CN114213352B - Preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate - Google Patents
Preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate Download PDFInfo
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Abstract
The invention discloses a preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the steps of preparing R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate; preparing R or S type 2- (p-toluenesulfonyl) propionic acid; adding R or S-type 2- (p-toluenesulfonyl) propionic acid and tetrahydrofuran into a reaction vessel, maintaining the temperature at-40 to-10 ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, and then adding 2-oxazolidone to obtain a reaction solution III; quenching with hydrochloric acid, extracting with dichloromethane, alkalizing with saturated sodium bicarbonate, washing with saturated saline, drying, filtering, and concentrating the reaction solution III to obtain R or S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate. The invention can reduce the preparation cost of R or S-type 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, improve the preparation efficiency and improve the preparation productivity.
Description
Technical Field
The invention relates to a preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, belonging to the technical field of synthesis of pharmaceutical intermediates.
Background
R or S form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is widely used as an important chemical or pharmaceutical intermediate, for example R form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate has been attracting attention because of its wide use in the synthesis of active pharmaceutical molecules for the treatment of various diseases. Such as synthesizing the medicines for treating lung infection, urinary tract infection, septicemia, meningitis, endocarditis and the like.
A large amount of experimental data show that chiral resolution into chiral compounds has a plurality of specific properties, such as that one chiral structure is a main active substance after resolution, and the other chiral structure is exactly the cause of side effects; therefore, the chiral compounds are greatly interested worldwide, and the chiral split compounds are independently used as a new medicine in the new medicine lot. However, the problem often exists in the actual synthesis is that the racemate is often synthesized, but not the single chiral structure, such as the resolution difficulty of the racemate is high, and the cost is high.
The application finds a method for preparing R or S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate with low cost, high efficiency and high yield through research.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, which can reduce the preparation cost of R or S type 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate and improve the preparation efficiency and productivity.
In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:
the invention provides a preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the following steps:
preparing R or S type ethyl 2- (p-toluenesulfonyloxy) propionate;
hydrolyzing the ethyl 2- (p-toluenesulfonyloxy) propionate of the R or S type to produce 2- (p-toluenesulfonyl) propionic acid of the R or S type;
adding R or S-type 2- (p-toluenesulfonyl) propionic acid and tetrahydrofuran into a reaction container, maintaining the temperature at-40 to-10 ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, and after the reaction time III is more than 30min, adding 2-oxazolidone, and after the reaction time IV is more than 3h, obtaining a reaction solution III;
quenching with hydrochloric acid, extracting with dichloromethane, alkalizing with saturated sodium bicarbonate, washing with saturated saline, drying, filtering, and concentrating the reaction solution III to obtain R or S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate.
Further, the preparation of R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate comprises the following steps:
adding p-toluenesulfonyl chloride and D-type or L-type ethyl lactate into an organic solvent I, maintaining the temperature of 0-25 ℃, and dropwise adding organic base, wherein the reaction time I is more than 7 hours, so as to obtain a reaction liquid I;
the reaction solution I is filtered, extracted and concentrated in sequence to obtain R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate.
Further, the organic base is triethylamine or N, N-diisopropylethylamine;
the organic solvent I is toluene or methylene dichloride;
the mol ratio of the tosyl chloride to the D-type or L-type ethyl lactate is (1-1.5): 1;
the molar ratio of the organic base to the D or L-type ethyl lactate is (1-2): 1;
the volume mass ratio of the organic solvent I to the D or L-type ethyl lactate is (3-6): 1mL/g.
Further, the reaction time I is 7-20 h.
Further, the hydrolysis of ethyl 2- (p-toluenesulfonyloxy) propionate of R or S form to 2- (p-toluenesulfonyl) propionic acid of R or S form comprises the steps of:
adding ethanol and R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate into a reaction vessel, keeping the temperature between 15 and 20 ℃, adding an inorganic alkaline aqueous solution, and reacting for more than 30 minutes to obtain a reaction solution II;
sequentially extracting, acidifying, extracting, drying, filtering and concentrating the reaction solution II to obtain R or S type 2- (p-toluenesulfonyl) propionic acid.
Further, the inorganic alkaline aqueous solution is a sodium hydroxide aqueous solution or a lithium hydroxide aqueous solution;
the volume-mass ratio of the ethanol to the R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate is (1-5) 1mL/g;
the mol ratio of the inorganic alkali aqueous solution to the R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate is (1-2) 1;
the concentration of the inorganic alkaline aqueous solution is 1.5mol/L.
Further, the reaction time II is 1 to 6 hours.
Further, the volume-mass ratio of the tetrahydrofuran to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (10-30) 1mL/g;
the mol ratio of the triethylamine to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (1-3) 1;
the mol ratio of the special acyl chloride to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (1-3) 1;
the molar ratio of the 2-oxazolidone to the R or S type 2- (p-toluenesulfonyl) propionic acid is (1-3): 1.
Further, the reaction time III is 0.5-2 h;
further, the reaction time IV is 3-5 h.
Compared with the prior art, the invention has the beneficial effects that:
the invention realizes the preparation of R or S-type 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate through 4 steps; the whole preparation process has mild reaction conditions, and no reaction conditions of ultrahigh temperature and ultralow temperature are needed; the preparation raw materials are simple and easy to obtain, and no raw material medicine is required to be applied for the record; the preparation cost is low, and large-scale equipment or specific custom equipment is not needed; the preparation process is relatively safe, and toxic and harmful byproducts are not generated, and high-toxicity and high-boiling intermediates are not generated;
in addition, the intermediate drug ethyl 2- (p-toluenesulfonyloxy) propionate of R or S form of the present application can be prepared by p-toluenesulfonyl chloride and ethyl lactate of D or L form; the R or S type 2- (p-toluenesulfonyl) propionic acid is generated by hydrolyzing the prepared R or S type 2- (p-toluenesulfonyloxy) propionic acid ethyl ester, so that the cost can be reduced, and the quality of intermediate medicaments can be controlled;
the chemical purity of the 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate obtained by the preparation method is as high as 99%, and the yield is as high as 85%.
Drawings
FIG. 1 is an HPLC chart of ethyl 2- (p-toluenesulfonyloxy) propionate of example 3 of the present invention.
FIG. 2 is a chiral HPLC chart of R-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 3 of the present invention.
FIG. 3 is a diagram of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 3 of the invention 1 H NMR spectrum.
FIG. 4 is a HPLC chart of S-type 2- (p-toluenesulfonyl) propionic acid of example 4 of the present invention.
FIG. 5 is a chiral HPLC chromatogram of S-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 4 of the present invention.
FIG. 6 is a diagram of S-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 4 of the invention 1 H NMR spectrum.
Detailed Description
The preparation method of the 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate comprises the following steps:
s1, preparing R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate R-2 (S-2);
s2, preparing R or S-type 2- (p-toluenesulfonyl) propionic acid R-3 (S-3);
s3 preparing R or S-1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate R-4 (S-4);
the reaction formula of the S1-S3 processes is as follows:
the invention is further described below with reference to the accompanying drawings. The following examples are only for more clearly illustrating the technical aspects of the present invention, and are not intended to limit the scope of the present invention.
Example 1
This example provides a process for the preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, comprising the following steps.
S1 preparation of R-type ethyl 2- (p-toluenesulfonyloxy) propionate
In a three-port reaction flask equipped with a stirrer, 120ml of toluene was added, followed by 40g of D-ethyl lactate and 77.5g of p-toluenesulfonyl chloride, and 51.4g of triethylamine was added dropwise while maintaining at 25℃to stir the reaction mixture I for 7 hours.
The stirred reaction solution I was filtered, the cake was washed twice with 120mL of toluene, the filtrate and the washing solution were combined, the combined solution was extracted with 180mL of 5wt% aqueous citric acid, and the organic phase was concentrated under reduced pressure to give 60g of ethyl 2- (p-toluenesulfonyloxy) propionate of R type, with a LC purity of 90% or more, yield: 65%.
S2 preparation of R-type 2- (p-toluenesulfonyl) propionic acid
In a three-port reaction flask with a stirrer, 250ml of ethanol and 50g of R-type ethyl 2- (p-toluenesulfonyloxy) propionate were added, a temperature of 15℃was maintained, 245ml of a 1.5M aqueous NaOH solution was slowly added dropwise, and after the addition, the reaction solution II was continuously stirred for 3 hours.
Firstly, 100ml of dichloromethane is measured and added into a reaction solution II, the reaction solution II is layered, then, a 6M hydrochloric acid aqueous solution is used for leading the pH value of an aqueous phase to be 1.5, then, 100ml of dichloromethane is used for carrying out two times of extraction, and organic phases are combined, and are dried by sodium sulfate, filtered and concentrated under reduced pressure in sequence, thus, 38.1g of R-type 2- (p-toluenesulfonyl) propionic acid is obtained, the LC purity is 98 percent, and the yield is: 85%.
S3 preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
Into a three-port reaction flask with a stirrer, 732ml of tetrahydrofuran and 24.4g of R-type 2- (p-toluenesulfonyl) propionic acid were added, followed by slowly dropwise adding 10.1g of triethylamine at a temperature of-10℃and then slowly dropwise adding 12.05g of pivaloyl chloride, and after the dropwise adding was completed, the mixture was continuously stirred for 0.5 hour, and then 8.7g of 2-oxazolidinone was continuously added and reacted for 3 hours to obtain a reaction solution III.
Firstly 150ml of 1M aqueous hydrochloric acid solution is taken and added into a reaction solution III, the reaction solution III is static and layered, aqueous phases are extracted twice by 150ml of dichloromethane and organic phases are combined, then the organic phases are washed twice by 150ml of saturated sodium bicarbonate and washed twice by 150ml of saturated salt water, finally the organic phases are dried by sodium sulfate, filtered and concentrated under reduced pressure in sequence, and 21.9g of R-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is prepared, the LC purity is 99%, the chiral LC purity is 99% ee, the yield is: 70%.
Example 2
This example provides a process for the preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, comprising the following steps.
S1 preparation of R-type ethyl 2- (p-toluenesulfonyloxy) propionate
In a three-port reaction flask with a stirrer, 240ml of methylene chloride was added, followed by 40g of ethyl D-lactate and 97g of p-toluenesulfonyl chloride, 68.5g of N, N-diisopropylethylamine was added dropwise while maintaining at 25℃and the reaction mixture I was stirred continuously for 14 hours after the addition.
The stirred reaction solution I was filtered, the cake was washed twice with 120mL of methylene chloride, the filtrate and the washing solution were combined, the combined solution was extracted with 180mL of 5wt% aqueous citric acid, and the organic phase was concentrated under reduced pressure to give 55.3g of ethyl 2- (p-toluenesulfonyloxy) propionate of R type, with LC purity of 85% or higher, yield: 60%.
S2 preparation of R-type 2- (p-toluenesulfonyl) propionic acid
In a three-port reaction flask with a stirrer, 250ml of ethanol and 50g of R-type ethyl 2- (p-toluenesulfonyloxy) propionate were added, and at a temperature of 20℃183ml of a 1.5M aqueous LiOH solution was slowly added dropwise, and after the addition, the reaction solution II was stirred continuously for 1 hour.
Firstly, 100ml of dichloromethane is measured and added into a reaction solution II, the reaction solution II is layered, then, a 6M hydrochloric acid aqueous solution is used for leading the pH value of an aqueous phase to be 1.5, then, 100ml of dichloromethane is used for carrying out two-time extraction, and organic phases are combined, and are dried by sodium sulfate, filtered and concentrated under reduced pressure in sequence, thus, 40.4g of R-type 2- (p-toluenesulfonyl) propionic acid is obtained, the LC purity is 98 percent, and the yield is: 90%.
S3 preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-port reaction flask with a stirrer, 488ml of tetrahydrofuran and 24.4g of R-type 2- (p-toluenesulfonyl) propionic acid were added, the temperature was maintained at-30℃and then 20.2g of triethylamine was slowly dropped, then 24.1g of pivaloyl chloride was slowly dropped, after the dropping was completed, the mixture was continuously stirred for 2 hours, and after 26.1g of 2-oxazolidone was continuously added, the reaction was continued for 5 hours, to obtain a reaction solution III.
Firstly 150ml of 1M aqueous hydrochloric acid solution is taken and added into a reaction solution III, the reaction solution III is static and layered, aqueous phases are extracted twice by using 150ml of dichloromethane and organic phases are combined, then the organic phases are washed twice by using 150ml of saturated sodium bicarbonate and then washed twice by using 150ml of saturated salt water, finally the organic phases are dried by using sodium sulfate, filtered and concentrated under reduced pressure in sequence, thus preparing 25g of R-1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, the LC purity is 99%, the chiral LC purity is 99% ee, the yield is as follows: 80%.
Example 3
This example provides a process for the preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, comprising the following steps.
S1, preparing R-type 2- (p-toluenesulfonyloxy) ethyl propionate;
120ml of toluene was added to a three-port reaction flask equipped with a stirrer, followed by 40g of ethyl D-lactate and 64.6g of p-toluenesulfonyl chloride; 34g of triethylamine is added dropwise at the temperature of 0-5 ℃, and the reaction solution I is stirred continuously for 20h after the addition.
The stirred reaction solution I was filtered, the cake was washed twice with 120mL of toluene, the filtrate and the washing solution were combined, the combined solution was extracted with 180mL of 5wt% aqueous citric acid, and the organic phase was concentrated under reduced pressure to obtain 76g of ethyl 2- (p-toluenesulfonyloxy) propionate of R type, with a LC purity of 98% or more, yield: 82.6%.
Ethyl 2- (p-toluenesulfonyloxy) propionate analysis
And (3) analyzing the prepared R-type ethyl 2- (p-toluenesulfonyloxy) propionate by high performance liquid chromatography.
The high performance liquid chromatography analysis conditions are as follows: instrument: HPLC1260; sample injection amount: 5.000 μl;
referring to fig. 1, the test results include 2 chromatographic peaks, and specific parameters of the chromatographic peaks are shown in table 1.
TABLE 1R high Performance liquid chromatography parameters for Ethyl 2- (p-toluenesulfonyloxy) propionate
| Chromatographic peak | Retention time/min | Peak height/ | Peak area | |
| 1 | 7.384 | 1217.56763 | 3.56195386×10 3 | |
| 2 | 8.402 | 1.70401 | 5.41245 | |
| Totals to | 1219.27163 | 3.56736631×10 3 |
S2 preparation of R-type 2- (p-toluenesulfonyl) propionic acid
In a three-port reaction flask with a stirrer, 50ml of ethanol and 50g of R-type ethyl 2- (p-toluenesulfonyloxy) propionate were added, and 147ml of a 1.5M aqueous LiOH solution was slowly added dropwise at 20℃and after the addition, the reaction solution II was continuously stirred for 3 hours.
Firstly, 100ml of dichloromethane is measured and added into a reaction solution II, the reaction solution II is layered, then, a 6M hydrochloric acid aqueous solution is used for leading the pH value of an aqueous phase to be 1.5, then, 100ml of dichloromethane is used for carrying out two-time extraction, and organic phases are combined, and are dried by sodium sulfate, filtered and concentrated under reduced pressure in sequence, so that 43g of R-type 2- (p-toluenesulfonyl) propionic acid is obtained, the LC purity is 99 percent, and the yield is: 96%.
S3 preparation of R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-port reaction flask with a stirrer, 488ml of tetrahydrofuran and 24.4g of R-type 2- (p-toluenesulfonyl) propionic acid were added, the temperature was maintained at-40℃and then 30.6g of triethylamine was slowly dropped, then 36.0g of pivaloyl chloride was slowly dropped, after the dropping was completed, the mixture was continuously stirred for 1 hour, 10.4g of 2-oxazolidone was continuously added and reacted for 5 hours to obtain a reaction solution III.
150ml of 1M aqueous hydrochloric acid solution is firstly taken and added into a reaction solution III, the reaction solution III is static and layered, aqueous phases are extracted twice by using 150ml of dichloromethane and organic phases are combined, then the organic phases are washed twice by using 150ml of saturated sodium bicarbonate and then washed twice by using 150ml of saturated salt water, finally the organic phases are dried by using sodium sulfate, filtered and concentrated under reduced pressure in sequence, and 27.6g of R-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is prepared, the LC purity is 99%, the chiral LC purity is 99% ee, the yield is: 88%.
R-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate analysis
And (3) performing high performance liquid chromatography and nuclear magnetic resonance analysis on the prepared R-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate.
The high performance liquid chromatography analysis conditions are as follows: instrument: HPLC1260; sample injection amount: 5.000 μl;
referring to fig. 2, the test results include 2 chromatographic peaks.
The nuclear magnetic resonance analysis conditions were: test frequency: 400MHz; solvent: deuterated CDCl 3 ；
Referring to FIG. 3, it is determined from the test results that the structural formula of the prepared R-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is
Example 4
This example provides a process for the preparation of S-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, comprising the following steps.
S1 preparation of S-type ethyl 2- (p-toluenesulfonyloxy) propionate
120ml of toluene was added to a three-port reaction flask equipped with a stirrer, followed by 40g of L-ethyl lactate and 64.6g of p-toluenesulfonyl chloride; 34g of triethylamine is added dropwise at the temperature of 0-5 ℃, and the reaction solution I is stirred continuously for 20h after the addition.
The stirred reaction solution I was filtered, the cake was washed twice with 120mL of toluene, the filtrate and the washing solution were combined, the combined solution was extracted with 180mL of 5wt% aqueous citric acid, and the organic phase was concentrated under reduced pressure to give 75g of ethyl S-2- (p-toluenesulfonyloxy) propionate with a LC purity of 98% or more, yield: 81.3 percent.
S2 preparation of S-2- (p-toluenesulfonyl) propionic acid
In a three-port reaction flask with a stirrer, 50ml of ethanol and 50g of ethyl S-type 2- (p-toluenesulfonyloxy) propionate were added, and at a temperature of 20℃120ml of a 1.5M aqueous LiOH solution was slowly added dropwise, and after the addition, the reaction solution II was continuously stirred for 3 hours.
Firstly, 100ml of dichloromethane is measured and added into a reaction solution II, the reaction solution II is layered, then, a 6M hydrochloric acid aqueous solution is used for leading the pH value of an aqueous phase to be 1.5, then 100ml of dichloromethane is used for carrying out two-time extraction, and organic phases are combined, and are dried by sodium sulfate, filtered and concentrated under reduced pressure in sequence, thus obtaining 44g of S-type 2- (p-toluenesulfonyl) propionic acid, the LC purity is 99 percent, and the yield is: 98%.
Analysis of S-type 2- (p-toluenesulfonyl) propionic acid
Performing high performance liquid chromatography analysis on the prepared S2-prepared S-type 2- (p-toluenesulfonyl) propionic acid;
the high performance liquid chromatography analysis conditions are as follows: instrument: HPLC1260; sample injection amount: 5.000 μl;
referring to fig. 4, the test results include 6 chromatographic peaks.
S3 preparation of S-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-port reaction flask with a stirrer, 488ml of tetrahydrofuran and 24.4g of S-type 2- (p-toluenesulfonyl) propionic acid were added, the temperature was maintained at-40℃and then 30.4g of triethylamine was slowly dropped, then 30g of pivaloyl chloride was slowly dropped, after the dropping was completed, the mixture was continuously stirred for 1 hour, 10.4g of 2-oxazolidone was continuously added and reacted for 5 hours to obtain a reaction solution III.
Firstly 150ml of 1M aqueous hydrochloric acid solution is taken and added into a reaction solution III, the reaction solution III is static and layered, aqueous phases are extracted twice by using 150ml of dichloromethane and organic phases are combined, then the organic phases are washed twice by using 150ml of saturated sodium bicarbonate and then washed twice by using 150ml of saturated salt water, finally the organic phases are dried by using sodium sulfate, filtered and concentrated under reduced pressure in sequence, thus 25g of S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate with LC purity of 99%, chiral LC purity of 99% ee and yield: 80%.
S-1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate analysis
And (3) performing high performance liquid chromatography and nuclear magnetic resonance analysis on the prepared S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate.
The high performance liquid chromatography analysis conditions are as follows: instrument: HPLC1260; sample injection amount: 5.000 μl;
referring to fig. 5, the test results include 2 chromatographic peaks.
The nuclear magnetic resonance analysis conditions were: test frequency: 400MHz; solvent: deuterated CDCl 3 ；
Referring to FIG. 6, it was determined from the test results that the structural formula of the prepared S-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate was
The foregoing is merely a preferred embodiment of the present invention, and it should be noted that modifications and variations could be made by those skilled in the art without departing from the technical principles of the present invention, and such modifications and variations should also be regarded as being within the scope of the invention.
Claims (10)
1. A process for the preparation of 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, comprising the steps of:
preparing R or S type ethyl 2- (p-toluenesulfonyloxy) propionate;
hydrolyzing the ethyl 2- (p-toluenesulfonyloxy) propionate of the R or S type to produce 2- (p-toluenesulfonyl) propionic acid of the R or S type;
adding R or S-type 2- (p-toluenesulfonyl) propionic acid and tetrahydrofuran into a reaction container, maintaining the temperature at-40 to-10 ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, and after the reaction time III is more than 30min, adding 2-oxazolidone, and after the reaction time IV is more than 3h, obtaining a reaction solution III;
quenching with hydrochloric acid, extracting with dichloromethane, alkalizing with saturated sodium bicarbonate, washing with saturated saline, drying, filtering, and concentrating the reaction solution III to obtain R or S-type 1-oxo-1- (2-oxo-oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate.
2. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 1, wherein the preparation of ethyl 2- (p-toluenesulfonyloxy) propionate of R or S form comprises the steps of:
adding p-toluenesulfonyl chloride and D-type or L-type ethyl lactate into an organic solvent I, maintaining the temperature of 0-25 ℃, and dropwise adding organic base, wherein the reaction time I is more than 7 hours, so as to obtain a reaction liquid I;
the reaction solution I is filtered, extracted and concentrated in sequence to obtain R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate.
3. A process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate as defined in claim 2,
the organic base is triethylamine or N, N-diisopropylethylamine;
the organic solvent I is toluene or methylene dichloride;
the mol ratio of the tosyl chloride to the D-type or L-type ethyl lactate is (1-1.5): 1;
the molar ratio of the organic base to the D or L-type ethyl lactate is (1-2): 1;
the volume mass ratio of the organic solvent I to the D or L-type ethyl lactate is (3-6): 1mL/g.
4. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 2, wherein the reaction time I is from 7 to 20 hours.
5. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 1, wherein the hydrolysis of ethyl 2- (p-toluenesulfonyloxy) propionate of R or S form to 2- (p-toluenesulfonyl) propionic acid of R or S form comprises the steps of:
adding ethanol and R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate into a reaction vessel, keeping the temperature between 15 and 20 ℃, adding an inorganic alkaline aqueous solution, and reacting for more than 30 minutes to obtain a reaction solution II;
sequentially extracting, acidifying, extracting, drying, filtering and concentrating the reaction solution II to obtain R or S type 2- (p-toluenesulfonyl) propionic acid.
6. The process for producing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 5, wherein,
the inorganic alkaline aqueous solution is sodium hydroxide aqueous solution or lithium hydroxide aqueous solution;
the volume-mass ratio of the ethanol to the R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate is (1-5) 1mL/g;
the mol ratio of the inorganic alkali aqueous solution to the R or S-type ethyl 2- (p-toluenesulfonyloxy) propionate is (1-2) 1;
the concentration of the inorganic alkaline aqueous solution is 1.5mol/L.
7. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 5, wherein the reaction time II is 1 to 6 hours.
8. A process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of the type according to claim 1,
the volume-mass ratio of the tetrahydrofuran to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (10-30) 1mL/g;
the mol ratio of the triethylamine to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (1-3) 1;
the mol ratio of the special acyl chloride to the R or S-type 2- (p-toluenesulfonyl) propionic acid is (1-3) 1;
the molar ratio of the 2-oxazolidone to the R or S type 2- (p-toluenesulfonyl) propionic acid is (1-3): 1.
9. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 1, wherein the reaction time III is from 0.5 to 2h.
10. The process for the preparation of 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 1, wherein the reaction time IV is 3 to 5 hours.
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