Preparation method of imrecoxib isomer impurity 4-(4-(methylsulfonyl) phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-alcohol

Abstract

The invention discloses a preparation method of an imrecoxib isomer impurity, and belongs to the field of synthesis of medical intermediates, the imrecoxib isomer impurity 4-(4-(methylsulfonyl) phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol is obtained in one step from imrecoxib under the action of strong base. The method is simple, convenient and stable to operate, the product is easy to separate, the yield is high, the method is environment-friendly, and a new synthesis way is provided for the compounds.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for preparing an isomer impurity of arbutin: 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol. Background Technology

[0002] Erricoxib is a highly effective and low-toxicity nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain symptoms of osteoarthritis. Erricoxib primarily targets COX-2, reducing inflammation by inhibiting the production of inflammatory prostaglandins. While suppressing inflammation and pain, it also maintains the balance of PGI2 and TxA2 in the body, thereby reducing the likelihood of gastrointestinal irritation and cardiovascular damage. Erricoxib has seen a positive sales trend in Chinese hospitals in recent years, maintaining a continuous upward trend, and is expected to become a first-line anti-inflammatory and analgesic drug.

[0003] Impurity research in active pharmaceutical ingredients (APIs) is the basis for setting API quality standards and is one of the key tasks in drug development and application. Obtaining impurity reference standards is a prerequisite for API impurity research. Currently, there are no publicly available literature reports on the preparation method of the isomer impurity of arbutin: 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a novel method for preparing 4-(4-(methylsulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol that is simple to operate, stable, has a high yield, is easy to separate, and is environmentally friendly.

[0005] This invention provides a method for preparing the isomer impurity of arbutin: 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol, the synthetic route of which is as follows:

[0006]

[0007] The specific reaction is as follows: Aristocobacterium reacts in an organic solvent under the action of a strong base to convert into the aristocobacterium isomer impurity 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol. After quenching the reaction, the product is purified to obtain the pure isomer.

[0008] Furthermore, the strong base is selected from sodium hydride, sodium bis(trimethylsilyl)amino, lithium diisopropylamino, lithium n-butyllithium, etc.;

[0009] Furthermore, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethaneamine, and toluene are used; their main function is dissolution, and they have no significant effect on the reaction yield; N,N-dimethylformamide is the preferred solvent.

[0010] Furthermore, the molar ratio of etoricoxib to the strong base is 1:0.8 to 1:2.5; preferably 1:2.5.

[0011] Instruction manual illustrations

[0012] Figure 1 This is a synthesis route diagram for an example;

[0013] Figure 2 The HNMR spectrum of 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol, an isomer of arbutin in Example 1;

[0014] Figure 3 The HNMR spectrum of ericoxib. Detailed Implementation

[0015] The present invention will be further illustrated below with reference to specific embodiments. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0016] Example 1

[0017] Synthesis of the isomer impurity 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol from arbutin

[0018] Irritoxib (37.0 g, 100.0 mmol) was dissolved in N,N-dimethylformamide (400 ml), and the reaction was heated to 50–55 °C. Sodium hydride (9.6 g, 250.0 mmol) was added in six portions, and the mixture was kept at 50–55 °C for 0.5 hours. The reaction was monitored by HPLC. After the reaction was complete, water (400 ml) was added to quench the reaction. The mixture was then washed with methyl tert-butyl ether (400 ml), separated, the organic layer dried, concentrated, and separated by column chromatography to obtain 26.3 g of white solid, with a yield of 71%. HPLC purity was 99.5%, ESI(+) m / z = 370.1. 1H NMR(500MHz,Chloroform-d)δ7.84–7.78(m,1H),7.71–7.65(m,1H),7.41–7.35(m,1H),7.28–7.22(m,1 H), 3.99 (t, J = 4.0Hz, 1H), 3.18 (s, 2H), 2.40 (s, 2H), 1.72 (qt, J = 7.1, 4.0Hz, 1H), 0.90 (t, J = 7.1Hz, 2H).

[0019] Example 2

[0020] Synthesis of the isomer impurity 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol from arbutin

[0021] Irritoxib (37.0 g, 100.0 mmol) was dissolved in tetrahydrofuran (400 ml), and the reaction was cooled to -80 to -75 °C. A 1 N n-butyllithium-tetrahydrofuran solution was added dropwise and the temperature was maintained at -80 to -75 °C for 0.5 hours. The temperature was then raised to -40 °C and maintained for 1 hour. The reaction was monitored by HPLC. After the reaction was complete, water (400 ml) was added dropwise to quench the reaction. The mixture was then washed with methyl tert-butyl ether (400 ml), separated, dried over the organic layer, concentrated, and separated by column chromatography to obtain 28.2 g of a white solid, with a yield of 76%. The HPLC purity was 99.8%.

[0022] Example 3

[0023] Synthesis of the impurity 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol, an isomer of arectobacterium: Arectobacterium (37.0 g, 100.0 mmol) was dissolved in tetrahydrofuran (400 ml), and the reaction was cooled to -0 to 5 °C. A 1 N solution of diisopropylaminolithium-tetrahydrofuran was added dropwise, and the mixture was kept at -0 to 5 °C for 2 hours. The reaction was monitored by HPLC. After the reaction was complete, water (400 ml) was added dropwise to quench the reaction. The mixture was then washed with methyl tert-butyl ether (400 ml), separated, dried over the organic layer, concentrated, and separated by column chromatography to obtain 22.6 g of a white solid, yield 61%. HPLC purity was 99.5%.

Claims

1. A method for preparing an isomer impurity of arbutin: 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol, the synthetic route is as follows: Its features are, Includes the following steps: Starting from arectobacterium, after strong alkali treatment and quenching reaction, the arectobacterium isomer impurity 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol was obtained through purification.

2. The method for preparing the isomer impurity of arbutin, 4-(4-(methanesulfonyl)phenyl)-1-propyl-3-(p-tolyl)-1H-pyrrole-2-ol, according to claim 1, is characterized in that: The strong base is selected from sodium hydride, sodium bis(trimethylsilyl)amino, lithium diisopropylamino, and lithium n-butyl; the reaction solvent is selected from N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethaneamine, and toluene; the reaction temperature is selected from -78 to 50°C; and the molar ratio of arbutin to the strong base is 1:0.8 to 1:2.5.

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