CN115197115A - Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid - Google Patents
Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid Download PDFInfo
- Publication number
- CN115197115A CN115197115A CN202211025942.6A CN202211025942A CN115197115A CN 115197115 A CN115197115 A CN 115197115A CN 202211025942 A CN202211025942 A CN 202211025942A CN 115197115 A CN115197115 A CN 115197115A
- Authority
- CN
- China
- Prior art keywords
- chiral
- oxopyrrolidine
- carboxylic acid
- diastereoisomers
- cas
- 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.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
Abstract
The invention belongs to the technical field of pharmaceutical chemistry and organic chiral compound preparation, and particularly relates to a preparation method and application of chiral 5-oxopyrrolidine-3-formic acid, wherein the method takes dimethyl itaconate (CAS: 617-52-7) and R (+) -p-methoxy methylbenzylamine (CAS: 22038-86-4) as starting raw materials to react to prepare a pair of diastereoisomers, and then the two diastereoisomers are separated by common silica gel column chromatography to obtain the two diastereoisomers; then the two diastereoisomers are respectively used for continuing chemical reaction, and two target chiral compounds (R) -A and (S) -A with two configurations can be obtained by ester hydrolysis and nitrogen protecting group removal, or nitrogen protecting group removal and ester hydrolysis.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and preparation of organic chiral compounds, and particularly relates to a preparation method and application of chiral 5-oxopyrrolidine-3-formic acid.
Background
5-oxopyrrolidine-3-formic acid (chemical structure is shown as A) is an important drug intermediate, for example, N-alkyl or benzyl substituted 5-oxopyrrolidine-3-formic acid is an essential intermediate raw material for synthesizing neratim; neracetam is a novel medicine (Nebrachetam) with a pyrrolidone structure, has the functions of improving brain energy metabolism and nerve transmission, and has obvious improvement effect on the dysfunction of a cholinergic system in the brain; and 5-oxo-pyrrolidine-3-formic acid with chiral R/S configuration can be used for preparing novel pyrrolidone derivatives.
In patent CN104447733A, researchers chemically couple 1-benzyl-2-pyrrolinone-4-carboxylic acid (1-benzyl-5-oxopyrrolidine-3-carboxylic acid) with 5-arylaminoyl-2-aminothiazole (Dasatinib), which is the main pharmacodynamic group fragment of Dasatinib, which is a protein kinase inhibitor antitumor drug, to obtain 1-benzyl-2-pyrrolinone-4-amide compounds, which have the following chemical structures:
the 2-pyrrolinone-4-amide compound with the dasatinib pharmacophore can effectively regulate signal conduction of tyrosine kinase, inhibit undesirable cell proliferation and blood vessel growth, and has relatively obvious antitumor activity.
In summary, 5-oxopyrrolidine-3-carboxylic acid (2-pyrrolinone-4-carboxylic acid) is a key intermediate for synthesizing nootropic drugs and antitumor compounds, and it is expected that chiral R or S configuration 5-oxopyrrolidine-3-carboxylic acid will have important practical value and wide application prospect in the field of pharmaceutical chemistry, so it is necessary to provide a preparation method and application of chiral R or S configuration 5-oxopyrrolidine-3-carboxylic acid.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method and application of chiral 5-oxopyrrolidine-3-carboxylic acid, a chiral center is introduced, each chiral intermediate product is easy to separate and purify, and the optical purity is high.
In order to achieve the technical effect of solving the technical problems, the invention is realized by the following technical scheme: a preparation method of chiral 5-oxopyrrolidine-3-formic acid is characterized by comprising the following steps:
s1, starting materials of dimethyl itaconate (CAS: 617-52-7) and R (+) -p-methoxy methyl benzylamine (CAS: 22038-86-4) are heated to react at 180 ℃.
Preferably, methanol (CH) formed in the reaction is separated out by a water separator without using any other organic solvent since both raw materials are liquid 3 OH) toThe reaction is promoted to be more complete; the equivalent molar ratio of the reaction substrates of dimethyl itaconate and R (+) -p-methoxymethyl benzylamine is 1; the reaction product is a mixture of a pair of diastereomers.
S2, separating a pair of diastereoisomers generated in the first step of reaction by adopting a common silica gel column chromatography separation method.
