CN107033051A - A kind of preparation method of ezetimibe - Google Patents
A kind of preparation method of ezetimibe Download PDFInfo
- Publication number
- CN107033051A CN107033051A CN201710427949.3A CN201710427949A CN107033051A CN 107033051 A CN107033051 A CN 107033051A CN 201710427949 A CN201710427949 A CN 201710427949A CN 107033051 A CN107033051 A CN 107033051A
- Authority
- CN
- China
- Prior art keywords
- ezetimibe
- reactor
- degrees celsius
- solution
- preparation
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a kind of preparation method of ezetimibe, comprise the following steps：Dichloromethane is placed in reactor, and add ezetimibe ketone thereto in whipping process, it is to be mixed it is uniform after, add (R) 2 methyl CBS oxazaborolidines, and reacted in the presence of catalyst, then move into toluene solution, mixing processing is carried out to it by puddler, and it is slowly added dichloromethane solution thereto in whipping process, add mixed solution thereto again, highly basic will be inserted thereto to be washed, it is dried with anhydrous sodium sulfate, then filtering and crystallization, filtering, the acid-base property of crystal is detected using pH test paper, until its presentation is neutral, dry, produce ezetimibe.The reaction yield is high, and product purity is high, and cost is low, and avoids and use toxic agent, and the influence to environment is significantly reduced, and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to chemicals preparing technical field, more particularly to a kind of preparation method of ezetimibe.
Background technology
Ezetimibe is the new selective cholesterol absorption inhibitor of a class, by with intestinal brush border film vesicles
Upper memebrane protein is combined, and suppresses the absorption that small intestine neutralizes the cholesterol being transported to through bile in enteron aisle to diet, reduction serum and liver
Cholesterol level in dirty.Different from cholic acid intercalating agent, ezetimibe does not influence cholesteryl ester, other steroid (such as cow-bezoar courages
Acid), the absorption of triacylglycerol and liposoluble vitamin.Its pharmacological action and acetyl coenzyme A-cholesterol acetyl transferase (ACAT)
Suppression and ldl receptor (scavenger receptor) expression it is whether unrelated.Ezetimibe absorbed after in liver with glucose
Through hepato-enteric circulation after aldehydic acid combination, small intestinal mucosa cell is almost specifically positioned at.Extensive, the road used with ezetimibe
Form docking reaction yield is low in line, and intermediate need to be by post purifying, it is difficult to mass produced, existing preparation method
Demand is can not meet, therefore, we have proposed a kind of preparation method of ezetimibe.
The content of the invention
The present invention proposes a kind of preparation method of ezetimibe, to solve the problems mentioned in the above background technology.
The present invention proposes a kind of preparation method of ezetimibe, comprises the following steps：
S1：It is raw material to choose ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution, and according to for
Rice shellfish -one, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 40-60 degrees Celsius, and is being stirred
Add ezetimibe -one during mixing thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and
Reacted in the presence of catalyst；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 12-18 degrees Celsius,
Mixing processing is carried out to it by puddler, and dichloromethane solution is slowly added thereto in whipping process, is completed
After addition, 8-10h is placed in stirring in the environment of 20-30 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and stir under conditions of 40-50 degrees Celsius 20-
It is layered after 40min, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, then
Secondary filtering；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, directly
It is neutral to its presentation, dry, produce ezetimibe.
It is preferred that, the catalyst in S2 is tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
It is preferred that, in above-mentioned, reactor before use, 10-13min need to be sterilized under conditions of 300-450 degrees Celsius,
Then so that reactor is in sealing state.
It is preferred that, mixed solution in S3 is the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide
Molal weight ratio with sulfuric acid is 3：2：0.5.
A kind of preparation method of ezetimibe proposed by the present invention, beneficial effect is：The preparation of the ezetimibe
Method it is simple to operate easily-controllable, reaction yield is high, and product purity is high, and cost is low, and avoids and use toxic agent, to environment
Influence is significantly reduced, and is suitable for large-scale industrial production.
Embodiment
With reference to specific embodiment, the present invention will be further described.
Embodiment 1
The present invention proposes a kind of preparation method of ezetimibe, comprises the following steps：
S1：It is raw material to choose ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution, and according to for
Rice shellfish -one, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 40 degrees Celsius, and stirred
Add ezetimibe -one in journey thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and in catalysis
Reacted in the presence of agent；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 12 degrees Celsius, is passed through
Puddler carries out mixing processing to it, and is slowly added dichloromethane solution thereto in whipping process, completes addition
Afterwards, 8h is placed in stirring in the environment of 20 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and after stirring 20min under conditions of 40 degrees Celsius
It is layered, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, then
Secondary filtering；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, directly
It is neutral to its presentation, dry, produce ezetimibe.
