Preparation method and application of edoxaban intermediate

Abstract

The invention relates to the technical field of pharmaceutical and chemical engineering, in particular to a preparation method and application of an edoxaban intermediate, N-[(1R, 2R, 5S)-5-(dimethyl carbamoyl)-2-hydroxycyclohexyl]-5-methyl-4, 5, 6, 7-thiazolidine-5, 4-c] pyridine-2-formamide is used as a starting material, a solvent is added, the mixture is subjected to a reaction at the temperature of 60-80 DEG C, and the edoxaban intermediate is obtained. In the presence of alkali, an organic phosphorus reagent and a condensing agent, a compound 2 is generated through a Mitsunobu reaction with an N-Boc substituted sulfonamide compound, t-butyloxycarboryl is removed under an acidic condition to generate the edoxaban intermediate, the reaction conditions are mild, no harsh reaction conditions such as high temperature and low temperature exist, and the method is suitable for industrial production. The method can avoid the use of highly toxic and poor-safety sodium azide, has the characteristics of good regioselectivity, high optical purity, simplicity in purification, low cost and the like, and has a very good industrial production prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical industry, and in particular to a method for preparing an edoxaban intermediate and an application thereof. Background Art

[0002] Edoxaban toluenesulfonate was developed by Daiichi Sankyo Co., Ltd. of Japan and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on April 22, 2011, and then approved for marketing by the U.S. Food and Drug Administration (FDA) on January 8, 2015, and approved for marketing by the European Medicines Agency (EMA) on June 19, 2015, and approved for marketing by the National Medical Products Administration (NMPA) on December 25, 2018. It is marketed in Japan by Daiichi Sankyo Co., Ltd. under the trade name Lixiana, as shown in Formula 2.

[0003] Edoxaban is a drug that mainly acts on coagulation factor X (FXa). During the blood coagulation process, the activated form of coagulation factor X (FXa) can convert prothrombin (FII) into active thrombin (FIIa). This process is the key to fibrinogenesis, which ultimately leads to the formation of blood clots. Edoxaban is used to prevent stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, and to treat deep vein thrombosis (DVT) and pulmonary embolism (PE) in adult patients and to prevent the recurrence of DVT and PE. Its efficacy is comparable to that of warfarin, but the risk of major bleeding and cardiovascular death is significantly reduced (2.75% vs 3.43% per year). Edoxaban's annual sales have exceeded US$1 billion, and sales continue to grow, and it is expected to become a "blockbuster" that exceeds US$10 billion.

[0004] The original research route of edoxaban was reported by Daiichi Pharmaceutical Co., Ltd. of Japan in 2001 (WO2001074774). The patent of this route has expired and there is no problem of intellectual property conflict. However, the whole route has many operation steps and the yield is very low, resulting in high cost and lack of market competitiveness. Its synthesis route is shown in Formula 3.

[0005] In 2009, Japan Daiichi Pharmaceutical Co., Ltd. improved its own process based on the original research route (WO2007032498). The improved process is more stable than the original process, and the yield is improved. However, there are still problems such as low yield and low optical purity. In addition, the use of explosive and dangerous reagent sodium azide cannot be avoided, which makes it difficult to meet the needs of industrialization. As shown in Formula 4, the reaction route is long, the use of sodium azide increases the risk of the experiment, and the optical purity of the reaction product is not high.

[0006] Patent WO 2024 / 053350 reports a production method in which intermediate 1 is used as a raw material and diphenylphosphoryl azide (DPPA) is used as an azidation reagent. In the presence of a condensation agent such as DIAD and an organophosphorus reagent, the intermediate 1 is first azidated and then reduced to intermediate 4, as shown in Formula 5. 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.

[0007] Therefore, it is of great significance to seek a method for preparing edoxaban intermediates with easily controllable reaction conditions and safety and environmental protection. Summary of the invention

[0008] In view of the above situation, in order to overcome the defects of the prior art, the present invention provides a method for preparing an edoxaban intermediate and its application. This route has mild reaction conditions, no harsh reaction conditions such as high temperature and low temperature, can avoid the use of highly toxic and unsafe sodium azide, has good regional selectivity, high optical purity, simple purification, low cost, etc., and has a good prospect for industrial production.

[0009] The technical solution adopted by the present invention is as follows: A method for preparing an edoxaban intermediate comprises the following steps:

[0010] Step 1, N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolidine[5,4-c]pyridine-2-carboxamide is used as a starting material, and in a solvent, in the presence of an organophosphorus reagent and a condensing agent, a N-Boc substituted sulfonamide compound is reacted by Mitsunobu reaction to generate compound 2, as shown in Formula 1;

[0011] Step 2, compound 2 is treated with thioglycolic acid and lithium hydroxide in a polar aprotic solvent to remove the substituted sulfonyl group to generate compound 3, as shown in formula 1;

[0012] Step three, compound three is subjected to acidic conditions to remove the tert-butyloxycarbonyl group to generate an edoxaban intermediate, as shown in formula 1.

[0013] Furthermore, the condensing agent in step 1 is one or more combinations of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), and azodicarbonamide (TMAD); preferably azodicarbonamide.

[0014] Furthermore, the organic group R in the N-Boc substituted sulfonamide compound in step 1 is one or more combinations of C1-C6 alkyl, phenyl, substituted phenyl, 2-(trimethylsilyl)ethyl; preferably p-tolyl.

[0015] Furthermore, the organophosphorus reagent in step 1 is one or more combinations of triphenylphosphine, tributylphosphine, cyanomethylene tri-n-butylphosphine and the like; preferably tributylphosphine.

[0016] Furthermore, the weight ratio of the starting material, N-Boc substituted sulfonamide compound, condensing agent and organophosphorus reagent in step 1 is starting material: N-Boc substituted sulfonamide compound: condensing agent: organophosphorus reagent = 1: (1-2): (1-2): (1-2.5).

[0017] Furthermore, in step 1, the reaction temperature of Mitsunobu is 0-90°C; preferably 40-60°C; and the reaction time is 0.5-10 hours.

[0018] Furthermore, the solvent in step 1 is one or more of benzene, toluene, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and dioxane, preferably toluene.

[0019] Furthermore, in step 2, the weight ratio of compound 2, thioglycolic acid and lithium hydroxide is compound 2:thioglycolic acid:lithium hydroxide=1:(1-5):(1-10).

[0020] Furthermore, in step 2, the reaction temperature is 0-90°C; preferably 40-60°C; and the reaction time is 0.5-10 hours.

[0021] Furthermore, the polar aprotic solvent in step 2 is one or more of dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone.

[0022] Furthermore, the acid for removing the tert-butyloxycarbonyl group in step three is one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, and camphoric acid.

[0023] The invention also discloses an application of an edoxaban intermediate in the medical field.

[0024] The beneficial effects achieved by the present invention using the above structure are as follows:

[0025] 1. The present invention has good stereospecificity and the obtained product has high optical purity;

[0026] 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;

[0027] 3. The raw materials of the method of the present invention are easily available, and the pollution caused by the intermediates can be avoided, and the product purity and yield are both high. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings are used to provide a further understanding of the present invention and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention and do not constitute a limitation of the present invention. In the accompanying drawings:

[0029] Figure 1 The reaction process of obtaining the edoxaban intermediate in this scheme;

[0030] Figure 2 is the molecular formula of edoxaban p-toluenesulfonate;

[0031] Figure 3 A reaction formula of edoxaban in the prior art

[0032] Figure 4 It is a reaction formula of edoxaban in the prior art;

[0033] Figure 5 It is a reaction formula of edoxaban in the prior art;

[0034] Figure 6 This is the reaction formula for obtaining compound 2 from the starting materials in this scheme;

[0035] Figure 7 This is the reaction formula for obtaining compound 3 from compound 2 in this scheme;

[0036] Figure 8 This is the reaction formula for obtaining the edoxaban intermediate from compound 3 in this scheme;

[0037] Fig. 9 This is the H NMR spectrum of the edoxaban intermediate;

[0038] Fig.10 This is the mass spectrum of edoxaban intermediate. DETAILED DESCRIPTION

[0039] The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0040] The solvent used herein is commercially available.

[0041] This scheme uses N-[(1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolidine[5,4-c]pyridine-2-carboxamide as the starting material, and reacts it with an N-Boc substituted sulfonamide compound in the presence of a base, an organophosphorus reagent and a condensation agent to generate compound 2 through a Mitsunobu reaction, and finally removes the tert-butyloxycarbonyl group under acidic conditions to generate an edoxaban intermediate.

[0042] According to the present invention, a most preferred embodiment is provided as follows:

[0043] Under nitrogen protection, 3.66 g of starting material (10 mmol, 1 eq) and 8.14 g N-Boc substituted p-toluenesulfonamide (30mmol, 3eq), 6.06g tributylphosphine (30mmol, 3eq) and 150mL tetrahydrofuran 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 5.16g azodicarbonamide (30mmol, 3eq) was slowly added dropwise while the temperature was kept below 10°C. After the addition was completed, the flask was taken out from the ice bath, and the reaction was stirred at room temperature for 14 hours; after the reaction was completed, 150ml of isopropyl ether was added for dilution, and the mixture was washed twice with 100ml of saturated sodium bicarbonate aqueous solution; the aqueous layers were combined and extracted with 100ml of ether; the organic layers were collected and dried with anhydrous sodium sulfate for 3h; the anhydrous sodium sulfate was removed by filtration, and the excess solvent and other volatile reaction components were removed under reduced pressure. The obtained oily mixture was slurried with 40ml of isopropyl ether, and 20ml of hexane was slowly added dropwise; a white solid was precipitated, and it was filtered under reduced pressure, and the filter cake was washed with 200ml The mixture was washed with 50% (v / v) isopropyl ether hexane solution; the solvent was removed by concentration under reduced pressure to obtain 5.14 g of a white solid (Compound II) with a yield of 83%, as shown in Formula 6.

[0044] Under nitrogen protection, 3.1g of compound 2 (5mmol, 1eq) and 1.15g of thioglycolic acid (12.5mmol, 2.5eq) were dissolved in 30mL of dimethyl sulfoxide solution, and 1.26g of lithium hydroxide monohydrate was gradually added in batches; the reaction was carried out at room temperature for 2h, and after the reaction was completed, 60mL of dichloromethane and 60mL of saturated sodium bicarbonate were used for extraction, and the organic layer was washed with 60mL of saturated brine, and the organic layer was dried with anhydrous sodium sulfate for 3h; the anhydrous sodium sulfate was filtered off, and the dichloromethane was removed under reduced pressure. A light yellow oil was obtained, and 10ml of 50% (v / v) isopropyl ether hexane solution was added to pulp, and solid precipitated. 1.84g of light yellow solid (compound III) was obtained by suction filtration, and the yield was 79.3%, as shown in Formula 7.

[0045] Under nitrogen protection, 1.00 g of compound III (2.15 mmol) was added to 2 M ethanolic hydrochloric acid solution (6 mL) and stirred at room temperature for 16 hours; the mixture was placed in a 50 ml three-necked round-bottom flask equipped with a stirring device and a thermometer; the reaction was stirred at room temperature and monitored by TLC. After the reaction was completed, a white solid was precipitated, the solvent was filtered off, and dichloromethane was added for washing to obtain 0.63 g of a white solid (edoxaban intermediate) with a yield of 67%, as shown in Formula 8.

[0046] 1 H NMR(CDCl3)δ7.52(d,J=6.3Hz,1H),4.24–4.22(m,1H),3.73(d,J=15.5Hz,1H),3.68(d,J=15 .5Hz,1H),3.14(ddd,J=12.0,4.0,4.0Hz,1H),2.99(s,3H),2.94(dd,J=5.7,5.7Hz,2H),2.9 1(s,3H),2.82(ddd,J=12.8,5.7,5.7Hz,1H),2.80(ddd,J=12.8,5.7,5.7Hz,1H),2.72(dddd ,J=11.7,11.7,3.4,3.4Hz,1H),2.51(s,3H),2.37–2.34(m,1H),1.83–1.68(m,4H),1.47(br s, 2H), 1.46 (dddd, J = 12.0, 12.0, 12.0, 4.0 Hz, 1H); MS (ESI +) m / z 367.17 [M + H], 389.14 [M + Na]; the purity was detected by high performance liquid chromatography, the conditions are as follows: chromatographic column: C18 (4.6mm x 250mm, 5μm); column temperature: 40 ° C; flow rate: 1.0mL / min; running time: 40min; detection wavelength: 210nm; injection volume: 10μL; mobile phase A: 3000mL aqueous solution containing 8.0g of potassium dihydrogen phosphate and 9.0g of sodium octane sulfonate, adjusted to pH 2.5 with phosphoric acid, mobile phase B: acetonitrile; gradient elution; liquid chromatography monitoring, the content is 99.3%, and the isomer content is 0.2%. The nuclear magnetic resonance hydrogen spectrum of the intermediate of edoxaban is shown in Fig. 9 , the mass spectrum of edoxaban intermediate is shown in Fig.10 .

[0047] It should be noted that, in this article, the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or apparatus.

[0048] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an edoxaban intermediate, characterized in that: The 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 as the starting material, in a solvent, in the presence of an organophosphorus reagent and a condensing agent, N -Boc substituted sulfonamide compounds are reacted by Mitsunobu reaction to generate compound 2; Step 2, compound 2 is subjected to desulfonyl substitution with thioglycolic acid and lithium hydroxide in a polar aprotic solvent to generate compound 3; Step three, compound three is subjected to acidic conditions to remove the tert-butyloxycarbonyl group to generate an edoxaban intermediate.

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

3. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: As described in step 1 N The organic group R in the -Boc substituted sulfonamide compound is one or more combinations of C1-C6 alkyl, phenyl, substituted phenyl, and 2-(trimethylsilyl)ethyl.

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

5. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: The starting material described in step 1, N -Boc substituted sulfonamide compound, condensation agent and organophosphorus reagent are used as starting materials in a weight ratio: N -Boc substituted sulfonamide compounds: condensation agent: organophosphorus reagent = 1: (1~2): (1~2): (1~2.5).

6. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: In step 1, the reaction temperature of Mitsunobu is 0-90°C, preferably 40-60°C, and the reaction time is 0.5-10 hours.

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

8. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: The weight ratio of compound 2, thioglycolic acid and lithium hydroxide in step 2 is compound 2:thioglycolic acid:lithium hydroxide = 1:(1-5):(1-10).

9. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: The reaction temperature in step 2 is 0-90°C; preferably 40-60°C; the reaction time is 0.5-10 hours; The polar aprotic solvent in step 2 is dimethyl sulfoxide, N,N- Dimethylformamide, N - one or more of methyl pyrrolidone.

10. The method for preparing an edoxaban intermediate according to claim 1, characterized in that: The acid for removing the tert-butyloxycarbonyl group in step 3 is one or more of hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, and camphoric acid.

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