CN102612519A - Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof - Google Patents

Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof Download PDF

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Publication number
CN102612519A
CN102612519A CN2010800519259A CN201080051925A CN102612519A CN 102612519 A CN102612519 A CN 102612519A CN 2010800519259 A CN2010800519259 A CN 2010800519259A CN 201080051925 A CN201080051925 A CN 201080051925A CN 102612519 A CN102612519 A CN 102612519A
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acid
compound
formula
prasugrel
salt
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哈纳·斯捷潘诺娃
K·卡明斯卡
约瑟夫·哈吉塞克
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Zentiva KS
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Zentiva KS
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Priority to CZ20090763A priority Critical patent/CZ2009763A3/en
Priority to CZPV2009-763 priority
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Priority to PCT/CZ2010/000115 priority patent/WO2011057592A1/en
Publication of CN102612519A publication Critical patent/CN102612519A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic 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
    • C07D495/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

A method for the production of 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate of formula (I) or its salts, characterized in that the compound of formula (III) in the form of a salt with an arene sulfonic acid is reacted with the compound of formula (XV), wherein Y means: chlorine, bromine, or an OR4 group, wherein R4 means an alkane sulfonic group or arene sulfonic group, in an organic solvent in the presence of an inorganic base or organic base, to give, after addition of an acetylating reagent and organic base to the reaction mixture, the compound of formula (I), which, after addition of a co-solvent, is crystallized from the reaction mixture, and the compound of formula (I) is optionally purified by crystallization and optionally converted to a salt by reaction with an organic or inorganic acid in a suitable solvent.

Description

The method for preparing high purity prasugrel and novel medicinal salt thereof
Technical field
The present invention relates to a kind of highly purified known material that alleviates blood coagulation, method of the prasugrel of formula I (prasugrel) of preparing
Background technology
Prasugrel, its preparation method and at first be documented in the patent that the patent No. is EP 0542411 as the purposes of anti-aggregation substance in suffering the patient of blood clotting occluding vascular harm.
In scheme 1, summarized preparation according to the prasugrel of this patent.
Scheme 1
According to this file, Grignard (Grinard) reagent and the cyclopropyl nitrile (X) that are prepared by 2-fluoro benzyl bromide (XI) react in ether, and obtain compound (IX).Compound (IX) is at CCl 4In with bromine or in the presence of BPO, be br-derivatives (VIII) with N-bromosuccinimide (NBS) bromination.(III) carries out nucleophilic substitution to compound, and preparation compound (II) obtains compound (II) with 35% productive rate at chromatogram purification with from DIPE after the crystallization.In above-mentioned replacement, said formula III compound uses with hydrochloride form, and the effect through salt of wormwood discharges free alkali from said hydrochloride original position.Compound (II) is through becoming final prasugrel (I) with the reaction conversion of diacetyl oxide in the presence of the NaH in DMF.Chromatogram purification and from DIPE after the crystallization productive rate in this stage be 65%.
From the patent No. of Ube company is the patent of US 5874581, can infer similar program, said program is with scheme 2 expressions.
Scheme 2
Thienopyridine-2-ketone (III) reacts the enol ether (XII) that silylanization is provided with trialkylchlorosilane in the presence of trialkylamine in organic solvent, said enol ether (XII) is compound (XIV) with compound (XIII) reaction.Pass through deprotection from material (XIV) then, prepare the prasugrel of final formula I subsequently with diacetyl oxide acetylize in the presence of dimethyl aminopyridine.Use with the form of tosilate at the compound of formula III described in this method.
Another part patented claim WO2007/114526 of Ube company has put down in writing a kind of preparation method of prasugrel more specifically of improvement, and it is produced by scheme 2.TERT-BUTYL DIMETHYL CHLORO SILANE is used as silylating reagent, and in the presence of triethylamine, in methylene dichloride, prepares formula XII compound, wherein R 1And R 2Be methyl and R 3It is the tertiary butyl.Under not separation situation, itself and formula XIII compound react then.Productive rate with 83.7% obtains compounds X IV, wherein R 1, R 2And R 3Has aforesaid identical meanings.Formula XIV compound original position deprotection, and acetylize in the presence of triethylamine and dimethyl aminopyridine in acetonitrile, the prasugrel of production I after the crystallization, obtains product from reaction mixture after adding water, and productive rate is 87%.
The patent No. of company of Sankyo Co., Ltd (Sankyo) is that the patent of EP 1 298 132 has been put down in writing prasugrel hydrochloride having and PHENRAMINE MALEATE; In another patented claim EP 2 003 136, two kinds of crystalline forms of prasugrel hydrochloride having have been characterized with the physical analysis method.Simultaneously, this application has also related to the polymorphic forms of prasugrel alkali.Usually patented claim EP 0 785 205 has put down in writing and has utilized the various hydrochlorides that prepare pharmaceutically active substances from the generated in-situ HCl of trialkylchlorosilane.Prasugrel hydrochloride having also is produced through this method and characterizes with Physical Analysis Methods.
Another patented claim WO 2009/066326 has put down in writing prasugrel fumarate, benzene sulfonate, tosilate and malate.
The patented claim WO 2009/062044 that has just announced has put down in writing new crystal C, B, the E and armorphous of prasugrel hydrochloride having.This application also relates to the new preparation process of prasugrel, and this method is with scheme 3 expressions.
Scheme 3
By the Thienopyridinone of trityl as protecting group (formula XVII compound), the effect through diacetyl oxide or Acetyl Chloride 98Min. prepares formula XVIII compound based on nitrogen-atoms, and behind the trityl deprotection, formula XVIII compound provides the midbody of formula XIX.The bromide of compounds X IX and formula VIII reacts in the presence of alkali, and the prasugrel of formula I is provided.
Summary of the invention
The invention provides a kind of prepare formula I with the known acetate 5-of nonproprietary name prasugrel [2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6; 7-THTP also [3; 2-c] pyridine-2-base ester (5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6; 7-tetrahydrothieno [3,2-c] pyr idin-2-yl acetate) and the novel method of its salt.
Compare with currently known methods, preparation in accordance with the present invention provides the possibility of formulating the program of art recognized, and this program provides prasugrel with high yield and high purity.It uses simple steps, need not to use the protection base.
Preparation in accordance with the present invention with scheme 4 expression has been utilized following newly discovered: if formula III 4; 5; 6,7-THTP also [3,2-c] pyridines-2 (3H)-ketone uses with the form of the salt of aryl sulfonic acid such as tosic acid; Then compare with the formula III compound of previously known use hydrochloride form, the productive rate of said reaction can be high a lot.
Scheme 4
Y in the scheme 4 representes halogen such as chlorine, bromine or OR 4Group, wherein R 4Expression alkane sulfonic acid base is such as the methylsulfonic acid base, or the aromatic hydrocarbons sulfonic group is such as the tosic acid base.
In a preferred embodiment of the invention, formula III compound and formula XV compound react in organic solvent in the presence of trialkylamine; The product that obtains is through adding diacetyl oxide by the original position acetylize.Then through adding cosolvent, the prasugrel of crystallization formula I from reaction mixture.In order to obtain highly purified prasugrel, through adding cosolvent, the rough prasugrel of recrystallize from organic solvent.
The high purity prasugrel is used for preparing the novel stabilising salt that is applicable to medical formulation, such as the salt of hydrobromate, hydriodate, hydrosulfate, cyclamate, esilate and 2-naphthene sulfonic acid.
Embodiment
Program with the prasugrel of the formula I produced according to the present invention of scheme 4 expression has been utilized following discovery; If said discovery is about 4,5 of formula III, 6; 7-THTP also [3; 2-c] pyridine-2 (3H)-ketone uses with the form of the salt of aryl sulfonic acid such as tosic acid, then compares with the formula III compound of former known use hydrochloride form, and reaction yield increases significantly.
Y in the scheme 4 representes halogen such as chlorine, bromine or OR 4Group, wherein R 4Expression alkane sulfonic acid base is such as methylsulfonic acid base or aryl sulfonic acid groups such as tosic acid base or Phenylsulfonic acid base.
In a preferred embodiment of the invention; Formula III compound and formula XV compound are in organic solvent such as acetonitrile, N or acetone; In the presence of mineral alkali such as yellow soda ash, salt of wormwood, cesium carbonate, sodium hydrogencarbonate, saleratus or cesium bicarbonate; Or at organic bases such as trialkylamine, for example down reaction of the existence of triethylamine or ethyl diisopropylamine, wherein Y representes halogen such as chlorine, bromine or OR 4Group, wherein R 4Expression alkane sulfonic acid base is such as methylsulfonic acid base or aromatic hydrocarbons sulfonic group such as tosic acid base or Phenylsulfonic acid base.
The product that obtains is through adding diacetyl oxide, preferably in the presence of dimethyl aminopyridine and organic bases, by the original position acetylize.Then through adding cosolvent, the prasugrel of crystallization formula I from reaction mixture.Cosolvent can be understood to include water, and the aqueous solution of inorganic salt is pure such as methyl alcohol, ethanol, propyl alcohol, the ethyl ester of acetic ester such as acetate, propyl ester and butyl ester, aliphatic hydrocarbon such as hexane or hexanaphthene.Be reflected at-20 ℃ to+100 ℃ temperature, advantageously under-20 ℃ to+40 ℃ temperature, carry out.
After adding cosolvent, make prasugrel, aptly-30 ℃ to+15 ℃ temperature crystallization-30 ℃ to+40 ℃ temperature.Thus obtained rough prasugrel contains and is less than 0.10% formula II compound.
Through adding cosolvent, recrystallization raw product from organic solvent, ethyl ester, propyl ester and the butyl ester of methyl alcohol of said organic solvent such as acetonitrile, acetone or lower alcohol-for example or ethanol, acetic ester such as acetate.Cosolvent can be understood to include water, the aqueous solution of inorganic salt, aliphatic hydrocarbon such as pentane, hexane or hexanaphthene, or their mixture.After adding cosolvent ,-30 ℃ to+40 ℃ temperature, crystallization prasugrel under-30 ℃ to+15 ℃ temperature aptly.Recrystallized product contains and is less than 0.10% formula II compound.
The high purity prasugrel is used for preparing the novel stabilising salt that is applicable to medical formulation then, such as the salt of hydrobromate, hydriodate, hydrosulfate, cyclamate, esilate and 2-naphthene sulfonic acid.The high purity prasugrel is dissolved in the appropriate organic solvent, and said organic solvent such as ketone is acetone and methylethylketone for example, and acetic ester is ethyl ester, propyl ester and the butyl ester of acetate for example, and lower alcohol is methyl alcohol, ethanol and propyl alcohol for example, or is dissolved in aromatic hydrocarbon such as in the toluene.0.95 to the 1.05 normal acid that is dissolved in above-mentioned any solvent or the water is added in the said alkaline solution.-30 ℃ of boiling temperatures, under the temperature of-30 to+25 ℃ of scopes, make the salt crystallization of generation aptly to solvent.
Embodiment
Go up the mensuration fusing point at Kofler block (Ke Fule module fusing point appearance).
Among the embodiment below, use following program, through the sample of X-ray diffraction analysis and evaluation prasugrel and salt thereof:
In X ' PERT PRO MPD PANalytical powder diffractometer, obtain diffractogram; This powder diffractometer has the graphite monochromator; Radioactive rays CuK α energizing voltage that uses: 45kV. anodic current: 40mA; Useful range: 2-40 ° of 2 θ, the increment when reflection delay is 50s: 0.01 ° of 2 θ; Be to measure on the flat sample of 10/0.5mm in area/thickness.
With Pyris 1 (Perkinelmer Inc.) measurement device DSC curve.The sample load is 3-4mg, 10 ℃/min of heating rate.
Temperature program(me):
1) 50 ℃ 1 minute
2) with 10 ℃/minute speed to 50-200 ℃ (except the hydrochloric acid prasugrel, its with the speed of 10 ℃/min to 50-250 ℃).
Carrier gas: N 220ml/min.
Among the embodiment below,, assess the sample of prasugrel and salt thereof by means of HPLC according to following program:
At octadecane pilum (250 * 4.6mm; 5 μ m) in, under 30 ℃ temperature, utilize 228nm UV to detect and carry out HPLC mensuration.For separating, utilize acetonitrile to adopt phosphate buffered saline buffer (0.01M KH with the flow velocity of 1.0ml/min 2PO 4PH 2.2) gradient elution, adopt following gradient: 80% damping fluid 0min; 10% damping fluid (linear gradient) 40min; 10% damping fluid 45min.The starting time of post is 10 minutes.Sprayed volume adds up to 10 μ l.The capacity factor of prasugrel is 4.3.Concentration through respective substance is dissolved to 1mg/ml in acetonitrile prepares sample.
Embodiment 1
With N-ethyl diisopropylamine (1.7ml; 9.7mmol) be added into 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (1.52g; 4.6mmol) acetonitrile (4ml) suspension in.The solution of preparation thus is added into 1-cyclopropyl-2-bromo-2-(2-fluorophenyl) ethyl ketone (1.13g; 4.4mmol) acetonitrile (2ml) solution in, reactant was stirring at room 1.5 hours.Subsequently, with diacetyl oxide (1.2ml; 13.2mmol), N-ethyl diisopropylamine (0.6ml; 3.5mmol) and the N of catalytic amount, the N-dimethyl aminopyridine is added in the solution.Reactant was stirring at room 2 hours.Then, reaction mixture is cooled to-15 ℃, adds 2.5ml water, at-12 to-8 ℃ of stirring reaction 2h.With the white crystal suction that obtains, with washing with alcohol and at air drying.Obtain 0.97g prasugrel alkali (58%), fusing point: 118-120 ℃, HPLC: purity 98.6%; The content 0.08% of formula II compound.
The crude product (0.9g) that obtains in this way is dissolved in the acetonitrile (10.5ml), add the 0.2ml diacetyl oxide after, with mixture at stirring at room 1h.Mixture is cooled to-15 ℃ then, adds entry (4ml), stirs-12 to-8 ℃ temperature, separates out white crystal., also dry after 2 hours with washing with alcohol with they suctions.Obtain 0.66g white prasugrel crystal.Fusing point: 120-121 ℃ .HPLC: purity 99.4%; The content 0.04% of formula II compound.
1H?NMR(250MHz,CDCl3)δ(ppm):7.47(ddd,J=14.7,7.4,1.7Hz,1H),7.31(m,1H),7.14(m,2H),6.26(s,1H),4.82(s,1H),3.51(m,2H),2.89(m,1H),2.79(m,3H),4.30(m,1H),2.25(s,3H),1.03(m,2H),0.85(m,2H); 13C?NMR(250MHz,CDCl3)δ(ppm):207.7,167.7,161.3(d,J CF=247.6Hz),149.5,130.6(d,J CF=3.5Hz),129.9(d,J CF=8.4Hz),129.4,125.8,124.4(d,J CF=3.5Hz),122.1(d,J CF=14.1Hz),115.8(d,J CF=22.9Hz),112.0,71.6,50.5,48.4,25.0,20.6,18.3,12.0,11.4.
X-ray analysis
Table 1: the characteristic peak of prasugrel alkali:
The X-ray powder diffraction pattern is shown among Fig. 1 a; The DSC curve is shown among Fig. 1 b.
Embodiment 2
With N-ethyl diisopropylamine (1.7ml; 9.7mmol) be added to hydrochloric acid 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine (0.89g; 4.6mmol) acetonitrile (4ml) suspension in.The solution of preparation thus dropwise is added to 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (1.13g; 4.4mmol) acetonitrile (2ml) solution in, stirring at room reaction 1.5 hours.Subsequently, with diacetyl oxide (1.2ml; 13.2mmol), N-ethyl diisopropylamine (0.6ml; 3.5mmol) and the N of catalytic amount, the N-dimethyl aminopyridine is added in the solution.Stirring at room reaction 2 hours.Then, reaction mixture was cooled to-15 ℃, adds 2.5ml water ,-12 to-8 ℃ of stirring reactions 2 hours.With the white crystal suction that obtains, with washing with alcohol and at air drying.Obtain 0.48g prasugrel alkali (29%).Fusing point: 117.5-119.5 ℃, HPLC: purity 98.5%; The content 0.09% of formula II compound.
The crude product (0.45g) that obtains in this way is dissolved in the acetonitrile (10.5ml), and after adding the 0.2ml diacetyl oxide, at stirring at room mixture 1h.Then, mixture is cooled to-15 ℃, adds entry (4ml), under-2 to-8 ℃ temperature, stirs and separates out white crystal., also dry after 2 hours with washing with alcohol with they suctions.Obtain 0, the white crystal of 31g prasugrel.Fusing point: 120-121 ℃ .HPLC: purity 99.4%; The content 0.07% of formula II compound.
Embodiment 3
With 12.22g 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine tosilate and 40ml acetonitrile are fed into the 250ml three-necked flask that magnetic stirring bar and TM are housed, and this three-necked flask seals with the calcium chloride test tube.When stirring, add the 13.6ml diisopropylethylamine to dense thick suspension, at the stirring at room mixture until producing solution (5-10 minute).Then, in flask, add 3-cyclopropyl-1-(2-fluorophenyl)-3-oxopropyl mesylate (9.68g) and 7.84g Et 4N +Br.The mixture that obtains then stirred 4 to 5 hours+22 to+25 ℃ temperature.Utilize the TLC monitoring reaction.After starting substance disappears, add 10ml Ac to reaction mixture 2O and 50mg dimethyl aminopyridine.Further stirred reaction mixture is other 1.5 to 2 hours under+22 to+25 ℃ temperature.In identical system, utilize the TLC monitoring reaction.After this stage, reaction mixture is cooled to-12 to-15 ℃ temperature; Add 25ml 20mM KH 2PO 4The aqueous solution.Make crystalline mixture, and make product keep crystallization 1.5 hours-12 to-15 ℃ temperature stirring.Wash on sintered glass with isolating product-prasugrel alkali-suction and with the cold ethanol of 20ml.Product is at room temperature dry voluntarily.Obtain 4.06g (30.5%) crude product, purity is 96.11% (HPLC); The content 0.08% of formula II compound.
Embodiment 4
68ml N-ethyl-N, N-Diisopropylamine (389mmol; 2eq.) be added to the 2-oxo-2,4,5,6 in the 160ml acetonitrile, 7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (66.86g; 204.2mmol; 1.05eq.) suspension.The solution of preparation thus dropwise is added in the solution of 50g 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (194.5mmol) that is contained in the 1L three-necked flask and 50ml acetonitrile; The tap funnel that said three-necked flask has magnetic stirring bar, TM and seals with the calcium chloride test tube; Make temperature be no more than 30 ℃; And with this mixture stirring 30min, with TLC (silica gel on glass, toluene: monitoring ETHYLE ACETATE 3: 1).After initial 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone disappears, in mixture, add diacetyl oxide (60ml; 3eq.), N-ethyl-N, the N of N-Diisopropylamine and catalytic amount, N-dimethyl aminopyridine, and reaction 1.5-2h.In identical system, utilize the TLC monitoring reaction.After this stage, mixture is cooled to-15 to-20 ℃, and by a part adding 150ml water.Made crystalline mixture in 1.5 to 2 hours-15 to-6 ℃ of abundant stirrings.Wash on sintered glass with isolating product-prasugrel alkali-suction and with the cold ethanol of 2 * 25ml, and dry voluntarily in air.Obtain the rough prasugrel alkali of 43.79g (60.3%), purity is 99.44% (HPLC); The content of formula II compound is less than 0.05%.
The crude product (43g) that mode is thus obtained is dissolved in the acetonitrile (480ml), adds diacetyl oxide (8ml), and after stirring 1 hour, is cooled to-15 ℃, and by part adding a 200ml water, product was-12 to-6 ℃ of crystallizations 2 hours.Through on sintered glass, aspirating, with the cold washing with alcohol of 2 * 25ml and at air drying, obtain the 34.81g white crystal, purity is 99.4% (HPLC); The content of formula II compound is less than 0.05%.
Embodiment 5
N-ethyl-N, N-Diisopropylamine (1.7ml; 9.7mmol) adding hydrochloric acid 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine (0.89g; 4.6mmol) acetonitrile (6ml) suspension in.With 2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl mesylate (1.18g; 4.4mmol) and 0.972g (4.62mmol) Tetraethylammonium bromide be added in the solution that obtains, and stirring at room reaction 1.5 hours.Subsequently, with diacetyl oxide (1.2ml; 13.2mmol), N-ethyl-N, N-Diisopropylamine (0.6ml; 3.5mmol) and the N of catalytic amount, the N-dimethyl aminopyridine is added to reaction mixture.Stirring at room reaction 2 hours.Reaction mixture is cooled to-15 ℃, adds 2.5ml water and at-12 to-8 ℃ of stirring reaction 2h.With the white crystal suction that obtains, with washing with alcohol and air-dry.Obtain 0.190g prasugrel alkali (12%).Fusing point: 118-120 ℃, HPLC: purity 96.9%, the content 0.22% of formula II compound.
The crude product (0.150g) that obtains in this way is dissolved in the acetonitrile (2ml), after adding the 0.1ml diacetyl oxide, with mixture at stirring at room 1h.Then, mixture is cooled to-15 ℃, adds entry (2ml), under-12 to-8 ℃ temperature, stirs and separates out white crystal., also dry after 2 hours with washing with alcohol with they suctions.Obtain the white crystal of 0.100g prasugrel.Fusing point: 120-121 ℃ .HPLC: purity 99.6%; The content 0.05% of formula II compound.
The X-ray powder diffraction pattern with in embodiment 1, appear identical.
Embodiment 6
With N-ethyl diisopropylamine (1.7ml; 9.7mmol) be added to 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (1.52g; 4.6mmol) acetonitrile (6ml) suspension in.With 2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl mesylate (1.18g; 4.4mmol) be added to the solution that obtains, and stirring at room reaction 1.5 hours.Subsequently, with diacetyl oxide (1.2ml; 13.2mmol), N-ethyl-N, N-Diisopropylamine (0.6ml; 3.5mmol) and the N of catalytic amount, the N-dimethyl aminopyridine is added in this solution.Stirring at room reaction 2 hours.Then, reaction mixture is cooled to-15 ℃, adds 2.5ml water and at-12 to-8 ℃ of stirring reaction 2h.With the white crystal suction that obtains, with washing with alcohol and air-dry.Obtain 0.52g prasugrel alkali (32%).Fusing point: 116.5-119.5 ℃, HPLC: purity 94%; The content 0.20% of formula II compound.
The crude product (0.47g) that obtains in this way is dissolved in the acetonitrile (6ml), after adding the 0.2ml diacetyl oxide, with mixture at stirring at room 1h.Then, mixture is cooled to-15 ℃, adds entry (2ml), and under-12 to-8 ℃ temperature, stirs and separate out white crystal., also dry after 2 hours with washing with alcohol with they suctions.Obtain 0.34g white prasugrel crystal.Fusing point: 120-121 ℃.
The X-ray powder diffraction pattern with in embodiment 1, appear identical.
Embodiment 7
With K 2CO 3(4.03g; 29.17) be added to 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (3.34g; 10.21mmol) acetone (25ml) suspension in.At room temperature stirred this suspension 10 minutes, then, with 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (2.51g; 9.72mmol) be added to reaction mixture, and stirring reaction 3.5 hours at room temperature.Utilize TLC monitoring (silica gel on glass; Toluene: the process of reaction ETHYLE ACETATE 3: 1).After this stage, filter undissolved part also with 15ml washing with acetone filter cake through the S2 sintered glass.With the N of 2.8ml diacetyl oxide (29.17mmol) and 1.4ml N-ethyl diisopropylamine (7.78mmol) and catalytic amount, the N-dimethyl aminopyridine is added in the filtrating.Reaction mixture at room temperature stirred 1.5 hours.Then, reaction mixture is cooled to-15 ℃, adds 25ml water, and at-12 to-8 ℃ of stirring reaction 2h.With isolating crystal suction, with washing with alcohol and air-dry.Obtain 2.05g prasugrel (56.5%).HPLC: purity 98.85%; The content 0.05% of formula II compound.
Embodiment 8
With K 2CO 3(4.03g; 29.17) be added to hydrochloric acid 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine (1.96g; 10.21mmol) acetone (25ml) suspension in.This suspension was at room temperature stirred 10 minutes, then with 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (2.51g; 9.72mmol) be added to reaction mixture, and stirring reaction 3.5 hours at room temperature.Utilize TLC (silica gel on glass; Toluene: the process of monitoring reaction ETHYLE ACETATE 3: 1).After this stage, filter undissolved part also with 15ml washing with acetone filter cake through the S2 sintered glass.With the N of 2.8ml diacetyl oxide (29.17mmol) and 1.4ml N-ethyl diisopropylamine (7.78mmol) and catalytic amount, the N-dimethyl aminopyridine is added in the filtrating.Reaction mixture at room temperature stirred 1.5 hours.Then, reaction mixture is cooled to-15 ℃, adds 25ml water, and at-12 to-8 ℃ of stirring reaction 2h.With isolating crystal suction, with washing with alcohol and air-dry.Obtain 1.83g prasugrel (50.4%).HPLC: purity 98.2%; The content of formula II compound is less than 0.05%.
Embodiment 9
With K 2CO 3(4.03g; 29.17) be added to 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (3.34g; 10.21mmol) acetonitrile (25ml) suspension in.This suspension was at room temperature stirred 10 minutes, then with 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (2.51g; 9.72mmol) be added to reaction mixture, and stirring reaction 3.5 hours under the room temperature.Utilize TLC (silica gel on glass; Toluene: the process of monitoring reaction ETHYLE ACETATE 3: 1).After this stage, filter undissolved part also with 15ml acetonitrile washing leaching cake through the S2 sintered glass.With the N of 2.8ml diacetyl oxide (29.17mmol) and 1.4ml N-ethyl diisopropylamine (7.78mmol) and catalytic amount, the N-dimethyl aminopyridine is added in the filtrating.Reaction mixture at room temperature stirred 1.5 hours.Then, reaction mixture is cooled to-15 ℃, adds 25ml water, and at-12 to-8 ℃ of stirring reaction 2h.With isolating crystal suction, with washing with alcohol and air-dry.Obtain 1.98g prasugrel (54.4%).HPLC: purity 98.8%; The content of formula II compound is less than 0.05%.
Embodiment 10
With K 2CO 3(4.03g; 29.17) be added to hydrochloric acid 2-oxo-2,4,5,6,7a-six hydrogen thieno-s [3,2-c] pyridine (1.96g; 10.21mmol) acetonitrile (25ml) suspension in.This suspension was at room temperature stirred 10 minutes, then with 1-cyclopropyl-2-bromo-2 (2-fluorophenyl) ethyl ketone (2.51g; 9.72mmol) be added to reaction mixture, and stirring reaction 3.5 hours at room temperature.Utilize TLC (silica gel on glass; Toluene: the process of monitoring reaction ETHYLE ACETATE 3: 1).After this stage, filter undissolved part also with 15ml washing with acetone filter cake through the S2 sintered glass.With the N of 2.8ml diacetyl oxide (29.17mmol) and 1.4ml N-ethyl diisopropylamine (7.78mmol) and catalytic amount, the N-dimethyl aminopyridine is added in the filtrating.Reaction mixture at room temperature stirred 1.5 hours.Then, reaction mixture is cooled to-15 ℃, adds 25ml water, and at-12 to-8 ℃ of stirring reaction 2h.With isolating crystal suction, with washing with alcohol and air-dry.Obtain 1.67g prasugrel (46%).HPLC: purity 99.0%; The content of formula II compound is less than 0.05%.
Embodiment 11
With triethylamine (36.5ml; 0.26mol) be added to the hydrochloric acid 2-oxo-2,4,5,6 in methyl alcohol (250ml) and acetone (250ml) mixture, 7a-six hydrogen thieno-s [3,2-c] pyridine (50g; 0.26mol) suspension.With tosic acid monohydrate (54.6g; 0.28mol) be added in this solution.Under 10 ℃ to 15 ℃ temperature, stir, from solution, separate out white crystal.After 2 hours they are aspirated, and obtain the 2-oxo-2,4,5,6 of 49.7g, first part's (58%) of 7a-six hydrogen thieno-s [3,2-c] pyridine tosilate (58%) thus.Through mother liquor is concentrated into 1/2 volume in rotary vacuum evaporator, and be cooled to 10 ℃, obtain the second section of other 26.2g (31%).2-oxo-2,4,5,6, the overall yield of 7a-six hydrogen thieno-s [3,2-c] pyridine tosilate is 89%.
Embodiment 12
To under 45 ℃ temperature, be dissolved in the ETHYLE ACETATE (50ml) according to the rough prasugrel (10.19g) of embodiment 1 preparation, add gac, and with the solution filtered while hot.(40ml) is added to hot soln with hexane.Crystal begins to separate out, and mixture is cooled to 0 ℃ gradually, stirs 2 hours at 0-5 ℃.Obtain 7.9g (79%) white crystal prasugrel, fusing point: 120-121 ℃ through suction; HPLC purity 99.3%; The content of formula II compound is less than 0.05%.The X-ray powder diffraction pattern with in embodiment 1, appear identical.
Embodiment 13
To under 50 ℃ temperature, be dissolved in the methyl alcohol (16ml) according to the rough prasugrel (1.03g) of embodiment 1 preparation, add gac and the solution filtered while hot.In hot soln, add entry (6.5ml).Crystal begins to separate out, and mixture is cooled to 5 ℃ gradually, and mixture was stirred 2 hours at 0-5 ℃.Obtain 0.77g (77%) white crystal, fusing point: 120-121 ℃ through suction; HPLC purity 99.4%; The content of formula II compound is less than 0.05%.
Embodiment 14
To at room temperature be dissolved in the acetone (20ml) according to the rough prasugrel (1.79g) of embodiment 8 preparations, add gac, filter this solution, with other 5ml washing with acetone filter cake.Be cooled under-15 to-10 ℃ the temperature, (12ml) dropwise is added to filtrating with water.Crystal begins to separate out and mixture is stirred 2h at-5 to-10 ℃.Suction obtains 1.53g (85%) white crystal, fusing point: 120-121 ℃; HPLC purity: 99.2%; The content of formula II compound is less than 0.05%.
Embodiment 15
Prasugrel hydrobromide, the preparation of A form
(3.15g 8.43mmol) is dissolved in the acetone (46ml), and this solution is cooled to 5-10 ℃ with prasugrel alkali.With Hydrogen bromide (0.90ml; 8.01mmol) 48% solution dropwise be added to this solution; Make this solution crystallization and under 5-10 ℃ temperature, stirred 1 hour.The crystal that suction is separated out.Obtain 3.60g (99%) prasugrel hydrobromide, the A form, fusing point is 137-141 ℃.
Embodiment 16
Prasugrel hydrobromide, the preparation of A form
With prasugrel alkali (3.089g; 8.27mmol) be dissolved in the acetone (46ml), and this solution is cooled to 5-10 ℃.To use the saturated toluene of hydrogen bromide (0.95eq.) dropwise to be added in this solution; Make this solution crystallization alternatively and under 5-10 ℃ temperature, stirred 2 hours.Obtain 2.87g prasugrel hydrobromide (80%).Fusing point: 134.7-136.3.
The X-ray of product record with in embodiment 15, appear identical.
Embodiment 17
Prasugrel hydrobromide, the preparation of B form
To be dissolved in while hot in the mixture of 8ml ethanol and 25ml ETHYLE ACETATE according to the 1.0g prasugrel hydrobromide of embodiment 14 preparations.The solution that obtains is filtered, and make its crystallization 24 hours under+5 ℃ temperature.The hydrobromate of isolated at suction obtains 0.25g (25%) prasugrel hydrobromide, the B form; Fusing point 148-153 ℃.
Embodiment 18
The preparation of prasugrel hydroiodic acid HI
With prasugrel alkali (3.028g; 8.11mmol) be dissolved in the acetone (16ml), in ice bath, be cooled to 5-10 ℃.The aqueous solution (0.95eq.) of 57% hydrogen iodide dropwise is added to this solution, and this solution of crystallization also stirs 1.5h under about 5 ℃ temperature.Obtain 2.99g light yellow crystal (74%), fusing point: 123-125 ℃.
Embodiment 19
The preparation of prasugrel benzene sulfonate
With prasugrel alkali (1.554g; 4.16mmol) under the temperature of height to 35 ℃, be dissolved in the acetone (15ml), and be cooled to room temperature.With Phenylsulfonic acid (0.625g; 3.95mmol) be dissolved in the diethyl ether (6.2ml), and this solution is added to prasugrel solution.Other 8ml diethyl ether is added in this solution, and this solution is cooled to-10 ℃, crystallization, and under-10 ℃ temperature, stir 12h.The crystal that suction is separated out is with diethyl ether washing and dry voluntarily.Obtain 1.96g (93%) white crystal, fusing point is 162.5-163.5 ℃.
Embodiment 20
The preparation of prasugrel cyclamate
With prasugrel alkali (2.2g; 5.41mmol) be dissolved in the acetone (20ml).With cyclamic acid (0.970g; 5.41mmol) be dissolved in the acetone (9ml), and this solution is added in the prasugrel solution, be cooled to-10 ℃, crystallization, and under-10 ℃ temperature, stir 12h.The crystal that suction is separated out is used washing with acetone, and dry voluntarily.Obtain 0.730g (45%) white crystal, fusing point is 162.5-163.5 ℃.
Description of drawings
The X-ray powder diffraction pattern of Fig. 1 a-prasugrel alkali;
The DSC curve of Fig. 1 b-prasugrel alkali.

Claims (20)

1. acetate 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6 who prepares formula I, 7-THTP be the method for [3,2-c] pyridine-2-base ester or its salt also,
It is characterized in that making formula III compound with the form of the salt of aromatic hydrocarbons sulfonic acid
With the reaction in the presence of mineral alkali or organic bases in organic solvent of formula XV compound,
Wherein Y representes: chlorine, bromine or OR 4Group, wherein R 4Expression alkane sulfonic acid base or aromatic hydrocarbons sulfonic group,
After in reaction mixture, adding acetylation reagent and organic bases, to obtain formula I compound; The crystallization from said reaction mixture after adding cosolvent of said formula I compound, and said alternatively formula I compound through crystallization by purifying and alternatively through in suitable solvent with organic acid or inorganic acid reaction conversion salify.
2. method according to claim 1 is characterized in that said formula III compound uses with the form of the salt of tosic acid or Phenylsulfonic acid.
3. method according to claim 1 and 2 is characterized in that said formula III compound uses with the form of the salt of tosic acid.
4. according to the described method of aforementioned each claim, it is characterized in that using formula XV compound, wherein Y representes: bromine or OR4 group, wherein R4 representes the methylsulfonic acid base.
5. according to the described method of aforementioned each claim, it is characterized in that employed organic solvent is selected from the group of being made up of acetonitrile, N, acetone and their mixture.
6. according to the described method of aforementioned each claim, it is characterized in that employed mineral alkali is selected from by yellow soda ash, salt of wormwood or cesium carbonate, and the group of sodium hydrogencarbonate, saleratus or cesium bicarbonate composition, and employed organic bases is a trialkylamine.
7. according to the described method of aforementioned each claim, it is characterized in that employed mineral alkali is yellow soda ash or salt of wormwood, and employed organic bases is triethylamine or ethyl diisopropylamine.
8. according to the described method of aforementioned each claim, it is characterized in that employed acetylation reagent is a diacetyl oxide.
9. according to the described method of aforementioned each claim; It is characterized in that said formula I compound is through adding cosolvent crystallization from said reaction mixture; Said cosolvent selects free water, the aqueous solution of inorganic salt, and alcohol is such as methyl alcohol, ethanol and propyl alcohol; Acetic ester such as ethyl ester, propyl ester or butyl ester, and the group formed of aliphatic hydrocarbon such as hexane or hexanaphthene.
10. method according to claim 9 is characterized in that the group that said cosolvent selects the aqueous solution, methyl alcohol, ethanol, ETHYLE ACETATE, hexane and the hexanaphthene of free water, inorganic salt to form.
11. method according to claim 1 is characterized in that compound I through from the solvent that is selected from the group of being made up of lower alcohol and lower ketones, ester and organic acid nitrile, adds the cosolvent crystallization by purifying alternatively.
12. method according to claim 1; It is characterized in that cosolvent crystallization that compound I selects the aqueous solution and the aliphatic hydrocarbon of free water and inorganic salt or the group that their mixture is formed through use by purifying, the preferred pentane of said aliphatic hydrocarbon, hexane or hexanaphthene.
13. according to claim 1,11 and 12 described methods, it is characterized in that said compound I through-30 ℃ to+40 ℃, preferred-30 ℃ extremely under+15 ℃ the temperature crystallization by purifying.
14. prasugrel, it contains and is less than 0.5% formula II compound
15. prasugrel according to claim 14, it contains and is less than 0.1% formula II compound.
16. according to the described method of claim 1-13, it is characterized in that compound I through transforming salify with acid-respons, said acid is selected from the group of being made up of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, cyclamic acid, ethyl sulfonic acid, Phenylsulfonic acid and 2-naphthene sulfonic acid.
17. according to claim 1-13 and 16 described methods; The conversion that it is characterized in that said salt is carried out through following step: with formula I compound dissolution in organic solvent; Add the acid of 0.95 to 1.05 molar equivalent then; And make reaction mixture-30 ℃ of crystallizations to the temperature of the boiling point of said solvent, said acid is selected from the group of being made up of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, hexamethylene ammonia sulphur, ethyl sulfonic acid, Phenylsulfonic acid and 2-naphthene sulfonic acid.
18. method according to claim 17 is characterized in that said organic solvent is selected from by ketone-preferred acetone or methylethylketone, acetic ester, lower alcohol-particular methanol and ethanol and group that aromatic hydrocarbon-preferred toluene is formed.
19. method according to claim 17; It is characterized in that said acid as the interpolation of the solution in organic solvent, said organic solvent is selected from the group of being made up of ketone-preferred acetone or methylethylketone, acetic ester, lower alcohol-particular methanol or ethanol, aromatic hydrocarbon-preferred toluene and water.
20. method according to claim 17 is characterized in that said crystallization carries out under-30 ℃ to+40 ℃ temperature.
CN2010800519259A 2009-11-16 2010-11-12 Method of producing highly pure prasugrel and pharmaceutically acceptable salts thereof Pending CN102612519A (en)

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CN102977115A (en) * 2012-11-16 2013-03-20 江苏先声药业有限公司 Novel synthetic method of prasugrel free base
CN103570741A (en) * 2012-07-26 2014-02-12 石药集团中奇制药技术(石家庄)有限公司 Prasugrel novel crystals and preparation method thereof
CN103772408A (en) * 2012-10-26 2014-05-07 江苏先声药物研究有限公司 Crystal of prasugrel-1,5-napadisylate
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CN103570741A (en) * 2012-07-26 2014-02-12 石药集团中奇制药技术(石家庄)有限公司 Prasugrel novel crystals and preparation method thereof
CN103772408A (en) * 2012-10-26 2014-05-07 江苏先声药物研究有限公司 Crystal of prasugrel-1,5-napadisylate
CN102977115B (en) * 2012-11-16 2015-01-21 江苏先声药业有限公司 Novel synthetic method of prasugrel free base
CN102977115A (en) * 2012-11-16 2013-03-20 江苏先声药业有限公司 Novel synthetic method of prasugrel free base
CN103848844A (en) * 2012-12-07 2014-06-11 天津市汉康医药生物技术有限公司 Prasugrel salt-forming compound and preparation method thereof
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CN102977116A (en) * 2012-12-24 2013-03-20 天津大学 Amorphous prasugrel hydrogen sulfate and preparation method thereof

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