A kind of synthetic method of edoxaban intermediate

Abstract

The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing an edoxaban intermediate, using N-[(1R, 2R, 5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-thiazolidine [5,4-c] and pyridine-2-formamide (compound 1) as a starting material, reacting with bis(tert-butyloxycarbonyl)amine under the conditions of the presence of an organophosphorus reagent and a condensing agent in a solvent by Mitsunobu reaction to generate compound 2, and removing the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate (compound 3). This route has low cost, and reaction conditions are easily industrialized and easy to achieve, without the characteristics of harsh reaction conditions. It is possible to avoid using expensive protective reagents, and easily explosive sodium azide. The resulting product has the characteristics of simple purification, reliable quality, and the intermediate produced by the method meets the relevant requirements for the production of edoxaban bulk drug.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing an edoxaban intermediate. Background Art

[0002] Edoxaban toluenesulfonate (trade name Lixiana, such as Figure 2 (shown in the figure) is a selective inhibitor of coagulation factor X (FXa) developed by Daiichi Sankyo Co., Ltd. of Japan. It was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on April 22, 2011, and then approved for marketing in my country by the National Medical Products Administration (NMPA) on December 25, 2018.

[0003] Edoxaban mainly acts on coagulation factor X (FXa), which can effectively prevent the formation of blood clots, and can also effectively prevent stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors. It is often used to treat deep vein blood and pulmonary embolism and prevent their recurrence. The effect is equivalent to warfarin, but the risk of major bleeding and cardiovascular death is significantly reduced (2.75% vs 3.43% per year). Edoxaban currently has a good market prospect.

[0004] In 2001, Japan Daiichi Pharmaceutical Co., Ltd. reported two synthetic routes of edoxaban (WO2001074774), such as Figure 3 and Figure 4 As shown. Wherein, the first route has operations such as protection and deprotection, and the process is relatively cumbersome, resulting in problems such as low yield and low purity, and it is difficult to meet the needs of industrialization using the explosive and dangerous reagent sodium azide. Compared with the first route, the second route uses another intermediate of edoxaban, 5-methyl-4,5,6,7-tetrahydrothiazol [5,4-c] pyridine-2-acid, to form amides with one of the amino groups, avoiding the cumbersome steps of protection and deprotection in the first route, and the route is more concise. Currently, there are a number of patents for the preparation of the intermediate (compound 3) reported.

[0005] In 2003, Daiichi Sankyo Co., Ltd. of Japan disclosed the synthetic route of compound 3, such as Figure 5As shown. This route uses (1R, 2S, 5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamic acid tert-butyl ester as raw material, J removes the tert-butyloxycarbonyl group with hydrochloric acid, and then reacts with 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid lithium to undergo amide condensation reaction, and finally catalytic hydrogenation is used to reduce the azide to generate amino groups to obtain compound 3. The preparation route of the starting material of this route is long, the operation steps are cumbersome, and more dangerous chemical reagents such as sodium azide are used, which has high requirements for safety facilities, resulting in expensive starting materials. The first step reaction in this route has a low yield, and the final product needs to be subjected to column chromatography, which is not conducive to industrial production.

[0006] In 2023, Huang Chengguan et al. (KR2022087933A) disclosed a new route for preparing cis-diamine structures by Mitsunobu reaction using phthalimide as a nitrogen source, such as Figure 6 As shown. Compound 1 is used as a raw material, a Mitsunobu reaction is carried out under DEAD / PPh3 conditions, and then a hydrazine hydrolysis reaction is carried out with hydrazine hydrate to obtain compound 3. This route utilizes the high stereoselectivity of the Mitsunobu reaction, but the overall yield is not high. In the final reaction, hydrazine hydrate is used for degradation, and the obtained product contains a large amount of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-acyl degradation products, and the product quality is not high.

[0007] In 2024, patent WO 2024 / 053350 reported a production method using compound 1 as a raw material and diphenylphosphoryl azide (DPPA) as an azidation reagent, first azidated and then reduced to intermediate 4 under the conditions of condensation agent DIAD and triphenylphosphine, such as Figure 7 Although this route has a shorter number of steps and the safety is greatly improved by replacing sodium azide with DPPA, it still has the disadvantages of poor reaction selectivity and high isomer content.

[0008] Therefore, it is of great significance to seek a method for preparing edoxaban intermediates (compound 3) with easily controllable reaction conditions and safety and environmental protection. Summary of the invention

[0009] In order to solve the above technical problems, the present invention provides a method for synthesizing an edoxaban intermediate. This route has mild reaction conditions, no harsh reaction conditions such as high temperature and low temperature, and can avoid the use of highly toxic and unsafe sodium azide. The reaction conditions are easy to control and are safe and environmentally friendly.

[0010] The technical scheme adopted by the present invention is as follows: a method for preparing an edoxaban intermediate, which uses N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolidine[5,4-c]pyridine-2-carboxamide (compound 1) as a starting material, reacts it with bis(tert-butyloxycarbonyl)amine through a Mitsunobu reaction in the presence of an organic phosphorus reagent and a condensation agent in a solvent to generate compound 2, and removes the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate (compound 3).

[0011]

[0012] The specific steps include:

[0013] Step 1), N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Compound 1) is used as a starting material, and reacts with bis(tert-butyloxycarbonyl)amine in the presence of a base, an organophosphorus reagent and a condensing agent to generate Compound 2 through Mitsunobu reaction;

[0014] Step 2), removing the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate (compound 3).

[0015] Furthermore, the condensing agent is one or more combinations of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and azodicarbonamide (TMAD). Preferably, diethyl azodicarboxylate (DEAD) is used.

[0016] Furthermore, the organophosphorus reagent is one or more combinations of triphenylphosphine, tributylphosphine, cyanomethylene tri-n-butylphosphine and analogs thereof, preferably triphenylphosphine.

[0017] Furthermore, the ratio of compound 1: bis(tert-butyloxycarbonyl)amine: condensing agent: organic phosphorus is 1: (1-2): (1-2): (1-2.5).

[0018] Furthermore, the Mitsunobu reaction includes reaction temperature and reaction time, the reaction temperature is 0-90°C, preferably 40-60°C; the reaction time is 0.5-10 hours.

[0019] Furthermore, the solvent is one or more combinations of benzene, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably toluene.

[0020] Furthermore, the acid for removing the tert-butyloxycarbonyl group is one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, and camphoric acid.

[0021] By adopting the above scheme, the technical effects and advantages of the present invention are as follows:

[0022] 1. Compared with the prior art, the reaction route of the present invention is shorter, the reagents used are low in cost, the purity of the obtained product is high, and the product quality can meet the subsequent requirements.

[0023] 2. The process conditions adopted by the method of the present invention are mild, avoiding the use of dangerous and highly toxic reagents such as sodium azide, making the reaction safer and easier to operate;

[0024] 3. The present invention adopts Mitsunobu reaction, which has good stereospecificity and the obtained product has high purity.

[0025] 4. The raw materials of the method of the present invention are cheap and easy to obtain, the product purity and yield are both high, and the economy is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is the synthesis route diagram of the edoxaban intermediate provided in the present application;

[0027] Figure 2 is the structural formula of edoxaban p-toluenesulfonate;

[0028] Figure 3 This is the first synthetic route reported in WO2001074774;

[0029] Figure 4 It is the second synthetic route reported in WO2001074774;

[0030] Figure 5 This is the synthetic route of compound 3;

[0031] Figure 6 It is a new route for preparing cis-diamine structures via Mitsunobu reaction using phthalimide as nitrogen source;

[0032] Figure 7 A synthetic route for reducing compound 1 to intermediate 4 is provided;

[0033] Figure 8 The hydrogen nuclear magnetic resonance spectrum of the edoxaban intermediate provided in this application;

[0034] Fig. 9 This is the mass spectrum of the edoxaban intermediate provided in this application. DETAILED DESCRIPTION

[0035] The present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. The embodiments of the present invention are provided for the purpose of illustration and description, and are not intended to be exhaustive or to limit the present invention to the disclosed forms. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiments are selected and described in order to better illustrate the principles and practical applications of the present invention, and to enable those of ordinary skill in the art to understand the present invention and thereby design various embodiments with various modifications suitable for specific uses.

[0036] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present invention. Such structures and technologies are also described in many publications.

[0037] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will apply, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0038] The following are only some specific embodiments of the present invention, and the present invention is not limited to the following embodiments, and there are many variations. All variations that can be directly derived or associated with the content disclosed by ordinary technicians in this field should be considered as the protection scope of the present invention.

[0039] The solvent used herein is commercially available.

[0040] According to the present invention, a most preferred embodiment is provided as follows:

[0041] Example 1

[0042] See also Figure 1 In this embodiment, a method for synthesizing an edoxaban intermediate is provided, comprising the following steps:

[0043]

[0044] Under nitrogen protection, 3.66g of compound 1 (10mmol, 1eq), 2.17g of bis(tert-butyloxycarbonyl)amine (15mmol, 1eq), 3.93g of triphenylphosphine (15mmol, 1.5eq) and 150mL of toluene were placed in a 250ml three-necked round-bottom flask equipped with a stirring device and a thermometer. The reaction device was moved into an ice bath, and 2.61g of diethyl azodicarboxylate (1.5mmol, 1.5eq) was slowly dripped in while the temperature was kept below 10°C. After the addition was completed, it was stirred for 15 minutes, the flask was removed from the ice bath, and the reaction was stirred at 50°C for 12 hours. After the reaction was completed, 100ml of saturated sodium bicarbonate aqueous solution was added to wash the organic layer twice. The aqueous layers were combined and extracted with 50ml of toluene. The organic layer was collected, anhydrous magnesium chloride was added, stirred for 30 minutes, and then dried for 5h. The solid was filtered out, and the excess solvent and other volatile reaction components were removed under reduced pressure. 40 ml of hexane was slowly added dropwise to the obtained oily mixture, and 5.14 g of a white solid (Compound 2) was obtained by suction filtration. The yield was 91%.

[0045]

[0046] Under nitrogen protection, 1.00 g of compound 2 (1.77 mmol) was dissolved in dichloromethane and placed in a 50 ml three-necked round-bottom flask equipped with a stirring device and a thermometer. 2M hydrochloric acid ethanol solution (3 mL) was slowly added and stirred at room temperature for 10 hours. After the reaction was completed, a white solid was precipitated, the solvent was filtered off, and dichloromethane was added for washing to obtain 0.68 g of a white solid (compound 3), with a yield of 88%.

[0047] MS (ESI+) m / z 366.28 [M+H]; 1 HNMR (400MHz, Chloroform-d) δ7.49 (d, J=6.3Hz, 1H), 4.34 (dd, J=8.9, 4.1Hz, 1H), 3.70 (d, J=9.8Hz, 4H), 3.02(s, 3H), 2.98–2.88(m, 8H), 2.82(d, J=5.3Hz, 2H), 2.50(s, 3H), 2.27–2.19(m, 1H), 1.73–1.58(m, 2H).

[0048] The purity was tested by high performance liquid chromatography and the purity was 98.2%. Figure 8 , the mass spectrum of edoxaban intermediate is shown in Fig. 9 .

[0049] Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field and related fields without creative work should fall within the scope of protection of the present invention. The structures, devices and operating methods not specifically described and explained in the present invention are implemented according to the conventional means in the field unless otherwise specified and limited.

Claims

1. A method for synthesizing an edoxaban intermediate, characterized in that: Using N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Compound 1) as the starting material, the following synthetic route was used to obtain: The method comprises the following steps: generating compound 2 by Mitsunobu reaction with bis(tert-butyloxycarbonyl)amine in the presence of an organic phosphorus reagent and a condensing agent in a solvent; and removing the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate (compound 3).

2. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The specific steps include: Step 1), N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Compound 1) is used as a starting material, and reacts with bis(tert-butyloxycarbonyl)amine in the presence of a base, an organophosphorus reagent and a condensing agent to generate Compound 2 through Mitsunobu reaction; Step 2), removing the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate (compound 3).

3. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The condensation agent is one or more combinations of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and azodicarbonamide (TMAD).

4. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The organophosphorus reagent is one or more combinations of triphenylphosphine, tributylphosphine, cyanomethylene tri-n-butylphosphine and the like.

5. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The ratio of the compound 1: bis(tert-butyloxycarbonyl)amine: condensing agent: organic phosphorus is 1: (1-2): (1-2): (1-2.5).

6. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The Mitsunobu reaction includes reaction temperature and reaction time. The reaction temperature is 0-90° C. and the reaction time is 0.5-10 hours.

7. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The solvent is one or more combinations of benzene, toluene, tetrahydrofuran, ethyl ether, methyl tert-butyl ether, isopropyl ether and dioxane.

8. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: The acid for removing the tert-butyloxycarbonyl group is one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, and camphoric acid.

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