CN111087379A - Preparation method of ticagrelor key intermediate A - Google Patents
Preparation method of ticagrelor key intermediate A Download PDFInfo
- Publication number
- CN111087379A CN111087379A CN201911125803.9A CN201911125803A CN111087379A CN 111087379 A CN111087379 A CN 111087379A CN 201911125803 A CN201911125803 A CN 201911125803A CN 111087379 A CN111087379 A CN 111087379A
- Authority
- CN
- China
- Prior art keywords
- key intermediate
- preparation
- steps
- ticagrelor
- filtering
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of a ticagrelor key intermediate A comprises the following steps: (1) the synthesis of an intermediate 9, (2) the synthesis of an intermediate 10, and (3) the synthesis of a key intermediate A, wherein the synthesis of the intermediate 9 is to drop glacial acetic acid into a mixture of an intermediate 4, tetrahydrofuran and zinc powder at room temperature, stir and preserve heat for 24 hours, neutralize with liquid alkali to be neutral, evaporate a solvent, extract, dry, filter and concentrate to obtain the intermediate 9. The preparation method of the ticagrelor key intermediate A greatly shortens the synthesis process and reduces the production cost by further improvement and optimization on the basis of the prior preparation technology, and the preparation method of the ticagrelor key intermediate A which is safe and convenient and suitable for industrial large-scale production is provided, so that the preparation method has good economic benefit and wide application prospect.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a ticagrelor key intermediate A.
Background
Ticagrelor, sold under the trade name of blindard, and having the chemical name (1S,2S,3R,5S) -3- [7- [ (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamino ] -5- (propylsulfanyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-3-yl ] -5- (2-hydroxyethoxy) cyclopentane-1, 2-diol of the formula:
ticagrelor is a novel oral selective small molecule anticoagulant drug developed by Astrazeneca. The medicine can act on P2Y12 receptor of platelet reversibly, can inhibit platelet caused by Adenosine Diphosphate (ADP) strongly, and has been verified and supported by platelet inhibition and patient outcome result research (PLATO research) and multiple subgroup researches thereof in clinical curative effect and safety. The PLATO research also shows that the curative effect of the ticagrelor is obviously better than that of clopidogrel, so that the ticagrelor is recommended by a plurality of guidelines at home and abroad in the first line, and the European guideline is that the recommended level of the ticagrelor is listed before the clopidogrel in the last two years, so that the clopidogrel can be used in patients who cannot use the ticagrelor, and the application prospect is wide.
Wherein, the intermediate 2- [ [ (3aR,4S,6R,6aS) -6-aminotetrahydro-2, 2-dimethyl-4H-cyclopenteno-1, 3-dioxolane-4-yl ] oxy ] ethanol is a key intermediate for synthesizing ticagrelor. The key intermediate A has the following structure:
the mainstream synthetic route of the intermediate is reported in journal literature (Bioorganic & Medicinal chemistry letters, 2012,22, 3598-3602) and patents WO2013092900 and CN201510289960 as follows:
the synthesis process has the advantages of longer synthesis steps and low overall yield. Therefore, in order to realize industrial production, popularization and economic benefits, a preparation method of the ticagrelor key intermediate a with shorter synthesis steps and higher overall yield is urgently needed to be developed.
Disclosure of Invention
The purpose of the invention is as follows: in order to overcome the defects, the invention aims to provide the preparation method of the ticagrelor key intermediate A, the preparation method is simple, the intermediate 4 is used as an initial raw material, the key intermediate A is directly obtained through 3 steps of reaction, the reaction steps are shortened, the total yield is improved, the production cost control is facilitated, the economic benefit is good, and the application prospect is wide.
