Preparation method of isoxazolopyridine derivative

Abstract

The invention provides a preparation method of a compound 2. The reaction is as follows: # imgabs0 #, wherein A1, A2, A3 and A4 are independently selected from C and N and are not N at the same time; r1 is any substituted alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group; m is selected from 0, 1 and 2; comprising the following steps: step 1, cooling a compound 1 and concentrated hydrochloric acid to-10 DEG C to 5 DEG C, adding NaNO2, and stirring to obtain a reaction solution; and 2, reacting the reaction liquid at 50-85 DEG C to obtain a compound 2. The invention provides a brand new preparation method of an isoxazolopyridine derivative compound 2, the inventor optimizes the reaction temperature, not only improves the raw material conversion rate by more than 25%, but also simplifies the post-treatment method, and compared with the prior art, the preparation method has the advantages of high conversion rate, simple operation, good reproducibility and high purity, is suitable for industrial production, and has a wide application prospect. Therefore, the method has better market value and profound practical significance.

Description

Technical Field

[0001] The present invention relates to a method for preparing isoxazolo[4,5 - b]pyridine derivatives, belonging to the technical fields of medicine and chemistry. Background Art

[0002] Isoxazolo[4,5 - b]pyridine derivatives are important pharmacophore groups in bioactive and pharmaceutical compounds and are also a class of important molecular building blocks. They have been widely studied and exhibit a series of biological activities. For example, a series of isoxazolo[4,5 - b]pyridine derivatives disclosed in WO2010102778A2 have shown biological activities as KCNQ2 / 3 regulators. For example, compound A:

[0003] In addition, Patent US9808445B2 discloses an IXa factor antagonist, which has beneficial effects in treating thrombotic diseases, improving pharmacokinetics, and reducing the risk of arrhythmia. Its core molecule contains the following fragment:

[0004]

[0005] In the prior art, there are few reports on the preparation methods of such compounds. Moreover, in the prior art, the reaction of preparing chlorine using amines as raw materials mostly uses sodium nitrite and copper salts, and such reactions usually result in a darker color of the product during post - treatment and there will be a residue of copper ions, which may lead to poor quality of the final product and the possibility of exceeding the copper ion content, and is not conducive to scale - up production.

[0006] The demand for such compounds is large. To meet the market demand, there is an urgent need for a synthetic method that is practical, economical, fast, simple to operate, easy to post - process, has a high yield, high purity, and can be industrially produced.

[0007] The present invention provides a method for preparing isoxazolo[4,5 - b]pyridine derivatives, which does not require the use of copper salt reagents and has the advantages of being economical, fast, simple to operate, easy to post - process, and having a high conversion rate. It is suitable for industrial production and thus has good market value and profound practical significance. Summary of the Invention

[0008] In view of the above technical background, the present invention provides a method for preparing isoxazolo[4,5 - b]pyridine derivative compound 2. The preparation method of the present invention is simple to operate, has a high atom utilization rate, high conversion rate, short time consumption, reduces costs, and is conducive to industrial production.

[0009] The present invention provides a method for preparing compound 2, and the reaction is as follows:

[0010]

[0011] Wherein A1, A2, A3, A4 are independently selected from C, N, and not all N at the same time;

[0012] R1 is an optionally substituted alkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl;

[0013] m is selected from 0, 1, 2;

[0014] As a further improvement of the present invention, including but not limited to, the alkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl is optionally substituted by one or more groups selected from cyano, ester group, oxo group, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, and heteroaryl;

[0015] As a further improvement of the present invention, including but not limited to, the above-mentioned term "alkyl" is a linear or branched hydrocarbon group, preferably a C1-C6 alkyl group, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and pivalyl;

[0016] As a further improvement of the present invention, including but not limited to, the above-mentioned term "cycloalkyl" is a cyclic saturated hydrocarbon group, preferably a C 4-8 bridged cycloalkyl, C 3-12 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0017] As a further improvement of the present invention, including but not limited to, the above-mentioned term "heterocyclic group" refers to a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkyl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, dihydro-1H-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridyl, and tetrahydro-2H-pyranyl;

[0018] As a further improvement of the present invention, including but not limited to, the above-mentioned term "heteroaryl" refers to a 5-membered, 6-membered, or 7-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, such as pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyridazinyl;

[0019] As a further improvement of the present invention, including but not limited to, the aryl refers to a monocyclic or polycyclic aromatic hydrocarbon, such as phenyl, naphthyl, and anthracenyl;

[0020] Comprising the following steps:

[0021] Step 1: Compound 1 and concentrated hydrochloric acid are cooled to -10°C to 5°C, and NaNO2 is added and stirred to obtain a reaction solution;

[0022] Step 2: The reaction solution reacts at 50°C to 85°C to obtain Compound 2;

[0023] As a further improvement of the present invention, in Step 2 of the present invention, the reaction is carried out within a preferred temperature range. Compared with the prior art where the reaction is carried out at 0°C, the yield is increased by more than 30%, the remaining raw materials are reduced, the post-treatment is simplified, the method of the present invention has the advantages of high conversion rate, cost reduction, and being conducive to production.

[0024] As a further improvement of the present invention, including but not limited to, the molar ratio of Compound 1 to NaNO2 in Step 1 is 1:(1 - 2), preferably 1:(1 - 1.5);

[0025] As a further improvement of the present invention, including but not limited to, the volume dosage ml of concentrated hydrochloric acid in Step 1 is 3 to 20 times the mass dosage g of Compound 1, preferably 3 to 15 times;

[0026] As a further improvement of the present invention, including but not limited to, the reaction time of Step 1 is 0.5 to 2 h, preferably 0.5 to 1.5 h;

[0027] As a further improvement of the present invention, including but not limited to, the reaction time of Step 2 is 0.5 to 3 h, preferably 0.5 to 2.5 h;

[0028] As a further improvement of the present invention, in some embodiments, in Step 1, Compound 1 and concentrated hydrochloric acid are mixed and cooled to 0°C, and NaNO2 is added and stirred at 0°C for 1 h to obtain a reaction solution;

[0029] As a further improvement of the present invention, in some embodiments, in Step 2, the reaction solution reacts at 50°C to 80°C for 1 to 2 h to obtain Compound 2.

[0030] As a further improvement of the present invention, including but not limited to, at least one of A1, A2, A3, and A4 is N; for example, one of A1, A2, A3, and A4 can be N, or two of them can be N, or three of them can be N;

[0031] As a further improvement of the present invention, including but not limited to, Compound 1 in Step 1 is selected from the following structures:

[0032]

[0033] As a further improvement of the present invention, including but not limited to, Compound 2 in Step 2 is selected from the following structures:

[0034]

[0035] As a further improvement of the present invention, in some embodiments, after the reaction in step 2 is complete, the reaction solution is poured into water, filtered by suction, washed, and dried to obtain compound 2;

[0036] As a further improvement of the present invention, in some embodiments, the obtained compound 2 can be optionally further purified, for example, by slurrying with ethyl acetate.

[0037] As a further improvement of the present invention, the inventors have tried conventional purification methods such as column chromatography and slurrying. However, due to the high similarity of compound 1 and compound 2 in key physicochemical parameters (especially polarity parameters), it is difficult to obtain high-purity compound 2 by traditional separation means. By using the method of the present invention, only slurrying with ethyl acetate is required for the final post-treatment, and the purity can reach 95%. This not only simplifies the post-treatment but also saves costs, providing the possibility for industrial production scale-up.

[0038] Advantageous technical effects of the present invention:

[0039] 1. The present invention has developed a controllable synthesis method for compound 2 for the first time. By innovatively designing the reaction system and process parameters, a complete preparation route for compound 2 has been successfully constructed, filling the technical gap of this compound in the field of synthetic chemistry and providing key raw material guarantees for fields such as pharmaceutical intermediates and functional materials.

[0040] 2. Through continuous attempts by the inventors, it was unexpectedly found that by optimizing the reaction temperature in step 2 to 50 - 85°C, compared with the low-temperature reaction at 0°C in the prior art, the yield was increased from about 30% to over 65%, an increase of more than 30%, significantly improving the production efficiency. And when the inventors repeated the low-temperature reaction at 0°C, it was found that about 25% of the raw materials remained. When the temperature was raised to 20°C for the reaction, a large amount of raw materials still remained. By optimizing the temperature control, the conversion rate of the raw materials exceeded 98%, and the residual amount of unreacted raw materials decreased from 25.7% to less than 3%, and no impurities were generated at the same time; in addition, the product selectivity was increased to over 95%, reducing the purification difficulty.

[0041] 3. The present invention also simplifies the post-treatment process. The traditional process requires operations such as extraction, column chromatography, and multiple filtrations. The low by-products enable the reaction solution to directly enter the crystallization step, eliminating complex operations such as extraction and multiple filtrations. Even in some embodiments, the present invention only needs to pour the reaction solution into ice water and then filter by suction to obtain a product with a purity > 95%; greatly shortening the purification time and significantly reducing the solvent consumption, reducing the treatment cost.

[0042] 4. The route provided by this invention has a high conversion rate and simple post-treatment, providing the possibility for large-scale production of this product. Description of the Drawings

[0043] Figure 1LCMS spectrum of the reaction solution of Example 1 of the present invention;

[0044] Figure 2 LCMS spectrum of the reaction solution of Example 2 of the present invention;

[0045] Figure 3 LCMS spectrum of the reaction solution of Example 5 of the present invention. Detailed implementation manners

[0046] The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following detailed description of the technical solutions of the present invention by way of examples will help to further understand the advantages and effects of the technical solutions of the present invention. The examples do not limit the protection scope of the present invention, and the protection scope of the present invention is determined by the claims.

[0047] For the experimental methods without specific conditions indicated in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0048] Unless otherwise specified, the raw materials or reagents used in the examples are all commercially available.

[0049] Unless otherwise specified, the reagents are used directly without purification. All solvents are purchased from commercial suppliers, such as Aldrich, and can be used without treatment.

[0050] Example 1:

[0051]

[0052] Compound 1A (1 g, 7.4 mmol) was added to concentrated hydrochloric acid (20 mL), cooled to 0 °C, and NaNO2 (540 mg, 7.83 mmol, 1.06 eq) was added. The mixture was stirred at 0 °C for 1 h to obtain a reaction solution, and the reaction solution was further reacted at 50 °C for 2 h. After the reaction was completed, the reaction solution was poured into water, filtered by suction, and the precipitated solid was washed with water. The remaining raw material detected by LCMS of the obtained solid was 2.9%, and the solid was dried under vacuum. Then it was slurried with EA under heating and filtered by suction while hot, and the filter cake was dried under vacuum to obtain compound 2A (690 mg, purity: 95.3%, yield: 60%) as a white solid. The LCMS of the reaction solution is as Figure 1 shown.

[0053] Example 2:

[0054]

[0055] Compound 1A (1 g, 7.4 mmol) was added to concentrated hydrochloric acid (20 mL), cooled to 0 °C, and NaNO2 (540 mg, 7.83 mmol, 1.06 eq) was added. The mixture was stirred at 0 °C for 1 h to obtain a reaction solution, and the reaction solution was further reacted at 80 °C for 1 h. After the reaction was completed, the reaction solution was poured into water, filtered by suction, and the precipitated solid was washed with water. The resulting solid was detected by LCMS, and 1.1% of the raw material remained. The solid was dried under vacuum. Then it was slurried with EA under heating and filtered by suction while it was hot. The filter cake was dried under vacuum to obtain Compound 2A (770 mg, purity: 97.1%, yield: 67.3%). The LCMS of the reaction solution was as Figure 2 shown.

[0056] Example 3:

[0057]

[0058] Compound 1A (30 g, 222.0 mmol) was added to concentrated hydrochloric acid (300 mL), cooled to 0 °C, and NaNO2 (16.1 g, 233.4 mmol) was added. The mixture was stirred at 0 °C for 1 h to obtain a reaction solution, and the reaction solution was further heated and stirred at 80 °C for 1 h. After the reaction was completed, the reaction solution was poured into water, filtered by suction, and the precipitated solid was washed with water and dried under vacuum. The resulting solid was slurried with ethyl acetate under heating and filtered by suction while it was hot. The filtrate was dried under vacuum to obtain Compound 2 (23 g, purity: 99.1%, yield 67%) as a white solid.

[0059] Example 4:

[0060]

[0061] Compound 1A (1 g, 7.4 mmol) was added to concentrated hydrochloric acid (20 mL), cooled to 0 °C, and NaNO2 (540 mg, 7.83 mmol, 1.06 eq) was added. The mixture was stirred at 0 °C for 1 h to obtain a reaction solution, and the reaction solution was further reacted at 100 °C for 1 h. After the reaction was completed, the reaction solution was poured into water, filtered by suction, and the precipitated solid was washed with water. The resulting solid was detected by TLC, and it was found that the TLC plate was very messy, there was no remaining raw material, and there was only a small amount of product.

[0062] Example 5:

[0063]

[0064] Compound 1A (1 g, 7.4 mmol) was added to concentrated hydrochloric acid (20 mL), cooled to 0 °C, and NaNO2 (540 mg, 7.83 mmol, 1.06 eq) was added. The mixture was stirred at 0 °C for 1 h to obtain a reaction solution, and the reaction solution was further reacted at 20 °C for 1 h. After the reaction was completed, a small amount of the reaction solution (a few drops) was poured into water, filtered by suction, and the precipitated solid was washed with water. The obtained solid was detected by LCMS, showing that 25.7% of the raw material remained. The reaction time was continued to be extended, and TLC was used to monitor at 1 h, 2 h, and 3 h respectively. The change was not significant, and there was still a large amount of raw material remaining. The LCMS of the reaction solution is as Figure 3 shown.

[0065] The inventors found that under conventional conditions, when the reaction in Step 2 was carried out at 0-20 °C, a large amount of raw material remained, about 25%. Moreover, due to the relatively close physical information of Compound 1 and Compound 2 itself, especially the polarity, it was very difficult to separate Compound 1 and Compound 2 during the post-treatment. The inventors tried conventional purification methods such as column chromatography and pulping, but in all cases, a large amount of Compound 1 remained, and it was difficult to obtain pure Compound 2.

[0066] The inventors surprisingly found that when the synthesis was carried out under conventional reaction conditions (0-20 °C), the residual amount of raw materials in the system was as high as more than 25%, significantly affecting the yield of the target product. When the reaction temperature was 50 °C to 85 °C, the remaining raw materials could be less than 3% (detected by LCMS). It should be noted that when the reaction temperature was raised to 100 °C, although there was no remaining raw material, a large amount of by-products were generated at the same time, and only a small amount of product was formed.

[0067] The above description of the embodiments is to enable those of ordinary skill in the art to understand and use the invention. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative labor. Therefore, the present invention is not limited to the above embodiments, and all improvements and modifications made by those skilled in the art without departing from the scope of the present invention according to the disclosure of the present invention should be within the protection scope of the present invention.

Claims

1. A preparation method of compound 2, the reaction is as follows: Wherein A1, A2, A3, A4 are independently selected from C, N, and not all N at the same time; R1 is an optionally substituted alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl; m is selected from 0, 1, 2; Comprising the following steps: Step 1: Cool compound 1 and concentrated hydrochloric acid to -10°C to 5°C, add NaNO2 and stir to obtain a reaction solution; Step 2: React the reaction solution at 50°C to 85°C to obtain compound 2.

2. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of compound 1 to NaNO2 is 1:(1 - 2).

3. The preparation method according to claim 2, characterized in that, In step 1, the molar ratio of compound 1 to NaNO2 is 1:(1 - 1.5).

4. The preparation method according to claim 1, wherein In step 1, the volume dosage ml of concentrated hydrochloric acid is 3 to 20 times the mass dosage g of compound 1.

5. The preparation method according to claim 1 or 4, characterized in that, In step 1, the volume dosage ml of concentrated hydrochloric acid is preferably 3 to 15 times the mass dosage g of compound 1.

6. The preparation method according to claim 1, wherein The reaction time of step 1 is 0.5 to 2 h, preferably 0.5 to 1.5 h.

7. The preparation method according to claim 1 or 6, characterized in that, The reaction time of step 2 is 0.5 to 3 h, preferably 0.5 to 2.5 h.

8. The preparation method according to claim 1, characterized in that, In step 1, compound 1 and concentrated hydrochloric acid are mixed and cooled to 0°C, add NaNO2 and stir at 0°C for 1 h to obtain a reaction solution; in step 2, the reaction solution reacts at 50°C to 80°C for 1 to 2 h to obtain compound 2.

9. The preparation method according to claim 1, characterized in that After the reaction in step 2 is complete, pour the reaction solution into water, filter by suction, wash, and dry to obtain compound 2, and the obtained compound 2 can be optionally further purified.

10. The preparation method according to claim 1, characterized in that, In step 1, compound 1 is selected from the following structures: In step 2, compound 2 is selected from the following structures:

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