CN105218394B - A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate - Google Patents
A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate Download PDFInfo
- Publication number
- CN105218394B CN105218394B CN201510549540.XA CN201510549540A CN105218394B CN 105218394 B CN105218394 B CN 105218394B CN 201510549540 A CN201510549540 A CN 201510549540A CN 105218394 B CN105218394 B CN 105218394B
- Authority
- CN
- China
- Prior art keywords
- ketohexamethylene
- methanamide
- under reduced
- synthesis technique
- reduced pressure
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate, which is on the basis of original technique, by adding new catalyst tetra isopropyl oxygen titanium in reaction system, while improve product quality, synthesis yield brings up to 90% from existing 82%, with significant economic benefit.
Description
Technical field
The present invention relates to a kind of synthesis technique of the intermediate of Gliclazide, especially in regard to a kind of 2- Methanamides Ketohexamethylene
Synthesis technique.
Background technology
Gliclazide is second filial generation sulphanylureas blood sugar lowering, and effect is relatively strong, and its mechanism is that to be selectively applied to islets of langerhans β thin
Born of the same parents, promote insulin secretion.By Insulin receptor INSR mechanism of action, increase the activity of glycogen synthetase in skeleton, promote muscle
Utilization to glucose, and hematoblastic aggregation and adhesion can be reduced, contribute to preventing and treating diabetic microvascular complication.
Existing Gliclazide intermediate 2- Methanamide Ketohexamethylene synthesis techniques make reaction dissolvent using ethyl acetate, anhydrous
Under the conditions of with carbamide and Ketohexamethylene through condensation, distillation, elutriation crystallization, filter, dry and obtain.It is low which is primarily present yield, product
By-product is more, the problems such as of poor quality etc..
Content of the invention
The purpose of this part be to summarize embodiments of the invention some in terms of and briefly introduce some and preferably implement
Example.May do a little simplified in this part and the description of the present application summary and denomination of invention or omit to avoid making our department
Point, the purpose of specification digest and denomination of invention obscure, and this simplification or omit and cannot be used for limiting the scope of the present invention.
In view of problem present in above-mentioned existing Gliclazide intermediate 2- Methanamide Ketohexamethylene synthesis techniques, it is proposed that this
Invention.
It is therefore an object of the present invention to provide a kind of synthesis for improving Gliclazide intermediate 2- Methanamide Ketohexamethylene yields
Technique, the synthesis yield bring up to 90% or so from original 82%, and product quality is also significantly improved, with significant economic effect
Benefit.
For solving above-mentioned technical problem, the invention provides following technical scheme：A kind of raising Gliclazide intermediate 2-
The synthesis technique of Methanamide Ketohexamethylene yield, comprises the steps：
(1) dimethylbenzene and carbamide are added in reaction bulb, adds catalyst tetra isopropyl oxygen titanium, controlling reaction temperature
At -30 DEG C to -20 DEG C, then Deca Ketohexamethylene, time for adding about 2 hours, after Ketohexamethylene completion of dropping, maintain the temperature at -20
To -15 DEG C of 16 hours, reaction end is detected by thin layer；
(2) detecting after reaction terminates, control temperature below 20 DEG C adds a certain amount of water toward reaction bulb, stirs
After mixing 30 minutes, then 1 hour is stood, then branch vibration layer, then be extracted twice with water；
(3) recovered under reduced pressure dimethylbenzene adds each 95% ethanol of 8 times of amounts and 20% sodium carbonate liquor to stir evenly to dry, and -5
After 1 hour is incubated DEG C at 0 DEG C, filter, filter cake drying under reduced pressure obtains Gliclazide intermediate 2- Methanamide Ketohexamethylene to dry.
One kind as the synthesis technique for improving Gliclazide intermediate 2- Methanamide Ketohexamethylene yields of the present invention
Preferred version, the mol ratio between tetra isopropyl oxygen titanium, Ketohexamethylene in wherein described step (1) are 1：20, in addition whole raw
Carbamide excess during product.
