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Novel preparation method of antithrombosis medicine

A compound, the technology of ticagrelor, which is applied in the new preparation field of ticagrelor, can solve the problems of small chlorine group activity, dark color, and many side reactions, etc.

Inactive Publication Date: 2013-01-16
CHANGZHOU PHARMA FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] First, the raw material Formula-2 used in the patent WO 00 / 34283 is protected by CBZ on the amino group, and reacted with ethyl bromoacetate under strong basic conditions to convert the hydroxyl group into an ethyl oxyacetate group, reduce the ester group, and finally reduce the A total of four steps of deprotection of CBZ are converted into raw material Formula-a. At the same time, the raw material Formula-3 in the above patent is nitro-reduced to obtain the raw material Formula-b. The patent US2003 / 0148888 uses Formula-a and Formula-b as raw materials. Condensation, and then react with sodium nitrite to form a triazole structure, continue to condense with the compound Formula-10, and finally hydrolyze under acidic conditions to remove the protection of the acetonide to obtain ticagrelor. The disadvantage of this route is that the raw material Formula-b has two A chlorine group has low activity, and it needs a high temperature of 100°C for a long time to react with the raw material Formula-a, and the structure of the raw material Formula-a has hydroxyl groups in addition to the amino group, and side reactions will occur during high temperature and long-term reactions. Contains amino groups and is unstable at high temperature. These factors lead to many side reactions in the condensation reaction, and the color is very dark, which brings difficulties to the purification of subsequent intermediates and the yield is difficult to guarantee.
[0014] The difference is that the raw material Formula-3 with higher activity of the chlorine group in the structure is used as the raw material to condense with the compound Formula-a, and then reduce to obtain the intermediate Formula-c. The subsequent reaction steps are consistent with the method reported in the patent US2003 / 0148888. The route also has the problem that the raw material Formula-a has amino groups and hydroxyl groups at the same time, and side reactions are prone to occur when it is condensed with Formula-3, which brings difficulties to the purification of subsequent intermediates

Method used

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  • Novel preparation method of antithrombosis medicine
  • Novel preparation method of antithrombosis medicine
  • Novel preparation method of antithrombosis medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Synthesis of formula Formula-E compound (R is ethyl in the structural formula):

[0075] Add 60g (0.23mol, 1.0eq) of the Formula-D compound (R in the structural formula is ethyl, see US2003 / 0148888 for the preparation method), 140mL (0.74mol, 3.0eq) of DIPEA into 900mL of THF, and stir at room temperature for 0.5 hours. use. Add 99.2g (0.37mol, 1.6eq) of Formula-3 compound into 180mLTHF, cool to 0-5°C, add the above-mentioned ready-to-use solution dropwise under nitrogen protection, and control the temperature at 0-5°C for about one hour. After the dropwise addition, keep the reaction system at 0-5° C. and stir for two hours. TLC detects that there is no remaining raw material. Add 250mL of ethyl acetate to dilute the solution, wash the organic phase with water (300mL), wash once with saturated brine (300mL), dry over anhydrous sodium sulfate, concentrate to obtain 150g of light yellow oil, add 500ml of dichloromethane to the oil and stir to dissolve Then add 300g of ...

Embodiment 2

[0078] Synthesis of formula Formula-F compound (R is ethyl in the structural formula):

[0079] 65g (132mmol) of the compound of formula F was dissolved in 70mL of methanol, and 6.5g of 10% palladium on carbon was added under the protection of nitrogen to replace the hydrogen. The reaction was carried out at room temperature and normal pressure for 20 hours, and there was no remaining raw material as detected by TLC. Palladium carbon was filtered, the filter cake was washed with 50 mL of methanol, and the filtrate was concentrated to obtain 57 g of oil, which was directly used in the next reaction without purification, with a yield of 93.4%.

[0080] NMR δH(CDCl 3 )6.32(1H, d, J=7.6Hz), 4.64(1H, t, J=7.2Hz), 4.57~4.54(2H, m), 4.33~4.20(3H, m), 4.12~4.07(1H, m ), 3.98(1H, d, J=4.0Hz), 3.76(2H, br s), 3.16~3.09(1H, m), 3.03~2.96(1H, m), 2.32~2.25(1H, m), 1.88 (1H, d, J=14.8Hz), 1.77~1.71(2H, m), 1.41(3H, s), 1.29(3H, t, J=7.2Hz), 1.24(3H, s), 1.01(3H, t, J=7.2Hz).

Embodiment 3

[0082] Synthesis of formula Formula-G compound (R is ethyl in the structural formula):

[0083] 52 g (113 mmol, 1.0 eq) of the compound of formula G were dissolved in 150 mL of acetonitrile. Add 30.4mL (226mmol, 2.0eq) of isoamyl nitrite, heat to 70°C and react for 1 hour, TLC detects that no raw material remains. After cooling the reaction to room temperature, it was concentrated to obtain 51.1 g of brown oil with a yield of 96.0%, which was directly used in the next reaction without further purification.

[0084] NMR δH(CDCl 3 )5.52 (1H, q, J=3.5Hz), 5.18 (1H, dt, J=10.0Hz, J=3.5Hz), 4.85 (1H, dd, J=6.5Hz, J=2.0Hz), 4.20~4.11 (3H, m), 4.08 (2H, d, J=4.0Hz), 3.24~3.18(2H, m), 2.79~2.73(2H, m), 1.87~1.80(2H, m), 1.55(3H, s ), 1.36(3H, s), 1.26(3H, t, J=7.5Hz), 1.09(3H, J=7.5Hz).

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Abstract

The invention provides a novel preparation method which is easily industrially achieved and is simple and convenient to carry out and is established under a new intermediate. The invention relates to a novel preparation method of micromolecule anticoagulant Ticagrelor, and synchronously relates to an intermediate body for synthesizing the Ticagrelor and a preparation method of the intermediate. With the adoption of the synthesis method provided by the invention, the side reaction in the reaction process can be effectively reduced, the purity of the intermediate is improved, and the purifying way of the intermediate is simplified.

Description

Technical field: [0001] The present invention relates to a new preparation method of ticagrelor, in addition, the present invention also relates to a new intermediate used in the method. Background technique: [0002] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist. Ticagrelor can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC), and has obvious inhibitory effect on ADP-induced platelet aggregation, and it takes effect rapidly after oral administration, so it can effectively improve acute Symptoms in patients with coronary heart disease. Because the antiplatelet effect of ticagrelor is reversible, it is especially suitable for patients who require surgery after prior anticoagulant therapy. [0003] The results of the study showed that compared with clopidogrel, ticagrelor can significantly ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D487/04
CPCC07D405/12C07D487/04
Inventor 王兵孙光祥顾斌王敏峰
Owner CHANGZHOU PHARMA FACTORY
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