CN104045620B - Preparation method of intermediate of ticagrelor - Google Patents
Preparation method of intermediate of ticagrelor Download PDFInfo
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- CN104045620B CN104045620B CN201310076605.4A CN201310076605A CN104045620B CN 104045620 B CN104045620 B CN 104045620B CN 201310076605 A CN201310076605 A CN 201310076605A CN 104045620 B CN104045620 B CN 104045620B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to a compound represented as formula (2) and a preparation method thereof, wherein the compound is used as a drug intermediate.
Description
Technical field
The present invention relates to a kind of preparation method of new anticoagulant ticagrelor intermediate.
Background technology
Ticagrelor（Trade name Brilinta, CAS：274693-27-5）, chemical name：(1S,2S,3R,5S)-3-[7-
[(1R, 2S) -2- (3,4- difluorophenyls) cyclopropyl amino] -5- (rosickyite base) -3H- [1,2,3] triazole [4,5-d] pyrimidine -3-
Base] -5- (2- hydroxyl-oxethyls) Pentamethylene. -1,2- glycol, structural formula such as following formula（I）It is shown：
（I）
Ticagrelor is a kind of new oral selectivity small molecule anticoagulation medicine that Astrazeneca companies develop.Should
Medicine can reversibly act on hematoblastic P2Y12Receptor, can suppress strongly by adenosine diphosphate（ADP）The blood for causing
Platelet is assembled.Because oral rear action is rapid, it can significantly improve the symptom of acute coronary patient.With clopidogrel phase
Than its own just has anti-platelet aggregation activity, it is not necessary to metabolic activation；In addition, it is similar to clopidogrel effect, but
Less side effect, with broader practice prospect.
Preparing the foreign patent route of Ticagrelor at present mainly has following several：
WO9905143 discloses the synthetic method of the Ticagrelor shown in following route 1：
Route 1
The method reaction scheme is long, severe reaction conditions, and the product yield for preparing for making Ticagrelor is greatly affected, uncomfortable
Close industrialized production.
WO0192263 discloses the method shown in following route 2 and prepares Ticagrelor：
Route 2
In the method, Formulas I -8 to I-11 compounds is oily mater, and intermediate is difficult to solidify, and causes every step reaction
Post processing is all extremely difficult, and the purity and yield of intermediate all receive extreme influence, the product quality of final impact Ticagrelor
Can not be protected.
WO2011017108 discloses the method described in following route 3 and prepares Ticagrelor：
Route 3
The method is compared with method disclosed in WO0192263, and nitro substituted-amino is used on pyrimidine ring so that the first step is reacted
It is easier to make for, reaction condition is optimized, whole course of reaction shortens；But still there is intermediate in oily, solidification is difficult,
The defect of final impact Ticagrelor product quality.
The content of the invention
It is an object of the invention to provide a kind of new purity be easily controlled with following formula（2）Shown Ticagrelor
Intermediate or its salt
。
It is a further object to provide a kind of formula（2）The synthetic method of shown compound, including：
By formula（3）Shown compound：
Slough protection group and obtain formula（2）Shown compound：
；
Described P1It is amino protecting group, preferred benzyloxycarbonyl group；Described P is H or hydroxyl protecting group, preferred H, or benzyl
Or imidazoles carbonyl.
Further, described formula（3）Shown compound is by by formula（4）Shown compound：
Carry out the cyclic carbonate ester protection acquisition of vicinal diamines；Wherein described P1It is all as described above with P.
The cyclic carbonate ester protection reaction of described vicinal diamines is in the basic conditions（For example pyridine, triethylamine etc. are organic
Alkali）, in appropriate solvent（Such as non-polar organic solvent, such as dichloromethane, chloroform）, in -100 to 30 DEG C of temperature
Under carry out.Described cyclic carbonate ester protection reagent, including two (trichloromethyl) carbonic esters, N, N- carbonyl dimidazoles, carbonic acid two
Methyl ester, or diethyl carbonate.Especially when P is imidazoles carbonyl, and cyclic carbonate ester protection reagent is N, during N- carbonyl dimidazoles, can
With directly from formula（6）The shown step of compound one protection formula（3）Shown compound, without through formula（5）Chemical combination
Thing intermediate, shortens course of reaction.
Further, described formula（4）Shown compound is by by formula（5）Shown compound：
What de- isopropylidene protection was obtained；Described method is included in suitable solvent（Such as alcohol, such as methanol, ethanol）In,
It is acid（Concentrated hydrochloric acid, concentrated sulphuric acid）Under the conditions of slough protection group.
Or by by formula（6）Shown compound：
Carry out hydroxyl protection acquisition；Described P1As mentioned above.
Further, described formula（5）Shown compound, is by formula（7）Shown compound：
And formula（8）Shown compound：
What reaction was obtained；
Or, described formula（5）Shown compound is by formula（7’）Shown compound：
And formula（8’）Shown compound:
What reaction was prepared
Described P1It is as described above with P；Described X be halogen, preferred iodine.
Further, described formula（6）Shown compound, is by formula（7’）Shown compound：
Slough what isopropylidene protection was obtained, described method is included in suitable solvent（Such as alcohol, such as methanol, ethanol）
In, it is acid（Concentrated hydrochloric acid, concentrated sulphuric acid）Under the conditions of slough protection group.
Described P1As mentioned above.
Described formula（7）And formula（7’）Can be obtained by commercially available purchase, or the method system with reference to disclosed in CN1432017
Standby to obtain, here citation is used as reference.
It is a further object to provide a kind of formula（2）The preparation method of shown compound, including：
1）By formula（7-a）Shown compound prepares formula with the iodo- 2- benzyloxies ethane reactions of 1-（5-a）Shown change
Compound, or（7’-a）Shown compound prepares formula with benzyl bromine reaction（5-a）Shown compound：
；
2）By formula（5-a）The de- isopropylidene protection of shown compound prepares formula（4-a）Shown compound：
；
3）By formula（4-a）Shown compound carries out the cyclic carbonate ester protection of vicinal diamines and prepares formula（3-a）Shown
Compound：
；
4）By formula（3-a）Shown compound carries out amino and hydroxyl deprotection prepares formula（2）Shown compound：
In above-mentioned preparation method, described step（1）Can be in the basic conditions（Such as sodium hydride, hydrofining, calcium hydride
Or potassium tert-butoxide）, in appropriate solvent（Tetrahydrofuran, DMF or N,N-dimethylacetamide）, -20
To at a temperature of -15 DEG C, by formula（7-a）Or（7’-a）Shown compound carries out substitution reaction formula（5-a）Shown chemical combination
Thing.Described substitution reaction, preferably will（7-a）Or（7’-a）Shown compound is in DMF with hydrogenation
Sodium is reacted as alkali.
Step（2）Can be in acidity（Concentrated hydrochloric acid or concentrated sulphuric acid）Under the conditions of, in appropriate solvent（Methanol, ethanol）, 70
To at a temperature of 80 DEG C, will（5-a）Shown compound carries out deprotection reaction formula（4-a）Shown compound.Described
Deprotection reaction, preferably under the conditions of concentrated hydrochloric acid, is reacted in ethanol.
Step（3）Can be in the basic conditions（Such as organic base such as pyridine, triethylamine）, in appropriate solvent（For example it is non-
Polar organic solvent, such as dichloromethane, chloroform）, at a temperature of -100 to 30 DEG C, will（4-a）Shown compound enters
Row cyclic carbonate ester protection reaction formula（3-a）Shown compound.Described cyclic carbonate ester protection reaction, preferably in dichloro
In methane, using cyclic carbonate ester reagent, such as preferably two (trichloromethyl) carbonic esters or N, N- carbonyl dimidazoles, carbonic acid two are protected
Methyl ester, diethyl carbonate is reacted.
Step（4）Can be in catalytic hydrogenation（Using Pd/C, Raney's nickel, Pt）Under the conditions of, in appropriate solvent（Methanol,
Ethanol）, at a temperature of 10 to 80 DEG C, under the conditions of Hydrogen Vapor Pressure >=0.4MPa, will（3-a）Shown compound carries out remove-insurance
Shield reaction formula（2）Shown compound.Described deprotection reaction, preferably under Pd/C catalysis, in methyl alcohol,
At a temperature of 20-30 DEG C, reacted under the conditions of Hydrogen Vapor Pressure 0.4MPa.
It is a further object to provide a kind of formula（2）The preparation method of shown compound, including：
Formula（2）The synthetic method of shown compound,
,
Including：
1）By formula（6-a）Shown compound carries out the cyclic carbonate ester protection of vicinal diamines, obtains formula（2-c’）Shown change
Compound：
；
2）By formula（2-c’）Shown compound carries out amino deprotection and prepares formula（2）Shown compound：
In above-mentioned preparation method, described step（1）Can be in the basic conditions（For example pyridine, triethylamine etc. are organic
Alkali）, in appropriate solvent（Such as non-polar organic solvent, such as dichloromethane, chloroform）, in -100 to 30 DEG C of temperature
Under, will（6-a）Shown compound carries out cyclic carbonate ester protection reaction formula（2-c’）Shown compound.Described ring carbon acid
Ester protection reaction, preferably in dichloromethane, using cyclic carbonate ester reagent, such as preferably two (trichloromethyl) carbonic esters is protected
Or N, N- carbonyl dimidazoles, dimethyl carbonate, diethyl carbonate reacted.
Step（2）Can be in catalytic hydrogenation（Using Pd/C, Raney's nickel, Pt）Under the conditions of, in appropriate solvent（Methanol,
Ethanol）, at a temperature of 10 to 80 DEG C, under the conditions of Hydrogen Vapor Pressure >=0.1MPa, will（2-c’）Shown compound carries out remove-insurance
Shield reaction formula（2）Shown compound.Described deprotection reaction, preferably under Pd/C catalysis, in methyl alcohol,
At a temperature of 20-30 DEG C, reacted under the conditions of Hydrogen Vapor Pressure 0.1MPa.
Further, the another kind of method described above is deformed into formula（2）The preparation method of shown compound, bag
Include：
1）By formula（7’-a）The de- isopropylidene protection of shown compound prepares formula（6-a）Shown compound：
；
2）By formula（6-a）Shown compound carries out the cyclic carbonate ester protection of vicinal diamines and prepares formula（3-b）Shown
Compound：
；
3）By formula（3-b）Shown compound carries out hydroxyl deprotection and prepares formula（2-c’）Shown compound：
；
4）By formula（2-c’）Shown compound carries out amino deprotection and prepares formula（2）Shown compound：
In above-mentioned preparation method, described step（1）Can be in acidity（Concentrated hydrochloric acid or concentrated sulphuric acid）Under the conditions of, appropriate ether
In class solvent（Tetrahydrofuran, Isosorbide-5-Nitrae-dioxane）, at a temperature of 60 to 110 DEG C, will（7’-a）Shown compound is taken off
Protection reaction formula（6-a）Shown compound.Described deprotection reaction, preferably under the conditions of concentrated hydrochloric acid, at 70 DEG C
At a temperature of, reacted in tetrahydrofuran.
Step（2）Can be in appropriate solvent（Such as non-polar organic solvent, such as dichloromethane, chloroform）,
At a temperature of 10 to 30 DEG C, will（6-a）Shown compound carries out cyclic carbonate ester protection reaction formula（3-b）Shown chemical combination
Thing.Described cyclic carbonate ester protection reaction, preferably in dichloromethane, using cyclic carbonate ester reagent is protected, such as preferred N,
N- carbonyl dimidazoles are reacted.
Step（3）Can be in acidity（Concentrated hydrochloric acid or concentrated sulphuric acid）Under the conditions of, appropriate homogeneous solvent（Tetrahydrofuran or Isosorbide-5-Nitrae-
Dioxane and water）Or two-phase solvent（Dichloromethane or chloroform and water）In, at a temperature of 20 to 110 DEG C, will（3-b）
Shown compound carries out deprotection reaction formula（2-c’）Shown compound.Described deprotection reaction, preferably dense
Under the conditions of hydrochloric acid, at a temperature of 40 DEG C, reacted in dichloromethane with water two-phase solvent.
Step（4）Can be in catalytic hydrogenation（Using Pd/C, Raney's nickel, Pt）Under the conditions of, in appropriate solvent（Methanol,
Ethanol）, at a temperature of 10 to 80 DEG C, under the conditions of Hydrogen Vapor Pressure >=0.1MPa, will（2-c’）Shown compound carries out remove-insurance
Shield reaction formula（2）Shown compound.Described deprotection reaction, preferably under Pd/C catalysis, in methyl alcohol,
At a temperature of 20-30 DEG C, reacted under the conditions of Hydrogen Vapor Pressure 0.1MPa.
When the technology of the present invention is used for ticagrelor midbody, whole synthesis technique is easier to carry out post-reaction treatment, makes
The quality and yield of ticagrelor midbody is protected and improves, and is conducive to environmental conservation, reduces production cost, especially fits
Together in industrialized production.
Specific embodiment
In order that technical problem solved by the invention, technical scheme and beneficial effect become more apparent, below in conjunction with
Specific embodiment, the present invention is further illustrated.In following embodiments, unless otherwise stated, described test method tool
The condition that concrete conditions in the establishment of a specific crime is generally advised according to normal condition or manufacturer is implemented；Described raw material, reagent is by commercially available purchase
Obtain；Described percentage ratio, ratio, ratio or number etc. are calculated according to weight.
Embodiment 1
In 50ml three neck round bottom flask, by the NaH of 0.2g 60%（4.8mmol）In adding DMF 5ml, temperature is cooled down
To less than -15 °C.By compound 7-a 1.0g（3.25mmol）In being dissolved in DMF 10ml, this solution is slowly added dropwise to above-mentioned
In the DMF suspensions of NaH, less than -15 °C are maintained the temperature at.After completion of dropping, continue to stir 0.5-1.0 hours, keeping temperature
Below -15 °C.By the iodo- 2- benzyloxies ethane 1.1g of compound 1-（3.96mmol）, in being dissolved in DMF 5ml, by this solution
It is slowly added dropwise into above-mentioned solution, maintains the temperature at less than -15 °C.After completion of dropping, by temperature improve to -10 to -5 °C after
Continuous reaction 3-5 hours.Post processing is carried out after the reaction completely of TLC detection compounds 7-a.20ml is slowly added dropwise in this reaction solution
Methanol, maintains the temperature at less than 0 °C.The purified water of 50ml is then slowly added dropwise, less than 0 °C is maintained the temperature at.Then add second
Acetoacetic ester 80ml × 3 time extraction point liquid.After merging organic faciess, decompression steams ethyl acetate, column chromatography（Silicagel column, eluant stone
Oily ether：Ethyl acetate=8：1）Compound 5-a product yellow oils 0.9g are obtained after separation, yield 65.0%, HPLC purity is big
In 98%.1H NMR（400MHz, CDCl3）δ: 7.22-7.37（M, 10H）, 5.05（S, 2H）, 4.58（S, 2H）, 4.39-4.52
（M, 1H）, 4.18-4.20（M, 1H）, 3.87-3.88（M, 1H）, 3.60-3.62（T, 2H,J=7.2Hz）, 3.52-3.54（T,
2H,J=7.2Hz）, 3.48-3.49（M, 1H）, 2.13-2.19（M, 1H）, 1.64-1.68（M, 1H）, 1.41（S, 3H）, 1.26
（S, 3H）.MS(m/z)：[M+H]+=442.40。
Compound 5-a also can be synthesized using following methods：In 250ml three neck round bottom flask, by the NaH of 2.05g 60%
（0.05mol）In adding DMF 30ml, temperature is cooled to into less than -20 °C.By-a the 3.6g of compound 7 '（0.01mol）Dissolving
In DMF 15ml, this solution is slowly added dropwise into the DMF suspensions of above-mentioned NaH, maintains the temperature at less than -20 °C.Deca
After finishing, continue to stir 0.5-1.0 hours, maintain the temperature at less than -20 °C.By compound benzyl bromine 2.1g（0.012mol）, it is molten
Solution is slowly added dropwise this solution into above-mentioned solution in DMF 15ml, maintains the temperature at less than -20 °C.After completion of dropping, will
Temperature improves to room temperature and continues to react 3-5 hours.Post processing is carried out after-a of TLC detection compounds 7 ' reactions completely.To this reaction
The purified water of 100ml is slowly added dropwise in solution, less than 0 °C is maintained the temperature at.Then add ethyl acetate 50ml × 2 time extraction point
Liquid.After merging organic faciess, decompression steams ethyl acetate, column chromatography（Silicagel column, eluent petroleum ether：Ethyl acetate=50：1 to
20：1）Compound 5-a product yellow oils 2.1g are obtained after separation, yield 47.0%, HPLC purity is more than 98%.1H NMR
（400MHz, CDCl3）Ibid.
Embodiment 2
In 500ml three neck round bottom flask, by compound 5-a 4.5g（0.01mol）, concentrated hydrochloric acid 60ml is dissolved in 180ml first
In alcohol, 80 °C of backflows are kept overnight（About 12h）.Post processing is carried out after the reaction completely of TLC detection compounds 5-a.Reactant liquor is subtracted
Pressure is concentrated to dryness, and adds saturated sodium carbonate solution to adjust to pH=7-8.Then add ethyl acetate 30ml × 2 time extraction point liquid.
After merging organic faciess, decompression steams ethyl acetate and obtains crude product.Crude product is shallow using 4-a is obtained after recrystallization from ethyl acetate/petroleum ether
Yellow solid 3.6g, yield 89.8%, HPLC purity is more than 98%.1H NMR（400MHz, MeOD）δ: 7.28-7.33（M,
10H）, 5.06（S, 2H）, 4.53（S, 2H）, 3.90-3.91（M, 1H）, 3.87-3.88（M, 1H）, 3.85-3.86（M, 1H）,
3.64-3.66（T, 2H,J=6.8Hz）, 3.61-3.63（T, 2H,J=6.8Hz）, 3.59-3.60（M, 1H）, 2.47-2.50
（M, 1H）, 1.39-1.43（M, 1H）.MS(m/z)：[M+H]+=402.25。
Embodiment 3
In 250ml three neck round bottom flask, by compound 4-a 5.0g（0.012mol）, N ', N ' and-carbonyl dimidazoles 3.0g
（0.018mol）In being dissolved in 100ml dichloromethane.1.5-2 hours are stirred at room temperature.The reaction of TLC detection compounds 4-a is completely laggard
Row post processing.Pour the hydrochloric acid solution 50ml × 2 time washing of 1.5N into in this reactant liquor.Divide liquid, dichloromethane is mutually using anhydrous
After sodium sulfate is dried, filter, remove solvent under reduced pressure, obtain compound 3-a product light yellow oils 4.7g, yield 88.0%,
HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）δ: 7.23-7.39（M, 10H）, 5.07（S, 2H）, 4.90（S, 2H）,
4.49-4.58（M, 1H）, 4.36-4.43（M, 1H）, 4.11-4.18（M, 1H）, 3.66-3.68（T, 2H,J=6.8Hz）,
3.63-3.65（T, 2H,J=6.8Hz）, 3.44-3.46（M, 1H）, 2.10-2.17（M, 1H）, 1.62-1.66（M, 1H）.MS
(m/z)：[M+H]+=428.25。
The compound of embodiment 4 it is 2-in-1 into
In 100ml round-bottomed flasks, compound 3-a 3.5g are added（7.0mmol）, 10% Pd/C 0.7g, ammonium formate
In 7.0g to methanol 50ml.Under stirring, hydrogen is passed through（0.4MPa）12 hours, maintain the temperature at 80 °C.TLC detection compounds 3-
Post processing is carried out after a reactions completely.Filter, filtrate steaming removal solvent obtains crude product.Crude product is produced using the extraction of acetone 50ml × 2 time
Product.Acetone is mutually used anhydrous sodium sulfate drying, is filtered, remove solvent under reduced pressure, obtain the product white solid 1.49g of compound 2,
Yield 90.0%, HPLC purity is more than 99%.1H NMR（400MHz, CDCl3）δ:5.08（D,J=6.8Hz, 1H）, 4.85（D,J =
6.8Hz, 1H）, 3.73-3.74（M, 2H）, 3.69-3.72（T,J=10.8Hz, 2H）, 3.66（D,J=6.8Hz, 1H）, 3.62
（D,J=6.4Hz, 1H）, 2.11-2.13（M, 1H）, 1.97-2.10（M, 1H）.MS(m/z)：[M+H]+=204.20。
Embodiment 5
In 150ml round-bottomed flasks, by-a the 3.6g of compound 7 '（10.2mmol）, it is added to the THF solution of 2.7N hydrochloric acid
52ml（Volume ratio=3：10）In.Maintain the temperature at 60 °C of stirring 2-3 hours.Carry out after-a of TLC detection compounds 7 ' reactions completely
Post processing.After removing THF and part HCl under reduced pressure, under condition of ice bath, in this mixed solution saturated sodium bicarbonate is slowly added dropwise
Solution is adjusted to pH=5-6.Remove solvent under reduced pressure, obtain white solid.Product is extracted from this solid using methanol 50ml × 2 time
Product, merge methanol solution, remove solvent under reduced pressure, obtain compound 6-a crude product light yellow solids.This solid uses methanol/dichloro
Methane is recrystallized to give compound 6-a white solid 2.0g, and yield 62.8%, HPLC purity is more than 98%.1H NMR（400MHz,
DMSO）δ: 7.30-7.36（M, 5H）, 5.00（S, 2H）, 4.61-4.65（M, 1H）, 4.52-4.55（M, 1H）, 3.65-3.69
（M, 2H）, 3.52-3.55（M, 1H）, 3.46-3.48（M, 1H）, 3.43-3.45（T, 2H,J=6.8Hz）, 2.26-2.29（M,
1H）, 1.19-1.24（M, 1H）.MS(m/z)：[M+H]+=312.25。
Embodiment 6
In 50ml three neck round bottom flask, by compound 6-a 1.9g（6.1mmol）, N ', N ' and-carbonyl dimidazoles 2.1g
（12.9mmol）In being added to 30ml dichloromethane.1.5-2 hours are stirred at room temperature.The reaction of TLC detection compounds 6-a is completely laggard
Row post processing.Pour the hydrochloric acid solution 25ml × 2 time washing of 0.5N into in this reactant liquor.Divide liquid, dichloromethane is mutually using anhydrous
After sodium sulfate is dried, filter, remove solvent under reduced pressure, obtain compound 3-b product light yellow oils 2.3g, yield 90.0%,
HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）δ: 8.10（S, 1H）, 7.38-7.46（M, 6H）, 7.10（M, 1H）,
5.08（S, 2H）, 4.50-4.56（M, 1H）, 4.35-4.42（M, 1H）, 4.28-4.30（T, 2H,J=7.2Hz）, 4.11-4.18
（M, 1H）, 3.63-3.65（T, 2H,J=7.2Hz）, 3.43-3.46（M, 1H）, 2.12-2.16（M, 1H）, 1.60-1.63（M,
1H）.MS(m/z)：[M+H]+=432.25。
Embodiment 7
In 100ml three neck round bottom flask, by compound 3-b 4.3g（0.01mol）The THF for being added to 1.5N hydrochloric acid is molten
Liquid 30ml（Volume ratio=1：9）In.1.5-2 hours are stirred at room temperature.Post processing is carried out after the reaction completely of TLC detection compounds 3-b.
After removing THF and part HCl under reduced pressure, dichloromethane 30ml is added.Under condition of ice bath, it is slowly added dropwise in this mixed solution full
Adjust to pH=5-6 with sodium bicarbonate solution.Liquid, dichloromethane is divided mutually using after anhydrous sodium sulfate drying, to filter, remove under reduced pressure
Solvent, obtains compound 2-c ' product light yellow oils 3.1g, and yield 92.0%, HPLC purity is more than 98%.1H NMR
（400MHz, CDCl3）δ: 7.34-7.38（M, 5H）, 5.12（S, 2H）, 5.07（D,J=6.4Hz, 1H）, 5.03（D,J =
6.4Hz, 1H）, 4.13（D,J=6.8Hz, 1H）, 4.09（D,J=7.2Hz, 1H）, 3.72-3.75（M, 2H）, 3.59-3.65
（T,J=10.0Hz, 2H）, 2.10-2.12（M, 1H）, 1.97-2.04（M, 1H）.MS(m/z)：[M-H]-=336.05。
Embodiment 8
In 250ml three neck round bottom flask, by compound 6-a 3.8g（12.2mmol）, N ', N ' and-carbonyl dimidazoles 4.2g
（25.8mmol）In being added to 60ml dichloromethane.1.5-2 hours are stirred at room temperature.After the reaction completely of TLC detection compounds 6-a,
Pour the hydrochloric acid solution 100ml of 3.0N into in this reactant liquor.Temperature is risen to into 40 °C, continues to be stirred overnight.TCL detections are given birth to completely
Post processing is carried out during into compound 2-c '.Water is mutually adjusted to pH=5-6 using saturated sodium bicarbonate solution.Liquid, organic faciess is divided to make
Washed with water 30ml × 2 time.Organic faciess are filtered using after anhydrous sodium sulfate drying.Concentrating under reduced pressure organic faciess obtain chemical combination to dry
Thing 2-c ' product light yellow oils 6.0g, yield 89.0%, HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）Ibid.
The compound of embodiment 9 it is 2-in-1 into
In 250ml round-bottomed flasks, compound 2-c ' 2.0g are added（6mmol）, methanol 100ml, 10% Pd/C 0.
2g.Under stirring, hydrogen is passed through（0.1MPa）2 hours.TLC detection compounds 2-c ' post processing is carried out after reaction completely.Filter, filter
Liquid is evaporated off solvent and obtains crude product.By dissolving crude product in ethyl acetate, after organic faciess washing, using anhydrous sodium sulfate drying, mistake
Filter, removes solvent under reduced pressure, obtains the product white solid 1.0g of compound 2, yield 83.3%, HPLC purity is more than 99%.1H NMR
（400MHz, CDCl3）δ:5.08（D,J=6.8Hz, 1H）, 4.85（D,J=6.8Hz, 1H）, 3.73-3.74（M, 2H）, 3.69-
3.72（T,J=10.8Hz, 2H）, 3.66（D,J=6.8Hz, 1H）, 3.62（D,J=6.4Hz, 1H）, 2.11-2.13（M, 1H）,
1.97-2.10（M, 1H）.MS(m/z)：[M+H]+=204.20。
Embodiment 10 passes through intermediate（2）The method for preparing Ticagrelor
1）, compound 1-b ' preparation
、
By compound 1-a ' 402mg（1.5mmol）, the 335mg of compound 2（1.65mmol）In being dissolved in 15ml THF,
0-10 °C of stirring 2-3 hour is maintained the temperature at, water 20ml is then added.Extracted using ethyl acetate 15ml × 3 time.Organic faciess make
After anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure and obtain light yellow solid crude product.Tied again using ethyl acetate/petroleum ether
Crystalline substance obtains 1-b ' light yellow solid 332mg, and yield 51.0%, HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）δ：8.60
(b, 1H), 4.63-4.74 (m, 2H), 4.50-4.56 (m, 1H), 3.97（D,J=7.6Hz, 1H）, 3.68-3.84 (m, 3H),
3.63-3.66 (m, 1H), 3.04-3.21 (m, 2H), 2.30-2.34 (m, 1H), 1.92-1.95 (m, 1H), 1.74-1.81 (m,
2H), 1.09（T,J=7.6Hz, 3H）.MS(m/z)：[M+H]+=435.20。
2）, compound 1-c ' preparation
By compound 1-b ' 1.5g（3.5mmol）, iron powder 2.0g（35mmol）, glacial acetic acid 2.1g（35mmol）It is added to
Water/alcohol mixed solvent（1：1）In 20ml.Under nitrogen protection, 60-70 °C of stirring 30-60min is maintained the temperature at.TLC detectionizations
Post processing is carried out after compound 1-b ' reactions completely.Filter, filtrate is extracted using dichloromethane 20ml × 3 time.Organic faciess use nothing
Aqueous sodium persulfate is dried, and then decompression steams solvent and obtains compound 1-c ' crude products, directly carry out next step without being further purified
Reaction.MS(m/z)：[M+H]+=405.87。
3）The preparation of compound 1-d '
By compound 1-c ' crude product about 1.4g（3.5mmol）, glacial acetic acid 1.3g（21mmol）In being dissolved in 20ml toluene.
By sodium nitrite 0.27g（4.0mmol）In being dissolved in 2ml water, this solution is added in above-mentioned toluene solution.It is maintained at room temperature
20-30 °C of stirring 30-60min.Saturated sodium bicarbonate is added by solution, modulation pH value to 8-9.Filter, organic faciess use acetic acid
Ethyl ester 20ml × 3 time extract.Combined ethyl acetate phase, using anhydrous sodium sulfate drying, filters, and decompression steams solvent.Will concentration
Thing uses column chromatography（Silicagel column, eluent petroleum ether：Ethyl acetate=15：1）Compound 1-d ' white solids are obtained after separation
0.77g, yield 55.2%, HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）δ: 5.54（Q, 1H）, 5.22-5.24
(m, 1H), 4.88（D,J=6.8Hz, 1H）, 4.03-4.08 (m, 1H), 3.48-3.64 (m, 4H), 3.23（T,J=7.6Hz,
2H）, 2.66-2.70 (m, 1H), 2.54-2.57 (m, 1H), 1.80-1.88 (m, 2H), 1.10（T,J=7.6Hz, 3H）.MS
(m/z)：[M+H]+=416.59。
4）, compound 1-e ' preparation
By compound 1-d ' 830mg（2.0mmol）,（1R, 2S）-2-（3,4）- difluorophenyl cyclopropylamine 338mg
（2.0mmol）, DIPEA 322mg（2.5mmol）In being dissolved in dichloromethane 15ml.It is maintained at room temperature 20-
30 °C of stirring 15-20 hours.TLC detection reaction 1-d ' carry out post processing after finishing.15ml water is added, is divided after stirring 10-25min
Liquid.Organic faciess are separated, water is mutually extracted using dichloromethane 15ml × 2 time.Combined dichloromethane phase, it is dry using anhydrous sodium sulfate
It is dry, to filter, decompression steams solvent.Crude product obtains compound 1-e ' white solids using recrystallization from ethyl acetate/petroleum ether
1.04g, yield 98%, HPLC purity is more than 98%.1H NMR（400MHz, CDCl3）δ:7.06-7.13 (m, 3H), 5.99 (q,
1H), 5.28-5.35（M, 1H）, 4.24-4.25（M, 1H）, 4.22-4.23（M, 1H）, 3.55-3.78（M, 4H）, 3.07-3.10
（M, 2H）, 3.03-3.05（M, 1H）, 2.98-2.99（M, 1H）, 2.16-2.32（M, 1H）, 2.14-2.15（M, 1H）, 1.68-
1.74（M, 2H）, 1.64-1.66（M, 2H）, 0.95（T,J=14.8Hz 3H）.MS(m/z)：[M+H]+=549.00, [M-H]-=
547.00。
5）The preparation of Ticagrelor
By sodium hydroxide 0.88g（22mmol）In being dissolved in 20ml water.By compound 1-e ' 0.6g（1.1mmol）It is dissolved in
In 15ml Isosorbide-5-Nitraes-dioxane, during above-mentioned sodium hydroxide solution is slowly added dropwise under ice bath.Room temperature is slowly increased to after completion of dropping
20-30 °C, continue to stir 2-3 hours.TLC detection compounds 1-e ' post processing is carried out after completion of the reaction.It is slowly added dropwise saturation chlorine
Change aqueous ammonium, pH value is modulated into 7-8.Reactant liquor is extracted using ethyl acetate 20ml × 3 time.Combined ethyl acetate phase, uses
Anhydrous sodium sulfate drying, filters, and decompression steams solvent.Crude product uses column chromatography（Silicagel column, eluant dichloromethane：Methanol=
100:1 to 50:1 gradient elution）Compound 1 is obtained after separation（Ticagrelor）White solid 0.48g, yield 85.2%,
HPLC purity is more than 99%.1H NMR（400MHz, CD3OD）δ:7.06-7.23 (m, 3H), 5.12 (q, 1H), 4.73-4.77（M,
1H）, 4.16-4.18（M, 1H）, 3.89-3.93（M, 1H）, 3.60-3.71（M, 4H）, 3.04-3.31（M, 2H）, 2.89-2.93
（M, 1H）, 2.73-2.80（M, 1H）, 2.19-2.26（M, 1H）, 2.10-2.18（M, 1H）, 1.58-1.64（M, 2H）, 1.45-
1.48（M, 1H）, 1.36-1.39（M, 1H）, 0.93（T,J=14.8Hz, 3H）. MS(m/z)：[M+H]+=523.00。
Claims (10)
1. the synthetic method of the compound shown in a kind of formula (2),
Including：
By the compound shown in formula (3)：
Slough the compound shown in protection group acquisition formula (2)：
Described P1It is amino protecting group；Described P is H or hydroxyl protecting group.
2. method according to claim 1, it is characterised in that described P1It is benzyloxycarbonyl group；Described P is H, or benzyl
Or imidazoles carbonyl.
3. method according to claim 1, it is characterised in that the compound shown in described formula (3) is by by formula (4)
Shown compound：
Carry out the cyclic carbonate ester protection acquisition of vicinal diamines.
4. method according to claim 3, it is characterised in that the compound shown in described formula (4) is by by formula (5)
Shown compound：
What de- isopropylidene protection was obtained；
Or by by the compound shown in formula (6)：
Carry out hydroxyl protection acquisition.
5. method according to claim 4, it is characterised in that the compound shown in described formula (5), is by formula (7)
Shown compound：
With the compound shown in formula (8)：
What reaction was obtained；
Or, the compound shown in described formula (5) is by the compound shown in formula (7 ')：
With the compound shown in formula (8 ')：
X-P
(8’)
What reaction was prepared；
Described X is halogen.
6. method according to claim 5, it is characterised in that the compound shown in described formula (6), is by formula (7 ')
Shown compound：
Slough what isopropylidene protection was obtained.
7. the synthetic method of the compound shown in a kind of formula (2),
Including：
1) compound shown in formula (7-a) and the iodo- 2- benzyloxies ethane reactions of 1- are prepared the chemical combination shown in formula (5-a)
Thing, or the compound shown in (7 '-a) and benzyl bromine reaction prepare the compound shown in formula (5-a)：
2) the de- isopropylidene protection of compound shown in formula (5-a) is prepared the compound shown in formula (4-a)：
3) the cyclic carbonate ester protection that the compound shown in formula (4-a) carries out vicinal diamines is prepared the chemical combination shown in formula (3-a)
Thing：
4) compound shown in formula (3-a) is carried out into amino and hydroxyl deprotection prepares compound shown in formula (2)：
。
8. the synthetic method of the compound shown in a kind of formula (2),
Including：
Compound shown in formula (6-a) is carried out into the cyclic carbonate ester protection of vicinal diamines, the compound shown in formula (2-c ') is obtained：
Compound shown in formula (2-c ') is carried out into amino deprotection and prepares compound shown in formula (2)：
。
9. the synthetic method of the compound shown in a kind of formula (2),
Including：
1) the de- isopropylidene protection of compound shown in formula (7 '-a) is prepared the compound shown in formula (6-a)：
2) compound shown in formula (6-a) is carried out cyclic carbonate ester protection and the hydroxyl protection of vicinal diamines, formula (3-b) is prepared
Shown compound：
3) compound shown in formula (3-b) is carried out into hydroxyl deprotection and prepares compound shown in formula (2-c ')：
4) compound shown in formula (2-c ') is carried out into amino deprotection and prepares compound shown in formula (2)：
。
10. a kind of compound being shown below：
。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128801C (en) * | 1998-12-04 | 2003-11-26 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2012139455A1 (en) * | 2011-04-15 | 2012-10-18 | 博瑞生物医药技术(苏州)有限公司 | Intermediates of ticagrelor and method for preparing ticagrelor |
-
2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128801C (en) * | 1998-12-04 | 2003-11-26 | 阿斯特拉曾尼卡有限公司 | Triazolo (4,5-D) pyrimidine compounds |
| CN102149716A (en) * | 2008-09-09 | 2011-08-10 | 阿斯利康(瑞典)有限公司 | Process for the preparation of [1S-[1α,2α,3β (1S*, 2R*), 5β]]-3-[7-[2-(3, 4-difluorophenyl)-cyclopropylamino]-5-(propylthio)-3H-1,2, 3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1, 2-diol and intermediates thereof |
| WO2012139455A1 (en) * | 2011-04-15 | 2012-10-18 | 博瑞生物医药技术(苏州)有限公司 | Intermediates of ticagrelor and method for preparing ticagrelor |
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