CN114213352A - Preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate - Google Patents
Preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate Download PDFInfo
- Publication number
- CN114213352A CN114213352A CN202111499811.7A CN202111499811A CN114213352A CN 114213352 A CN114213352 A CN 114213352A CN 202111499811 A CN202111499811 A CN 202111499811A CN 114213352 A CN114213352 A CN 114213352A
- Authority
- CN
- China
- Prior art keywords
- type
- oxo
- methylbenzenesulfonate
- ethyl
- propionate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methylbenzenesulfonate, which comprises the steps of preparing R or S type ethyl 2- (p-tolylsulfonyloxy) propionate; preparing 2- (p-tolylsulfonyl) propionic acid of R or S type; adding R or S type 2- (p-tolyl sulfonyl) propionic acid and tetrahydrofuran in a reaction container, maintaining the temperature at-40 to (-10) ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, and adding 2-oxazolidinone to obtain a reaction solution III; quenching with hydrochloric acid, extracting with dichloromethane, basifying with saturated sodium bicarbonate, washing with saturated brine, drying, filtering, and concentrating the reaction solution III to obtain R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) prop-2-yl 4-methylbenzenesulfonate. The invention can reduce the preparation cost of R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methyl benzene sulfonate, 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) propane-2-yl 4-methylbenzenesulfonate, belonging to the technical field of synthesis of drug intermediates.
Background
R or S type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is widely used as an important chemical or pharmaceutical intermediate, and R type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is attracting attention because it is widely used for synthesizing active drug molecules for treating various diseases. For example, the compound can be used for synthesizing medicaments 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, for example, after the chiral resolution, one chiral structure is a main active substance, and the other chiral structure is just the reason of side effect; therefore, there is a great interest in chiral compounds worldwide, and new drug lots solely use the compounds after chiral resolution as a new drug. However, the problem in the actual synthesis is that the synthesized racemate is not a single chiral structure, and if the racemate is subjected to resolution, the difficulty is high and the cost is high.
The research of the application discovers a method for preparing R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methylbenzenesulfonate with low cost, high efficiency and high yield.
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) propyl-2-yl 4-methylbenzenesulfonate, which can reduce the preparation cost of R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methylbenzenesulfonate and improve the preparation efficiency and the production rate.
In order to achieve the 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) propane-2-yl 4-methylbenzenesulfonate, which comprises the following steps:
preparing R or S type 2- (p-tolyl sulfonyl oxy) ethyl propionate;
hydrolyzing R or S type 2- (p-tolylsulfonyl oxy) ethyl propionate to generate R or S type 2- (p-tolylsulfonyl) propionic acid;
adding R or S type 2- (p-tolyl sulfonyl) propionic acid and tetrahydrofuran in a reaction container, maintaining the temperature at-40 to (-10) ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, reacting for more than 30min, then adding 2-oxazolidinone, and reacting for more than 3h to obtain a reaction solution III;
quenching with hydrochloric acid, extracting with dichloromethane, basifying with saturated sodium bicarbonate, washing with saturated brine, drying, filtering, and concentrating the reaction solution III to obtain R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) prop-2-yl 4-methylbenzenesulfonate.
Further, the preparation of R or S form of ethyl 2- (p-tolylsulfonyloxy) propionate includes the following steps:
adding p-toluenesulfonyl chloride and D or L type ethyl lactate into an organic solvent I, keeping the temperature at 0-25 ℃, dropwise adding organic base, and obtaining a reaction solution I after the reaction time I is longer than 7 hours;
the reaction solution I is sequentially filtered, extracted and concentrated to obtain R or S type ethyl 2- (p-tolylsulfonyloxy) propionate.
Further, the organic base is triethylamine or N, N-diisopropylethylamine;
the organic solvent I is toluene or dichloromethane;
the molar ratio of the p-toluenesulfonyl chloride to the D or L type ethyl lactate is (1-1.5): 1;
the molar ratio of the organic alkali to the D or L type ethyl lactate is (1-2) to 1;
the volume-mass ratio of the organic solvent I to the D or L type ethyl lactate is (3-6): 1 mL/g.
Further, the reaction time I is 7-20 h.
Further, the hydrolysis of R or S form of ethyl 2- (p-tolylsulfonyloxy) propionate to R or S form of 2- (p-tolylsulfonyl) propionic acid comprises the following steps:
adding ethanol and R or S type ethyl 2- (p-tolyl sulfonyl oxy) propionate into a reaction container, keeping the temperature at 15-20 ℃, adding an inorganic alkaline aqueous solution, and reacting for more than 30min to obtain a reaction solution II;
and sequentially extracting, acidifying, extracting, drying, filtering and concentrating the reaction solution II to obtain the R or S type 2- (p-tolylsulfonyl) 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-tolyl sulfonyl oxy) propionate is (1-5) to 1 mL/g;
the molar ratio of the inorganic alkaline aqueous solution to R or S type ethyl 2- (p-tolyl sulfonyl oxy) propionate is (1-2) to 1;
the concentration of the inorganic alkaline water solution is 1.5 mol/L.
Further, the reaction time II is 1-6 h.
Further, the volume mass ratio of the tetrahydrofuran to the R or S type 2- (p-tolylsulfonyl) propionic acid is (10-30) to 1 mL/g;
the molar ratio of the triethylamine to the R or S type 2- (p-tolylsulfonyl) propionic acid is (1-3) to 1;
the molar ratio of the special acyl chloride to R or S type 2- (p-tolyl sulfonyl) propionic acid is (1-3) to 1;
the molar ratio of the 2-oxazolidinone to the R or S type 2- (p-tolylsulfonyl) 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 following beneficial effects:
the invention realizes the preparation of R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methyl benzene sulfonate through 4 steps; the whole preparation process has mild reaction conditions, and does not need reaction conditions of ultrahigh temperature and ultralow temperature; the preparation raw materials are simple and easy to obtain, and no drug substance needs to be applied for record; the preparation cost is low, and large-scale equipment or specific customized equipment is not needed; the preparation process is relatively safe, and no toxic and harmful by-product is generated, and no high-toxicity and high-boiling intermediate is generated;
in addition, the intermediate drug R or S-form ethyl 2- (p-toluenesulfonyloxy) propionate of the present application can be prepared from p-toluenesulfonyl chloride and D or L-form ethyl lactate; the R or S type 2- (p-tolyl sulfonyl) propionic acid is generated by hydrolyzing the prepared R or S type 2- (p-tolyl sulfonyl oxy) ethyl propionate, so that the cost can be reduced, and the quality of an intermediate medicament can be controlled;
the chemical purity of the 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate obtained by the preparation method is up to 99 percent, and the yield is up to 85 percent.
Drawings
FIG. 1 is an HPLC chromatogram of R-form ethyl 2- (p-tolylsulfonyloxy) propionate of example 1 of the present invention.
FIG. 2 is a chiral HPLC chromatogram of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 1 of the present invention.
FIG. 3 is a diagram of R-type 1-oxo-1- (2-oxooxazolidin-3-yl) prop-2-yl 4-methylbenzenesulfonate as in example 1 of the present invention1H NMR spectrum.
FIG. 4 is an HPLC chromatogram of S-form 2- (p-tolylsulfonyl) propionic acid of example 1 of the present invention.
FIG. 5 is a chiral HPLC chromatogram of S-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 1 of the present invention.
FIG. 6 is a drawing showing the preparation of S-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate of example 1 of the present invention1H NMR spectrum.
Detailed Description
The preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate comprises the following steps:
s1 preparation of R or S form of ethyl 2- (p-tolylsulfonyloxy) propionate R-2 (S-2);
s2 preparation of R or S form of R-3(S-3) 2- (p-tolylsulfonyl) propionic acid;
s3 preparation of R or S form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate R-4 (S-4);
the reaction formulas of the processes from S1 to S3 are as follows:
the invention is further described below with reference to the accompanying drawings. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
This example provides a process for the preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the following steps.
S1 preparation of R-form of ethyl 2- (p-tolylsulfonyloxy) propionate
120ml of toluene is added into a three-mouth reaction bottle with a stirrer, 40g of D-ethyl lactate and 77.5g of p-toluenesulfonyl chloride are added into the reaction bottle, 51.4g of triethylamine is dropwise added under the condition of keeping the temperature at 25 ℃, and the reaction solution I is continuously stirred for 7 hours after the dropwise addition.
The stirred reaction solution i was filtered, and the filter cake was washed twice with 120mL of toluene, and after the filtrate and the washing liquids were combined, the combined solution was extracted with 180m l5 wt% aqueous citric acid solution, and the organic phase was concentrated under reduced pressure to obtain 60g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate having an LC purity of 90% or more, yield: 65 percent.
S2 preparation of R-type 2- (p-tolylsulfonyl) propionic acid
250ml of ethanol and 50g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate were added to a three-necked reaction flask with a stirrer, 245ml of a 1.5M aqueous NaOH solution was slowly dropped into the flask at 15 ℃ and the reaction solution II was stirred for 3 hours after the dropping.
First, 100ml of methylene chloride was measured and added to the reaction solution II to cause the reaction solution II to be separated into layers, then the pH of the aqueous phase was made to be 1.5 with 6M aqueous hydrochloric acid, and the aqueous phase was extracted twice with 100ml of methylene chloride to combine organic phases, which were dried over sodium sulfate, filtered and concentrated under reduced pressure in this order to obtain 38.1g of R-type 2- (p-tolylsulfonyl) propionic acid having an LC purity of 98%, yield: 85 percent.
S3 preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-necked reaction flask with a stirrer, 732ml of tetrahydrofuran and 24.4g of R-type 2- (p-tolylsulfonyl) propionic acid were added, the temperature was maintained at-10 ℃, 10.1g of triethylamine was then slowly added dropwise, 12.05g of pivaloyl chloride was then slowly added dropwise, the mixture was continuously stirred for 0.5h after the dropwise addition, 8.7g of 2-oxazolidinone was further added, and the reaction solution III was obtained after 3h of reaction.
Firstly, 150ml of 1M hydrochloric acid aqueous solution is weighed and added into reaction liquid III, the reaction liquid III is statically layered, the aqueous phase is extracted twice by 150ml of dichloromethane and the organic phase is merged, then the organic phase is washed twice by 150ml of saturated sodium bicarbonate, then the organic phase is washed twice by 150ml of saturated saline, finally the organic phase is dried by sodium sulfate, filtered and decompressed and concentrated, thus obtaining 21.9g of R type 1-oxo-1- (2-oxo oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, the purity of LC is 99%, the purity of chiral LC is 99% ee, and the yield is: 70 percent.
Example 2
This example provides a process for the preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the following steps.
S1 preparation of R-form of ethyl 2- (p-tolylsulfonyloxy) propionate
240ml of dichloromethane is firstly added into a three-mouth reaction bottle with a stirrer, 40g of D-ethyl lactate and 97g of p-toluenesulfonyl chloride are then added, 68.5g of N, N-diisopropylethylamine is dropwise added under the condition of keeping the temperature at 25 ℃, and reaction liquid I is continuously stirred for 14 hours after the dropwise addition.
The stirred reaction solution i was filtered, the filter cake was washed twice with 120mL of dichloromethane, the filtrate and the washings were combined, the combined solution was extracted with 180m l5 wt% aqueous citric acid, and the organic phase was concentrated under reduced pressure to obtain 55.3g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate having an LC purity of 85% or more, yield: 60 percent.
S2 preparation of R-type 2- (p-tolylsulfonyl) propionic acid
250ml of ethanol and 50g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate were added to a three-necked reaction flask with a stirrer, 183ml of a 1.5M aqueous solution of LiOH was slowly dropped into the flask while maintaining the temperature at 20 ℃, and the reaction solution II was stirred for 1 hour after the dropping.
First, 100ml of methylene chloride was measured and added to the reaction solution II to cause the reaction solution II to be separated into layers, then the pH of the aqueous phase was made to be 1.5 with 6M aqueous hydrochloric acid, and the organic phase was extracted twice with 100ml of methylene chloride and combined, and then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 40.4g of R-type 2- (p-tolylsulfonyl) propionic acid having an LC purity of 98% and a yield: 90 percent.
S3 preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-neck reaction flask with a stirrer, 488ml of tetrahydrofuran and 24.4g of R-type 2- (p-tolylsulfonyl) propionic acid are added, the temperature is kept at minus 30 ℃, then 20.2g of triethylamine is slowly dropped, then 24.1g of pivaloyl chloride is slowly dropped, after dropping, the mixture is continuously stirred for 2h, 26.1g of 2-oxazolidinone is continuously added, and then the reaction solution III is obtained after 5h of reaction.
Firstly, 150ml of 1M hydrochloric acid aqueous solution is weighed and added into reaction liquid III, the reaction liquid III is statically layered, 150ml of dichloromethane is used for extracting water phases twice and merging organic phases, 150ml of saturated sodium bicarbonate is used for washing the organic phases twice, 150ml of saturated saline is used for washing the organic phases twice, and finally sodium sulfate is used for drying, filtering and decompression concentration of the organic phases in sequence to obtain 25g of R type 1-oxo-1- (2-oxo oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate, the purity of LC is 99%, the purity of chiral LC is 99% ee, and the yield is as follows: 80 percent.
Example 3
This example provides a process for the preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the following steps.
S1 preparation of R-type ethyl 2- (p-tolylsulfonyloxy) propionate;
in a three-mouth reaction bottle with a stirrer, 120ml of toluene is added firstly, and then 40g of D-ethyl lactate and 64.6g of p-toluenesulfonyl chloride are added; 34g of triethylamine is added dropwise at the temperature of 0-5 ℃, and the reaction solution I is continuously stirred for 20 hours after the dropwise addition.
The stirred reaction solution i was filtered, and the filter cake was washed twice with 120mL of toluene, and after the filtrate and the washings were combined, the combined solution was extracted with 180m l5 wt% aqueous citric acid solution, and the organic phase was concentrated under reduced pressure to obtain 76g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate having an LC purity of 98% or more and a yield: 82.6 percent.
Analysis of R-form ethyl 2- (p-tolylsulfonyloxy) propionate
The R-form ethyl 2- (p-tolylsulfonyloxy) propionate thus obtained was subjected to high performance liquid chromatography.
The analysis conditions of the high performance liquid chromatography are as follows: the instrument comprises the following steps: HPLC 1260; sample introduction amount: 5.000 μ l;
referring to fig. 1, the test results included 2 chromatographic peaks, the specific parameters of which are shown in table 1.
TABLE 1 HPLC analysis parameters for R-type ethyl 2- (p-tolylsulfonyloxy) propionate
| Chromatographic peak | Retention time/min | Peak height/ | Peak area | |
| 1 | 7.384 | 1217.56763 | 3.56195386×103 | |
| 2 | 8.402 | 1.70401 | 5.41245 | |
| Total of | 1219.27163 | 3.56736631×103 |
S2 preparation of R-type 2- (p-tolylsulfonyl) propionic acid
50ml of ethanol and 50g of R-type ethyl 2- (p-tolylsulfonyloxy) propionate were added to a three-necked reaction flask with a stirrer, 147ml of a 1.5M aqueous solution of LiOH was slowly dropped into the flask while maintaining the temperature at 20 ℃, and the reaction solution II was stirred for 3 hours after the dropping.
First, 100ml of methylene chloride was measured and added to the reaction solution II to cause the reaction solution II to be separated into layers, then the pH of the aqueous phase was made to be 1.5 with 6M aqueous hydrochloric acid, the aqueous phase was extracted twice with 100ml of methylene chloride and the organic phases were combined, and the organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure in this order to obtain 43g of R-type 2- (p-tolylsulfonyl) propionic acid with an LC purity of 99%, yield: 96 percent.