Catalyst in S2 is tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
In above-mentioned, reactor is before use, 10min need to be sterilized under conditions of 300 degrees Celsius, then so that reactor
In sealing state.
Mixed solution in S3 is the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide and sulfuric acid
Molal weight ratio is 3：2：0.5.
Embodiment 2
The present invention proposes a kind of preparation method of ezetimibe, comprises the following steps：
S1：It is raw material to choose ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution, and according to for
Rice shellfish -one, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 45 degrees Celsius, and stirred
Add ezetimibe -one in journey thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and in catalysis
Reacted in the presence of agent；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 14 degrees Celsius, is passed through
Puddler carries out mixing processing to it, and is slowly added dichloromethane solution thereto in whipping process, completes addition
Afterwards, 8.5h is placed in stirring in the environment of 24 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and after stirring 25min under conditions of 44 degrees Celsius
It is layered, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, then
Secondary filtering；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, directly
It is neutral to its presentation, dry, produce ezetimibe.
Catalyst in S2 is tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
In above-mentioned, reactor is before use, 11min need to be sterilized under conditions of 350 degrees Celsius, then so that reactor
In sealing state.
Mixed solution in S3 is the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide and sulfuric acid
Molal weight ratio is 3：2：0.5.
Embodiment 3
The present invention proposes a kind of preparation method of ezetimibe, comprises the following steps：
S1：It is raw material to choose ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution, and according to for
Rice shellfish -one, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 55 degrees Celsius, and stirred
Add ezetimibe -one in journey thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and in catalysis
Reacted in the presence of agent；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 16 degrees Celsius, is passed through
Puddler carries out mixing processing to it, and is slowly added dichloromethane solution thereto in whipping process, completes addition
Afterwards, 9h is placed in stirring in the environment of 28 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and after stirring 30min under conditions of 48 degrees Celsius
It is layered, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, then
Secondary filtering；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, directly
It is neutral to its presentation, dry, produce ezetimibe.
Catalyst in S2 is tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
In above-mentioned, reactor is before use, 12min need to be sterilized under conditions of 400 degrees Celsius, then so that reactor
In sealing state.
Mixed solution in S3 is the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide and sulfuric acid
Molal weight ratio is 3：2：0.5.
Embodiment 4
The present invention proposes a kind of preparation method of ezetimibe, comprises the following steps：
S1：It is raw material to choose ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution, and according to for
Rice shellfish -one, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 60 degrees Celsius, and stirred
Add ezetimibe -one in journey thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and in catalysis
Reacted in the presence of agent；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 18 degrees Celsius, is passed through
Puddler carries out mixing processing to it, and is slowly added dichloromethane solution thereto in whipping process, completes addition
Afterwards, 10h is placed in stirring in the environment of 30 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and after stirring 40min under conditions of 50 degrees Celsius
It is layered, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, then
Secondary filtering；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, directly
It is neutral to its presentation, dry, produce ezetimibe.
Catalyst in S2 is tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
In above-mentioned, reactor is before use, 13min need to be sterilized under conditions of 450 degrees Celsius, then so that reactor
In sealing state.
Mixed solution in S3 is the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide and sulfuric acid
Molal weight ratio is 3：2：0.5.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its
Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (4)
1. a kind of preparation method of ezetimibe, it is characterised in that comprise the following steps：
S1：Ezetimibe -one, (R) -2- methyl-CBS- oxazaborolidines, dichloromethane solution are chosen for raw material, and ezetimibe -
Ketone, the molal weight ratio of (R) -2- methyl-CBS- oxazaborolidines are 3：1；
S2：Dichloromethane is placed in reactor, and the temperature in reactor is increased to 40-60 degrees Celsius, and stirred
Add ezetimibe -one in journey thereto, it is to be mixed it is uniform after, add (R) -2- methyl-CBS- oxazaborolidines, and in catalysis
Reacted in the presence of agent；
S3：Toluene solution is moved into the reactor stated then up again, and quickly cools the temperature to 12-18 degrees Celsius, is passed through
Puddler carries out mixing processing to it, and is slowly added dichloromethane solution thereto in whipping process, completes addition
Afterwards, 8-10h is placed in stirring in the environment of 20-30 degrees Celsius；
S3：After reaction terminates, mixed solution is added thereto again, and stir under conditions of 40-50 degrees Celsius 20-40min
It is layered afterwards, removes upper solution, highly basic will be inserted thereto and be washed；
S4：After the completion of above-mentioned, it is dried using anhydrous sodium sulfate, then filtering and crystallization, are completed after crystallization, again mistake
Filter；
S5：The acid-base property of crystal is detected using pH test paper, if crossing alkali or peracid, washing process is carried out to it, until its
It is presented neutral, dries, produce ezetimibe.
2. a kind of preparation method of ezetimibe according to claim 1, it is characterised in that：Catalyst in S2 is
Tetraisopropyl titanate, ether, acetone or tetrahydrofuran.
3. a kind of preparation method of ezetimibe according to claim 1, it is characterised in that：In above-mentioned, reactor
Before use, 10-13min need to be sterilized under conditions of 300-450 degrees Celsius, then so that reactor is in sealing state.
4. a kind of preparation method of ezetimibe according to claim 1, it is characterised in that：Mixed solution in S3
It is 3 for the molal weight ratio of the mixture of methanol, sodium peroxide and sulfuric acid, and methanol, sodium peroxide and sulfuric acid：2：0.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710427949.3A CN107033051A (en) | 2017-06-08 | 2017-06-08 | A kind of preparation method of ezetimibe |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710427949.3A CN107033051A (en) | 2017-06-08 | 2017-06-08 | A kind of preparation method of ezetimibe |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107033051A true CN107033051A (en) | 2017-08-11 |
Family
ID=59541977
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710427949.3A Pending CN107033051A (en) | 2017-06-08 | 2017-06-08 | A kind of preparation method of ezetimibe |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107033051A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997045406A1 (en) * | 1996-05-31 | 1997-12-04 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
-
2017
- 2017-06-08 CN CN201710427949.3A patent/CN107033051A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997045406A1 (en) * | 1996-05-31 | 1997-12-04 | Schering Corporation | 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones |
Non-Patent Citations (1)
| Title |
|---|
| GUANGZHONG WU等: "A Novel One-Step Diastereo- and Enantioselective Formation of", 《J.ORG.CHEM》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1184897A (en) | Process for the separation of sterols or mixtures of sterols | |
| CN108558636A (en) | A kind of preparation method of 4- bromobenzoic acids | |
| CN106699831B (en) | A method of liquid crystal cholesterol is prepared using lanolin using complexometry | |
| CN108794557A (en) | A kind of preparation method of chenodeoxycholic acid and intermediate | |
| CN104892623A (en) | Preparation method for isosorbide 5-mononitrate | |
| CN107033051A (en) | A kind of preparation method of ezetimibe | |
| CN105622696B (en) | Method for purifying dehydroepiandrosterone by emulsifying leaching process | |
| CN108299540A (en) | A kind of synthetic method of Tauro ursodesoxy cholic acid | |
| CN108586206A (en) | One kettle way prepares 4,4 '-butylidenebis（6- tertiary butyl metacresols）Method | |
| CN103665078B (en) | A kind of preparation method of 17 Alpha-hydroxy steroidal esters | |
| CN101812107B (en) | Method for synthesizing clobetasol propionate intermediate | |
| CN107501374A (en) | A kind of method that dehydroepiandros-sterone is reclaimed in the mother liquor thing from dehydroepiandros-sterone | |
| CN106866677A (en) | The purifying of Ticagrelor and preparation method | |
| CN108997464A (en) | A kind of processing method of testosterone mother liquor object | |
| CN106831923A (en) | A kind of preparation method of chenodeoxycholic acid | |
| CN105315244A (en) | Preparation method of L-ascorbic acid-6-palmitate | |
| PL81228B1 (en) | ||
| CN107365341A (en) | The preparation method of flurogestone acetate | |
| CN105753747B (en) | A kind of industrialized production new method for preparing high-purity docusate sodium PEG solution | |
| CN104356187B (en) | Method for recycling hydrocortisone in hydrocortisone butyrate mother liquor | |
| CN110127640A (en) | The method and apparatus for refining hydroxylamine hydrochloride product | |
| CN108554340A (en) | A kind of hydrogen fluoride ammonia process units | |
| CN103121960B (en) | Efficient recrystallization method of tetraacetylethylenediamine | |
| CN109734765B (en) | Preparation method of 17 a-dehydroxyacetic acid prednisolone product | |
| CN104031003A (en) | Complex solvent refining method of MBT (2-mercaptobenzothiazole) |
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: 20170811 |