CN102675318A - Chiral synthesis of Eszopiclone - Google Patents
Chiral synthesis of Eszopiclone Download PDFInfo
- Publication number
- CN102675318A CN102675318A CN2011100570891A CN201110057089A CN102675318A CN 102675318 A CN102675318 A CN 102675318A CN 2011100570891 A CN2011100570891 A CN 2011100570891A CN 201110057089 A CN201110057089 A CN 201110057089A CN 102675318 A CN102675318 A CN 102675318A
- Authority
- CN
- China
- Prior art keywords
- lunesta
- pyridyl
- dihydro
- pyrazine
- compound method
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a chiral synthesis method for Eszopiclone and belongs to the technical field of medicine. The chiral synthesis method for Eszopiclone comprises the following two steps of reaction: (1), reducing under the action of a 6-(5-chlorine-2-pyridyl)-5,6-dioxo-6,7-dihydro-5H-pyrrol(3,4-b)pyrazine chiral reagent to obtain 6-(5-chlorine-2-pyridyl)-5(S)-hydroxyl-7-oxo-6,7-dihydro-5H-pyrrol(3,4-b)pyrazine; and (2), reacting the 6-(5-chlorine-2-pyridyl)-5(S)-hydroxyl-7-oxo-6,7- dihydro-5H-pyrrol(3,4-b)pyrazine with 1-chloroformyl-4-methylpiperazine hydrochloride under the action of organic base to obtain the Eszopiclone. The chiral synthesis method for the Eszopiclone has the advantages of high atom utilization ratio, short steps and advanced technology.
Description
Technical field
That the present invention relates to is a kind of preparation method of medical technical field, specifically is a kind of chirality compound method of Lunesta.
Technical background
Lunesta (Eszopiclone) is the sedative hypnotic of the latest generation of U.S. Sepracor company exploitation, goes on the market in the U.S. first in December, 2004.These article are first insomnia medicines of getting permission life-time service, can be used to improve initial sleep (having difficulty in going to sleep) for a long time and keep sleep quality (awaken night or awaken too early between morning), and market outlook are wide.
Literature search to prior art finds that prior art is (like Tetrahedron:Asymmetry 8,995-997,1997; Tetrahedron:Asymmetry11,4623-4627,2000) the preparation Lunesta generally is earlier synthetic Zopiclone, with chemistry or biological the fractionation, obtains the Lunesta of single chiral then.Not enough below prior art exists: 1. split Lunesta and the left Zopiclone that obtains equivalent, wherein left Zopiclone is useless, and the disassemble technique atom utilization is low; 2. the preparation route is long, and production cost is high.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, a kind of preparation method of Lunesta is provided, with the directly synthetic Lunesta of chiral reagent, atom utilization is high, and is reasonable in design, advanced technology.
Synthetic route of the present invention is following:
The invention provides a kind of preparation method of Lunesta, may further comprise the steps:
(1) 6-(5-chloro-2-pyridyl)-5; 7-dioxo-6,7-dihydro-5H-pyrrolo-(3,4-b) reduce down and obtain 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6 by pyrazine (compound 1) chiral reagent effect;-dihydro-5H-pyrrolo-(3,4-b) pyrazine (compound 2).
(2) 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6, (3,4-b) pyrazine (compound 2) obtains Lunesta (compound 4) with 1-chloroformyl-4-N-METHYL PIPERAZINE hydrochloride (compound 3) to 7-dihydro-5H-pyrrolo-under the organic bases effect.
In the step 1; Used chiral reduction agent can be Peng Qinghuana/D-proline(Pro), Peng Qinghuana/D-tartrate, Peng Qinghuana/D-oxysuccinic acid or POTASSIUM BOROHYDRIDE 97MIN/D-proline(Pro), POTASSIUM BOROHYDRIDE 97MIN/D-tartrate, POTASSIUM BOROHYDRIDE 97MIN/D-oxysuccinic acid; The consumption of reductive agent is the 0.2-1.0 equivalent of substrate; Solvent for use is THF or 1, the 4-dioxane, and temperature of reaction is between 0-50 ℃.Preferred reductive agent is POTASSIUM BOROHYDRIDE 97MIN/D-proline(Pro).
In the step 2, used organic bases is pyridine or triethylamine or N, and N-diisopropylethylamine or 4-Dimethylamino pyridine, the consumption of organic bases are the 2-4 equivalent of substrate, and solvent for use is a methylene dichloride, and temperature of reaction is 20-50 ℃, and the reaction times is 2-4 hour.Preferred organic bases is a triethylamine.
Description of drawings
Accompanying drawing is a synthetic route synoptic diagram of the present invention.Shown with 6-(5-chloro-2-pyridyl)-5,7-dioxo-6, (3,4-b) pyrazine is a raw material to 7-dihydro-5H-pyrrolo-, the building-up process of stereoselective synthetic Lunesta under the chiral reagent effect.
In conjunction with content of the present invention following examples are provided, but the present invention is not limited by the following examples.
Embodiment 1.
6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-(3,4-b) pyrazine (compound 1; 23.4 the gram, 0.09mol) join in 200 milliliters of THFs, drip then POTASSIUM BOROHYDRIDE 97MIN (3.1 the gram, 0.054mol)/the D-proline(Pro) (6.2 the gram; 0.054mol) solution in 50 milliliters of THFs, stirring at room reaction response 5 hours, reaction solution slowly is punched in 2 premium on currency, separates out solid; Leave standstill suction filtration, washing, drying; Get 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6, and 7-dihydro-5H-pyrrolo-(3,4-b) pyrazine (compound 2) yellow powder 16.4 grams.(molar yield 70%)
6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6, and 7-dihydro-5H-pyrrolo-(3,4-b) pyrazine (compound 2,4.5 grams; 0.018mol) join in 50 milliliters of methylene dichloride, add successively triethylamine (7 milliliters, 0.051mol), 1-chloroformyl-N methyl piperazine hydrochloride (compound 3; 5.1 gram, 0.026mol), back flow reaction 3 hours, cooling; Suction filtration, mother liquor is concentrated into dried, adds 100 ml waters and stirs suction filtration; Washing, drying, the acetonitrile crystallization gets Lunesta (compound 4) off-white color crystalline powder 4.0 grams.(molar yield 57%)
Claims (7)
1. the chirality compound method of a Lunesta is characterized in that, comprises following two-step reaction:
(1) 6-(5-chloro-2-pyridyl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo-(3,4-b) effect of pyrazine chiral reagent is reduced down and is obtained 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6, and 7-dihydro-5H-pyrrolo-(3,4-b) pyrazine.
(2) 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6, (3,4-b) pyrazine and 1-chloroformyl-4-N-METHYL PIPERAZINE hydrochloride obtains Lunesta to 7-dihydro-5H-pyrrolo-under the organic bases effect.
2. the chirality compound method of Lunesta according to claim 1 is characterized in that, 6-(5-chloro-2-pyridyl)-5 in the step (1); 7-dioxo-6, (3,4-b) pyrazine reduces with chiral reagent 7-dihydro-5H-pyrrolo-; Be reflected in the solvent and carry out, temperature of reaction is between 0-50 ℃.
3. the chirality compound method of Lunesta according to claim 2; It is characterized in that chiral reagent is Peng Qinghuana/D-proline(Pro), Peng Qinghuana/D-tartrate, Peng Qinghuana/D-oxysuccinic acid or POTASSIUM BOROHYDRIDE 97MIN/D-proline(Pro), POTASSIUM BOROHYDRIDE 97MIN/D-tartrate, POTASSIUM BOROHYDRIDE 97MIN/D-oxysuccinic acid.
4. the chirality compound method of Lunesta according to claim 3 is characterized in that, the consumption of chiral reagent is the 0.2-1.0 equivalent of substrate.
5. the chirality compound method of Lunesta according to claim 1 is characterized in that, solvent is THF or 1, the 4-dioxane.
6. the chirality compound method of Lunesta according to claim 1; It is characterized in that; 6-(5-chloro-2-pyridyl)-5 (S)-hydroxyl-7-oxo-6 in the step (2); (3,4-b) pyrazine and 1-chloroformyl-4-N-METHYL PIPERAZINE hydrochloride reacts under the organic bases effect 7-dihydro-5H-pyrrolo-, and temperature of reaction is between 20-50 ℃.
7. the chirality compound method of Lunesta according to claim 6 is characterized in that, organic bases is pyridine or triethylamine or N, N-diisopropylethylamine or 4-Dimethylamino pyridine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100570891A CN102675318A (en) | 2011-03-10 | 2011-03-10 | Chiral synthesis of Eszopiclone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100570891A CN102675318A (en) | 2011-03-10 | 2011-03-10 | Chiral synthesis of Eszopiclone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102675318A true CN102675318A (en) | 2012-09-19 |
Family
ID=46807929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100570891A Pending CN102675318A (en) | 2011-03-10 | 2011-03-10 | Chiral synthesis of Eszopiclone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102675318A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503881A (en) * | 2015-12-11 | 2016-04-20 | 天津华津制药有限公司 | Preparation method for pyrrolo-pyrazine |
-
2011
- 2011-03-10 CN CN2011100570891A patent/CN102675318A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503881A (en) * | 2015-12-11 | 2016-04-20 | 天津华津制药有限公司 | Preparation method for pyrrolo-pyrazine |
| CN105503881B (en) * | 2015-12-11 | 2017-10-10 | 天津华津制药有限公司 | A kind of preparation method of Pyrrolopyrazine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102584795B (en) | Preparing method of crizotinib | |
| CN101307015B (en) | Process for preparing cilastatin sodium | |
| CN101219997B (en) | Synthesis of 2-chlorine-5- amido pyrimidine | |
| CN103396451B (en) | The preparation method of tenofovir disoproxil fumarate intermediate | |
| CN102617481A (en) | Preparation method of rosuvastatin calcium | |
| CN102702232A (en) | Method for preparation of fine cefamandole nafate | |
| CN102321086B (en) | Synthesizing method of adenine | |
| CN102391128B (en) | Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate | |
| CN102675318A (en) | Chiral synthesis of Eszopiclone | |
| CN103601777A (en) | Preparation method of capecitabine | |
| CN102453023A (en) | Production process of azelnidipine | |
| CN105315286A (en) | Preparation of Sitagliptin | |
| CN101033234A (en) | Direct process for the production of the dihydrochloride of an amino acid | |
| CN102351861A (en) | Industrial preparation method of ertapenem | |
| CN102675319A (en) | Method for preparing dexzopiclone | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| CN102603740B (en) | Synthetic method of 4-nitro-7-azaindole | |
| CN104151291A (en) | Preparation method for benzoic acid alogliptin polycrystalline type crystal | |
| CN104177408B (en) | (Z) preparation method of-2-(5-dichlor-phosphoryl amino-1,2,4-thiadiazoles-3-base)-2-ethoxyimino chloroacetic chloride | |
| CN103030599B (en) | Gefitinib intermediate and preparation method thereof | |
| CN101906052B (en) | Method for preparing D-m-hydroxyphenylglycine | |
| CN101239984A (en) | Penicillin G sulfoxide composite crystal and preparation method thereof | |
| CN101555248B (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| CN103539789A (en) | Preparation method of quinazoline derivative as tyrosine kinase inhibitor | |
| CN103113392B (en) | A kind of preparation method of Prulifloxacin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120919 |