One kind as the synthesis technique for improving Gliclazide intermediate 2- Methanamide Ketohexamethylene yields of the present invention
In preferred version, wherein step (3), the pressure in the recovered under reduced pressure and drying under reduced pressure is -0.09mpa.
Compared with prior art, the present invention has the advantages that：
1st, product reaction yield is high, brings up to 90% or so from 82%；
2nd, product quality is high, and by-product is few, and before efficient liquid phase detection main peak, impurity is reduced；
3rd, product cost reduces, and product per kilogram reduces by 15.8 yuan of cost of material.
Specific embodiment
Understandable for enabling the above objects, features and advantages of the present invention to become apparent from, with reference to specific embodiment pair
The specific embodiment of the present invention is described in detail.
A lot of details are elaborated in the following description in order to fully understand the present invention, but the present invention can be with
Alternate manner described here is different from using other to implement, those skilled in the art can be without prejudice to intension of the present invention
In the case of do similar popularization, therefore the present invention do not limited by following public specific embodiment.
Secondly, " one embodiment " or " embodiment " referred to herein is referred to and may be included at least one realization side of the invention
Special characteristic, structure or characteristic in formula." in one embodiment " that different places occur in this manual not refers both to
Same embodiment, nor single or selectively mutually exclusive with other embodiment embodiment.
Embodiment 1
Dimethylbenzene and excess urea is added in reaction bulb, and adds the new catalyst four of Ketohexamethylene mole 4.5%
Isopropyl oxygen titanium, at -20 DEG C, Deca Ketohexamethylene, time for adding about 2 hours are finished, -20 DEG C to -15 DEG C controlling reaction temperature
Insulation 16 hours, by thin layer detection control reaction end.After reaction terminates, control temperature is added a certain amount of below 20 DEG C
Water, stir 30 minutes, stand 1 hour, after branch vibration layer, then with water extract secondary, finish.Recovered under reduced pressure dimethylbenzene to dry,
Add 95% ethanol and 20% sodium carbonate liquor to stir evenly, after 1 hour being incubated at -5 DEG C to 0 DEG C, filter, filter cake is decompressed to -
Dry to dry after 0.09mpa, obtain Gliclazide intermediate 2- Methanamide Ketohexamethylene, yield 89.05%.
Embodiment 2
Dimethylbenzene and excess urea is added in reaction bulb, and adds the new catalyst four of Ketohexamethylene mole 5% different
Propyl group oxygen titanium, at -20 DEG C, Deca Ketohexamethylene, time for adding about 2 hours are finished controlling reaction temperature, -20 DEG C to -15 DEG C guarantors
Temperature 16 hours, by thin layer detection control reaction end.After reaction terminates, control temperature is added a certain amount of below 20 DEG C
Water, stirs 30 minutes, stands 1 hour, after branch vibration layer then secondary with water extraction, finishes.Recovered under reduced pressure dimethylbenzene to dry, plus
Enter 95% ethanol and 20% sodium carbonate liquor is stirred evenly, after 1 hour being incubated at -5 DEG C to 0 DEG C, filter, filter cake is decompressed to -
Dry to dry after 0.09mpa, obtain Gliclazide intermediate 2- Methanamide Ketohexamethylene, yield 90.44%.
Embodiment 3
Dimethylbenzene and excess urea is added in reaction bulb, and adds the new catalyst four of Ketohexamethylene mole 5.5%
Isopropyl oxygen titanium, at -20 DEG C, Deca Ketohexamethylene, time for adding about 2 hours are finished, -20 DEG C to -15 DEG C controlling reaction temperature
Insulation 16 hours, by thin layer detection control reaction end.After reaction terminates, control temperature is added a certain amount of below 20 DEG C
Water, stir 30 minutes, stand 1 hour, after branch vibration layer, then with water extract secondary, finish.Recovered under reduced pressure dimethylbenzene to dry,
Add 95% ethanol and 20% sodium carbonate liquor to stir evenly, after 1 hour being incubated at -5 DEG C to 0 DEG C, filter, filter cake is decompressed to -
Dry to dry after 0.09mpa, obtain Gliclazide intermediate 2- Methanamide Ketohexamethylene, yield 90.25%.
