CN105481922A - Preparation method of cangrelor intermediate - Google Patents
Preparation method of cangrelor intermediate Download PDFInfo
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- CN105481922A CN105481922A CN201510881033.6A CN201510881033A CN105481922A CN 105481922 A CN105481922 A CN 105481922A CN 201510881033 A CN201510881033 A CN 201510881033A CN 105481922 A CN105481922 A CN 105481922A
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- MVTGXPHKBGAXTE-ZECRFQQMSA-N CC(O[C@H]([C@@H]1OC(C)=O)[C@H]([n]2c(nc(nc3NCCSC)SCCC(F)(F)F)c3nc2)O/C1=C/OC(C)=O)=O Chemical compound CC(O[C@H]([C@@H]1OC(C)=O)[C@H]([n]2c(nc(nc3NCCSC)SCCC(F)(F)F)c3nc2)O/C1=C/OC(C)=O)=O MVTGXPHKBGAXTE-ZECRFQQMSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The purpose of the invention is to solve defects in the prior art by providing a new preparation method of a cangrelor intermediate (represented by formula I). The preparation method comprises the following steps: carrying out a sealed tube reaction on a compound represented by formula II, and ammonifying the above obtained material to form a compound represented by formula III; coupling the amino compound III with tetraacetylribofuranose under the action of a catalyst to obtain a compound represented by formula V; reducing the nitro compound V through a reducing system to obtain a compound represented by formula VI; carrying out a cyclization reaction on the amino compound VI and ortho-formate to obtain a compound represented by VII; coupling the compound VII with 2-methylthioethylamine (represented by formula VIII) in the presence of an alkali to obtain a compound represented by IX; and removing protection groups from the compound IX in the presence of the alkali to obtain the cangrelor intermediate (represented by the formula I). The preparation method adopting the above technical route has the advantages of mild reaction conditions, high yield, wide sources of raw materials, and environmental protection.
Description
Technical field:
The invention relates to a kind of chemical preparation process of cangrelor intermediate (formula I), there is reaction conditions gentleness, yield is high, raw material sources are extensive, advantages of environment protection.
Background technology:
Cangrelor is developed by AstraZeneca, authorizes the reversibility P2Y of TheMedicinesCompany exploitation
12receptor antagonist, there is the features such as rapid-action, the transformation period is short, be a kind of desirable vein antiplatelet drug, blood clot harmful in prevention heart coronary artery is formed, and the potentiality for the acute thrombus such as percutaneous coronary intervention (pci) and acute coronary syndrome is prevented.On June 22nd, 2015, cangrelor was through FDA approval listing, and preparation specification is 50mg lyophilized injectable powder, trade(brand)name Kengreal.
The structural formula of cangrelor is as follows:
The cangrelor preparation method of current bibliographical information, Jin You Astrazeneca AB is following operational path disclosed in patent CN1042430:
Formula I involved in route is a key intermediate in cangrelor preparation process, and its stable source and cheap synthesis cost are the keys of producing cangrelor bulk drug.
Development company TheMedicinesCompany discloses its preparation process of a kind of formula I in document (J.Med.Chem.1999,42,213-220):
Wherein, the preparation of formula 1 can the preparation method of reference Chem.Pharm.Bull.25 (8) 1959-1969 (1977), and route is as follows:
This synthesis route uses the hazardous agents such as sodium hydride, iodo class expensive starting materials and source is rare, amplifies and produces difficulty.Synthesize total recovery on the low side, the rearrangement ring-closure reaction yield building pyrimidine ring only has 50-75%, without production cost advantage simultaneously.The market supply of raw material 2-sulfydryl adenosine is few, needs the dithiocarbonic anhydride using severe toxicity during oneself synthesis, and has the hydrogen sulfide of severe toxicity to produce, and to producers and environmental pollution, is unfavorable for suitability for industrialized production.
The preparation method of another kind of formula I is disclosed in patent CN105061431:
In this synthetic route, raw material sources are extensive.But the building process of adenosine ring, needs the SBA using more than monovalent to carry out amido protecting, and uses the catalyzer TMSOTF of more than monovalent, add production cost, and bring difficulty to separation and purification, be unfavorable for the requirement of environmental protection.
Summary of the invention:
The object of the present invention is to provide a kind of preparation method of new cangrelor intermediate (formula I), to solve defect of the prior art.The present invention adopt technological line has reaction conditions gentleness, yield is high, raw material sources are extensive, advantages of environment protection.
