CN105884793A - Preparation method of antiplatelet medicine Prasugrel - Google Patents
Preparation method of antiplatelet medicine Prasugrel Download PDFInfo
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- CN105884793A CN105884793A CN201610411341.7A CN201610411341A CN105884793A CN 105884793 A CN105884793 A CN 105884793A CN 201610411341 A CN201610411341 A CN 201610411341A CN 105884793 A CN105884793 A CN 105884793A
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- cyclopropyl
- fluorophenyl
- ethyl ketone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a preparation method of antiplatelet medicine Prasugrel. The method includes the steps that 1, 1-cyclopropyl-2-(2-fluoro-phenyl)-2-butanone, iodine monobromide and 1-butyl-3-methyl bromide imidazolium conduct a contact reaction, and 1-cyclopropyl-2-bromine-2-(2-fluoro-phenyl)-2-butanone is obtained; 2, under existence of iodine and alkali, a product of step 1 reacts with 2-oxygen generation-2, 4, 5, 6, 7-7a-tetrahydrothiophene and [3, 2-c] pyridine hydrochloride, and 5-(alpha-ciprofloxacin carbonyl-2-fluorobenzyl)-2-oxygen generation-2, 4, 5, 6, 7, 7a-tetrahydrothiophene and [3, 2-c] pyridine; 3, an obtained product is mixed with triethylamine, then acetic anhydride is dropwise added, the mixture is stirred for a reaction, and the Prasugrel is obtained. The preparation method of the Prasugrel is high in yield, easy to process and suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to the preparation method of a kind of antiplatelet drug prasugrel.
Background technology
Prasugrel (Prasugrel) is a kind of platelet adp receptor inhibitor, for Sankyo company of Japan and Li Lai company
The new drug developed jointly, is used for treating thrombosis, has good anticoagulant effect, have good bioavailability simultaneously.General
The glug thunder entitled 2-acetoxyl group-5-of chemistry (α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-Tetramethylene sulfides also [3,2-c] pyridine, specifically tie
Structure is as follows:
Study of synthesis method currently, with respect to prasugrel is more.CN101402643A discloses one and is applicable to industrial
The preparation method of prasugrel, the method uses cyclopropyl-2-luorobenzyl ketone, and through enol esterification, oxidation, semi-annular jade pendant is acylated, condensation is closed
Becoming prasugrel, although the method raw material is easy to get, environmental pollution is little, but yield is on the low side, and two step yields are less than 50%.Specifically
Process route is as follows:
CN103923101A discloses the preparation method of a kind of prasugrel, and the method uses 1-cyclopropyl-2 bromo-2-(2-fluorobenzene
Base)-2-ethyl ketone is initiation material, with 2-oxo-2 under the conditions of alkalescence, 4,5,6,7-7a-Tetramethylene sulfides also [3,2-c] pyridine hydrochloride replaces,
Then butyl lithium boration, oxidation under low temperature, obtains prasugrel with anhydride reaction the most again.The method condition is harsh, especially
Being that butyl lithium reaction needs stringent low-temperature should not be amplified industrialized production, the most overall yield is the highest.The concrete work of the method
Skill process is as follows:
In view of the good market value of prasugrel, this area still needs to that a kind of method is simple, mild condition and the high system of yield
The method of standby prasugrel.
Summary of the invention
It is an object of the invention to overcome the existing defect preparing prasugrel, it is provided that a kind of new antiplatelet drug pula lattice
The preparation method of thunder intermediate.
Inventor has been surprisingly found that under study for action, can be at gentle especially bar by iodine monobromide and 1-butyl-3-methy limidazolium
Under part, the α position of 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone being carried out halo (bromo), reaction yield is effectively improved；It addition,
Inventor also finds, in the presence of a base by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone and 2-oxo-2,4,5,6,7-7a-tetrahydrochysenes
In the course of reaction of thieno [3,2-c] pyridine hydrochloride, add a small amount of iodine, it is possible to be greatly improved the yield of reaction, and improve anti-
The speed answered.
To achieve these goals, the present invention provides a kind of method preparing prasugrel, and the method comprises the following steps:
1) 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone carries out haptoreaction obtain with iodine monobromide and 1-butyl-3-methy limidazolium
To the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone；
2) in the presence of iodine and alkali, by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone and 2-oxo-2,4,5,6,7-7a-tetrahydrochysene thiophenes
The reaction of fen also [3,2-c] pyridine hydrochloride obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c]
Pyridine；
3) step 2) 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine of obtaining with
Triethylamine mixes, and then drips acetic anhydride, and prasugrel is reacted to obtain in stirring.
In the present invention, it is preferred to, in step 1) in, 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone and iodine monobromide, 1-fourth
The consumption mol ratio of base-3-methy limidazolium is 1:2～5:0.2～0.4.Preferably, step 1) haptoreaction at 35～40 DEG C
Carrying out, reaction dissolvent is anhydrous tetrahydro furan.
In the present invention, it is preferred to, in step 2) in, the bromo-2-of 1-cyclopropyl-2 (2-fluorophenyl)-2-ethyl ketone and 2-oxo
-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride, iodine, the consumption mol ratio of alkali are 1:1.1～1.5:0.05～0.15:
2～3.Preferably, the step 2 of the present invention) in stirring reaction carry out at 70～85 DEG C, reaction dissolvent is Isosorbide-5-Nitrae-dioxane.
In the present invention, inventor also finds, in step 2) in alkali used carry out most important for reaction, described alkali
It is preferably one or more in sodium hydroxide, sodium carbonate, potassium phosphate.It is further preferred that described alkali is potassium phosphate.
In the present invention, step 3) in, the consumption of each reactant does not has special requirement, is referred to prior art
Method, triethylamine as acid binding agent consumption more than raw material, the prior art being referred to such as: CN101402643A,
It is expressly incorporated herein at this.
In the present invention, reaction is monitored following the tracks of by the method that this area can be used conventional, such as TLC, LCMS, GCMS
Deng, react complete finger TLC monitor not excess raw material disappeared or in LCMS, GCMS not excess raw material residue less than 2%.
The prasugrel that the method that the present invention provides obtains can carry out crystallizing the required crystalline substance obtaining prasugrel according to conventional methods
Type.
The concrete route that the present invention prepares the method for prasugrel is as follows:
Compared with prior art, the method preparing prasugrel using the present invention to provide, use new halogenation mode, condition
Gentleer, yield is higher；At the bromo-2-of 1-cyclopropyl-2 (2-fluorophenyl)-2-ethyl ketone and 2-oxo-2,4,5,6,7-7a-Tetramethylene sulfide
And in the nucleophilic substitution of [3,2-c] pyridine hydrochloride, add iodine and be catalyzed, yield is greatly improved；1-cyclopropyl-2 bromo-2-(2-
Fluorophenyl)-2-ethyl ketone and 2-oxo-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride nucleophilic substitution in use
Potassium phosphate, as alkali, further increases and reacts to obtain yield, achieves unexpected technique effect.
Other features and advantages of the present invention will be described in detail in detailed description of the invention part subsequently.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.But these embodiments are only limitted to illustrate rather than this
The further restriction of the protection domain of invention.
In the examples below, 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone, iodine monobromide, 1-butyl-3-methy limidazolium
It is purchased from lark prestige Science and Technology Ltd..
Embodiment 1
The synthesis of the bromo-2-of 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone
By 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 17.8g (100mmol), iodine monobromide 51.7g (250mmol) and 1-butyl-3-
Methy limidazolium 6.5g (30mmol) is 35 DEG C of haptoreactions 4 hours in 150ml anhydrous tetrahydro furan, after reaction terminates,
Being cooled to room temperature, be poured in frozen water, ethyl acetate extracts, and saturated sodium sulfite washs, and organic facies concentrates, ethyl alcohol recrystallization
Obtaining the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 24.7g, yield is 96.1%, purity 99.61%.
Embodiment 2
The synthesis of the bromo-2-of 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone
By 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 17.8g (100mmol), iodine monobromide 41.4g (200mmol) and 1-butyl
-3-methy limidazolium 6.5g (30mmol) is 40 DEG C of haptoreactions 5 hours in 150ml anhydrous tetrahydro furan, after reaction terminates,
Being cooled to room temperature, be poured in frozen water, ethyl acetate extracts, and saturated sodium sulfite washs, and organic facies concentrates, ethyl alcohol recrystallization
Obtaining the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 24.6g, yield is 95.8%, purity 99.57%.
Embodiment 3
The synthesis of the bromo-2-of 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone
By 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 17.8g (100mmol), iodine monobromide 62g (300mmol) and 1-butyl-3-
Methy limidazolium 8.7g (40mmol) is 40 DEG C of haptoreactions 4 hours in 150ml anhydrous tetrahydro furan, after reaction terminates,
Being cooled to room temperature, be poured in frozen water, ethyl acetate extracts, and saturated sodium sulfite washs, and organic facies concentrates, ethyl alcohol recrystallization
Obtaining the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 24.5g, yield is 95.3%, purity 99.73%.
Embodiment 4
Such as the synthetic method of the 1-bromo-2-of cyclopropyl-2-(2-the fluorophenyl)-2-ethyl ketone of embodiment 1, except that, the use of iodine monobromide
Amount is 20.7g (100mmol), obtains the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 23.5g, and yield is 91.4%, purity 99.66%.
Embodiment 5
Such as the synthetic method of the 1-bromo-2-of cyclopropyl-2-(2-the fluorophenyl)-2-ethyl ketone of embodiment 1, except that, 1-butyl-3-methyl
The consumption of limidazolium is 2.2g (10mmol), obtains the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 23.2g, and yield is
90.2%, purity 99.43%.
Embodiment 6
The synthesis of 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine
In 100ml reaction bulb, by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone 2.6g (10mmol) 2-oxo
-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride 2.9g (15mmol), iodine 0.05g (0.5mmol), potassium phosphate 5.3g
(25mmol) in 50ml Isosorbide-5-Nitrae-dioxane 80 DEG C react 4 hours, reaction terminate after, be cooled to room temperature, be poured into frozen water
In, dichloromethane extracts, and saturated sodium thiosulfate washs, and organic facies concentrates, and dichloromethane mixes with petroleum ether (1:10)
Solvent recrystallization obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfides also [3,2-c] pyridine 2.9g, receives
Rate is 87.6%, purity 99.19%.
Embodiment 7
The synthesis of 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine
In 100ml reaction bulb, by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone 2.6g (10mmol) 2-oxo
-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride 2.1g (11mmol), iodine 0.25g (1mmol), potassium phosphate 4.2g
(20mmol) in 50ml Isosorbide-5-Nitrae-dioxane 70 DEG C react 4 hours, reaction terminate after, be cooled to room temperature, be poured into frozen water
In, dichloromethane extracts, and saturated sodium thiosulfate washs, and organic facies concentrates, and dichloromethane mixes with petroleum ether (1:10)
Solvent recrystallization obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfides also [3,2-c] pyridine 2.86g, receives
Rate is 86.4%, purity 99.38%.
Embodiment 8
The synthesis of 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine
In 100ml reaction bulb, by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone 2.6g (10mmol) 2-oxo
-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride 2.5g (13mmol), iodine 0.38g (1.5mmol), potassium phosphate 6.4g
(30mmol) in 50ml Isosorbide-5-Nitrae-dioxane 80 DEG C react 5 hours, reaction terminate after, be cooled to room temperature, be poured into frozen water
In, dichloromethane extracts, and saturated sodium thiosulfate washs, and organic facies concentrates, and dichloromethane mixes with petroleum ether (1:10)
Solvent recrystallization obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfides also [3,2-c] pyridine 2.87g, receives
Rate is 87.1%, purity 99.73%.
Embodiment 9
Such as 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine in embodiment 6
Synthetic method, except that, described alkali is sodium carbonate, obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-
Tetramethylene sulfide also [3,2-c] pyridine 2.41g, yield is 72.7%, purity 98.74%.
Embodiment 10
Such as 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine in embodiment 6
Synthetic method, except that, described alkali is sodium hydroxide, obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-
Tetramethylene sulfide also [3,2-c] pyridine 2.15g, yield is 64.9%, purity 99.10%.
Embodiment 11
The synthesis of prasugrel
By 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine 3.3g (10mmol), three
Ethamine 3g (30mmol) mixes, 0 DEG C of dropping acetic anhydride 2.1g (20mmol), drips complete being stirred at room temperature and reacts 4 hours, second
Acetoacetic ester extracts, anhydrous slufuric acid ammonium dry filter, concentrates ethyl acetate, and absolute methanol recrystallization obtains prasugrel 2.87g, yield
It is 76.8%, purity 99.64%.
Comparative example 1
Such as the synthetic method of the 1-bromo-2-of cyclopropyl-2-(2-the fluorophenyl)-2-ethyl ketone in embodiment 1, except that, it is added without monobromo
Changing iodine, obtain the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 14.1g, yield is 54.8%, purity 98.43%.
Comparative example 2
Such as the synthetic method of the 1-bromo-2-of cyclopropyl-2-(2-the fluorophenyl)-2-ethyl ketone in embodiment 1, except that, it is added without 1-fourth
Base-3-methy limidazolium, obtains the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone 12.2g, and yield is 47.6%, purity 97.63%.
Comparative example 3
Such as 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine in embodiment 6
Synthetic method, except that, it is added without iodine, obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-tetrahydrochysene thiophenes
Fen also [3,2-c] pyridine 2g, yield is 61.3%, purity 99.41%.
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to the tool in above-mentioned embodiment
Body details, in the technology concept of the present invention, can carry out multiple simple variant to technical scheme, these
Simple variant belongs to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention, in reconcilable feelings
Under condition, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention is to various possible groups
Conjunction mode illustrates the most separately.Additionally, combination in any can also be carried out between the various different embodiment of the present invention, as long as
It is without prejudice to the thought of the present invention, and it should be considered as content disclosed in this invention equally.
Claims (7)
1. the preparation method of an antiplatelet drug prasugrel, it is characterised in that the method comprises the following steps:
1) 1-cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone carries out haptoreaction obtain with iodine monobromide and 1-butyl-3-methy limidazolium
To the 1-bromo-2-of cyclopropyl-2-(2-fluorophenyl)-2-ethyl ketone；
2) in the presence of iodine and alkali, by bromo-for 1-cyclopropyl-2 2-(2-fluorophenyl)-2-ethyl ketone and 2-oxo-2,4,5,6,7-7a-tetrahydrochysene thiophenes
The reaction of fen also [3,2-c] pyridine hydrochloride obtains 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c]
Pyridine；
3) step 2) 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxo-2,4,5,6,7,7a-Tetramethylene sulfide also [3,2-c] pyridine of obtaining with
Triethylamine mixes, and then drips acetic anhydride, and prasugrel is reacted to obtain in stirring.
Method the most according to claim 1, it is characterised in that in step 1) in, 1-cyclopropyl-2-(2-fluorophenyl)-2-
Ethyl ketone is 1:2～3:0.3～0.4 with iodine monobromide, the consumption mol ratio of 1-butyl-3-methy limidazolium.
Method the most according to claim 1, it is characterised in that in step 2) in, the bromo-2-of 1-cyclopropyl-2 (2-fluorophenyl)-2-
Ethyl ketone is 1:1.1～1.5 with 2-oxo-2,4,5,6,7-7a-Tetramethylene sulfide also [3,2-c] pyridine hydrochloride, iodine, the consumption mol ratio of alkali:
0.05～0.15:2～3.
4. according to the method described in claim 1-3, it is characterised in that step 1) haptoreaction carry out at 35～40 DEG C,
Reaction dissolvent is anhydrous tetrahydro furan.
Method the most according to claim 1, it is characterised in that step 2) in stirring reaction carry out at 70～85 DEG C, instead
Answering solvent is 1,4-dioxane.
6. according to the method described in claim 1 or 3, it is characterised in that described alkali is sodium hydroxide, sodium carbonate, potassium phosphate
In one or more.
Method the most according to claim 6, it is characterised in that described alkali is potassium phosphate.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
| WO2009062044A2 (en) * | 2007-11-09 | 2009-05-14 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of prasugrel, and its salts and polymorphs |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
| WO2012018791A2 (en) * | 2010-08-06 | 2012-02-09 | Dr. Reddy's Laboratories Ltd. | Preparation of prasugrel hydrochloride |
| WO2014114964A2 (en) * | 2013-01-24 | 2014-07-31 | Egis Pharmaceuticals Public Limited Company | Improved process for the preparation of prasugrel and intermediate thereof |
-
2016
- 2016-06-09 CN CN201610411341.7A patent/CN105884793A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009062044A2 (en) * | 2007-11-09 | 2009-05-14 | Dr. Reddy's Laboratories Ltd. | Processes for the preparation of prasugrel, and its salts and polymorphs |
| WO2009066326A2 (en) * | 2007-11-19 | 2009-05-28 | Msn Laboratories Limited | Improved process for the preparation of prasugrel and its pharmaceutically acceptable salts |
| CN101402643A (en) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | Industrial production method for prasugrel |
| WO2012018791A2 (en) * | 2010-08-06 | 2012-02-09 | Dr. Reddy's Laboratories Ltd. | Preparation of prasugrel hydrochloride |
| WO2014114964A2 (en) * | 2013-01-24 | 2014-07-31 | Egis Pharmaceuticals Public Limited Company | Improved process for the preparation of prasugrel and intermediate thereof |
Non-Patent Citations (2)
| Title |
|---|
| OLGA BORTOLINI，等: "Trihalide-based ionic liquids. Reagent-solvents for stereoselective iodination of alkenes and alkynes", 《THE ROYAL SOCIETY OF CHEMISTRY》 * |
| 代黎，等: "盐酸普拉格雷合成工艺的改进", 《药学实践杂志》 * |
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Application publication date: 20160824 |