CN116514864A - Preparation method of (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid - Google Patents
Preparation method of (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid Download PDFInfo
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- CN116514864A CN116514864A CN202310473843.2A CN202310473843A CN116514864A CN 116514864 A CN116514864 A CN 116514864A CN 202310473843 A CN202310473843 A CN 202310473843A CN 116514864 A CN116514864 A CN 116514864A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
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- 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
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Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid. The preparation method of the (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid provided by the invention is a brand new preparation method and has the advantages of safety, environmental protection and easiness in large-scale production.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid.
Background
(2S, 4R) -1- (tert-Butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is an important pharmaceutical intermediate with CAS number 1374161-77-9. The preparation principle of the existing method is as follows after searching:
the method adopts Boc-L-trans-hydroxyproline as a starting material, and obtains a target product through four steps of reactions. Step one, methyl esterification reaction is carried out by adopting thionyl chloride, more hydrogen chloride and sulfur dioxide irritant gas can be generated in reaction neutralization post-treatment, and the operation is more complicated; step two adopts methyl iodide with 3A type carcinogen and lower atmospheric boiling point as a methylating agent, has stronger toxicity and is not beneficial to mass preparation, and the yield of the intermediate obtained in step three is less ideal (77%).
Therefore, it is necessary to provide a novel, safe, environment-friendly process for preparing (2S, 4R) -1- (t-butyldimethylsilyloxy) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid which is easy to mass-produce.
Disclosure of Invention
The present invention has been made to overcome the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a method for preparing (2 s,4 r) -1- (t-butyldimethylsilyloxy) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-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 (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid comprises the steps of taking Boc-L-trans-hydroxyproline as a starting material, and performing four steps of methyl esterification, TBS protection, methylation and demethylation 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 methanol, p-toluenesulfonic acid and Boc-L-trans-hydroxyproline into a reaction kettle, stirring for dissolving, heating, stirring, and refluxing for reacting for a period of time; TLC monitoring the reaction completion of the raw materials, cooling to room temperature, transferring into a rotary evaporator, concentrating the reaction liquid, adding saturated sodium bicarbonate aqueous solution and ethyl acetate extraction liquid, extracting the aqueous phase with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating the filtrate under reduced pressure to obtain an intermediate A.
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: adding dichloromethane, imidazole and an intermediate A into a reaction kettle, stirring and cooling at 0 ℃, dissolving tert-butyl dimethyl chlorosilane with dichloromethane, then dropwise adding the mixture into a reaction system for reaction, and after the addition, keeping the temperature and stirring for reaction for a period of time; TLC monitors that the raw materials are completely reacted, saturated sodium bicarbonate aqueous solution is added for separating, an organic phase is washed by saturated sodium chloride aqueous solution, the organic phase is dried by anhydrous sodium sulfate, a drying agent is removed by filtration, the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product, and the crude product is subjected to rapid silica gel column chromatography to obtain an intermediate B.
Further, the reaction in the third step is shown in a formula (III), and an intermediate C is obtained after the reaction:
further, the reaction in the third step comprises the following specific steps: adding dry tetrahydrofuran and an intermediate B into a reaction kettle, cooling and stirring at the temperature of minus 20 ℃ under the protection of nitrogen, taking tetrahydrofuran solution of lithium diisopropylamide, dripping the tetrahydrofuran solution into the reaction system by using a dry dripping funnel, carrying out heat preservation reaction for a period of time after the dripping is finished, taking methyl triflate, dripping the methyl triflate into the reaction system by using the dry dripping funnel, and carrying out heat preservation reaction for a period of time after the dripping is finished; HPLC monitors the reaction completion of the raw materials, drops saturated ammonium chloride aqueous solution to quench the reaction, adds ethyl acetate for extraction, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters to remove the desiccant, and evaporates to dryness to obtain intermediate C.
Further, the reaction in the fourth step is shown as a formula (IV), and a finished product is obtained after the reaction:
further, the reaction in the fourth step comprises the following specific steps: adding tetrahydrofuran, an intermediate C and water into a reaction kettle, stirring and dissolving at room temperature, adding lithium hydroxide into a reaction system, and carrying out heat preservation reaction for a period of time after adding; TLC monitors the completion of the reaction of the starting materials, drops saturated aqueous ammonium chloride solution to quench the reaction, extracts with ethyl acetate, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters off the drying agent, and evaporates to dryness to give the (2S, 4R) -1- (tert-butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product.
Further, the (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product is purified by the following steps: dispersing the crude product with n-hexane and methanol, heating to reflux and dissolve, stirring at a cooling rate of 10 ℃/h, cooling, crystallizing, maintaining at room temperature, stirring for a period of time, suction filtering, washing the filter cake with a solution prepared by n-hexane and methanol according to a volume ratio of 15:1, suction drying the filter cake, and vacuum drying at room temperature to obtain a refined finished product.
The beneficial effects of the invention are as follows:
the preparation of (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is carried out by taking Boc-L-trans-hydroxyproline as initial raw material, and carrying out four steps of reactions of methyl esterification, TBS protection reaction, methylation reaction and demethylation esterification reaction to obtain the finished 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 schematic diagram of LCMS detection results of the finished product of the present invention;
FIG. 2 is a schematic representation of HPLC detection results for 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: boc-L-trans-hydroxyproline
Boc: boc-group
MeOH: methanol
PTS: para-toluene sulfonic acid
TBS: tertiary butyl dimethylsilyl group
DCM: dichloromethane (dichloromethane)
LDA: lithium diisopropylamide
THF: tetrahydrofuran (THF)
The specific embodiment of the invention is as follows:
example 1
A process for the preparation of (2 s,4 r) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid, characterized in that: the preparation of the (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is to take Boc-L-trans-hydroxyproline as a starting raw material, and obtain a finished product through four steps of reactions including methyl esterification reaction, TBS protection reaction, methylation reaction and demethylation esterification reaction.
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: methanol (5.0L), PTS (59.6 g,0.2 eq) and SM (400 g,1.0 eq) were added into a reaction kettle in sequence, stirred and dissolved, heated and refluxed for 4h. TLC monitors that the raw materials are completely reacted, cooling to room temperature, transferring into a rotary evaporator, concentrating the reaction liquid to about 2L, adding saturated sodium bicarbonate aqueous solution (4L) and 5L ethyl acetate, extracting the aqueous phase twice with 2L ethyl acetate, combining the organic phase, drying with anhydrous sodium sulfate for 2h, filtering to remove a drying agent, concentrating the filtrate under reduced pressure to obtain 417.5g of crude oil of the intermediate A, and obtaining the yield of 98.4%.
Mass spectrometry: MS-ESI:246.1[ 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: dichloromethane (5L), imidazole (173.6, 1.5 eq) and intermediate a (417.5 g,1.0 eq) were added to the reaction vessel, stirred and cooled at 0 ℃, tert-butyldimethylchlorosilane (282.2 g,1.1 eq) was taken and dissolved in dichloromethane (1L), then the mixture was added dropwise to the reaction system, the mixture was reacted for 1 hour, and the reaction was carried out under heat preservation and stirring for 8 hours. TLC monitors that the raw materials are completely reacted, saturated sodium bicarbonate aqueous solution (4L) is added for separating, an organic phase is washed once by saturated sodium chloride aqueous solution (4L), 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 intermediate B pure product 545.8g is obtained by rapid silica gel column chromatography, and the yield is 89.2%.
Mass spectrometry: MS-ESI:360.4[ M+H ]] + 。
The reaction in the third step is shown in a formula (III), and an intermediate C is obtained after the reaction:
the reaction in the third step comprises the following specific steps: dried tetrahydrofuran (5L) and an intermediate B (545.8 g,1.0 eq.) are added into a reaction kettle, cooled and stirred at the temperature of minus 20 ℃ under the protection of nitrogen, 1mol/L of LDA tetrahydrofuran solution (1.67L, 1.1 eq.) is taken and added dropwise into the reaction system by using a dried dropping funnel, the reaction is carried out for 1.5 hours after the addition, the reaction is carried out for 0.5 hours after the addition, methyl triflate (266.4 g,1.05 eq.) is taken and added dropwise into the reaction system by using a dried dropping funnel, and the reaction is carried out for 6 hours after the addition. HPLC monitors the reaction completion of the raw materials, drops saturated ammonium chloride aqueous solution (4L) to quench the reaction, adds ethyl acetate (4L) to extract, extracts the aqueous phase twice with ethyl acetate (2L), combines the organic phases, dries with anhydrous magnesium sulfate, filters, evaporates to dryness to obtain intermediate C crude product 512.6g, yield: 90.4%.