The two chiral compounds isolated are chemically (1R, 3R) -methyl 1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylate (the former of the product in the above reaction scheme) and (1R, 3S) -methyl 1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylate (the latter of the product in the above reaction scheme), respectively, in chemical yields of more than 60% and d.e. values of more than 90% as determined by High Pressure Liquid Chromatography (HPLC).
Preferably, the eluent used for column chromatography is petroleum ether (60-90 ℃) and ethyl acetate, and the ratio (volume ratio) is 3; petroleum ether (60-90 deg.C) can also be used in 30-60 deg.C range, or n-hexane can be used instead; the silica gel used for column chromatography can be 100-200 mesh or 200-300 mesh, preferably 200-300 mesh.
And S3, continuously reacting the two diastereoisomers separated in the previous step respectively, and hydrolyzing and removing the protecting group on nitrogen by ester, or firstly removing the protecting group on nitrogen and hydrolyzing ester to obtain the target chiral compounds (R) -A and (S) -A with two configurations.
Preferably, the two diastereoisomers obtained by column separation in S2 are oils, the molar ratio of the two diastereoisomers to lithium hydroxide (LiOH) is 1 to 1.5, the reaction uses mixed solvents of methanol and water (volume ratio is 1); the names of the two products are (1R, 3R) -1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid and (1R, 3S) -1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid, respectively; since both of these carboxylic acid intermediates are solid, their optical purity can be increased by recrystallization.
Preferably, the carboxylic acid products are also diastereomerically relatedIsomers, again with the rare earth compound ceric nitrate amine (Ce (NH) 4 ) 2 (NO 3 ) 6 ) Reacting, removing the protecting group on N (generating p-methoxyacetophenone) to obtain (3R) 5-oxopyrrolidine-3-formic acid and (3S) 5-oxopyrrolidine-3-formic acid; the molar ratio of the chiral carboxylic acid substrate to the ceric nitrate amine is 1 to 1, preferably 1; the solvent is acetonitrile and water (volume ratio is 1).
Preferably, the product (1R, 3R) or (1R, 3S) -1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid methyl ester in S2 can also be reacted with ceric amine nitrate in acetonitrile and water to remove the protecting group on N to produce two chiral 5-oxopyrrolidine-3-carboxylic acid methyl esters of configuration (3R or 3S), which are also two solids that can be purified by recrystallization to improve their optical purity; the chemical reaction conditions were the same as described in (2). Then, lithium hydroxide is used as a solvent in methanol and water to hydrolyze methyl ester, and two target products of (3R) 5-oxopyrrolidine-3-formic acid and (3S) 5-oxopyrrolidine-3-formic acid are respectively obtained; the chemical reaction conditions are the same as those described in (1); the chemical yield is also similar.
The invention also aims to provide an application of the chiral 5-oxopyrrolidine-3-carboxylic acid.
The invention has the beneficial effects that:
1. the method takes a chiral compound R (+) -p-methoxy methyl benzylamine (CAS: 22038-86-4) as a raw material for the first time, and introduces a chiral center carbon atom after the reaction with dimethyl itaconate; and the para-methoxyl of the benzene ring increases the polarity of the intermediate product, is beneficial to post-treatment and purification and separation of diastereoisomers, and has certain innovation.
2. A pair of chiral diastereoisomers generated in the first step of reaction can be conveniently separated by common silica gel column chromatography, so that other complicated and expensive methods and reagents such as chiral resolution or chiral preparative chromatography are avoided, and the optical purity (d.e value) of two chiral intermediates exceeds 90%.
3. The chiral compound in the first step after separation and purification is continuously hydrolyzed by lithium hydroxide (LiOH) to obtain (1R, 3R) or (1R, 3S) -1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid which is solid, and the optical purity (d.e value) can be improved by recrystallization and purification. Similarly, the two configurational chiral (3R/3S) -5-oxopyrrolidine-3-carboxylic acid methyl esters obtained by reaction with ceric amine nitrate to remove the protecting group on N are also solid and can be purified, again conveniently by recrystallization, to increase their optical purity (e.e. value). This effectively ensures the optical purity of the final product (3R)/(3S) -5-oxopyrrolidine-3-carboxylic acid.
4. The synthesis process has the advantages of novel route, cheap and easily-obtained raw material reagents, convenient post-treatment, mild reaction conditions and high chemical yield; especially, the chiral center is skillfully introduced, and each chiral intermediate product is easy to separate and purify and has higher optical purity; has wide application value and potential in chiral drug synthesis.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic diagram of the chemical structure;
FIG. 2 shows the reaction scheme of dimethyl itaconate (CAS: 617-52-7) and R (+) -p-methoxymethyl benzylamine (CAS: 22038-86-4) heated at 180 ℃;
FIG. 3 shows the chemical reaction formula obtained by a conventional silica gel column chromatography;
FIG. 4 shows the chemical reaction formulas of two diastereomers, which are sequentially reacted, to obtain two target chiral compounds (R) -A and (S) -A via ester hydrolysis and removal of the nitrogen-protecting group, or via removal of the nitrogen-protecting group and ester hydrolysis.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Respectively weighing and adding 15.85 g of dimethyl itaconate (0.1 mol) and 15.12 g of R (+) -p-methoxy methyl benzylamine (0.1 mol) into a round-bottom flask, heating by a silicon oil bath to react for 2-3 hours at 180 ℃, and simultaneously separating methanol generated by the reaction by using a water separator; thin layer plate spotting (TLC) the two spots of material disappeared and the reaction was stopped when about 3.5-4.0 ml of methanol had separated; after cooling the oily reaction residue, directly performing column chromatography separation on common silica gel of 200-300 meshes, sequentially using petroleum ether (60-90 ℃) and ethyl acetate as eluent, performing gradient elution according to the volume ratio (ethyl acetate: petroleum ether) from 1; the following more polar product, 9.5 g, was obtained in 68.6% yield.
The d.e. value of the optical purity is measured by using a C-18 common chromatographic column and using normal hexane and methanol as mobile phases, and measuring the d.e. values of the diastereoisomers by High Pressure Liquid Chromatography (HPLC) to be 93.56 percent of a product with smaller polarity and 95.23 percent of a product with larger polarity respectively. It is worth noting that we could not correlate the less or more polar products in the chromatography (TLC & HPLC) with the absolute configuration products, i.e. (1R, 3R) or (1R, 3S) methyl 1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylate.
Nuclear magnetic resonance hydrogen spectrum ( 1 HNMR-CDCl 3 ) And (3) structure identification: (1), less polar product: δ (ppm): 1.50 (d, 3H), 2.63-2.78 (m, 2H), 3.09 (q, 1H), 3.18 (t, 1H), 3.52 (dd, 1H), 3.72 (s, 3H), 3.80 (s, 3H), 5.44 (q, 1H), 6.86 (d, 2H), 7.22 (d, 2H). (2), more polar products: delta (ppm): 1.51 (d, 3H), 2.63-2.78 (m, 2H), 3.08-3.22 (m, 2H), 3.52 (m, 1H), 3.65 (s, 3H), 3.80 (s, 3H), 5.45 (q, 1H), 6.86 (d, 2H), 7.22 (d, 2H), and the chemical shifts of the methyl hydrogen atoms of the para-methoxy groups of the benzene ring are obviously different from the hydrogen spectrum, the polarity is small at 3.72 ppm, the polarity is large at 3.65ppm, and the like 1 HNMR spectra distinguish the significant signs of two chiral diastereomers.
Example 2
Taking 4.8 g (17.3 mmol) of the product 1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid methyl ester with lower polarity in the previous step, dissolving the oily substance with 20mL of methanol, adding 20mL of water, uniformly stirring, weighing 0.65 g (27.1 mmol) of LiOH, slowly and directly adding a solid when the amount of lithium hydroxide is small, and adding the solid after dissolving in proper amount of water if the amount of lithium hydroxide is large; stirring at room temperature for reaction for 3-4 hours, and stopping the reaction after TLC spot plate detects that substrate spots disappear; adjusting the pH of the reaction solution to be 5-6 by using 10% hydrochloric acid, evaporating methanol, adding a proper amount of water, extracting with ethyl acetate for three times, combining organic layers, washing the organic layers with saturated saline water and water once respectively, drying the organic layers with anhydrous sodium sulfate or anhydrous magnesium sulfate, and rotationally evaporating the dry organic solvent to obtain a light yellow solid; the solid was recrystallized from a white crystal using a mixed solvent (n-hexane: tetrahydrofuran = 1), and the white crystal was allowed to stand and filtered, and the mother liquor was concentrated to precipitate a solid crystal again, and the solid crystal was filtered, combined, dried, and weighed to be 4.1 g in total, and the chemical yield was 89.9%.
Nuclear magnetic resonance hydrogen spectrum ( 1 HNMR-CDCl 3 ），δ(ppm)：1.50(d, 3H), 2.70-2.84(o&qq, 2H), 3.09-3.16 (m, 1H), 3.18-3.23 (t, 1H), 3.56-3.60 (q, 1H), 3.78 (s, 3H), 5.45 (q, 1H), 5.78 (br, 1H, COOH), 6.87 (d, 2H), 7.22 (d, 2H), NMR spectrum 13 CNMR(CD Cl 3 ), δ(ppm)：16.10, 34.38, 35.86, 44.48, 48.94, 55.26, 114.01, 128.34, 131.27, 159.05, 172.41, 176.21.
In the same reaction method and conditions and post-treatment operation, 4.5 g of carboxylic acid methyl ester isomer with larger polarity is fed and hydrolyzed by lithium hydroxide to obtain 3.8 g of carboxylic acid product with another configuration, namely white solid, and the chemical yield is 88.9%. Nuclear magnetic resonance hydrogen spectrum ( 1 HNMR-CDCl 3 ），δ(ppm)：1.51(d, 3H), 2.69-2.84(m, 2H), 3.08-3.13(m, 1H), 3.18-3.24(m, 1H), 3.52-3.60(m, 1H), 3.80(s, 3H), 5.44 (q, 1H), 6.40 (br, 1H, COOH), 6.86 (d, 2H), 7.22 (d, 2H) NMR carbon Spectroscopy 13 CNMR(CD Cl 3 ), δ(ppm)：16.43, 34.56, 35.89, 44.68, 49.02, 55.38, 114.01, 128.34, 131.47, 159.13, 172.62, 176.32.
Example 3
Taking about 2.5 g (9 mmol) of either of the two chiral isomers in example 1, adding 40mL of acetonitrile and 40mL of water for dissolving, stirring uniformly, weighing 8.1 g (15 mmol) of ceric amine nitrate, adding in portions, stirring at room temperature for about 1 hour, changing the color of the reaction solution from brown red to red yellow to bright yellow, detecting the disappearance of the raw material point by TLC point plate, adding 30mL of NaHCO 3 Terminating the reaction with the aqueous solution, distilling off part of acetonitrile under reduced pressure, adding a proper amount of water, extracting with ethyl acetate for three times, combining organic layers, washing with water twice, drying with anhydrous sodium sulfate or anhydrous magnesium sulfate, and performing rotary evaporation on the dried organic solvent to obtain a jelly; the gum is separated by flash silica gel column chromatography, petroleum ether (60-90 ℃) and ethyl acetate (5) are used as eluent, the product with the strong fluorescent spot on the upper surface is collected and is sent to a flash column chromatography column after being evaporated to dryness 1 HNMR（CDCl 3 ) Identifying as a byproduct p-methoxyacetophenone; finally, the following product spots (iodine color) were eluted with ethyl acetate in dichloromethane (volume ratio 1), combined and the solvent was evaporated to dryness to give about 1.05 g of a white solid in 81.4% yield, which was identified as the product (3R/3S) -5-oxopyrrolidine-3-carboxylic acid methyl ester by nmr spectrum structure.
Nuclear magnetic resonance hydrogen spectrum ( 1 HNMR-CDCl 3 ) δ (ppm): 2.54-2.70 (o, 2H), 3.12-3.40 (q, 1H), 3.59-3.67 (m, 2H), 3.75 (s, 3H), 6.96 (br, 1H, NH) 13 CNMR, CD Cl 3 ), δ(ppm)：33.15, 38.77, 44.40, 52.45, 173.16, 176.66.
Example 4
The product (1R, 3R) or (1R, 3S) -1- (1- (4-methoxyphenyl) ethyl) -5-oxopyrrolidine-3-carboxylic acid of example 2 was subjected to oxidative deprotection of the N-protecting group using ceric amine nitrate of example 3 to give chiral target product (3R)/(3S) -5-oxopyrrolidine-3-carboxylic acid (gum). The product of methyl (3R/3S) -5-oxopyrrolidine-3-carboxylate of example 3 was hydrolyzed using lithium hydroxide of example 2 to remove the methyl ester, and the chiral target product of (3R)/(3S) -5-oxopyrrolidine-3-carboxylic acid was obtained as a gum.
In the description herein, references to the description of "one embodiment," "an example," "a specific example" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments 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 the invention for and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (6)
1. A preparation method of chiral 5-oxopyrrolidine-3-formic acid is characterized by comprising the following steps:
s1, preparing a pair of diastereoisomers by taking dimethyl itaconate (CAS: 617-52-7) and R (+) -p-methoxy methyl benzylamine (CAS: 22038-86-4) as starting raw materials;
s2, separating by common silica gel column chromatography to obtain two diastereoisomers;
and S3, respectively carrying out chemical reactions with the two diastereoisomers, and respectively carrying out ester hydrolysis and nitrogen-protecting group removal, or firstly removing the nitrogen-protecting group and then hydrolyzing the ester to respectively obtain two target compounds with chiral configurations, namely (3R) -5-oxopyrrolidine-3-carboxylic acid ((R) -A) (CAS: 428518-37-0) and (3S) -5-oxopyrrolidine-3-carboxylic acid ((S) -A) (CAS: 30948-17-5).
2. The process according to claim 1, wherein the chiral 5-oxopyrrolidine-3-carboxylic acid is prepared by: the reaction conditions of the two starting materials in the S1 are that the heating is carried out for 2 to 3 hours at the temperature of 180 ℃, and the generated methanol is fractionated.
3. The process of claim 1, wherein the chiral 5-oxopyrrolidine-3-carboxylic acid is prepared by: the purification and separation method for the two diastereoisomers generated after the two raw materials in the S2 react is common silica gel column chromatography, wherein the eluent used for the column chromatography preferentially adopts petroleum ether (60-90 ℃) and ethyl acetate, and the volume ratio is 3; petroleum ether (60-90 deg.C) can also be used in 30-60 deg.C range, or n-hexane can be used instead; the silica gel used for column chromatography can be 100-200 mesh or 200-300 mesh, preferably 200-300 mesh.
4. The process according to claim 1, wherein the chiral 5-oxopyrrolidine-3-carboxylic acid is prepared by: the hydrolysis method of the carboxylic acid methyl ester in the S3 adopts lithium hydroxide (LiOH), the molar ratio of the carboxylic acid methyl ester to the lithium hydroxide (LiOH) is 1 to 1.5, the solvent is methanol and water, the volume ratio is 1.
5. The process according to claim 1, wherein the chiral 5-oxopyrrolidine-3-carboxylic acid is prepared by: the removal of the protecting group on the nitrogen atom in S3 uses a rare earth compound ceric nitrate (Ce (NH) 4 ) 2 (NO 3 ) 6 ) The molar ratio of the chiral carboxylic acid substrate to the ceric nitrate amine is 1 to 1, the solvent is acetonitrile and water, the volume ratio is 1.
6. The process for the preparation of chiral 5-oxopyrrolidine-3-carboxylic acid according to claim 1, which discloses the use of chiral 5-oxopyrrolidine-3-carboxylic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211025942.6A CN115197115A (en) | 2022-08-25 | 2022-08-25 | Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211025942.6A CN115197115A (en) | 2022-08-25 | 2022-08-25 | Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115197115A true CN115197115A (en) | 2022-10-18 |
Family
ID=83571766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211025942.6A Pending CN115197115A (en) | 2022-08-25 | 2022-08-25 | Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115197115A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013107855A (en) * | 2011-11-22 | 2013-06-06 | Mitsubishi Tanabe Pharma Corp | Pharmaceutical composition |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
| CN105555780A (en) * | 2013-07-31 | 2016-05-04 | 吉利德科学公司 | Syk inhibitors |
| US20170107240A1 (en) * | 2013-07-03 | 2017-04-20 | Takeda Pharmaceutical Company Limited | Amide compound |
| BR102016020905A2 (en) * | 2016-09-09 | 2018-03-20 | Boehringer Ingelheim International Gmbh | REPLACED HETEROARIS PIRAZOLIL AND ITS USE AS MEDICINAL PRODUCTS |
| CN108026080A (en) * | 2015-09-11 | 2018-05-11 | 勃林格殷格翰国际有限公司 | The heteroaryl compound of pyrazolyl substitution and its purposes as medicine |
-
2022
- 2022-08-25 CN CN202211025942.6A patent/CN115197115A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013107855A (en) * | 2011-11-22 | 2013-06-06 | Mitsubishi Tanabe Pharma Corp | Pharmaceutical composition |
| CN104520300A (en) * | 2012-06-04 | 2015-04-15 | 第一三共株式会社 | Imidazo[1,2-b]pyridazine derivative as kinase inhibitor |
| US20170107240A1 (en) * | 2013-07-03 | 2017-04-20 | Takeda Pharmaceutical Company Limited | Amide compound |
| CN105555780A (en) * | 2013-07-31 | 2016-05-04 | 吉利德科学公司 | Syk inhibitors |
| CN108026080A (en) * | 2015-09-11 | 2018-05-11 | 勃林格殷格翰国际有限公司 | The heteroaryl compound of pyrazolyl substitution and its purposes as medicine |
| BR102016020905A2 (en) * | 2016-09-09 | 2018-03-20 | Boehringer Ingelheim International Gmbh | REPLACED HETEROARIS PIRAZOLIL AND ITS USE AS MEDICINAL PRODUCTS |
Non-Patent Citations (3)
| Title |
|---|
| FULVIA FELLUGA等: "A chemoenzymatic approach to the synthesis of enantiomerically pure aza analogues of paraconic acid methyl ester and both enantiomers of methyl β-proline", 《TETRAHEDRON: ASYMMETRY》, vol. 12, no. 23, pages 3241 * |
| ROBERTA GALEAZZI等: "Conformationally restricted analogues of both (S)-b-homoserine and (S)-aspartic acid from chiral 3-acylamino pyrrolidin-2-ones", 《TETRAHEDRON》, vol. 61, no. 23, pages 5465 * |
| 刘耕陶，等: "《中草药现代研究 第5卷》", 中国协和医科大学出版社, pages: 310 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112739683B (en) | Preparation method of brivaracetam and intermediate thereof | |
| WO2008062460A2 (en) | Crystalline forms of pregabalin | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| JP2691442B2 (en) | Novel proline derivative | |
| EA018376B1 (en) | New chiral intermediate, process for producing the same and its use in the manufacture of tolterodine, fesoterodine, or the active metabolite thereof | |
| EP2914574B1 (en) | New process | |
| US6090971A (en) | Resolution process for cyclohexylphenyl glycolic acid | |
| CN113214320A (en) | Preparation method of Reidesciclovir compound | |
| KR100734069B1 (en) | Process for the preparation of N5-ethylglutamine | |
| CN116751136A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN115197115A (en) | Preparation method and application of chiral 5-oxopyrrolidine-3-formic acid | |
| WO2012167413A1 (en) | Method for preparing optically pure (-)-clausenamide compound | |
| Matsuda et al. | A Practical Synthesis of threo-3-Amino-2-hydroxycarboxylic Acids. | |
| JP2002516896A (en) | Chemical method for the stereoselective synthesis of R-(-)-carnitine | |
| DK152752B (en) | METHOD OF PREPARING L-SULPIRIDE | |
| WO2021044230A1 (en) | Process for the synthesis of the sodium salt of 4-[[(lr)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)-phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-l(2h)-pyrimidinyl]-l- phenylethyl]amino]-butanoic acid (elagolix sodium salt) and intermediates of said process | |
| GB2036744A (en) | Eburnane derivatives | |
| Li et al. | Novel stereoselective syntheses of N-octyl-β-valienamine (NOV) and N-octyl-4-epi-β-valienamine (NOEV) from (−)-shikimic acid | |
| JPH0859517A (en) | Optical resolution agent and production of optically active tetrahydrofuran-carboxylic acid using the same | |
| JPH037272A (en) | Production of optically active tetrahydro-2-furoic acid | |
| US5280122A (en) | Resolution of 2-benzyl-4-piperidone-succinic acid | |
| US7122696B2 (en) | Processes for preparation of N-protected-β-amino alcohols and N-protected-β-amino epoxides | |
| KR100911720B1 (en) | A process for preparing crystal foam of sarpogrelate hcl | |
| IT202100025997A1 (en) | PROCESS FOR THE PREPARATION OF ZANUBRUTINIB | |
| CN117886708A (en) | Synthesis method of milbelin benzenesulfonate |
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 |