Preparation method for ticagrelor intermediate

Abstract

The invention provides a preparation method for ticagrelor intermediate. The preparation method comprises the following steps: using tertiary amine as an acid-binding agent, performing N-aromatic alkylated reaction on a compound (II) or salt of the compound (II) and a compound (III) in an appropriate solvent at the temperature of 90 to 130 DEG C, and generating a compound (I). The preparation method provided by the invention has the following advantages: side reaction of impurity generated in the reaction of the solvent and raw materials can be effectively avoided, the preparation method has obvious superiority on product quality, the raw material conversion rate and productive rate of the product compound (I) are improved, the productive rate is 85.8% to 89.5%, the HPLC purity of the product is 98.8% to 99.5%, the preparation method has obvious superiority on raw material conversion rate, sealed reaction is not needed, equipment is simple, a pressure-resistant reaction kettle is not needed to be used, and compared with the prior art, the preparation method has obvious superiority on equipment use.

Description

technical field

[0001] The invention belongs to the technical field of medicine, in particular to a preparation method of a ticagrelor intermediate. Background technique

[0002] Ticagrelor, chemical name [1S-[1α,2α,3β(1S,2R),5β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino ]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol is a new type of selective antiplatelet drug developed by AstraZeneca AB of Sweden. The drug can reversibly act on the purine 2 (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells, and has obvious inhibitory effect on ADP-induced platelet aggregation. Incidence of a composite endpoint of vascular death, myocardial infarction, or stroke.

[0003] The structural formula of ticagrelor is as follows:

[0004]

[0005] (ticagrelor)

[0006] Compound (I) is a key intermediate for the synthesis of ticagrelor,

[0007]

[0008] (I)

[0009] Patent WO 0192263 discloses the following meth...

Examples

Embodiment 1

[0066] Example 1, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0067]

[0068] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-dibenzoyl- L-tartrate (17.3 g, 68 mmol), N,N-diisopropylethylamine (34.3 g, 340 mmol) and n-butanol (49 mL). The resulting reaction mixture was heated to 90 °C under airtight and kept at this temperature for 35 h. It was then cooled to 30°C. The solvent was evaporated. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-brown oil. Aft...

Embodiment 2

[0069] Example 2, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0070]

[0071] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-L-tartrate ( 25.0 g, 68 mmol), triethylamine (68.7 g, 680 mmol), and ethylene glycol monomethyl ether (50 mL). The resulting reaction mixture was heated to 120 °C in a closed manner and maintained at this temperature for 40 h. It was then cooled to 30°C. The solvent was evaporated. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-br...

Embodiment 3

[0072] Example 3, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0073]

[0074] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-oxalate (20.9 g, 68 mmol), triethylamine (103.0 g, 1020 mmol) and ethylene glycol monomethyl ether (161 mL). The resulting reaction mixture was heated to 130 °C under airtight and kept at this temperature for 45 h. It was then cooled to 30°C. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-brown oil. After adding n-heptane for beat...

technical field

[0001] The invention belongs to the technical field of medicine, in particular to a preparation method of a ticagrelor intermediate. Background technique

[0002] Ticagrelor, chemical name [1S-[1α,2α,3β(1S,2R),5β]]-3-[7-[2-(3,4-difluorophenyl)-cyclopropylamino ]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1 ,2-diol is a new type of selective antiplatelet drug developed by AstraZeneca AB of Sweden. The drug can reversibly act on the purine 2 (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells, and has obvious inhibitory effect on ADP-induced platelet aggregation. Incidence of a composite endpoint of vascular death, myocardial infarction, or stroke.

[0003] The structural formula of ticagrelor is as follows:

[0004]

[0005] (ticagrelor)

[0006] Compound (I) is a key intermediate for the synthesis of ticagrelor,

[0007]

[0008] (I)

[0009] Patent WO 0192263 discloses the following meth...

Examples

Embodiment 1

[0066] Example 1, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0067]

[0068] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-dibenzoyl- L-tartrate (17.3 g, 68 mmol), N,N-diisopropylethylamine (34.3 g, 340 mmol) and n-butanol (49 mL). The resulting reaction mixture was heated to 90 °C under airtight and kept at this temperature for 35 h. It was then cooled to 30°C. The solvent was evaporated. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-brown oil. Aft...

Embodiment 2

[0069] Example 2, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0070]

[0071] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-L-tartrate ( 25.0 g, 68 mmol), triethylamine (68.7 g, 680 mmol), and ethylene glycol monomethyl ether (50 mL). The resulting reaction mixture was heated to 120 °C in a closed manner and maintained at this temperature for 40 h. It was then cooled to 30°C. The solvent was evaporated. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-br...

Embodiment 3

[0072] Example 3, 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2- Preparation of Dimethyltetrahydro-3aH-Cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound Ⅰ)

[0073]

[0074] Take a 250mL reaction bottle, add 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1 g, 68 mmol), 2-[[(3aR,4S,6R,6aS)-6-amino -2,2-Dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy]-1-ethanol-oxalate (20.9 g, 68 mmol), triethylamine (103.0 g, 1020 mmol) and ethylene glycol monomethyl ether (161 mL). The resulting reaction mixture was heated to 130 °C under airtight and kept at this temperature for 45 h. It was then cooled to 30°C. Isopropyl acetate and water were added and the phases were separated. The aqueous phase was extracted with isopropyl acetate, and the organic phases were combined and washed with water. Dry over anhydrous magnesium sulfate. filter. The solvent was evaporated to obtain a reddish-brown oil. After adding n-heptane for beat...

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