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Preparation method of ticagrelor intermediate

A technology for ticagrelor and intermediates, which is applied in the field of preparation of ticagrelor intermediates, can solve problems such as being unsuitable for industrial production, cumbersome operations, increase production costs and the like, and achieves mature and reliable preparation methods, high atom economy, and reduced production costs. Effects of unit operations

Inactive Publication Date: 2013-10-16
SINOPHARM ZHIJUN (SHENZHEN) PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The disadvantages of this method are: (1) The preparation of the target product 2 from compound 3 requires the use of benzyloxycarbonyl for amine protection, which has poor atom economy, and benzyl chloroformate is highly toxic and seriously pollutes the environment
(2) Intermediates 6 and 7 are oily at room temperature and cannot be purified by recrystallization or salt formation. The literature uses column chromatography for purification, which is costly and cumbersome to operate, and is not suitable for industrial production
(3) This route needs to use palladium-carbon catalytic hydrogenation twice, which increases the production cost, and intermediate 4 has no absorption under ultraviolet light, which is not conducive to the real-time monitoring of the reaction
This shows, the cost of above-mentioned synthetic method is higher, and environmental pollution is serious, is not suitable for industrialization

Method used

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  • Preparation method of ticagrelor intermediate
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  • Preparation method of ticagrelor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] [3aR-(3aα,4α,6α,6aα)]-6-(Benzyl)amino-tetrahydro-2,2-dimethyl-4H-cyclopentadieno-1,3-dioxa Preparation of cyclopentan-4-ol (8)

[0066]

[0067] (1S,2S,6S,7S)-9-Benzylamino-4,4-dimethyl-3,5,8-trioxa-9-aza-tricyclo[5.2.1.0 2,6 ] Decane (3) (39.0g, 0.15mol), zinc powder (19.5g, 0.30mol) and methyl tert-butyl ether (230mL) were added to a 1000mL reaction flask, and glacial acetic acid (43ml) was slowly added at 0°C , Stir at room temperature for 24h after addition. Filter, adjust the pH of the filtrate to 8-9 with saturated sodium carbonate aqueous solution, separate the liquids, extract the aqueous phase with methyl tert-butyl ether (100mL×2), combine the organic phases, wash with saturated aqueous sodium chloride solution (100mL), wash with anhydrous sulfuric acid Sodium dry. Filter and concentrate to dryness under reduced pressure to obtain 39.1 g of a brown oily substance with a yield of 99%.

[0068] ESI-MS(m / z):264.15[M+H] + ;

[0069] 1 HNMR (400MHz, CDCl ...

Embodiment 2

[0071] 3aR-(3aα,4α,6α,6aα)]-2-[[6-(Benzyl)amino-tetrahydro-2,2-dimethyl-4H-cyclopentadiene-1,3- Preparation of dioxol-4-yl]oxy]-ethyl acetate (10-1)

[0072]

[0073] Methyl tert-butyl ether (40mL) and potassium tert-butoxide (5.3g, 47.5mmol) were added to a 250mL reaction flask, and compound 8 (5.0g, 19.0mmol) in methyl tert-butyl ether ( 20mL) solution, add and keep stirring for 20min. At -15°C, methyl tert-butyl ether (10 mL) dissolved in ethyl chloroacetate (5.8 g, 47.3 mmol) was added dropwise, and stirred at room temperature for 30 min after the drop was completed. Add oxalic acid dihydrate (2.5g) in batches and stir for 30min, wash with water (30mL), separate the liquids, wash the organic phase with water (30mL) and combine the water phase, adjust the pH to 8-9 with saturated sodium carbonate aqueous solution, methyl tert-butyl Extracted with ether (30mL×2), washed with saturated sodium chloride (30mL), dried over anhydrous sodium sulfate and concentrated to drynes...

Embodiment 3

[0077] [3aR-(3aα,4α,6α,6aα)]-2-[[6-(Benzyl)amino-tetrahydro-2,2-dimethyl-4H-cyclopentadiene-1,3 Preparation of -dioxol-4-yl]oxy]-isobutyl acetate (10-2)

[0078]

[0079] Add dry ethylene glycol dimethyl ether (40mL) and sodium hydride (60%w / w, 4.6g, 116mmol) into a 250mL reaction flask, and add compound 8 (8.7g, 33.0mmol) in ethylene glycol dropwise at -20°C Alcohol dimethyl ether (20mL) solution, after adding, keep stirring for 6h. At -20°C, a solution of isobutyl bromoacetate (32.5 g, 116 mol) in ethylene glycol dimethyl ether (10 mL) was added dropwise, and the solution was raised to room temperature and stirred for 12 h after the drop. Add oxalic acid dihydrate (4.2g) in batches and stir for 30min, wash with water (30mL), separate the liquids, wash the organic phase with water (30mL) and combine the water phase, adjust the pH to 8-9 with saturated aqueous sodium carbonate solution, and add ethylene glycol dimethyl Extracted with ether (30mL×2), washed with saturated ...

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Abstract

The invention discloses a preparation method of a ticagrelor intermediate. The preparation method comprises the following steps: (1) reacting a compound in formula (8) with a compound in formula (9), so as to obtain a compound in formula (10); (2) carrying out ester group reduction on the compound in formula (10), so as to obtain a compound in formula (11); (3) desorbing benzyl protection of the compound in formula (11), so as to obtain a compound in formula (2). A synthetic method and a path provided by the invention have the advantages of short reaction step, high atom economy and low cost, and are environmentally friendly and suitable for industrial production. General formulas are as follows (as shown in the specification).

Description

technical field [0001] The present invention relates to ticagrelor intermediate [3aR-(3aα, 4α, 6α, 6aα)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1 , The preparation method of 3-dioxol-4-yl]oxy]-ethanol or its salt. Background technique [0002] Ticagrelor is a novel, selective small molecule anticoagulant drug developed by AstraZeneca, which reversibly acts on the purine 2 receptor subtype on vascular smooth muscle cells P2Y 12 , has obvious inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP), and takes effect rapidly after oral administration, and can effectively improve the symptoms of patients with acute coronary syndrome (ACS). In July 2011, ticagrelor was approved for marketing by the US Food and Drug Administration (FDA), and has been widely used in clinical practice. [0003] The compound ticagrelor was first disclosed in WO2000034283, the chemical name is (1S,2S,3R,5S)-3-{7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino...

Claims

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Application Information

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IPC IPC(8): C07D317/44
CPCY02P20/55
Inventor 李建其马志龙周峰黄雷
Owner SINOPHARM ZHIJUN (SHENZHEN) PHARMA CO LTD
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