Certainly, other steps of the synthetically produced process of the intermediate of the method without modification, and test show：Embodiment 1
～3 Gliclazide intermediate 2- Methanamide Ketohexamethylene quality for obtaining meet inner controlling standard of enterprise, and final products Gliclazide is accorded with
Close 2010 editions standards of Chinese Pharmacopoeia
It should be noted that above example is only unrestricted in order to technical scheme to be described, although with reference to preferably
Embodiment has been described in detail to the present invention, it will be understood by those within the art that, can be to the technology of the present invention
Scheme is modified or equivalent, and without deviating from the spirit and scope of technical solution of the present invention, which all should be covered at this
In the middle of bright right.
Claims (3)
1. a kind of synthesis technique of Gliclazide intermediate 2- Methanamide Ketohexamethylene yields, it is characterised in that：Comprise the steps：
(1) dimethylbenzene and carbamide are added in reaction bulb, adds catalyst tetra isopropyl oxygen titanium, controlling reaction temperature is -30
DEG C to -20 DEG C, then Deca Ketohexamethylene, time for adding 2 hours, after Ketohexamethylene completion of dropping, maintain the temperature at -20 DEG C to -15
DEG C 16 hours, detect reaction end by thin layer；
(2) detecting after reaction terminates, control temperature adds a certain amount of water toward reaction bulb less than 20 DEG C, stirs 30
After minute, then 1 hour is stood, then branch vibration layer, then be extracted twice with water；
(3) recovered under reduced pressure dimethylbenzene adds each 95% ethanol of 8 times of amounts and 20% sodium carbonate liquor to stir evenly to dry, -5 DEG C to 0
After 1 hour is incubated at DEG C, filter, filter cake drying under reduced pressure obtains Gliclazide intermediate 2- Methanamide Ketohexamethylene to dry.
2. the synthesis technique of Gliclazide intermediate 2- Methanamide Ketohexamethylene yields according to claim 1, its feature exist
In：The mol ratio between tetra isopropyl oxygen titanium, Ketohexamethylene in step (1) is 1：20, in addition urinate in whole production process
Plain excessive.
3. the synthesis technique of Gliclazide intermediate 2- Methanamide Ketohexamethylene yields according to claim 1, its feature exist
In：In step (3), the pressure in the recovered under reduced pressure and drying under reduced pressure is -0.09MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510549540.XA CN105218394B (en) | 2015-08-31 | 2015-08-31 | A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510549540.XA CN105218394B (en) | 2015-08-31 | 2015-08-31 | A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105218394A CN105218394A (en) | 2016-01-06 |
| CN105218394B true CN105218394B (en) | 2017-03-15 |
Family
ID=54987736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510549540.XA Active CN105218394B (en) | 2015-08-31 | 2015-08-31 | A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105218394B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112661664A (en) * | 2020-12-30 | 2021-04-16 | 安徽金鼎医药股份有限公司 | Synthesis process of gliclazide intermediate 2-formamide cyclohexanone |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3694450A (en) * | 1971-03-17 | 1972-09-26 | American Home Prod | 2-substituted-4,5,6,7-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters |
| DD112987A1 (en) * | 1974-07-10 | 1975-05-12 | ||
| US4169952A (en) * | 1977-03-14 | 1979-10-02 | E. I. Du Pont De Nemours And Company | Process for the preparation of cyclohexanone-2-carboxamide |
| CN103159642A (en) * | 2011-12-17 | 2013-06-19 | 山东方明药业集团股份有限公司 | Preparation method of gliclazide intermediate cyclohexanone-2-methanmide |
| CN103664682A (en) * | 2013-11-22 | 2014-03-26 | 中国矿业大学 | Synthetic method for 2-formamide cyclohexanone |
-
2015
