g (20 mmol) of sodium cyanoborohydride was added. The reaction was stirred for another 3 days. The reaction system was filtered to remove and recover the supported catalyst. The solid was washed three times with 25 mL each of methanol, water, and methanol, and then dried under vacuum at 40–45 °C to obtain 22 g of silica gel-supported catalyst.

[0068] 1. Preparation of IM1 (N-Boc-4-oxo-D-proline)

[0069]

[0070] Anhydrous ethyl acetate (2400 mL), SM (400 g, 1.73 mol), and SilicaCAT-TEMPO (2 g, 0.005% / w) were added to a 5000 mL stirred reactor. The temperature was lowered to 0-5 °C, and TCCA (442.5 g, 1.9 mol) was added in batches. The reaction was stirred at this temperature for 2 h until the reaction was complete. After filtering out the catalyst, the reaction was quenched with 1000 mL of 10% sodium thiosulfate solution. The mixture was extracted by separation, and the organic phase was dried with 100 g of anhydrous sodium sulfate. The temperature was controlled at 35-40 °C, and then the organic phase was concentrated at 40-45 °C to obtain IM1, 392 g, with a yield of 99%, requiring no further purification.

[0071] Example 2

[0072] 2. Preparation of IM2 (N-BOC-trans-4-hydroxy-D-proline)

[0073]

[0074] In a 2000 mL reactor with stirring, anhydrous dichloromethane (900 mL) was added, IM1 (60 g, 0.26 mol), anhydrous acetic acid (18.8 g, 0.31 mol), sodium triacetoxyborohydride (89 g, 0.42 mol) was added in five batches, and the reaction was carried out at room temperature for 30 h. After adding 200 mL of saturated sodium chloride solution, the organic phase was obtained by liquid-liquid extraction, and then concentrated and dried at 40-45 °C to obtain crude IM2 (60 g) containing 8% chiral isomers. Without further purification, it was directly used in the next step reaction.

[0075] 3. Preparation of TM ((2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride)

[0076]

[0077] In a 500 mL reactor with stirring, anhydrous methanol (300 mL) was added, IM2 (60 g, crude), SOCl2 (37 g), and the reaction was carried out at 70 °C under reflux for 2 h. The reaction system was concentrated under reduced pressure at 40-45 °C, and the crude product was slurried with 120 mL of ethyl acetate at room temperature for 2 h, and then filtered to obtain the final product TM, 40.4 g, with a two-step yield of 85%.

[0078] The relevant test results are shown in Figure 1 、 Figure 2 and Table 1, from Figure 2 and Table 1, it can be seen that the target compound with a purity of 99.5% can be obtained by the slurry process of a single solvent ethyl acetate. Compared with the existing published process technology, the overall process has the advantages of short route, simple work-up, high chemical atom economy, etc., and does not need the cumbersome operation of column chromatography purification, which is an optimal scheme for future industrial production.

[0079] Table 1 Area percentage table

[0080]

[0081] Although the embodiments of the present application are disclosed for illustrative purposes, those skilled in the art can understand that various alternatives, changes and modifications are possible without departing from the spirit and scope of the present application and the appended claims, therefore, the scope of the present application is not limited to the disclosed content of the embodiments.

Claims

1. A process for the synthesis of (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride, characterized in that: The method adds anhydrous ethyl acetate, N-Boc-cis-4-hydroxy-D-proline SM, uses trichloroisocyanuric acid as an oxidant, adds silica gel loaded 2,2,6,6-tetramethylpiperidine oxide as a novel supported catalyst, removes and recovers the supported catalyst by filtration, and obtains an oxidation product IM1; then trans-chiral reduction of the ketone carbonyl group is performed by using sodium triacetoxyborohydride as a reducing agent, and a trans-amino acid product IM2 that cannot be obtained by a fermentation method is obtained; finally, the target product (2R,4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride is synthesized in one step by a heating reaction condition of thionyl chloride in a methanol system; The oxidation product IM1 has the structural formula ; The trans amino acid product IM2 has the structure .

2. The method of synthesis of claim 1, wherein: The preparation method of the silica gel loaded 2,2,6,6-tetramethylpiperidine oxide comprises the following steps: Anhydrous methanol is added to 3-aminopropyl functionalized silica gel, then 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl is added, stirring is continued at room temperature for 1 h, sodium cyanoborohydride is then added, and the reaction is continuously stirred for 3 days; the reaction system is filtered to remove and recover the supported catalyst, the solid is sequentially washed with methanol, water and methanol three times, and then the silica gel loaded catalyst 2,2,6,6-tetramethylpiperidine oxide is obtained by vacuum drying at 40-45 DEG C.

3. The method of synthesis of claim 2, wherein: The ratio g:ml: g: g of 3-aminopropyl functionalized silica gel: anhydrous methanol: 4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl: sodium cyanoborohydride is 20:60:3.40:1.26; Alternatively, 25 ml of methanol, water and methanol are used for washing per 20 g of 3-aminopropyl functionalized silica gel.

4. The method of synthesis of claim 1, wherein: The ratio g:g of trichloroisocyanuric acid:2,2,6,6-tetramethylpiperidine oxide is 442.5:

2.

5. The method of synthesis according to any one of claims 1 to 4, wherein: The specific steps are as follows: (1) Preparation of IM1 Anhydrous ethyl acetate, N-Boc-cis-4-hydroxy-D-proline SM and silica gel loaded 2,2,6,6-tetramethylpiperidine oxide are added to a stirred reactor, cooled to 0-5 DEG C, and trichloroisocyanuric acid is added in batches, and the reaction is stirred at this temperature for 2 h after which the reaction is completed; the catalyst is filtered out from the reaction system, and the reaction is quenched with a 10% sodium thiosulfate solution, and the organic phase is dried with sodium sulfate, and then the organic phase is concentrated at 35-40 DEG C to obtain IM1; The ratio mL:g:g:g:mL:g of ethyl acetate:SM:silica gel loaded 2,2,6,6-tetramethylpiperidine oxide:trichloroisocyanuric acid:10% sodium thiosulfate solution:sodium sulfate is 2400:400:2:442.5:1000:150; (2) Preparation of IM2 Anhydrous dichloromethane, IM1, anhydrous acetic acid and sodium triacetoxyborohydride are added to a N2-replaced stirred reactor, and the reaction is performed at room temperature for 30 h; after saturated sodium chloride solution is added, the organic phase is obtained by liquid separation, dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product IM2; The ratio of dichloromethane: IM1: anhydrous acetic acid: sodium triacetoxyborohydride: saturated sodium chloride solution is 900: 60: 18.8: 89: 200 mL: g: g: g: mL. (3) Preparation of (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride In a reactor with stirring, anhydrous methanol, IM2, thionyl chloride are added, and the reaction is refluxed at 70°C. After concentration under reduced pressure, the crude product is slurried with ethyl acetate at room temperature for 2 h, and the final product (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride is obtained by filtration. The ratio of anhydrous methanol: IM2: thionyl chloride: ethyl acetate is 300: 60: 37: 120 mL: g: g: mL.

6. Use of the synthetic method according to any one of claims 1 to 5 in the preparation of (2R, 4S)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester hydrochloride.

Images