S3 preparation of R-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
In a three-neck reaction flask with a stirrer, 488ml of tetrahydrofuran and 24.4g of R-type 2- (p-tolylsulfonyl) propionic acid are added, the temperature is kept at-40 ℃, then 30.6g of triethylamine is slowly dropped, then 36.0g of pivaloyl chloride is slowly dropped, after dropping, the mixture is continuously stirred for 1h, 10.4g of 2-oxazolidinone is continuously added, and then the reaction solution III is obtained after 5h of reaction.
Firstly, 150ml of 1M hydrochloric acid aqueous solution is weighed and added into reaction liquid III, the reaction liquid III is statically layered, the aqueous phase is extracted twice by 150ml of dichloromethane and the organic phase is merged, then the organic phase is washed twice by 150ml of saturated sodium bicarbonate, then the organic phase is washed twice by 150ml of saturated saline, finally the organic phase is dried by sodium sulfate, filtered and decompressed and concentrated, 27.6g of R type 1-oxo-1- (2-oxo oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate is prepared, the purity of LC is 99%, the purity of chiral LC is 99% ee, and the yield is as follows: 88 percent.
Analysis of R-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
The prepared R-type 1-oxo-1- (2-oxo oxazolidin-3-yl) prop-2-yl 4-methylbenzenesulfonate is analyzed by high performance liquid chromatography and nuclear magnetic resonance.
The analysis conditions of the high performance liquid chromatography are as follows: the instrument comprises the following steps: HPLC 1260; sample introduction amount: 5.000 μ l;
referring to fig. 2, the test results included 2 chromatographic peaks.
The nuclear magnetic resonance analysis conditions were: testing frequency: 400 MHz; solvent: deuterated CDCl3；
Referring to FIG. 3, it was judged from the test results that the R-type 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate prepared has the structural formula
Example 4
This example provides a process for the preparation of S-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, which comprises the following steps.
S1 preparation of S-form ethyl 2- (p-tolylsulfonyloxy) propionate
In a three-mouth reaction bottle with a stirrer, 120ml of toluene is firstly added, and then 40g of L-ethyl lactate and 64.6g of p-toluenesulfonyl chloride are added; 34g of triethylamine is added dropwise at the temperature of 0-5 ℃, and the reaction solution I is continuously stirred for 20 hours after the dropwise addition.
The stirred reaction solution i was filtered, and the filter cake was washed twice with 120mL of toluene, and after the filtrate and the washings were combined, the combined solution was extracted with 180m l5 wt% aqueous citric acid solution, and the organic phase was concentrated under reduced pressure to obtain 75g of form-S ethyl 2- (p-tolylsulfonyloxy) propionate having an LC purity of 98% or more, yield: 81.3 percent.
S2 preparation of S-type 2- (p-tolylsulfonyl) propionic acid
50ml of ethanol and 50g of S-type ethyl 2- (p-tolylsulfonyloxy) propionate were added to a three-necked reaction flask with a stirrer, and 120ml of a 1.5M aqueous solution of LiOH was slowly dropped into the flask at a temperature of 20 ℃ and then the reaction solution II was stirred for 3 hours.
First, 100ml of methylene chloride was measured and added to the reaction solution II to cause the reaction solution II to be separated into layers, then the pH of the aqueous phase was made to be 1.5 with 6M aqueous hydrochloric acid, and the aqueous phase was extracted twice with 100ml of methylene chloride to combine organic phases, which were dried over sodium sulfate, filtered and concentrated under reduced pressure in this order to obtain 44g of S-type 2- (p-tolylsulfonyl) propionic acid with an LC purity of 99%, yield: 98 percent.
Analysis of S-form 2- (p-tolylsulfonyl) propionic acid
Performing high performance liquid chromatography analysis on S-type 2- (p-tolylsulfonyl) propionic acid prepared from the obtained S2;
the analysis conditions of the high performance liquid chromatography are as follows: the instrument comprises the following steps: HPLC 1260; sample introduction amount: 5.000 μ l;
referring to fig. 4, the test results included 6 chromatographic peaks.
