CN105669699B - A kind of preparation method of prasugrel hydrochloride - Google Patents
A kind of preparation method of prasugrel hydrochloride Download PDFInfo
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- CN105669699B CN105669699B CN201610126077.2A CN201610126077A CN105669699B CN 105669699 B CN105669699 B CN 105669699B CN 201610126077 A CN201610126077 A CN 201610126077A CN 105669699 B CN105669699 B CN 105669699B
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- 0 C*(C1)[C@@]1C(C[C@](*1IC1)[C@@]1NC1)=C(C)F Chemical compound C*(C1)[C@@]1C(C[C@](*1IC1)[C@@]1NC1)=C(C)F 0.000 description 2
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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 invention belongs to field of medicine and chemical technology, more particularly to a kind of preparation method of prasugrel hydrochloride, by 4,5,6,7 thiophanes simultaneously the acetic ester hydrochloride (chemical compounds I) of 2 hydroxyl of [3,2 c] pyridine 2 and (2 fluorophenyl) ethyl ketone (compound ii) of 2 hydroxyl, 1 cyclopropyl 2 in the presence of trialkyl phosphine, azo agents, Mitsunobu reactions occur in organic solvent, hydrochloric acid salt obtains prasugrel hydrochloride (compound III).The advantages that present invention has that reaction condition is gentle, technique advantages of simple, and the reaction time is short, convenient post-treatment, high product yield.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of prasugrel hydrochloride.
Background technology
Prasugrel hydrochloride is by the oral of the first pharmacy Sankyo Co., Ltd joint development of Lilly Co., Eli. and Japan
Antithrombotic reagent, it is a kind of pro-drug, forms bioactive molecule after metabolism in vivo, with the adenosine triphosphate on platelet membrane
Sour P2Y12Acceptor with reference to and play the activity of platelet aggregation-against.In July, 2009, ratify through FDA in U.S.'s Initial Public Offering, commodity
Name Efient, clinically it is used to treat atherosclerosis and acute coronary syndrome.It is as the gland on platelet membrane
Guanosine triphosphate P2Y12 receptor antagonists, clinic show that it suppresses the similar drugs chlorine pyrrole that the effect of platelet aggregation has listed
Gray faster, it is stronger and more longlasting, therefore before it will have very wide application as efficiently antithrombotic reagent of new generation
Scape.
Prasugrel hydrochloride is the derivative of a kind of tetrahydrochysene thiophene hydrogen and pyridine, and wherein science of culture title is：(±)-2-[2-
Acetoxyl group -6,7- dihydro-thiophenes simultaneously [3,2-c] pyridine -5 (4H)-yl] -1- cyclopropyl -2- (2- difluorophenyls) ethyl ketone hydrochloric acid
Salt, molecular formula：C20H20FNO3SHCl, molecular weight：409.90 structure is as follows：
The synthesis document on prasugrel hydrochloride mainly has following several process routes, patent CN981092209 at present
Process route one using raw material 2- fluorine bromobenzyl (6) with reactive magnesium generation grignard reagent, react to obtain 1- rings with cyclopropyl cyanogen
Propyl group -2- (2- fluorophenyls) ethyl ketone (7), then by bromo, obtain intermediate 2- bromo- 1- cyclopropyl -2- (2- fluorophenyls) second
Ketone (8), using the thiophane of raw material 4,5,6,7-, simultaneously [3,2-c] pyridine hydrochloride (2) reacts with triethylamine, trityl chloride,
Obtain N- trityls -4,5,6,7- thiophanes simultaneously [3,2-c] pyridine (3), then with n-BuLi, tri-n-butyl borate and
Hydrogen peroxide reacts to obtain N- trityls -4,5,6,7a- thiophanes simultaneously [3,2-c] pyridin-2-ones (4), is deprotected with hydrochloric acid
Base simultaneously obtains 4,5,6,7a- thiophanes simultaneously [3,2-c] pyridin-2-ones hydrochloride (5) into salt, with the bromo- 1- rings third of intermediate 2-
Base -2- (2- fluorophenyls) ethyl ketones (8) reaction obtains 5- (α-cyclopropyl carbonyl -2- luorobenzyls) -2- carbonyls -4,5,6,7a- tetrahydrochysene thiophenes
Fen simultaneously [3,2-c] pyridine (9), then obtains prasugrel (1) with acetic anhydride in the presence of sodium hydrogen and DMF.
This method feature be dock when using compound 5 (thienone) directly with compound 8 (halogenated hydrocarbons) being condensed into
There is hydroxyl ketone change in compound 9, the ketone group that defect is in compound 5 (thienone), during condensation, ketone group can be formed with intermediate 8
Ether compound, poor selectivity, post processing needs to purify by column chromatography, and to be used than relatively hazardous sodium during acetylation
Hydrogen.This method cost is too high, cumbersome, is not suitable for industrialized production.
Process route two is most of and process route one is identical, is distinguished as using raw material o fluorobenzaldehyde (7) and trimethyl
Silylation cyanogen reacts to obtain 2- (2- fluorophenyls) -2- trimethylsiloxy groups acetonitrile (8), reacts to obtain 1- rings third with cyclopropyl cyanogen
Base -2- (2- fluorophenyls) -2- hydroxyethanones (9), then by the esterification of benzene sulfonyl chloride, obtain intermediate benzene sulfonic acid -2-
Cyclopropyl -1- (2- fluorophenyls) -2- oxoethyl esters (10), and 4, simultaneously [3,2-c] pyridin-2-ones (6) are anti-for 5,6,7a- thiophanes
It should obtain 5- (α-cyclopropyl carbonyl -2- luorobenzyls) -2- carbonyls -4,5,6,7a- thiophanes simultaneously [3,2-c] pyridine (11), then
With acetic anhydride prasugrel is obtained in the presence of sodium hydrogen and DMF.
The characteristics of this method, is that dock reaction substitutes halogen as leaving group to carry out condensation reaction using sulphonic acid ester,
It is the improvement of method one.This method poor selectivity during condensation, is received again without avoiding the ketone group on thienone from hydroxyl ketone change being present
The defects of rate is low, and it also requires using sodium hydrogen, it is not suitable for industrialized production.
Patent US5874581 process route three uses raw material 1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone, then by chlorine
In generation, obtain intermediate 2- chloro- 1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone；Using the thiophane of raw material 4,5,6,7a- simultaneously [3,2-
C] pyridin-2-ones hydrochloride reacts to obtain 2- tert-butyl groups dimethylsilyloxy -4 in triethylamine with tert-butyl chloro-silicane,
5,6,7a- thiophanes simultaneously [3,2-c] pyridine, reacts to obtain with intermediate 2- chloro- 1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone
2- tert-butyl group dimethylsilyloxies -5- (α-cyclopropyl carbonyl -2- luorobenzyls) -4,5,6,7a- thiophanes simultaneously [3,2-c] pyridine, so
Afterwards prasugrel is obtained with acetic anhydride in the presence of 4- dimethylamino pyridines and triethylamine.
The advantages of this method, is to carry out the ketone group of 5,6,7,7a- thiophanes simultaneously [3,2-c] pyridine -2 (4H) -one
Protection, substantially increases the selectivity of condensation reaction, but extends reactions steps, increases equipment cost, and yield reduces.
The content of the invention
The purpose of the present invention is to overcome defect present in existing synthetic method, there is provided a kind of technique is simple, production cost
It is low, the preparation method of the prasugrel hydrochloride of product purity and high income.
Problem of the present invention solves by the following technical programs：
A kind of preparation method of prasugrel hydrochloride, it is characterised in that it comprises the following steps：
4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- hydroxyl -2- acetic ester hydrochlorides (chemical compounds I) and 2- hydroxyls -
1- cyclopropyl -2- (2- fluorophenyls) ethyl ketones (compound ii) are initiation material, in the presence of trialkyl phosphine, azo agents, Yu You
Mitsunobu reactions occur in solvent, hydrochloric acid salt obtains prasugrel hydrochloride (compound III).
The synthetic route of the present invention is as follows：
Preferably, the trialkyl phosphine is triphenylphosphine, tributylphosphine, cyclohexyl phosphine, the positive phosphorus of (cyanogen methylene) tributyl
Or (cyanogen methylene) trimethyl phosphorane (CMMP) (CMBP).
Preferably, the azo agents be diethyl azodiformate (DEAD), diisopropyl azodiformate (DIAD),
Azodicarbonamide (TMAD), tert-butyl azodicarboxylate (DBAD), the ring pentyl ester (DCpAD) of azoformic acid two, azo two
- 4- cyano group the benzyl ester (DCyAD) of formic acid two, 1,1 '-(phosphinylidyne of diimide two) two piperidines (ADDP), N, N, N ', N '-tetra isopropyl azo
Diformamide (TIPA), N, N, N ', N '-tetramethyl azodicarbonamide (TMAD) or 4,7- dimethyl -3,4,5,6,7,8- six
Azepine Xin Yin -3,8- the diketone (DHTD) of hydrogen-l, 2,4,7- tetra-.
It is further preferred that the azo agents are preferably 1,1 '-(phosphinylidyne of diimide two) two piperidines (ADDP), N, N, N ',
N '-tetra isopropyl azodicarbonamide (TIPA), N, N, N ', N '-tetramethyl azodicarbonamide (TMAD) or 4,7- dimethyl-
Azepine Xin Yin -3,8- the diketone (DHTD) of 3,4,5,6,7,8- hexahydros-l, 2,4,7- tetra-.
Preferably, the organic solvent is benzene, tetrahydrofuran, 2- methyltetrahydrofurans, ether, t-butyl methyl ether, first
Benzene, N,N-dimethylformamide (DMF), acetonitrile, dichloromethane, ethyl acetate or dioxane.
It is further preferred that organic solvent preferred tetrahydrofuran, acetonitrile or the dichloromethane.
Preferably, the reaction is carried out in the range of 0 DEG C -80 DEG C, preferably 20 DEG C -40 DEG C.
Preferably, chemical compounds I, compound ii, trialkyl phosphine and azo agents mol ratio are 1：1.1~1.5：1.2~
3.0：1.2~3.0.
Preferably, reagent used during hydrochloric acid salt is 0.1mol/L hydrochloric acid propanol solution or 0.1mol/L hydrochloric acid isopropanols
Solution.
The present invention uses 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- hydroxyls -2- acetic ester hydrochloride (compounds
I) with 2- hydroxyl -1- cyclopropyl -2- (2- fluorophenyls) ethyl ketones (compound ii) in the presence of trialkyl phosphine, azo agents, Yu You
Mitsunobu reactions occur in solvent, hydrochloric acid salt obtains prasugrel hydrochloride (compound III).
At present, the azo agents being most often used in general Mitsunobu reactions have diisopropyl azodiformate
(DIAD) and diethyl azodiformate (DEAD), they in most cases can be general and be easier to buy, and need
It should be noted that both reagents are sensitive to light, heat and strong impact, easily blast, therefore it is dry typically to require that low-temperature dark is stored in
Dry place, classical Mitsunobu reactions also have the limitation of its application, and the acidity of preceding nucleophile must be sufficiently strong, general to require
Pka≤13, in order to overcome this problem, we make the compound application activity for pka >=11 using new azo agents
Higher azo agents are such as：1,1 '-(phosphinylidyne of diimide two) two piperidines (ADDP), N, N, N ', N '-tetra isopropyl azodicarbonamide
(TIPA), N, N, N ', N '-tetramethyl azodicarbonamide (TMAD) or 4,7- dimethyl -3,4,5,6,7,8- hexahydro-l, 2,4,
Azepine Xin Yin -3,8- diketone (DHTH) of 7- tetra- etc. and tributylphosphine (TBP) or trimethyl-phosphine Me3P counterpart applications, these reagents
Amino instead of instead of the alkoxy in diethyl azodiformate (DEAD) with the alkyl acted on stronger supplied for electronic, make idol
The alkalescence raising for the glycine betaine analog that nitrogen reagent is generated with trivalent phosphine, the ability of the proton of nucleophile before enhancing is captured.Its
Accessory substance in reaction has water solubility, can remove accessory substance by washing.
Relative to prior art, it is an advantage of the invention that：
(1) method of preparation prasugrel hydrochloride of the invention, synthetic route shorten dramatically, and only two steps, simplify behaviour
Make technique, reaction condition is more gentle, and post processing is simple and easy to do, and obtained product yield is high and purity is high, is more suitable for industrializing
Production requirement, production time and labour cost are not only saved, and reduce production cost, the receipts of reaction are greatly improved
Rate.
(2) what classical reagent Mitsunobu reacted is limited in that preceding nucleopilic reagent NuH must have sufficiently strong acid
Property (pka<13), can not be reacted if pka is more than 13.In fact, if nucleopilic reagent NuH pka will be led in 10~13 scopes
Yield is caused to decline.In order to overcome the limitation of classical reagent Mitsunobu reactions, the present invention uses new azo agents, kept away
The appearance of disadvantages mentioned above is exempted from.
Embodiment
The invention will be further described with reference to embodiments.
Chemical compounds I outsourcing or self-control, outsourcing producer are Protheragen Inc：Content is：＞ 98.0%.
Self-control is made by oneself with reference to WO2009122440, is prepared using following process route.
N- trityls -5,6,7,7a- thiophanes simultaneously [3,2-c] pyridin-2-ones sodium acid carbonate effect under through acetic anhydride
Acetylation obtains acetic acid-N- trityls -5,6,7,7- thiophanes simultaneously [3,2-c] pyridine -2- esters, the remove-insurance under hydrochloric acid effect
Shield base obtains acetic acid -5,6,7,7- thiophanes simultaneously [3,2-c] pyridine -2- ester hydrochlorides.
Compound ii outsourcing or self-control, outsourcing producer are：Wei Ta Chemical Co., Ltd.s, Protheragen Inc, content
For：＞ 98.0%.
Embodiment 1：The synthesis of prasugrel hydrochloride (compound III)
First triphenylphosphine (31.5g, 120mmol) is suspended in 200ml tetrahydrofurans, adds azoformic acid at room temperature
Diethylester (DEAD, 20.9g, 120mmol), react 0.5 hour, add 2- hydroxyl -1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone
4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- hydroxyls -2- is added dropwise in (compound ii) 21.3g (110mmol), 25 DEG C of temperature control
Acetic ester hydrochloride (chemical compounds I) 23.4g (100mmol) tetrahydrofuran solution 100ml, thin layer are monitored after completion of the reaction, used
Saturated common salt water washing, water washing, organic phase anhydrous sodium sulfate drying are purified, organic phase is concentrated under reduced pressure, residue 0.1mol/
L hydrochloric acid propanol solution recrystallizes, and vacuum drying, obtains compound III 32.9g, yield 80.3%, purity 98.7% (HPLC methods).
Embodiment 2：The synthesis of prasugrel hydrochloride (compound III)
First tributylphosphine (60.7g, 300mmol) is suspended in 200ml acetonitriles, adds 1, the 1 '-(carbon of diimide two at room temperature
Acyl) two piperidines (ADDP) (75.7g, 300mmol), react 0.5 hour, add 2- hydroxyl -1- cyclopropyl -2- (2- fluorophenyls) second
Ketone (compound ii) 29.1g (150mmol), 40 DEG C of temperature control be added dropwise 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- hydroxyls -
2- acetic ester hydrochlorides (chemical compounds I) 23.4g (100mmol) acetonitrile solution 100ml, thin layer monitors after completion of the reaction, organic
Mutually it is concentrated under reduced pressure, concentrate adds dichloromethane dissolving, with saturated common salt water washing, purifies water washing, organic phase anhydrous slufuric acid
Sodium is dried, and organic phase is concentrated under reduced pressure, and residue is recrystallized with 0.1mol/L hydrochloric acid aqueous isopropanol, vacuum drying, obtains chemical combination
The 36.7g of thing III, yield 89.5%, purity 99.7% (HPLC methods).
Embodiment 3：The synthesis of prasugrel hydrochloride (compound III)
First triphenylphosphine (36.7g, 140mmol) is suspended in 200ml dichloromethane, adds N, N, N at room temperature ', N '-
Tetramethyl azodicarbonamide (TMAD) (24.1g, 140mmol), react 0.5 hour, add 2- hydroxyl -1- cyclopropyl -2- (2-
Fluorophenyl) ethyl ketone (compound ii) 25.2g (130mmol), 4,5,6,7- thiophanes simultaneously [3,2-c] pyrrole is added dropwise in 20 DEG C of temperature control
Pyridine -2- hydroxyl -2- acetic ester hydrochlorides (chemical compounds I) 23.4g (100mmol) dichloromethane solution 100ml, thin layer monitoring are anti-
After answering, with saturated common salt water washing, water washing, organic phase anhydrous sodium sulfate drying are purified, organic phase is concentrated under reduced pressure, remaining
Thing is recrystallized with 0.1mol/L hydrochloric acid propanol solution, vacuum drying, obtains compound III 38.3g, yield 93.5%, purity
99.8% (HPLC methods).
Embodiment 4：The synthesis of prasugrel hydrochloride (compound III)
First triphenylphosphine (34.1g, 130mmol) is suspended in 200ml dichloromethane, adds N, N, N at room temperature ', N '-
Tetra isopropyl azodicarbonamide (TIPA) (37.0g, 130mmol), react 0.5 hour, add 2- hydroxyl -1- cyclopropyl -2-
4,5,6,7- thiophanes are added dropwise simultaneously [3,2-c] in (2- fluorophenyls) ethyl ketone (compound ii) 25.2g (130mmol), 20 DEG C of temperature control
Pyridine -2- hydroxyl -2- acetic ester hydrochlorides (chemical compounds I) 23.4g (100mmol) dichloromethane solution 100ml, thin layer monitoring
After completion of the reaction, with saturated common salt water washing, water washing is purified, organic phase anhydrous sodium sulfate drying, organic phase is concentrated under reduced pressure, residual
Excess is recrystallized with 0.1mol/L hydrochloric acid propanol solution, vacuum drying, obtains compound III 38.3g, yield 94.2%, purity
99.6% (HPLC methods).
Claims (6)
1. a kind of preparation method of prasugrel hydrochloride, it is characterised in that it comprises the following steps：
By 4,5,6,7- thiophanes simultaneously [3,2-c] pyridine -2- hydroxyl -2- acetic ester hydrochlorides (chemical compounds I) and 2- hydroxyls -1-
Cyclopropyl -2- (2- fluorophenyls) ethyl ketones (compound ii) occur in the presence of trialkyl phosphine, azo agents in organic solvent
Mitsunobu reacts, and hydrochloric acid salt obtains prasugrel hydrochloride (compound III), and described trialkyl phosphine is triphenylphosphine or three
Butyl phosphine；Described azo agents are azodicarbonamide (TMAD), 1,1 '-(phosphinylidyne of diimide two) two piperidines (ADDP) or N, N,
N ', N '-tetra isopropyl azodicarbonamide (TIPA)；
Chemical compounds I：Compound ii：Compound III：
2. preparation method as claimed in claim 1, it is characterised in that：The organic solvent is benzene, tetrahydrofuran, 2- methyl four
Hydrogen furans, ether, t-butyl methyl ether, toluene, N,N-dimethylformamide (DMF), acetonitrile, dichloromethane, ethyl acetate or
Dioxane.
3. preparation method as claimed in claim 2, it is characterised in that：The organic solvent is tetrahydrofuran, acetonitrile or dichloro
Methane.
4. preparation method as claimed in claim 1, it is characterised in that：The reaction is carried out in the range of 0 DEG C -80 DEG C.
5. preparation method as claimed in claim 1, it is characterised in that：Chemical compounds I, compound ii, trialkyl phosphine and azo try
Agent mol ratio is 1：1.1~1.5：1.2~3.0：1.2~3.0.
6. preparation method as claimed in claim 1, it is characterised in that：Reagent used is 0.1mol/L hydrochloric acid during hydrochloric acid salt
Propanol solution or 0.1mol/L hydrochloric acid aqueous isopropanols.
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