Preparation method of argatroban intermediate
Patent Information
- Application Number
- CN202510520732.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-24
- Publication Date
- 2025-08-15
AI Technical Summary
[0018]目前有报道以氯甲酸异丁酯作为缩合剂制备(R)-4-甲基-1-(N8-硝基-N2-Boc-L-精氨酰基)-2-哌啶甲酸乙酯，但是氯甲酸异丁酯属于剧毒试剂，而且反应需要在低温(-20℃)下进行，对设备和环境的要求高，成本昂贵；
[0035] The invention uses N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester as raw materials, uses 2-chloro-4,6-dimethoxy-1,3,5-triazine as a condensing agent, and reacts in a solvent in the presence of an organic base N-methylmorpholine to obtain an argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester. The condensing agent used in the preparation method and the impurities introduced are easy to remove, the post-processing operation is simple, the product yield is high, the purity is high, the residual condensing agent and by-products in the product are easy to detect and control, and the preparation method is suitable for commercial production.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing an argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester. Background Art
[0002] Argatroban is a low-molecular-weight thrombin inhibitor derived from L-arginine. Its chemical name is (2R,4R)-4-methyl-1-[N2-((R,S)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate. Its CAS number is 141396-28-3. Its structural formula is as follows:
[0003]
[0004] There are two main synthetic routes for argatroban reported in the literature. One involves condensing N-Boc-N'-nitro-L-arginine with (2R,4R)-4-methyl-2-piperidinylcarboxylate, removing the protecting agent, and then condensing with 3-methyl-8-quinolinesulfonyl chloride. Alkaline hydrolysis and hydrogenation are followed by hydration to obtain argatroban monohydrate. The key intermediate in this synthetic route, (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinylcarboxylate, is obtained by condensing N-Boc-N'-nitro-L-arginine with (2R,4R)-4-methyl-2-piperidinylcarboxylate. The main condensing agents currently used in organic synthesis reactions are:
[0005]
[0006] (1) DCC and EDCI act as condensation agents, and the mechanism is as follows:
[0007]
[0008] This condensation reaction produces the following impurities:
[0009] This impurity is a genotoxic impurity that is poorly soluble but slightly soluble and extremely difficult to remove;
[0010] (2) EDCI is used as a condensation agent, and the mechanism is as follows:
[0011]
[0012] This condensation reaction requires low temperature to prevent racemization, has high requirements on equipment and environment, is expensive, and the purity of the synthesized product is low;
[0013] (3) HATU as a condensing agent, the mechanism is as follows:
[0014]
[0015] This condensation reaction is expensive and produces by-products, which increases the difficulty of purification and the complexity of the process;
[0016] (4) Isobutyl chloroformate as condensing agent:
[0017]
[0018] Currently, there are reports on the use of isobutyl chloroformate as a condensing agent to prepare (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinylcarboxylate. However, isobutyl chloroformate is a highly toxic reagent, and the reaction needs to be carried out at a low temperature (-20°C), which places high demands on equipment and the environment, and is expensive.
[0019] In summary, the above-mentioned condensing agents and condensation reactions all show different shortcomings: for example, the condensing agent or impurities are difficult to remove, the process is complex, the cost is high, and the product purity or yield is low. For the synthesis of (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester, how to ensure that the product has high purity, the condensing agent and impurities are easily removed, and the cost is low and the process is simple, has become a difficult problem that limits the widespread use of this intermediate and even the commercial production of argatroban. Therefore, it is very important to develop a method for preparing (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester with low cost, high yield and high product purity. Summary of the Invention
[0020] Based on the technical problems existing in the background technology, the present invention proposes a preparation method of argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
[0021] The present invention provides a preparation method of an argatroban intermediate. The method comprises the following steps: using N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester as raw materials, using 2-chloro-4,6-dimethoxy-1,3,5-triazine as a condensing agent, and reacting in a solvent in the presence of an organic base N-methylmorpholine to obtain the argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
[0022] The present invention adopts a 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) / N-methylmorpholine (NMM) condensation system to prepare argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester. The synthetic reaction route (using DMF as solvent) is as follows:
[0023]
[0024] The condensing agent used in the method and the impurities introduced are easy to remove, the post-processing operation is simple, the yield and purity of the obtained product are high, the residual condensing agent and by-products in the product are easy to detect and control, and the method is suitable for commercial production.
[0025] Preferably, the preparation method of the argatroban intermediate comprises the following steps:
[0026] 2-Chloro-4,6-dimethoxy-1,3,5-triazine is added to a solvent and fully dissolved, and then N-methylmorpholine is added dropwise and stirred evenly. Then, N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester are added and reacted under stirring to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
[0027] Preferably, after the stirring reaction, a post-treatment step is further included, and the post-treatment step includes: after the reaction is completed, filtering, adding water to the obtained filtrate, stirring and crystallizing, collecting crystals, and obtaining (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinylcarboxylate.
[0028] Preferably, the solvent is N,N-dimethylformamide (DMF) or ethyl acetate.
[0029] Preferably, the molar ratio of N-Boc-N'-nitro-L-arginine to 2-chloro-4,6-dimethoxy-1,3,5-triazine is 1:1-5.
[0030] Preferably, the molar ratio of N-Boc-N'-nitro-L-arginine to N-methylmorpholine is 1:1-5.
[0031] Preferably, the molar ratio of N-Boc-N'-nitro-L-arginine to ethyl (2R, 4R)-4-methyl-2-piperidinic acid ester is 1:0.9-1.1.
[0032] Preferably, the reaction temperature is 10-30°C.
[0033] Preferably, the reaction time is 6 to 8 hours.
[0034] The beneficial effects of the present invention are as follows:
[0035] The invention uses N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester as raw materials, uses 2-chloro-4,6-dimethoxy-1,3,5-triazine as a condensing agent, and reacts in a solvent in the presence of an organic base N-methylmorpholine to obtain an argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester. The condensing agent used in the preparation method and the impurities introduced are easy to remove, the post-processing operation is simple, the product yield is high, the purity is high, the residual condensing agent and by-products in the product are easy to detect and control, and the preparation method is suitable for commercial production. DETAILED DESCRIPTION
[0036] The technical solution of the present invention is described in detail below through specific embodiments.
[0037] Example 1
[0038] At room temperature, 500 mL of DMF and 165 g of CDMT were added to a reaction flask, and the mixture was stirred at room temperature until completely dissolved. Then, 105 g of NMM was added dropwise, and the mixture was stirred at room temperature for 1 h. Then, 300 g of N-Boc-N'-nitro-L-arginine and 150 g of (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester were added, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was filtered, and 1000 mL of water was added to the obtained filtrate, and the mixture was stirred for crystallization and filtered. The crystals obtained by filtration were washed and dried to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester with a yield of 92.5% and a purity of 99.3%.
[0039] Example 2
[0040] At room temperature, 750 mL of DMF and 248 g of CDMT were added to a reaction flask, and the mixture was stirred at room temperature until completely dissolved. Then, 158 g of NMM was added dropwise, and the mixture was stirred at room temperature for 1 h. Then, 300 g of N-Boc-N'-nitro-L-arginine and 150 g of (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester were added, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was filtered, and 1500 mL of water was added to the obtained filtrate, and the mixture was stirred for crystallization and filtered. The crystals obtained by filtration were washed and dried to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester with a yield of 91.7% and a purity of 99.1%.
[0041] Example 3
[0042] At room temperature, 1000 mL of DMF and 330 g of CDMT were added to a reaction flask, and the mixture was stirred at room temperature until completely dissolved. 210 g of NMM was then added dropwise, and the mixture was stirred at room temperature for 1 h. 300 g of N-Boc-N'-nitro-L-arginine and 150 g of (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester were then added, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was filtered, and 2000 mL of water was added to the obtained filtrate, and the mixture was stirred for crystallization and filtered. The filtered crystals were washed and dried to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester with a yield of 92.0% and a purity of 98.9%.
[0043] Example 4
[0044] At room temperature, 2500 mL of DMF and 825 g of CDMT were added to a reaction flask, and the mixture was stirred at room temperature until completely dissolved. 525 g of NMM was then added dropwise, and the mixture was stirred at room temperature for 1 h. 300 g of N-Boc-N'-nitro-L-arginine and 150 g of (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester were then added, and the mixture was stirred at room temperature for 6 h. The mixture was filtered. After completion of the reaction, the mixture was filtered, and 5000 ml of water was added to the obtained filtrate. The mixture was stirred for crystallization, and filtered. The crystals obtained by filtration were washed and dried to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester with a yield of 90.4% and a purity of 98.8%.
[0045] Comparative Example 1
[0046] At room temperature, 500 mL of DMF and 165 g of CDMT were added to the reaction flask, and the mixture was stirred at room temperature until completely dissolved. Then, 300 g of N-Boc-N'-nitro-L-arginine and 150 g of (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester were added, and the reaction was stirred at room temperature for 24 hours. The TLC plate showed that a large amount of starting raw materials remained, indicating that when only CDMT was used as a condensing agent and NMM was not present, the reaction could not proceed fully, the raw material reaction was incomplete, and the raw material conversion rate and product yield were extremely low.
[0047] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.
Claims
1. A method for preparing an argatroban intermediate, characterized in that: Using N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester as raw materials and 2-chloro-4,6-dimethoxy-1,3,5-triazine as a condensation agent, in the presence of an organic base N-methylmorpholine, a reaction is carried out in a solvent to obtain the argatroban intermediate (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
2. The method for preparing an argatroban intermediate according to claim 1, wherein The specific steps include: 2-Chloro-4,6-dimethoxy-1,3,5-triazine is added to a solvent and fully dissolved, and then N-methylmorpholine is added dropwise and stirred evenly. Then, N-Boc-N'-nitro-L-arginine and (2R,4R)-4-methyl-2-piperidinic acid ethyl ester are added and reacted under stirring to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
3. The method for preparing an argatroban intermediate according to claim 2, wherein After the reaction is stirred, a post-treatment step is also included, which includes: filtering after the reaction is completed, adding water to the obtained filtrate, stirring and crystallizing, and collecting crystals to obtain (R)-4-methyl-1-(N8-nitro-N2-Boc-L-arginyl)-2-piperidinic acid ethyl ester.
4. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The solvent is N,N-dimethylformamide or ethyl acetate.
5. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The molar ratio of the N-Boc-N'-nitro-L-arginine to 2-chloro-4,6-dimethoxy-1,3,5-triazine is 1:1-5.
6. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The molar ratio of the N-Boc-N'-nitro-L-arginine to N-methylmorpholine is 1:1-5.
7. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The molar ratio of the N-Boc-N'-nitro-L-arginine to (2R, 4R)-4-methyl-2-piperidinic acid ethyl ester is 1:0.9-1.
1.
8. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The reaction temperature is 10-30°C.
9. The method for preparing an argatroban intermediate according to any one of claims 1 to 3, characterized in that: The reaction time is 6 to 8 hours.