CN116496314A - Preparation method of (2S, 4S) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid - Google Patents

Abstract

The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of (2S, 4S) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid. The preparation method of the (2S, 4S) -1- (tert-butyldimethylsilyloxy) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid provided by the invention is a brand new preparation method and has the advantages of safety, environmental protection and easiness in large-scale production.

Description

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

technical field

The invention belongs to the technical field of pharmaceutical intermediates, in particular to a (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2 - Process for the preparation of carboxylic acids.

Background technique

(2S,4S)-1-(tert-butoxycarbonyl)-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:

The above method adopts Boc-L-cis-hydroxyproline as the starting material, and obtains the target substance through four steps of reaction. Step 1 adopts thionyl chloride to carry out methyl esterification reaction, and reaction neutralization aftertreatment can produce more hydrogen chloride and sulfur dioxide irritating gas, and operation is comparatively loaded down with trivial details; Step 2 adopts 3A carcinogens and methyl iodide with lower normal pressure boiling point as Methylating reagents are highly toxic and unfavorable for mass production.

Therefore, it is necessary to provide a brand-new (2S, 4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methyl (2S,4S)-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methyl compound that is safe, environmentally friendly and easy to scale up. Process for the preparation of pyrrolidine-2-carboxylic acid.

Contents of the invention

The object of the present invention is to overcome the above-mentioned problems existing in the conventional technology, and to provide a kind of (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methyl Process for the preparation of pyrrolidine-2-carboxylic acid.

In order to achieve the above-mentioned technical purpose and achieve the above-mentioned technical effect, the present invention is realized through the following technical solutions:

A preparation method of (2S, 4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid, the (2S, 4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is prepared from Boc-L-cis-hydroxyproline Amino acid is used as the starting material, and the finished product is obtained through a four-step reaction of methyl esterification reaction, TBS protection reaction reaction, methylation reaction, and demethylation reaction reaction.

Further, the reaction of the first step is shown in formula (I), and intermediate A is obtained after the reaction:

Further, the specific steps of the first step of the reaction are: add methanol, p-toluenesulfonic acid, Boc-L-cis-hydroxyproline to the reactor in turn, stir and dissolve, heat, stir and reflux for a period of time; TLC monitors the reaction of raw materials Completely, cool down to room temperature, transfer to a rotary evaporator to concentrate the reaction solution, add saturated aqueous sodium bicarbonate and ethyl acetate to extract and separate the liquid, extract the aqueous phase with ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, filter The desiccant was removed, and the filtrate was concentrated under reduced pressure to obtain Intermediate A.

Further, the reaction of the second step is shown in formula (II), and intermediate B is obtained after the reaction:

Further, the specific steps of the second step of the reaction are: add dichloromethane, imidazole, intermediate A to the reaction kettle, stir and cool at 0°C, take tert-butyldimethylsilyl chloride and dissolve it in dichloromethane, then pour it into the reaction system After the addition, the mixture was stirred and reacted for a period of time; TLC monitored the complete reaction of the raw materials, adding saturated aqueous sodium bicarbonate solution to separate the liquid, the organic phase was washed with saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and removed by filtration. desiccant, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product, which was subjected to flash silica gel column chromatography to obtain Intermediate B.

Further, the reaction of the third step is shown in formula (III), and intermediate C is obtained after the reaction:

Further, the specific steps of the third step reaction are: add dry tetrahydrofuran and intermediate B into the reaction kettle, cool and stir at -20°C under the protection of nitrogen, take the tetrahydrofuran solution of lithium hexamethyldisilazide with dry Add the dropping funnel dropwise to the reaction system, keep warm for a period of time after the addition, take methyl trifluoromethanesulfonate and add dropwise to the reaction system with a dry dropping funnel, keep warm for a while after the addition; HPLC monitors the raw materials After the reaction is complete, add saturated aqueous ammonium chloride dropwise to quench the reaction, add ethyl acetate for extraction, extract the aqueous phase with ethyl acetate, combine the organic phases and dry with anhydrous magnesium sulfate, filter to remove the desiccant, and evaporate to dryness to obtain intermediate C .

Further, the reaction of the fourth step is shown in formula (IV), and the finished product is obtained after the reaction:

Further, the specific steps of the reaction in the fourth step are as follows: add tetrahydrofuran, intermediate C, and water into the reaction kettle, stir and dissolve at room temperature, add lithium hydroxide into the reaction system, and keep it warm for a period of time; TLC monitors the reaction of raw materials Completely, quench the reaction by adding saturated ammonium chloride aqueous solution dropwise, add ethyl acetate for extraction, extract the aqueous phase with ethyl acetate, combine the organic phases and dry with anhydrous magnesium sulfate, filter to remove the drying agent, and evaporate to dryness to obtain (2S, 4S )-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid product.

Further, the specific steps for refining (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid products are: Disperse the crude product with n-hexane and methanol, heat to reflux to dissolve, stir and crystallize at a cooling rate of 10°C/h, heat and stir for a period of time when it reaches room temperature, and filter with suction. The filter cake is mixed with n-hexane and methanol at a volume ratio of 15: The solution prepared in 1 was washed, the filter cake was drained, and vacuum-dried at room temperature to obtain a refined product.

The beneficial effects of the present invention are:

The preparation of (2S, 4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid of the present invention is based on Boc-L- Cis-hydroxyproline is used as the starting material, and the finished product is obtained through four steps of methyl esterification reaction, TBS protection reaction reaction, methylation reaction, and demethylation reaction reaction; this is a brand new preparation method. It has the advantages of safety, environmental protection and easy scale-up production.

Of course, implementing any product of the present invention does not necessarily need to achieve all the above advantages at the same time.

Description of drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the accompanying drawings that are required for the description of the embodiments. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. Those of ordinary skill in the art can also obtain other drawings based on these drawings without any creative effort.

Fig. 1 is the schematic diagram of the LCMS detection result of finished product of the present invention;

Fig. 2 is a schematic diagram of the HPLC detection results of the finished product of the present invention.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

The specific references of each abbreviation in this embodiment are as follows:

SM: Boc-L-cis-hydroxyproline

Boc: tert-butoxycarbonyl

MeOH: Methanol

PTS: p-toluenesulfonic acid

TBS: tert-butyldimethylsilyl

DCM: dichloromethane

LiHMDS: lithium hexamethyldisilazide

Specific embodiments of the present invention are:

Example 1

A preparation method of (2S, 4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid, characterized in that: The preparation of (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-methylpyrrolidine-2-carboxylic acid is based on Boc-L-cis The formula - hydroxyproline is used as the starting material, and the finished product is obtained through a four-step reaction of methyl esterification reaction, TBS protection reaction reaction, methylation reaction, and demethylation reaction reaction.

The reaction of the first step is shown in formula (I), obtains intermediate A after the reaction:

The specific steps of the first step of the reaction are: add methanol (5.0L), PTS (59.6g, 0.2eq), SM (400g, 1.0eq) into the reactor in turn, stir and dissolve, heat and stir under reflux for 4h. TLC monitors that the reaction of raw materials is complete, cool down to room temperature, transfer to a rotary evaporator to concentrate the reaction solution to about 2L, add saturated aqueous sodium bicarbonate (4L) and 5L ethyl acetate for extraction and separation, and extract the aqueous phase with 2L ethyl acetate Twice, the organic phases were combined and dried over anhydrous sodium sulfate for 2 h, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 417.1 g of intermediate A crude oil, with a yield of 99.6%.

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

The reaction of the second step is shown in formula (II), obtains intermediate B after the reaction:

The specific steps of the second step reaction are: add dichloromethane (5L), imidazole (173.2, 1.5eq), intermediate A (417.1g, 1.0eq) into the reaction kettle, stir and cool at 0°C, and take tert-butyldi Methylchlorosilane (281.8g, 1.1eq) was dissolved in dichloromethane (1L) and then added dropwise to the reaction system for 1h to complete the reaction, then kept stirring for 8h. TLC monitors that the reaction of raw materials is complete, adding saturated aqueous sodium bicarbonate solution (4L) for separation, the organic phase is washed once with saturated aqueous sodium chloride solution (4L), the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product , fast silica gel column chromatography, to obtain 556.9 g of pure intermediate B, yield 91.1%.

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

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

The specific steps of the third step reaction are as follows: add dry tetrahydrofuran (5L) and intermediate B (556.9g, 1.0eq.) into the reaction kettle, cool and stir at -20°C under nitrogen protection, and take 1mol/L LiHMDS THF solution ( 1.71L, 1.1eq) was added dropwise to the reaction system with a dry dropping funnel, and the addition was completed after 1.5h. The liquid funnel was added dropwise to the reaction system, and the addition was completed in 1 hour. After the addition, the reaction was incubated for 6 hours. HPLC monitors that the reaction of the raw materials is complete, and the saturated ammonium chloride aqueous solution (4L) is added dropwise to quench the reaction, and ethyl acetate (4L) is added for extraction, and the aqueous phase is extracted twice with ethyl acetate (2L), the organic phases are combined, and anhydrous magnesium sulfate After drying, filtering and evaporating to dryness, 527.7 g of intermediate C crude product was obtained, yield: 91.2%.

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

The reaction of the 4th step is shown in formula (IV), obtains finished product after the reaction:

The specific steps of the reaction in the fourth step are: add tetrahydrofuran (5L), intermediate C (527.7g, 1.0eq.), and water (1L) into the reaction kettle, stir and dissolve at room temperature, and take lithium hydroxide (68.9g, 2.0 eq) was added to the reaction system, and after the addition was completed, the reaction was kept for 4 hours. TLC monitors that the reaction of the raw materials is complete, dropwise adding saturated aqueous ammonium chloride (4L) to quench the reaction, adding ethyl acetate (4L) for extraction, and extracting the aqueous phase twice with ethyl acetate (2L), combining the organic phases, anhydrous magnesium sulfate Dry, filter, and evaporate to dryness to obtain the crude product. Disperse the crude product with n-hexane (8L) and methanol (1.5L), heat to reflux to dissolve, stir and crystallize at a cooling rate of 10°C/h, keep stirring at room temperature for 2h, filter with suction, and use n-hexane for the filter cake: The methanol=15:1 solution was washed twice, the filter cake was sucked dry, and vacuum-dried at room temperature for 12 hours to obtain 416.9 g of the target product, with a yield of 82.1% and a purity of 97%.

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

The related tests and results of the finished product are shown in Figure 1-Figure 2.

The preferred embodiments of the invention disclosed above are only to help illustrate the invention. The preferred embodiments do not exhaust all details nor limit the invention to specific implementations. Obviously, many modifications and variations can be made based on the contents of this specification. This description selects and specifically describes these embodiments in order to better explain the principle and practical application of the present invention, so that those skilled in the art can well understand and utilize the present invention. The invention is to be limited only by the claims, along with their full scope and equivalents.

Claims (10)

1. A method for preparing (2S, 4S) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is characterized by comprising the steps of: the preparation of the (2S, 4S) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is to take Boc-L-cis-hydroxyproline as a starting raw material, and obtain a finished product through four steps of reactions including methyl esterification reaction, TBS protection reaction, methylation reaction and demethylation esterification reaction.

2. The process for preparing (2S, 4S) -1- (tert-butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 1, wherein the reaction in the first step is represented by formula (I), wherein intermediate A is obtained after the reaction:

3. the method for producing (2 s,4 s) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 2, wherein the reaction of the first step is specifically as follows: sequentially adding methanol, p-toluenesulfonic acid and Boc-L-cis-hydroxyproline into a reaction kettle, stirring for dissolving, heating, stirring, and refluxing for reacting for a period of time; TLC monitoring the reaction completion of the raw materials, cooling to room temperature, transferring into a rotary evaporator, concentrating the reaction liquid, adding saturated sodium bicarbonate aqueous solution and ethyl acetate extraction liquid, extracting the aqueous phase with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating the filtrate under reduced pressure to obtain an intermediate A.

4. The process for producing (2S, 4S) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 3, wherein the reaction in the second step is represented by the following formula (II):

5. the method for producing (2 s,4 s) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 4, wherein the second step of reacting comprises the specific steps of: adding dichloromethane, imidazole and an intermediate A into a reaction kettle, stirring and cooling at 0 ℃, dissolving tert-butyl dimethyl chlorosilane with dichloromethane, then dropwise adding the mixture into a reaction system for reaction, and after the addition, keeping the temperature and stirring for reaction for a period of time; TLC monitors that the raw materials are completely reacted, saturated sodium bicarbonate aqueous solution is added for separating, an organic phase is washed by saturated sodium chloride aqueous solution, the organic phase is dried by anhydrous sodium sulfate, a drying agent is removed by filtration, the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product, and the crude product is subjected to rapid silica gel column chromatography to obtain an intermediate B.

6. The process for preparing (2S, 4S) -1- (tert-butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 5, wherein the reaction in the third step is represented by formula (III), wherein intermediate C is obtained after the reaction:

7. the method for producing (2 s,4 s) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 6, wherein the reaction of the third step is specifically: adding dry tetrahydrofuran and an intermediate B into a reaction kettle, cooling and stirring at the temperature of minus 20 ℃ under the protection of nitrogen, dripping a tetrahydrofuran solution of hexamethyldisilazane lithium amide into the reaction system by using a dry dropping funnel, carrying out heat preservation reaction for a period of time after the dripping is finished, dripping methyl triflate into the reaction system by using the dry dropping funnel, and carrying out heat preservation reaction for a period of time after the dripping is finished; HPLC monitors the reaction completion of the raw materials, drops saturated ammonium chloride aqueous solution to quench the reaction, adds ethyl acetate for extraction, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters to remove the desiccant, and evaporates to dryness to obtain intermediate C.

8. The method for producing (2 s,4 s) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 7, wherein the reaction in the fourth step is represented by formula (IV):

9. the method for preparing (2 s,4 s) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 8, wherein the reaction of the fourth step is specifically: adding tetrahydrofuran, an intermediate C and water into a reaction kettle, stirring and dissolving at room temperature, adding lithium hydroxide into a reaction system, and carrying out heat preservation reaction for a period of time after adding; TLC monitors the completion of the reaction of the starting material, drops saturated aqueous ammonium chloride solution to quench the reaction, extracts with ethyl acetate, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters off the drying agent, and evaporates to dryness to give the (2S, 4S) -1- (tert-butyldimethylsilyloxy) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product.

10. The method for producing (2S, 4S) -1- (t-butyloxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 9, wherein the purification of the (2S, 4S) -1- (t-butyldimethylsilyloxy) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product comprises the following steps: dispersing the crude product with n-hexane and methanol, heating to reflux and dissolve, stirring at a cooling rate of 10 ℃/h, cooling, crystallizing, maintaining at room temperature, stirring for a period of time, suction filtering, washing the filter cake with a solution prepared by n-hexane and methanol according to a volume ratio of 15:1, suction drying the filter cake, and vacuum drying at room temperature to obtain a refined finished product.