A process for the synthesis of a key intermediate of apixaban

Abstract

The application discloses a synthesis process of a key intermediate of apixaban. The process comprises the following steps: dissolving compound I in an organic solvent, adding compound II, adding a catalyst base reagent, reacting at room temperature, separating the product after the reaction is completed, and obtaining compound III; dissolving the compound III obtained in the second step reaction in an organic solvent, passing hydrogen, adding a catalyst, reacting at room temperature, detecting by sampling and using a proper analysis technique to ensure that selective reduction is being carried out, stopping the hydrogen passing when a required degree is reached, passing nitrogen, replacing the hydrogen with nitrogen, separating the product, and obtaining the target product compound IV. The application has the advantages of saving raw material cost, increasing reaction selectivity, improving reaction yield, having few by-products and being easy to separate, being simple in operation, having few process steps, and being suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a synthesis process for apixaban intermediate. Background Technology

[0002] Apixaban (I), chemically named 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, is a novel direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It was approved in the European Union in March 2011 and by the US FDA on December 28, 2012, under the brand name Eliquis. It is used to prevent venous thromboembolism (VTE) and atrial fibrillation in adult patients who have undergone hip or knee replacement surgery.

[0003] US Patent 8884016 discloses a technical route for the synthesis of apixaban via 1-(4-iodophenyl)piperidine-2,3-dione. The reaction route is as follows:

[0004] Route 1

[0005]

[0006] As one of the key intermediates in this synthetic route, 1-(4-iodophenyl)piperidine-2,3-dione is obtained in the prior art through the synthesis of the compound... It is prepared by decarboxylation and hydrolysis to remove the Z group (carboxyl, ester, or cyano). This method is only mentioned in US8884016, without a specific procedure.

[0007] Bristol-Myers Squibb's 2003 world patent WO2003049681 uses p-iodoaniline and 5-bromopentanoyl chloride as starting materials, and proceeds sequentially through amidation-cyclization, α-dichlorination of the amide, condensation elimination, cyclization elimination, and Ullmann coupling to obtain the target compound apixaban; the synthetic route is as follows:

[0008] Route 2

[0009]

[0010] The disadvantages of this route are: the starting materials (p-iodoaniline and 5-bromopentanoyl chloride) are expensive, increasing production costs; the Ullmann coupling reaction requires high temperature and high pressure, which are harsh conditions; and the overall yield of this route is only 1.3%.

[0011] To overcome the above-mentioned shortcomings of this synthetic route, East China University of Science and Technology, in its Chinese patent CN101967145 published in 2011, used p-nitroaniline as the starting material, and successively carried out amidation cyclization, dichlorination, elimination, cyclization elimination, catalytic hydrogenation reduction, and amidation cyclization to obtain the intermediate of the target compound apixaban; the synthetic route is shown below:

[0012] Route 3

[0013]

[0014] This route has a high synthesis yield, with an overall yield of 35%, and the raw materials are readily available and low in cost.

[0015] Route 1 above requires polycarbonyl cyclic amide compounds as starting materials, which are not easy to obtain. Compounds containing polycarbonyl groups and with Z (carboxyl, ester, or cyano) groups are not easy to synthesize. Similar structures often require coupling reactions catalyzed by noble metals to complete, which is costly and not suitable for mass production.

[0016] In Routes 2 and 3, the cyclization reaction between halopentanoyl chloride and amino groups is necessary to obtain the cyclic amide product before further reactions can proceed. Therefore, the cyclic amide product is a key step in the synthesis. The starting materials (p-iodoaniline and 5-bromopentanoyl chloride) in Route 2 are relatively expensive, while the starting materials in Route 3 are readily available and have low cost. However, sodium hydride, as a condensing agent in the amidation cyclization step, has high production costs and is highly dangerous to operate. 5-Halopentanoyl chloride is a genotoxic impurity that affects the yield and purity of the product. Summary of the Invention

[0017] To address the shortcomings of the cyclic amide compound synthesis steps in the above-mentioned routes, this invention aims to provide a novel synthetic scheme for the cyclic amide compound (compound III), a key intermediate of apixaban, which makes the starting materials readily available, reduces reaction raw material costs, and improves reaction yield. The reaction route of this invention is shown below:

[0018]

[0019] This invention provides the following technical solution:

[0020] A synthetic process for a key intermediate of apixaban includes the following steps:

[0021] First, compound I was dissolved in an organic solvent, compound II was added, and a catalyst and base reagent were added. The reaction was carried out at room temperature for 6-8 hours. After the reaction was completed, the product was separated to obtain compound III.

[0022] In the second step, compound III obtained from the second step reaction was dissolved in an organic solvent, hydrogen gas was introduced, a catalyst was added, and the reaction was carried out at room temperature. The reaction progress was monitored by HPLC. When the desired extent was reached, the hydrogen gas was stopped, and nitrogen gas was introduced to replace the hydrogen gas. The products were then separated to obtain the target product compound IV.

[0023] Furthermore, the solvent for the first step reaction is N-methylpyrrolidone.

[0024] Furthermore, the solvent for the second reaction step is chloroform.

[0025] Furthermore, the catalyst base reagent used in the first step reaction is one of the organic base reagents triethylamine and tripropylamine.

[0026] Furthermore, the catalyst used in the second step reaction is a complex of rhodium chloride and triphenylphosphine, a Wilkinson catalyst.

[0027] Furthermore, the amount of catalyst used in the first step is 1.5 to 2.5 times the molar amount of reactant compound I.

[0028] Furthermore, the catalyst used in the second step reaction is 5-10 mol% of compound III.

[0029] Furthermore, the molar ratio of compound I to compound II in the first step reaction is 1:1.

[0030] Furthermore, the reaction temperature for the second step is 35–40°C.

[0031] Furthermore, the catalyst used in the second step reaction is Wilkinson's catalyst with a ratio of rhodium chloride to triphenylphosphine of 1:3.

[0032] The beneficial effects of the present invention are: 1. The raw materials of the present invention are readily available and easy to purchase or synthesize. For example, glutarimide can be obtained from glutaric anhydride. The raw material price of the product is low, which helps to save production costs.

[0033] 2. The reaction of this invention has high selectivity. In the first step of the reaction, the amino group between the carbonyl groups is more active, and the reactivity and selectivity with haloalkanes are improved. Therefore, there are fewer by-products in the reaction. In the second step, the carbonyl group is reduced. Under its symmetrical structure and the action of a suitable reducing agent, the reduction is achieved. The by-products are simple, few and easy to separate and process. The post-processing is simple. The product can be obtained with high purity and high yield, saving production costs and reducing waste generation.

[0034] 3. This invention is simple to operate, has a short process route, high product yield, and mild reaction conditions, making it suitable for large-scale industrial production. Attached Figure Description

[0035] Figure 1 This is a schematic diagram of the process flow for the comparative example synthesis route of the present invention;

[0036] Figure 2 This is a schematic diagram of the process flow for the second synthetic route of the present invention;

[0037] Figure 3 This is a schematic diagram of the process flow for the third synthetic route of the present invention;

[0038] Figure 4 This is a schematic diagram of the synthesis route process of the present invention. Detailed Implementation

[0039] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0040] Example 1

[0041] In the first step, under nitrogen protection, 0.1 mol (11.3 g) of compound I was dissolved in 200 ml of organic solvent N-methylpyrrolidone, 0.1 mol of compound II was added, and 0.2 mol of triethylamine was added as a catalyst and base reagent. The mixture was stirred at room temperature for 6-8 h. After the reaction was completed, dilute hydrochloric acid was added dropwise to adjust the pH of the solution to neutral, and 300 ml of distilled water was added. The mixture was extracted with 80 ml of chloroform 2-3 times. The organic phase was washed with 100 ml of saturated brine 2-3 times. The organic phase was separated, evaporated and crystallized to obtain 21.8 g of compound II, with a yield of 93.1% and a purity of 95.9%.

[0042] In the second step, under nitrogen protection, 0.1 mol (23.4 g) of compound III obtained in the second step was dissolved in 250 ml of chloroform, an organic solvent. Hydrogen gas was introduced, and 0.005 mol of a complex of rhodium chloride and triphenylphosphine (combination ratio 1:3) was added as a catalyst. The reaction was heated to 35–40 °C, and the reaction progress was monitored by HPLC. When the desired extent was reached, the hydrogen gas was stopped, and nitrogen gas was introduced to replace the hydrogen gas. The catalyst was removed by washing with saturated brine, the organic phase was separated, the solvent was evaporated, and the product was recrystallized from 50 ml of toluene to obtain 20.5 g of the target intermediate product compound IV, with a yield of 92.3% and a purity of 94.6%.

[0043] Example 2

[0044] In the first step, under nitrogen protection, 0.1 mol (11.3 g) of compound I was dissolved in 200 ml of organic solvent N-methylpyrrolidone, 0.1 mol of compound II was added, and 0.15 mol of triethylamine was added as a catalyst and base reagent. The mixture was stirred at room temperature for 6-8 h. After the reaction was completed, dilute hydrochloric acid was added dropwise to adjust the pH of the solution to neutral, and 300 ml of distilled water was added. The mixture was extracted with 80 ml of chloroform 2-3 times. The organic phase was washed with 100 ml of saturated brine 2-3 times. The organic phase was separated, evaporated and crystallized to obtain 21.2 g of compound II, with a yield of 90.6% and a purity of 94.9%.

[0045] Example 3

[0046] In the first step, under nitrogen protection, 0.1 mol (11.3 g) of compound I was dissolved in 200 ml of organic solvent N-methylpyrrolidone, 0.1 mol of compound II was added, and 0.3 mol of triethylamine was added as a catalyst and base reagent. The mixture was stirred at room temperature for 6-8 h. After the reaction was completed, dilute hydrochloric acid was added dropwise to adjust the pH of the solution to neutral, and 300 ml of distilled water was added. The mixture was extracted with 80 ml of chloroform 2-3 times. The organic phase was washed with 100 ml of saturated brine 2-3 times. The organic phase was separated, evaporated and crystallized to obtain 21.9 g of compound II, with a yield of 93.6% and a purity of 95.7%.

[0047] Example 4

[0048] In the second step, under nitrogen protection, 0.1 mol (23.4 g) of compound III obtained in the second step was dissolved in 250 ml of chloroform, an organic solvent. Hydrogen gas was introduced, and a catalyst of 0.010 mol of a complex of rhodium chloride and triphenylphosphine (combination ratio 1:3) was added. The reaction was heated at 35–40 °C, and the reaction progress was monitored by HPLC. When the desired extent was reached, the hydrogen gas was stopped, and nitrogen gas was introduced to replace the hydrogen gas. The catalyst was removed by washing with saturated brine, the organic phase was separated, the solvent was evaporated, and the product was recrystallized from 50 ml of toluene to obtain 20.8 g of the target intermediate product compound IV, with a yield of 93.7% and a purity of 94.3%.

[0049] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0050] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A synthetic process for a key intermediate of apixaban, characterized in that... Includes the following steps: First, compound I was dissolved in an organic solvent, compound II was added, and a catalyst and base reagent were added. The reaction was carried out at room temperature for 6-8 hours. After the reaction was completed, the product was separated to obtain compound III. In the second step, compound III obtained from the second step reaction was dissolved in an organic solvent, hydrogen gas was introduced, a catalyst was added, and the reaction was carried out at room temperature. The reaction progress was monitored by HPLC. When the desired extent was reached, the hydrogen gas was stopped, nitrogen gas was introduced, the hydrogen gas was replaced with nitrogen gas, and the product was separated to obtain the target product compound IV. The solvent for the first step reaction is N-methylpyrrolidone, and the solvent for the second step reaction is chloroform. The catalyst used in the first step reaction is either triethylamine or tripropylamine, and the catalyst used in the second step reaction is Wilkinson's catalyst, which is a complex of rhodium chloride and triphenylphosphine. The amount of catalyst used in the first step is 1.5 to 2.5 times the molar amount of reactant compound I. The amount of catalyst used in the second step reaction is 5 to 10 mol% of compound III. The molar ratio of compound I to compound II in the first step reaction is 1:

1. The reaction temperature in the second step reaction is 35 to 40°C. The ratio of rhodium chloride to triphenylphosphine in the Wilkinson's catalyst used in the second step reaction is 1:3.

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