Process for the one-pot preparation of an intermediate of idoxaban tosylate

Abstract

The present application relates to a method for preparing an intermediate of idoxaban tosylate by one-pot method, and belongs to the field of drug synthesis, which uses 2-amino-5-chloropyridine and oxalyl monomethyl chloride as raw materials, heats and reacts for 1-5 hours, then directly adds a base, an additive and compound 4 into the reaction solution, continues to heat and reflux for 6-18 hours, filters, separates and dries after adding water, to obtain the intermediate, the process reduces the use amount of reagent oxalyl monomethyl (or ethyl) ester and organic solvent, reduces the influence on operators and the pollution to the environment, and the one-pot preparation does not need to separate the intermediate product, and simplifies the operation process. The intermediate can be used for preparing idoxaban tosylate.

Description

Technical Field

[0001] This invention relates to a method for preparing an intermediate of the antithrombotic drug edoxaban tosylate, which employs a one-pot preparation method. Background Technology

[0002] Edoxaban tosylate tablets are a small-molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd. of Japan. The active ingredient, edoxaban tosylate, is a selective factor Xa inhibitor, clinically used to treat venous thromboembolism in patients undergoing total knee arthroplasty, total hip arthroplasty, and hip fracture surgery. The chemical name of edoxaban tosylate is: N-(5-chloro-2-pyridinyl)-N'-[(1S,2R,4S)-4-[(dimethylamino)formyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazo[5,4-c]pyridin-2-yl)formyl]amino]cyclohexyl]glyoxalamide p-tosylate monohydrate, with the following structural formula:

[0003]

[0004] International application WO2007 / 032498A (CN103214414B, prior art 1) describes a method for synthesizing an optically active diamine as an important intermediate (compound 5) in the synthesis of the drug edoxaban tosylate. However, the reaction system becomes hard and solidified after the tertiary amine neutralizes the oxalate, making stirring difficult and easily leading to a decrease in yield.

[0005]

[0006] To address the aforementioned issues, WO 2010 / 104078 (CN102348688B, Reference Document 2) proposes a new material addition sequence that effectively solves the solidification problem in the reaction system.

[0007]

[0008] However, there are still problems that need to be overcome, such as the large amount of oxaloyl chloride monoethyl ester used in the preparation of compound 10, low production efficiency, large amount of organic solvent used, and environmental pollution. Summary of the Invention

[0009] To overcome the above-mentioned technical problems, the present invention aims to provide a one-pot method for preparing edoxaban toluenesulfonic acid intermediate, which is simple in process, has a high product yield, and is suitable for industrial production.

[0010] To achieve the above-mentioned objectives, the present invention specifically adopts the following technical solution:

[0011] Idoxaban toluenesulfonic acid intermediate (compound 5), chemical name: [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl]tert-butyl carbamate:

[0012]

[0013] The synthesis process of the above intermediate is as follows:

[0014]

[0015] Where Boc represents tert-butyloxycarbonyl, and R represents methyl or ethyl.

[0016] Specifically, the reaction process of the above reaction formula is as follows:

[0017] Step (a): Compound 1 and Compound 2 are reacted in an organic solvent at 40°C to reflux temperature for 1-5 hours to generate Compound 3;

[0018] The organic solvent is acetonitrile or dichloromethane;

[0019] The molar ratio of compound 1 to compound 2 is 1.0-1.2:1.0.

[0020] In step (b), without separation, alkali, additive (oxalic acid or acetic acid) and compound 4 are directly added to the reaction solution, and the reaction is continued at 58°C to reflux temperature for 6-18 hours. After solvent removal, water is added, the mixture is filtered, separated, and dried to obtain the intermediate (compound 5).

[0021] The base is triethylamine or diisopropylethylamine, and the molar ratio of compound 3 to the base is 1.0:3.5-5.2.

[0022] The molar ratio of compound 3 to compound 4 is 1.0-1.2:1.0.

[0023] The present invention also discloses the use of the obtained intermediate (compound 5) in the preparation of edoxaban tosylate (compound 6):

[0024]

[0025] The specific process is as follows: Compound 5 is deprotected under acidic conditions to obtain Compound 7, and then condensed with Compound 8 under basic conditions to obtain Compound 9, as shown in the following reaction formula:

[0026]

[0027] Then, compound 9 reacts with p-toluenesulfonic acid monohydrate to form a salt, yielding compound 6, as shown in the following reaction formula:

[0028]

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. This invention uses 2-amino-5-chloropyridine and oxaloyl chloride monomethyl ester as raw materials to first prepare compound 3. Without the need for separation steps, compound 4 is directly added to generate edoxaban tosylate intermediate. This eliminates the separation and washing processes after preparing compound 3 in the prior art, and reduces the amount of oxaloyl chloride monomethyl ester and organic solvent acetonitrile used.

[0031] 2. The present invention uses a one-pot method to prepare the intermediate of edoxaban tosylate, and does not require the addition of a tertiary amine in the fractionation portion to avoid the decomposition of the free form of compound 2 as described in prior art 2. This simplifies the operation process, avoids the lengthy separation process and purification process of the intermediate compound in the post-processing, thereby saving time and resources and increasing the yield, and greatly improving production efficiency. Detailed implementation method:

[0032] The present invention will be described in more detail below through examples, but these should not be construed as limiting the present invention.

[0033] The chemical names of the compounds involved in this application are listed below:

[0034] Compound 1: 2-Amino-5-chloropyridine;

[0035] Compound 2: Oxaloyl chloride monomethyl ester;

[0036] Compound 3: methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate;

[0037] Compound 4: (1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]tert-butyl carbamate;

[0038] Compound 5: [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl] tert-butyl carbamate;

[0039] Compound 6: Edoxaban tosylate;

[0040] Compound 9: N-(5-chloro-2-pyridinyl)-N'-[(1S,2R,4S)-4-[(dimethylamino)formyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazo[5,4-c]pyridin-2-yl)formyl]amino]cyclohexyl]glycan.

[0041] Comparative Example 1

[0042] This comparative example uses a separation method to prepare the intermediate, and the process flow is as follows:

[0043]

[0044] Step 1: Preparation of methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate (compound 3): In a constant-pressure dropping funnel, acetonitrile solution (80 mL) was added to 10 g of 2-amino-5-chloropyridine, and the mixture was preheated and shaken until completely dissolved. At 70 °C, acetonitrile solution (80 mL) of 10 g of 2-amino-5-chloropyridine (preheated and dissolved) was added to 80 mL of acetonitrile solution of 11.44 g of oxaloyl chloride, and the mixture was stirred at this temperature for 1 hour. Then, methanol (12.4 mL) was added to quench the reaction, and the internal temperature was lowered to 10 °C for filtration. The mixture was washed with acetonitrile solution (20 mL) and dried to obtain title compound 3, totaling 18.10 g.

[0045] NMR data: 1 H-NMR (CDCL3) δ: 8.31-8.32 (d, 1H, J = 2.4Hz), 7.73-7.75 (dd, 1H, J = 8.9, 2.5Hz), 8.22-8.24 (d, 1H, J = 8.9Hz), 9.48 (s, 1H), 3.99 (s, 1H).

[0046] Step 2: Preparation of edoxaban tosylate intermediate (compound 5):

[0047] At room temperature, 7.35 g of compound 3 obtained in step one was dissolved in 55 mL of acetonitrile solution, followed by the addition of 12.13 g of triethylamine, 7.6 g of compound 4, and 2.4 g of oxalic acid. After stirring at 70 °C for 6 hours, the solvent was concentrated under reduced pressure, then cooled to room temperature. Water (30 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The solution was filtered and washed with a mixture of acetonitrile and water (15 mL). After drying, 11.46 g of the title compound was obtained, with a yield of 90% and a purity of 98.2%.

[0048] Example 1

[0049] [(1R,2S,5S)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylaminocarbonyl)cyclohexyl] tert-butyl carbamate (compound 5) was prepared by a one-pot method:

[0050]

[0051] Oxaloyl chloride monomethyl ester (compound 2, 4.72 g) was added to an acetonitrile solution (73 mL) of 2-amino-5-chloropyridine (compound 1, 5.05 g) at 70 °C, and stirred at this temperature for 1 hour. The temperature was then lowered to 20 °C, and 15.96 g of triethylamine, 10 g of compound 4, and 3.15 g of oxalic acid were added. The temperature was raised to 70 °C, and after stirring for 8 hours, the reaction solution was cooled to room temperature. 40 mL of water was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The solution was filtered and washed with 20 mL of acetonitrile-water mixture, and dried to obtain 14.93 g of intermediate (compound 5), with a yield of 92% and a purity of 99.0%.

[0052] NMR data: 1 H-NMR(DMSO-d6)δ:8.45-8.46(d,1H,J=2.3Hz),8.01-8.03(dd,1H,J=8.8,2.4Hz),8.05-8.07 (d,1H,J=8.9Hz),10.21(s,1H),8.64-8.66(d,1H,J=7.7Hz),3.94-3.96(dd,1H,J=7.0,3.4Hz ),1.76-1.90(m,2H),1.70-2.57(m,2H),2.93-2.97(t,1H,J=12.5Hz),1.43-1.55(m,2H),3.8 3-3.84 (d, 1H, J = 3.0Hz), 7.02-7.04 (d, 1H, J = 6.5Hz), 2.81 (s, 3H), 3.01 (s, 3H), 1.40 (s, 9H).

[0053] Comparing the comparative example with Example 1, it can be seen that the present application adopts a one-pot method, which carries out continuous chemical reactions in one reactor, avoiding the most time-consuming reaction quenching, intermediate product separation, extraction and purification processes in organic synthesis, and purifying intermediate compounds to save time and resources.

[0054] Example 2

[0055] Use of the intermediate obtained in Example 1 for the preparation of edoxaban tosylate

[0056] Step 1, Preparation of Compound 9:

[0057]

[0058] At room temperature, 7.4 g of methanesulfonic acid was added to an acetonitrile solution of compound 5 prepared in Example 1 (mass-volume ratio of 12 g: 204 mL). After stirring at 40 °C for 4 hours, the protection was removed to obtain compound 7. 8.4 g of compound 8 and 14.9 g of triethylamine were added, and the mixture was stirred at this temperature for 1 hour. Compounds 7 and 8 condensed to form compound 9. 408 mL of water was added to the reaction system, and the mixture was filtered. The filter cake was refluxed with 72 mL of acetonitrile and stirred for 6 hours. The mixture was cooled to room temperature, filtered, washed with 24 mL of ethanol, and dried to obtain compound 9, totaling 12.7 g.

[0059] Step 2, Preparation of edoxaban tosylate:

[0060]

[0061] At 50°C, an aqueous solution of p-toluenesulfonic acid (3.47 g: 21 mL) was added to an ethanol solution of compound 9 (10 g: 49 mL). The temperature was raised to 70°C, and 0.1 g of activated carbon was added. The mixture was stirred at this temperature for 0.5 hours. The activated carbon was filtered and washed with a mixture of ethanol and water (17 mL: 3 mL). The temperature was lowered to 10°C after 3–5 hours, and stirring was continued for 2 hours. The mixture was filtered, washed with a mixture of ethanol and water (19 mL: 1 mL), and dried to obtain edoxaban toluenesulfonic acid, totaling 12.36 g, with a yield of 91.8% and a purity of 99.6%.

[0062] NMR data: 1 H-NMR (DMSO-d6) δ: 8.44-8.45 (d, 1H, J = 1.8Hz), 7.98-7.99 (d, 1H, J = 2.4Hz), 8.00-8.05 (dd, 1H, J = 16.8, 8.9Hz), 10.25 (s, 1H) , 9.19-9.21 (d, 1H, J = 7.1Hz), 4.45-4.46 (d, 1H, J = 3.1Hz), 1.68-1.71 (dd, 2H, J = 14.5, 10.7Hz), 1.47-1.69 (m, 2H), 2.98 (s, 1H ), 2.04-2.13 (dd, 2H, J = 28.9, 12.5Hz), 4.00-4.06 (m, 1H), 8.73-8.75 (d, 1H, J = 7.3Hz), 4.62 (s, 2H), 3.67 (s, 2H), 3.20 (s, 2H) , 2.27 (s, 3H), 2.94 (s, 3H), 2.79 (s, 3H), 7.09-7.11 (d, 2H, J = 7.9Hz), 7.45-7.47 (d, 2H, J = 8.0Hz), 3.01 (s, 3H), 10.15 (s, 1H).

Claims

1. A method for preparing edoxaban tosylate intermediate, characterized in that, The synthesis process is as follows: R represents methyl or ethyl; Step (a): Compound 1 and Compound 2 are reacted in an organic solvent at 40°C to reflux temperature for 1-5 hours to generate Compound 3; The organic solvent is acetonitrile or dichloromethane; the molar ratio of compound 1 to compound 2 is 1.0-1.2:1.0; In step (b), without separation, alkali, oxalic acid or acetic acid and compound 4 are directly added to the reaction solution, and the reaction is continued at 58°C to reflux temperature for 6-18 hours. After solvent removal, water is added, the mixture is filtered, separated, and dried to obtain edoxaban toluenesulfonic acid intermediate. The base is triethylamine or diisopropylethylamine; The molar ratio of compound 3 to the base is 1.0:3.5-5.2; The molar ratio of compound 3 to compound 4 is 1.0-1.2:1.0.

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