CN103524530A - Prasugrel hydrobromide and preparation method thereof - Google Patents
Prasugrel hydrobromide and preparation method thereof Download PDFInfo
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- CN103524530A CN103524530A CN201310512460.8A CN201310512460A CN103524530A CN 103524530 A CN103524530 A CN 103524530A CN 201310512460 A CN201310512460 A CN 201310512460A CN 103524530 A CN103524530 A CN 103524530A
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- 0 C[C@@](C(C1CC1)=O)(c1c(C*)cccc1)Br Chemical compound C[C@@](C(C1CC1)=O)(c1c(C*)cccc1)Br 0.000 description 4
- DWBGTJUQWKWYGB-UHFFFAOYSA-N O=C(Cc(cccc1)c1F)C1CC1 Chemical compound O=C(Cc(cccc1)c1F)C1CC1 DWBGTJUQWKWYGB-UHFFFAOYSA-N 0.000 description 1
- PYQVFGJHIWJNFS-UHFFFAOYSA-N O=C1SC(CCNC2)C2=C1 Chemical compound O=C1SC(CCNC2)C2=C1 PYQVFGJHIWJNFS-UHFFFAOYSA-N 0.000 description 1
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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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Abstract
The invention discloses a preparation method of prasugrel hydrobromide. A hydrobromic acid aqueous solution and an aqueous hydrogen peroxide solution are adopted as halogenating reagents; benzyl o-cyclopropyl ketone is converted into alpha-cyclopropane carbonyl-2-benzyl bromide fluorine, then condensed together with 2-oxo-4,5,6,7-tetrahydro-thiophene [3,2-c] pyridine hydrochloride, and acylated, so as to prepare prasugrel; high-purity prasugrel crystal is prepared by taking acetonitrile as a recrystallization solvent; the prasugrel reacts with the hydrobromic acid aqueous solution, so as to prepare the high-purity prasugrel hydrobromide.
Description
Technical field
The preparation and the purification process that the present invention relates to a kind of prasugrel and hydrobromate thereof, belong to medical technical field.
Background technology
Prasugrel (Prasugrel) structure is shown below, chemical name is 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also, the oral antithrombotic reagent of thiophene pyridines of new generation of Shi Youlilai company and the first pharmacy San Gong company joint development, prasugrel hydrochloride having is in July, 2009 through FDA approval listing, and trade(brand)name is Effient.
First Chinese patent CN1214031C discloses prasugrel hydrochloride having and maleate and preparation method thereof, and its synthesis technique flow process is summarized as follows:
First the Grignard reagent of adjacent fluorobenzyl bromide being produced with reactive magnesium in this patent reacts with cyclopropanecarbonitrile, and gained intermediate 3 and N-bromo-succinimide and benzoyl peroxide are at CCl
4in solvent, there is bromo and obtain intermediate 4; intermediate 4 and hydrochloride 5 are made acid binding agent with saleratus, and through intermolecular nucleophilic substitution reaction synthetic intermediate 6, intermediate 6 is under diacetyl oxide, NaH condition; in DMF solvent, through acetylize, synthesize prasugrel.Total recovery is 22.7%.Gained prasugrel and hydrochloric acid or toxilic acid, adopt ordinary method salify to obtain its hydrochloride or maleate.
In this patent, second step bromo bromide reagent NBS used cost is higher, and makes solvent with tetracol phenixin, and toxicity is higher; And intermediate 6 and prasugrel 7 all adopt the method for purification of the separated recrystallization again of first post, and complex operation, is unfavorable for scale operation.
Summary of the invention
A kind of method that the object of the present invention is to provide high yield, safety, economy, low pollution, the simple synthesis of high purity prasugrel of separation and Extraction and hydrobromate thereof, is suitable for large-scale industrial production.
For achieving the above object, the preparation method of prasugrel hydrobromide provided by the invention, reaction process is as follows:
Step is:
1) temperature of reaction is 0 ℃～80 ℃, 1-cyclopropyl-the 2-shown in formula II (2-fluorophenyl) ethyl ketone of take is raw material, dioxane, acetic acid, tetrahydrofuran (THF), ethanol, methyl alcohol or Virahol are solvent, the bromine that hydrobromic acid aqueous solution and aqueous hydrogen peroxide solution reaction produce is halogenating agent, generates the bromo-2-of 2-(2-the fluorophenyl)-1-cyclopropyl ethyl ketone shown in formula III;
Wherein 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and hydrobromic mol ratio are 1:1～5, and the mol ratio of 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and hydrogen peroxide is 1:1～10;
2) temperature of reaction is 20 ℃～80 ℃, more than one in salt of wormwood, sodium carbonate, sodium bicarbonate, triethylamine, diisopropyl ethyl amine of take are acid binding agent, N, dinethylformamide, acetonitrile, acetone, ethyl acetate or methylene dichloride are solvent, 2-oxygen-4 shown in the bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone and formula IV, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride under acid binding agent effect, the 5-[2-cyclopropyl-1-shown in production V (2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is [3,2-C] pyridine-2 (4H)-one also;
The bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone and 2-oxygen-4 wherein, 5,6, the 7-tetramethylene sulfide also mol ratio of [3,2-c] pyridine hydrochloride is 1:1.0～1.5;
3) temperature of reaction is-10 ℃～30 ℃, take sodium hydride or triethylamine as acid binding agent, N, more than one in dinethylformamide, acetonitrile, methylene dichloride are solvent, by 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is [3,2-C] pyridine-2 (4H)-one and acetic anhydride also, and the product of generation is with obtaining the prasugrel shown in formula VI after acetonitrile recrystallization;
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl wherein]-5,6,7, the 7A-tetramethylene sulfide also mol ratio of [3,2-C] pyridine-2 (4H)-one and diacetyl oxide is 1:2.0～3.0;
4) prasugrel and hydrobromic acid aqueous solution salify in the mixed solvent of methyl alcohol and methyl tertiary butyl ether, crystallization obtains prasugrel hydrobromide;
Wherein prasugrel and hydrobromic mol ratio are 1:0.95～1.1;
The volume ratio of methyl alcohol and methyl tertiary butyl ether is 1:5.
In described preparation method, the solvent in step 1 is ethanol or Virahol; Temperature of reaction is 50 ℃～60 ℃.
In described preparation method, the acid binding agent in step 2 is sodium carbonate or salt of wormwood; Solvent is acetonitrile; Temperature of reaction is 40 ℃～50 ℃.
In described preparation method, the acid binding agent in step 3 is triethylamine; Solvent is methylene dichloride; Temperature of reaction is 0 ℃～5 ℃.
In described preparation method, repeat the operation of acetonitrile recrystallization in step 3.
Of the present invention focusing on, adopt novel method to prepare the bromo-2-of intermediate 2-(2-the fluorophenyl)-1-cyclopropyl ethyl ketone (formula III) for the synthesis of prasugrel and salt thereof, adopt the bromine of Hydrogen bromide and hydrogen peroxide generation as brominated reagent, substitute former N-bromo-succinimide and the benzoyl peroxide adopting in patent that grind, saved production cost; Use ethanol simultaneously instead and make solvent, avoid the use of tetracol phenixin or chloroform etc., more economical, safety.
Emphasis of the present invention is also, adopts the prasugrel of acetonitrile purifying, and purity is greater than 99.5%, and can directly obtain highly purified prasugrel hydrobromide after continuation and Hydrogen bromide salify, without adopting the operations such as recrystallization to purify again.
Embodiment
The synthetic method of prasugrel hydrobromide of the present invention, comprises the steps:
1) by compound 1-cyclopropyl base-2-(2-fluorophenyl) ethyl ketone (II), in solvent, under the bromine effect of hydrobromic acid aqueous solution and aqueous hydrogen peroxide solution reaction generation, through bromo-reaction, prepare the bromo-2-of compound 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (III);
Wherein, formula II compound and hydrobromic mol ratio are 1:1～5, preferably 1:2～3; The mol ratio of Compound I I and hydrogen peroxide is 1:1～10, preferably 1:4～6;
Described solvent is the organic solvent that can dissolve each other with water, comprises a kind of in dioxane, acetic acid, tetrahydrofuran (THF), ethanol, methyl alcohol, Virahol, preferred alcohol, Virahol;
Bromo-reaction temperature is 0 ℃～80 ℃, preferably 50 ℃～60 ℃.
2) the bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (III) and 2-oxygen-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride (IV) as acid binding agent, reacts production V compound at organic bases or mineral alkali in specific solvent, 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine also;
Wherein the mol ratio of formula III compound and formula IV compound is 1:1.0～1.5;
Acid binding agent used is more than one in salt of wormwood, sodium carbonate, sodium bicarbonate, triethylamine, diisopropyl ethyl amine, preferably sodium carbonate or salt of wormwood;
Described solvent is more than one in DMF, acetonitrile, acetone, ethyl acetate, methylene dichloride, preferably acetonitrile;
Temperature of reaction is 20 ℃～80 ℃, preferably 40 ℃～50 ℃.
3) 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine (V) also, under alkaline acid binding agent effect, in specific solvent, with acetic anhydride, through extraction, dry, filter operation, obtain prasugrel (VI) crude product;
Wherein, the mol ratio of formula V compound and diacetyl oxide is 1:2.0～3.0;
Acid binding agent used is sodium hydride or triethylamine, preferably triethylamine;
Described solvent is more than one in DMF, acetonitrile, methylene dichloride, preferably methylene dichloride;
Temperature of reaction is-10 ℃～30 ℃, preferably 0 ℃～5 ℃.
4) in the resulting prasugrel of above-mentioned steps (VI) crude product, add acetonitrile, be heated to 60 ℃～80 ℃ and make it to dissolve, cooling stirring and crystallizing, filter, dry, obtain prasugrel (VI), repeat aforesaid operations, obtain prasugrel (I) highly finished product that purity is greater than 99.5%;
Wherein, adding the amount (mL) of acetonitrile is 2.5～3 times of crude product prasugrel (VI) quality (g);
5) prasugrel that gained purity is greater than 99.5%, in the tertiary ether mixed solvent of methyl alcohol/first, reacts and obtains prasugrel hydrobromide with hydrobromic acid aqueous solution;
Wherein, prasugrel (VI) is 1:0.95～1.1 with hydrobromic mol ratio;
The volume ratio of methyl alcohol used and methyl tertiary butyl ether is 1:5.
By the following examples, can further describe the present invention, yet invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.
Embodiment
1) preparation of the bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (formula III)
In reaction flask, add 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone (formula II) 26.7g, ethanol 150ml, stirring at room drips 30% hydrogen peroxide 90mL and 40%HBr aqueous solution 81.5mL, drip complete post-heating back flow reaction 2 hours, steam solvent, in residue, add 150mL water and 150mL ethyl acetate, standing after repeating to stir, separatory, organic phase is concentrated, obtains the bromo-2-of light yellow liquid 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (formula III) 35.4g.HPLC purity: 90.3%.
2) 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is the preparation of [3,2-C] pyridine-2 (4H)-one (formula V) also
In reaction flask, add 4,5,6,7-tetramethylene sulfide [3,2-c] pyridine hydrochloride (formula IV) 23.8g, acetonitrile 240mL, sodium carbonate 26.3g, stirring at room, the step bromo-2-of gained crude product 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (III) in dropping) acetonitrile solution (70mL) of 35.4g, 40 ℃ of stirring reactions 6 hours, filter, filtrate is concentrated, obtains brown soup compound, 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is [3,2-C] pyridine-2 (4H)-one (formula V) 32.5g also.HPLC purity: 87.2%.
It should be noted that, 4,5,6 of formula IV, 7-tetramethylene sulfide [3,2-c] pyridine hydrochloride is existing goods, can directly buy and obtain.
3) preparation of prasugrel (formula VI)
In reaction flask, add 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6, also [3,2-C] pyridine-2 (4H)-one (formula V) 32.5g, the methylene dichloride 325ml dissolving of 7,7A-tetramethylene sulfide, triethylamine 8.6g, diacetyl oxide 8.7g, ice bath stirring reaction 1.5 hours, add water 45ml, fully stir separatory, organic phase is concentrated into brown thickness soup compound, crude product prasugrel 37.5g.
Get above-mentioned solid, add 94mL acetonitrile, be heated to 60 ℃, solution clarification, filtered while hot, filtrate room temperature stirring and crystallizing, filters, and obtains prasugrel, repeats aforesaid operations, obtains prasugrel highly finished product 24.4g.HPLC purity: 99.84%, single assorted < 0.05%.
4) be extracted into prasugrel highly finished product
In reaction flask, add prasugrel highly finished product 24g, methyl alcohol 48mL, the tertiary ether 240mL of first, stirring at room, drips 40% hydrobromic acid aqueous solution 15.5g, and stirring and crystallizing is filtered, and vacuum-drying obtains prasugrel hydrobromide 26.9g.HPLC purity: 99.81%, single assorted < 0.05%.
Claims (5)
1. a preparation method for prasugrel hydrobromide, reaction process is as follows:
Step is:
1) temperature of reaction is 0 ℃～80 ℃, 1-cyclopropyl-the 2-shown in formula II (2-fluorophenyl) ethyl ketone of take is raw material, dioxane, acetic acid, tetrahydrofuran (THF), ethanol, methyl alcohol or Virahol are solvent, the bromine that hydrobromic acid aqueous solution and aqueous hydrogen peroxide solution reaction produce is halogenating agent, generates the bromo-2-of 2-(2-the fluorophenyl)-1-cyclopropyl ethyl ketone shown in formula III;
Wherein 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and hydrobromic mol ratio are 1:1～5, and the mol ratio of 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone and hydrogen peroxide is 1:1～10;
2) temperature of reaction is 20 ℃～80 ℃, more than one in salt of wormwood, sodium carbonate, sodium bicarbonate, triethylamine, diisopropyl ethyl amine of take are acid binding agent, N, dinethylformamide, acetonitrile, acetone, ethyl acetate or methylene dichloride are solvent, 2-oxygen-4 shown in the bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone and formula IV, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride under acid binding agent effect, the 5-[2-cyclopropyl-1-shown in production V (2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is [3,2-C] pyridine-2 (4H)-one also;
The bromo-2-of 2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone and 2-oxygen-4 wherein, 5,6, the 7-tetramethylene sulfide also mol ratio of [3,2-c] pyridine hydrochloride is 1:1.0～1.5;
3) temperature of reaction is-10 ℃～30 ℃, take sodium hydride or triethylamine as acid binding agent, N, more than one in dinethylformamide, acetonitrile, methylene dichloride are solvent, by 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-5,6,7,7A-tetramethylene sulfide is [3,2-C] pyridine-2 (4H)-one and acetic anhydride also, and the product of generation is with obtaining the prasugrel shown in formula VI after acetonitrile recrystallization;
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl wherein]-5,6,7, the 7A-tetramethylene sulfide also mol ratio of [3,2-C] pyridine-2 (4H)-one and diacetyl oxide is 1:2.0～3.0;
4) prasugrel and hydrobromic acid aqueous solution salify in the mixed solvent of methyl alcohol and methyl tertiary butyl ether, crystallization obtains prasugrel hydrobromide;
Wherein prasugrel and hydrobromic mol ratio are 1:0.95～1.1;
The volume ratio of methyl alcohol and methyl tertiary butyl ether is 1:5.
2. preparation method according to claim 1, wherein, the solvent in step 1 is ethanol or Virahol; Temperature of reaction is 50 ℃～60 ℃.
3. preparation method according to claim 1, wherein, the acid binding agent in step 2 is sodium carbonate or salt of wormwood; Solvent is acetonitrile; Temperature of reaction is 40 ℃～50 ℃.
4. preparation method according to claim 1, wherein, the acid binding agent in step 3 is triethylamine; Solvent is methylene dichloride; Temperature of reaction is 0 ℃～5 ℃.
5. preparation method according to claim 1, wherein, repeats the operation of acetonitrile recrystallization in step 3.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109311907A (en) * | 2016-06-23 | 2019-02-05 | 吉瑞工厂 | The preparation method of high-purity prasugrel |
| CN110950885A (en) * | 2019-12-06 | 2020-04-03 | 南京恒道医药科技有限公司 | Method and device for continuously preparing prasugrel intermediate through countercurrent extraction |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| WO2010060389A1 (en) * | 2008-11-26 | 2010-06-03 | Zentiva, K.S. | A method for the manufacture of highly pure prasugrel |
| CN102260275A (en) * | 2010-05-27 | 2011-11-30 | 鲁南制药集团股份有限公司 | Prasugrel hydrobromide, its pharmaceutical composition and application |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343278A (en) * | 2007-12-11 | 2009-01-14 | 鲁南制药集团股份有限公司 | Preparation method for hydrogenated pyridine derivant and its salt |
| WO2010060389A1 (en) * | 2008-11-26 | 2010-06-03 | Zentiva, K.S. | A method for the manufacture of highly pure prasugrel |
| CN102260275A (en) * | 2010-05-27 | 2011-11-30 | 鲁南制药集团股份有限公司 | Prasugrel hydrobromide, its pharmaceutical composition and application |
Non-Patent Citations (2)
| Title |
|---|
| 段妍琴等: "合成盐酸普拉格雷的工艺改进", 《合成化学》, vol. 20, no. 1, 31 December 2012 (2012-12-31), pages 125 - 127 * |
| 荆亚萍等: "普拉格雷中间体的合成研究", 《广东药学院学报》, vol. 25, no. 3, 30 June 2009 (2009-06-30) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109311907A (en) * | 2016-06-23 | 2019-02-05 | 吉瑞工厂 | The preparation method of high-purity prasugrel |
| CN110950885A (en) * | 2019-12-06 | 2020-04-03 | 南京恒道医药科技有限公司 | Method and device for continuously preparing prasugrel intermediate through countercurrent extraction |
| CN110950885B (en) * | 2019-12-06 | 2022-04-15 | 南京恒道医药科技有限公司 | Method and device for continuously preparing prasugrel intermediate through countercurrent extraction |
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Address after: 529080 No. 33, min Lu, hi tech Development Zone, Guangdong, Jiangmen Applicant after: Guangdong Bangmin Pharmaceutical Co., Ltd. Address before: 529080 No. 33, min Lu, hi tech Development Zone, Guangdong, Jiangmen Applicant before: Guangzhou company limited of Bang Min pharmaceutical factory |
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Application publication date: 20140122 |