CN111116498A - Preparation method of homopiperazine-5-ketone hydrochloride - Google Patents
Preparation method of homopiperazine-5-ketone hydrochloride Download PDFInfo
- Publication number
- CN111116498A CN111116498A CN201911279662.6A CN201911279662A CN111116498A CN 111116498 A CN111116498 A CN 111116498A CN 201911279662 A CN201911279662 A CN 201911279662A CN 111116498 A CN111116498 A CN 111116498A
- Authority
- CN
- China
- Prior art keywords
- hydrochloride
- homopiperazine
- ketone
- homopiperazin
- ethyl acetate
- 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
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of homopiperazine-5-ketone hydrochloride, which is characterized by comprising the following steps: 4-piperidone hydrochloride reacts with sodium azide to generate homopiperazine-5-ketone; and reacting the homopiperazine-5-ketone with hydrochloric acid in a solvent to obtain homopiperazine-5-ketone hydrochloride. Compared with the prior art, the method has the advantages of short synthetic route, easily obtained and cheap raw materials, capability of obtaining the high piperazine-5-ketone hydrochloride with high yield and high purity, and easy industrial production.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, relates to a preparation process of a medical intermediate, and particularly relates to a preparation method of a compound homopiperazine-5-ketone hydrochloride.
Background
Homopiperazine-5-ketone and its derivative are important medicine intermediate. It has wide biological and pharmaceutical activities, including antibacterial (Bioorg Med Chem Lett. 2012, 3816-21, WO 2006/056877), anti-HIV viral (Bioorg Med Chem Lett.2011,398-404), herbicide performance (Farmaco.1996, 609-. Homopiperazine compounds are inhibitors of human nitric oxide synthesis (J.enzyme inhib. Med.chem. 2007, 709-.
At present, the synthesis method of homopiperazine-5-ketone hydrochloride mainly comprises the following steps: 1) generating oxime by 4-piperidone protected by benzyl or benzyloxycarbonyl and hydroxylamine hydrochloride; then enlarging ring to obtain homopiperazine-5-ketone protected by benzyl or benzyloxycarbonyl, then deprotecting to obtain homopiperazine-5-ketone, and finally salifying to obtain the compound; 2) one-step cyclization of ethylenediamine and methyl acrylate to obtain homopiperazine-5-ketone, and salifying to obtain the final product. The main disadvantages of the above methods are long process, expensive raw materials, not easy to obtain, low yield and not easy to industrialize.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a preparation method for obtaining homopiperazine-5-ketone hydrochloride by taking 4-piperidone hydrochloride and sodium azide as raw materials to react.
In order to achieve the purpose, the invention adopts the technical scheme that: a preparation method of homopiperazine-5-ketone hydrochloride is provided, which is characterized in that: 4-piperidone hydrochloride reacts with sodium azide to generate homopiperazine-5-ketone; and reacting the homopiperazine-5-ketone with hydrochloric acid in a solvent to obtain homopiperazine-5-ketone hydrochloride.
As a preferable scheme, the method comprises the following steps:
(1) dissolving 4-piperidone hydrochloride in acetic acid, then sequentially adding sulfuric acid and sodium azide, and obtaining an ethyl acetate solution of homopiperazine-5-ketone after complete reaction;
(2) adding an ethyl acetate hydrochloride solution into the ethyl acetate solution of the homopiperazine-5-ketone, and reacting to obtain the homopiperazine-5-ketone hydrochloride.
As a more preferable scheme, in the step (1), the adding temperature of the sulfuric acid and the sodium azide is 0-20 ℃; the reaction temperature is 0-20 ℃.
As a more preferable scheme, in the step (1), the molar ratio of sodium azide to 4-piperidone hydrochloride is 1-4: 1; the molar ratio of the sulfuric acid to the 4-piperidone hydrochloride is 1-4: 1.
as a more preferable scheme, in the step (1), the volume weight ratio of acetic acid to 4-piperidone hydrochloride is 5-10 ml: 1g of the total weight of the composition.
As a more preferable mode, in the step (2), the dropping temperature of the ethyl acetate hydrochloride solution is 0-30 ℃.
As a more preferable scheme, in the step (2), the molar ratio of the ethyl acetate hydrochloride solution to the homopiperazin-5-one is 1-4: 1.
compared with the prior art, the invention has the beneficial technical effects that: provides a preparation method of homopiperazine-5-ketone hydrochloride; compared with the prior art, the method has the advantages of short synthetic route, easily obtained and cheap raw materials, capability of obtaining the high piperazine-5-ketone hydrochloride with high yield and high purity, and easy industrial production.
Drawings
The invention is further illustrated with reference to the following figures and examples.
FIG. 1 is a synthetic route to the process.
Detailed Description
The invention is further described with reference to specific examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
As shown in FIG. 1, 162 ml of acetic acid and 27.0 g of 4-piperidone hydrochloride were added to a three-necked reaction flask equipped with a stirrer; at the temperature of 10 ℃, 19.5 g of concentrated sulfuric acid and 13.0 g of sodium azide are sequentially dripped; after the addition, the reaction was carried out at 10 ℃ for 12 hours; cooled to 0 ℃, 4N aqueous sodium hydroxide solution was added dropwise (to pH = 9-10), and extracted with ethyl acetate. Transferring the organic layer to a three-necked reaction flask with a stirrer; 50 ml of 4N ethyl acetate hydrochloride solution is dripped at the temperature of 10 ℃; after dropping, stirring at 10 ℃ for 2 hours, filtering, collecting the solid and drying to obtain 24.0 g of homopiperazine-5-one hydrochloride as a white solid with a yield of 80% and a purity of 97%.
And (3) nuclear magnetic detection results:1H NMR (400 MHz,d 6 -DMSO). delta.2.40 (m, 2H),2.65-2.72(m,4H), 3.05 (m, 2H), 3.17 (s,1H), 7.48 (s, 1H). Shows that: by the method, the homopiperazine-5-one hydrochloride is successfully prepared.
Example 2
As shown in fig. 1, 203 ml of acetic acid and 40.5 g of 4-piperidone hydrochloride were added to a three-necked reaction flask with a stirrer; at the temperature of 0 ℃, 58.6 g of concentrated sulfuric acid and 39.0 g of sodium azide are sequentially dripped; after the addition, the reaction was carried out at 5 ℃ for 12 hours; cooled to 0 ℃, 4N aqueous sodium hydroxide solution was added dropwise (to pH = 9-10), and extracted with ethyl acetate. Transferring the organic layer to a three-necked reaction flask with a stirrer; at the temperature of 20 ℃, 150 ml of 4N ethyl acetate hydrochloride solution is dripped; after dropping, stirring was carried out at 20 ℃ for 2 hours, filtering, collecting the solid and drying to obtain 37.4 g of homopiperazin-5-one hydrochloride as a white solid with a yield of 83% and a purity of 96%.
Example 3
As shown in FIG. 1, 405 ml of acetic acid and 54.0 g of 4-piperidone hydrochloride were added to a three-necked reaction flask equipped with a stirrer; at the temperature of 20 ℃, 156.0 g of concentrated sulfuric acid and 104.0 g of sodium azide are sequentially added dropwise; after the addition, the reaction was carried out at 20 ℃ for 12 hours; cooled to 0 ℃, 4N aqueous sodium hydroxide solution was added dropwise (to pH = 9-10), and extracted with ethyl acetate. Transferring the organic layer to a three-necked reaction flask with a stirrer; at 30 ℃, adding 400 ml of 4N ethyl acetate hydrochloride solution dropwise; after dropping, stirring was carried out at 30 ℃ for 2 hours, filtering, collecting the solid and drying to obtain 49.4 g of homopiperazin-5-one hydrochloride as a white solid with a yield of 82% and a purity of 96%.
Example 4
1215 ml of acetic acid and 121.5 g of 4-piperidone hydrochloride were added to a three-necked reaction flask with a stirrer as shown in FIG. 1; at the temperature of 10 ℃, 263.4 g of concentrated sulfuric acid and 175.5 g of sodium azide are sequentially dripped; after the addition, the reaction was carried out at 10 ℃ for 12 hours; cooled to 0 ℃, 4N aqueous sodium hydroxide solution was added dropwise (to pH = 9-10), and extracted with ethyl acetate. Transferring the organic layer to a three-necked reaction flask with a stirrer; 675 ml of 4N ethyl acetate hydrochloride solution is dripped at the temperature of 0 ℃; after dropping, stirring was carried out at 0 ℃ for 2 hours, filtering, collecting the solid and drying to obtain 109.3 g of homopiperazin-5-one hydrochloride as a white solid with a yield of 81% and a purity of 97%.
In light of the foregoing description of the preferred embodiment of the present invention, it is to be understood that various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (7)
1. The preparation method of homopiperazine-5-ketone hydrochloride is characterized in that: 4-piperidone hydrochloride reacts with sodium azide to generate homopiperazine-5-ketone; and reacting the homopiperazine-5-ketone with hydrochloric acid in a solvent to obtain homopiperazine-5-ketone hydrochloride.
2. The method for preparing homopiperazin-5-one hydrochloride according to claim 1, characterized in that: the method comprises the following steps:
(1) dissolving 4-piperidone hydrochloride in acetic acid, then sequentially adding sulfuric acid and sodium azide, and obtaining an ethyl acetate solution of homopiperazine-5-ketone after complete reaction;
(2) adding an ethyl acetate hydrochloride solution into the ethyl acetate solution of the homopiperazine-5-ketone, and reacting to obtain the homopiperazine-5-ketone hydrochloride.
3. The method for preparing homopiperazin-5-one hydrochloride according to claim 2, characterized in that: in the step (1), the adding temperature of the sulfuric acid and the sodium azide is 0-20 ℃; the reaction temperature is 0-20 ℃.
4. The method for preparing homopiperazin-5-one hydrochloride according to claim 2, characterized in that: in the step (1), the molar ratio of sodium azide to 4-piperidone hydrochloride is 1-4: 1; the molar ratio of the sulfuric acid to the 4-piperidone hydrochloride is 1-4: 1.
5. the method for preparing homopiperazin-5-one hydrochloride according to claim 4, characterized in that: in the step (1), the volume-weight ratio of acetic acid to 4-piperidone hydrochloride is 5-10 ml: 1g of the total weight of the composition.
6. The method for preparing homopiperazin-5-one hydrochloride according to claim 2, characterized in that: in the step (2), the dropping temperature of the ethyl acetate hydrochloride solution is 0-30 ℃.
7. The method for preparing homopiperazin-5-one hydrochloride according to claim 2, characterized in that: in the step (2), the molar ratio of the ethyl acetate hydrochloride solution to the homopiperazin-5-one is 1-4: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911279662.6A CN111116498A (en) | 2019-12-13 | 2019-12-13 | Preparation method of homopiperazine-5-ketone hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911279662.6A CN111116498A (en) | 2019-12-13 | 2019-12-13 | Preparation method of homopiperazine-5-ketone hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111116498A true CN111116498A (en) | 2020-05-08 |
Family
ID=70500005
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911279662.6A Pending CN111116498A (en) | 2019-12-13 | 2019-12-13 | Preparation method of homopiperazine-5-ketone hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111116498A (en) |
-
2019
- 2019-12-13 CN CN201911279662.6A patent/CN111116498A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| BARON, LEE ANN FISHER: ""Cobalt and copper promoted amide hydrolysis. Model reactions for carboxypeptidase A"", 《DISS. ABSTR. INT. B》 * |
| S.C.DICKERMAN 等: ""STUDIES IN PIPERIDONE CHEMISTRY. I. A SYNTHESIS OF 5-HOMOPIPERAZINONES"", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5247728B2 (en) | Method for producing benzimidazole derivative | |
| JP2005516011A (en) | Crystalline dihydrate cefnidir potassium | |
| CN103804386B (en) | 4,5-dihydroxyl-3-H-spiral shell [furans-2,3 '-indoles]-2 '-one derivative and synthetic method thereof and application | |
| Tang et al. | Synthesis of novel β-amino ketones containing ap-aminobenzoic acid moiety and evaluation of their antidiabetic activities | |
| CN111848535B (en) | Process for synthesizing 1H-tetrazole acetic acid | |
| US8853395B2 (en) | Process for the preparation of lurasidone hydrochloride | |
| US10556868B2 (en) | Method for synthesizing 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and intermediates thereof | |
| CN111116498A (en) | Preparation method of homopiperazine-5-ketone hydrochloride | |
| KR101810515B1 (en) | 4-benzyl-1-phenethyl-piperazine-2,6-dione preparation method, and intermediate and preparation method thereof | |
| WO2020134137A1 (en) | Method for synthesizing r-3-chloroalanine methyl ester hydrochloride | |
| JP2015526507A (en) | Method for purifying fluvoxamine free base and method for producing high purity fluvoxamine maleate using the same | |
| CN108084093B (en) | Method for synthesizing 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid by one-pot method | |
| KR100881890B1 (en) | Process for preparation of Sarpogrelate HCl salt | |
| CN104496900A (en) | Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline | |
| CN115197119B (en) | Preparation method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione | |
| JP4699582B2 (en) | Method for producing 1H-4 (5) -aminoimidazole-5 (4) -carboxamide | |
| US7482476B2 (en) | Process for the preparation of 5-cyanophthalide starting from 5-carboxyphthalide | |
| EP3162796B1 (en) | Method for producing 2-amino-6-methylnicotinic acid | |
| RU2199524C2 (en) | Method of purification of 2-(3,4-dihydroxyphenyl)-ethylamine hydrochloride | |
| CN111187232A (en) | Method for synthesizing pramipexole dihydrochloride key intermediate by one-pot method | |
| CN112624995A (en) | Novel synthesis method of 2, 4-diphenyl-4, 5-dihydrooxazoline compound | |
| KR101266224B1 (en) | An improved process for the preparation of trityl olmesartan medoxomil | |
| CN116102454A (en) | Preparation method of 2- (hydroxyimino) acetic acid | |
| CN113461709A (en) | Synthesis method of penethamate hydroiodide | |
| KR20110054670A (en) | A process for preparing 2-cyano-3-hydroxy-n-[(4-trifluoromethyl)phenyl] but-2-enamide |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200508 |