CN108658989B - Preparation method and application of cangrelor intermediate - Google Patents
Preparation method and application of cangrelor intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method and application of a cangrelor intermediate. The intermediate comprises 2-chloro-N- (2- (methylthio) ethyl) -7H-purine-6-amine and is obtained by reacting 2, 6-dichloropurine with 2-methylthioethylamine. In addition, the cangrelor intermediate also comprises 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine, and is obtained by reacting 2-chloro-N- (2- (methylthio) ethyl) -7H-purin-6-amine with S-3,3, 3-trifluoropropylisothiourea hydrohalide, S-3,3, 3-trifluoropropylisothiourea, 3,3, 3-trifluoropropyl-1-thiol or an alkali metal salt of 3,3, 3-trifluoropropyl-1-thiol. The method has the advantages of simple and feasible technical route, wide raw material source, mild conditions, low production cost, high yield and environmental friendliness, and provides a more effective synthesis method for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method and application of a cangrelor intermediate.
Background
Cangrelor is an intravenous P2Y12 inhibitor that blocks Adenosine Diphosphate (ADP) -induced platelet activation and aggregation, and has a chemical structure similar to Adenosine Triphosphate (ATP). It is the first intravenous anti-platelet aggregation medicine for preventing coronary artery blockage caused by blood coagulation in percutaneous coronary artery intervention (PCI) process of adult patients, and can effectively reduce myocardial infarction and wind of thrombus in stentAnd (5) risking. 22 Rieglerolalo is approved by FDA in US to be marketed in 6.6.2015, and The development of The medicinal Company is authorized, and The preparation specification is 50mg freeze-dried powder injection with The trade name of KENGREALTM。
Chemical name of cangrelor: n6- [2- (methylthio) ethyl ] -2- [ (3,3, 3-trifluoropropyl) thio ] -5 '-adenylic acid, tetrasodium salt of the monoanhydride with dichloromethylene diphosphate (N6- [2- (methylthio) ethyl ] -2- [ (3,3,3, trifluropropyl) ] -5' -adenosic acid, monocarboxide with (dichloromethyl) bisphoponic acid). Empirical formula C17H21N5Cl2F3Na4O12P3S2 and molecular weight 864.3 g/mol. The chemical structural formula is shown as the formula I.
The preparation of cangrelor is not widely reported in the literature and patents, and the development company (Medicines company) in the literature (J.Med.chem.1999,42,213-220) uses 2-mercaptoadenosine as the starting material, and its preparation can be referred to the preparation method of chem.pharm.Bull.25(8)1959-1969(1977), see scheme 1. Another method takes thiobarbituric acid as a starting material, and performs seven-step lengthy reaction path (CN105061431) to obtain the key intermediate formula IV of cangrelor, which is shown in a synthetic route 2. The starting raw materials adopted in the synthesis route 1 have rare sources and high price, and the highly toxic carbon disulfide and the pressurization reaction are needed during self synthesis, and the highly toxic hydrogen sulfide is generated, so that the method causes harm to production personnel and environment, is difficult to enlarge production and is not suitable for industrial production. The synthetic route 2 is long, the total yield is low, Raney nickel hydrogenation high-pressure reaction and methyl iodide are needed, and the method is also not suitable for industrial production.
Scheme 1:
scheme 2:
furthermore, in terms of purification, the prior art such as WO9418216A1(US5721219A) and the literature (J.Med.chem.1999,42, p213) mostly gives the ammonium salt form and further converts it to the sodium salt form with sodium iodide or sodium bicarbonate, as shown in the previous scheme 1, from the compound of formula IX to the compound of formula I, a three-step reaction is required and the yield is only 4%.
In patent CN1613864A (see purification scheme 1), although the purification preparation yield is already 6 times higher than that of the above patent, two times of ion exchange resin separation and purification are required, the steps are complicated, and a large amount of eluent is generated, which makes concentration difficult and increases cost, and the obtained ammonium salt form is further converted into the compound shown in formula I with sodium iodide or sodium bicarbonate.
Purification scheme 1:
in addition, in patent CN105061431A, although the yield is also obviously improved to 54% by using DEAE-Sephadex a25 ion exchange resin for separation and purification once, the obtained ammonium salt form is further converted into the compound shown in formula I with sodium iodide or sodium bicarbonate.
Disclosure of Invention
In view of the deficiencies of the prior art, the inventors have studied to obtain a method for synthesizing a compound represented by formula IV, comprising the steps of:
step one, preparing a compound shown as a formula III;
step two, preparing a compound shown as a formula IV from the compound shown as the formula III;
further, in the first step, a compound (2, 6-dichloropurine) shown in a formula II and a compound (2- (methylthio) ethylamine) shown in a formula V are reacted to obtain a compound shown in a formula III;
further, the first step is specifically as follows: reacting a compound shown as a formula II, a compound shown as a formula V, a protic solvent and alkali at 30-120 ℃ to obtain a compound shown as a formula III. The base in the first step is selected from sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine or a combination thereof, and is preferably triethylamine or potassium carbonate. The protic solvent is selected from methanol, ethanol, isopropanol, n-butanol, 2-butanol and tert-butanol or their combination, preferably ethanol and n-butanol.
Further, the first step is specifically as follows: adding a compound shown as a formula II, a compound shown as a formula V, ethanol and triethylamine into a reaction bottle, heating to 110-120 ℃, refluxing at normal pressure until the reaction is finished, cooling to room temperature, filtering to obtain a filter cake, stirring the filter cake with a saturated sodium bicarbonate solution, filtering, and washing with water to obtain a compound shown as a formula III.
Further, in the second step, a compound shown in the formula III and a compound shown in the formula VI-1, or a compound shown in the formula VI-2, or a compound shown in the formula VII-1, or a compound shown in the formula VII-2 are reacted to obtain a compound shown in the formula IV; in the chemical formula, X represents halogen; m represents a metal element;
further, M represents an alkali metal.
Further, M represents Na, K or Li.
Further, X represents Cl, Br or I.
Further, the reaction in the second step is carried out in the presence of a base. The base in the second step is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine or a combination thereof. And the reaction solvent in the second step is a protic solvent or an aprotic solvent. The protic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol and water or their combination. The aprotic solvent is selected from tetrahydrofuran, acetonitrile, dioxane, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, N-Dimethylacetamide (DMA) and N-methylpyrrolidone or a combination thereof. The reaction temperature of the second step is 40-150 ℃.
The invention also discloses a method for synthesizing the compound shown in the formula IX, which comprises the method for synthesizing the compound shown in the formula IV;
further, the method also comprises the following steps:
step three, condensing the compound shown in the formula IV and the compound shown in the formula XI to prepare the compound shown in the formula VIII;
step four, hydrolyzing and removing acetyl protecting groups from the compound shown in the formula VIII to obtain a compound shown in the formula IX;
wherein R is1Represents Ac or Bz; r2Represents Ac or Bz.
Further, the third step is specifically: firstly, adding a compound shown as a formula IV into a solution I, dropwise adding N, O-bis (trimethylsilyl) acetamide, dropwise adding trimethylsilyl trifluoromethanesulfonate, dropwise adding 1,2,3, 5-tetraacetyl-beta-D-ribofuranose dissolved in the solution I, and reacting to obtain a compound shown as a formula VIII; the first solution is selected from acetonitrile, DMF, Dimethoxyethane (DME), DMA, toluene, tetrahydrofuran, acetone and DMAc or a combination thereof. Further, the third step is specifically: adding the compound shown as the formula IV and 1,2,3, 5-tetraacetyl-beta-D-ribofuranose into the second solution under the protection of nitrogen, adding stannic chloride, and reacting to obtain a compound shown as the formula VIII; the second solution is selected from acetonitrile, DMF, DME, DMA, toluene and tetrahydrofuran or a combination thereof.
Further, the fourth step is specifically: dissolving the compound shown as the formula VIII in an ammonia-methanol solution, and hydrolyzing and deacetylating a protecting group to obtain the compound shown as the formula IX.
The invention also discloses application of the compound shown in the formula IV in synthesizing the compound shown in the formula IX and/or cangrelor, namely the compound shown in the formula IV is obtained by the method.
The invention also discloses application of the compound shown in the formula IX in synthesis of cangrelor, namely the compound shown in the formula IX is obtained by the method.
The invention also relates to a synthesis method of cangrelor, which comprises the method for synthesizing the compound shown in the formula IX, and also comprises the following steps: and step five, reacting the compound shown as the formula IX with phosphorus oxychloride and chlorotetracycline monophosphate salt, quenching by alkalescent sodium salt, and purifying to obtain cangrelor.
Further, the weakly basic sodium salt in step five is selected from sodium bicarbonate, sodium carbonate, sodium acetate, sodium citrate, sodium phosphate and sodium hydrogen phosphate.
Further, the reaction temperature of the compound shown as the formula IX in the step five, phosphorus oxychloride and chlorochrysophanic acid mono-tri-n-butylamine salt is-20 ℃ to 0 ℃. Preferably-10 ℃.
Further, the fifth step is specifically: adding a compound shown as a formula IX and proton sponge into phosphate, cooling to-20-0 ℃, dropwise adding phosphorus oxychloride, adding chlorotetracycline mono-tri-n-butylamine salt and tri-n-butylamine after the compound shown as the formula IX is consumed, stirring for 2-10 hours at-20-0 ℃, reacting, quenching by alkalescent sodium salt, and purifying to obtain cangrelor.
In one embodiment, the proton sponge in step five is 1, 8-bis-dimethylamino-naphthalene; the molar ratio of the compound shown as the formula IX, 1, 8-bis-dimethylamino-naphthalene, phosphorus oxychloride, chlorochrysophanic acid mono-tri-n-butylamine salt and tributylamine is 1 (1-3) to (2-6) to (3-8).
In another embodiment, the compound of formula IX and the proton sponge are added to the phosphate in step five such that the concentration of the compound of formula IX in the phosphate solvent is from 0.1 to 0.2M; dissolving reaction substrates of chlorotetraphosphate mono-tri-N-butylamine salt and tri-N-butylamine in anhydrous N, N-dimethylformamide at concentrations of 1-2M and 1.5-3M respectively, and then adding the mixture into a reaction system for reaction.
Further, the purification in the fifth step is separation purification by reversed phase resin purification.
Further, the purification in step five is a gradient purification with reversed phase resin, eluent is 1-15% 2-propanol aqueous solution, and cangrelor is obtained. Preferably, the reverse phase resin is AberchromTM。
Further, after quenching treatment by using weak alkaline sodium salt in the step five, separating out a water phase, separating out solid in the water phase by using a solution III to obtain a precipitate, and purifying the precipitate to obtain cangrelor; the solution III is selected from dichloromethane, methyl ethyl ketone, acetone, diethyl ether, butyl methyl ether, chloroform, methanol, ethanol, tetrahydrofuran and butanone or a combination thereof.
Further, the quenching and purification in step five is: slowly pouring a product obtained by reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline phosphate mono-tri-n-butylamine salt into an alkalescent sodium salt aqueous solution, stirring for 2-18 hours at 15-60 ℃, standing and separating phases; adding the water phase into the third solution to obtain a precipitate; and collecting the precipitate, purifying by using a reverse phase chromatographic column, wherein an eluent is 2-8% of 2-propanol aqueous solution or a solution with similar polarity, and collecting pure components to obtain cangrelor.
Further, the quenching and purification in the fifth step are specifically: slowly pouring a product obtained by reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline phosphate mono-tri-n-butylamine salt into an alkalescent sodium salt aqueous solution, stirring for 2-18 hours at 15-50 ℃, standing to separate phases, and washing an upper organic phase by using the alkalescent sodium salt aqueous solution; mixing the water phases, and slowly adding the water phases into the third solution to obtain a precipitate; and filtering and collecting the precipitate, washing a filter cake with the solution III, drying, purifying by using a reverse phase chromatographic column, performing gradient elution, collecting pure components, and drying to obtain cangrelor, wherein an eluent is a 1-15% 2-propanol aqueous solution. Preferably, the eluent is 2-8% 2-propanol aqueous solution. Preferably, vacuum drying is used followed by purification by reverse phase chromatography.
The invention also relates to a synthesis method of cangrelor, which adopts the compound shown as the formula III as a cangrelor intermediate;
according to the synthesis method of cangrelor, a product obtained by reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline phosphate mono-tri-n-butylamine salt is quenched by adopting a weakly alkaline sodium salt and purified to obtain cangrelor;
further, the weakly basic sodium salt is selected from sodium bicarbonate.
Further, separating out a water phase from the quenched product, separating out solid in the water phase by using a solution III to obtain a precipitate, and purifying the precipitate to obtain cangrelor; the solution III is selected from dichloromethane, methyl ethyl ketone, acetone, diethyl ether, butyl methyl ether and chloroform.
Further, the purification is performed using a reverse phase resin.
Further, a reverse phase resin is usedGradient purification is carried out, and eluent is 1-15% 2-propanol aqueous solution. Preferably, the reverse phase resin is AberchromTM Or other similar typesThe reversed phase resin of (1).
The cangrelor purification method provided by the invention adopts reversed-phase resin for purification to obtain cangrelor.
Further, gradient purification is carried out by adopting reverse phase resin, and eluent is 1-15% 2-propanol aqueous solution, so as to obtain cangrelor.
The invention provides a new method for purifying and preparing cangrelor, which aims to overcome the defect that the yield is low by twice separation and purification by using weak-base anion exchange resin such as anion exchange resin, DEAE-Sephadex A25 and the like or anion and cation exchange resin in the prior art. The production process is characterized by comprising the following steps: 1.6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) adenosine (formula IX) is condensed with phosphorus oxychloride and (dichloromethylene) diphosphoric acid tri-N-butyl ammonium salt (formula X) by a one-pot method to obtain a cangrelor reaction crude product solution; 2. complete separation and purification by reverse phase resin gradient purification directly yields the purified cangrelor (formula I) tetrasodium salt form.
The above synthetic schemes are only examples of the preparation methods of the compounds of the present invention, and the skilled person can synthesize the compounds of the present invention by similar methods based on the above synthetic schemes according to the well-known techniques in the art.
The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form; the optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compounds" of the present invention also include tautomeric forms; tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The invention also includes all isotopic atoms, whether in the intermediate or final compound; isotopic atoms include those having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium.
The synthesis technical route and the purification technology adopted by the invention are simple and easy to implement, the raw material sources are wide, the conditions are mild, the production cost is low, the yield is high, the environment is friendly, the available purity is higher than 98%, and a more effective synthesis method is provided for industrial production.
Drawings
Fig. 1 is a synthetic scheme for cangrelor.
FIG. 2 is a hydrogen spectrum of a compound represented by formula IX.
FIG. 3 is of cangrelor1H NMR and31p NMR spectrum.
Detailed Description
The present invention will be further described with reference to the following embodiments and drawings, and the present invention is not limited to the following embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
FIG. 1 shows a synthetic route for cangrelor in one embodiment of the invention. In this embodiment, the method includes:
step one, reacting a compound (2, 6-dichloropurine) shown as a formula II with a compound (2- (methylthio) ethylamine) shown as a formula V to obtain a compound (2-chloro-N- (2- (methylthio) ethyl) -7H-purine-6-amine) shown as a formula III.
And step two, reacting the compound shown as the formula III with the compound shown as the formula VI-2 or the compound shown as the formula VII-2 to obtain the compound shown as the formula IV (6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine). M in the compound represented by the formula VII-2 represents an alkali metal such as Na, K or Li. X in the compound represented by the formula VI-2 represents a halogen such as Cl, Br or I.
And step three, condensing the compound shown as the formula IV and the compound shown as the formula XI to prepare the compound shown as the formula VIII. R in the formula1Represents Ac or Bz; r2Represents Ac or Bz.
And step four, hydrolyzing and removing the acetyl protecting group from the compound shown in the formula VIII in the presence of alkali to obtain the compound shown in the formula IX.
Step five:
step 5.1, reacting the compound shown in the formula IX with phosphorus oxychloride to obtain a compound shown in the formula XII;
step 5.2, reacting the compound shown in the formula XII with a compound shown in the formula X (chlorotetraphosphate mono-tri-n-butylamine salt), and then quenching by weakly alkaline sodium salt;
and 5.3, purifying the quenched product in the step 5.2 by using reverse phase resin to obtain the compound (cangrelor) shown in the formula I.
Example 1: synthesis of 2-chloro-N- (2- (methylthio) ethyl) -7H-purin-6-amine (2-chloro-N- (2- (methylthio) ethyl) -7H-purin-6-amine, a compound represented by formula III)
In a 100ml flask, 2- (methylthio) ethylamine (6.8 g, 57.5 mmol, 1.2 equivalents), butanol (50 ml), triethylamine (11.6 g, 115 mmol, 2 equivalents) and 2, 6-dichloropurine (8.96 g, 48 mmol, 1 equivalent) were added. The mixture was heated to 100 ℃ and stirred for 6 hours. The mixture was cooled to room temperature and filtered to give a white filter cake. The filter cake was added to 150 ml of saturated sodium bicarbonate solution, stirred for 30 minutes, filtered and the filter cake washed with water (100 ml). The filter cake was dried under vacuum to give 10.9 g of the product, i.e. the compound of formula III. Yield 93%, HPLC purity 96%.
Hydrogen spectrum data for the compound of formula III: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)。
example 2: synthesis of 2-chloro-N- (2- (methylthio) ethyl) -7H-purin-6-amine (compound shown as formula III)
In a 250 ml flask, 2- (methylthio) ethylamine (21 g, 230 mmol, 1.5 equivalents), ethanol (50 ml), triethylamine (39 g, 389 mmol, 2.5 equivalents) and 2, 6-dichloropurine (29 g, 150 mmol, 1 equivalent) were added. The mixture was heated to 100 ℃ and stirred for 6 hours. The mixture was cooled to room temperature and stirred with 200ml of water for 30 minutes. Filtration gave a white filter cake. The filter cake was added to 400ml of saturated sodium bicarbonate solution, stirred for 30 minutes, filtered and the filter cake washed with water (150 ml). The filter cake was dried in vacuo to give 28.4 g of the product, i.e., the compound of formula III. Yield 78% and HPLC purity 97%.
Example 3: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
The compound represented by the formula III (0.243 g, 1 equivalent, 1 mmol), isothiourea salt compound (the compound represented by the formula VI-2, 0.45 g, 1.5 equivalents, 1.5 mmol) and sodium hydroxide (120 mg, 3 equivalents, 3 mmol) were dissolved in 2 ml of dry DMF, heated to 100 ℃ and stirred for 3 days. After the reaction was completed, isothiourea salt compound (a compound represented by the formula VI-2, 0.3 g, 1 equivalent, 1 mmol) and NaOH (0.08 mg, 2 equivalents, 2mmol) were added and the reaction was continued by heating to 115 ℃ for 24 hours. The progress of the reaction was monitored by HPLC, the reaction was cooled to room temperature and water (6 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20 ml). Drying in vacuo afforded the pure product (0.250 g, 77% yield; HPLC purity 98.5%), a compound of formula IV.
Hydrogen spectrum data for the compound of formula IV: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).
example 4: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
The compound of formula III (0.6 g, 1 equivalent, 2.48 mmol), isothiourea salt compound (compound of formula VI-2, 2.23 g, 3 equivalents, 7.45 mmol) and CsOH (2.23 mg, 6 equivalents, 14.9 mmol) were dissolved in 6 ml of dry DMF and heated to 115 deg.C and stirred for 2 days. After the reaction was completed, isothiourea salt compound (a compound represented by the formula VI-2, 0.75 g, 1 equivalent, 2.48 mmol) and CsOH (0.75 mg, 2 equivalents, 4.96 mmol) were added and the reaction was continued by heating to 115 ℃ for 24 hours. The progress of the reaction was monitored by HPLC and the reaction was complete. The reaction was cooled to room temperature and water (60 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20 ml). Drying in vacuo afforded the pure product (0.668 g, 80% yield). The mother liquor is concentrated and separated by column chromatography to obtain 0.111 g of product, namely the compound shown in the formula IV. The combined yields were 92% (0.779 g) with 99% HPLC purity.
Example 5: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
A compound represented by the formula III (2 g, 1 equivalent, 8.23 mmol), sodium 3,3, 3-trifluoropropane-1-thiolate (a compound represented by the formula VII-2, M is Na, 1.5 g, 1.2 equivalents, 9.9 mmol) and cesium carbonate (2.67 g, 1 equivalent, 8.23 mmol) were dissolved in 10 ml of dry DMF, heated to 100 ℃ and stirred for 8 hours. The progress of the reaction was monitored by HPLC and the reaction was complete. The reaction was cooled to room temperature and water (40 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20 ml). The product obtained was dried in vacuo and isolated using a silica gel column to give 0.9 g of product. The yield was 27%.
Example 6: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
The compound of formula III (0.486 g, 1 eq, 2mmol), 3,3, 3-trifluoropropane-1-thiol (compound of formula VII-1, 0.583 g, 1.2eq, 2.4 mmol) and sodium hydroxide (240 mg, 3eq, 6 mmol) were dissolved in 2 ml of dry DMF and heated to 100 deg.C and stirred for 8 hours. The progress of the reaction was monitored by HPLC and the reaction was complete. The reaction was cooled to room temperature and water (40 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20 ml). The product obtained was dried in vacuo and isolated using a silica gel column to give 0.28 g of product. The yield was 41%.
Example 7: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
A compound represented by the formula III (1.2 g, 1 equivalent, 4.96 mmol), an isothiourea compound (a compound represented by the formula VI-1, 2.56 g, 3 equivalents, 14.9 mmol) and potassium hydroxide (1.67 g, 6 equivalents, 29.8 mmol) were dissolved in 10 ml of dried DMSO, heated to 115 ℃ and stirred for 2 days. After the reaction was completed, an isothiourea compound (a compound represented by the formula VI-2, 0.85 g, 1 equivalent, 4.96 mmol) and potassium hydroxide (834 mg, 3 equivalents, 14.9 mmol) were added and the reaction was continued at 115 ℃ for 24 hours. The progress of the reaction was monitored by HPLC and the reaction was complete. The reaction was cooled to room temperature and water (100 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (30 ml). Drying in vacuo afforded the pure product (0.56 g, 73% yield, 98.7% HPLC purity).
Example 8: synthesis of 6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thio) -9H-purine (Compound shown in formula IV)
The compound represented by the formula III (0.6 g, 1 equivalent, 2.48 mmol), the isothiourea salt compound (the compound represented by the formula VI-2, 2.23 g, 3 equivalents, 7.45 mmol) and potassium hydroxide (834 mg, 6 equivalents, 14.9 mmol) were dissolved in 6 ml of dried DMSO, heated to 115 ℃ and stirred for 2 days. After the reaction was completed, isothiourea salt compound (a compound represented by the formula VI-2, 0.75 g, 1 equivalent, 2.48 mmol) and potassium hydroxide (417 mg, 3 equivalents, 7.5 mmol) were added and the reaction was continued by heating to 115 ℃ for 24 hours. The progress of the reaction was monitored by HPLC and the reaction was complete. The reaction was cooled to room temperature and water (60 ml) was added. The mixture was stirred for 30 minutes to form a pale yellow precipitate. The solid was isolated by vacuum filtration and the filtrate was discarded. The filter cake was washed with water (20 ml). Drying in vacuo afforded the pure product (0.56 g, 67% yield).
Example 9: o, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine (compound shown as formula VIII, R)1＝Ac，R2Ac) synthesis
At room temperature, 19.38g (60mmol) of the compound shown as the formula IV is added into 200mL of acetonitrile, the system is in a suspension state, N, O-bis (trimethylsilyl) acetamide (BSA) (19.62 g, 96mmol, 1.6eq.) is added dropwise into the mixture at room temperature, the mixture is heated to 60 ℃, and the mixture is stirred for 1 hour, so that the system gradually becomes clear. Cooling the mixture to room temperature, adding trimethylsilyl trifluoromethanesulfonate (TMSOTF) (15.98 g, 72mmol, 1.6eq.) dropwise into the system, stirring for 30min, and adding 1,2,3, 5-tetraacetyl-beta-D-ribofuranose (compound shown as formula XI, R)1＝Ac，R2Ac, 22.9g, 72mmol, 1.2eq.) was dissolved in 200mL of acetonitrile, added dropwise to the reaction system, heated to 60 ℃ for reaction for 6 hours, HPLC monitored that the reaction of the starting materials was substantially completed, the reaction was stopped, cooled to room temperature, and concentrated to dryness. To the system was added 400mL of ethyl acetate and dissolved. The organic phase was washed with saturated sodium bicarbonate and saturated brine for 2 times, dried and vacuum dried at 50 ℃ to give 42g of an oil, i.e., O, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine, which was directly subjected to the next step without separation, thus giving the compound (R) represented by formula VIII1＝Ac，R2Ac) was obtained.
Example 10: synthesis of Compounds represented by formula IX
The compound (R) represented by the formula VIII obtained in example 9 was reacted at room temperature1＝Ac，R2Ac) was dissolved in 600mL of 0.1mol/L sodium hydroxide-ethanol solution, stirred for 30min, TLC monitored for completion of the reaction of the starting material, and 7 was added to the system2g (120mmol) of glacial acetic acid, stirring for 20min, carrying out vacuum rotary evaporation on the system at 50 ℃ until the residual 50mL is obtained, adding 350mL of water into the system, separating out a large amount of solid, filtering, and drying at 50 ℃ to obtain 23g of off-white product, namely the compound shown as the formula IX, wherein the yield is 85% and the HPLC purity is 98.5%.
Molecular weight and hydrogen profile data for compounds of formula IX: the hydrogen spectrum of the compound of formula IX is shown in fig. 2, and the following are the molecular weight and hydrogen spectrum data thereof:
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)
example 11: o, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine (compound shown as formula VIII, R)1＝Bz，R2Bz) synthesis
At room temperature, 3.23g (10mmol) of the compound shown as the formula IV is added into 30ml of toluene, the system is in a suspension state, N, O-bis (trimethylsilyl) acetamide (BSA) (6.05 g, 30mmol, 3eq.) is added dropwise into the mixture at room temperature, the mixture is heated to 100 ℃, and the mixture is stirred for half an hour, so that the system is gradually clarified. Cooling the mixture to room temperature, adding trimethylsilyl trifluoromethanesulfonate (TMSOTF) (4.4 g, 30mmol, 3eq.) dropwise into the system, stirring for 30min, and adding 1-acetyl-2, 3, 5-benzoyl-beta-D-ribofuranose (compound shown as formula XI, R)1＝Bz，R2Dissolve Bz, 15.1g, 30mmol, 3eq.) in 30mL toluene, add dropwise to the reaction system, heat to 100 ℃ for 1 hour, monitor by HPLC that the raw materials are basically reacted, stop the reaction, cool to room temperature, and concentrate to dryness. To the system was added 50mL of ethyl acetate and dissolved. The organic phase is washed 2 times with saturated sodium bicarbonate and with saturated brine, respectively, dried and spin-dried in vacuo at 50 ℃ to give 7.5g of an oil, i.e. O, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine, which is directly taken to the next step without isolation, thus being, for example, aA compound of formula VIII (R)1＝Bz，R2Bz).
Example 12: synthesis of Compounds represented by formula IX
The compound (R) represented by the formula VIII obtained in example 11 was reacted at room temperature1＝Bz，R2Bz) is dissolved in 100mL of ammonia-methanol solution with the concentration of 0.1mol/L, the mixture is stirred and reacted for 1 hour, TLC monitors that the raw material reaction is finished, 1.2 g (20mmol) of glacial acetic acid is added into the system, the mixture is stirred for 20min, the system is vacuum-evaporated at the temperature of 50 ℃ until 50mL of the rest, 350mL of water is added into the system, a large amount of solid is separated out, the solid is filtered and dried at the temperature of 50 ℃, and 2.6g of off-white product, namely the compound shown as the formula IX, is obtained, the yield is 57%, and the HPLC purity is 97.5%.
Example 13: o, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine (compound shown as formula VIII, R)1＝Ac，R2Ac) synthesis
At room temperature under the protection of nitrogen, 3.8g (12mmol) of the compound shown in the formula IV and 1,2,3, 5-tetraacetyl-beta-D-ribofuranose (the compound shown in the formula XI, R)1＝Ac，R2Ac, 4.6g, 72mmol, 1.2eq.) was added to 100mL of acetonitrile, the system was suspended, and tin (IV) chloride (2.8mL, 24mmol, 2eq.) was added dropwise at room temperature, and the system gradually turned into a clear pale yellow solution. The mixture was allowed to cool to room temperature, stirred for about 18 hours, HPLC monitored that the starting material was substantially reacted, stopped, and concentrated to dryness. To the system was added 50mL of ethyl acetate and dissolved. The organic phase was washed with saturated sodium bicarbonate and saturated brine for 2 times, dried and vacuum dried at 50 ℃ to give 8.6g of an oil, i.e., O, O, O-triacetyl-6-N- (2- (methylthio) ethyl) -2- ((3,3, 3-trifluoropropyl) thioadenosine, which was directly subjected to the next step without isolation, thus giving a compound represented by the formula VIII (R)1＝Ac，R2Ac) was obtained.
Example 14: synthesis of Compounds represented by formula IX
The compound (R) represented by the formula VIII obtained in example 13 was reacted at room temperature1＝Ac，R2Ac) in 60mL concentrationStirring and reacting for 1.5 hours in 0.1mol/L ammonia water-methanol solution, monitoring by TLC that the raw material reaction is finished, adding 1.44 g (24mmol) of glacial acetic acid into the system, stirring for 20min, carrying out vacuum rotary evaporation on the system at 50 ℃ until 5mL of residual raw material is obtained, adding 70mL of water into the system, separating out a large amount of solid, filtering, and drying at 50 ℃ to obtain 4.1g of off-white product, namely the compound shown as the formula IX, wherein the yield is 75% and the HPLC purity is 97%.
Example 15: synthesis of cangrelor (compound shown as formula I)
A compound of formula IX (5.00 g, 1.0 equivalent, 10.6 mmol) and proton sponge (3.42 g, 1.5 equivalents, 16.0 mmol) were added to an oven dried round bottom flask. Triethyl phosphate (95 ml) was then added and the solution was cooled to-10 ℃ and degassed with nitrogen for 30 minutes. Phosphorus oxychloride (4.90 g, 3eq, 31.9 mmol) was added to the cooled solution at a rate of about 0.5 ml/20 min. After 2.5 hours, LC-MS detected the completion of the consumption of the compound represented by formula IX. While maintaining the solution at-10 deg.C, chlorotetracycline phosphate mono-tri-n-butylamine salt (9.1 g, 4.0 eq, 21.3 mmol) and tributylamine (4.95 g, 5 eq, 26.6 mmol) were dissolved in 30ml of DMF and added dropwise to the vigorously stirred reaction solution. The reaction was stirred at-10 ℃ for 2 hours. The crude mixture was slowly poured into aqueous sodium bicarbonate (1.0 l). After stirring at room temperature for 18 hours, the solution was allowed to stand, the phases were separated and the upper organic phase was washed with a fresh solution of aqueous sodium bicarbonate (200 ml). The combined aqueous phases were slowly added to acetone and stirred to give a white precipitate. The precipitate was collected by vacuum filtration and the filter cake was washed with acetone. The collected white powder was dried in vacuo for 18 hours to give a crude solid. The crude product was purified by reverse phase chromatography. The pure fractions were collected and concentrated to 100mL by rotary evaporation. The remaining solvent was lyophilized to give a white powder (5.9g, 71% yield), which was cangrelor (compound of formula I) with an HPLC purity of 98.7%. FIG. 3 is of cangrelor1H NMR and31p NMR spectrum. The molecular weight of cangrelor,1H NMR and31p NMR spectrum data:
MS:774，776，778[M-H+]
1H NMR(300MHz,D2O)δ8.25(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)δ8.35(d,J＝13.8Hz),3.61–1.05(m),-10.63(d,J＝30.7Hz).
example 16: synthesis of cangrelor (compound shown as formula I)
A compound of formula IX (5.00 g, 1.0 equivalent, 10.6 mmol) and proton sponge (3.42 g, 1.5 equivalents, 16.0 mmol) were added to an oven dried round bottom flask. Triethyl phosphate (95 ml) was then added and the solution was cooled to-10 ℃ and degassed with nitrogen for 30 minutes. Phosphorus oxychloride (4.90 g, 3eq, 31.9 mmol) was added to the cooled solution at a rate of about 0.5 ml/20 min. After 2.5 hours, LC-MS detected the completion of the consumption of the compound represented by formula IX. While maintaining the solution at-10 deg.C, chlorotetracycline phosphate mono-tri-n-butylamine salt (9.1 g, 4.0 eq, 21.3 mmol) and tributylamine (4.95 g, 5 eq, 26.6 mmol) were dissolved in 30ml of DMF and added dropwise to the vigorously stirred reaction solution. The reaction was added at-10 ℃. The reaction was stirred at-10 ℃ for 2 hours. The crude mixture was slowly poured into aqueous sodium bicarbonate (1.0 l). Stirring was carried out at room temperature for 18 hours and then at 50 ℃ for 4 hours. The solution was allowed to stand, the phases were separated and the upper organic phase was washed with a fresh solution of aqueous sodium bicarbonate (200 ml). The combined aqueous phases were slowly added to methanol and stirred to give a white precipitate. The precipitate was collected by vacuum filtration and the filter cake was washed with methanol. The collected white powder was dried in vacuo for 18 hours to give a crude solid. The crude product was purified by reverse phase chromatography. The pure fractions were collected and concentrated to 100mL by rotary evaporation. The remaining solvent was lyophilized under vacuum to give a white powder (4.5g, 54% yield; 98.5% HPLC purity), which was cangrelor (compound of formula I).
Example 17: synthesis of cangrelor (compound shown as formula I)
A compound of formula IX (25.00 g, 1.0 equivalent, 53 mmol) and proton sponge (17.1 g, 1.5 equivalents, 80 mmol) were added to an oven dried round bottom flask. Triethyl phosphate (475 ml) was then added and the solution was cooled to-10 ℃ and degassed with nitrogen for 30 minutes. Phosphorus oxychloride (20.4 g, 2.5 eq, 132 mmol) was added to the cooled solution at a rate of about 5 ml/20 min. After 2.5 hours, LC-MS detected the completion of the consumption of the compound represented by formula IX. While maintaining the solution at-10 deg.C, chlorotetracycline phosphate mono-tri-n-butylamine salt (91.0 g, 4.0 eq, 212 mmol), tributylamine (50 g, 5 eq, 265 mmol) was dissolved in 30mL of DMF and added dropwise to the vigorously stirred reaction solution. The reaction was stirred at-10 ℃ for 2 hours. The crude mixture was slowly poured into aqueous sodium bicarbonate (3.5 l). Stirring was carried out at room temperature for 18 hours and then at 50 ℃ for 2 hours, the solution was allowed to stand, the phases were separated and the upper organic phase was washed with a fresh solution of aqueous sodium bicarbonate (500 ml. times.2). The combined aqueous phases were slowly added to acetone and stirred to give a white precipitate. The precipitate was collected by vacuum filtration and the filter cake was washed with acetone. The collected white powder was dried in vacuo for 18 hours to give a crude solid. The crude product was purified by reverse phase chromatography. The pure fractions were collected and concentrated to 100mL by rotary evaporation. The remaining solvent was lyophilized to give a white powder (26.6g, 58% yield; 98.8% HPLC purity), which was cangrelor (compound of formula I).
The above detailed description of the preferred embodiments of the present invention is provided for the purpose of illustrating the technical concepts and features of the present invention, and is intended to enable those skilled in the art to understand the present invention and implement the present invention, and not to limit the scope of the present invention. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (24)
1. A method for synthesizing a compound represented by formula IV, comprising the steps of:
step one, reacting a compound shown as a formula II with a compound shown as a formula V to obtain a compound shown as a formula III;
secondly, reacting a compound shown as a formula III with a compound shown as a formula VI-1, or with a compound shown as a formula VI-2, or with a compound shown as a formula VII-1, or with a compound shown as a formula VII-2 to obtain a compound shown as a formula IV; in the chemical formula, X represents halogen; m represents a metal element;
2. the method for synthesizing the compound shown in the formula IV according to claim 1, wherein the step I is specifically as follows: reacting a compound shown as a formula II, a compound shown as a formula V, a protic solvent and alkali at 30-120 ℃ to obtain a compound shown as a formula III.
3. The method of claim 2, wherein the base in step one is selected from sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine and N-methylmorpholine, or a combination thereof.
4. The method for synthesizing the compound shown in the formula IV according to claim 1, wherein the step I is specifically as follows: adding a compound shown as a formula II, a compound shown as a formula V, ethanol and triethylamine into a reaction bottle, heating to 110-120 ℃, refluxing at normal pressure until the reaction is finished, cooling to room temperature, filtering to obtain a filter cake, stirring the filter cake with a saturated sodium bicarbonate solution, filtering, and washing with water to obtain a compound shown as a formula III.
5. The method of claim 1, wherein M represents an alkali metal.
6. The method for synthesizing the compound shown in the formula IV according to claim 1, wherein the reaction in the second step is carried out in the presence of a base.
7. The method of claim 6, wherein the base in step two is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, and combinations thereof.
8. The method of claim 1, wherein the reaction solvent in step two is methanol, ethanol, N-propanol, isopropanol, N-butanol, t-butanol, water or tetrahydrofuran, acetonitrile, dioxane, N-dimethylformamide, dimethyl sulfoxide, acetone, N-dimethylacetamide, N-methylpyrrolidone or a combination thereof.
9. The method for synthesizing the compound shown in the formula IV according to claim 1, wherein the reaction temperature in the second step is 40-150 ℃.
10. A process for the synthesis of a compound of formula IX comprising the synthesis of a compound of formula IV using a process as claimed in any one of claims 1 to 9 and the steps of:
step three, preparing a compound shown as a formula VIII by condensing a compound shown as a formula IV and a compound shown as a formula XI;
step four, hydrolyzing and removing the acetyl protecting group by using a compound shown as a formula VIII to obtain a compound shown as a formula IX;
in formulae XI and VIII, R1 represents Ac or Bz; r2 represents Ac or Bz;
11. the method of claim 10, wherein step three is specifically: firstly, adding a compound shown as a formula IV into a solution I, dropwise adding N, O-bis (trimethylsilyl) acetamide, dropwise adding trimethylsilyl trifluoromethanesulfonate, dropwise adding 1,2,3, 5-tetraacetyl-B-D-ribofuranose dissolved in the solution I, and reacting to obtain a compound shown as a formula VIII; the first solution is selected from acetonitrile, DMF, DME, DMA, toluene, tetrahydrofuran and acetone or a combination thereof.
12. The method of claim 10, wherein step three is specifically: adding the compound shown as the formula IV and 1,2,3, 5-tetraacetyl-beta-D-ribofuranose into the second solution under the protection of nitrogen, adding stannic chloride, and reacting to obtain a compound shown as the formula VIII; the second solution is selected from acetonitrile, DMF, DME, DMA, toluene and tetrahydrofuran or a combination thereof.
13. The method of claim 10, wherein step four is specifically: dissolving the compound shown as the formula VIII in an ammonia-methanol solution, and hydrolyzing and deacetylating a protecting group to obtain the compound shown as the formula IX.
14. A synthesis method of cangrelor is characterized by comprising the following steps:
step one, reacting a compound shown as a formula II with a compound shown as a formula V to obtain a compound shown as a formula III;
secondly, reacting a compound shown as a formula III with a compound shown as a formula VI-1, or with a compound shown as a formula VI-2, or with a compound shown as a formula VII-1, or with a compound shown as a formula VII-2 to obtain a compound shown as a formula IV; in the chemical formula, X represents halogen; m represents a metal element;
step three, preparing a compound shown as a formula VIII by condensing a compound shown as a formula IV and a compound shown as a formula XI;
step four, hydrolyzing and removing the acetyl protecting group by using a compound shown as a formula VIII to obtain a compound shown as a formula IX; in formulae XI and VIII, R1 represents Ac or Bz; r2 represents Ac or Bz;
reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline monotributylamine salt, quenching by alkalescent sodium salt, and purifying to obtain cangrelor shown as a formula I;
15. the method of synthesizing cangrelor of claim 14, wherein the weakly basic sodium salt in step five is selected from sodium bicarbonate, sodium carbonate, sodium acetate, sodium citrate, sodium phosphate, and sodium hydrogen phosphate.
16. The method for synthesizing cangrelor according to claim 14, wherein the reaction temperature of the reaction of the compound shown in formula IX with phosphorus oxychloride and mono-n-butylamine chlorochrysophanate in step five is-20 ℃ to 0 ℃.
17. The method for synthesizing cangrelor according to claim 14, wherein the step five is specifically: adding a compound shown as a formula IX and proton sponge into phosphate, cooling to-20-0 ℃, dropwise adding phosphorus oxychloride, adding chlorotetracycline mono-tri-n-butylamine salt and tri-n-butylamine after the compound shown as the formula IX is consumed, stirring for 2-10 hours at-20-0 ℃, reacting, quenching by alkalescent sodium salt, and purifying to obtain cangrelor; wherein the proton sponge is 1, 8-bis-dimethylamino naphthalene.
18. The method for synthesizing cangrelor according to claim 17, wherein the molar ratio of the compound shown in formula IX to 1, 8-bis-dimethylamino-naphthalene to phosphorus oxychloride to chlorotetracycline phosphate to tributylamine is 1: (1-3): (2-6): (3-8): (3-8).
19. The method of synthesizing cangrelor of claim 17, wherein in step five, the compound of formula IX and the proton sponge are added to the phosphate ester such that the concentration of the compound of formula IX in the phosphate ester solvent is 0.1-0.2M; dissolving reaction substrates of chlorotetraphosphate mono-tri-N-butylamine salt and tri-N-butylamine in anhydrous N, N-dimethylformamide at concentrations of 1-2M and 1.5-3M respectively, and then adding the mixture into a reaction system for reaction.
20. The method of claim 14, wherein the purification in step five is performed by separation and purification using reverse phase resin purification.
21. The method of claim 14, wherein the purification in step five is performed by gradient purification on reversed phase resin with eluent of 1-15% 2-propanol in water to obtain cangrelor.
22. The method of synthesizing cangrelor according to claim 14, wherein after quenching with weakly basic sodium salt in step five, separating out an aqueous phase, precipitating solids in the aqueous phase with solution three to obtain a precipitate, and purifying the precipitate to obtain cangrelor; the solution III is selected from dichloromethane, methyl ethyl ketone, acetone, diethyl ether, butyl methyl ether, chloroform, methanol, ethanol, tetrahydrofuran and butanone or a combination thereof.
23. The method of synthesizing cangrelor of claim 22, wherein the quenching and purifying in step five is: slowly pouring a product obtained by reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline phosphate mono-tri-n-butylamine salt into an alkalescent sodium salt aqueous solution, stirring for 2-18 hours at 15-60 ℃, standing and separating phases; adding the water phase into the third solution to obtain a precipitate; and collecting the precipitate, purifying by using a reverse phase chromatographic column, wherein an eluent is 2-8% of 2-propanol aqueous solution, and collecting pure components to obtain cangrelor.
24. The method for synthesizing cangrelor according to claim 22, wherein the quenching and purifying in step five are specifically: slowly pouring a product obtained by reacting a compound shown as a formula IX with phosphorus oxychloride and chlorotetracycline phosphate mono-tri-n-butylamine salt into an alkalescent sodium salt aqueous solution, stirring for 2-18 hours at 15-50 ℃, standing to separate phases, and washing an upper organic phase by using the alkalescent sodium salt aqueous solution; mixing the water phases, and slowly adding the water phases into the third solution to obtain a precipitate; and filtering and collecting the precipitate, washing a filter cake with the solution III, drying, purifying by using a reverse phase chromatographic column, collecting pure components, and drying to obtain cangrelor, wherein an eluent is a 2-8% 2-propanol aqueous solution.
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| CN106008632A (en) * | 2016-05-24 | 2016-10-12 | 伊泰(北京)合成技术有限公司 | Preparation method of Cangrelor intermediate |
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