The technical solution used in the present invention is:
In step one, reaction solvent is protonic solvent, comprises water, methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols, the trimethyl carbinol;
In step one, temperature of reaction is 30 ~ 120 DEG C;
In step 2, catalyzer is methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, tosic acid, Phenylsulfonic acid or sulfuric acid;
In step 2, the temperature of reaction is 40 ~ 140 DEG C;
In step 3, reductive agent can adopt the reduction system of this area routine to carry out, preferred following reduction system: hydrogen/palladium, hydrogen/nickel, zinc powder/acetic acid, iron powder/acetic acid, formic acid/nickel, hydrazine hydrate/nickel;
In step 3, the temperature of reduction reaction is-20 ~ 140 DEG C;
In step 4, described ortho-formiate is triethyl orthoformate or trimethyl orthoformate;
In step 5, described alkali is salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, N-methyl piperidine or N-methylmorpholine, preferred triethylamine or salt of wormwood.
In step 5, temperature of reaction is 40 ~ 150 DEG C.
The preparation process of cangrelor intermediate (formula I) comprising:
Formula II and ammonia carry out tube sealing reaction, and ammonification obtains formula III; Aminocompound III, under the effect of catalyzer, obtains formula V with tetra-acetylated ribose IV coupling; Nitro-compound V is through the effect of reduction system, and reduction obtains formula VI; Aminocompound VI and ortho-formiate obtain formula VII through ring-closure reaction; Formula VII in the presence of base, obtains formula IX with 2-methylthio group ethamine (formula VIII) coupling; In the presence of base, deprotection base obtains cangrelor intermediate formula I to Compound I X.
In the present invention, the method that formula II can refer to patent CN102718749 is prepared.
Method of the present invention has reaction conditions gentleness, raw material is easy to get, post-reaction treatment facilitates, environmental friendliness, product yield advantages of higher, is suitable for industrialization and produces.
Embodiment:
Each embodiment further illustrates the present invention below, but does not form any limitation of the invention.
The preparation of the chloro-5-nitro of embodiment 1:6--4-amino-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (III):
Under room temperature, chloro-for Compound II per 4,6-bis-5-nitro-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (32.2g, 100mmol) is dissolved in 80ml dehydrated alcohol, then adds 150ml ammoniacal liquor in system.System be transferred in enclosed high pressure valve, system is reacted 3 hours at outer temperature 80 DEG C, is down to room temperature and stirs 1 hour again, filters, 50% washing with alcohol, dry, obtains faint yellow title compound 24.8g, yield 82%.ESI-MS：[M+H]
+＝303.61。
The preparation of the chloro-5-nitro of embodiment 2:6--4-amino-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (III):
Under room temperature, chloro-for Compound II per 4,6-bis-5-nitro-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (32.2g, 100mmol) is dissolved in the 80ml trimethyl carbinol, then adds 150ml ammoniacal liquor in system.System be transferred in enclosed high pressure valve, system is reacted 6 hours at outer temperature 30 DEG C, is down to room temperature and stirs 1 hour again, filters, 50% trimethyl carbinol washing, dry, obtains faint yellow title compound 25.7g, yield 85%.ESI-MS：[M+H]
+＝303.61。
The preparation of the chloro-5-nitro of embodiment 3:6--4-amino-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (III):
Under room temperature, chloro-for Compound II per 4,6-bis-5-nitro-2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine (32.2g, 100mmol) is suspended in 80ml water, then adds 150ml ammoniacal liquor in system.System be transferred in enclosed high pressure valve, system is reacted 2 hours at outer temperature 120 DEG C, is down to room temperature and stirs 1 hour again, filters, 50% washing with alcohol, dry, obtains faint yellow title compound 24.2g, yield 80%.ESI-MS：[M+H]
+＝303.61。
Embodiment 4:(2R, 3R, 4S, 5R)-2-(the chloro-5-nitro of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (V):
Under nitrogen protection, the chloro-5-nitro of compound III 6--4-amino-2-(3,3; 3-trifluoropropyl sulfenyl) pyrimidine (30.3g, 100mmol) is suspended in 100ml dimethylbenzene, adds trifluoromethanesulfonic acid (0.45g; 3mmol), reaction system is warming up to 140 DEG C.Slowly drip the solution that the tetra-acetylated ribose (63.6g, 200mmol) of compound IV is dissolved in 100ml dimethylbenzene, rate of addition is 8ml/min, dropwises rear back flow reaction 1 hour.Stopped reaction, is down to room temperature, adds water 100ml, regulates PH=8-9 with sodium hydrogen carbonate solution, leave standstill separatory, after organic phase drying concentrating under reduced pressure as, obtain title compound as oil 51.6g, yield 92%.ESI-MS：[M+H]
+＝561.9。
Embodiment 5:(2R, 3R, 4S, 5R)-2-(the chloro-5-nitro of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (V):
Under nitrogen protection, the chloro-5-nitro of compound III 6--4-amino-2-(3,3; 3-trifluoropropyl sulfenyl) pyrimidine (30.3g, 100mmol) is suspended in 100ml toluene, adds sulfuric acid (0.30g; 3mmol), reaction system is warming up to 110 DEG C.Slowly drip the solution that the tetra-acetylated ribose (63.6g, 200mmol) of compound IV is dissolved in 100ml toluene, rate of addition is 8ml/min, dropwises rear back flow reaction 1 hour.Stopped reaction, is down to room temperature, adds water 100ml, regulates PH=8-9 with sodium hydrogen carbonate solution, and leave standstill separatory, be evaporated to dry after organic phase drying, obtain title compound as oil 49.9g, yield 89%, product is directly used in the next step.ESI-MS：[M+H]
+＝561.9。
Embodiment 6:(2R, 3R, 4S, 5R)-2-(the chloro-5-nitro of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (V):
Under nitrogen protection, the chloro-5-nitro of compound III 6--4-amino-2-(3,3; 3-trifluoropropyl sulfenyl) pyrimidine (30.3g, 100mmol) is dissolved in 100ml acetonitrile, adds tosic acid (0.52g; 3mmol), reaction system is warming up to 40 DEG C.Slowly drip the solution that the tetra-acetylated ribose (63.6g, 200mmol) of compound IV is dissolved in 100ml toluene, rate of addition is 8ml/min, dropwises rear back flow reaction 1 hour.Stopped reaction, is down to room temperature, is evaporated to 60ml volume, adds 100ml water and 100ml toluene, regulate PH=8-9 with sodium hydrogen carbonate solution, leave standstill separatory, be evaporated to dry after organic phase drying, obtain title compound as oil 52.7g, yield 94%, product is directly used in the next step.ESI-MS：[M+H]
+＝561.9。
Embodiment 7:(2R, 3R, 4S, 5R)-2-(the chloro-5-amino of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (VI):
Under 40psi pressure, compound V (2R, 3R, 4S, 5R)-2-(the chloro-5-nitro of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl amino)-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (56.1g, 100mmol) and 2% (w/w) 5%Pt/C are suspended in the mixture of tetrahydrofuran (THF), hydrogenation 5 hours at 25-30 DEG C.By mixed solution diatomite filtration, and wash with tetrahydrofuran (THF).Merging filtrate, is evaporated to 150ml volume, and add water precipitation solid, filters, and washing is dry, obtains title compound 50.4g, yield 95%.ESI-MS：[M+H]
+＝531.9，
1HNMR-δ(CDCl
3)/300MHz)：6.15(d，1H，J＝5.2)，5.91(t，1H)，5.63(t，1H)，4.40-4.36(m，2H，)，4.33(m，1H)，3.19(m，2H)，2.79(m，2H)，2.13(s，3H)，2.12(s，3H)，2.11(s，3H)。
Embodiment 8:(2R, 3R, 4S, 5R)-2-(the chloro-5-amino of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (VI):
Under nitrogen protection; compound V (2R; 3R; 4S; 5R)-2-(the chloro-5-nitro of 6--2-(3; 3; 3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino)-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (56.1g, 100mmol) and zinc powder (32.5g; 500mmol) be suspended in dimethylbenzene; be incubated at 140 DEG C, slowly add acetic acid (12.0g, 200mmol); insulated and stirred half an hour, filter and also wash 2 times with hot dimethylbenzene.Merging filtrate, is evaporated to 20ml volume, and add water precipitation solid, filters, and washing is dry, obtains title compound 48.8g, yield 92%.ESI-MS：[M+H]
+＝531.9，
1HNMR-δ(CDCl
3)/300MHz)：6.15(d，1H，J＝5.2)，5.91(t，1H)，5.63(t，1H)，4.40-4.36(m，2H，)，4.33(m，1H)，3.19(m，2H)，2.79(m，2H)，2.13(s，3H)，2.12(s，3H)，2.11(s，3H)。
Embodiment 9:(2R, 3R, 4S, 5R)-2-(the chloro-5-amino of 6--2-(3,3,3-trifluoropropyl sulfenyl) pyrimidine-4-yl is amino) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (VI):
Under nitrogen protection; compound V (2R; 3R; 4S; 5R)-2-(the chloro-5-nitro of 6--2-(3; 3; 3-trifluoropropyl sulfenyl) pyrimidine-4-yl amino)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (56.1g, 100mmol) and Raney's nickel (2.5g) are suspended in ethanol, are incubated at-20 DEG C; slowly add the hydrazine hydrate (7.5g of 80%; 120mmol), insulated and stirred 2 hours, filters and washs 2 times with hot ethanol.Merging filtrate, is evaporated to 40ml volume, and add water precipitation solid, filters, and washing is dry, obtains title compound 51.0g, yield 96%.ESI-MS：[M+H]
+＝531.9，
1HNMR-δ(CDCl
3)/300MHz)：6.15(d，1H，J＝5.2)，5.91(t，1H)，5.63(t，1H)，4.40-4.36(m，2H，)，4.33(m，1H)，3.19(m，2H)，2.79(m，2H)，2.13(s，3H)，2.12(s，3H)，2.11(s，3H)。
Embodiment 10:(2R, 3R, 4S, 5R)-2-(the chloro-2-(3 of 6-, 3,3-trifluoropropyl sulfenyl) pyrimidine-9H-purine-9-base) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (VII):
Under nitrogen protection; compound (2R; 3R; 4S, 5R)-2-(the chloro-5-amino of 6--2-(3,3; 3-trifluoropropyl sulfenyl) pyrimidine-4-yl amino)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (53.1g, 100mmol) joins in 260ml triethyl orthoformate, in suspension liquid.Under room temperature condition, slowly drip concentrated hydrochloric acid (30.0g, 300mmol), reaction system becomes muddiness again after becoming clarification from muddiness.After dropwising, stirred at ambient temperature half an hour, stopped reaction.Filtering reacting liquid, by petroleum ether, dry, obtain title compound 49.2g, yield 91%.ESI-MS：[M+H]
+＝541.9，
1HNMR-δ(CDCl
3)/300MHz)：8.10(s，1H)，6.14(d，1H，J＝5.3)，5.92(t，1H)，5.62(t，1H)，4.44-4.37(m，2H，)，4.34(m，1H)，3.18(m，2H)，2.78(m，2H)，2.12(s，3H)，2.11(s，3H)，2.10(s，3H)。
Embodiment 11:(2R, 3R, 4S, 5R)-2-(the chloro-2-(3 of 6-, 3,3-trifluoropropyl sulfenyl) pyrimidine-9H-purine-9-base) preparation of-5-acetyl-o-methyl-3,4-bis-(acetoxyl group) tetrahydrofuran (THF) (VII):
Under nitrogen protection; compound (2R; 3R; 4S, 5R)-2-(the chloro-5-amino of 6--2-(3,3; 3-trifluoropropyl sulfenyl) pyrimidine-4-yl amino)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (53.1g, 100mmol) joins in 250ml trimethyl orthoformate, in suspension liquid.Under room temperature condition, slowly drip concentrated hydrochloric acid (30.0g, 300mmol), reaction system becomes muddiness again after becoming clarification from muddiness.After dropwising, stirred at ambient temperature half an hour, stopped reaction.Filtering reacting liquid, by petroleum ether, dry, obtain title compound 48.7g, yield 90%.ESI-MS：[M+H]
+＝541.9，
1HNMR-δ(CDCl
3)/300MHz)：8.10(s，1H)，6.14(d，1H，J＝5.3)，5.92(t，1H)，5.62(t，1H)，4.44-4.37(m，2H，)，4.34(m，1H)，3.18(m，2H)，2.78(m，2H)，2.12(s，3H)，2.11(s，3H)，2.10(s，3H)。
The preparation of embodiment 12:O, O, O-triacetyl-6-N-(2-methylmercaptoethyl)-2-(3,3,3-trifluoropropyl sulfenyl) adenosine (IX):
Under nitrogen protection; compound VI I (2R; 3R; 4S; 5R)-2-(the chloro-2-(3 of 6-; 3; 3-trifluoropropyl sulfenyl) pyrimidine-9H-purine-9-base)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (54.1g; 100mmol) be suspended in 200ml tetrahydrofuran (THF) with compound VI II2-(methylthio group) ethamine (9.1g, 100mmol), add triethylamine (30.3g; 300mmol), stirring reaction 2 hours at 65 DEG C.Reaction solution is cooled to room temperature, concentrating under reduced pressure reaction solution, adds toluene and water, regulate PH to 8-9 with dilute hydrochloric acid, separatory.After organic phase drying, be evaporated to dry, obtain title compound as oil 55.3g, yield 93%, product is directly used in the next step.ESI-MS：[M+H]
+＝596.6。
The preparation of embodiment 13:O, O, O-triacetyl-6-N-(2-methylmercaptoethyl)-2-(3,3,3-trifluoropropyl sulfenyl) adenosine (IX):
Under nitrogen protection; compound VI I (2R; 3R; 4S; 5R)-2-(the chloro-2-(3 of 6-; 3; 3-trifluoropropyl sulfenyl) pyrimidine-9H-purine-9-base)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (54.1g; 100mmol) be suspended in 200mlDMF with compound VI II2-(methylthio group) ethamine (9.1g, 100mmol), add salt of wormwood (41.4g; 300mmol), stirring reaction 1 hour at 150 DEG C.Be cooled to room temperature, concentrating under reduced pressure reaction solution, add toluene and water, regulate PH to 8-9 with dilute hydrochloric acid, separatory.After organic phase drying, be evaporated to dry, obtain title compound as oil 52.4g, yield 88%, product is directly used in the next step.ESI-MS：[M+H]
+＝596.6。
The preparation of embodiment 14:O, O, O-triacetyl-6-N-(2-methylmercaptoethyl)-2-(3,3,3-trifluoropropyl sulfenyl) adenosine (IX):
Under nitrogen protection; compound VI I (2R; 3R; 4S; 5R)-2-(the chloro-2-(3 of 6-; 3; 3-trifluoropropyl sulfenyl) pyrimidine-9H-purine-9-base)-5-acetyl-o-methyl-3; 4-bis-(acetoxyl group) tetrahydrofuran (THF) (54.1g; 100mmol) be suspended in 200ml acetonitrile with compound VI II2-(methylthio group) ethamine (9.1g, 100mmol), add pyridine (23.7g; 300mmol), stirring reaction 6 hours at 40 DEG C.Concentrating under reduced pressure reaction solution, adds toluene and water, regulates PH to 8-9, separatory with dilute hydrochloric acid.After organic phase drying, be evaporated to dry, obtain title compound as oil 54.1g, yield 91%, product is directly used in the next step.ESI-MS：[M+H]
+＝596.6。
The preparation of embodiment 15:6-N-(2-methylmercaptoethyl)-2-(3,3,3-trifluoropropyl sulfenyl) adenosine (I):
Under nitrogen protection; Compound I XO; O; O-triacetyl-6-N-(2-methylmercaptoethyl)-2-(3; 3,3-trifluoropropyl sulfenyl) adenosine (59.6g, 100mmol) is suspended in the sodium hydroxide-ethanol (667ml of 0.15mol/l; 100mmol), in stirred at ambient temperature 1 hour.Drip acetic acid (12.0g, 200mmol), after dripping off, stir half an hour.Reaction solution is evaporated to residue 80ml, adds water, separate out solid, filter, washing, dry, obtain title compound 41.7g, HPLC purity 99.75%, yield 89%.ESI-MS：[M+H]
+＝470.5，
1HNMR-δ(DMSO-d6)/300MHz)：8.28(s，1H，)，8.15(s，1H)，5.82(d，1H，J＝6.2)，5.45(d，1H，J＝6.2)，5.21(d，1H，J＝4.9)，5.09(t，1H)，4.56(m，1H)，4.12(m，1H)，3.90(m，1H)，3.57(m，4H)，3.28(m，2H)，2.71(m，4H)，2.09(s，3H)。
Claims (10)
1. a preparation method for new cangrelor intermediate (formula I), comprises the steps:
(1) formula II and ammonia carry out tube sealing reaction, and ammonification obtains formula III;
(2) aminocompound III is under the effect of catalyzer, obtains formula V with tetra-acetylated ribose IV coupling;
(3) nitro-compound V is through the effect of reduction system, and reduction obtains formula VI;
(4) aminocompound VI and ortho-formiate obtain formula VII through ring-closure reaction;
(5) formula VII in the presence of base, obtains formula IX with 2-methylthio group ethamine (formula VIII) coupling;
(6) Compound I X in the presence of base, and deprotection base obtains cangrelor intermediate formula I.
。
2. preparation method according to claim 1, is characterized in that, in step one, reaction solvent is protonic solvent, comprises water, methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols, the trimethyl carbinol.
3. preparation method according to claim 1, is characterized in that, in step one, temperature of reaction is 30 ~ 120 DEG C.
4. preparation method according to claim 1, is characterized in that, in step 2, catalyzer is methylsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, tosic acid, Phenylsulfonic acid or sulfuric acid.
5. preparation method according to claim 1, is characterized in that, in step 2, the temperature of reaction is 40 ~ 140 DEG C.
6. preparation method according to claim 1, it is characterized in that, in step 3, reductive agent can adopt the reduction system of this area routine to carry out, preferred following reduction system: hydrogen/palladium, hydrogen/nickel, zinc powder/acetic acid, iron powder/acetic acid, formic acid/nickel, hydrazine hydrate/nickel.
7. preparation method according to claim 1, is characterized in that, in step 3, the temperature of reduction reaction is-20 ~ 140 DEG C.
8. preparation method according to claim 1, is characterized in that, in step 4, described ortho-formiate is triethyl orthoformate or trimethyl orthoformate.
9. preparation method according to claim 1, it is characterized in that, in step 5, described alkali is salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, diisopropylethylamine, pyridine, N-methyl piperidine or N-methylmorpholine, preferred triethylamine or salt of wormwood.
10. preparation method according to claim 1, is characterized in that, in step 5, temperature of reaction is 40 ~ 150 DEG C.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061431A (en) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof |
| CN105949258A (en) * | 2016-05-06 | 2016-09-21 | 浙江永宁药业股份有限公司 | Synthesis method of cangrelor intermediate |
| CN106397516A (en) * | 2016-08-30 | 2017-02-15 | 田博 | Kengreal intermediates as well as preparation methods and application thereof |
| CN109320574A (en) * | 2017-08-01 | 2019-02-12 | 北京桦冠医药科技有限公司 | A kind of industrialized process for preparing of cangrelor intermediate |
| CN109369756A (en) * | 2018-12-21 | 2019-02-22 | 山东铂源药业有限公司 | A kind of capecitabine impurity and its synthetic method |
| CN109912673A (en) * | 2017-12-12 | 2019-06-21 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
Citations (1)
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| CN105061431A (en) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof |
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| CN105061431A (en) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061431A (en) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-N-(2-(methylthio)ethyl)-2-((3,3,3-trifluoropropyl)sulfo)-9H-purine, and preparation method and application thereof |
| CN105949258A (en) * | 2016-05-06 | 2016-09-21 | 浙江永宁药业股份有限公司 | Synthesis method of cangrelor intermediate |
| CN105949258B (en) * | 2016-05-06 | 2019-05-31 | 浙江永宁药业股份有限公司 | A kind of synthetic method of cangrelor intermediate |
| CN106397516A (en) * | 2016-08-30 | 2017-02-15 | 田博 | Kengreal intermediates as well as preparation methods and application thereof |
| CN106397516B (en) * | 2016-08-30 | 2019-09-27 | 北京沣瑞医药科技有限公司 | Cangrelor intermediate and its preparation method and application |
| CN109320574A (en) * | 2017-08-01 | 2019-02-12 | 北京桦冠医药科技有限公司 | A kind of industrialized process for preparing of cangrelor intermediate |
| CN109320574B (en) * | 2017-08-01 | 2021-01-05 | 北京桦冠生物技术有限公司 | Industrial preparation method of cangrelor intermediate |
| CN109912673A (en) * | 2017-12-12 | 2019-06-21 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
| CN109912673B (en) * | 2017-12-12 | 2022-01-25 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
| CN109369756A (en) * | 2018-12-21 | 2019-02-22 | 山东铂源药业有限公司 | A kind of capecitabine impurity and its synthetic method |
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