CN108658989A - The preparation method and application of cangrelor intermediate - Google Patents
The preparation method and application of cangrelor intermediate Download PDFInfo
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- CN108658989A CN108658989A CN201710189979.5A CN201710189979A CN108658989A CN 108658989 A CN108658989 A CN 108658989A CN 201710189979 A CN201710189979 A CN 201710189979A CN 108658989 A CN108658989 A CN 108658989A
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/24—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one nitrogen and one sulfur atom
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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Abstract
The invention discloses a kind of preparation method and application of cangrelor intermediate.The intermediate includes 2 chlorine N (2 (methyl mercapto) ethyl) 7H purine, 6 amine, is obtained by the reaction using 2,6 dichloropurines and 2 methyl mercapto ethamine.In addition, further including 6 N (2 (methyl mercapto) ethyl) 2 ((3,3 among the cangrelor, 3 trifluoro propyls) thio) 9H purine, and using 2 chlorine N (2 (methyl mercapto) ethyl) 7H purine, 6 amine and 3,3,3 trifluoro propyl isothiourea halogen acid salts of S, S 3,3,3 trifluoro propyl isothioureas, 3,3,3 trifluoro propyl, 1 mercaptan or 3,3,3 trifluoro propyl, 1 mercaptan alkali metal salt is obtained by the reaction.The technology path of the present invention is simple and practicable, and raw material sources are extensive, and mild condition, production cost is low, and high income is environmental-friendly, and more effective synthetic method is provided for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, more particularly, to the preparation method and application of cangrelor intermediate.
Background technology
Cangrelor is a kind of intravenous injection P2Y12 inhibitor, and it is sharp that it blocks adenosine diphosphate (ADP) (ADP)-to induce blood platelet
It lives and gathers, chemical constitution is similar to atriphos (ATP).It is the anti-platelet aggregation medicine of first intravenously administrable, is used for
Prevent adult patients during percutaneous coronary intervention (pci) (PCI), because of coronary artery blockage caused by blood coagulation, can have
Effect reduces the risk of myocardial infarction and thrombus in stents.On June 22nd, 2015, cangrelor was ratified to list through U.S. FDA, authorized
The Medicines Company exploitations, preparation specification are 50mg freeze drying powder injections, trade name KENGREALTM。
The chemical name of cangrelor:N6- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyls) is thio] -5 '-glands
Thuja acid, with dichloromethylene diphosphonic acid single acid anhydride (N6- [2- (methylthio) ethyl] -2- [(3,3,3,
Trifluoropropyl)] -5 '-adenylicacid, monanhydride with (dichloromethylene)
Bisphosphonic acid) tetrasodium salt.Empirical formula is C17H21N5Cl2F3Na4O12P3S2 and molecular weight is 864.3g/
mol.Chemical structural formula is as follows, is indicated with Formulas I.
The preparation method of cangrelor is reported seldom on document and patent, and development company (Medicines companies) exists
(J.Med.Chem.1999,42,213-220) uses 2- sulfydryls adenosine for starting material in document, and preparation can refer to document
The preparation method of Chem.Pharm.Bull.25 (8) 1959-1969 (1977), is shown in synthetic route 1.Another method is with thio
Barbiturates is starting material, is carried out in the key that the interminable response path of seven steps (CN105061431) just obtains cangrelor
Mesosome formula IV is shown in synthetic route 2.The source for the starting material that synthetic route 1 uses is rare, expensive, is needed when oneself is synthesized
The carbon disulfide and compressive reaction of severe toxicity are used, and has the hydrogen sulfide of severe toxicity to generate, producers and environment are caused
Injury, amplification production is difficult, is not suitable for industrialized production.Synthetic route 2 is tediously long, and total recovery is low, needs to use Raney's nickel hydrogenation
Reaction under high pressure and iodomethane, are equally not suitable for industrialized production.
Synthetic route 1:
Synthetic route 2:
In addition, in terms of purifying, the prior art such as WO9418216A1 (US5721219A) and document
(J.Med.Chem.1999,42, p213) obtain ammonium salts is further converted to sodium with sodium iodide or sodium bicarbonate mostly
Salt form needs three steps as shown in front synthetic route 1 from such as Formula IX compound represented to from compound shown in formula I
It reacts and yield only has 4%.
(see purification circuit 1) in patent CN1613864A, although purification prepares yield and improves 6 times than above-identified patent,
But ion exchange resin separating-purifying, complex steps twice are needed, and will produce a large amount of eluent and cause concentration difficult,
Cost improve, and obtained ammonium salts must be further converted to sodium iodide or sodium bicarbonate it is shown in formula I
Compound.
Purification circuit 1:
In addition in patent CN105061431A, although being detached using a DEAE-Sephadex A25 ion exchange resin
Purifying, yield are also significantly improved to 54%, but the ammonium salts of gained must further with sodium iodide or sodium bicarbonate
Be converted to compound shown in formula I.
Invention content
In view of the deficiencies of the prior art, the present inventors' research obtains a kind of side of synthesis such as formula IV compound represented
Method includes the following steps:
Step 1: preparing such as formula III compound represented;
Step 2: preparing such as formula IV compound represented by such as formula III compound represented;
Further, step 1 is used such as Formula II compound represented (2,6- dichloropurine) and chemical combination shown as a formula V
Object (2- (methyl mercapto) ethamine) is obtained by the reaction such as formula III compound represented;
Further, step 1 is specially:By such as Formula II compound represented, compound shown as a formula V, proton solvent
It reacts, obtains such as formula III compound represented at 30 DEG C~120 DEG C with alkali.Alkali in the step 1 be selected from sodium hydroxide,
Potassium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N- methyl piperidines and N-methylmorpholine or combinations thereof object, it is excellent
It is selected as triethylamine or potassium carbonate.The proton solvent be selected from methanol, ethyl alcohol, isopropanol, n-butanol, 2- butanol and the tert-butyl alcohol or its
Composition, preferably ethyl alcohol and n-butanol.
