Synthesis method of an edoxaban intermediate

Abstract

The present invention discloses a method for synthesizing an edoxaban intermediate. First, the raw material (S)-(−)-3-cyclohexene carboxylic acid is oxidized by potassium permanganate to generate intermediate 2; intermediate 2 reacts with methanesulfonyl chloride to generate intermediate 3; intermediate 3 reacts with ammonia in ethanol to generate intermediate 4; intermediate 4 undergoes a self-cyclization reaction under the catalysis of EDCI and HOBt to generate intermediate 5; intermediate 5 reacts with benzyl chloride to generate intermediate 6; intermediate 6 is hydrolyzed under alkaline conditions and reacts with Boc2O simultaneously to generate intermediate 7; intermediate 7 undergoes a condensation reaction with dimethylamine to generate intermediate 8; intermediate 8 is hydrogenated to remove the benzyl group to generate the edoxaban intermediate. The synthesis method of the present invention has simple operation steps, high chiral selectivity, is beneficial to improving the product yield and reducing the production cost, and does not use the dangerous reagent sodium azide, reducing the production risk and ensuring the safety and operability of the reaction.

Description

Technical Field

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

[0002] Edoxaban is an antiplatelet aggregation drug, which can inhibit thrombin activity and prevent thrombosis, and can be used for the treatment or prevention of thrombotic diseases. It is used for adult patients with non-valvular atrial fibrillation with one or more risk factors (such as congestive heart failure, hypertension, age ≥ 75 years, diabetes, history of previous stroke or transient ischemic attack) to prevent stroke and systemic embolism. It is used for the treatment of adult deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrence of adult deep vein thrombosis and pulmonary embolism.

[0003] [(1R,2S,5S)-2-Amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamic acid tert-butyl ester is a key intermediate in the synthesis of edoxaban, and edoxaban can be prepared by condensing this intermediate with two side chains. The common synthetic process routes of the existing edoxaban intermediate [(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamic acid tert-butyl ester are as follows.

[0004] Synthetic Route 1: This route uses (S)-(-)-3-cyclohexene carboxylic acid as the starting material, and obtains Intermediate VI through 7 steps of reactions. Then, through mesylation, azidation, hydrolysis, amidation, and hydroamination, a total of 11 steps of reactions are carried out to obtain the edoxaban intermediate. The reaction equation is as shown below. In the process of azidating the mesylate in this route, the reaction yield is only about 30%, the diastereoselectivity is not high, and the steps are relatively long, the yield is low, and the cost is high.

[0005]

[0006] Synthetic Route 2: The synthetic method disclosed in Patent CN 111606826A is as follows: Diene synthesis is carried out on the compound II thiophene derivative and acrylic acid, and after chiral resolution, Compound IV is obtained; amidation reaction is carried out with dimethylamine hydrochloride to obtain Compound V; reaction is carried out with di-tert-butyl dicarbonate in a hydrogen atmosphere to obtain Compound VI and Compound VI'; finally, through deprotection of the amino group and chiral resolution, Compound I, that is, the edoxaban intermediate, is obtained. Although this route has a shorter synthetic route, the raw materials and reagents used are relatively expensive, and chiral resolution is required, the yield is low, and the cost is high.

[0007]

[0008] In summary, the existing synthetic process route is long, the synthetic technology is complex, the raw materials used are expensive and dangerous, and no satisfactory results have been achieved in the improvement of the synthetic process. Therefore, it is of great significance to develop a route with short steps, high yield, environmental friendliness and suitable for industrial scale-up production. SUMMARY OF THE INVENTION

[0009] In view of the above technical problems existing in the synthesis process of the existing edoxaban intermediate, the present invention provides a preparation method of an edoxaban intermediate, which uses (S)-(-)-3-cyclohexene carboxylic acid as a starting material, and is subjected to potassium permanganate oxidation, sulfonylation, ammonia substitution, catalytic ring closure, benzyl protection, hydrolysis and Boc substitution, amidation and hydrogenation to remove benzyl to generate the edoxaban intermediate. The synthesis method of the present invention has simple operation steps, high chiral selectivity, is beneficial to improving the product yield and reducing the production cost, and does not use the dangerous reagent sodium azide, reducing the production risk and ensuring the safety and operability of the reaction.

[0010] In order to achieve the above invention object, the technical scheme adopted by the present invention is as follows: A preparation method of an edoxaban intermediate, characterized in that its synthesis route is as follows:

[0011]

[0012] The specific reaction steps include:

[0013] S1: The raw material (S)-(-)-3-cyclohexene carboxylic acid is oxidized by potassium permanganate to generate intermediate 2;

[0014] S2: Intermediate 2 reacts with methanesulfonyl chloride to generate intermediate 3;

[0015] S3: Intermediate 3 reacts with ammonia in ethanol to generate intermediate 4;

[0016] S4: Intermediate 4 undergoes a self-cyclization reaction under the catalysis of EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and HOBt (1-hydroxybenzotriazole) to generate intermediate 5;

[0017] S5: Intermediate 5 reacts with benzyl chloride to generate intermediate 6;

[0018] S6: Intermediate 6 is hydrolyzed under alkaline conditions and reacts with Boc2O to generate intermediate 7;

[0019] S7: Intermediate 7 undergoes a condensation reaction with dimethylamine to generate intermediate 8;

[0020] S8: Intermediate 8 is hydrogenated to remove benzyl to generate the edoxaban intermediate.

[0021] Further, in step S1, the oxidation reaction temperature is -10 to 0 °C, the reaction solvent used is ethyl acetate, and tetrabutylammonium bromide can be further used for catalysis. The molar ratio of raw material (S)-(-)-3-cyclohexeneformic acid to potassium permanganate is 1:1.1 to 1.3.

[0022] Further, in step S2, the reaction temperature is 20 to 30 °C, the reaction solvent used is ethyl acetate, and triethylamine and sodium bicarbonate can be further added as acid-binding agents. The molar ratio of methanesulfonyl chloride, acid-binding agent to (S)-(-)-3-cyclohexeneformic acid is 1.8 to 2.2:2.0 to 3.0:1.

[0023] Further, in step S3, the reaction temperature is 50 to 60 °C, and the reaction solvent used is ethanol.

[0024] Further, in step S4, the catalysts are EDCI and HOBt, the reaction temperature is 20 - 30 °C, and the reaction solvent used is dichloromethane. The molar ratio of intermediate 4, EDCI to HOBt is 1:1.0 to 1.2:1.0 to 1.2.

[0025] Further, in step S5, the reaction temperature is 10 to 20 °C, the reaction solvent used is dichloromethane, and triethylamine and sodium bicarbonate can be further added as acid-binding agents. The molar ratio of intermediate 5, acid-binding agent to benzyl chloride is 1:1.2 to 1.5:1.0 to 1.2.

[0026] Further, in step S6, the reaction temperature is reflux, and the reaction solvent used is ethanol. The molar ratio of intermediate 6 to Boc2O is 1:1.0 to 1.2.

[0027] Further, in step S7, the reaction temperature is 20 to 30 °C, the reaction solvent used is dichloromethane. Triethylamine, EDCI and HOBt can be further added for catalysis. The molar ratio of intermediate 7, dimethylamine, triethylamine, EDCI to HOBt is 1:1.2 to 2.0:1.2 to 2.0:1.0 to 1.1:1.0 to 1.1.

[0028] Further, in step S8, the hydrogen pressure is 0.05 - 0.1 MPa, and the solvent used is methanol.

[0029] The specific steps of the present invention are as follows:

[0030] S1: Dissolve (S)-(-)-3-cyclohexeneformic acid in ethyl acetate, add tetrabutylammonium bromide, cool down to -10 to 0 °C, dropwise add an aqueous solution of potassium permanganate. After dropping, keep the temperature at -10 to 0 °C for the reaction. After the reaction is completed, add sodium thiosulfate, warm up to room temperature, separate the layers, and directly subject the organic phase to the next step of reaction after washing with water;

[0031] S2: Add triethylamine or sodium bicarbonate to the ethyl acetate solution of intermediate 2, dropwise add methanesulfonyl chloride, after dropping, keep the temperature at 20 - 30 °C for reaction, after the reaction is completed, add water, separate the layers, adjust the pH of the aqueous phase to 5 - 6 to precipitate a solid, filter, and dry to obtain intermediate 3;

[0032] S3: Add intermediate 3 to the ammonia ethanol solution, keep the temperature at 50 - 60 °C overnight, then evaporate to dryness under reduced pressure to obtain the crude intermediate 4 and directly carry out the next step of the reaction;

[0033] S4: Add dichloromethane to dissolve intermediate 4, add EDCI and HOBt, keep the temperature at 20 - 30 °C for reaction, after the reaction is completed, add water, separate the layers, and obtain the dichloromethane solution of intermediate 5 and directly carry out the next step of the reaction;

[0034] S5: Add triethylamine or sodium bicarbonate to the dichloromethane solution of intermediate 5, control the temperature at 10 - 20 °C, dropwise add benzyl chloride, after dropping, stir at room temperature overnight, wash with water, add n - heptane or petroleum ether dropwise to the organic phase for crystallization, filter, and dry to obtain intermediate 6;

[0035] S6: Add intermediate 6 to ethanol, add sodium hydroxide solution, then add Boc2O, heat to reflux overnight, after the reaction is completed, adjust the pH to 6.5 - 7 with dilute hydrochloric acid, precipitate a solid and filter to obtain intermediate 7;

[0036] S7: Add intermediate 7 to dichloromethane, add dimethylamine hydrochloride and triethylamine, stir for reaction, then add EDCI and HOBt, keep the temperature at 20 - 30 °C for reaction, after the reaction is completed, add water, separate the layers, and evaporate the organic phase to dryness to obtain intermediate 8;

[0037] S8: Dissolve intermediate 8 in methanol, add palladium - carbon, after purging with nitrogen, at 20 - 30 °C, keep the hydrogen pressure at 0.05 - 0.1 MPa for reaction, after the reaction is completed, filter to remove palladium - carbon, concentrate, add water to precipitate a solid, filter, and dry to obtain the edoxaban intermediate.

[0038] The technical effect of the present invention is as follows: The synthesis method of the present invention has simple operation steps, high chiral selectivity, is beneficial to improving the product yield (the yield is about 45% or so) and reducing the production cost, and does not use the dangerous reagent sodium azide, reducing the production risk and ensuring the safety and operability of the reaction. Brief Description of the Drawings

[0039] Figure 1 It is the chiral detection spectrum of edoxaban;

[0040] Figure 2 It is the hydrogen spectrum of the edoxaban intermediate. Detailed Embodiments

[0041] The following describes its effects in combination with embodiments and accompanying drawings.

[0042] Example 1:

[0043] S1: Dissolve 50 g of (S)-(-)-3-cyclohexene carboxylic acid in 800 mL of ethyl acetate, add 0.5 g of tetrabutylammonium bromide, cool down to -10°C, dropwise add 750 g of 10% aqueous potassium permanganate solution. After dropping, keep the temperature at -10 to 0°C for 1 h, then add 130 g of sodium thiosulfate, warm up to room temperature, separate the layers, and directly use the organic phase for the next step after washing with water;

[0044] S2: Add 100 g of triethylamine to the ethyl acetate solution of Intermediate 2, dropwise add the ethyl acetate solution of 185.5 g of methanesulfonyl chloride at 20 - 30°C. After dropping, keep the temperature for 3 h, add 400 ml of water, separate the layers, adjust the pH of the aqueous phase to 5 - 6 to precipitate a solid, filter, and dry to obtain 104.6 g of white solid Intermediate 3 with a purity of 98.6% (evaporative light scattering detection), and the two-step yield is 83.4%;

[0045] S3: Add 80 g of Intermediate 3 to 350 mL of ammonia ethanol solution, keep the temperature at 50 - 60°C overnight, then evaporate to dryness under reduced pressure, and directly use the crude Intermediate 4 for the next step;

[0046] S4: Add 300 mL of dichloromethane to Intermediate 4. After dissolution, add 48.5 g of EDCI and 38 g of HOBt, keep the temperature at 20 - 30°C for 1 h, add 400 mL of water, separate the layers, and obtain the dichloromethane solution of Intermediate 5 for the next step;

[0047] S5: Add 38.4 g of triethylamine to the dichloromethane solution of Intermediate 5, control the temperature at 10 - 20°C, dropwise add 33.5 g of benzyl chloride. After dropping, stir at room temperature overnight, add 500 mL of water for washing, dropwise add 1 L of n-heptane to the organic phase to crystallize, filter, and dry to obtain 44.5 g of white solid Intermediate 6 with a purity of 97.8% (evaporative light scattering detection), and the three-step reaction yield is 76.4%;

[0048] S6: Add 50 g of Intermediate 6 to 500 mL of ethanol, add 100 g of 20% sodium hydroxide solution, then add 44 g of Boc2O, heat to reflux overnight. After the reaction is completed, adjust the pH to 6.5 - 7 with dilute hydrochloric acid, precipitate a solid and filter to obtain 62.6 g of white solid Intermediate 7 with a purity of 99.1% (HPLC detection) and a yield of 89.2%;

[0049] S7: Add 40 g of Intermediate 7 to 300 ml of dichloromethane, add 14.1 g of dimethylamine hydrochloride and 17.5 g of triethylamine, stir for 0.5 h, then add 23.1 g of EDCI and 18.1 g of HOBt, keep the temperature at 20 - 30°C for 1 h, add 400 mL of water, separate the layers, and evaporate the organic phase to dryness to obtain the crude Intermediate 8;

[0050] S8: After the upper-step intermediate 8 was dissolved in 500 mL of methanol, 2 g of palladium on carbon was added. After purging with nitrogen, the mixture was kept at 20 - 30 °C and hydrogenated at a hydrogen pressure of 0.05 - 0.1 MPa for 1.5 h. After the reaction was completed, the palladium on carbon was removed by filtration. The solution was evaporated to 80 g, 200 g of water was added dropwise, and a solid precipitated. After filtration and drying, 25.7 g of edoxaban intermediate was obtained, with a purity of 99.3% (detected by HPLC). The yield of the two-step reaction was 78.4%, and the chiral purity was 99.78% (as Figure 1 shown). 1 The 1H-NMR spectrum is as Figure 2 shown.

[0051] Example 2:

[0052] S1: 50 g of (S)-(-)-3-cyclohexene carboxylic acid was dissolved in 1000 mL of ethyl acetate. 0.5 g of tetrabutylammonium bromide was added, and the temperature was lowered to -5 °C. 1500 g of 5% aqueous potassium permanganate solution was added dropwise. After the addition was complete, the mixture was kept at -10 - 0 °C for 1 h, 130 g of sodium thiosulfate was added, and the temperature was raised to room temperature. After phase separation, the organic phase was washed with water and directly used in the next step;

[0053] S2: 83 g of sodium bicarbonate was added to the ethyl acetate solution of intermediate 2. 185.5 g of ethyl acetate solution of methanesulfonyl chloride was added dropwise at 20 - 30 °C. After the addition was complete, the mixture was kept at the same temperature for 3 h. 400 ml of water was added, and after phase separation, the pH of the aqueous phase was adjusted to 5 - 6 to precipitate a solid. After filtration and drying, 100.8 g of white solid intermediate 3 was obtained, with a purity of 98.9% (detected by evaporative light scattering). The yield of the two-step reaction was 80.4%;

[0054] S3: 80 g of intermediate 3 was added to 350 mL of ammonia in methanol solution. The mixture was kept at 50 - 60 °C overnight, and then evaporated to dryness under reduced pressure. The crude intermediate 4 was directly used in the next step;

[0055] S4: 400 ml of dichloromethane was added to intermediate 4. After dissolution, 53.4 g of EDCI and 41.8 g of HOBt were added. The mixture was kept at 20 - 30 °C for 0.5 h. 400 mL of water was added, and after phase separation, the dichloromethane solution of intermediate 5 was obtained and used in the next step;

[0056] S5: 31.9 g of sodium bicarbonate was added to the dichloromethane solution of intermediate 5. The temperature was controlled at 10 - 20 °C, and 33.5 g of benzyl chloride was added dropwise. After the addition was complete, the mixture was stirred at room temperature overnight. 500 mL of water was added for washing. Petroleum ether (1 L) was added dropwise to the organic phase to crystallize. After filtration and drying, 45.7 g of white solid intermediate 6 was obtained, with a purity of 97.5% (detected by evaporative light scattering). The yield of the three-step reaction was 78.4%;

[0057] S6: Add 50 g of Intermediate 6 into 500 mL of ethanol, then add 100 g of 25% sodium hydroxide solution, and further add 44 g of Boc2O. Heat the mixture to reflux overnight. After the reaction is completed, adjust the pH to 6.5 - 7 with dilute hydrochloric acid. Filter the precipitated solid to obtain 62.2 g of white solid Intermediate 7 with a purity of 99.0% (detected by HPLC) and a yield of 88.7%;

[0058] S7: Add 40 g of Intermediate 7 into 300 ml of dichloromethane, then add 12.2 g of dimethylamine hydrochloride and 15.2 g of triethylamine. After stirring for 0.5 h, add 23.1 g of EDCI and 18.1 g of HOBt. Keep the temperature at 20 - 30 °C for 1 h, then add 300 mL of water. Separate the layers, and evaporate the organic phase to dryness to obtain the crude product Intermediate 8;

[0059] S8: Dissolve the above Intermediate 8 in 500 mL of ethanol, then add 2.5 g of palladium on carbon. After purging with nitrogen, keep the temperature at 20 - 30 °C and maintain the hydrogen pressure at 0.05 - 0.1 MPa for 1.5 h. After the reaction is completed, filter off the palladium on carbon, evaporate to 80 g, add 200 g of water dropwise. Filter the precipitated solid, and after drying, obtain 26.0 g of edoxaban intermediate with a purity of 99.5% (detected by HPLC), a two-step reaction yield of 79.5%, and a chiral purity of 99.4%.

[0060] From the above data, it can be seen that the preparation method of the edoxaban intermediate provided by the present invention has simple operation steps, high chiral selectivity, which is beneficial to improving the product yield and reducing the production cost. Moreover, there is no use of the dangerous reagent sodium azide, reducing the production risk and ensuring the safety and operability of the reaction.

Claims

1. A method for synthesizing an edoxaban intermediate, characterized in that, The specific reaction steps include: S1: The raw material (S)-(-)-3-cyclohexene carboxylic acid is oxidized by potassium permanganate to form intermediate 2; S2: Intermediate 2 reacts with methanesulfonyl chloride to form intermediate 3; S3: Intermediate 3 reacts with ammonia in ethanol to form intermediate 4; S4: Intermediate 4 undergoes a self-cyclization reaction under the catalysis of EDCI and HOBt to form intermediate 5; S5: Intermediate 5 reacts with benzyl chloride to form intermediate 6; S6: Intermediate 6 is hydrolyzed with sodium hydroxide solution and reacts with Boc2O simultaneously to form intermediate 7; S7: Intermediate 7 undergoes a condensation reaction with dimethylamine to form intermediate 8; S8: Intermediate 8 is hydrogenated to remove the benzyl group to form the edoxaban intermediate.

2. The synthesis method of an edoxaban intermediate as claimed in claim 1, wherein In the step S1, the oxidation reaction temperature is -10 to 0 °C, and the reaction solvent used is ethyl acetate.

3. The synthetic method of an edoxaban intermediate as claimed in claim 1, characterized in that, In the step S2, the reaction temperature is 20 to 30 °C, and the reaction solvent used is ethyl acetate.

4. The synthesis method of an edoxaban intermediate according to claim 1, characterized in that, In the step S3, the reaction temperature is 50 to 60 °C.

5. The synthesis method of an edoxaban intermediate as claimed in claim 1, wherein In the step S4, the reaction temperature is 20 - 30 °C, and the reaction solvent used is dichloromethane.

6. The synthesis method of an edoxaban intermediate according to claim 1, characterized in that, In the step S5, the reaction temperature is 10 to 20 °C, and the reaction solvent used is dichloromethane.

7. The synthesis method of an edoxaban intermediate as described in claim 1, characterized in that, In the step S6, the reaction temperature is reflux, and the reaction solvent used is ethanol.

8. The synthesis method of an edoxaban intermediate as claimed in claim 1, wherein In the step S7, the reaction temperature is 20 to 30 °C, and the reaction solvent used is dichloromethane.

9. The synthesis method of an edoxaban intermediate according to claim 1, characterized in that, In the step S8, the hydrogen pressure is 0.05 - 0.1 MPa, and the solvent used is methanol.

10. A method for synthesizing an edoxaban intermediate according to any one of claims 1-9, characterized in that, The specific steps are as follows: S1: Dissolve (S)-(-)-3-cyclohexene carboxylic acid in ethyl acetate, add tetrabutylammonium bromide, cool down to -10 to 0 °C, dropwise add an aqueous solution of potassium permanganate. After dropping, keep the temperature at -10 to 0 °C for the reaction. After the reaction is completed, add sodium thiosulfate, warm up to room temperature, separate the layers, and directly carry out the next step reaction on the organic phase after washing with water; S2: Add triethylamine or sodium bicarbonate to the ethyl acetate solution of intermediate 2, dropwise add methanesulfonyl chloride. After dropping, keep the temperature at 20 to 30 °C for the reaction. After the reaction is completed, add water, separate the layers, adjust the pH of the aqueous phase to 5 - 6 to precipitate a solid, filter, and dry to obtain intermediate 3; S3: Add intermediate 3 to an ammonia ethanol solution, keep the temperature at 50 to 60 °C overnight, then evaporate to dryness under reduced pressure to obtain the crude intermediate 4 and directly carry out the next step reaction; S4: Add dichloromethane to dissolve intermediate 4, add EDCI and HOBt, keep the temperature at 20 to 30 °C for the reaction. After the reaction is completed, add water, separate the layers, and obtain the dichloromethane solution of intermediate 5 and directly carry out the next step reaction; S5: Add triethylamine or sodium bicarbonate to the dichloromethane solution of intermediate 5, control the temperature at 10 to 20 °C, dropwise add benzyl chloride. After dropping, stir at room temperature overnight, wash with water, add n-heptane or petroleum ether dropwise to the organic phase to crystallize, filter, and dry to obtain intermediate 6; S6: Add intermediate 6 to ethanol, add sodium hydroxide solution, then add Boc2O, heat to reflux overnight. After the reaction is completed, adjust the pH to 6.5 - 7 with dilute hydrochloric acid, precipitate a solid and filter to obtain intermediate 7; S7: Add intermediate 7 into dichloromethane, add dimethylamine hydrochloride and triethylamine, stir for reaction, then add EDCI and HOBt, keep the reaction at 20 - 30 °C, after the reaction is completed, add water, separate the layers, and evaporate the organic phase to dryness to obtain intermediate 8; S8: Dissolve intermediate 8 in methanol, add palladium on carbon, replace with nitrogen, keep the hydrogen pressure at 0.05 - 0.1 MPa and keep the reaction at 20 - 30 °C, after the reaction is completed, filter to remove palladium on carbon, concentrate, add water to precipitate solids, filter, and dry to obtain the edoxaban intermediate.

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