A preparation method of a rivaroxaban intermediate

Abstract

The present invention relates to a preparation method of a rivaroxaban intermediate. This method has fewer reaction steps, a high yield, and at the same time avoids the use of precious metal catalysts, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a preparation method of a rivaroxaban intermediate, belonging to the field of chemistry. Background Art

[0002] Rivaroxaban (English name: Rivaroxaban), an oral antithrombotic drug developed by Bayer, has the following chemical structure: 4-(4-Aminophenyl)-3-morpholinone (the compound shown in formula (I)) is a key intermediate for the synthesis of rivaroxaban. Its synthesis method has been extensively studied, and there are many literature reports on the synthesis method of 4-(4-aminophenyl)-3-morpholinone, which are basically obtained by first preparing 4-(4-nitrophenyl)-3-morpholinone and then reducing the nitro group, such as WO0147919, US7365088, CN102746288, CN102603665, CN102320988, etc. CN103772310A provides a method for obtaining 4-(4-aminophenyl)-3-morpholinone through the degradation reaction of an amide bond, but the preparation step of its amide compound is long, resulting in a significant reduction in the yield. Therefore, there is still room for optimization in the preparation method of this intermediate. Summary of the Invention

[0003] The present invention provides a preparation method of a compound shown in formula (II), including the step of obtaining the compound shown in formula (II) by hydrolysis of the compound shown in formula (III).

[0004]

[0005] In some embodiments, for the preparation method of the compound shown in formula (II) provided by the present invention, the hydrolysis reaction occurs in an acidic environment.

[0006] In some embodiments, for the preparation method of the compound shown in formula (II) provided by the present invention, the acid providing the acidic environment is a strong acid with a pKa less than 1.

[0007] In an optional embodiment, for the preparation method of the compound shown in formula (II) provided by the present invention, the acid providing the acidic environment is selected from sulfuric acid.

[0008] Further, in order to avoid the carbonization phenomenon of the compound of formula III due to the use of concentrated sulfuric acid and ensure the quality of the cyanide hydrolysis reaction, the concentration of sulfuric acid in the present invention is selected from 70% to 90%.

[0009] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, the acid providing the acidic environment is sulfuric acid with a concentration of 70% to 90%. In some other embodiments, the sulfuric acid concentration in the present disclosure includes, but is not limited to, 70%, 75%, 80%, 85%, 90%, or a number between any two of these values.

[0010] On the other hand, the amount of sulfuric acid used in the present invention is 1.5 to 5 equivalents (equiv. or eq.) relative to the amount of the compound of formula III charged (in moles). In embodiments, it can be 1.5 equivalents, 2.0 equivalents, 2.5 equivalents, 3.0 equivalents, 3.5 equivalents, 4.0 equivalents, 4.5 equivalents, 5.0 equivalents, or a number between any two of these values.

[0011] Furthermore, the solvent for the cyano hydrolysis reaction is selected from water. In some embodiments, the cyano hydrolysis reaction is carried out in an 85% aqueous sulfuric acid solution.

[0012] In some embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, it further includes the step of oxidizing the compound represented by formula (IV) to obtain the compound represented by formula (III).

[0013]

[0014] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, the oxidizing agent for the oxidation reaction is sodium chlorite.

[0015] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, it further includes the step of reacting the compound represented by formula (VI) with the compound represented by formula (V).

[0016]

[0017] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, formula (VI)

[0018] The reaction of the compound shown with the compound represented by formula (V) occurs under basic conditions. Optionally, the basic conditions are provided by sodium hydroxide or potassium hydroxide.

[0019] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, formula (VI)

[0020] The reaction of the compound shown with the compound represented by formula (V) occurs under sodium hydroxide conditions.

[0021] In alternative embodiments, for the method for preparing the compound represented by formula (II) provided by the present invention, formula (VI)

[0022] The reaction of the compound shown and the compound shown by formula (V) occurs under the action of a phase transfer catalyst. Optionally, the phase transfer catalyst is tetrabutylammonium bromide.

[0023] In an alternative embodiment, the method for preparing the compound shown by formula (II) provided by the present invention, formula (VI)

[0024] The reaction temperature of the compound shown and the compound shown by formula (V) is selected from 50 - 120 °C.

[0025] In an alternative embodiment, the method for preparing the compound shown by formula (II) provided by the present invention, formula (VI)

[0026] The reaction temperature of the compound shown and the compound shown by formula (V) is selected from 80 - 110 °C.

[0027] In an alternative embodiment, the method for preparing the compound shown by formula (II) provided by the present invention, formula (VI)

[0028] The reaction temperature of the compound shown and the compound shown by formula (V) is selected from 90 - 105 °C.

[0029] In an alternative embodiment, the method for preparing the compound shown by formula (II) provided by the present invention, formula (VI)

[0030] The reaction temperature of the compound shown and the compound shown by formula (V) is selected from 50 °C, 55 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 85 °C, 90 °C, 95 °C, 100 °C, 105 °C, 110 °C, 115 °C or 120 °C, or a value between any two of these point values.

[0031] The present invention provides a method for preparing the compound shown by formula (I), including the preparation step of the compound shown by formula (II) described above, and further including the step of subjecting the compound shown by formula (II) to a Hofmann degradation reaction.

[0032]

[0033] The said Hofmann degradation reaction occurs under the catalysis of sodium hypobromite or sodium hypochlorite.

[0034] In an alternative embodiment, the step of subjecting the compound shown by formula (II) to a Hofmann degradation reaction occurs under the catalysis of sodium hypochlorite.

[0035] The method for preparing the compound shown by formula (I) provided by the present invention has the following specific synthetic route:

[0036]

[0037] The present invention provides a method for preparing rivaroxaban, which includes the preparation steps of the compound shown in the foregoing formula (II) and / or the preparation steps of the compound shown in formula (I).

[0038] A large number of methods for preparing rivaroxaban have been disclosed in the art. Specifically, reference can be made to patents WO2003000256A, WO2005068456A, WO2008052671A, WO2010124385A, CN112538080A, CN104860936A, CN104860936A, etc. The method for preparing rivaroxaban provided in this application can use the compound shown in formula (I) prepared by the foregoing method as an intermediate to further react to obtain the final product.

[0039] The phase transfer catalyst described in the present invention is a type of catalyst that can help the reactants transfer from one phase to another phase where the reaction can occur, thereby accelerating the reaction rate of the heterogeneous system. For example, polyethers, cyclic crown ethers, quaternary ammonium bases, quaternary ammonium salts, tertiary amines, and quaternary phosphonium salts, etc.

[0040] The "to form" and "form" described in the present invention do not specifically refer to the conversion reaction between two substrates as a single-step reaction, and can be a single-step or multi-step reaction between two substrates. If the intermediate contains an amino protecting group, the intermediate is deprotected by an amino protecting agent in one step, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0041] In the present invention, the numerical values are instrument measurement values or calculated values after instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% belongs to the reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, for the content of total impurities, the error of this numerical value after measurement does not exceed plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%. Specific Embodiments

[0042] The present invention will be explained in more detail below in combination with examples or experimental examples. The examples or experimental examples in the present invention are only used to illustrate the technical solutions in the present invention, and do not limit the essence and scope of the present invention.

[0043] The raw materials and equipment used in the specific implementation schemes of the present invention are all known products and are obtained by purchasing commercially available products.

[0044] Example 1. Synthesis of 4-(3-oxomorpholine)benzamide

[0045]

[0046] Add 0.8 g of liquid alkali (30%), 3.5 g of methanol and 17.8 ml of water into the reaction flask. Control the temperature to about 15 - 20 °C. While stirring, add 0.7 g (0.35 mol) of 4-(4-cyanophenyl)morpholin-3-one into the reaction flask in portions. Control the temperature at 30 - 40 °C, and dropwise add 8 g (0.7 mol) of 30% hydrogen peroxide. After adding, keep the temperature for reaction for 1.5 - 2 h.

[0047] After the reaction is completed, cool to room temperature, adjust the pH to 5 - 6 with hydrochloric acid, extract the aqueous phase with dichloromethane, wash with sodium dithionite solution, combine the organic phases, dry, concentrate under reduced pressure, and purify by column chromatography to obtain 5.98 g of a pale yellow solid with a yield of 78% and an HPLC purity of 90.2%.

[0048] Example 2. Synthesis of 4-(3-oxomorpholino)benzamide

[0049]

[0050] Add 7.0 g of 98% sulfuric acid solution into the reaction flask, cool to about 15 °C with ice-salt water. While stirring, add 7 g of 4-(4-cyanophenyl)morpholin-3-one into the reaction flask in portions. Heat to 60 - 70 °C and keep the temperature for reaction for 1.5 - 2 h. After the reaction is completed, cool to room temperature, add ice water. After adding, then dropwise add concentrated ammonia water (25 - 27%) into the reaction, adjust the pH to 6 - 7, extract the aqueous phase with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and purify by column chromatography to obtain 4.98 g of a solid with a yield of 65%.

[0051] Example 3. Synthesis of 4-(3-oxomorpholino)benzamide

[0052]

[0053] Add 7.62 g of 90% sulfuric acid aqueous solution into the reaction flask, cool to about 15 °C with ice-salt water. While stirring, add 7 g of 4-(4-cyanophenyl)morpholin-3-one into the reaction flask in portions. Heat to 60 - 70 °C and keep the temperature for reaction for 2 h. After the reaction is completed, cool to room temperature, add ice water. After adding, then dropwise add concentrated ammonia water (25 - 27%) into the reaction, adjust the pH to 6 - 7, extract the aqueous phase with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and purify by column chromatography to obtain 7.05 g of a solid with a yield of 92%.

[0054] Example 4.

[0055] According to the synthesis method of Example 3, investigate the reaction conditions for synthesizing 4-(3-oxomorpholino)benzamide by adding sulfuric acid with different concentrations, and consider the influence of the amount of sulfuric acid used on the reaction yield. The specific results are shown in Table 1.

[0056] Table 1

[0057] Sequence Sulfuric acid equivalent Sulfuric acid concentration Reaction phenomenon Yield a (%) 1 2 95％ The reaction solution is black 72.2％ 2 2 80％ The reaction solution is light yellow 88.2％ 3 2 70％ The reaction solution is light yellow 85.4％ 4 2 60％ The reaction solution is light yellow A small amount of product 5 2 85％ The reaction solution is yellow 87.3％ 6 4 85％ The reaction solution is yellow 89.7％ 7 4 90％ The reaction solution is yellow 93.2％

[0058] Note: a is the yield after separation.

[0059] Example 5. Synthesis of 4-(4-cyanophenyl)morpholine

[0060]

[0061] Add 5.52 g of 4-chlorobenzonitrile, 17.36 g of morpholine, 30 mL of water, 2.4 g of sodium hydroxide and 0.3 g of tetrabutylammonium bromide to the reaction flask in sequence. Stir and heat up to reflux for reaction for 12 - 14 h. TLC detects that the raw materials have completely reacted. After the reaction is completed, cool down to 20 - 30 °C and stir for 0.5 - 1 h, filter, wash the filter cake with 60 ml of water, and dry to obtain 6.68 g of the compound, with a yield of 87.1% and an HPLC purity of 95%.

[0062] Example 6. Synthesis of 4-(4-cyanophenyl)morpholine

[0063]

[0064] Add 5.52 g of 4-chlorobenzonitrile, 17.36 g of morpholine, 30 mL of anhydrous tetrahydrofuran, and 2.4 g of 60% sodium hydride to the reaction flask in sequence. Stir and heat up to reflux for reaction for 14 h. Cool down to 20 - 30 °C, filter, wash the filter cake with water, and dry to obtain 5.29 g of the compound, with a yield of 68.9% and an HPLC purity of 95%.

[0065] Example 7. Synthesis of 4-(4-aminophenyl)-3-morpholinone

[0066]

[0067] Step 1. Synthesis of 4-(4-cyanophenyl)morpholine (VI)

[0068] Add 688 g of 4-chlorobenzonitrile, 2170 g of morpholine, 3 L of water, 300 g of sodium hydroxide and 34 g of tetrabutylammonium bromide to a 1.0 L reaction flask in sequence. Stir and heat up to 98 - 102 °C for reaction for 12 - 14 h. TLC detects that the raw materials have completely reacted. After the reaction is completed, cool down to 20 - 30 °C and stir for 0.5 - 1 h, filter, wash the filter cake with water, and dry to obtain 827 g of the compound, with a yield of 86.2%. Directly put it into the next-step reaction.

[0069] Step 2. Synthesis of 4-(4-cyanophenyl)morpholin-3-one (III)

[0070] Add 2 L of water, 905 g of sodium chlorite, 72 g of acetic acid and 4 L of acetonitrile to the reaction flask in sequence, and stir until dissolved and clear. Heat up to 40 - 45 °C, and add a total of 753 g of 4-(4-cyanophenyl)morpholine in 4 portions within 2 h. After the addition is complete, control the temperature at 40 - 45 °C and continue the reaction for 2 - 3 h. After the reaction is complete, cool down to below 10 - 20 °C, add about 20% sodium sulfite solution, and stir for 10 min. Then, under the condition of not exceeding 45 °C, recover acetonitrile by vacuum distillation. Filter, wash the filter cake with water, and dry to obtain a wet product, and dry it under vacuum at 50 - 55 °C to obtain 753 g of compound III, with a yield of 93.1%. Directly put it into the next reaction step.

[0071] Step 3, 4-(3-oxomorpholine)benzamide (II)

[0072] Add 760 g of 90% sulfuric acid aqueous solution to the reaction flask, cool it down to about 15 °C with ice-salt water, and add 700 g of 4-(4-cyanophenyl)morpholin-3-one to the reaction flask in portions with stirring. Heat up to 60 - 70 °C and keep the temperature for about 2 h. After the reaction is over, cool it down to room temperature, add 600 g of ice water. After adding, then dropwise add 210 g of concentrated ammonia water (25 - 27%) to the reaction, adjust the pH to 6 - 7, extract the aqueous phase with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and recrystallize with ethyl acetate / petroleum ether to obtain 728 g of a pale yellow solid, with a yield of 94.5%. HPLC purity: 98.3%.

[0073] Step 4, Synthesis of 4-(4-aminophenyl)-3-morpholinone (I)

[0074] Add 500 g of water, 430 g of liquid alkali (30%), and 700 g of 4-(3-oxomorpholine)benzamide (II) to the reaction flask. At 25 - 30 °C, slowly add 1.82 kg of sodium hypochlorite (13%) solution. After the addition is complete, heat up to 70 - 75 °C and keep the temperature for 1.0 - 1.5 h. After the reaction is over, cool it down to room temperature, filter, stir and slurry the filter cake with methanol, and dry it to obtain 510 g of a yellow solid, with a yield of 83.5%, and HPLC purity: 99.1%.

Claims

1. A method for preparing a compound represented by formula (II), comprising the step of subjecting the compound represented by formula (III) to a hydrolysis reaction to obtain the compound represented by formula (II).

2. The preparation method according to claim 1, wherein the hydrolysis reaction occurs in an acidic environment, and the acid providing the acidic environment has a pKa less than 1.

3. The preparation method according to claim 2, wherein the acid providing the acidic environment is selected from sulfuric acid.

4. The preparation method according to claim 3, wherein the acid providing the acidic environment is selected from sulfuric acid with a concentration of 70% - 90%.

5. The preparation method according to claim 1, further comprising the step of oxidizing the compound represented by formula (IV) to obtain the compound represented by formula (III). The oxidizing agent for the oxidation reaction is sodium chlorite.

6. The preparation method according to claim 5, further comprising the step of reacting the compound represented by formula (VI) with the compound represented by formula (V).

7. The preparation method according to claim 6, wherein the reaction between the compound represented by formula (VI) and the compound represented by formula (V) occurs under basic conditions.

8. The preparation method according to claim 7, wherein the basic conditions are provided by sodium hydroxide or potassium hydroxide.

9. The preparation method according to claim 6, wherein the reaction between the compound represented by formula (VI) and the compound represented by formula (V) occurs under the action of a phase transfer catalyst, and the phase transfer catalyst is tetrabutylammonium bromide.

10. The preparation method according to claim 6, wherein the reaction temperature is selected from 50 - 120 °C.

11. The preparation method according to claim 10, wherein the reaction temperature is selected from 80 - 110 °C.

12. The preparation method according to claim 10, wherein the reaction temperature is selected from 90 - 105 °C.

13. A method for preparing a compound represented by formula (I), comprising the preparation steps of the compound represented by formula (II) according to any one of claims 1 to 12, and further comprising the step of subjecting the compound represented by formula (II) to a Hofmann degradation reaction. The Hofmann degradation reaction occurs under the catalysis of sodium hypobromite or sodium hypochlorite.

14. The preparation method according to claim 13, wherein the Hofmann degradation reaction occurs under the catalysis of sodium hypochlorite.

15. A method for preparing rivaroxaban, comprising the preparation steps of the compound represented by formula (II) according to any one of claims 1 to 12 and / or the preparation steps of the compound represented by formula (I) according to claim 13.

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