S3 preparation of S form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
488ml of tetrahydrofuran and 24.4g of S-type 2- (p-tolylsulfonyl) propionic acid are added into a three-mouth reaction bottle with a stirrer, the temperature is kept at minus 40 ℃, then 30.4g of triethylamine is slowly dropped, then 30g of pivaloyl chloride is slowly dropped, after dropping, the mixture is continuously stirred for 1h, 10.4g of 2-oxazolidinone is continuously added, and then the reaction solution III is obtained after 5h of reaction.
Firstly, 150ml of 1M hydrochloric acid aqueous solution is weighed and added into reaction liquid III, the reaction liquid III is statically layered, 150ml of dichloromethane is used for extracting water phases twice and merging organic phases, 150ml of saturated sodium bicarbonate is used for washing the organic phases twice, 150ml of saturated saline is used for washing the organic phases twice, and finally sodium sulfate is used for drying, filtering and decompression concentration of the organic phases in sequence to obtain 25g of S-type 1-oxo-1- (2-oxo oxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate, the purity of LC is 99%, the purity of chiral LC is 99% ee, and the yield is as follows: 80 percent.
Analysis of S-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate
The resulting S-form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate was subjected to high performance liquid chromatography and nuclear magnetic resonance analysis.
The analysis conditions of the high performance liquid chromatography are as follows: the instrument comprises the following steps: HPLC 1260; sample introduction amount: 5.000 μ l;
referring to fig. 5, the test results include 2 chromatographic peaks.
The nuclear magnetic resonance analysis conditions were: testing frequency: 400 MHz; solvent: deuterated CDCl3；
Referring to FIG. 6, according to the test knotThe structural formula of the S-type 1-oxo-1- (2-oxo oxazolidine-3-yl) propyl-2-yl 4-methyl benzene sulfonate prepared by fruit judgment is shown in the specification
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate is characterized by comprising the following steps:
preparing R or S type 2- (p-tolyl sulfonyl oxy) ethyl propionate;
hydrolyzing R or S type 2- (p-tolylsulfonyl oxy) ethyl propionate to generate R or S type 2- (p-tolylsulfonyl) propionic acid;
adding R or S type 2- (p-tolyl sulfonyl) propionic acid and tetrahydrofuran in a reaction container, maintaining the temperature at-40 to (-10) ℃ under the protection of nitrogen, sequentially adding triethylamine and pivaloyl chloride, reacting for more than 30min, then adding 2-oxazolidinone, and reacting for more than 3h to obtain a reaction solution III;
quenching with hydrochloric acid, extracting with dichloromethane, basifying with saturated sodium bicarbonate, washing with saturated brine, drying, filtering, and concentrating the reaction solution III to obtain R or S type 1-oxo-1- (2-oxo oxazolidine-3-yl) prop-2-yl 4-methylbenzenesulfonate.
2. The method for preparing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate according to claim 1, wherein the preparation of R or S type ethyl 2- (p-tolylsulfonyloxy) propionate comprises the following steps:
adding p-toluenesulfonyl chloride and D or L type ethyl lactate into an organic solvent I, keeping the temperature at 0-25 ℃, dropwise adding organic base, and obtaining a reaction solution I after the reaction time I is longer than 7 hours;
the reaction solution I is sequentially filtered, extracted and concentrated to obtain R or S type ethyl 2- (p-tolylsulfonyloxy) propionate.
3. The process for producing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl-4-methylbenzenesulfonate as claimed in claim 2,
the organic base is triethylamine or N, N-diisopropylethylamine;
the organic solvent I is toluene or dichloromethane;
the molar ratio of the p-toluenesulfonyl chloride to the D or L type ethyl lactate is (1-1.5): 1;
the molar ratio of the organic alkali to the D or L type ethyl lactate is (1-2) to 1;
the volume-mass ratio of the organic solvent I to the D or L type ethyl lactate is (3-6): 1 mL/g.
4. The process for preparing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl-4-methylbenzenesulfonate as claimed in claim 2, wherein the reaction time I is 7 to 20 hours.
5. The process for preparing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate as claimed in claim 1, wherein the hydrolysis of ethyl R or S type 2- (p-tolylsulfonyloxy) propanoate to R or S type 2- (p-tolylsulfonyl) propanoate comprises the steps of:
adding ethanol and R or S type ethyl 2- (p-tolyl sulfonyl oxy) propionate into a reaction container, keeping the temperature at 15-20 ℃, adding an inorganic alkaline aqueous solution, and reacting for more than 30min to obtain a reaction solution II;
and sequentially extracting, acidifying, extracting, drying, filtering and concentrating the reaction solution II to obtain the R or S type 2- (p-tolylsulfonyl) propionic acid.
6. The process for producing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl-4-methylbenzenesulfonate according to claim 5,
the inorganic alkaline water solution is sodium hydroxide water solution or lithium hydroxide water solution;
the volume mass ratio of the ethanol to the R or S type ethyl 2- (p-tolyl sulfonyl oxy) propionate is (1-5) to 1 mL/g;
the molar ratio of the inorganic alkaline aqueous solution to R or S type ethyl 2- (p-tolyl sulfonyl oxy) propionate is (1-2) to 1;
the concentration of the inorganic alkaline water solution is 1.5 mol/L.
7. The process for preparing 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl-4-methylbenzenesulfonate as claimed in claim 5, wherein the reaction time II is 1 to 6 hours.
8. The process for the preparation of form 1-oxo-1- (2-oxooxazolidin-3-yl) propan-2-yl 4-methylbenzenesulfonate as claimed in claim 1,
the volume-to-mass ratio of the tetrahydrofuran to the R or S type 2- (p-tolylsulfonyl) propionic acid is (10-30) to 1 mL/g;
the molar ratio of the triethylamine to the R or S type 2- (p-tolylsulfonyl) propionic acid is (1-3) to 1;
the molar ratio of the special acyl chloride to R or S type 2- (p-tolyl sulfonyl) propionic acid is (1-3) to 1;
the molar ratio of the 2-oxazolidinone to the R or S type 2- (p-tolylsulfonyl) propionic acid is (1-3): 1.
9. The process according to claim 1, wherein the reaction time III is 0.5 to 2 hours.
10. The process according to claim 1, wherein the reaction time IV is 3 to 5 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111499811.7A CN114213352B (en) | 2021-12-09 | 2021-12-09 | Preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111499811.7A CN114213352B (en) | 2021-12-09 | 2021-12-09 | Preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114213352A true CN114213352A (en) | 2022-03-22 |
| CN114213352B CN114213352B (en) | 2023-05-05 |
Family
ID=80700501
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111499811.7A Active CN114213352B (en) | 2021-12-09 | 2021-12-09 | Preparation method of 1-oxo-1- (2-oxo-oxazolidine-3-yl) propan-2-yl 4-methylbenzenesulfonate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114213352B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| US20080176862A1 (en) * | 2006-12-20 | 2008-07-24 | Astrazeneca Ab | New Compounds 617 |
| CN102766096A (en) * | 2012-07-20 | 2012-11-07 | 苏州汉德创宏生化科技有限公司 | Method for preparing 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid and ester thereof |
| CN104663674A (en) * | 2007-10-23 | 2015-06-03 | 杜邦公司 | Fungicidal Mixtures |
| CN107365329A (en) * | 2016-05-12 | 2017-11-21 | 华东师范大学 | A kind of preparation method of 3- methyl -2- oxos -5- heptynyl dimethyl phosphates |
| CN110423227A (en) * | 2019-08-29 | 2019-11-08 | 苏州汉德创宏生化科技有限公司 | A kind of synthetic method of 2- formoxyl -4- carboxylic acid, ethyl ester thiazole |
-
2021
- 2021-12-09 CN CN202111499811.7A patent/CN114213352B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001094342A1 (en) * | 2000-06-05 | 2001-12-13 | Dong A Pharm. Co., Ltd. | Novel oxazolidinone derivatives and a process for the preparation thereof |
| US20080176862A1 (en) * | 2006-12-20 | 2008-07-24 | Astrazeneca Ab | New Compounds 617 |
| CN104663674A (en) * | 2007-10-23 | 2015-06-03 | 杜邦公司 | Fungicidal Mixtures |
| CN102766096A (en) * | 2012-07-20 | 2012-11-07 | 苏州汉德创宏生化科技有限公司 | Method for preparing 3-difluoromethyl-1-methyl-1-hydrogen-pyrazole-4-carboxylic acid and ester thereof |
| CN107365329A (en) * | 2016-05-12 | 2017-11-21 | 华东师范大学 | A kind of preparation method of 3- methyl -2- oxos -5- heptynyl dimethyl phosphates |
| CN110423227A (en) * | 2019-08-29 | 2019-11-08 | 苏州汉德创宏生化科技有限公司 | A kind of synthetic method of 2- formoxyl -4- carboxylic acid, ethyl ester thiazole |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114213352B (en) | 2023-05-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110372487A (en) | A kind of 3-hydroxybutyrate sodium product and preparation method thereof | |
| KR101371045B1 (en) | Synthesis Method of Ramalin and Ramalin Analogues Using Glutamic Acid Derivative and Hydroxy Aniline or Hydroxy Aniline with Protected Hydroxy Group | |
| CN114213352A (en) | Preparation method of 1-oxo-1- (2-oxo oxazolidine-3-yl) propane-2-yl 4-methylbenzenesulfonate | |
| CN105399667A (en) | Preparation method of edoxaban intermediate | |
| CN112679498A (en) | Sulfonic acid quaternary ammonium salt compound and preparation method and application thereof | |
| CN110015978B (en) | Synthesis method of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine | |
| KR20110005470A (en) | Bifunctional bis-cinchona alkaloid thiourea organo catalysts, preparation method thereof, and method for preparing chiral amino acid from azlactones using the same | |
| CN101492382A (en) | Novel method for preparing levetiracetam midbody S-(+)-2-aminobutyrate hydrochlorate | |
| CN103539796B (en) | Preparation method of levo praziquantel as well as intermediate thereof | |
| CN110950818B (en) | Method for purifying cis-2, 6-dimethyl morpholine | |
| CN113214123A (en) | Synthetic method of S-trityl-L-cysteine amide | |
| CN105523957A (en) | Method for preparing Lacosamide by one-pot method | |
| CN111393426A (en) | Rivaroxaban thiophene carboxylate impurity reference substance and preparation method thereof | |
| CN111039814A (en) | Propacetamol crystal form and preparation method thereof | |
| CN114031601B (en) | Preparation method of landiolol hydrochloride | |
| CN110498750B (en) | Synthesis method of (R) -4-hydroxy-1-methoxybutyl-2-ylcarbamate | |
| CN116143695B (en) | Synthesis method of 1, 1-difluoro-5-azaspiro [2.5] octane hydrochloride | |
| CN111662233B (en) | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method | |
| CN107892666B (en) | 5-phenylpyrrole derivative and preparation method and application thereof | |
| EA026337B1 (en) | Processes for resolution of nitrogen substituted (s)-5-alkoxy-2-aminotetralin derivatives | |
| KR20010000195A (en) | Process for preparing (2r)- and (2s)-aziridine-2-carboxylates, and (2r)- and (2s)-2-hydroxymethylaziridines | |
| KR20090056527A (en) | Improved process for the preparation of atorvastatin calcium salt | |
| CN118146110A (en) | N-difluoromethyl carbonyl compound and preparation method thereof | |
| CN117551150A (en) | Ai Tuoge column cleaner synthesis method | |
| CN118063418A (en) | Preparation method of 2-methyl-7-nitrobenzofuran-4-formic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |