CN116396241A - A preparation method of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical intermediates, in particular to the preparation of a tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid Method, the preparation of the tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid is (R)-2-amino- 1-butanol is used as the starting material, and the finished product is obtained through three steps of acylation ring closure reaction, Oxone oxidation reaction, and Boc protection reaction. The preparation method of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid provided by the present invention is a brand-new preparation method, The invention has the advantages of safety, environmental protection and easy scale-up production.

Description

A tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine- The preparation method of 3-carboxylic acid

technical field

The invention belongs to the technical field of pharmaceutical intermediates, in particular to the preparation of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid method.

Background technique

tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid is an important pharmaceutical intermediate, CAS No. 1417287-40-1 , the molecular formula is C ₉ H ₁₇ NO ₅ S.

After retrieval, there are two main methods for preparing tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid:

1) The principle of the first preparation method is as follows:

Ref: 1) Journal of Organic Chemistry, 2010, vol.75, #3, p.937-940.

2) Advanced Synthesis and Catalysis, 2015, vol.357, #9, p.2132-2142.

The above method mainly uses N-Boc-(R)-2-amino-1-butanol as the starting material. Step 1 uses thionyl chloride/pyridine for acylation reaction, the post-treatment is more cumbersome, and the cyclization yield is not ideal; Step 2 uses heavy metal catalyst ruthenium trichloride, which is expensive and not conducive to large-scale preparation;

2) The principle of the second preparation method is as follows:

Ref: 1) CN202010253576.

The above method mainly uses N-Boc-(R)-2-amino-1-butanol as the starting material, and synthesizes the target product in one step. However, the amount of solvent used in this reaction is large, and sulfuryl chloride with higher toxicity and worse safety is used as the acylating reagent, which is difficult to prepare in large quantities.

Therefore, it is necessary to provide a new and safe, environmentally friendly, easy-to-scale-up production of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3- Methods for the preparation of carboxylic acids.

Contents of the invention

The purpose of the present invention is to overcome the above-mentioned problems existing in the traditional technology, and to provide a kind of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3- Methods for the preparation of carboxylic acids.

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 tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid, the tert-butyl (R)-4 -Ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid is prepared from (R)-2-amino-1-butanol as starting material, through acyl Cyclization reaction, Oxone oxidation reaction, Boc protection reaction, a total of three steps to obtain the finished product.

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 reaction in the first step are as follows: add dry dichloromethane, triethylamine, (R)-2-amino-1-butanol, and 4-dimethylaminopyridine into the reaction kettle and stir to dissolve, Stir and lower the temperature under a nitrogen protection atmosphere and at a temperature of -20°C, and take another dichloromethane to dissolve thionyl chloride, add dropwise to the reaction system, and keep it warm for a period of time; TLC monitors that the reaction of the raw materials is complete, and then quenched by adding saturated aqueous sodium bicarbonate solution. To quench the reaction, the organic phase was first washed with saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, and then dried with anhydrous sodium sulfate, filtered to remove the desiccant, 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 reaction are: add acetonitrile and water to the reaction kettle, add intermediate A to the reaction kettle, add potassium persulfate compound salt into the reaction system, raise the temperature to 80°C and stir for a period of time ; TLC monitors that the reaction of raw materials is complete, adding water for liquid separation, washing the organic phase with saturated aqueous sodium chloride 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. Column chromatography yields Intermediate B.

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

。

.

Further, the specific steps of the reaction in the third step are as follows: add intermediate B into the reaction kettle, add acetonitrile, triethylamine, and 4-dimethylaminopyridine and stir evenly, add tert-butoxy chloroformate dropwise at room temperature, and complete the addition After that, the temperature was raised to 60°C and reacted for a period of time; TLC monitored the complete reaction of the raw materials, cooled to room temperature, added saturated aqueous sodium bicarbonate solution to quench the reaction, added ethyl acetate for extraction, the aqueous phase was extracted twice with ethyl acetate, and the organic phase was combined. The phase was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was evaporated to dryness to obtain tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3 - Carboxylic acid finished products.

Further, the finished product of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid can be purified by silica gel column chromatography.

The beneficial effects of the present invention are:

In the present invention, the preparation of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid is based on (R)-2-amino- 1-butanol is used as the starting material, and the finished product is obtained through three steps of acylation ring closure reaction, Oxone oxidation reaction, and Boc protection reaction; this is a brand-new preparation method, which 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 a schematic diagram 1 of the NMR detection result of the finished product of the present invention;

Fig. 2 is the second schematic diagram of the NMR detection result of the finished product of the present invention;

Fig. 3 is the schematic diagram of the measurement result of the optical rotation value of the finished product of the present invention;

Figure 4 is a schematic diagram of the LCMS 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: (R)-2-amino-1-butanol

DMAP: 4-Dimethylaminopyridine

TEA: Triethylamine

DCM: dichloromethane

Oxone: Potassium persulfate complex salt

Boc-Cl: tert-butoxy chloroformate

Boc: tert-butoxycarbonyl

MeCN: Acetonitrile

Specific embodiments of the present invention are:

Example 1

A preparation method of tert-butyl (R)-4-ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid, the tert-butyl (R)-4 -Ethyl-2,2-dioxide-1,2,3-oxathiazolidine-3-carboxylic acid is prepared from (R)-2-amino-1-butanol as starting material, through acyl Cyclization reaction, Oxone oxidation reaction, Boc protection reaction, a total of three steps to obtain the finished product.

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 dry DCM (3.0L), TEA (340.1g, 1.5eq), SM (200g, 1.0eq), DMAP (54.8g, 0.2eq) into the reaction kettle and stir to dissolve , Stir and cool down at -20°C under the protection of nitrogen, and dissolve thionyl chloride (280.4g, 1.05eq) in DCM (1L), add dropwise to the reaction system, add 1h, keep warm for 4h. TLC monitors that the reaction of the raw material is complete, adding saturated aqueous sodium bicarbonate (2L) to quench the reaction, washing the organic phase once with saturated aqueous ammonium chloride (2L), washing once with saturated aqueous sodium chloride (2L), and washing the organic phase with anhydrous sodium sulfate After drying for 2 h, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 273.7 g of intermediate A crude oil, with a yield of 90.2%.

Mass Spectrum: MS-ESI: 136.0 [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 of the reaction are: add acetonitrile (3L) and water (1L) to the reaction kettle, add intermediate A (273.7g, 1.0eq) to the reaction kettle, take Oxone (1367.5g, 1.1eq) and add In the reaction system, the temperature was raised to 80° C. and stirred for 4 h. TLC monitors that the reaction of the raw material is complete, adding water (2L) to separate the liquid, the organic phase is washed once with a saturated aqueous sodium chloride solution (3L), the organic phase is dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product, and the fast silica gel column Chromatography gave 288.6 g of pure intermediate B, with a yield of 94.3%.

Mass spectrum: MS-ESI: 152.0 [M+H] ⁺ .

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

。

.

The specific steps of the third step reaction are: add IM2 (288.6g, 1.0eq.) into the reactor, add MeCN (4L), TEA (288.0g, 1.5eq), DMAP (46.4g, 0.2eq) and stir evenly, Boc-Cl (389.3g, 1.5eq) was added dropwise at room temperature, and after the addition was completed, the temperature was raised to 60°C for 8 hours. TLC monitored the complete reaction of the raw materials, cooled to room temperature, and quenched the reaction by adding saturated aqueous sodium bicarbonate solution (4L), and adding acetic acid Ethyl ester (4L) was extracted, and the aqueous phase was extracted twice with ethyl acetate (2L). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The obtained crude product was purified by column chromatography to obtain 432.4 g of the finished product. Rate: 90.5%.

Mass spectrum: MS-ESI: 274.1 [M+Na] ⁺ .

The related tests and results of the finished product are shown in Figures 1 to 4.

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 (8)

1. A process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid, characterised in that: the preparation of the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid takes (R) -2-amino-1-butanol as an initial raw material, and the product is obtained through three steps of reaction, namely acylation cyclization reaction, oxone oxidation reaction and Boc protection reaction.

2. The process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 1, characterised in that the reaction in the first step is as shown in formula (I) to give intermediate a:

。

3. the process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 2, characterised in that the reaction of the first step comprises the following specific steps: sequentially adding dried dichloromethane, triethylamine, (R) -2-amino-1-butanol and 4-dimethylaminopyridine into a reaction kettle, stirring and dissolving, stirring and cooling at-20 ℃ under the nitrogen protection atmosphere, taking dichloromethane to dissolve sulfoxide chloride, dropwise adding into a reaction system, and reacting for a period of time at a constant temperature; TLC monitors that the raw materials are reacted completely, saturated sodium bicarbonate aqueous solution is added for quenching reaction, an organic phase is firstly washed by saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, the organic phase is dried by anhydrous sodium sulfate, a drying agent is removed by filtration, and filtrate is concentrated under reduced pressure to obtain an intermediate A.

4. A process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 3, characterised in that the reaction in the second step is as shown in formula (II) to give intermediate B after reaction:

。

5. the process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 4, wherein the reaction in the second step comprises the specific steps of: acetonitrile and water are added into a reaction kettle, an intermediate A is added into the reaction kettle, potassium hydrogen persulfate composite salt is added into a reaction system, and the temperature is raised to 80 ℃ and the mixture is stirred for reaction for a period of time; TLC monitors that the raw materials are completely reacted, water 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 decompressed and concentrated 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 the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 5, wherein the reaction in the third step is of formula (III) to give the final product after reaction:

。

7. the process for the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 6, wherein the reaction in the third step comprises the following specific steps: adding the intermediate B into a reaction kettle, adding acetonitrile, triethylamine and 4-dimethylaminopyridine, uniformly stirring, dropwise adding tert-Ding Yangzhi chloroformate at room temperature, and heating to 60 ℃ for reaction for a period of time after adding; TLC monitors the completion of the reaction of the raw materials, cools to room temperature, quench the reaction with saturated aqueous sodium bicarbonate, extract with ethyl acetate, extract the aqueous phase twice with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter to remove the desiccant, evaporate the filtrate to dryness, get the finished product of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid.

8. The process for producing t-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid according to claim 7, wherein the finished product of t-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is purified by silica gel column chromatography.

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