CN116396241A - Preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid - Google Patents
Preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid Download PDFInfo
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- CN116396241A CN116396241A CN202310384645.9A CN202310384645A CN116396241A CN 116396241 A CN116396241 A CN 116396241A CN 202310384645 A CN202310384645 A CN 202310384645A CN 116396241 A CN116396241 A CN 116396241A
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- JCBPETKZIGVZRE-SCSAIBSYSA-N (2r)-2-aminobutan-1-ol Chemical compound CC[C@@H](N)CO JCBPETKZIGVZRE-SCSAIBSYSA-N 0.000 claims abstract description 9
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 230000010933 acylation Effects 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- 239000002274 desiccant Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010791 quenching Methods 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002131 composite material Substances 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 14
- 239000007858 starting material Substances 0.000 abstract description 9
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 238000010586 diagram Methods 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 2
- LQRGWGOFPUXNOV-SSDOTTSWSA-N tert-butyl n-[(2r)-1-hydroxybutan-2-yl]carbamate Chemical compound CC[C@H](CO)NC(=O)OC(C)(C)C LQRGWGOFPUXNOV-SSDOTTSWSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid, wherein 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 a starting material, and the (R) -2-amino-1-butanol is subjected to acylation cyclization reaction, oxone oxidation reaction and Boc protection reaction to obtain a finished product. The preparation method of the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-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
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid.
Background
Tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid as important medical intermediate with CAS number of 1417287-40-1 and molecular formula of C 9 H 17 NO 5 S。
Through searching, the prior preparation methods of the tertiary butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid mainly comprise two methods:
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 method mainly adopts N-Boc- (R) -2-amino-1-butanol as a starting material. Step one, adopting thionyl chloride/pyridine for acylation reaction, so that the post-treatment is complicated, and the cyclization yield is not ideal; the second step adopts heavy metal catalyst ruthenium trichloride, which is expensive and is unfavorable for mass preparation;
2) The principle of the second preparation method is as follows:
Ref:1)CN202010253576.
the method mainly adopts N-Boc- (R) -2-amino-1-butanol as a starting material, and synthesizes a target product by a one-step method. However, the reaction solvent is used in a large amount, and the sulfonyl chloride with higher toxicity and poorer safety is used as an acylating agent, so that the mass preparation is difficult.
Therefore, there is a need to provide a novel, safe, environment-friendly process for preparing tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid which is easy to produce in a large scale.
Disclosure of Invention
The present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a process for preparing t-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
a preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is characterized in that (R) -2-amino-1-butanol is used as a starting material for preparing the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid, and the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is subjected to three steps of reaction, namely, acylation cyclization reaction, oxone oxidation reaction and Boc protection reaction to obtain a finished product.
Further, the reaction in the first step is shown as a formula (I), and an intermediate A is obtained after the reaction:
further, the reaction in 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.
Further, the reaction in the second step is shown in a formula (II), and an intermediate B is obtained after the reaction:
further, the reaction of the second step comprises the following specific steps: 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.
Further, the reaction in the third step is shown in a formula (III), and a finished product is obtained after the reaction:
further, 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.
Further, the finished 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 invention are as follows:
the preparation of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is carried out by taking (R) -2-amino-1-butanol as initial raw material, and carrying out three steps of acylation cyclization reaction, oxone oxidation reaction and Boc protection reaction to obtain the final product; the preparation method is a brand new preparation method and has the advantages of safety, environmental protection and easy scale-up production.
Of course, it is not necessary for any one product to practice the invention to achieve all of the advantages set forth above at the same time.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed for the description of the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing the NMR detection result of the product of the present invention;
FIG. 2 is a second diagram of the NMR detection result of the product of the invention;
FIG. 3 is a schematic diagram of the result of the determination of the optical rotation value of the finished product of the invention;
FIG. 4 is a schematic diagram of LCMS detection results of the finished product of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The concrete terms of the embodiment are as follows:
SM: (R) -2-amino-1-butanol
DMAP: 4-dimethylaminopyridine
TEA: triethylamine
DCM: dichloromethane (dichloromethane)
Oxone: potassium hydrogen persulfate composite salt
Boc-Cl: chloroformate tert-Ding Yangzhi
Boc: boc-group
MeCN: acetonitrile
The specific embodiment of the invention is as follows:
example 1
A preparation method of tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is characterized in that (R) -2-amino-1-butanol is used as a starting material for preparing the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid, and the tert-butyl (R) -4-ethyl-2, 2-dioxide-1, 2, 3-oxathiazolidine-3-carboxylic acid is subjected to three steps of reaction, namely, acylation cyclization reaction, oxone oxidation reaction and Boc protection reaction to obtain a finished product.
The reaction in the first step is shown in a formula (I), and an intermediate A is obtained after the reaction:
the reaction in the first step comprises the following specific steps: dried DCM (3.0L), TEA (340.1 g,1.5 eq), SM (200 g,1.0 eq) and DMAP (54.8 g,0.2 eq) are added into a reaction kettle in sequence, stirred and dissolved, stirred and cooled at-20 ℃ under the protection of nitrogen, DCM (1L) is taken to dissolve sulfoxide chloride (280.4 g,1.05 eq), dropwise added into the reaction system, and the reaction is carried out for 4 hours after 1 hour. TLC monitored complete reaction of the starting material, quenched by addition of saturated aqueous sodium bicarbonate (2L), washed once with saturated aqueous ammonium chloride (2L), dried over anhydrous sodium sulfate for 2h, filtered to remove the drying agent, and the filtrate concentrated under reduced pressure to give 273.7g of crude intermediate A oil in 90.2% yield.
Mass spectrometry: MS-ESI:136.0[ M+H ]] +
The reaction in the second step is shown in a formula (II), and an intermediate B is obtained after the reaction:
the second step of reaction comprises the following specific steps: acetonitrile (3L) and water (1L) were added to the reaction vessel, intermediate A (273.7 g,1.0 eq) was added to the reaction vessel, oxone (1367.5 g,1.1 eq) was added to the reaction system, and the temperature was raised to 80℃and the reaction was stirred for 4 hours. TLC monitors that the raw materials are completely reacted, water (2L) is added for separating, an organic phase is washed once by saturated sodium chloride aqueous solution (3L), the organic phase is dried by anhydrous sodium sulfate, the filtrate is filtered, the solvent is removed by decompression concentration, crude products are obtained, and the crude products are subjected to rapid silica gel column chromatography, thus obtaining 288.6g of pure intermediate B, and the yield is 94.3%.
Mass spectrometry: MS-ESI:152.0[ M+H ]] + 。
The reaction in the third step is shown in the formula (III), and a finished product is obtained after the reaction:
the reaction in the third step comprises the following specific steps: IM2 (288.6 g,1.0 eq.) was added to the reactor, meCN (4L), TEA (288.0 g,1.5 eq.) and DMAP (46.4 g,0.2 eq.) were added and stirred well, boc-Cl (389.3 g,1.5 eq.) was added dropwise at room temperature, after addition, the reaction was allowed to proceed for 8h at 60 ℃, TLC monitored the starting material was complete, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate solution (4L), extracted with ethyl acetate (4L), the aqueous phase was extracted twice with ethyl acetate (2L), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and the crude product obtained was purified by column chromatography to give 432.4g of the final product, yield: 90.5%.
Mass spectrometry: MS-ESI:274.1[ M+Na] + 。
The results of the product related tests are shown in fig. 1 to 4.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not exhaustive or to limit the invention to the precise form disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
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.
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.
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.
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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