Further, step 1 is specially:Such as Formula II compound represented, chemical combination shown as a formula V are added in reaction bulb
Object, ethyl alcohol and triethylamine, after being warming up to 110 DEG C~120 DEG C, atmospheric pressure reflux is cooled to room temperature, filter is obtained by filtration to completion is reacted
Cake, the filter cake are stirred with saturated sodium bicarbonate solution, and filtering is washed with water, obtains such as formula III compound represented.
Further, step 2 use as formula III compound represented with such as -1 compound represented of Formula IV, or with such as
- 2 compound represented of Formula IV, it is either anti-with such as -1 compound represented of Formula VII or with such as -2 compound represented of Formula VII
It should obtain such as formula IV compound represented;In chemical formula, X indicates halogen;M indicates metallic element;
Further, M indicates alkali metal.
Further, M indicates Na, K or Li.
Further, X indicates Cl, Br or I.
Further, the reaction in the step 2 carries out in the presence of base.Alkali in the step 2 is selected from hydrogen-oxygen
Change sodium, potassium hydroxide, cesium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N- methyl piperidines and N-methylmorpholine
Or combinations thereof object.Reaction dissolvent in the step 2 is proton solvent or aprotic solvent.Proton solvent is selected from methanol, second
Alcohol, normal propyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol and water or combinations thereof object.Aprotic solvent is selected from tetrahydrofuran, acetonitrile, dioxy
Six rings, n,N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, n,N-dimethylacetamide (DMA) and N- methyl
Pyrrolidones or combinations thereof object.The reaction temperature of the step 2 is 40 DEG C~150 DEG C.
The invention also discloses a kind of methods of synthesis such as Formula IX compound represented, including are synthesized as described above such as formula
The method of IV compounds represented;
Further, further comprising the steps of:
Step 3: being prepared as shown in Formula VIII by such as formula IV compound represented and such as Formula XI compound represented condensation
Compound;
Step 4: obtaining the chemical combination as shown in Formula IX by such as Formula VIII compound represented hydrolysis deacetylation protecting group
Object;
Wherein, R1Indicate Ac or Bz;R2Indicate Ac or Bz.
Further, step 3 is specially:It will be first added to such as formula IV compound represented in solution one, then N is added dropwise, O-
Double trimethylsilyl acetamides, are then added dropwise Trimethylsilyl trifluoromethanesulfonate, are then added dropwise and are dissolved in the 1 of the solution one, 2,3,
Tetra- acetyl-β of 5--D-RIBOSE, reaction, obtain such as Formula VIII compound represented;The solution one is selected from acetonitrile, DMF, two
Ethyl Methyl Ether (DME), DMA, toluene, tetrahydrofuran, acetone and DMAc or combinations thereof object.Further, step 3 is specially:
It will be added in solution two such as formula IV compound represented and 1,2,3,5- tetra- acetyl-β-D-RIBOSE under nitrogen protection,
Butter of tin is added, reacts, obtains such as Formula VIII compound represented;The solution two be selected from acetonitrile, DMF, DME, DMA,
Toluene and tetrahydrofuran or combinations thereof object.
Further, step 4 is specially:It will be dissolved in ammonia water-methanol solution, hydrolyze such as Formula VIII compound represented
Deacetylation protecting group is obtained such as Formula IX compound represented.
The invention also discloses such as formula IV compounds represented in synthesis such as Formula IX compound represented and/or cangrelor
In application, i.e., if formula IV compound represented is that method as described above obtains.
Invention also discloses application of such as Formula IX compound represented in synthesizing cangrelor, i.e., described such as Formula IX
Compound represented is that method as described above obtains.
The invention further relates to a kind of synthetic methods of cangrelor, including synthesize the chemical combination as shown in Formula IX as described above
The method of object, and further include:Step 5: as Formula IX compound represented and phosphorus oxychloride and chlorine bend mono phosphoric acid ester tri-n-butylamine salt
Reaction, after processing is quenched in alkalescent sodium salt, purifying obtains cangrelor.
Further, the alkalescent sodium salt in step 5 is selected from sodium bicarbonate, sodium carbonate, sodium acetate, sodium citrate, phosphoric acid
Sodium and dibastic sodium phosphate.
Further, mono phosphoric acid ester tri-n-butylamine salt is bent such as Formula IX compound represented and phosphorus oxychloride and chlorine in step 5
- 20 DEG C of reaction temperature~0 DEG C of reaction.Preferably -10 DEG C.
Further, step 5 is specially:It will be added in phosphate such as Formula IX compound represented and proton sponge, it is cooling
To -20 DEG C~0 DEG C dropwise addition phosphorus oxychloride, after the consumption of such as Formula IX compound represented, chlorine is added and bends mono phosphoric acid ester tri-n-butylamine salt
And tri-n-butylamine, -20 DEG C~0 DEG C is stirred 2~10 hours, reaction, and after processing is quenched in alkalescent sodium salt, purifying obtains Kan Ge
Lei Luo.
In a specific embodiment, proton sponge is the bis- dimethylamino naphthalenes of 1,8- in step 5;As shown in Formula IX
The bis- dimethylamino naphthalenes of compound, 1,8-, phosphorus oxychloride, chlorine bend mono phosphoric acid ester tri-n-butylamine salt, the molar ratio of tri-n-butylamine is 1:(1~
3):(2~6):(3~8):(3~8).
In another embodiment, phosphoric acid will be added such as Formula IX compound represented and proton sponge in step 5
In ester so that such as a concentration of 0.1-0.2M of the Formula IX compound represented in phosphate ester solvent;Reaction substrate chlorine bends mono phosphoric acid ester
Tri-n-butylamine salt and tri-n-butylamine are first dissolved in anhydrous n,N-Dimethylformamide, and concentration is respectively 1-2M and 1.5-3M, so
After be then added in reaction system and reacted.
Further, the purifying in step 5 is isolated and purified with reversed-phase resin purification.
Further, the purifying in step 5 is to carry out gradient purification with reversed-phase resin, and eluant, eluent is the 2- third of 1-15%
Alcohol solution obtains cangrelor.Preferably, reversed-phase resin AberchromTM。
Further, water phase is isolated after processing is quenched in alkalescent sodium salt in step 5, is precipitated in water phase with solution three
Solid, obtain sediment, purify the sediment, obtain cangrelor;The solution three be selected from dichloromethane, methyl ethyl ketone,
Acetone, ether, butyl methyl ether, chloroform, methanol, ethyl alcohol, tetrahydrofuran and butanone or combinations thereof object.
Further, being quenched in step 5 and purifying be:It will be bent with phosphorus oxychloride and chlorine such as Formula IX compound represented
The product of mono phosphoric acid ester tri-n-butylamine reactant salt is poured slowly into alkalescent sodium-salt aqueous solution, and 2~18 are stirred at 15 DEG C~60 DEG C
Hour, each phase of standing separation;Water phase is added in the solution three, sediment is obtained;The sediment is collected, reverse phase is passed through
Chromatography, the 2- aqueous propanol solutions or similar polar solution that eluant, eluent is 2~8%, collects pure component, obtains Kan Ge
Lei Luo.
Further, being quenched in step 5 and purifying be specially:Will such as Formula IX compound represented and phosphorus oxychloride and
The product that chlorine bends mono phosphoric acid ester tri-n-butylamine reactant salt is poured slowly into alkalescent sodium-salt aqueous solution, and 2 are stirred at 15 DEG C~50 DEG C
~18 hours, each phase of standing separation was used in combination alkalescent sodium-salt aqueous solution to wash upper organic phase;It is slowly added into after merging water phase
In the solution three, sediment is obtained;The sediment is collected by filtration, with drying after three filter wash cake of the solution, is then led to
Reverse-phase chromatography column purification, gradient elution are crossed, eluant, eluent is the 2- aqueous propanol solutions of 1-15%, collects pure component, dry, obtains bank
Gray Lip river.Preferably, the 2- aqueous propanol solutions that eluant, eluent is 2~8%.Preferably, using passing through reversed color after vacuum drying again
Compose column purification.
The invention further relates to a kind of synthetic methods of cangrelor, i.e., using if formula III compound represented is as bank lattice
Thunder Lip river intermediate;
A kind of synthetic method of cangrelor in the present invention, using alkalescent sodium salt to such as Formula IX compound represented with
Phosphorus oxychloride and chlorine bend the product that mono phosphoric acid ester tri-n-butylamine reactant salt obtains and carry out that processing is quenched, and purify, obtain cangrelor;
Further, alkalescent sodium salt is selected from sodium bicarbonate.
Further, it is quenched that treated to described product isolates water phase, consolidating in the water phase is precipitated with solution three
Body obtains sediment, purifies the sediment, obtains cangrelor;The solution three be selected from dichloromethane, methyl ethyl ketone, acetone,
Ether, butyl methyl ether and chloroform.
Further, the purifying is to be purified using reversed-phase resin.
Further, gradient purification is carried out using reversed-phase resin, eluant, eluent is the 2- aqueous propanol solutions of 1-15%.It is preferred that
Ground, reversed-phase resin AberchromTM Or other similar typesReversed-phase resin.
A kind of purification process of cangrelor in the present invention is purified to obtain cangrelor using reversed-phase resin.
Further, gradient purification is carried out using reversed-phase resin, eluant, eluent is the 2- aqueous propanol solutions of 1-15%, obtains bank
Gray Lip river.
The present invention provides the new method that a kind of purification prepares cangrelor, to solve to utilize anion exchange in the prior art
Separating-purifying produces twice for resin, the weak-base anion-exchange resins such as DEAE-Sephadex A25 or anion-cation exchange resin
The low defect of rate.It is characterized in that the production technology includes the following steps:1.6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3-
Trifluoro propyl) thio) adenosine (Formula IX), with three one pot of n-butyl (Formula X) of phosphorus oxychloride and (dichloromethylene) diphosphonic acid
Method is condensed to obtain cangrelor crude reaction solution;2. carrying out being completely separated purifying with reversed-phase resin gradient purification and directly obtaining purification
Cangrelor (Formulas I) tetrasodium salt form.
Above-mentioned synthetic schemes is the preparation method for listing part of compounds in the present invention, according to the known skill of this field
Art, technical staff can also synthesize the compound of the present invention on the basis of above-mentioned synthetic schemes, using similar method.
" compound " of the present invention, including all stereoisomers, geometric isomer, tautomer and same position
Element.
" compound " of the present invention can be asymmetric, for example, with one or more stereoisomers.It removes
Non- to be otherwise noted, all stereoisomers all include, such as enantiomter and diastereoisomer.Contain asymmetry in the present invention
The compound of carbon atom, can be in the form of optical activity be pure or racemic form is separated;The pure form of optical activity can
To be synthesized from racemic mixture, or by using chiral raw material or chiral reagent.
" compound " of the present invention, further includes tautomeric forms;Tautomeric forms derive from a list
Key exchanges with adjacent double bond and together with the migration of a proton.
The invention also includes the atoms of all isotopes, either in intermediate or last compound;The original of isotope
Attached bag includes atomicity having the same but different quality number, for example, the isotope of hydrogen includes deuterium and tritium.
The synthetic technology route and purification technique that the present invention uses are simple and practicable, and raw material sources are extensive, mild condition, production
At low cost, high income is environmental-friendly, and available purity is higher than 98%, and more effective synthesis side is provided for industrialized production
Method.
Description of the drawings
Fig. 1 is the synthetic route chart of cangrelor.
Fig. 2 is that the hydrogen of Formula IX compound represented such as is composed.
Fig. 3 is cangrelor1H NMR and31P H NMR spectroscopies.
Specific implementation mode
The present invention will be further described with specific embodiment below in conjunction with the accompanying drawings, and of the invention protects content not limit to
In following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that variation and excellent
Point is all included in the present invention, and using appended claims as protection domain.Implement the present invention process, condition,
Reagent, experimental method etc. are among the general principles and common general knowledge in the art, this hair in addition to the following content specially referred to
It is bright that content is not particularly limited.
Fig. 1 shows the synthetic route of cangrelor in the specific embodiment of the present invention.In this embodiment,
Including:
Step 1: using such as Formula II compound represented (2,6- dichloropurines) and compound (2- (first shown as a formula V
Sulfenyl) ethamine) it is obtained by the reaction such as formula III compound represented (the chloro- N- of 2- (2- (methyl mercapto) ethyl) -7H- purine -6- amine).
Step 2: using as formula III compound represented with such as -2 compound represented of Formula IV, or with such as Formula VII -2
Compound represented is obtained by the reaction such as formula IV compound represented (6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoropropyls
Base) thio) -9H- purine).As the M in -2 compound represented of Formula VII indicates alkali metal, such as Na, K or Li.Such as Formula IV -2
X in compound represented indicates halogen, such as Cl, Br or I.
Step 3: being prepared as shown in Formula VIII by such as formula IV compound represented and such as Formula XI compound represented condensation
Compound.R in chemical formula1Indicate Ac or Bz;R2Indicate Ac or Bz.
Step 4: in the presence of a base, being obtained such as Formula IX by such as Formula VIII compound represented hydrolysis deacetylation protecting group
Compound represented.
Step 5:
Step 5.1, such as Formula IX compound represented and phosphorus oxychloride reaction are obtained such as Formula XII compound represented;
Step 5.2, such as Formula XII compound represented and compound represented by a formula X (chlorine bends mono phosphoric acid ester tri-n-butylamine salt)
Reaction, is then quenched processing through alkalescent sodium salt;
Step 5.3 purifies with reversed-phase resin step 5.2 product that is quenched that treated to obtain compound shown in formula I
(cangrelor).
Embodiment 1:The chloro- N- of 2- (2- (methyl mercapto) ethyl) -7H- purine -6- amine (2-chloro-N- (2-
(methylthio) ethyl) -7H-purin-6-amine, for such as formula III compound represented) synthesis
In 100 milliliters of flasks, 2- (methyl mercapto) ethamine (6.8 grams, 57.5 mMs, 1.2 equivalents), butanol (50 is added
Milliliter), triethylamine (11.6 grams, 115 mMs, 2 equivalents) and 2,6- dichloropurines (8.96 grams, 48 mMs, 1 equivalent).Add
Hot mixt to 100 DEG C stir 6 hours.White filter cake is obtained by filtration to room temperature in cooling mixture.150 millis are added in this filter cake
It rises saturated sodium bicarbonate solution to stir 30 minutes, filtering, filter cake is washed with water (100 milliliters).Vacuum dry filter cake obtains 10.9 grams
Product, i.e., such as formula III compound represented.Yield 93%, HPLC purity 96%.
Such as the hydrogen modal data of formula III compound represented:1H NMR(300MHz,D6-DMSO)δ12.93(s,1H),8.17
(s, 1H), 8.12 (s, 1H), 3.62 (dd, J=13.4,6.4Hz, 2H), 2.7 (q, 2H), 2.1 (s, 3H).
Embodiment 2:The conjunction of the chloro- N- of 2- (2- (methyl mercapto) ethyl) -7H- purine -6- amine (such as formula III compound represented)
At
In 250 milliliters of flasks, 2- (methyl mercapto) ethamine (21 grams, 230 mMs, 1.5 equivalents), ethyl alcohol (50 millis are added
Rise), triethylamine (39 grams, 389 mMs, 2.5 equivalents) and 2,6- dichloropurines (29 grams, 150 mMs, 1 equivalent).Heating is mixed
Close object to 100 DEG C stir 6 hours.Cooling mixture adds 200ml water to continue stirring 30 minutes to room temperature.White filter is obtained by filtration
Cake.400 milliliters of saturated sodium bicarbonate solutions are added in this filter cake to stir 30 minutes, filtering, filter cake is washed with water (150 milliliters).Very
Empty dry cake obtains 28.4 grams of products, i.e., such as formula III compound represented.Yield 78%, HPLC purity 97%.
Embodiment 3:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (0.243 gram, 1 equivalent, 1 mM), isothiuronium salts compound is (such as -2 institute of Formula IV
The compound shown, 0.45 gram, 1.5 equivalents, 1.5 mMs) and sodium hydroxide (120 milligrams, 3 equivalents, 3 mMs) be dissolved in 2
In the dry DMF of milliliter, it is heated to 100 DEG C and stirs 3 days.Unreacted is complete, adds isothiuronium salts compound (such as -2 institute of Formula IV
The compound shown, 0.3 gram, 1 equivalent, 1 mM) and NaOH (0.08 milligram, 2 equivalents, 2 mMs) continue to be heated to 115 DEG C
Reaction 24 hours.The process of the reaction is monitored by HPLC, and reactant is cooled to room temperature, and water (6 milliliters) is added.By mixture
Stir 30 minutes formed light yellow precipitates.The solid is by isolated by vacuum filtration, and filtrate abandons.Filter cake is with water (20ml)
It washes.Vacuum drying obtain pure product (0.250 gram, 77% yield;HPLC purity 98.5%), i.e. the chemical combination as shown in formula IV
Object.
Such as the hydrogen modal data of formula IV compound represented:1H NMR(300MHz,D6-DMSO)δ12.82(s,1H),7.98
(s, 1H), 7.89 (s, 1H), 3.63 (dd, J=13.4,6.4Hz, 2H), 3.24 (dd, J=9.9,5.6Hz, 2H), 2.80-
2.59(m,4H),2.09(s,3H).
Embodiment 4:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (0.6 gram, 1 equivalent, 2.48 mMs), isothiuronium salts compound is (such as -2 institute of Formula IV
The compound shown, 2.23 grams, 3 equivalents, 7.45 mMs) and CsOH (2.23 milligrams, 6 equivalents, 14.9 mMs) be dissolved in 6 millis
It rises in dry DMF, is heated to 115 DEG C and stirs 2 days.Unreacted is complete, adds isothiuronium salts compound (as shown in Formula IV -2
Compound, 0.75 gram, 1 equivalent, 2.48 mMs) and CsOH (0.75 milligram, 2 equivalents, 4.96 mMs) continue to be heated to
115 DEG C are reacted 24 hours.The process of the reaction is monitored by HPLC, and the reaction was complete.Reactant is cooled to room temperature, water is added
(60 milliliters).Stir the mixture for 30 minutes formed light yellow precipitates.The solid is by isolated by vacuum filtration, and filtrate is lost
It abandons.Filter cake is washed with water (20ml).Vacuum drying obtains pure product (0.668 gram, 80% yield).Mother liquor concentrations column chromatography point
From 0.111 gram of product is obtained, i.e., such as formula IV compound represented.Merge yield 92% (0.779 gram) HPLC purity 99%.
Embodiment 5:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (2 grams, 1 equivalent, 8.23 mMs), 3,3,3- trifluoro propane -1- sodium mercaptides are (such as
- 2 compound represented of Formula VII, M Na, 1.5 grams, 1.2 equivalents, 9.9 mMs) and cesium carbonate (2.67 grams, 1 equivalent, 8.23
MM) be dissolved in 10 milliliters of dry DMF, it is heated to 100 DEG C and stirs 8 hours.The process of the reaction is monitored by HPLC,
The reaction was complete.Reactant is cooled to room temperature, water (40 milliliters) is added.Stir the mixture for 30 minutes formed pale yellow precipitates
Object.The solid is by isolated by vacuum filtration, and filtrate abandons.Filter cake is washed with water (20ml).Obtained product is dried in vacuo to use
The isolated 0.9 gram of product of silicagel column.Yield 27%.
Embodiment 6:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (0.486 gram, 1 equivalent, 2 mMs), 3,3,3- trifluoro propane -1- mercaptan are (such as formula
VII-1 compounds represented, 0.583 gram, 1.2 equivalents, 2.4 mMs) and sodium hydroxide (240 milligrams, 3 equivalents, 6 mMs)
It is dissolved in 2 milliliters of dry DMF, is heated to 100 DEG C and stirs 8 hours.The process of the reaction is monitored by HPLC, has been reacted
Entirely.Reactant is cooled to room temperature, water (40 milliliters) is added.Stir the mixture for 30 minutes formed light yellow precipitates.It should
Solid is by isolated by vacuum filtration, and filtrate abandons.Filter cake is washed with water (20ml).It is dried in vacuo obtained product and uses silicagel column
Isolated 0.28 gram of product.Yield 41%.
Embodiment 7:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (1.2 grams, 1 equivalent, 4.96 mMs), isothiourea compounds are (as shown in Formula IV -1
Compound, 2.56 grams, 3 equivalents, 14.9 mMs) and potassium hydroxide (1.67 grams, 6 equivalents, 29.8 mMs) be dissolved in 10
In the dry DMSO of milliliter, it is heated to 115 DEG C and stirs 2 days.Unreacted is complete, adds isothiourea compounds (such as -2 institute of Formula IV
The compound shown, 0.85 gram, 1 equivalent, 4.96 mMs) and potassium hydroxide (834 milligrams, 3 equivalents, 14.9 mMs) continue plus
Heat to 115 DEG C react 24 hours.The process of the reaction is monitored by HPLC, and the reaction was complete.Reactant is cooled to room temperature, is added
Water (100 milliliters).Stir the mixture for 30 minutes formed light yellow precipitates.The solid is filtered by isolated by vacuum filtration
Liquid abandons.Filter cake is washed with water (30ml).Vacuum drying obtains pure product (0.56 gram, 73% yield, HPLC purity 98.7%).
Embodiment 8:6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) is thio) -9H- purine (such as formula IVs
Compound represented) synthesis
Such as formula III compound represented (0.6 gram, 1 equivalent, 2.48 mMs), isothiuronium salts compound is (such as -2 institute of Formula IV
The compound shown, 2.23 grams, 3 equivalents, 7.45 mMs) and potassium hydroxide (834 milligrams, 6 equivalents, 14.9 mMs) be dissolved in
In 6 milliliters of dry DMSO, it is heated to 115 DEG C and stirs 2 days.Unreacted is complete, adds isothiuronium salts compound (such as Formula IV -2
Compound represented, 0.75 gram, 1 equivalent, 2.48 mMs) and (417 milligrams, 3 equivalents, 7.5 mMs) continuation of potassium hydroxide
115 DEG C are heated to react 24 hours.The process of the reaction is monitored by HPLC, and the reaction was complete.Reactant is cooled to room temperature, is added
Enter water (60 milliliters).Stir the mixture for 30 minutes formed light yellow precipitates.The solid is filtered by isolated by vacuum filtration
Liquid abandons.Filter cake is washed with water (20ml).Vacuum drying obtains pure product (0.56 gram, 67% yield).
Embodiment 9:O, O, O- triacetyl -6-N- (2- (methyl mercapto) ethyl) -2- ((3,3,3- trifluoro propyls) thio glands
Glycosides (such as Formula VIII compound represented, R1=Ac, R2=Ac) synthesis
At room temperature, it will be added in 200mL acetonitriles such as formula IV compound represented 19.38g (60mmol), system is in suspended
State, by N, the bis- trimethylsilyl acetamides (BSA) (19.62 grams, 96mmol, 1.6eq.) of O- are added dropwise to mixture, add at room temperature
Heat stirs 1 hour, system gradually becomes clarification to 60 DEG C.Mixture is down to room temperature, Trimethylsilyl trifluoromethanesulfonate
(TMSOTF) (15.98 grams, 72mmol, 1.6eq.) are added drop-wise in system, 30min are stirred, by 1,2,3,5- tetra- acetyl-β-D- furans
Mutter ribose (such as Formula XI compound represented, R1=Ac, R2=Ac, 22.9g, 72mmol, 1.2eq.) it is dissolved in 200mL acetonitriles, it drips
It is added in reaction system, is warming up to 60 DEG C and reacts 6 hours, HPLC monitorings raw material fundamental reaction finishes, and stops reaction, is down to room
Temperature is concentrated to dryness.400mL ethyl acetate, dissolving are added into system.Organic phase uses saturated sodium bicarbonate and saturated common salt successively
Water respectively washing 2 times, dry, 50 DEG C of vacuum are spin-dried for, and obtain 42g grease, i.e. O, O, O- triacetyls -6-N- (2- (methyl mercapto) second
Base) ((3,3,3- trifluoro propyl) thio adenosine, product does not have to separation directly to carry out in next step -2-, therefore for as shown in Formula VIII
Compound (R1=Ac, R2=Ac) crude product.
