CN102276623A - Novel method of preparing prasugrel with organosilicon protectant - Google Patents
Novel method of preparing prasugrel with organosilicon protectant Download PDFInfo
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- CN102276623A CN102276623A CN2011101577402A CN201110157740A CN102276623A CN 102276623 A CN102276623 A CN 102276623A CN 2011101577402 A CN2011101577402 A CN 2011101577402A CN 201110157740 A CN201110157740 A CN 201110157740A CN 102276623 A CN102276623 A CN 102276623A
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Abstract
The invention discloses a novel method of preparing prasugrel with a organosilicon protectant, relating to the chemical synthesis of prasugrel, comprising the following steps: letting PRA-3 and toluenesulfonic acid be subject to sulfonation reaction in the presence of tetrahydrofuran as a solvent at the temperature of 45-75 DEG C to generate PRA-4B; then letting PRA-4B react with tert-butyldimethylsilyl chloride in the presence of dichloromethane as a solvent at the temperature of -5-10 DEG C to protect the hydroxyl in the intermediate, and then letting PRA-4B and PRA-7 be subject to condensation reaction in the presence of organic base as a binding agent at the temperature of -5-10 DEG C to generate PRA-5B; and finally, letting PRA-5B and acetic anhydride be subject to acylation reaction in the presence of tetrahydrofuran as a solvent, triethylamine or pyridine as a binding agent, and 4-dimethylamino-pyridine as an acylation catalyst, at normal temperature to generate PRA-6B, that is, prasugrel. The beneficial effects of the invention are that: the whole reaction process is completed by only three steps without using NaH, toluene, methanol and other raw materials which has bad security, strong corrosivity and high toxicity, and is very mild and easy to control, and the products of the three steps are solids, the post-treatment is simple, the product yield is high, and the purity is high. The method is easy to apply in industry.
Description
Technical field
The present invention relates to the chemosynthesis of prasugrel, specifically is a kind of novel method of utilizing the organosilicon protective material to be prepared prasugrel.
Background technology
Prasugrel is thiophene chloropyridine, chlorine pyrrole thunder lattice analogue, English Prasugrel by name, be called for short PRA, chemical name: 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridine also, by Japan three altogether, the P2Y12 purinoceptor antagonist with oral property of Ube Industries, the common exploitation of Lilly, be the lead compound in a series of tetramethylene sulfides and the pyridine derivatives, structural formula is
As platelet aggregation inhibitor, with prevention and treatment thrombosis.
This medicine original chemical patent is that Japanese Sankyo Co., Ltd " contains the preparation method of hydrogenation pyridine derivate as the medicinal compositions of its activeconstituents " and (writes by the process for preparing medicine patent; application number 98109220.9; 2012.9.8 expire), this patent protection the prasugrel free alkali.The substance patent of mandate " hydrogenated pyridine derivative as one kind of acid added salt " (01815108.6 of the prasugrel pharmacologically acceptable salt of the said firm's application simultaneously; 2021.7.2 expire) to prasugrel hydrochloride having and maleate, and the conventional formulation that contains them is protected.
Shandong University has applied for the patent " prasugrel salt and preparation method thereof " (200810014873.2, substantive examination) of this medicine desalination hydrochlorate and outer other pharmacologically acceptable salt commonly used of maleate, but for want of creative mandate prospect is little.
The patent of preparation method aspect comprises " a kind of medicine intermediate and preparation method thereof " (200810034996.2 of Shanghai medical professionals institute application, substantive examination), " intermediate of preparation prasugrel and preparation method thereof " (200810034995.8, substantive examination), " 5-(α-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2; 4; 5; 6,7, the preparation method of 7a-six hydrogen thieno-s [3; 2-c] pyridine " (200810035041.9, substantive examination), " preparation method of hydrogenated pyridine derivative and salt thereof " (200710195018.1, deemed withdrawal) of Shandong southern Shandong pharmaceutical applications.
The preparation aspect, the conventional formulation of having protected in the aforementioned substances patent, the patent of Lilly Co., Eli. " thienopyridine platelet aggregation inhibitor preparation " (200680020528.9, substantive examination) protected a kind of packing and dosage of solid preparation.Gift comes company also to apply for dosage regimen for prasugrel patent (200680021794.3, substantive examination) in addition.
In recent years, along with the aging day by day of China's population, vascular thrombosis plug morbidity is soaring year by year, on the market demand of prevention and treatment thrombotic diseases medicine is presented the gesture of growth year by year.
And antiplatelet drug mainly is salicylic acid, thiophene pyridines (Ticlopidine, clopidogrel) and glycoprotein iib/iiia antagonist.The platelet aggregation-against class medicine of China's clinical application comprises clopidogrel, ozagrel, Cilostazole, acetylsalicylic acid, Ticlopidine and Dipyridamole, and market presents the feature of high concentration.The standard Antiplatelet therapy scheme that acetylsalicylic acid and a kind of thiophene pyridine drug combination are present acute superior mesenteric artery syndromes.Weak point is that about 20% patient has non-responsiveness to clopidogrel, and drug combination can not reduce this type of patient's ischemic conditions, and simultaneously individual difference is big, onset slow, untoward reaction and acetylsalicylic acid are approaching.
Simultaneously, the inventor understands in numerous documents, and the prasugrel synthetic route has all related to 2 important intermediate, 2-fluoro-α-ring propionyl bromobenzyl and 2-carbonyl-2,4,5,6,7,7 α-six hydrogen thieno-[3,2-c] pyridine hydrochloride, its reaction rules commonly used are summarized as follows:
First intermediate
Second intermediate
Alignment analysis: reaction type is a popular response, does not have obvious severe condition restriction, and yield is general.Difficult point is to obtain 1,3 starting raw materials, also can synthesize starting raw material, and according to present domestic synthetic result, the synthetic difficulty of this product can not become the bottleneck of exploitation.
In sum; this medicine hyle patent is near the phase, but the patent of its hydrochloride and maleate also has patent protection period for a long time, if this medicine of exploitation; need avoid its hydrochloride and maleate, and the patent of avoiding other preparation method and preparation aspect.
Summary of the invention
Technical problem solved by the invention is to provide strong toxicities such as a kind of NaH of avoiding, toluene, methyl alcohol, corrodibility rough property supplementary material strong, poor stability to prepare the method for prasugrel; adopt the mildness supplementary material, and reactions steps reduces, process shortens, operation utilizes the organosilicon protective material to be prepared the novel method of prasugrel easily.
Technical problem solved by the invention realizes by the following technical solutions:
A kind of novel method of utilizing the organosilicon protective material to be prepared prasugrel is characterized in that may further comprise the steps:
A, at first make solvent at tetrahydrofuran (THF), carry out the sulfonate PRA-4B that sulfonation reaction generates corresponding ketone with tosic acid under 45 ℃～75 ℃ the condition by PRA-3 (5,6,7,7A-tetrahydrochysene-5-(trityl) thieno-[3,2-c] pyridone);
B, the PRA-4B that obtains by step a make solvent at methylene dichloride, triethylamine is done the constraint agent, generates organosilyl ketone compound PRA-5B with 2-bromo-2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (PRA-7) generation condensation reaction again under-5 ℃～10 ℃ and do constraint agent conditions such as organic bases such as triethylamine, pyridine after with dimethyl tertiary butyl chloride silane reaction the hydroxyl in the intermediate being protected under-5 ℃～10 ℃ conditions;
C, last organosilyl ketone compound PRA-5B do solvent, triethylamine or pyridine do constraint agent at tetrahydrofuran (THF), the 4-Dimethylamino pyridine is made acylation catalyst; normal temperature condition descends and aceticanhydride generation acylation reaction finally generates target product PRA-6B; PRA-9-prasugrel-the 2-[2-(acetoxyl group)-6 of reaction rules promptly commonly used preparation; the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl also]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone.
In the present invention, described PRA-3 is prepared from by following process
Described organosilicon protective material is a dimethyl tertiary butyl chloride silane.
The beneficial effect that has in the present invention is that entire reaction course only had only for three steps, do not use poor stability such as NaH, toluene, methyl alcohol, corrodibility is strong, toxicity is big supplementary material in the reaction process, process is easy to control as mild as a dove, and the product of three-step reaction all is a solids, aftertreatment is simple, product yield height, purity height are easy to suitability for industrialized production.Transformation efficiency of product reaches (traditional technology is up to 85%) more than 92%; Also improved labour productivity on the other hand, reduced the consumption of supplementary material, also reduced production cost (having reduced more than 5%) than traditional technology; Working condition is gentle friendly simultaneously, facility simple to operate.
