CN103626745B - A kind of preparation method of ticagrelor midbody - Google Patents
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- 0 CCCS*(cc1)*c(C)c1[N+2] Chemical compound CCCS*(cc1)*c(C)c1[N+2] 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a kind of preparation method of ticagrelor midbody, this preparation method is acid binding agent with tertiary amine, in suitable solvent, at 90-130 DEG C, there is N-aralkyl glycosylation reaction in compound (II) or its salt and compound (III), generates compound (I).Preparation method provided by the invention has the following advantages: effectively prevent solvent and raw material reaction and generate the side reaction of impurity, the present invention has clear superiority qualitatively product; Improve the productive rate of feed stock conversion and product Compound (I), productive rate is 85.8% ~ 89.5%, and product HPLC purity is 98.8% ~ 99.5%, and the transformation efficiency of raw material has clear superiority; Need not confined reaction, equipment is simple, does not need to use withstand voltage reactor, has clear superiority on equipment use compared with prior art.
Description
Technical field
The invention belongs to medical art, particularly relate to a kind of preparation method of ticagrelor midbody.
Background technology
ADZ6140 (ticagrelor), chemical name [1S-[1 α, 2 α, 3 β (1S, 2R), 5 β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropyl amino]-5-(rosickyite base)-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl]-5-(2-hydroxy ethoxy) pentamethylene-1,2-glycol, be by Astrazeneca AB of Sweden (AstraZenecaAB) research and develop a kind of novel, there is optionally antiplatelet drug.The purine 2(purinoceptor2 of this medicine reversibly on vasoactive smooth muscle cell, P2) hypotype P2Y12, obvious restraining effect is had to the platelet aggregation that ADP causes, and oral onset is rapid, effectively can reduce the incidence of acute coronary patient cardiovascular death, myocardial infarction or palsy composite end points.
The structural formula of ADZ6140 is as follows:
(ADZ6140)
Compound (I) is the key intermediate of synthesis ADZ6140,
(Ⅰ)
Patent WO0192263 discloses the following method being prepared ADZ6140 by compound (I):
Step (a): formula I compound and Sodium Nitrite react to obtain formula IV compound in 0-40 DEG C in acetic acid;
Step (b): formula IV compound and formula VI compound react, to obtain formula (V) compound being no more than at the temperature of 40 DEG C;
Step (c): formula (V) compound deprotection in acid condition, with obtained ADZ6140.
The synthetic method disclosing formula I compound in the embodiment 4 of WO0192263 is as follows.
Formula II and formula III compound, in alcohol solvent, take triethylamine as acid binding agent, are airtightly warming up to 120-125 DEG C, reaction 30h, and obtained formula I compound, yield is not counted.
The synthetic method disclosing formula I compound in the embodiment 3,4 of WO1030224 is as follows:
formula II and formula III compound, in ethylene glycol solvent, take triethylamine as acid binding agent, and in 100 DEG C of reaction 9h, yield is respectively 88% and 84%.
Carry out repeating experiment to the existing preparation method of compound (I) to find, with reference to the method for the embodiment 4 of WO0192263, take triethylamine as acid binding agent, ethanol is solvent, airtightly be warming up to 120-125 DEG C, reaction 30h, find that the HPLC content of compound (I) in product only has 3.8%, feed stock conversion is extremely low.And the method for the embodiment 3,4 of reference WO1030224, take triethylamine as acid binding agent, ethylene glycol is solvent, in 100 DEG C of reaction 9h, then find that feedstock conversion is complete, in product, the HPLC content of compound (I) is 72.6%, but there is a content is the impurity of 19.9%.This impurity is carried out being separated and through MS,
1it is compound (VII) that H-NMR confirms impurity:
(Ⅶ)
Compound (VII) is starting compound (III) and the reaction product of solvent ethylene glycol.
So there is following problem in existing preparation method: (1) take ethanol as reaction solvent, and the transformation efficiency of raw material is extremely low; (2) take ethylene glycol as reaction solvent, though feed stock conversion is high, but can there is serious side reaction in solvent and raw material; (3) be reaction solvent with ethanol, need confined reaction, have requirement of withstand voltage to equipment.The problems referred to above have had a strong impact on the preparation efficiency of compound (I).
Summary of the invention
For the problems referred to above that existing preparation method exists, the invention provides a kind of preparation method of ticagrelor midbody, object improves feed stock conversion, avoids starting compound (III) and solvent generation side reaction, reduce the requirement to conversion unit.
The present invention is with 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (compound III) and 2-[[(3aR, 4S, 6R, 6aS)-6-amino-2, 2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, 3]-dioxane penta-4-base] oxygen base]-1-ethanol-L-TARTARIC ACID salt (salt of compound ii) is raw material, triethylamine is acid binding agent, in following different solvents, in 100 DEG C of confined reaction 30h, (chemical compounds I is 2-[((3aR for generation ticagrelor midbody and chemical compounds I, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2, 2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, 3] dioxole-4-base) oxygen base] ethanol).
Extract reaction solution and carry out HPLC detection, result is as shown in table 1:
The L-TARTARIC ACID salt of table 1 compound (II) and compound (III) response situation in different solvents
Numbering | Reaction solvent | The percentage composition (%) of chemical compounds I | The percentage composition (%) of starting compound III |
1 | 2-butanone | 4.27 | 94.08 |
2 | Virahol | 16.59 | 83.32 |
3 | Triethylene glycol | 60.79 | 38.12 |
4 | The trimethyl carbinol | 41.43 | 58.27 |
5 | Isopropylcarbinol | 65.54 | 34.29 |
6 | Glycol dimethyl ether | 19.26 | 80.09 |
7 | Ethylene glycol monomethyl ether | 80.37 | 11.40 |
8 | Dimethyl sulfoxide (DMSO) | 80.79 | 0 |
9 | Propyl carbinol | 88.74 | 5.65 |
As seen from Table 1, with 2-butanone, Virahol, triethylene glycol, the trimethyl carbinol, isopropylcarbinol, glycol dimethyl ether for reaction solvent, feed stock conversion is lower; With ethylene glycol monomethyl ether, dimethyl sulfoxide (DMSO), propyl carbinol for reaction solvent, feed stock conversion is very high, wherein preferred propyl carbinol.When using above-mentioned reaction solvent, do not find that starting compound (III) generates corresponding impurity to solvent reaction.
HPLC condition: WatersX-Bridge250mm*4.6mm5um; Moving phase: water: acetonitrile, gradient is in table 2; Flow velocity: 1mL/min; Ultraviolet detection wavelength: 270nm; Column temperature: 30 DEG C; Retention time 16.8min is compound (I), and retention time 17.5min is starting compound (III).
Table 2 eluent gradient
Time (min) | Water (%) | Acetonitrile (%) |
0 | 75 | 25 |
5 | 75 | 25 |
15 | 20 | 80 |
23 | 20 | 80 |
23.1 | 75 | 25 |
30 | 75 | 25 |
Based on above-mentioned result of study, the present invention proposes the preparation method of a kind of compound (I).This preparation method effectively prevent the side reaction of raw material and reaction solvent, improves the productive rate of product Compound I, can provide highly purified chemical compounds I.
The chemical name of compound (II) is 2-[[(3aR, 4S, 6R, 6aS)-6-amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3]-dioxane penta-4-base] oxygen base]-1-ethanol, can prepare according to described in WO0192263A1.
The chemical name of compound (III) is the chloro-2-of 4,6-bis-(rosickyite base) pyrimidine-5-amine, can prepare according to described in WO05095358A2.
For achieving the above object, the present invention is achieved by the following technical solutions:
The invention provides a kind of method preparing compound (I) with compound (II) and compound (III), reaction formula is as follows:
Formula II compound or its salt, under tertiary amine exists, with propyl carbinol or ethylene glycol monomethyl ether or dimethyl sulfoxide (DMSO) for reaction solvent, reacts with formula III compound, to obtain formula I compound and ticagrelor midbody.
The salt of described compound (II) comprises L-TARTARIC ACID salt, oxalate, dibenzoyl-L-tartaric salt.
Described tertiary amine acid binding agent, includes but not limited to triethylamine or DIPEA.
The molar ratio reacted, temperature, reaction times are tested, to determine best reaction conditions, with the L-TARTARIC ACID salt of (II) compound, formula III compound for starting raw material, triethylamine is acid binding agent, propyl carbinol is solvent, confined reaction, and result as shown in Table 3-5.
Table 3 molar ratio is on the impact (100 DEG C, 40h) of reaction
Molar ratio (the L-TARTARIC ACID salt of (II) compound: formula III compound: triethylamine) | The percentage composition (%) of chemical compounds I | |
1 | 1:1:3 | 83.2 |
2 | 1:1:5 | 87.9 |
3 | 1:1:10 | 88.8 |
4 | 1:1:15 | 88.6 |
5 | 1:1:20 | 85.4 |
Table 4 temperature is on the impact (molar ratio is 1:1:10,40h) of reaction
Temperature (DEG C) | The percentage composition (%) of chemical compounds I | |
1 | 80 | 75.8 |
2 | 90 | 85.6 |
3 | 100 | 88.8 |
4 | 110 | 89.2 |
5 | 120 | 89.8. |
6 | 130 | 90.1 |
140 | 76.4 |
Table 5 time is on the impact (molar ratio is 1:1:10,100 DEG C) of reaction
Time (h) | The percentage composition (%) of chemical compounds I | |
1 | 30 | 82.2 |
2 | 35 | 87.5 |
3 | 45 | 88.1 |
4 | 55 | 88.7 |
5 | 65 | 86.3 |
Based on above-mentioned result of study, the present invention selects best reaction parameter as follows.
Reacting molar ratio in the present invention is formula II compound or its salt: formula III compound: triethylamine=1:1:5 ~ 15.
In the present invention, reaction solvent consumption is the 3-10 of formula II compound charging capacity doubly (reaction solvent volume/compound feed intake quality).
Temperature of reaction of the present invention is within the scope of 90-130 DEG C.
The preferred reaction time of the present invention is 35-55h.
The present invention take propyl carbinol as solvent, and triethylamine is acid binding agent, can carry out under unsealed condition.With molar ratio 1:1:10,100 DEG C of reaction 40h, result is as table 6:
The contrast of the airtight and non-confined reaction result of table 6
Pressure (Mpa) | The percentage composition (%) of chemical compounds I | |
1(is airtight) | 0.1 | 88.8 |
2(is non-airtight) | 0 | 88.6 |
As seen from the data in Table 6, the present invention airtight and non-airtight under implementation result suitable, thus avoid using voltage-resistant reactor, reduce equipment requirements; And in the embodiment 4 of WO0192263, with ethanol being solvent, triethylamine is acid binding agent, 130 DEG C of reactions, ethyl alcohol boiling point 78 DEG C, triethylamine boiling point 89 DEG C, and in reactor, pressure is up to 0.3Mpa, high to equipment requirement of withstand voltage.
Preparation method provided by the invention take tertiary amine as acid binding agent, and N-aralkyl glycosylation reaction occurs for compound (II) or its salt and compound (III), obtained compound (I).
Experimental result shows, preparation method provided by the invention has the following advantages: (1) effectively prevent solvent and raw material reaction and generates the side reaction of impurity, and the method for the embodiment 3,4 of reference WO1030224, the content of this side reaction impurity is 19.9%, the present invention compared with prior art, has clear superiority qualitatively at product; (2) improve the productive rate of feed stock conversion and product Compound (I), productive rate is 85.8% ~ 89.5%, and product HPLC purity is 98.8% ~ 99.5%, and the method for the embodiment 4 of reference WO0192263, feed stock conversion is less than 5%, and the transformation efficiency of raw material has clear superiority; (3) need not confined reaction, equipment is simple, does not need to use withstand voltage reactor, has clear superiority on equipment use compared with prior art.
To sum up, preparation method of the present invention is easy and simple to handle, and yield is higher, good product purity, compared with prior art, has obvious advantage.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.Following examples are intended to describe the present invention in detail, and unrestricted the present invention.
Embodiment 1,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask; add the chloro-2-of 4,6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR; 4S; 6R, 6aS) amino-2, the 2-dimethyl tetrahydro-3aH-cyclopentas [d] [1 of-6-; 3]-dioxane penta-4-base] oxygen base]-1-ethanol-dibenzoyl-L-tartaric salt (17.3g; 68mmol), DIPEA (34.3g, 340mmol) and propyl carbinol (49mL).Be heated to 90 DEG C by airtight for gained reaction mixture, keep 35h in this temperature.Then 30 DEG C are cooled to.Steaming desolventizes.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.5g, yield 85.8%.HPLC purity is 98.8%.
Embodiment 2,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask, add 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR, 4S, 6R, 6aS) amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, the 3]-dioxane penta-4-bases of-6-] oxygen base]-1-ethanol-L-TARTARIC ACID salt (25.0g, 68mmol), triethylamine (68.7g, 680mmol) and ethylene glycol monomethyl ether (50mL).Be heated to 120 DEG C by airtight for gained reaction mixture, keep 40h in this temperature.Then 30 DEG C are cooled to.Steaming desolventizes.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.5g, yield 85.8%.HPLC purity is 99.2%.
Embodiment 3,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask, add 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR, 4S, 6R, 6aS) amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, the 3]-dioxane penta-4-bases of-6-] oxygen base]-1-ethanol-oxalate (20.9g, 68mmol), triethylamine (103.0g, 1020mmol) and ethylene glycol monomethyl ether (161mL).Be heated to 130 DEG C by airtight for gained reaction mixture, keep 45h in this temperature.Then 30 DEG C are cooled to.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.8g, yield 86.9%.HPLC purity is 99.1%.
Embodiment 4,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask, add 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR, 4S, 6R, 6aS) amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, the 3]-dioxane penta-4-bases of-6-] oxygen base]-1-ethanol-L-TARTARIC ACID salt (25.0g, 68mmol), triethylamine (68.7g, 680mmol) and propyl carbinol (100mL).Under normal pressure, gained reaction mixture is heated to 100 DEG C, back flow reaction 45h.Then 30 DEG C are cooled to.Steaming desolventizes.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.6g, yield 86.5%.HPLC purity is 99.2%.
Embodiment 5,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask, add 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR, 4S, 6R, 6aS) amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, the 3]-dioxane penta-4-bases of-6-] oxygen base]-1-ethanol (14.8g, 68mmol), triethylamine (34.3g, 340mmol) and propyl carbinol (150mL).100 DEG C are heated to, reaction 50h by airtight for gained reaction mixture.Then 30 DEG C are cooled to.Steaming desolventizes.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.7g, yield 86.9%.HPLC purity is 98.9%.
Embodiment 6,2-[((3aR, 4S, 6R, 6aS)-6-[[the chloro-2-of 5-amino-6-(rosickyite base) pyrimidine-4-yl] is amino]-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1,3] dioxole-4-base) oxygen base] preparation of ethanol (chemical compounds I)
Get 250mL reaction flask, add 4, the chloro-2-of 6-bis-(rosickyite base) pyrimidine-5-amine (16.1g, 68mmol), 2-[[(3aR, 4S, 6R, 6aS) amino-2,2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, the 3]-dioxane penta-4-bases of-6-] oxygen base]-1-ethanol (14.8g, 68mmol), triethylamine (68.7g, 680mmol) and propyl carbinol (100mL).Under normal pressure, gained reaction mixture is heated to 100 DEG C, back flow reaction 55h.Then 30 DEG C are cooled to.Steaming desolventizes.Add isopropyl acetate and water, separation of phases.Aqueous phase isopropyl acetate extracts, and merges organic phase, washing.Anhydrous magnesium sulfate drying.Filter.Steaming desolventizes, and obtains brown-red oil.After adding normal heptane making beating, obtain white solid 24.9g, yield 87.2%.HPLC purity is 99.4%.
Above embodiment only in order to technical scheme of the present invention to be described, but not is limited; Although with reference to previous embodiment to invention has been detailed description, for the person of ordinary skill of the art, still can modify to the technical scheme described in previous embodiment, or equivalent replacement is carried out to wherein portion of techniques feature; And these amendments or replacement, do not make the essence of appropriate technical solution depart from the spirit and scope of the present invention's technical scheme required for protection.
Claims (4)
1. a preparation method for ticagrelor midbody, is characterized in that,
Formula II compound or its salt, under tertiary amine exists, take ethylene glycol monomethyl ether as reaction solvent, reacts with formula III compound, to obtain formula I compound and ticagrelor midbody; The salt of wherein said formula II compound comprises L-TARTARIC ACID salt, oxalate, dibenzoyl-L-tartaric salt; Described temperature of reaction is 90-130 DEG C, and the reaction times is 35-55h.
2. the preparation method of ticagrelor midbody according to claim 1, is characterized in that: described tertiary amine is triethylamine or DIPEA.
3. the preparation method of ticagrelor midbody according to claim 1, is characterized in that: the volumetric usage of described reaction solvent: compound (II) or its salt quality that feeds intake is 3-10mL/g.
4. the preparation method of ticagrelor midbody according to claim 1, is characterized in that: the molar ratio of reactant is compound (II) or its salt: compound (III): tertiary amine=1:1:5-15.
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CN105503876B (en) * | 2014-09-24 | 2017-09-05 | 海门慧聚药业有限公司 | The preparation method of Ticagrelor |
CN105198864B (en) * | 2015-10-21 | 2018-11-06 | 华仁药业股份有限公司 | A kind of non-solvent preparation of cyclopenta pyrimidine compound |
CN105301142A (en) * | 2015-11-28 | 2016-02-03 | 重庆植恩药业有限公司 | Method for detecting Ticagrelor and related substances by use of performance liquid chromatography |
CN107976497B (en) * | 2017-11-23 | 2020-11-10 | 重庆华邦制药有限公司 | Method for determining synthesis reaction degree of ticagrelor intermediate 1 and application thereof |
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