CN106365973B - A kind of synthetic method of lipoic acid intermediate - Google Patents
A kind of synthetic method of lipoic acid intermediate Download PDFInfo
- Publication number
- CN106365973B CN106365973B CN201510422911.8A CN201510422911A CN106365973B CN 106365973 B CN106365973 B CN 106365973B CN 201510422911 A CN201510422911 A CN 201510422911A CN 106365973 B CN106365973 B CN 106365973B
- Authority
- CN
- China
- Prior art keywords
- cyclohexanone
- lipoic acid
- ethoxyethyl group
- synthetic method
- acid intermediate
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/69—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to carbon-to-carbon double or triple bonds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A kind of synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, using hydrogen peroxide and ozone as initiator, cyclohexanone and vinyl ethyl ether occur Radical Addition and obtain purpose object, it is characterized in that, using shell and tube reactor, cyclohexanone is added from material inlet 1, the vinyl ethyl ether of mixing and hydrogen peroxide are added from material inlet 2, ozone is passed through from material inlet 3, continuous hybrid reaction in the reactor, product is collected in shell and tube reactor material outlet, is terminated until the reaction is complete.The method of the present invention solves the preparation 2- many Industrializations of (2- ethoxyethyl group) cyclohexanone, it can be achieved that successive reaction, is easily operated automatically, and reaction condition is mildly easily-controllable, and product yield and purity are higher, is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to organic synthetic route design and its bulk pharmaceutical chemicals and intermediate preparation technical field, in particular to a kind of
The preparation method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone.
Background technique
2- (2- ethoxyethyl group) cyclohexanone, structure are shown below, be it is a kind of for synthesize lipoic acid it is important in
Mesosome.
One of reported lipoic acid synthetic method is first carried out certainly with vinyl ethyl ether using cyclohexanone as starting material
By base addition, then aoxidize to obtain lactone using Baeyer-Villiger, then lactone open loop obtains dihydrolipoic acid, most
Cyclization obtains lipoic acid afterwards.
The synthetic route of above-mentioned lipoic acid is as follows:
Wherein the first step is Radical Addition, uses cyclohexanone and vinyl ethyl ether for raw material, with di-t-butyl mistake
Oxide is that Radical Addition occurs for initiator, obtains 2- (2- ethoxyethyl group) cyclohexanone through distillation after reaction.
To guarantee fully reacting, in existing conventional production process, it joined large excess of cyclohexanone, on the one hand result in cost mistake
Height, on the other hand, crude intermediate purity is relatively low, and subsequent reactions could be used for by needing to distill.In addition, after step reaction optimization
Temperature is 140 DEG C, and the reaction time 6 ~ 8 hours, energy consumption was higher, and only about Lee 60%(passes jade-like stone etc. to yield, " synthesis of alpha-lipoic acid ",
Zhejiang University's master's thesis, 2002).
It is therefore necessary to seek one kind, the operation is more convenient, and side reaction is less, and the period is short, lipoic acid intermediate at low cost
2- (2- ethoxyethyl group) cyclohexanone new synthetic method, it is important for promoting the economic technology development of lipoic acid bulk pharmaceutical chemicals to have
Realistic meaning.
Summary of the invention
It is an object of the invention to overcome the deficiencies of existing technologies, according to the synthesis theory of Green Chemistry, provide a kind of new
Lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone synthetic method, the preparation method simplicity, economy, environmental safety
Height is conducive to the industrialized production of the drug, and the economic technology of lipoic acid bulk pharmaceutical chemicals can be promoted to develop.
For achieving the above object, the present invention adopts the following technical scheme:
A kind of synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone is to cause with hydrogen peroxide and ozone
Agent, cyclohexanone and vinyl ethyl ether occur Radical Addition and obtain purpose object, which is characterized in that use tubular reaction
Cyclohexanone is added device from material inlet 1, and the vinyl ethyl ether of mixing and hydrogen peroxide are added from material inlet 2, and ozone is from object
Material import 3 is passed through, in the reactor continuous hybrid reaction, product is collected in shell and tube reactor material outlet, until having reacted
Terminate entirely.
The molar ratio of raw material cyclohexanone and vinyl ethyl ether is 1:1-1.5 in the Radical Addition, preferably
1:0.8-1.2。
It is hydrogen peroxide/ozone system that free radical, which causes reagent, in the Radical Addition.
The molar ratio of raw material cyclohexanone and hydrogen peroxide is 1:0.05-0.15 in the Radical Addition, excellent
Select 1:0.08-0.11.
The concentration of radical initiator ozone is 11-16mg/L, preferably 13-15mg/L in the Radical Addition.
The temperature of the Radical Addition are as follows: 80-120 DEG C, preferably 90-110 DEG C.
The time of the Radical Addition are as follows: 1-2 hours.
Compared to document report technology, lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone according to the present invention
Preparation method, using tubular reactor, using hydrogen peroxide and ozone as initiator, cyclohexanone and vinyl ethyl ether occur free radical and add
Purpose object is obtained at reaction, technical process is simple, and the period is short, and it is at low cost, it is highly-safe.The method of the present invention specifically includes following excellent
Point:
A) the method for the present invention prepares 2- (2- ethoxyethyl group) hexamethylene through tubular reactor compared with traditional stirring-type reaction
Ketone synthesis step is succinct, easy to operate, can successive reaction, it is easy to accomplish automatic operation；
B) the method for the present invention is compared with traditional di-tert-butyl peroxide reaction system, using hydrogen peroxide/ozone body
System is mildly easily-controllable as free radical initiation reagent conditions, and reaction temperature is at 80 ~ 120 DEG C, and the reaction time is short, the entire reaction time
At 1 ~ 2 hour；
C) the method for the present invention and the successive reaction in tubular reactor, sufficiently completely, product yield improves closely compared with document
20%；
D) cyclohexanone is excessively used due to not needing in the method for the present invention, and product purity is high, reduces distilation steps, is suitable for
Large-scale industrial production.
Detailed description of the invention
The process equipment schematic diagram of Fig. 1 lipoic acid intermediate 2- of the present invention (2- ethoxyethyl group) cyclohexanone synthetic method.
Specific embodiment
Embodiment 1:
Cyclohexanone (50.0kg, 0.51mol) is added from material inlet 1, by the vinyl ethyl ether of mixing (36.8kg,
0.51mol) it is added with hydrogen peroxide (1.7kg, 0.05mol) from material inlet 2, import 3 is passed through the gaseous ozone of 15mg/L,
Continuous hybrid reaction in reactor, reaction temperature are kept for 90 DEG C, the residence time 2 hours, received in shell and tube reactor material outlet
Collect product, obtain 2-(2- ethoxyethyl group) cyclohexanone 76.4kg, purity 96.3%, yield 88.0%.
Embodiment 2:
Cyclohexanone (50.0kg, 0.51mol) is added from material inlet 1, by the vinyl ethyl ether of mixing (29.6kg,
0.41mol) it is added with hydrogen peroxide (1.7kg, 0.05mol) from material inlet 2, import 3 is passed through the gaseous ozone of 13mg/L,
Continuous hybrid reaction in reactor, 100 DEG C of reaction temperature holding, the residence time 1.5 hours, in shell and tube reactor material outlet
Product is collected, 2-(2- ethoxyethyl group is obtained) cyclohexanone 57.9kg, purity 95.5%, yield 82.9%.
Embodiment 3:
Cyclohexanone (50.0kg, 0.51mol) is added from material inlet 1, by the vinyl ethyl ether of mixing (40.5kg,
0.56mol) it is added with hydrogen peroxide (1.7kg, 0.05mol) from material inlet 2, import 3 is passed through the gaseous ozone of 14mg/L,
Continuous hybrid reaction in reactor, reaction temperature are kept for 110 DEG C, the residence time 1 hour, received in shell and tube reactor material outlet
Collect product, obtain 2-(2- ethoxyethyl group) cyclohexanone 73.8kg, purity 96.1%, yield 85.0%.
It is pointed out that the technical concepts and features of above-mentioned preferred embodiment only to illustrate the invention, its object is to
Those skilled in the art can understand the contents of the present invention and implements accordingly, and protection of the invention can not be limited with this
Range.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (7)
1. a kind of synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone is to cause with hydrogen peroxide and ozone
Agent, cyclohexanone and vinyl ethyl ether occur Radical Addition and obtain purpose object, which is characterized in that use tubular reaction
Cyclohexanone is added device from material inlet 1, and the vinyl ethyl ether of mixing and hydrogen peroxide are added from material inlet 2, and ozone is from object
Material import 3 is passed through, and continuous hybrid reaction, material are put after fully reacting from material outlet in shell and tube reactor in the reactor
Collect out terminates until the reaction is complete.
2. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 1
In: the molar ratio of raw material cyclohexanone and vinyl ethyl ether is 1:1-1.5 in Radical Addition.
3. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 1
In: it is hydrogen peroxide/ozone system that free radical, which causes reagent, in Radical Addition.
4. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 1
In: the molar ratio of raw material cyclohexanone and hydrogen peroxide is 1:0.05-0.15 in Radical Addition.
5. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 1
In: the concentration of radical initiator ozone is 11-16mg/L in Radical Addition.
6. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 1
In: the temperature of Radical Addition are as follows: 80-120 DEG C.
7. the synthetic method of lipoic acid intermediate 2- (2- ethoxyethyl group) cyclohexanone, feature exist according to claim 4
In: the time of Radical Addition are as follows: 1-2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510422911.8A CN106365973B (en) | 2015-07-20 | 2015-07-20 | A kind of synthetic method of lipoic acid intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510422911.8A CN106365973B (en) | 2015-07-20 | 2015-07-20 | A kind of synthetic method of lipoic acid intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106365973A CN106365973A (en) | 2017-02-01 |
| CN106365973B true CN106365973B (en) | 2018-12-11 |
Family
ID=57880388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510422911.8A Active CN106365973B (en) | 2015-07-20 | 2015-07-20 | A kind of synthetic method of lipoic acid intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106365973B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107673972A (en) * | 2017-10-30 | 2018-02-09 | 福安药业集团烟台只楚药业有限公司 | A kind of preparation method of 6,8 dicloro caprylate ethyl ester |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1272487A (en) * | 1999-04-29 | 2000-11-08 | 国家医药管理局上海医药工业研究院 | New synthesizing method of 2-(2-substituting ethyl) cyclohexanone |
| CN101607955A (en) * | 2008-06-18 | 2009-12-23 | 上海津力化工有限公司 | A kind of preparation method of low-residue lipoic acid |
-
2015
- 2015-07-20 CN CN201510422911.8A patent/CN106365973B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1272487A (en) * | 1999-04-29 | 2000-11-08 | 国家医药管理局上海医药工业研究院 | New synthesizing method of 2-(2-substituting ethyl) cyclohexanone |
| CN101607955A (en) * | 2008-06-18 | 2009-12-23 | 上海津力化工有限公司 | A kind of preparation method of low-residue lipoic acid |
Non-Patent Citations (1)
| Title |
|---|
| 微波辐射合成a-硫辛酸;周国平等;《化学试剂,》;20090331;第31卷(第3期);207-208，235 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106365973A (en) | 2017-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108409516B (en) | Method for synthesizing benzophenone derivative by continuous flow microreactor | |
| CN102241662A (en) | Synthetic method of thiophene-3-ethanol | |
| CN105254610A (en) | Method for preparing difluoro piperonal by utilizing continuous flow microchannel reactor | |
| CN103224447A (en) | Preparation method of trifluoromethyl ketone | |
| CN104370724A (en) | Fluorenone derivative, preparation method of fluorenone derivative and redox method of synthetic fluorenone | |
| CN106365973B (en) | A kind of synthetic method of lipoic acid intermediate | |
| CN109020849B (en) | Preparation method of deuterated dimethyl sulfoxide | |
| CN103694169B (en) | Micro passage reaction is utilized to synthesize the method for 2,2,4-trimethylammonium-1,2-dihydroquinoline and polymkeric substance thereof | |
| CN103880852B (en) | The continuous production processes of four aryl porphines | |
| CN102344344B (en) | Synthesis method of hydroxytyrosol | |
| CN105731401A (en) | Device and method for producing hydroxylamine hydrochloride | |
| WO2012068284A3 (en) | Efficient method for preparing functionalized benzosuberenes | |
| CN104447230A (en) | Method for preparing 4-methoxystyrene | |
| CN102757390B (en) | Method for preparing 2-methoxy-4-diazanyl-5-fluoropyrimidine | |
| CN104447215B (en) | A kind of continuously acidizing technique of synthesizing beta naphthal | |
| CN204661588U (en) | A kind of device of continuous prodution vinylene carbonate | |
| CN103641676A (en) | Method for preparing methyl cyclopentadiene | |
| CN102731556A (en) | Process for preparing tetramethyldivinyldisilazane by conversion of divinyl tetramethyl disiloxane | |
| CN103408413B (en) | Method for preparing deuterated chloroform by using hexachloroacetone as intermediate | |
| CN104292104B (en) | The preparation method of a kind of methylfluoracetate and equipment | |
| CN101781217A (en) | Method for high-selectivity co-production of nitrocyclohexane and adipic acid | |
| CN102212044B (en) | Synthesis method for oxetane compounds | |
| CN112321400A (en) | Synthetic method for improving yield of 2, 5-difluorobenzaldehyde by adopting negative ion stabilizer | |
| CN105085469A (en) | Preparation method of 5-chlorothienyl-2-carboxylic acid | |
| CN104151150A (en) | Preparation method of 3,4-di(3,4,5-trifluorophenyl)-2,5-diphenylcyclopentyldienone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |