CN106083885A - The preparation method of prasugrel hydrobromide - Google Patents
The preparation method of prasugrel hydrobromide Download PDFInfo
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- CN106083885A CN106083885A CN201610390528.3A CN201610390528A CN106083885A CN 106083885 A CN106083885 A CN 106083885A CN 201610390528 A CN201610390528 A CN 201610390528A CN 106083885 A CN106083885 A CN 106083885A
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- prasugrel
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- solvent
- prasugrel hydrobromide
- hydrobromide
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- 0 *c1cc(CN(CC2)C(C(C3CC3)=O)c(cccc3)c3F)c2[s]1 Chemical compound *c1cc(CN(CC2)C(C(C3CC3)=O)c(cccc3)c3F)c2[s]1 0.000 description 1
Classifications
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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
Abstract
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of a kind of prasugrel hydrobromide.The preparation method of described prasugrel hydrobromide is first to be dissolved in by prasugrel or be suspended in organic solvent, after adding proton solvent, then drips acylbromide, and finally crystallization obtains prasugrel hydrobromide.The present invention can synthesize prasugrel hydrobromide quickly and easily, and it is easy and simple to handle, product purity is higher, is suitable for industrialized great production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to the preparation method of a kind of prasugrel hydrobromide.
Background technology
In recent years, cardiovascular and cerebrovascular disease sickness rate is in rising trend, serious harm human health.Wherein thrombosis or thromboembolism
The relevant disease caused is currently to cause disabled and dead primary factor.The preventing and treating of thrombosis and complication thereof has become world doctor
The important topic that educational circles faces.Suppression platelet aggregation can be effectively improved the cardiovascular and cerebrovascular disease caused with pre-preventing thrombosis, therefore,
The drug research of antiplatelet aggregation has become the focus for the treatment of cardiovascular disease.
At present, representative platelet suppressant drug class antithrombotic reagent is bisulfate clopidogrel, little for a kind of blood
Plate adenosine diphosphate (ADP) P2Y12Receptor blocking agent, is applied to treat arteriosclerosis disease, acute coronary artery syndrome, pre-clinically
Restenosis and thrombotic complications etc. in anti-coronary stenting after-poppet, belong to one of " cookle " medicine.
Prasugrel, English entitled Prasugrel, chemical entitled 2-[2-(acetoxyl group)-6,7-dihydro-thiophene also [3,
2-c] pyridine-5 (4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, by Sankyo company of Japan and U.S. Eli Lilly
Company's joint development, and in the platelet adenosine diphosphate (ADP) P of new generation of Huo European Union approval listing February 23 in 20092Y12Receptor
Blocker, structure is as shown in formula II:
Prasugrel is a kind of hemostasis new drug of Thienopyridines, is a kind of prodrug, in vivo after metabolism
Form bioactive molecule, with platelet P2Y12Receptor combines and plays the effect of antiplatelet aggregation.Clinical trial shows, with chlorine pyrrole
Gray compares, and prasugrel has more preferable anticoagulant effect, can make heart of patient onste, apoplexy, because of deaths from heart disease
Integrated risk reduces by 20%.Prasugrel has good toleration and bioavailability simultaneously, and toxicity is relatively low.Both domestic and external
Research all show, prasugrel than clopidogrel in terms of antiplatelet more potential, its than approval dosage clopidogrel exist
In suppression adenosine diphosphate ADP induced platelet cohesion effect is higher, onset individual variation faster, between patient is less.BMO
Capital market company analyzes and represents, prasugrel there is also a bright spot, i.e. diabetics and uses this medicine to meet with
Hemorrhage danger, for the diabetics accepting stent procedure, prasugrel can be by successfully special as one
Medicine uses.
Prasugrel is as a kind of adp receptor blocker, and in water, dissolubility is less, in the impact of pharmaceutic adjuvant with prevent
Under, can produce and be unfavorable for the preparation of pharmaceutical preparation and in pharmaceutical preparation, be not easy to the problems such as dissolution.Do not changing pula lattice
Under the pharmacological properties premise of thunder, this compound pharmaceutically acceptable salt need to be prepared, to improve its water solublity, stability and to be administered orally
Bioavailability.
The hydrobromate of prasugrel i.e. prasugrel hydrobromide has a structure as shown in formula I:
The hydrobromate of medical compounds generally uses the solution of hydrogen bromide acidifying medical compounds to prepare, and wherein uses
The aqueous solution of hydrogen bromide or the organic solution of gaseous state hydrogen bromide or hydrogen bromide are relatively common, use hydrobromic acid aqueous solution to prepare hydrogen bromine
Hydrochlorate is then most straightforward approach.But, medical compounds hydrobromate all has dissolubility in various degree to cause in water
The yield of medical compounds hydrobromate is relatively low.If additionally, need the form of anhydrous hydrobromate, then use hydrobromic acid water
Solution is in many cases and infeasible.If water interference solid crystallized product is formed and separates, then can use from steel
The anhydrous hydrogen bromide gas of bottle or the hydrogen bromide gas in anhydrous aprotic solvent.But these operations significantly increase equipment
This and increase gas-operated risk.
Patent WO2011057593A2, WO201105759A1 and CN201310512460 use and dissociate to prasugrel
The 40% hydrobromic acid aqueous solution method that drips in the organic solvent of alkali is to prepare prasugrel hydrobromide.Patent
WO2011057593A2, EP2415774A1 and CN201110356498 use in the organic solvent of prasugrel free alkali
Drip hydrobromic organic solution method to prepare prasugrel hydrobromide.Said method is preparing the mistake of prasugrel hydrobromide
, there is the defects such as product purity is low, be difficult to crystallize, equipment corrosion is serious in Cheng Zhong.
Therefore, need badly exploitation one operation the easiest, product purity is higher, the hydrobromic acid being suitable for industrialized production is general
The new preparation method of glug thunder.
Summary of the invention
It is an object of the invention to provide that a kind of operation is the easiest, product purity is higher, is suitable for the hydrogen of industrialized production
The preparation method of bromic acid prasugrel.
The preparation method of prasugrel hydrobromide of the present invention is, is first dissolved in by prasugrel or is suspended in organic molten
In agent, after adding proton solvent, then dripping acylbromide, finally crystallization obtains prasugrel hydrobromide.
Wherein:
Described prepare the solvent that prasugrel hydrobromide used and be not particularly limited, any can dissolve to a certain extent
Prasugrel free alkali and the organic solvent not suppressing reaction to occur all can use.
Preferably one or more in ketones solvent, nitrile solvents, esters solvent or ether solvent；Ketones solvent is third
One or more in ketone, butanone or methyl tertbutyl ketone；Nitrile solvents is one or more in acetonitrile or propionitrile；Esters is molten
Agent is one or more in Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate or vinyl acetate；
Ether solvent is one or more in oxolane, 1,4-dioxane, ether or diisopropyl ether.More preferably acetone, acetonitrile, second
Acetoacetic ester, oxolane or Isosorbide-5-Nitrae-dioxane, most preferably acetone.
Described proton solvent is the compound of hydroxyl, including water, aliphatic or aromatic alcohols, silanol or can enol
The ketone changed, the preferably alkylol of water, C1～C6.
Described acylbromide structural formula is R1COBr, wherein, R1 be C1～C18 alkyl or containing 1～3 halogen atom C1～
C10 haloalkyl, preferably acetyl bromide or bromoacetyl bromide, most preferably acetyl bromide.
Described prasugrel concentration in organic solvent is 10～500 mM/ls, preferably 50～400 mMs/
Rise, most preferably 100～300 mM/ls；
Described proton solvent consumption is 0.1～10 times of prasugrel molal weight, preferably 1～3 times, most preferably 1.2～
1.5 again；
Described acylbromide consumption is 0.5～5 times of prasugrel molal weight, preferably 1～2 times, most preferably 1.1～1.2 times.
Reaction temperature and the response time of preparing prasugrel hydrobromide slightly become according to the difference of reagent, solvent etc.
Change.
Described reaction temperature is-20～100 DEG C, preferably 10～60 DEG C, most preferably 20～40 DEG C.
The described response time is 1min～24h, preferably 30min～5h, most preferably 2～3h.
The reaction equation of the present invention is as follows:
Beneficial effects of the present invention is as follows:
The present invention can synthesize prasugrel hydrobromide quickly and easily, and it is easy and simple to handle, product purity is higher, is suitable for
In industrialized great production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1
The preparation of prasugrel hydrobromide:
10.0g (26.8mmol) prasugrel is suspended in 100.0mL acetone by 250mL round-bottomed flask, stirs at 20 DEG C
Add 3.1ml (40.2mmol) isopropanol after being completely dissolved, be then slowly added dropwise 2.6mL (32.1mmol) acetyl bromide, drip
After Bi Baowen 30min, stop heating, Temperature fall, crystallization.Filter after 3h, 20.0mL washing with acetone, be vacuum dried at 40 DEG C
16h obtains 12.0g prasugrel hydrobromide white solid, HPLC purity 99.1%；1H NMR(400MHz,CDCl3)δ13.38(d,
J=109.9Hz, 1H), 7.97 (d, J=71.5Hz, 1H), 7.55 (d, J=6.0Hz, 1H), 7.38 (t, J=7.0Hz, 1H),
7.29 7.21 (m, 2H), 6.38 (s, 1H), 5.67 (s, 1H), 4.63 (s, 1H), 4.01 (d, J=179.2Hz, 2H), 3.55
(s, 1H), 3.27 (s, 1H), 2.89 (s, 1H), 2.30 (s, 3H), 1.81 (s, 1H), 1.28 (d, J=23.0Hz, 1H), 1.15
(s,1H),1.04(s,1H),0.89(s,1H).
Embodiment 2
The preparation of prasugrel hydrobromide:
10.0g (26.8mmol) prasugrel is dissolved in 100.0mL acetonitrile by 250mL round-bottomed flask, has stirred at 40 DEG C
Add 5.1ml (51.0mmol) water after CL, be then slowly added dropwise 3.3mL (40.2mmol) acetyl bromide, drip complete insulation
After 30min, stop heating, Temperature fall, crystallization.Filtering after 2h, 20.0mL acetonitrile washs, and is vacuum dried 16h and obtains at 40 DEG C
10.7g prasugrel hydrobromide white solid, HPLC purity 99.0%.
Embodiment 3
The preparation of prasugrel hydrobromide:
5.0g (13.4mmol) prasugrel is dissolved in 100.0mL oxolane by 250mL round-bottomed flask, stirs at 60 DEG C
Add 3.1ml (40.2mmol) isopropanol after being completely dissolved, be then slowly added dropwise 2.9mL (32.1mmol) propionyl bromide, drip
After Bi Baowen 30min, stop heating, Temperature fall, crystallization.Filtering after 3h, 20.0mL oxolane washs, and at 40 DEG C, vacuum is done
Dry 16h obtains 5.1g prasugrel hydrobromide white solid, HPLC purity 99.2%.
Embodiment 4
The preparation of prasugrel hydrobromide:
5.0g (13.4mmol) prasugrel is dissolved in 100.0mL1,4-dioxane by 250mL round-bottomed flask, at 40 DEG C
Stirring adds 2.3ml (40.2mmol) ethanol after being completely dissolved, and is then slowly added dropwise 1.6mL (20.1mmol) acetyl bromide, dropping
After complete insulation 30min, stop heating, Temperature fall, crystallization.Filtering after 5h, 20.0mL1,4-dioxane washs, at 40 DEG C
Vacuum drying 16h obtains 5.1g prasugrel hydrobromide white solid, HPLC purity 98.8%.
Embodiment 5
The preparation of prasugrel hydrobromide:
10.0g (26.8mmol) prasugrel is dissolved in 100.0mL ethyl acetate by 250mL round-bottomed flask, stirs at 40 DEG C
Mix addition 3.1ml (40.2mmol) isopropanol after being completely dissolved, be then slowly added dropwise 2.6mL (32.1mmol) acetyl bromide, dropping
After complete insulation 30min, stop heating, Temperature fall, crystallization.Filtering after 5h, 20.0mL ethyl acetate is washed, vacuum at 40 DEG C
Dry 16h obtains 5.7g prasugrel hydrobromide white solid, HPLC purity 96.8%.
Embodiment 6
The preparation of prasugrel hydrobromide:
10.0g (26.8mmol) prasugrel is suspended in 100.0mL acetone by 250mL round-bottomed flask, stirs at 40 DEG C
Add 2.7ml (67.0mmol) methanol after being completely dissolved, be then slowly added dropwise 2.8mL (32.1mmol) bromoacetyl bromide, drip
After Bi Baowen 30min, stop heating, Temperature fall, crystallization.Filter after 1h, 20.0mL washing with acetone, at 40 DEG C, be vacuum dried 6h
Obtain 10.5g prasugrel hydrobromide white solid, HPLC purity 98.7%.
Claims (10)
1. the preparation method of a prasugrel hydrobromide, it is characterised in that: first prasugrel it is dissolved in or is suspended in organic molten
In agent, after adding proton solvent, then dripping acylbromide, finally crystallization obtains prasugrel hydrobromide.
The preparation method of prasugrel hydrobromide the most according to claim 1, it is characterised in that: organic solvent is that ketone is molten
One or more in agent, nitrile solvents, esters solvent or ether solvent.
The preparation method of prasugrel hydrobromide the most according to claim 2, it is characterised in that: ketones solvent be acetone,
One or more in butanone or methyl tertbutyl ketone；Nitrile solvents is one or more in acetonitrile or propionitrile；Esters solvent
For one or more in Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate or vinyl acetate；Ether
Kind solvent is one or more in oxolane, 1,4-dioxane, ether or diisopropyl ether.
The preparation method of prasugrel hydrobromide the most according to claim 3, it is characterised in that: organic solvent be acetone,
Acetonitrile, ethyl acetate, oxolane or Isosorbide-5-Nitrae-dioxane, preferably acetone.
The preparation method of prasugrel hydrobromide the most according to claim 1, it is characterised in that: proton solvent is hydroxyl
Compound, including water, aliphatic or aromatic alcohols, silanol or can the ketone of enolization.
The preparation method of prasugrel hydrobromide the most according to claim 5, it is characterised in that: proton solvent is water or C1
～the alkylol of C6.
The preparation method of prasugrel hydrobromide the most according to claim 1, it is characterised in that: acylbromide structural formula is
R1COBr, wherein, R1 is C1～C18 alkyl or C1～the C10 haloalkyl containing 1～3 halogen atom.
The preparation method of prasugrel hydrobromide the most according to claim 7, it is characterised in that: acylbromide is acetyl bromide or bromine
Acetyl bromide.
The preparation method of prasugrel hydrobromide the most according to claim 1, it is characterised in that: prasugrel is organic molten
Concentration in agent is 10～500 mM/ls, preferably 50～400 mM/ls, most preferably 100～300 mM/ls；Matter
Sub-solvent load is 0.1～10 times of prasugrel molal weight, preferably 1～3 times, most preferably 1.2～1.5 times；Acylbromide consumption
For 0.5～5 times of prasugrel molal weight, preferably 1～2 times, most preferably 1.1～1.2 times.
The preparation method of prasugrel hydrobromide the most according to claim 1, it is characterised in that: reaction temperature be-20～
100 DEG C, preferably 10～60 DEG C, most preferably 20～40 DEG C；Response time is 1min～24h, preferably 30min～5h, most preferably 2～
3h。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108892641A (en) * | 2018-09-18 | 2018-11-27 | 湖北博瑞生物科技股份有限公司 | A kind of preparation method of Lappaconitine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105601643A (en) * | 2015-12-23 | 2016-05-25 | 山东鲁抗医药股份有限公司 | Preparation method of high-purity prasugrel hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105601643A (en) * | 2015-12-23 | 2016-05-25 | 山东鲁抗医药股份有限公司 | Preparation method of high-purity prasugrel hydrochloride |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108892641A (en) * | 2018-09-18 | 2018-11-27 | 湖北博瑞生物科技股份有限公司 | A kind of preparation method of Lappaconitine |
| CN108892641B (en) * | 2018-09-18 | 2021-07-20 | 湖北博瑞生物科技股份有限公司 | Preparation method of lappaconitine hydrobromide |
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Application publication date: 20161109 |
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