The purpose of the invention is realized by the following technical scheme:
a preparation method of a ticagrelor key intermediate A is characterized by comprising the following steps:
(1) synthesis of intermediate 9: at room temperature, dropwise adding glacial acetic acid into the mixture of the intermediate 4, tetrahydrofuran and zinc powder, stirring and preserving heat for 24 hours, neutralizing with liquid alkali to be neutral, evaporating the solvent, extracting, drying, filtering and concentrating to obtain an intermediate 9;
(2) synthesis of intermediate 10: adding the intermediate 9 into ethylene glycol and toluene, adding a catalyst Nafion-H acid resin, carrying out reflux heat preservation for 2-6 hours, filtering the catalyst, concentrating to dryness, pulping petroleum ether, and recrystallizing to obtain an intermediate 10;
(3) synthesis of key intermediate a: and adding the intermediate 10 and palladium carbon into absolute ethyl alcohol, introducing hydrogen for hydrogenation, filtering the palladium carbon, and concentrating to be dry to obtain the key intermediate A.
The preparation method of the ticagrelor key intermediate A provided by the invention has the advantages that the intermediate 4 is used as an initial raw material, an N-O bond is opened through zinc powder reduction, benzyl is not removed, the complex process of CBZ protection after deprotection is omitted, then ethylene glycol is used as a raw material, the intermediate 10 is directly obtained through etherification in the presence of a catalyst, and finally palladium-carbon catalytic hydrogenation is carried out to directly obtain the key intermediate A, so that the reaction steps are shortened, the total yield is improved, and the production cost control is facilitated.
Further, in the preparation method of the ticagrelor key intermediate A, the temperature is controlled to be 5-10 ℃ in the dropping process of the glacial acetic acid in the step (1), and the temperature is raised to 20-25 ℃ after the dropping, stirred and kept for 24 hours.
Further, in the above preparation method of ticagrelor key intermediate a, the liquid base in step (1) is neutralized to neutrality, which comprises the following steps: stirring, maintaining the temperature, filtering, adjusting the pH of the mother liquor to 7-8 with 2M sodium hydroxide aqueous solution, and concentrating under negative pressure until no liquid is discharged.
Further, the above preparation method of ticagrelor key intermediate a, wherein the extraction, drying, filtration and concentration in step (1), comprises the following steps: ethyl acetate was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the intermediate 9.
Further, in the preparation method of the key intermediate A of ticagrelor, the reflux insulation time in the step (2) is 5 hours, and the temperature is 60 ℃.
Further, in the above preparation method of ticagrelor key intermediate a, the catalyst in step (2) is filtered off and then concentrated to dryness, which comprises the following steps: after the reflux and heat preservation are finished, cooling to room temperature, filtering, washing the mother liquor with distilled water once, separating out a water phase, and concentrating an organic layer under negative pressure until no liquid is discharged.
Further, in the above preparation method of ticagrelor key intermediate a, the petroleum ether pulping and recrystallization in the step (2) comprises the following steps: adding petroleum ether, stirring, cooling to 0-5 deg.C, and holding for 2 hr.
Further, in the above preparation method of ticagrelor key intermediate a, the hydrogen hydrogenation in step (3) comprises the following steps: displacing with nitrogen, introducing hydrogen to 0.1MPa, heating to 50-60 deg.C, stirring for 12 hr, and cooling to room temperature.
Further, in the above preparation method of ticagrelor key intermediate a, the step (3) of filtering off palladium on carbon and then concentrating to dryness includes the following steps: filtering until the mother liquor is concentrated under negative pressure until no liquid is discharged.
Compared with the prior art, the invention has the following beneficial effects: the preparation method of the ticagrelor key intermediate A is improved and optimized on the basis of the prior preparation technology, is simple and reasonable, takes the intermediate 4 as a starting material, directly obtains the key intermediate A through 3 steps of reaction, shortens the reaction steps, improves the total yield, is beneficial to controlling the production cost, provides a safe and convenient preparation method suitable for industrial large-scale production, and has good economic benefit and wide application prospect.
Detailed Description
The technical solutions in the embodiments of the present invention will be described clearly and completely with reference to the following embodiments and specific experimental data, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following example provides a preparation method of ticagrelor key intermediate a, comprising the following steps:
(1) synthesis of intermediate 9: at room temperature, dropwise adding glacial acetic acid into the mixture of the intermediate 4, tetrahydrofuran and zinc powder, stirring and preserving heat for 24 hours, neutralizing with liquid alkali to be neutral, evaporating the solvent, extracting, drying, filtering and concentrating to obtain an intermediate 9;
(2) synthesis of intermediate 10: adding the intermediate 9 into ethylene glycol and toluene, adding a catalyst Nafion-H acid resin, carrying out reflux heat preservation for 2-6 hours, filtering the catalyst, concentrating to dryness, pulping petroleum ether, and recrystallizing to obtain an intermediate 10;
(3) synthesis of key intermediate a: and adding the intermediate 10 and palladium carbon into absolute ethyl alcohol, introducing hydrogen for hydrogenation, filtering the palladium carbon, and concentrating to be dry to obtain the key intermediate A.
Further, the liquid caustic soda in the step (1) is neutralized to be neutral, and the method comprises the following steps: stirring, maintaining the temperature, filtering, adjusting the pH of the mother liquor to 7-8 with 2M sodium hydroxide aqueous solution, and concentrating under negative pressure until no liquid is discharged.
The extraction, drying, filtration and concentration in the step (1) comprise the following steps: ethyl acetate was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the intermediate 9.
Further, the reflux heat preservation time in the step (2) is 5 hours, and the temperature is 60 ℃.
Further, the step (2) of filtering the catalyst and concentrating to dryness comprises the following steps: after the reflux and heat preservation are finished, cooling to room temperature, filtering, washing the mother liquor with distilled water once, separating out a water phase, and concentrating an organic layer under negative pressure until no liquid is discharged. The petroleum ether pulping and recrystallizing step (2) comprises the following steps: adding petroleum ether, stirring, cooling to 0-5 deg.C, and holding for 2 hr.
Further, the hydrogen hydrogenation in the step (3) comprises the following steps: displacing with nitrogen, introducing hydrogen to 0.1MPa, heating to 50-60 deg.C, stirring for 12 hr, and cooling to room temperature. Further, in the step (2), acrylic acid or maleic anhydride is further added to obtain the carboxyl-and epoxy-containing acrylic polymer.
In addition, the step (3) of filtering off the palladium-carbon and concentrating to be dry comprises the following steps: filtering until the mother liquor is concentrated under negative pressure until no liquid is discharged.
Example 1
Synthesis of intermediate 9
The specific synthetic steps are as follows: adding 420 g (0.077mol) of intermediate, 100ml of tetrahydrofuran and 15g (0.231mol) of zinc powder into a reaction bottle, dropwise adding 10ml (0.167mol) of glacial acetic acid under stirring, controlling the temperature to be 5-10 ℃ in the dropwise adding process, raising the temperature to 20-25 ℃, stirring, preserving the temperature for 24 hours, filtering, adjusting the pH of mother liquor to 7-8 by using 2M sodium hydroxide aqueous solution, concentrating under negative pressure until no liquid is discharged, adding 200ml of ethyl acetate for extraction, drying an organic layer by using anhydrous sodium sulfate, filtering, and concentrating until the organic layer is dry to obtain 918.5 g of intermediate.
The yield of intermediate 9 was 92% and the HPLC purity (peak area normalization) was 98.3%.
The reaction route is as follows:
example 2
Synthesis of intermediate 10
The specific synthetic steps are as follows: adding 918.5 g (0.07mol) of the intermediate, 8.7g (0.14mol) of ethylene glycol, 100ml of toluene and 1.5g of Nafion-H acid resin into a reaction bottle, heating and refluxing for 5 hours at the reflux temperature of 60 ℃, then cooling to room temperature, filtering, washing mother liquor once with 100ml of water, separating out an aqueous phase, concentrating an organic layer under negative pressure until no liquid is discharged, adding 50ml of petroleum ether, stirring, cooling to 0-5 ℃, preserving heat for 2 hours, and filtering to obtain 1018.4 g of the intermediate.
The yield of intermediate 10 was 85% and the HPLC purity (peak area normalization) was 99%.
The reaction route is as follows:
example 3
Synthesis of key intermediate A
The specific synthetic steps are as follows: adding 1018.4 g of the intermediate, 0.9g of palladium carbon and absolute ethyl alcohol into an autoclave, replacing with nitrogen, introducing hydrogen to 0.1MPa, heating to 50-60 ℃, stirring for 12 hours, cooling to room temperature, filtering, and concentrating mother liquor under negative pressure until no liquid is discharged to obtain 12.7g of key intermediate A12.7g of light yellow oily matter.
The yield of the key intermediate A was 98% and the GC purity was 99.5%.
The reaction route is as follows:
in conclusion, the preparation method of the ticagrelor key intermediate A provided by the invention has the advantages that the intermediate 4 is used as a raw material, an N-O bond is opened through zinc powder reduction, benzyl is not removed, and the complicated process of protecting by CBZ after deprotection is omitted; using ethylene glycol as a raw material, and directly obtaining an intermediate 10 by etherification in the presence of a catalyst; the palladium-carbon catalytic hydrogenation directly obtains the key intermediate A. The key intermediate A is directly obtained through the 3-step reaction, the reaction steps are shortened, the total yield is improved, the production cost control is facilitated, and the method has good economic benefits and wide application prospects.
The invention has many applications, and the above description is only a preferred embodiment of the invention. It should be noted that the above examples are only for illustrating the present invention, and are not intended to limit the scope of the present invention. It will be apparent to those skilled in the art that various modifications can be made without departing from the principles of the invention and these modifications are to be considered within the scope of the invention.
Claims (9)
1. A preparation method of a ticagrelor key intermediate A is characterized by comprising the following steps:
(1) synthesis of intermediate 9: at room temperature, dropwise adding glacial acetic acid into the mixture of the intermediate 4, tetrahydrofuran and zinc powder, stirring and preserving heat for 24 hours, neutralizing with liquid alkali to be neutral, evaporating the solvent, extracting, drying, filtering and concentrating to obtain an intermediate 9;
(2) synthesis of intermediate 10: adding the intermediate 9 into ethylene glycol and toluene, adding a catalyst Nafion-H acid resin, carrying out reflux heat preservation for 2-6 hours, filtering the catalyst, concentrating to dryness, pulping petroleum ether, and recrystallizing to obtain an intermediate 10;
(3) synthesis of key intermediate a: and adding the intermediate 10 and palladium carbon into absolute ethyl alcohol, introducing hydrogen for hydrogenation, filtering the palladium carbon, and concentrating to be dry to obtain the key intermediate A.
2. The preparation method of ticagrelor key intermediate a according to claim 1, wherein the temperature is controlled to be 5-10 ℃ during the dropwise addition of glacial acetic acid in the step (1), and the temperature is raised to 20-25 ℃ after the dropwise addition, stirred and kept for 24 h.
3. The process for preparing ticagrelor key intermediate a according to claim 1, wherein the liquid base neutralization to neutrality in step (1) comprises the steps of: stirring, maintaining the temperature, filtering, adjusting the pH of the mother liquor to 7-8 with 2M sodium hydroxide aqueous solution, and concentrating under negative pressure until no liquid is discharged.
4. The preparation method of ticagrelor key intermediate a according to claim 1, wherein the extraction, drying, filtration and concentration in step (1) comprise the following steps: ethyl acetate was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the intermediate 9.
5. The process for preparing ticagrelor key intermediate a according to claim 1, wherein the reflux incubation time in step (2) is 5h and the temperature is 60 ℃.
6. The preparation method of ticagrelor key intermediate a according to claim 1, wherein the catalyst in step (2) is filtered off and then concentrated to dryness, and the method comprises the following steps: after the reflux and heat preservation are finished, cooling to room temperature, filtering, washing the mother liquor with distilled water once, separating out a water phase, and concentrating an organic layer under negative pressure until no liquid is discharged.
7. The preparation method of ticagrelor key intermediate a according to claim 1, wherein the petroleum ether beating recrystallization in the step (2) comprises the following steps: adding petroleum ether, stirring, cooling to 0-5 deg.C, and holding for 2 hr.
