Oxazole compound and preparation method thereof

Abstract

The invention provides an oxazole compound and a preparation method thereof. The invention provides a compound shown in a formula I or pharmaceutically acceptable salt thereof. The invention also provides a preparation method of the compound as shown in the formula I. In a solvent, in the presence of alkali, the compound 1 reacts with N, N-carbonyldiimidazole or N, N '-disuccinimido carbonate to generate the compound as shown in the formula I. The invention further provides a preparation method of the compound as shown in the formula I. The preparation method is simple, convenient and easy to process, and contributes to quality research of defamilast. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to an oxazole compound and a preparation method thereof. Background Art

[0002] Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by red, swollen, cracked skin and intense itching.

[0004] PDE4 inhibitors increase the intracellular cAMP concentration by inhibiting the hydrolysis of cAMP by PDE4. High levels of cAMP can activate protein kinase A (PKA) and exchange protein activated by cAMP1 / 2 (Epac1 / 2), thereby regulating multiple signaling pathways. On the one hand, activated PKA phosphorylates cAMP response element-binding protein (CREB), activating transcription factor 1 (ATF-1) and cAMP response element modulator (CREM), thereby increasing anti-inflammatory cytokines. On the other hand, activated PKA regulates the transcriptional activity of the nuclear factor-κB (NF-κB) pathway by competitively recruiting CREB binding protein (CBP) or homologous protein p300, leading to a reduction in proinflammatory cytokines such as interleukin-2 (IL-2), IL-4, IL-6, IL-31, and tumor necrosis factor alpha (TNF-α). In addition, PKA activation can also interfere with the synthesis of proinflammatory cytokines and the proliferation of immune cells mediated by Bcl-6. At the same time, the Epac1 / 2-mediated bypass pathway is activated after the increase of cAMP levels, interacting with the small GTPase protein Rap, inhibiting the synthesis of proinflammatory cytokines and cell proliferation. Since PDE4 is expressed in many types of immune-competent cells, PDE4 inhibitors can regulate the innate and adaptive immune systems.

[0005] Difamilast is a non-steroidal, topical anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor discovered by Otsuka. It was first approved for marketing in Japan in September 2021 for use in children over 2 years old and adults with mild to moderate AD.

[0006] According to data, there are currently 20 PDE4 inhibitors under development for atopic dermatitis worldwide. Among them, two have been approved for marketing, in addition to Otsuka's Difamilast, there is also Crisaborole developed by Pfizer, which was approved by the FDA in December 2016. In addition, Arcutis Biopharmaceuticals' Roflumilast Cream / Roflumilast / ARQ151 is currently in Phase III trials.

[0007] Pfizer's non-steroidal PDE4 inhibitor Crisaborole (trade name: Eucrisa) was approved for marketing in July 2020 for topical treatment of mild to moderate atopic dermatitis in patients aged 2 years and above, becoming China's first non-hormonal topical PDE4 inhibitor.

[0008] There is no report on the impurities of Difamilast in the prior art. In the process of new drug development, it is of great significance to study impurities. The study of impurities is an important part of drug quality research and formulation research. Its content can directly reflect the purity of the drug and further affect the safety evaluation of the drug. Therefore, it is urgent to study the impurities of Difamilast. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the lack of research on oxazole compounds and preparation methods thereof in the prior art. The present invention provides an oxazole compound and a preparation method thereof, and the preparation method is simple and easy to handle.

[0010] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0011] .

[0012] The present invention also provides a method for preparing the compound of formula I, which comprises the following steps: in a solvent, in the presence of a base, reacting compound 1 with N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to produce the compound of formula I,

[0013] .

[0014] In some embodiments, the solvent is a nitrile solvent or a halogenated alkane solvent; the nitrile solvent is a conventional nitrile solvent in the art, preferably acetonitrile; the halogenated alkane solvent is a conventional halogenated alkane solvent in the art, preferably dichloromethane.

[0015] In some embodiments, the mass volume ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the solvent is 0.01-0.1 g / mL, preferably 0.04-0.095 g / mL, such as 0.04 g / mL or 0.095 g / mL.

[0016] In some embodiments, the base is a conventional base in the art, preferably diisopropylethylamine (DIPEA).

[0017] In some embodiments, the molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the base is 1:(2-5); preferably 1:3.

[0018] In some embodiments, the molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the compound 1 is 1:(1-3); for example, 1:2.3.

[0019] In some embodiments, the reaction temperature is room temperature.

[0020] In some embodiments, the reaction time is 10-20 h, such as 16 h.

[0021] In some embodiments, after the reaction is completed, a post-treatment step is further included, and the post-treatment includes filtering, pulping and filtering and drying.

[0022] In some embodiments, the slurrying solvent is a nitrile solvent or a halogenated alkane solvent; the nitrile solvent is a conventional nitrile solvent in the art, preferably acetonitrile; the halogenated alkane solvent is a conventional halogenated alkane solvent in the art, preferably dichloromethane.

[0023] In some embodiments, the solvent is acetonitrile or dichloromethane, the mass volume ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the solvent is 0.04~0.095g / mL, the base is diisopropylethylamine, the molar ratio of N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the base is 1:3, the molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the compound 1 is 1:2.3, and the reaction temperature is room temperature.

[0024] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0025] The reagents and raw materials used in the present invention are commercially available.

[0026] The positive progressive effect of the present invention is that it provides an oxazole compound and a preparation method thereof, wherein the compound can be used as a reference substance in industrial synthesis to optimize the detection method, and the preparation method has a simple route and is easy to handle, thus contributing to the quality research of defamilastat. DETAILED DESCRIPTION

[0027] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0028]

[0029] Example 1

[0030] 3.3 g of compound 1 was added to 20 mL of acetonitrile, 1.9 g of DIPEA was added dropwise, and the mixture was stirred until dissolved. 0.8 g of N,N-carbonyldiimidazole was added to the above solution, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the solid was slurried with 20 mL of acetonitrile, filtered, and dried to obtain 2.2 g of white solid compound 2 ( 1 H NMR (400 MHz, CD3OD+(CD3)2SO) δ 7.97 (s, 2H), 7.61(d, J = 1.9 Hz, 2H), 7.55 (dd, J = 8.4, 1.9 Hz, 2H), 7.34 – 6.91 (m, 4H),6.45 (t, J = 5.7 Hz, 2H), 4.73 (dt, J = 12.1, 6.0 Hz, 2H), 4.20 (d, J = 5.2Hz, 4H), 1.32 (d, J = 6.0 Hz, 12H).), yield 71.8%, purity 95.3%.

[0031] Example 2

[0032] 5 g of compound 1 was added to 20 mL of dichloromethane, 2.9 g of DIPEA was added dropwise, and the mixture was stirred until dissolved. 1.9 g of N,N'-disuccinimidyl carbonate was added to the above solution, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the solid was slurried with 20 mL of dichloromethane, filtered and dried to obtain 3.3 g of white solid compound 2, with a yield of 71.5% and a purity of 93.4%.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: 。 2. A method for preparing a compound of formula I, comprising the following steps: reacting compound 1 with N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate in a solvent in the presence of a base to produce a compound of formula I, 。 3. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The solvent is a nitrile solvent or a halogenated alkane solvent; (2) The mass volume ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the solvent is 0.01-0.1 g / mL; (3) The base is diisopropylethylamine; (4) The molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the base is 1:(2-5); (5) The molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the compound 1 is 1:(1-3); (6) The reaction temperature is room temperature.

4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The nitrile solvent is acetonitrile; (2) The halogenated alkane solvent is dichloromethane; (3) The mass volume ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the solvent is 0.04-0.095 g / mL; (4) The molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the base is 1:3; (5) The molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the compound 1 is 1:2.

3.

5. The preparation method according to claim 2, characterized in that: After the reaction is completed, a post-processing step is further included, and the post-processing includes filtering, beating and filtering and drying.

6. The preparation method according to claim 5, characterized in that: The solvent for pulping is a nitrile solvent or a halogenated alkane solvent.

7. The preparation method according to claim 6, characterized in that: It meets one or both of the following conditions: (1) The nitrile solvent used in pulping is acetonitrile; (2) The halogenated alkane solvent used in pulping is dichloromethane.

8. The preparation method according to claim 2, characterized in that: The solvent is acetonitrile or dichloromethane, the mass volume ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the solvent is 0.04-0.095 g / mL, the base is diisopropylethylamine, the molar ratio of N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the base is 1:3, the molar ratio of the N,N-carbonyldiimidazole or N,N'-disuccinimidyl carbonate to the compound 1 is 1:2.3, and the reaction temperature is room temperature.

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