CN112645833A - Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid - Google Patents
Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid Download PDFInfo
- Publication number
- CN112645833A CN112645833A CN202110122652.2A CN202110122652A CN112645833A CN 112645833 A CN112645833 A CN 112645833A CN 202110122652 A CN202110122652 A CN 202110122652A CN 112645833 A CN112645833 A CN 112645833A
- Authority
- CN
- China
- Prior art keywords
- compound
- diamino
- acid
- generate
- reacting
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid. Mainly solves the technical problem of the amplified production of (S) -2, 6-diamino-5-oxohexanoic acid. The synthesis method comprises the following steps: in a mixed solution of water and acetone, L-2-aminoadipic acid reacts with 9-fluorenylmethyl-N-succinimidyl carbonate to generate a compound 1; under the catalysis of p-toluenesulfonic acid, reacting the compound 1 with paraformaldehyde in a toluene solution to generate a compound 2; reacting the compound 2 with di-tert-butyl dicarbonate, pyridine and ammonium carbonate in an ethyl acetate solution at room temperature to generate a compound 3; in a mixed solution of ethanol and water, the compound 3 reacts with lithium hydroxide to produce the target compound 4. As derivatives of (S) -2-aminoadipic acid, (S) -2, 6-diamino-5-oxohexanoic acid has become an important intermediate for the synthesis of alpha-aminoadipic acid peptides.
Description
Technical Field
The invention relates to a method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid (CAS: 7433-32-1).
Background
With the intensive research on cephalosporin antibiotics, alpha-aminoadipic acid peptide has been isolated as a degradation product of antibiotics. Because of the structural similarity to the glutamic acid peptide, the pharmaceutical and biological activities of α -aminoadipic acid peptide are increasingly valued by pharmacologists; as derivatives of (S) -2-aminoadipic acid, (S) -2, 6-diamino-5-oxohexanoic acid is becoming an important intermediate for the synthesis of α -aminoadipic acid peptides.
A synthesis method reported in the chemical Kuntze (chem. pharm. Bull) by Ito (Yoshifuji) et al in 1987, using ruthenium tetroxide as an oxidizing agent, yielded the target compound 4; a new synthetic method was reported in Tetrahedron (Tetrahedron) by satherland, 2010, et al, but the intermediates and the target products need to be purified by chromatography columns. None of the above methods is suitable for scale-up production.
Disclosure of Invention
The invention mainly aims to provide a method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid, which mainly solves the technical problem that the synthesis of the (S) -2, 6-diamino-5-oxohexanoic acid is not suitable for large-scale production at present.
The technical scheme of the invention is as follows: a method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid is characterized by comprising the following steps: step one, in a mixed solution of water and acetone, reacting L-2-aminoadipic acid with 9-fluorenylmethyl-N-succinimidyl carbonate to generate a compound 1; secondly, reacting the compound 1 with paraformaldehyde in a toluene solution under the catalysis of p-toluenesulfonic acid to generate a compound 2; thirdly, reacting the compound 2 with di-tert-butyl dicarbonate, pyridine and ammonium carbonate in an ethyl acetate solution at room temperature to generate a compound 3; and fourthly, reacting the compound 3 with a lithium hydroxide aqueous solution in a mixed solution of ethanol and water, hydrolyzing to generate carboxylic acid, and removing the protecting group to generate the target compound 4. The synthesis route is as follows:
in the fourth step, the compound 3 reacts with 2 equivalents of lithium hydroxide aqueous solution; in the fourth step, after the reaction is finished, the pH value of the reaction solution is adjusted to 6-7 by using 1N hydrochloric acid; the fourth step, after adjusting the pH value, concentrating at 50 ℃ to remove ethanol, and then washing the water phase with ethyl acetate; and in the fourth step, the water phase is decompressed and concentrated at the temperature of 50 ℃ to obtain the target compound 4.
The invention has the beneficial effects that: the invention discovers in research that in a four-step reaction process by using L-2-aminoadipic acid, 9-fluorenylmethyl-N-succinimidyl carbonate, lithium hydroxide and the like as raw materials, an intermediate compound 3 reacts with a lithium hydroxide aqueous solution, and can remove protective groups while hydrolyzing to generate carboxylic acid, thereby providing a novel method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid. Compared with the reported method, the method has the advantages of simple raw materials, simple purification of the intermediate and the target compound, high yield of 93 percent and suitability for the scale-up production of (S) -2, 6-diamino-5-oxohexanoic acid.
Detailed Description
Step 1:
water (400 mL) and L-2-aminoadipic acid (80.0 g, 0.50 mol) were added to a 2L reaction flask, sodium bicarbonate (126.0 g, 1.50 mol) was added, Fmoc-OSu (175.8 g, 0.52 mol) and acetone (800 mL) were added, the reaction was allowed to react overnight at room temperature, the reaction mixture was concentrated under reduced pressure at 50 ℃ and then water (400 mL) was added, extracted with ethyl acetate (300 mL. times.2), impurities were washed off, the aqueous phase was adjusted to pH 3-4 with citric acid, extracted again with ethyl acetate (300 mL. times.2), the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated at 50 ℃ to give a white solid, Compound 1 (166 g, 0.43 mol, 96%). LC-MS (ESI) M/z 382.13 [ M-H ]]+。
Step 2:
toluene (1L) and Compound 1 (166.0 g, 0.43 mol) were charged in a 2L reaction flask, and paraformaldehyde (39.0 g, 1.30 mol) and p-toluenesulfonic acid (11.0 g, 0.06 mol) were added, followed by heating and refluxing for 1 hour. After cooling to room temperature, the mixture was diluted with ethyl acetate (1L), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated at 50 ℃ to give compound 2 (169 g, 0.42 mol, 98%) as a yellow liquid. LC-MS (ESI) M/z 396.16 [ M + H [ ]]+。
And step 3:
A2L reaction flask was charged with ethyl acetate (1L), compound 2 (260 g, 0.66 mol), di-tert-butyl dicarbonate (172.4 g,0.79 mol) and pyridine (62.5 g, 0.79 mol) at room temperature for 30 minutes, ammonium carbonate (96.1 g, 1.00 mol) was added, stirring was carried out at room temperature overnight, 1N hydrochloric acid (1L) was added, the organic phase was washed with water (1L), dried over anhydrous sodium sulfate, filtered and concentrated at 50 ℃ to give compound 3 (256.1 g, 065 mol, 98%) as a pale yellow viscous liquid. LC-MS (ESI) M/z 395.18 [ M + H [ ]]+。
And 4, step 4:
ethanol (300 mL) and Compound 3 (70 g, 177.8 m mol) were added to a 1L reaction flask, and a lithium hydroxide solution (LiOH) was added thereto with stirring.H2O：14.9 g，350 mmol； H2O: 300 mL), stirred at room temperature overnight. The reaction solution was adjusted to pH 6-7 with 1N hydrochloric acid and concentrated at 50 ℃ to remove the organic phase. The aqueous phase was washed with ethyl acetate (300 mL) and concentrated under reduced pressure at 50 ℃ to give title compound 4 (26.4 g, 165 mmol, 93%) as a white solid.1H NMR (400 MHz, D2O) 3.89（t, J = 6.2 Hz, 1H），2.42-2.48（m，2H） 1.83-1.97（m, 2H），1.65-1.80（m ,2H）；LC-MS (ESI): m/z 161.11 [M+H]+。
Claims (5)
1. A method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid is characterized by comprising the following steps: the method comprises the following steps: step one, in a mixed solution of water and acetone, reacting L-2-aminoadipic acid with 9-fluorenylmethyl-N-succinimidyl carbonate to generate a compound 1; secondly, reacting the compound 1 with paraformaldehyde in a toluene solution under the catalysis of p-toluenesulfonic acid to generate a compound 2; thirdly, reacting the compound 2 with di-tert-butyl dicarbonate, pyridine and ammonium carbonate in an ethyl acetate solution at room temperature to generate a compound 3; fourthly, in a mixed solution of ethanol and water, reacting the compound 3 with a lithium hydroxide aqueous solution, hydrolyzing to generate carboxylic acid, and removing a protecting group to generate a target compound 4; the synthesis route is as follows:
2. the method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid according to claim 1, wherein: in the fourth step, compound 3 is reacted with 2 equivalents of aqueous lithium hydroxide solution.
3. The method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid according to claim 1, wherein: and in the fourth step, after the reaction is finished, the pH value of the reaction solution is adjusted to 6-7 by using 1N hydrochloric acid.
4. The method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid according to claim 1, wherein: and the fourth step, after adjusting the pH value, concentrating at 50 ℃ to remove ethanol, and then washing the aqueous phase with ethyl acetate.
5. The method for synthesizing (S) -2, 6-diamino-5-oxohexanoic acid according to claim 1, wherein: and in the fourth step, the water phase is decompressed and concentrated at the temperature of 50 ℃ to obtain the target compound 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110122652.2A CN112645833A (en) | 2021-01-29 | 2021-01-29 | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110122652.2A CN112645833A (en) | 2021-01-29 | 2021-01-29 | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112645833A true CN112645833A (en) | 2021-04-13 |
Family
ID=75371129
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110122652.2A Withdrawn CN112645833A (en) | 2021-01-29 | 2021-01-29 | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112645833A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102570658B1 (en) | 2022-10-12 | 2023-08-25 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method |
| KR102634384B1 (en) | 2023-03-28 | 2024-02-06 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and their derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080300251A1 (en) * | 2005-09-05 | 2008-12-04 | Sattigeri Jitendra A | Derivatives of 3-Azabicyclo[3.1.0] Hexane as Dipeptidyl Peptidase-IV Inhibitors |
| US20180127463A1 (en) * | 2015-02-25 | 2018-05-10 | William Marsh Rice University | Desacetoxytubulysin h and analogs thereof |
| CN112174854A (en) * | 2020-10-16 | 2021-01-05 | 上海吉奉生物科技有限公司 | Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid |
-
2021
- 2021-01-29 CN CN202110122652.2A patent/CN112645833A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080300251A1 (en) * | 2005-09-05 | 2008-12-04 | Sattigeri Jitendra A | Derivatives of 3-Azabicyclo[3.1.0] Hexane as Dipeptidyl Peptidase-IV Inhibitors |
| US20180127463A1 (en) * | 2015-02-25 | 2018-05-10 | William Marsh Rice University | Desacetoxytubulysin h and analogs thereof |
| CN112174854A (en) * | 2020-10-16 | 2021-01-05 | 上海吉奉生物科技有限公司 | Process for preparing (S) -2- ((9H-fluorene-9-methoxy carbonyl) methylamino) -5-amino-5-oxo pentanoic acid |
Non-Patent Citations (2)
| Title |
|---|
| SHIGEYUKI YOSHIFUJI 等: "Chemical conversion of L-α,ω-diamino acids to L-ω-carbamoyl-α-amino acids by ruthenium tetroxide oxidation", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| 刘建等: "具有抗糖尿病活性(拟)二肽分子的设计、合成及生物活性", 《中国科学:化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102570658B1 (en) | 2022-10-12 | 2023-08-25 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method |
| KR102634384B1 (en) | 2023-03-28 | 2024-02-06 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and their derivatives |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN111153818B (en) | Method for preparing antiviral drug Tamiflu intermediate tert-butylamine derivative I | |
| WO2017096996A1 (en) | Preparation method for cobimetinib | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| CN107501112A (en) | A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN110054574B (en) | Synthesis method of fluorenylmethyloxycarbonyl-2, 3-dehydro-valine | |
| US3878043A (en) | Method for preparing L-dopa and novels compounds useful therein | |
| CN112225647A (en) | Method for synthesizing 5-bromo-2-methoxyphenol | |
| CN110551123A (en) | Preparation method of 5- (tert-butyloxycarbonyl) -2-methyl-4, 5,6, 7-tetrahydro-2H-pyrazolo [4,3-C ] pyridine-7-carboxylic acid | |
| KR20010066863A (en) | Process for producing erythro-3-amino-hydroxybutyric acid derivatives | |
| CN114315609A (en) | Process for preparing cis-2-aminocyclohexanol | |
| CN108947908B (en) | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof | |
| CN111943870A (en) | Synthesis method of L-2- (9H-fluorene-9-methoxycarbonylamino) -3-iodopropionic acid methyl ester | |
| US6610855B2 (en) | Synthesis of 3-amino-3-aryl propanoates | |
| CN111662233B (en) | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method | |
| CN114989045B (en) | Intermediate for synthesizing Namactetvir and preparation method thereof and method for synthesizing Namactetvir | |
| CN113004245B (en) | Preparation method of desloratadine | |
| CN113387874B (en) | Method for synthesizing 6, 6-dialkyl piperidine-2-carboxylic acid compound | |
| CN113372235B (en) | Process for preparing 1-amino-2-phenylcyclopropanecarboxylic acids | |
| CN111471001B (en) | Preparation method of 4- [ (1R) -1-amino-2-hydroxyethyl ] -3-fluoro-benzonitrile | |
| CN111039838B (en) | Preparation method of 3-acetylmercapto-2-methylpropanoic acid | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN117658879A (en) | Method for preparing (S) -2-methyl cysteine hydrochloride | |
| CN114436877A (en) | Synthesis process of heart failure resistant drug Shakuba koji |
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 | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210413 |
|
| WW01 | Invention patent application withdrawn after publication |