Mass spectrometry: MS-ESI:374.5[ M+H ]] + 。
The fourth step of reaction is shown as a formula (IV), and a finished product is obtained after the reaction:
the reaction in the fourth step comprises the following specific steps: tetrahydrofuran (5L), intermediate C (512.6 g,1.0 eq.) and water (1L) were added to the reaction vessel, and the mixture was stirred and dissolved at room temperature, lithium hydroxide (65.9 g,2.0 eq.) was added to the reaction system, and the reaction was carried out at a constant temperature for 4 hours after the addition. TLC monitors the completion of the reaction of the raw materials, drops saturated ammonium chloride aqueous solution (4L) to quench the reaction, adds ethyl acetate (4L) to extract, extracts the aqueous phase twice with ethyl acetate (2L), combines the organic phases, dries with anhydrous magnesium sulfate, filters, and evaporates to obtain the crude product. Dispersing the crude product with n-hexane (8L) and methanol (1.5L), heating to reflux and dissolve, stirring at a cooling rate of 10 ℃/h, cooling and crystallizing, keeping the temperature and stirring for 2h at room temperature, filtering, and filtering a filter cake with n-hexane: the solution with methanol=15:1 is washed twice, the filter cake is pumped down, and the filter cake is dried for 12 hours at room temperature in vacuum, thus obtaining 411.9g of target pure product with yield: 83.5%.
Mass spectrometry: MS-ESI:360.6[ M+H ]] + 。
The results of the product related tests are shown in fig. 1-2.
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 (10)
1. A process for the preparation of (2 s,4 r) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid, characterized in that: the preparation of the (2S, 4R) -1- (tert-butyloxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid is to take Boc-L-trans-hydroxyproline as a starting raw material, and obtain a finished product through four steps of reactions including methyl esterification reaction, TBS protection reaction, methylation reaction and demethylation esterification reaction.
2. The process for preparing (2S, 4R) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 1, wherein the reaction in the first step is represented by the formula (I), wherein the intermediate A is obtained after the reaction:
3. the method for preparing (2 s,4 r) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 2, wherein the reaction of the first step comprises the following steps: sequentially adding methanol, p-toluenesulfonic acid and Boc-L-trans-hydroxyproline into a reaction kettle, stirring for dissolving, heating, stirring, and refluxing for reacting for a period of time; TLC monitoring the reaction completion of the raw materials, cooling to room temperature, transferring into a rotary evaporator, concentrating the reaction liquid, adding saturated sodium bicarbonate aqueous solution and ethyl acetate extraction liquid, extracting the aqueous phase with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering to remove a drying agent, and concentrating the filtrate under reduced pressure to obtain an intermediate A.
4. The process for preparing (2S, 4R) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 3, wherein the reaction in the second step is represented by the following formula (II):
。
5. the method for preparing (2S, 4R) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 4, wherein the second step comprises the following steps: adding dichloromethane, imidazole and an intermediate A into a reaction kettle, stirring and cooling at 0 ℃, dissolving tert-butyl dimethyl chlorosilane with dichloromethane, then dropwise adding the mixture into a reaction system for reaction, and after the addition, keeping the temperature and stirring for reaction for a period of time; TLC monitors that the raw materials are completely reacted, saturated sodium bicarbonate aqueous solution is added for separating, an organic phase is washed by saturated sodium chloride aqueous solution, the organic phase is dried by anhydrous sodium sulfate, a drying agent is removed by filtration, the filtrate is concentrated under reduced pressure to remove the solvent to obtain a crude product, and the crude product is subjected to rapid silica gel column chromatography to obtain an intermediate B.