- 2015-08-31 CN CN201510549540.XA patent/CN105218394B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3694450A (en) * | 1971-03-17 | 1972-09-26 | American Home Prod | 2-substituted-4,5,6,7-tetrahydrobenzothiazole-4-carboxylic acids and their alkyl esters |
| DD112987A1 (en) * | 1974-07-10 | 1975-05-12 | ||
| US4169952A (en) * | 1977-03-14 | 1979-10-02 | E. I. Du Pont De Nemours And Company | Process for the preparation of cyclohexanone-2-carboxamide |
| CN103159642A (en) * | 2011-12-17 | 2013-06-19 | 山东方明药业集团股份有限公司 | Preparation method of gliclazide intermediate cyclohexanone-2-methanmide |
| CN103664682A (en) * | 2013-11-22 | 2014-03-26 | 中国矿业大学 | Synthetic method for 2-formamide cyclohexanone |
Non-Patent Citations (4)
| Title |
|---|
| 2-甲酰胺环己酮的简便合成;李国防;《应用化工》;20100531;第39卷(第5期);第641-644页 * |
| A simple synthesis of cyclohexanone-2-carboxamide and its reactions;Bischoff, Christian and Herma,Hannelore;《Journal fuer Praktische Chemie》;19761231;第318卷(第5期);第773-778页 * |
| Facile carbethoxylation and carbamoylation of ketones;Pazdera, Pavel and Simbera, Jan;《Organic Preparations and Procedures International》;20110609;第43卷(第3期);第297-301页 * |
| the synthesis of 2-carboethoxy-△2-cyclohexenone;JOSEPH E. BREBBER;《Journal of Organic Chemistry》;19611231;第26卷(第1期);第22-27页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105218394A (en) | 2016-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103290081B (en) | Extraction method of rice bran active polysaccharide | |
| JP5313327B2 (en) | Low sugar fermented malt beverage and method for producing the same | |
| CN102675257B (en) | Cabazitaxel crystal and preparation method thereof | |
| CN106755234B (en) | Preparation method and application of green tea hypoglycemic peptide | |
| CN106279450A (en) | A kind of preparation method of porous starch octenyl succinate anhydride | |
| CN105218394B (en) | A kind of synthesis technique for improving 2 Methanamide Ketohexamethylene yield of Gliclazide intermediate | |
| CN103880966A (en) | Method for preparing special hydroxypropyl methyl cellulose for controlled release | |
| CN106632137A (en) | Method for preparing ethyl 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetate | |
| Guerrero et al. | Fed-batch operation for the synthesis of lactulose with β-galactosidase of Aspergillus oryzae | |
| CN107674056B (en) | Its application in treating hyperuricemia of Versulin derivative | |
| CN104496937B (en) | The synthetic method of BPTA | |
| CN102924609A (en) | Method for producing low-substituted hydroxypropyl cellulose via fractional step method | |
| CN108330041A (en) | A kind of white wine and its brewing method | |
| CN104087467B (en) | A kind of brewing method of cereal wine | |
| CN109232574B (en) | Effective folic acid purification method | |
| CN105254556B (en) | A kind of method for preparing picosulfate sodium | |
| CN103834525A (en) | Red yeast preparation method | |
| CN104673861B (en) | A method of improving farinose enzymolysis efficiency | |
| CN104762166B (en) | A kind of fed-batch cultivation method preparing yellow wine with high alcohol content | |
| CN103609833A (en) | Processing method of potato protein peptide | |
| CN103044573A (en) | Production method of amidated pectin for improving stability of baking jam | |
| CN105001273B (en) | A kind of preparation method of mannose | |
| CN104098458B (en) | A kind of preparation method of voglibose intermediate | |
| CN102617486B (en) | Process for preparing 6-chlorine-1,3-dimethyl uracil | |
| CN103319376B (en) | The preparation method of creatine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 224100 Yancheng City Dafeng marine biological medicine industrial park Applicant after: Jiangsu Ruike medicine science and Technology Co Ltd Address before: 224145 Jiangsu province Yancheng City Dafeng marine Biomedical Industry Park Applicant before: JIANGSU RUIKE PHARMACEUTICAL CO., LTD. |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |