CN110981883A - Preparation method of ticagrelor key intermediate iodide - Google Patents
Preparation method of ticagrelor key intermediate iodide Download PDFInfo
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- CN110981883A CN110981883A CN201911125817.0A CN201911125817A CN110981883A CN 110981883 A CN110981883 A CN 110981883A CN 201911125817 A CN201911125817 A CN 201911125817A CN 110981883 A CN110981883 A CN 110981883A
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
A preparation method of a ticagrelor key intermediate iodide comprises the following steps: (1) synthesizing an intermediate 1 and (3) synthesizing a key intermediate iodide, wherein D-ribose is used as a raw material, methanol and acetone are used as solvents, thionyl chloride is added as a catalyst, and the solvent is removed by concentration after the reaction is finished, so that the intermediate 1 is obtained; the key intermediate iodide is synthesized by taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water after the reaction is finished to carry out quenching reaction, distilling off the acetonitrile, extracting the solvent, and concentrating to obtain the key intermediate iodide. According to the preparation method of the key intermediate iodide of ticagrelor, disclosed by the invention, in the synthesis process of the intermediate 1, thionyl chloride is used for replacing hydrochloric acid as a catalyst, so that the reaction conversion rate is greatly improved, and then trimethylchlorosilane/sodium iodide is used as an iodizing agent, so that the reaction condition is mild, the post-treatment is simple and the conversion rate is high.
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 iodide.
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 key intermediate (3aS, 4S, 6R, 6aR) -4-iodomethyl-6-methoxy-2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxolane has the following structural formula:
the key intermediate (3aS, 4S, 6R, 6aR) -4-iodomethyl-6-methoxy-2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxolane is synthesized by the following two methods:
the method comprises the following steps: chinese patent application No. CN201510289960.9 discloses a preparation method of a ticagrelor key intermediate, and the disclosed synthetic route is as follows:
the second method comprises the following steps: the synthetic route reported by John K G, Efthygia G et al in J.chem.Soc Perkin Trans 1994,613-614 is as follows:
the synthesis process of the first method obtains the target compound through three steps of reaction, the reaction steps are long, the yield is low, and equimolar sodium p-toluenesulfonate by-products are generated, which is not favorable for industrial production.
The synthesis process of the second method uses iodine, triphenylphosphine and imidazole system iodine, the reaction yield is low, a large amount of triphenylphosphine oxide byproducts are generated, and the removal is difficult. Therefore, in order to realize industrial production, popularization and economic benefits, a preparation method of a key intermediate iodo product of ticagrelor, which has a shorter synthesis step, a faster reaction speed and a higher conversion rate, 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 key intermediate iodo-compound of ticagrelor, which is simple, adopts a two-step method to directly synthesize a target compound, has high reaction speed and high conversion rate, improves the total yield, is beneficial to controlling the production cost, and has good economic benefit and wide application prospect.
The purpose of the invention is realized by the following technical scheme:
a preparation method of a ticagrelor key intermediate iodide is characterized by comprising the following steps:
(1) synthesis of intermediate 1: taking D-ribose as a raw material, taking methanol and acetone as solvents, adding thionyl chloride as a catalyst, and concentrating to remove the solvents after the reaction is finished to obtain an intermediate 1;
(2) synthesis of key intermediate iodide: and (2) taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water after the reaction is finished to carry out quenching reaction, distilling off the acetonitrile, extracting the solvent, and concentrating to obtain the key intermediate iodo.
According to the preparation method of the key intermediate iodide of ticagrelor, provided by the invention, in the first step, thionyl chloride is used as a catalyst to synthesize an intermediate 1, and the yield can reach over 90%; and in the second step, trimethylchlorosilane/sodium iodide is used as an iodizing agent, acetonitrile is used as a solvent, the target compound is synthesized, the reaction speed is high, the conversion rate is high, the post-treatment is convenient, the reaction steps are shortened, the total yield is improved, and the production cost control is facilitated.
Further, in the above preparation method of the key intermediate iodide of ticagrelor, the temperature is controlled to be 10-15 ℃ when thionyl chloride is added in the step (1).
Further, according to the preparation method of the key intermediate iodo-compound of ticagrelor, after thionyl chloride is added in the step (1), the temperature is raised to 25 +/-3 ℃ and kept for 24 hours.
Further, the above preparation method of a key intermediate iodide of ticagrelor, in which the solvent is removed by concentration in step (1), comprises the following steps: recovering the solvent under negative pressure until no liquid is discharged.
Further, in the above preparation method of a key intermediate iodide of ticagrelor, the step (2) further includes the following steps: and (3) adding the intermediate 1 and sodium iodide into a reaction system by taking acetonitrile as a solvent, and introducing nitrogen for protection.
Further, in the preparation method of the key intermediate iodo-compound of ticagrelor, when trimethylchlorosilane is dropwise added in the step (2), the temperature is controlled to be 20 +/-2 ℃.
Further, according to the preparation method of the key intermediate iodo-compound of ticagrelor, trimethylchlorosilane is dropwise added in the step (2), and the mixture is stirred at room temperature and kept warm for 1 hour.
Further, in the above preparation method of a key intermediate iodide of ticagrelor, the quenching reaction in step (2) includes the following steps: adding water, recovering solvent under negative pressure, adding water, extracting with toluene for three times, mixing organic layers, and concentrating under negative pressure.
Compared with the prior art, the invention has the following beneficial effects: the preparation method of the key intermediate iodide of ticagrelor is improved and optimized on the basis of the prior preparation technology, is simpler and more reasonable, adopts a two-step method to directly synthesize a target compound, adopts thionyl chloride to replace hydrochloric acid as a catalyst in the synthesis process of the intermediate 1, greatly improves the reaction conversion rate, then adopts trimethylchlorosilane/sodium iodide as an iodinating agent, has mild reaction conditions, simple post-treatment and high conversion rate, improves the total yield, is beneficial to the control of production cost, has good economic benefit and has 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 method for preparing a key intermediate iodide of ticagrelor, comprising the following steps:
(1) synthesis of intermediate 1: taking D-ribose as a raw material, taking methanol and acetone as solvents, adding thionyl chloride as a catalyst, and concentrating to remove the solvents after the reaction is finished to obtain an intermediate 1;
(2) synthesis of key intermediate iodide: and (2) taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water after the reaction is finished to carry out quenching reaction, distilling off the acetonitrile, extracting the solvent, and concentrating to obtain the key intermediate iodo.
Further, the liquid caustic soda in the step (1) is neutralized to be neutral, and when the thionyl chloride is added in the step (1), the temperature is controlled to be 10-15 ℃.
And (2) after adding thionyl chloride in the step (1), heating to 25 +/-3 ℃ and keeping the temperature for 24 hours.
Further, the concentration and solvent removal in the step (1) comprises the following steps: recovering the solvent under negative pressure until no liquid is discharged.
Further, the catalyst in the step (2) is filtered and then concentrated to be dry, and the step (2) further comprises the following steps: and (3) adding the intermediate 1 and sodium iodide into a reaction system by taking acetonitrile as a solvent, and introducing nitrogen for protection.
Further, when the trimethylchlorosilane is dropwise added in the step (2), the temperature is controlled to be 20 +/-2 ℃. And (3) dropwise adding trimethylchlorosilane in the step (2), stirring at room temperature and keeping the temperature for 1 hour.
Further, the quenching reaction in the step (2) comprises the following steps: adding water, recovering solvent under negative pressure, adding water, extracting with toluene for three times, mixing organic layers, and concentrating under negative pressure.
Example 1
Synthesis of intermediate 1
The specific synthetic steps are as follows: adding 100ml of acetone, 100ml of methanol and 20g (0.133mol) of D-ribose into a 250ml reaction bottle, dropwise adding 2g of thionyl chloride at the temperature of 10-15 ℃, heating to 25 +/-3 ℃ after the addition, keeping the temperature for 24 hours, and recovering the solvent under negative pressure until no liquid is discharged to obtain 127g of an intermediate, wherein the yield is 99% and the purity is 90%.
The yield of intermediate 1 was 99% with a purity of 90%.
The reaction route is as follows:
example 2
Synthesis of key intermediate iodide
The specific synthetic steps are as follows: adding 127g (0.132mol) of the intermediate, 200ml of acetonitrile and 29.8g (0.198mol) of sodium iodide into a 500ml reaction bottle, controlling the temperature to be 20 +/-2 ℃ under the protection of nitrogen, dropwise adding 21.5g (0.198mol) of trimethylchlorosilane, preserving the temperature for 1 hour after the addition is finished, adding 20ml of water, recovering the solvent under negative pressure till the liquid does not flow out, adding 100ml of water, extracting with 100ml of toluene for three times, combining organic layers, and concentrating under negative pressure till the liquid does not flow out to obtain 35.3g of a key intermediate iodide.
The yield of key intermediate iodide was 85% with a purity of 95%.
The reaction route is as follows:
in conclusion, the preparation method of the key intermediate iodide of ticagrelor provided by the invention adopts a two-step method to directly synthesize a target compound, and in the first step, thionyl chloride is used as a catalyst to synthesize an intermediate 1, so that the yield can reach over 90%; and in the second step, trimethylchlorosilane/sodium iodide is used as an iodizing agent, acetonitrile is used as a solvent, the target compound is synthesized, the reaction speed is high, the conversion rate is high, the post-treatment is convenient, the total yield is improved, the production cost control is facilitated, the economic benefit is good, and the application prospect is wide. .
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 (8)
1. A preparation method of a ticagrelor key intermediate iodide is characterized by comprising the following steps:
(1) synthesis of intermediate 1: taking D-ribose as a raw material, taking methanol and acetone as solvents, adding thionyl chloride as a catalyst, and concentrating to remove the solvents after the reaction is finished to obtain an intermediate 1;
(2) synthesis of key intermediate iodide: and (2) taking acetonitrile as a solvent, adding the intermediate 1 and sodium iodide into a reaction system, dropwise adding trimethylchlorosilane, adding a small amount of water after the reaction is finished to carry out quenching reaction, distilling off the acetonitrile, extracting the solvent, and concentrating to obtain the key intermediate iodo.
2. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the temperature is controlled to 10-15 ℃ when thionyl chloride is added in the step (1).
3. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 2, wherein the temperature is raised to 25 ± 3 ℃ and maintained for 24 hours after adding thionyl chloride in the step (1).
4. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the step (1) of concentrating to remove the solvent comprises the following steps: recovering the solvent under negative pressure until no liquid is discharged.
5. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the step (2) further comprises the following steps: and (3) adding the intermediate 1 and sodium iodide into a reaction system by taking acetonitrile as a solvent, and introducing nitrogen for protection.
6. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the temperature of the dropwise addition of trimethylchlorosilane in the step (2) is controlled to be 20 ± 2 ℃.
7. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the step (2) is carried out by adding trimethylchlorosilane dropwise and stirring at room temperature for 1 hour.
8. The method for preparing a ticagrelor key intermediate iodide as claimed in claim 1, wherein the quenching reaction in step (2) comprises the following steps: adding water, recovering solvent under negative pressure, adding water, extracting with toluene for three times, mixing organic layers, and concentrating under negative pressure.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101356178A (en) * | 2006-01-30 | 2009-01-28 | Irm责任有限公司 | Compounds and compositions as PPAR modulators |
| US20160102101A1 (en) * | 2013-06-24 | 2016-04-14 | Suzhou Miracpharma Technology Co., Ltd. | Preparation method of Ticagrelor and intermediates thereof |
| CN106279095A (en) * | 2015-06-01 | 2017-01-04 | 重庆圣华曦药业股份有限公司 | A kind of preparation method of ticagrelor key intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101356178A (en) * | 2006-01-30 | 2009-01-28 | Irm责任有限公司 | Compounds and compositions as PPAR modulators |
| US20160102101A1 (en) * | 2013-06-24 | 2016-04-14 | Suzhou Miracpharma Technology Co., Ltd. | Preparation method of Ticagrelor and intermediates thereof |
| CN106279095A (en) * | 2015-06-01 | 2017-01-04 | 重庆圣华曦药业股份有限公司 | A kind of preparation method of ticagrelor key intermediate |
Non-Patent Citations (2)
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| DR.HARALD WEINSTABL ET AL.: "Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction", 《ANGEW. CHEM. INT. ED》 * |
| 马定娜: "替卡格雷合成工艺研究", 《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》 * |
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