A preparation method of (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid

Abstract

The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid, wherein the preparation of the (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is based on Boc-L-cis-hydroxyproline as a starting material, and a methyl esterification reaction, a TBS protection reaction, a methylation reaction, and a demethylation reaction are performed to obtain a finished product in four steps. The method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid provided by the invention is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and specifically relates to a method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid. Background Art

[0002] (2S,4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is an important pharmaceutical intermediate. After searching, the preparation principle of the existing method is as follows:

[0003]

[0004] The above method uses Boc-L-cis-hydroxyproline as a starting material and obtains the target product through four steps of reaction. In step 1, thionyl chloride is used for methylation reaction, and the neutralization and post-treatment of the reaction will produce a large amount of irritating gases such as hydrogen chloride and sulfur dioxide, and the operation is relatively cumbersome; in step 2, methyl iodide, a Class 3A carcinogen with a low boiling point at normal pressure, is used as a methylation reagent, which is highly toxic and not conducive to mass production.

[0005] Therefore, it is necessary to provide a new, safe, environmentally friendly, and easily scaled-up method for preparing (2S,4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid. Summary of the invention

[0006] The purpose of the present invention is to overcome the above problems existing in the conventional technology and provide a method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid.

[0007] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0008] A method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid comprises the following steps: using Boc-L-cis-hydroxyproline as a starting material, and performing methylation reaction, TBS protection reaction, methylation reaction, and demethylation reaction to obtain a finished product.

[0009] Furthermore, the reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0010]

[0011] Furthermore, the specific steps of the first step are: methanol, p-toluenesulfonic acid, and Boc-L-cis-hydroxyproline are added to a reaction kettle in sequence, stirred and dissolved, heated, stirred and refluxed for a period of time; TLC monitors the complete reaction of the raw materials, cools to room temperature, transfers the reaction solution to a rotary evaporator for concentration, adds saturated sodium bicarbonate aqueous solution and ethyl acetate for extraction and separation, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous sodium sulfate, filters to remove the desiccant, and concentrates the filtrate under reduced pressure to obtain intermediate A.

[0012] Furthermore, the reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0013]

[0014] Furthermore, the specific steps of the reaction in the second step are: adding dichloromethane, imidazole, and intermediate A to the reaction kettle, stirring and cooling at 0°C, dissolving tert-butyldimethylsilyl chloride in dichloromethane and then adding dropwise to the reaction system for reaction, and keeping warm and stirring for a period of time after the addition is completed; monitoring the reaction of the raw materials by TLC, adding saturated sodium bicarbonate aqueous solution for separation, washing the organic phase with saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, filtering to remove the desiccant, and concentrating the filtrate under reduced pressure to remove the solvent to obtain a crude product, and performing rapid silica gel column chromatography to obtain intermediate B.

[0015] Furthermore, the reaction in the third step is shown in formula (III), and the intermediate C is obtained after the reaction:

[0016]

[0017] Furthermore, the specific steps of the reaction in the third step are: adding dry tetrahydrofuran and intermediate B to a reaction kettle, cooling and stirring at -20°C under nitrogen protection, taking a tetrahydrofuran solution of lithium hexamethyldisilazide and dropping it into the reaction system with a dry dropping funnel, and keeping the temperature for a period of time after the addition is completed, taking methyl trifluoromethanesulfonate and dropping it into the reaction system with a dry dropping funnel, and keeping the temperature for a period of time after the addition is completed; HPLC monitors the reaction of the raw materials to be complete, adding saturated ammonium chloride aqueous solution to quench the reaction, adding ethyl acetate for extraction, extracting the aqueous phase with ethyl acetate, combining the organic phases and drying them with anhydrous magnesium sulfate, filtering to remove the desiccant, and evaporating to dryness to obtain intermediate C.

[0018] Furthermore, the reaction in the fourth step is shown in formula (IV), and the finished product is obtained after the reaction:

[0019]

[0020] Furthermore, the specific steps of the reaction of the fourth step are: adding tetrahydrofuran, intermediate C, and water into a reaction kettle, stirring and dissolving at room temperature, taking lithium hydroxide and adding it into the reaction system, and keeping the temperature for a period of time after the addition; TLC monitoring shows that the reaction of the raw materials is complete, adding saturated ammonium chloride aqueous solution to quench the reaction, adding ethyl acetate for extraction, extracting the aqueous phase with ethyl acetate, combining the organic phases and drying them with anhydrous magnesium sulfate, filtering to remove the desiccant, and evaporating to dryness to obtain (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid product.

[0021] Furthermore, the specific steps for refining the (2S,4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid product are as follows: the crude product is dispersed with n-hexane and methanol, heated to reflux to dissolve, cooled with stirring at a cooling rate of 10°C / h for crystallization, kept warm and stirred for a period of time at room temperature, filtered, the filter cake is washed with a solution of n-hexane and methanol in a volume ratio of 15:1, the filter cake is drained, and vacuum dried at room temperature to obtain a refined product.

[0022] The beneficial effects of the present invention are:

[0023] The preparation method of (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid of the present invention uses Boc-L-cis-hydroxyproline as a starting material, and undergoes four steps of methyl esterification reaction, TBS protection reaction, methylation reaction, and demethylation reaction to obtain a finished product; this is a brand-new preparation method, which has the advantages of safety, environmental protection, and easy scale-up production.

[0024] Of course, any product implementing the present invention does not necessarily need to achieve all of the above advantages at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative work.

[0026] Figure 1 This is a schematic diagram of the LCMS test results of the finished product of the present invention;

[0027] Figure 2 It is a schematic diagram of the HPLC test results of the finished product of the present invention. DETAILED DESCRIPTION

[0028] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] The specific designations of the abbreviations in this embodiment are as follows:

[0030] SM: Boc-L-cis-hydroxyproline

[0031] Boc: tert-butyloxycarbonyl

[0032] MeOH: Methanol

[0033] PTS: p-toluenesulfonic acid

[0034] TBS: tert-butyldimethylsilyl

[0035] DCM: dichloromethane

[0036] LiHMDS: Lithium Hexamethyldisilazide

[0037] The specific embodiments of the present invention are:

[0038] Example 1

[0039] A method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is characterized in that the preparation of (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is carried out by using Boc-L-cis-hydroxyproline as a starting material, and undergoing methyl esterification reaction, TBS protection reaction, methylation reaction, and demethylation reaction to obtain a finished product.

[0040] The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

[0041]

[0042] The specific steps of the first step are: methanol (5.0L), PTS (59.6g, 0.2eq), and SM (400g, 1.0eq) are added to the reaction kettle in sequence, stirred and dissolved, and heated and stirred to reflux for 4h. TLC monitors the complete reaction of the raw materials, cools to room temperature, and transfers the reaction liquid to a rotary evaporator to concentrate to about 2L, adds saturated sodium bicarbonate aqueous solution (4L) and 5L ethyl acetate to extract and separate, and the aqueous phase is extracted twice with 2L ethyl acetate, and the organic phases are combined and dried over anhydrous sodium sulfate for 2h, and the desiccant is filtered to remove the desiccant, and the filtrate is concentrated under reduced pressure to obtain 417.1g of crude intermediate A oil, with a yield of 99.6%.

[0043] Mass spectrum: MS-ESI: 246.1[M+H] + .

[0044] The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction:

[0045]

[0046] The specific steps of the second step are: add dichloromethane (5L), imidazole (173.2, 1.5eq), intermediate A (417.1g, 1.0eq) to the reactor, stir and cool at 0°C, take tert-butyldimethylsilyl chloride (281.8g, 1.1eq) and dissolve it in dichloromethane (1L) and then drop it into the reaction system for reaction, add it for 1h, keep warm and stir for 8h. TLC monitors the reaction of the raw materials, add saturated sodium bicarbonate aqueous solution (4L) for separation, wash the organic phase with saturated sodium chloride aqueous solution (4L) once, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to remove the solvent to obtain a crude product, and perform rapid silica gel column chromatography to obtain 556.9g of pure intermediate B with a yield of 91.1%.

[0047] Mass spectrum: MS-ESI: 360.4 [M+H] + .

[0048] The reaction in the third step is shown in formula (III), and intermediate C is obtained after the reaction:

[0049]

[0050] The specific steps of the reaction of the third step are as follows: dry tetrahydrofuran (5L) and intermediate B (556.9g, 1.0eq.) are added to the reaction kettle, cooled and stirred at -20°C under nitrogen protection, 1mol / L LiHMDS tetrahydrofuran solution (1.71L, 1.1eq) is added dropwise to the reaction system with a dry dropping funnel, the addition is completed in 1.5h, and the reaction is kept warm for 0.5h after the addition, methyl trifluoromethanesulfonate (272.4g, 1.05eq) is added dropwise to the reaction system with a dry dropping funnel, the addition is completed in 1h, and the reaction is kept warm for 6h after the addition is completed. HPLC monitors that the raw material reaction is complete, saturated ammonium chloride aqueous solution (4L) is added dropwise to quench the reaction, ethyl acetate (4L) is added for extraction, the aqueous phase is extracted twice with ethyl acetate (2L), the organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to obtain 527.7g of crude intermediate C, with a yield of 91.2%.

[0051] Mass spectrum: MS-ESI: 374.5 [M+H] + .

[0052] The reaction in the fourth step is shown in formula (IV), and the finished product is obtained after the reaction:

[0053]

[0054] The specific steps of the reaction of the fourth step are: tetrahydrofuran (5L), intermediate C (527.7g, 1.0eq.), and water (1L) are added to a reaction kettle, stirred and dissolved at room temperature, lithium hydroxide (68.9g, 2.0eq) is added to the reaction system, and the reaction is kept warm for 4h. TLC monitors the complete reaction of the raw materials, saturated ammonium chloride aqueous solution (4L) is added dropwise to quench the reaction, ethyl acetate (4L) is added for extraction, the aqueous phase is extracted twice with ethyl acetate (2L), the organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to obtain a crude product. The crude product was dispersed with n-hexane (8 L) and methanol (1.5 L), heated to reflux and dissolved, cooled with stirring at a cooling rate of 10 ° C / h for crystallization, kept warm and stirred for 2 h at room temperature, filtered, and the filter cake was washed twice with a solution of n-hexane: methanol = 15:1. The filter cake was drained and vacuum dried at room temperature for 12 h to obtain 416.9 g of the pure target product with a yield of 82.1% and a purity of 97%.

[0055] Mass spectrum: MS-ESI: 360.6 [M+H] + .

[0056] Finished product related tests and results such as Figure 1-Figure 2 shown.

[0057] The preferred embodiments of the present invention disclosed above are only used to help explain the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to specific implementation methods. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid, Features: The preparation of (2S,4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is carried out by using Boc-L-cis-hydroxyproline as a starting material, and undergoing methyl esterification reaction, TBS protection reaction, methylation reaction, and demethylation reaction to obtain a finished product in four steps. The reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction: The reaction in the second step is shown in formula (II), and intermediate B is obtained after the reaction: The reaction of the third step is shown in formula (III), and intermediate C is obtained after the reaction; the specific steps of the reaction of the third step are: adding dry tetrahydrofuran and intermediate B into a reaction kettle, cooling and stirring at -20°C under nitrogen protection, taking a tetrahydrofuran solution of lithium hexamethyldisilazide and dropping it into the reaction system with a dry dropping funnel, and keeping the temperature for a period of time after the addition is completed, taking methyl trifluoromethanesulfonate and dropping it into the reaction system with a dry dropping funnel, and keeping the temperature for a period of time after the addition is completed; HPLC monitors the reaction of the raw materials, drops a saturated aqueous ammonium chloride solution to quench the reaction, add ethyl acetate for extraction, extract the aqueous phase with ethyl acetate, combine the organic phases and dry them with anhydrous magnesium sulfate, filter to remove the desiccant, and evaporate to dryness to obtain intermediate C; The reaction in the fourth step is shown in formula (IV), and the finished product is obtained after the reaction:

2. The method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid according to claim 1, It is characterized in that The specific steps of the first step are: methanol, p-toluenesulfonic acid, and Boc-L-cis-hydroxyproline are added to a reaction kettle in sequence, stirred and dissolved, heated, stirred and refluxed for a period of time; TLC monitors the complete reaction of the raw materials, cools the temperature to room temperature, transfers the reaction liquid to a rotary evaporator for concentration, adds saturated sodium bicarbonate aqueous solution and ethyl acetate for extraction and separation, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous sodium sulfate, filters to remove the desiccant, and concentrates the filtrate under reduced pressure to obtain intermediate A.

3. The method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid according to claim 2, It is characterized in that The specific steps of the reaction in the second step are: add dichloromethane, imidazole and intermediate A to the reaction kettle, stir and cool at 0°C, take tert-butyldimethylsilyl chloride, dissolve it in dichloromethane and then add it dropwise to the reaction system for reaction, keep warm and stir for a period of time after the addition is completed; monitor the reaction of the raw materials by TLC, add saturated sodium bicarbonate aqueous solution for separation, wash the organic phase with saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter to remove the desiccant, concentrate the filtrate under reduced pressure to remove the solvent to obtain a crude product, and perform rapid silica gel column chromatography to obtain intermediate B.

4. The method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid according to claim 3, It is characterized in that The specific steps of the reaction of the fourth step are: adding tetrahydrofuran, intermediate C and water into a reaction kettle, stirring and dissolving at room temperature, taking lithium hydroxide and adding it into the reaction system, and keeping the temperature for a period of time after the addition; TLC monitoring shows that the reaction of the raw materials is complete, adding saturated ammonium chloride aqueous solution to quench the reaction, adding ethyl acetate for extraction, extracting the aqueous phase with ethyl acetate, combining the organic phases and drying them with anhydrous magnesium sulfate, filtering to remove the desiccant, and evaporating to dryness to obtain (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid product.

5. The method for preparing (2S, 4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid according to claim 4, It is characterized in that The specific steps for refining the (2S,4S)-1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid product are as follows: the crude product is dispersed with n-hexane and methanol, heated to reflux to dissolve, cooled with stirring at a cooling rate of 10°C / h for crystallization, kept warm and stirred for a period of time when the temperature reaches room temperature, filtered, the filter cake is washed with a solution prepared with n-hexane and methanol in a volume ratio of 15:1, the filter cake is drained, and vacuum dried at room temperature to obtain a refined product.

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