6. The process for preparing (2S, 4R) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 5, wherein the reaction in the third step is represented by the following formula (III):
7. the method for preparing (2 s,4 r) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 6, wherein the reaction in the third step comprises the following steps: adding dry tetrahydrofuran and an intermediate B into a reaction kettle, cooling and stirring at the temperature of minus 20 ℃ under the protection of nitrogen, taking tetrahydrofuran solution of lithium diisopropylamide, dripping the tetrahydrofuran solution into the reaction system by using a dry dripping funnel, carrying out heat preservation reaction for a period of time after the dripping is finished, taking methyl triflate, dripping the methyl triflate into the reaction system by using the dry dripping funnel, and carrying out heat preservation reaction for a period of time after the dripping is finished; HPLC monitors the reaction completion of the raw materials, drops saturated ammonium chloride aqueous solution to quench the reaction, adds ethyl acetate for extraction, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters to remove the desiccant, and evaporates to dryness to obtain intermediate C.
8. The process for preparing (2S, 4R) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 7, wherein the reaction in the fourth step is as shown in formula (IV), and the final product is obtained after the reaction:
9. the method for preparing (2 s,4 r) -1- (t-butoxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 8, wherein the reaction in the fourth step is as follows: adding tetrahydrofuran, an intermediate C and water into a reaction kettle, stirring and dissolving at room temperature, adding lithium hydroxide into a reaction system, and carrying out heat preservation reaction for a period of time after adding; TLC monitors the completion of the reaction of the starting materials, drops saturated aqueous ammonium chloride solution to quench the reaction, extracts with ethyl acetate, extracts the aqueous phase with ethyl acetate, combines the organic phases and dries with anhydrous magnesium sulfate, filters off the drying agent, and evaporates to dryness to give the (2S, 4R) -1- (tert-butoxycarbonyl) -4- (tert-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product.
10. The process for preparing (2S, 4R) -1- (t-butyloxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid according to claim 9, wherein the refining of the (2S, 4R) -1- (t-butyloxycarbonyl) -4- (t-butyldimethylsilyloxy) -2-methylpyrrolidine-2-carboxylic acid product comprises the following steps: dispersing the crude product with n-hexane and methanol, heating to reflux and dissolve, stirring at a cooling rate of 10 ℃/h, cooling, crystallizing, maintaining at room temperature, stirring for a period of time, suction filtering, washing the filter cake with a solution prepared by n-hexane and methanol according to a volume ratio of 15:1, suction drying the filter cake, and vacuum drying at room temperature to obtain a refined finished product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372472A (en) * | 2007-08-24 | 2009-02-25 | 扬子江药业集团上海海尼药业有限公司 | Method for synthesizing Zofenopril |
| CN105517574A (en) * | 2013-07-09 | 2016-04-20 | 百时美施贵宝公司 | Combinations of hepatitis c virus inhibitors |
| CN112898177A (en) * | 2021-03-03 | 2021-06-04 | 浙江司太立制药股份有限公司 | Preparation method of iomeprol impurity |
| WO2023041756A1 (en) * | 2021-09-20 | 2023-03-23 | F. Hoffmann-La Roche Ag | New compounds and their use in the treatment of bacterial infection |
-
2023
- 2023-04-28 CN CN202310473843.2A patent/CN116514864A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101372472A (en) * | 2007-08-24 | 2009-02-25 | 扬子江药业集团上海海尼药业有限公司 | Method for synthesizing Zofenopril |
| CN105517574A (en) * | 2013-07-09 | 2016-04-20 | 百时美施贵宝公司 | Combinations of hepatitis c virus inhibitors |
| CN112898177A (en) * | 2021-03-03 | 2021-06-04 | 浙江司太立制药股份有限公司 | Preparation method of iomeprol impurity |
| WO2023041756A1 (en) * | 2021-09-20 | 2023-03-23 | F. Hoffmann-La Roche Ag | New compounds and their use in the treatment of bacterial infection |
Non-Patent Citations (2)
| Title |
|---|
| JOHN WATTS等: "Structure-Reactivity Studies of Simple 4-Hydroxyprolinamide Organocatalysts in the Asymmetric Michael Addition Reaction of Aldehydes to Nitroolefins", ADVANCED SYNTHESIS & CATALYSIS, vol. 354, no. 6, 12 April 2012 (2012-04-12), pages 1035 - 1042 * |
| VINCENT FEREY等: "Asymmetric Synthesis of α-Alkylproline Derivatives from a Chiral Borane−Amine Adduct: Inversion of Enantioselectivity in the Presence of a Crown Ether", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 61, no. 21, 18 October 1996 (1996-10-18), pages 7244 - 7245 * |
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