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Rivaroxaban intermediate preparation method

A compound and organic solvent technology, applied in the field of drug synthesis, can solve problems such as high requirements for production equipment, difficult removal, environmental pollution, etc., and achieve the effects of avoiding the use of high-temperature and high-pressure equipment, improving process safety, and reducing production costs.

Inactive Publication Date: 2019-07-26
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1) Methylamine is a gas under normal pressure, and can form an explosive mixture when mixed with air, which leads to high safety risks in industrialized production, and methylamine waste gas in the production process pollutes the environment, which is not conducive to environmental protection;
[0008] 2) The use of methylamine gas for aminolysis requires the use of a closed pressure-resistant reactor, which has high requirements for production equipment and restricts the increase in production capacity;
[0009] 3) When methylamine is used for aminolysis, the amount of methylamine used is usually greater than 50 equivalents. After the reaction, it is necessary to remove a large excess of methylamine residues through complex procedures such as filtration, neutralization, extraction, and washing. Low, high production cost;
[0010] 4) The compound of the intermediate formula I obtained by using the methylamine aminolysis process has a high content of the compound of the impurity formula III, which is difficult to remove and is not conducive to controlling the quality of the subsequent rivaroxaban bulk drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Put the compound of formula II (42.1g), ethanol (252mL) and n-butylamine (47.2g, 8eq) into the reaction flask, heat up to 75-80°C, and keep the reaction for 8-12 hours. After the reaction, the reaction solution was cooled to Stir at 0-5°C for 1 hour, then filter the obtained solid, rinse the filter cake with ethanol (20 mL) and dry to obtain the intermediate compound of formula I (23.3 g), with a purity (HPLC) of 99.57% and a yield of 80%.

[0031] The characterization data of the intermediate formula I compound prepared in Example 1 are as follows: mp: 149-151° C.; [α] 20 D (C=0.01g / mL, water)=-59.4°; TOF-MS (ES + ): 292.16[M+H]; 1 H NMR (DMSO-d 6 , 400MHz) δ: 7.56(d, J=8.8Hz, 2H), 7.41(d, J=8.8Hz, 2H), 4.93~4.88(m, 2H), 4.18(s, 2H), 4.15(m, 1H ), 4.16(d, J=8.8Hz, 1H), 3.98~3.92(m, 3H), 3.71(t, J=5.2Hz, 2H), 3.14~3.10(m, 2H); 13 C NMR (DMSO-d 6 , 100MHz) δ: 166.16, 153.98, 137.34, 136.57, 126.03, 118.70, 70.84, 67.87, 63.63, 49.17, 47.45, 42.32.

Embodiment 2 to Embodiment 9

[0033] According to the operation process of embodiment 1, under the situation that the charging capacity (42.1g) of compound of formula II remains constant, change solvent and consumption thereof, the consumption of n-butylamine and reaction temperature, the results are shown in the following table 1.

[0034] Table 1

[0035] Example number Solvent and dosage The dosage of n-butylamine temperature reflex yield 2 Ethanol (252mL) 64.9g (11eq) 75～80℃ 88％ 3 Ethanol (252mL) 88.5g (15eq) 75～80℃ 86％ 4 Ethanol (421mL) 64.9g (11eq) 75～80℃ 84％ 5 Methanol (252mL) 64.9g (11eq) 60～65℃ 78％ 6 n-propanol (252mL) 64.9g (11eq) 75～80℃ 83％ 7 Isopropanol (252mL) 64.9g (11eq) 75～80℃ 82％ 8 n-Butanol (252mL) 64.9g (11eq) 95～100℃ 85％ 9 tert-butanol (252mL) 64.9g (11eq) 75～80℃ 81％

[0036] As can be seen from Table 1, embodiment 2 is optimum process condition.

[0037] After testing, the characterizat...

Embodiment 10

[0038] Embodiment 10: under above-mentioned optimal process condition, replace n-butylamine with n-propylamine

[0039] Put the compound of formula II (42.1g), ethanol (252mL), and n-propylamine (64.9g, 11eq) into the reaction flask, raise the temperature to 75-80°C, and keep the reaction for 20-24 hours. After the reaction, cool the reaction solution to 0 ~5°C, heat preservation and stirring for 1 hour, filter the resulting solid, rinse the filter cake with ethanol (10 mL) and dry to obtain the intermediate compound of formula I (23.9 g), with a purity (HPLC) of 99.8% and a yield of 82%.

[0040] After testing, the characterization data of the intermediate formula I compound prepared in Example 10 is consistent with the characterization data of the intermediate formula I compound prepared in Example 1.

[0041] The above embodiments are only a part of the preferred implementation of the present invention, and from a technical perspective, some optimizations in the described i...

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Abstract

The invention provides a preparation method of a Rivaroxaban intermediate compound in a formula I. The method includes dissolving a compound in a formula II in an organic solvent; and carrying out ammonolysis reaction by taking C3-4 alkyl primary ammonia as an ammonia source to obtain the compound in the formula I. The preparation method is safer, economical, simple and convenient, environment-friendly and suitable for industrialization.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a rivaroxaban intermediate. Background technique [0002] Rivaroxaban (Rivaroxaban) is a new type of anticoagulant drug developed by Bayer, and is a highly selective oral drug for factor Xa inhibitors. Rivaroxaban can highly selectively and competitively inhibit the activity of free and bound factor Xa and prothrombin, and is used to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients after hip and knee arthroplasty It can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the risk of coronary artery syndrome recurrence. Rivaroxaban was first launched in Canada in September 2008. It was subsequently approved in more than 120 countries around the world. The chemical name of rivaroxaban is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3- Ox...

Claims

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Application Information

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IPC IPC(8): C07D413/10
CPCC07D413/10
Inventor 杨会林吕华成王臻朱国荣屠勇军
Owner ZHEJIANG TIANYU PHARMA
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