Embodiment
For technique means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below by specific embodiment, further set forth the present invention.
A kind of novel method of utilizing the organosilicon protective material to be prepared prasugrel, its reaction rules are as follows:
At first PRA-3 is prepared from by following process
Secondly, in reactor, add tosic acid, THF, stirring and dissolving; Add PRA-3 then, interior temperature refluxed 2 hours for 64 ℃, and cooling has solids to separate out naturally, and filtering drying gets PRA-4B;
Secondly, in reactor, add PRA-4, methylene dichloride, triethylamine, stirring and dissolving under the nitrogen protection again;-5 ℃～10 ℃ add dimethyl tertiary butyl chloride silane down, and the question response heat release finishes, and removes ice bath, rises to stirring at room 2 hours; Be cooled to-5 ℃～10 ℃ again, drip PRA-7/ triethylamine mixed solution, after dropwising, add Nal, rise to room temperature; Rise to 45 ℃, stirred 2 hours, after reacting completely, reduce to room temperature; With damping fluid (KH
2PO
4With Na
2HPO
4.12H
2The aqueous solution of O) pour in the reaction solution, stir 10 minutes standing demix, water layer PH=7-8 also uses methylene dichloride extracting 3 times, merges organic layer, uses the damping fluid washed twice again, and anhydrous sodium sulfate drying concentrates, and obtains oily matter; In oily matter, add acetonitrile and stir, had solid to separate out in about 5 minutes, stirred 2 hours, place 2 hours dry PRA-5B of getting of after-filtration down for 0 ℃;
Add PRA-5B at last in reactor, the THF dissolving adds triethylamine under the room temperature (25 ℃-28 ℃) again, DMAP (4-Dimethylamino pyridine), and nitrogen stirs after 15 minutes down, drips AC
2O/THF after dripping about 10 minutes, stirred 1.5 hours; Be cooled to-10 ℃, slowly drip 10mol/LKH
2PO
4Solution stirred one hour, dripped mixed solution (10mol/LKH again
2PO
4And ethanol), stirring has solid to separate out after 0.5 hour-1 hour; Filter, cold 95% washing with alcohol, placing under the room temperature and getting PRA-6B to dry weight a night is the PRA-9 prasugrel.
Embodiment one
PRA-4B
1. add tosic acid 4.77 grams in the reaction flask, 150mlTHF, stirring and dissolving;
2. add PRA-3,10 grams, interior temperature refluxed 2 hours for 64 ℃, cooling has solid filtering naturally, solid is with the THF washing of 15ml*3, weight in wet base 11.13 grams, the room temperature baking is expected to such an extent that 9.78 restrain yield 97.8%;
PRA-5B
1. add PRA-4B in the there-necked flask, 16 grams, methylene dichloride 30ml, triethylamine 7.8ml, stirring and dissolving under the nitrogen protection;
2.0 ℃ once add dimethyl tertiary butyl chloride silane 8.42ml, the question response heat release finishes, and removes ice bath, rises to stirring at room 2 hours;
3. be cooled to 0 ℃ again, (mixed solution of 11.92 grams/13.6ml) after dropwising, adds the Nal0.25 gram, rises to room temperature to drip the PRA-7/ triethylamine;
4. rise to 45 ℃, stirred 2 hours, the TLC detection reaction is complete, reduces to room temperature;
5. damping fluid 50ml is poured in the reaction solution, stir (damping fluid configuration: 9.5 gram KH in 10 minutes
2PO
4With 0.95 gram Na
2HPO
4.12H
2The about 400ml of the aqueous solution 358 grams of O);
6. layering, water layer PH=7-8,20ml*3 methylene dichloride extracting merges organic layer, and with the washing of 250ml*2 damping fluid, anhydrous sodium sulfate drying concentrates, and obtains oily matter 24.33 grams;
7. add the 50ml acetonitrile and stir, had solid to separate out in about 5 minutes, stirred 2 hours, place down for 0 ℃ and filtered in 2 hours, obtain weight in wet base 20.1 grams, dry 1.5 hours of 30 ℃ of Rotary Evaporators, constant weight 15.91 restrains yield 99.4%.
PRA-6B
1. add PRA-5B in the there-necked flask, 10g, the 30mlTHF dissolving adds triethylamine under the room temperature (25 ℃-28 ℃) again, DMAP0.287g (4-Dimethylamino pyridine), nitrogen stirs after 15 minutes down, drips AC
2O/THF (6.4ml/10ml) after dripping about 10 minutes, stirred TLC 1.5 hours;
2. be cooled to-10 ℃, slowly drip 10mol/LKH
2PO
4Solution 2ml stirred one hour, dripped mixed solution (10mol/LKH again
2PO
415ml/ ethanol 17ml), stirring has solid to separate out after 0.5 hour-1 hour;
3. filter, cold 95% ethanol 15ml*3 washing obtains weight in wet base 11.43 grams, and placing a night under the room temperature is 9.38 grams to dry weight, yield 93.8%, HPLC:99.5%, single impurity: 0.11%, 0.11486%.
Little test result: product yield is 93.8%, and quality product is 99.8%.
Embodiment two
PRA-4B
3. add tosic acid 23.85 grams in the reaction flask, 750mlTHF, stirring and dissolving;
4. add PRA-3,50 grams, interior temperature refluxed 2 hours for 64 ℃, cooling has solid filtering naturally, solid is with the THF washing of 75ml*3, weight in wet base 55.68 grams, the room temperature baking is expected to such an extent that 48.32 restrain yield 96.7%;
PRA-5B
8. add PRA-4B in the there-necked flask, 80 grams, methylene dichloride 150ml, triethylamine 39ml, stirring and dissolving under the nitrogen protection;
9.0 ℃ once add dimethyl tertiary butyl chloride silane 42.1ml, the question response heat release finishes, and removes ice bath, rises to stirring at room 2 hours;
10. be cooled to 0 ℃ again, (mixed solution of 59.6 grams/68ml) after dropwising, adds the Nal1.25 gram, rises to room temperature to drip the PRA-7/ triethylamine;
11. rise to 45 ℃, stirred 2 hours, the TLC detection reaction is complete, reduces to room temperature;
12. damping fluid 250ml is poured in the reaction solution, stirs (damping fluid configuration: 47.5 gram KH in 10 minutes
2PO
4With 4.75 gram Na
2HPO
4.12H
2The about 2000ml of the aqueous solution 1790 grams of O);
13. layering, water layer PH=7-8,100ml*3 methylene dichloride extracting merges organic layer, and with the washing of 1250ml*2 damping fluid, anhydrous sodium sulfate drying concentrates, and obtains oily matter 122.03 grams;
Stir 14. add the 250ml acetonitrile, had solid to separate out in about 5 minutes, stirred 2 hours, place down for 0 ℃ and filtered in 2 hours, obtain weight in wet base 100.8 grams, dry 1.5 hours of 30 ℃ of Rotary Evaporators, constant weight 79.43 restrains yield 99.3%.
PRA-6B
4. add PRA-5B in the there-necked flask, 50g, the 150mlTHF dissolving adds triethylamine 32 grams again under the room temperature (25 ℃-28 ℃), and DMAP1.435 restrains (4-Dimethylamino pyridine), and nitrogen stirs after 15 minutes down, drips AC
2O/THF (32ml/50ml) after dripping about 10 minutes, stirred TLC 1.5 hours;
5. be cooled to-10 ℃, slowly drip 10mol/LKH
2PO
4Solution 10ml stirred one hour, dripped mixed solution (10mol/LKH again
2PO
475ml/ ethanol 85ml), stirring has solid to separate out after 0.5 hour-1 hour;
6. filter, cold 95% ethanol 15ml*3 washing obtains weight in wet base 57.51 grams, and placing a night under the room temperature is 46.3 grams to dry weight, yield 93.8%, HPLC:99.5%, single impurity: 0.11%, 0.11486%.
Little test result: product yield is 92.6%, and quality product is 99.7%.
Embodiment three
PRA-4B
5. add tosic acid 47.7 grams in the reaction flask, 1500mlTHF, stirring and dissolving;
6. add PRA-3,100 grams, interior temperature refluxed 2 hours for 64 ℃, cooling has solid filtering naturally, solid is with the THF washing of 150ml*3, weight in wet base 112.5 grams, the room temperature baking is expected to such an extent that 98.2 restrain yield 98.2%;
PRA-5B
15. add PRA-4B in the there-necked flask, 160 grams, methylene dichloride 300ml, triethylamine 78ml, stirring and dissolving under the nitrogen protection;
16.0 ℃ once add dimethyl tertiary butyl chloride silane 84.2ml, the question response heat release finishes, and removes ice bath, rises to stirring at room 2 hours;
17. be cooled to 0 ℃ again, (mixed solution of 119.2 grams/136ml) after dropwising, adds the Nal2.5 gram, rises to room temperature to drip the PRA-7/ triethylamine;
18. rise to 45 ℃, stirred 2 hours, the TLC detection reaction is complete, reduces to room temperature;
19. damping fluid 500ml is poured in the reaction solution, stirs (damping fluid configuration: 95 gram KH in 10 minutes
2PO
4With 9.5 gram Na
2HPO
4.12H
2The about 4000ml of the aqueous solution 3580 grams of O);
20. layering, water layer PH=7-8,200ML*3 methylene dichloride extracting merges organic layer, and with the washing of 2500ml*2 damping fluid, anhydrous sodium sulfate drying concentrates, and obtains oily matter 245.3 grams;
Stir 21. add the 500ml acetonitrile, had solid to separate out in about 5 minutes, stirred 2 hours, places 0 ℃ and filtered in 2 hours, obtain weight in wet base 201.5 grams, 30 ℃ of Rotary Evaporators dryings 1.5 hours, constant weight 158.9 restrains yield 99.3%.
PRA-6B
7. add PRA-5B in the there-necked flask, 100 grams, the 300mlTHF dissolving adds triethylamine 64 grams again under the room temperature (25 ℃-28 ℃), and DMAP2.87 restrains (4-Dimethylamino pyridine), and nitrogen stirs after 15 minutes down, drips AC
20/THF (64ml/100ml) after dripping about 10 minutes, stirred TLC 1.5 hours;
8. be cooled to-10 ℃, slowly drip 10mol/LKH
2PO
4Solution 20ml stirred one hour, dripped mixed solution (10mol/LKH again
2PO
4150ml/ ethanol 170ml), stirring has solid to separate out after 0.5 hour-1 hour;
9. filter, cold 95% ethanol 15ml*3 washing obtains weight in wet base 115.1 grams, and placing a night under the room temperature is 92.9 grams to dry weight, yield 92.9%, HPLC:99.6%, single impurity: 0.11%, 0.11486%.
Little pilot-scale experiment: product yield is 92.9%, and quality product is 99.6%.
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (3)
1. novel method of utilizing the organosilicon protective material to be prepared prasugrel is characterized in that may further comprise the steps:
A, at first make solvent at tetrahydrofuran (THF), carry out the sulfonate PRA-4B that sulfonation reaction generates corresponding ketone with tosic acid under 45 ℃～75 ℃ the condition by PRA-3 (5,6,7,7A-tetrahydrochysene-5-(trityl) thieno-[3,2-c] pyridone);
B, the PRA-4B that obtains by step a make solvent at methylene dichloride, triethylamine is done the constraint agent, generates organosilyl ketone compound PRA-5B with 2-bromo-2-(2-fluorophenyl)-1-cyclopropyl ethyl ketone (PRA-7) generation condensation reaction again under-5 ℃～10 ℃ and do constraint agent conditions such as organic bases such as triethylamine, pyridine after with dimethyl tertiary butyl chloride silane reaction the hydroxyl in the intermediate being protected under-5 ℃～10 ℃ conditions;
C, last organosilyl ketone compound PRA-5B do solvent, triethylamine or pyridine do constraint agent at tetrahydrofuran (THF), the 4-Dimethylamino pyridine is made acylation catalyst; normal temperature condition descends and aceticanhydride generation acylation reaction finally generates target product PRA-6B; PRA-9-prasugrel-the 2-[2-(acetoxyl group)-6 of reaction rules promptly commonly used preparation; the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-yl also]-1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone.
2. according to the novel method of the described preparation prasugrel of claim 1, it is characterized in that: described PRA-3 is prepared from by following process
3. according to the novel method of the described preparation prasugrel of claim 1, it is characterized in that: described organosilicon protective material is a dimethyl tertiary butyl chloride silane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20121494A1 (en) * | 2012-09-07 | 2014-03-08 | Erregierre Spa | PRASUGREL CHLORIDRATE PRODUCTION PROCESS |
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| ITMI20121494A1 (en) * | 2012-09-07 | 2014-03-08 | Erregierre Spa | PRASUGREL CHLORIDRATE PRODUCTION PROCESS |
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