Embodiment 10:Such as the synthesis of Formula IX compound represented
At room temperature, by embodiment 9 obtain such as Formula VIII compound represented (R1=Ac, R2=Ac) crude product
(60mmol) is dissolved in sodium hydroxide-ethanol solution of a concentration of 0.1mol/L of 600mL, is stirred to react 30min, and TLC monitorings are former
Material reaction finishes, and 7.2 grams of (120mmol) glacial acetic acids are added into system, stirs 20min, and 50 DEG C of vacuum of system are rotated to surplus
Remaining 50mL, then 350mL water is added into system, a large amount of solids are precipitated, filter, such as 50 DEG C of drying obtain 23g off-white color products, i.e.,
Formula IX compound represented, yield 85%, HPLC purity 98.5%.
Such as the molecular weight and hydrogen modal data of Formula IX compound represented:If the hydrogen spectrogram of Formula IX compound represented is shown in Fig. 2,
It is its molecular weight and hydrogen modal data below:
MS:470[M+H]
1H NMR(400MHz,DMSO-d6),ppm:8.27 (s, 1H), 8.13-8.11 (m, 1H), 5.82-5.81 (d, J=
6Hz, 2H), 5.43-5.42 (s, J=6.4Hz, 1H), 5.18-5.17 (s, J=4.8Hz, 1H), 5.08-5.05 (s, J=
5.6Hz, 1H), 4.59-4.54 (m, 1H), 4.13-4.10 (m, 1H), 3.93-3.92 (d, J=3.6Hz, 1H), 3.67-3.61
(m,3H),3.56-3.51(m,1H),3.29-3.24(m,2H),2.73-2.69(m,4H),2.09(s,3H)
Embodiment 11:((3,3,3- trifluoro propyls) is thio by -2- by O, O, O- triacetyl -6-N- (2- (methyl mercapto) ethyl)
Adenosine (such as Formula VIII compound represented, R1=Bz, R2=Bz) synthesis
At room temperature, it will be added in 30ml toluene such as formula IV compound represented 3.23g (10mmol), system is in suspended shape
State, by N, the bis- trimethylsilyl acetamides (BSA) (6.05 grams, 30mmol, 3eq.) of O- are added dropwise to mixture, are heated at room temperature
100 DEG C, half an hour is stirred, system gradually becomes clarification.Mixture is down to room temperature, Trimethylsilyl trifluoromethanesulfonate
(TMSOTF) (4.4 grams, 30mmol, 3eq.) are added drop-wise in system, 30min are stirred, by 1- acetyl -2,3,5- benzoyl-β-D-
Ribofuranose (such as Formula XI compound represented, R1=Bz, R2=Bz, 15.1g, 30mmol, 3eq.) it is dissolved in 30mL toluene, it drips
It is added in reaction system, is warming up to 100 DEG C and reacts 1 hour, HPLC monitorings raw material fundamental reaction finishes, and stops reaction, is down to room
Temperature is concentrated to dryness.50mL ethyl acetate, dissolving are added into system.Organic phase uses saturated sodium bicarbonate and saturated common salt successively
Water respectively washing 2 times, dry, 50 DEG C of vacuum are spin-dried for, and obtain 7.5g grease, i.e. O, O, O- triacetyls -6-N- (2- (methyl mercapto) second
Base) ((3,3,3- trifluoro propyl) thio adenosine, product does not have to separation directly to carry out in next step -2-, therefore for as shown in Formula VIII
Compound (R1=Bz, R2=Bz) crude product.
Embodiment 12:Such as the synthesis of Formula IX compound represented
At room temperature, by embodiment 11 obtain such as Formula VIII compound represented (R1=Bz, R2=Bz) crude product
(10mmol) is dissolved in the ammonia water-methanol solution of a concentration of 0.1mol/L of 100mL, is stirred to react 1 hour, and it is anti-that TLC monitors raw material
It should finish, 1.2 grams of (20mmol) glacial acetic acids are added into system, stir 20min, 50 DEG C of vacuum of system are rotated to residue
50mL, then 350mL water is added into system, a large amount of solids are precipitated, filter, 50 DEG C of drying obtain 2.6g off-white color products, i.e., such as formula
IX compounds represented, yield 57%, HPLC purity 97.5%.
Embodiment 13:((3,3,3- trifluoro propyls) is thio by -2- by O, O, O- triacetyl -6-N- (2- (methyl mercapto) ethyl)
Adenosine (such as Formula VIII compound represented, R1=Ac, R2=Ac) synthesis
In room temperature and under nitrogen protection, by formula IV compound 3.8g (12mmol) and 1,2,3,5- tetra- acetyl-β-D- furans
Mutter ribose (such as Formula XI compound represented, R1=Ac, R2=Ac, 4.6g, 72mmol, 1.2eq.) it is added in 100mL acetonitriles,
System is in suspended state, will be added dropwise to stannic chloride (IV) (2.8ml, 24mmol, 2eq.) at room temperature, it is shallow that system gradually becomes clarification
Yellow solution.Mixture to be down to room temperature, continues stir about 18 hours, HPLC monitorings raw material fundamental reaction finishes, and stops reaction,
It is concentrated to dryness.50mL ethyl acetate, dissolving are added into system.Organic phase uses saturated sodium bicarbonate and saturated salt solution each successively
Washing 2 times, dry, 50 DEG C of vacuum are spin-dried for, and obtain 8.6g grease, i.e. O, O, O- triacetyls -6-N- (2- (methyl mercapto) ethyl) -
((3,3,3- trifluoro propyl) thio adenosine, product does not have to separation directly to carry out in next step 2-, therefore to change as shown in Formula VIII
Close object (R1=Ac, R2=Ac) crude product.
Embodiment 14:Such as the synthesis of Formula IX compound represented
At room temperature, by embodiment 13 obtain such as Formula VIII compound represented (R1=Ac, R2=Ac) crude product
(12mmol) is dissolved in the ammonia water-methanol solution of a concentration of 0.1mol/L of 60mL, is stirred to react 1.5 hours, and it is anti-that TLC monitors raw material
It should finish, 1.44 grams of (24mmol) glacial acetic acids are added into system, stir 20min, 50 DEG C of vacuum of system are rotated to residue
5mL, then 70mL water is added into system, a large amount of solids are precipitated, filter, 50 DEG C of drying obtain 4.1g off-white color products, i.e., such as Formula IX
Compound represented, yield 75%, HPLC purity 97%.
Embodiment 15:The synthesis of cangrelor (compound shown in formula I)
Will as Formula IX compound represented (5.00 grams, 1.0 equivalents, 10.6 mMs) and proton sponge (3.42 grams, 1.5
Equivalent, 16.0 mMs) it is added in the round-bottomed flask through oven drying.Then triethyl phosphate (95 milliliters) and will be molten is added
Liquid is cooled to -10 DEG C and is deaerated 30 minutes with nitrogen.Phosphorus oxychloride (4.90 grams, 3 equivalents, 31.9 mMs) is with about 0.5 milli
The rate risen/20 minutes is added in the solution of the cooling.After 2.5 hours, LC-MS detections such as Formula IX compound represented consumes
It finishes.Solution is maintained to bend mono phosphoric acid ester tri-n-butylamine salt (9.1 grams, 4.0 equivalents, 21.3 mMs), tri-n-butylamine in -10 DEG C of chlorine
(4.95 grams, 5 equivalents, 26.6 mMs) are dissolved in 30 milliliters of DMF, are added dropwise in the reaction solution being vigorously stirred.It will reaction
It is stirred 2 hours at -10 DEG C.Crude mixture is poured slowly into sodium bicarbonate aqueous solution (1.0 liters).It is small to be stirred at room temperature 18
When, by solution left standstill, each phase is detached, the fresh solution of sodium bicarbonate aqueous solution (200 milliliters) is used in combination to wash upper organic phase.It will
Combined water phase is slowly added into acetone, and stirring generates white depositions.Sediment is collected by vacuum filtration, acetone is used
Filter wash cake.Collected white powder is dried in a vacuum 18 hours, obtains thick solid.Crude product is pure by reverse-phase chromatographic column
Change.It collects pure component and rotary evaporation is concentrated into 100mL.Remaining solvent, by freeze-drying obtain white powder (5.9g,
Yield 71%), as cangrelor (compound shown in formula I), HPLC purity is 98.7%.Fig. 3 is cangrelor1H
NMR and31P H NMR spectroscopies.The molecular weight of cangrelor,1H NMR and31P H NMR spectroscopy data:
MS:774,776,778 [M-H+]
1H NMR(300MHz,D2O) δ 8.25 (s, 1H), 5.96 (d, J=5.5Hz, 1H), 4.67-4.62 (m, 1H),
4.57-4.46 (m, 1H), 4.35-4.08 (m, 3H), 3.67 (s, 2H), 3.20 (dd, J=8.9,6.6Hz, 2H), 2.71 (t, J
=6.7Hz, 2H), 2.67-2.47 (m, 2H), 2.03 (s, 3H)31P NMR(122MHz,D2O) δ 8.35 (d, J=13.8Hz),
3.61-1.05 (m) ,-10.63 (d, J=30.7Hz)
Embodiment 16:The synthesis of cangrelor (compound shown in formula I)
Will as Formula IX compound represented (5.00 grams, 1.0 equivalents, 10.6 mMs) and proton sponge (3.42 grams, 1.5
Equivalent, 16.0 mMs) it is added in the round-bottomed flask through oven drying.Then triethyl phosphate (95 milliliters) and will be molten is added
Liquid is cooled to -10 DEG C and is deaerated 30 minutes with nitrogen.Phosphorus oxychloride (4.90 grams, 3 equivalents, 31.9 mMs) is with about 0.5 milli
The rate risen/20 minutes is added in the solution of the cooling.After 2.5 hours, LC-MS detections such as Formula IX compound represented consumes
It finishes.Solution is maintained to bend mono phosphoric acid ester tri-n-butylamine salt (9.1 grams, 4.0 equivalents, 21.3 mMs), tri-n-butylamine in -10 DEG C of chlorine
(4.95 grams, 5 equivalents, 26.6 mMs) are dissolved in 30 milliliters of DMF, are added dropwise in the reaction solution being vigorously stirred.At -10 DEG C
Reaction solution is added.Reaction is stirred 2 hours at -10 DEG C.Crude mixture is poured slowly into sodium bicarbonate aqueous solution (1.0 liters).
It is stirred at room temperature 18 hours, is then stirred 4 hours at 50 DEG C.By solution left standstill, each phase is detached, sodium bicarbonate aqueous solution is used in combination
The fresh solution of (200 milliliters) washs upper organic phase.Combined water phase is slowly added into methanol, it is heavy that stirring generates white
Starch.Sediment is collected by vacuum filtration, with methanol filter wash cake.It is small that collected white powder is dried in a vacuum 18
When, obtain thick solid.Crude product passes through reverse-phase chromatography column purification.It collects pure component and rotary evaporation is concentrated into 100mL.It is remaining
Solvent obtains white powder (4.5g, yield 54% by vacuum freeze drying;HPLC purity is 98.5%) as bank Gray
Lip river (compound shown in formula I).
Embodiment 17:The synthesis of cangrelor (compound shown in formula I)
It will be as (17.1 grams, 1.5 work as Formula IX compound represented (25.00 grams, 1.0 equivalents, 53 mMs) and proton sponge
Amount, 80 mMs) it is added in the round-bottomed flask through oven drying.Then triethyl phosphate (475 milliliters) is added and by solution
It is cooled to -10 DEG C and is deaerated 30 minutes with nitrogen.Phosphorus oxychloride (20.4 grams, 2.5 equivalents, 132 mMs) with about 5 milliliters/
20 minutes rates are added in the solution of the cooling.After 2.5 hours, LC-MS detection such as Formula IX compounds represented run out of
Finish.Maintain solution -10 DEG C of chlorine bend mono phosphoric acid ester tri-n-butylamine salt (91.0 grams, 4.0 equivalents, 212 mMs), tri-n-butylamine (50 grams,
5 equivalents, 265 mMs) it is dissolved in 30 milliliters of DMF, it is added dropwise in the reaction solution being vigorously stirred.It will react at -10 DEG C
Stirring 2 hours.Crude mixture is poured slowly into sodium bicarbonate aqueous solution (3.5 liters).It is stirred at room temperature 18 hours, then 50
DEG C stirring 2 hours, by solution left standstill, detach each phase, the fresh solution of sodium bicarbonate aqueous solution (500 milliliters × 2) be used in combination to wash
Upper organic phase.Combined water phase is slowly added into acetone, stirring generates white depositions.Sediment is passed through into vacuum mistake
Filter is collected, with acetone filter wash cake.Collected white powder is dried in a vacuum 18 hours, obtains thick solid.Crude product passes through
Reverse-phase chromatography column purification.It collects pure component and rotary evaporation is concentrated into 100mL.Remaining solvent is obtained white by freeze-drying
Color powder (26.6g, yield 58%;HPLC purity is 98.8%) as cangrelor (compound shown in formula I).
The preferred embodiment of the present invention has been described in detail above, only for illustrate the present invention technical concept and spy
Point can not limit this its object is to allow those skilled in the art to can understand the content of the present invention and implement it accordingly with this
The protection domain of invention.It should be appreciated that those skilled in the art can be according to the present invention without creative work
Many modifications and variations are made in design.Therefore, all technician in the art are under this invention's idea in the prior art
On the basis of by the available technical solution of logical analysis, reasoning, or a limited experiment, all should be by claims institute
In determining protection domain.
Claims (10)
1. a kind of method of synthesis such as formula IV compound represented, which is characterized in that include the following steps:
Step 1: preparing such as formula III compound represented;
Step 2: preparing such as formula IV compound represented by such as formula III compound represented;
2. the method for synthesis according to claim 1 such as formula IV compound represented, which is characterized in that the step 1 is adopted
It is obtained by the reaction such as formula III compound represented with such as Formula II compound represented and compound shown as a formula V;
3. the method for synthesis according to claim 1 such as formula IV compound represented, which is characterized in that the step 2 is adopted
With such as formula III compound represented with such as -1 compound represented of Formula IV, or with such as -2 compound represented of Formula IV, Huo Zheyu
It is obtained by the reaction such as formula IV compound represented such as -1 compound represented of Formula VII, or with such as -2 compound represented of Formula VII;
In chemical formula, X indicates halogen;M indicates metallic element;
4. a kind of method of synthesis such as Formula IX compound represented, which is characterized in that including according to any one of claim 1-3 institutes
The method stated;
5. the method for synthesis according to claim 4 such as Formula IX compound represented, which is characterized in that further include following step
Suddenly:
Step 3: being condensed preparation chemical combination as shown in Formula VIII by such as formula IV compound represented and such as Formula XI compound represented
Object;
Step 4: being obtained such as Formula IX compound represented by such as Formula VIII compound represented hydrolysis deacetylation protecting group;
Wherein, R1Indicate Ac or Bz;R2Indicate Ac or Bz.
6. the method for synthesis according to claim 5 such as Formula IX compound represented, which is characterized in that the step 3 tool
Body is:It will be first added to such as formula IV compound represented in solution one, then N is added dropwise, then the bis- trimethylsilyl acetamides of O- are added dropwise
1,2,3, the 5- tetra- acetyl-β-D-RIBOSE for being dissolved in the solution one is then added dropwise, instead in Trimethylsilyl trifluoromethanesulfonate
It answers, obtains such as Formula VIII compound represented;The solution one is selected from acetonitrile, DMF, DME, DMA, toluene, tetrahydrofuran and third
Ketone or combinations thereof object.
7. the method for synthesis according to claim 5 such as Formula IX compound represented, which is characterized in that the step 3 tool
Body is:Solution will be added to such as formula IV compound represented and tetra- acetyl-β of 1,2,3,5--D-RIBOSE under nitrogen protection
In two, butter of tin is added, reacts, obtains such as Formula VIII compound represented;The solution two be selected from acetonitrile, DMF, DME,
DMA, toluene and tetrahydrofuran or combinations thereof object.
8. a kind of synthetic method of cangrelor, which is characterized in that including according to the method described in claim 5, and also wrapping
It includes:Step 5: as Formula IX compound represented and phosphorus oxychloride and chlorine bend mono phosphoric acid ester tri-n-butylamine reactant salt, through alkalescent sodium salt
After processing is quenched, purifying obtains cangrelor.
9. the synthetic method of cangrelor according to claim 8, which is characterized in that the purifying in the step 5 is to use
Reversed-phase resin purification is isolated and purified.
10. the synthetic method of cangrelor according to claim 9, which is characterized in that through alkalescent in the step 5
After processing is quenched in sodium salt, water phase is isolated, the solid in the water phase is precipitated with solution three, obtains sediment, it is described heavy to purify
Starch obtains cangrelor;The solution three be selected from dichloromethane, methyl ethyl ketone, acetone, ether, butyl methyl ether, chloroform, methanol,
Ethyl alcohol, tetrahydrofuran and butanone or combinations thereof object.
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