8. The process for preparing ticagrelor key intermediate a according to claim 1, wherein the hydrogenation of hydrogen in step (3) comprises the steps of: displacing with nitrogen, introducing hydrogen to 0.1MPa, heating to 50-60 deg.C, stirring for 12 hr, and cooling to room temperature.
9. The preparation method of ticagrelor key intermediate a according to claim 1, wherein the step (3) of filtering off palladium on carbon and then concentrating to dryness comprises the following steps: filtering until the mother liquor is concentrated under negative pressure until no liquid is discharged.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911125803.9A CN111087379B (en) | 2019-11-18 | 2019-11-18 | Preparation method of ticagrelor key intermediate A |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911125803.9A CN111087379B (en) | 2019-11-18 | 2019-11-18 | Preparation method of ticagrelor key intermediate A |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111087379A true CN111087379A (en) | 2020-05-01 |
| CN111087379B CN111087379B (en) | 2022-04-12 |
Family
ID=70393086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911125803.9A Active CN111087379B (en) | 2019-11-18 | 2019-11-18 | Preparation method of ticagrelor key intermediate A |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111087379B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN103275056A (en) * | 2013-05-24 | 2013-09-04 | 浙江普洛医药科技有限公司 | Preparation method of ticagrelor midbody |
| CN107200745A (en) * | 2017-07-07 | 2017-09-26 | 浙江永宁药业股份有限公司 | Deuterated ticagrelor derivative, preparation method and its application in anticoagulant is prepared |
-
2019
- 2019-11-18 CN CN201911125803.9A patent/CN111087379B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011017108A2 (en) * | 2009-07-27 | 2011-02-10 | Auspex Pharmaceuticals, Inc. | Cyclopropyl modulators of p2y12 receptor |
| CN103275056A (en) * | 2013-05-24 | 2013-09-04 | 浙江普洛医药科技有限公司 | Preparation method of ticagrelor midbody |
| CN107200745A (en) * | 2017-07-07 | 2017-09-26 | 浙江永宁药业股份有限公司 | Deuterated ticagrelor derivative, preparation method and its application in anticoagulant is prepared |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111087379B (en) | 2022-04-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103087059B (en) | Preparation method for high-purity olprinone hydrochloride | |
| CN103539773B (en) | Method for preparing ticagrelor key intermediate | |
| CN103145670A (en) | Semisynthesis luteolin preparation new process | |
| CN111087379B (en) | Preparation method of ticagrelor key intermediate A | |
| WO2000062782A1 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN109988167A (en) | A kind of preparation method of Tadalafei | |
| CN103342707B (en) | For the preparation of the preparation method of A Sainaping intermediate | |
| WO2021259051A1 (en) | Method for improving synthesis process of hypidone free base | |
| CN106432195B (en) | Method for preparing (R) -2- (2-methylpyrrolidine-2-yl) -1H-benzimidazole-4-formamide | |
| CN101066987B (en) | Preparation process of brivudine | |
| CN107739328B (en) | Preparation method of key intermediate 1 for synthesizing barretinib | |
| CN109369772B (en) | Synthetic method and anti-tumor application of phenanthridine nitidine derivatives | |
| CN103044361B (en) | Preparation method of (2R,3S)-epoxidation amino-benzene butane | |
| CN110981883B (en) | Preparation method of ticagrelor key intermediate iodide | |
| CN111500652A (en) | Method for preparing florfenicol | |
| CN114249724B (en) | Preparation method of zolpidem intermediate | |
| CN102863445A (en) | Novel method for synthesizing 9-substituted adenine compound | |
| CN102816141A (en) | Method for preparing nebivolol racemate hydrochloride | |
| CN115477653B (en) | Preparation method of trehalfline key intermediate and trehalfline | |
| CN115260200B (en) | Preparation method of sitagliptin intermediate | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| CN112062763B (en) | Hydroxypyrimido [1,2-b ] [1,2,5] triazepine derivative, preparation and application | |
| CN114085209B (en) | Method for purifying loratadine key intermediate | |
| CN112094241B (en) | Preparation method of 1, 4-diazaspiro [5,5] undecane-3-ketone | |
| CN103804280A (en) | Preparation method of donepezil HCl |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |