Preparation method of N-(4-(tert-butyl) thiazole-2-yl)-3-fluorobenzamide

Abstract

The invention provides a preparation method of N-(4-(tert-butyl) thiazole-2-yl)-3-fluorobenzamide, which comprises the following steps: mixing a compound as shown in a formula I, N, N-diisopropylethylamine and 2-succinimido-1, 1, 3, 3-tetramethylurea tetrafluoroborate for reaction, then adding a compound as shown in a formula II for amidation reaction, and finally obtaining the N-(4-(tert-butyl) thiazole-2-yl)-3-fluorobenzamide. And reacting the N-(4-(tert-butyl) thiazole-2-yl)-3-fluorobenzamide to obtain the N-(4-(tert-butyl) thiazole-2-yl)-3- According to the preparation method provided by the invention, by innovatively changing the reaction sequence, firstly activating the raw materials and then carrying out amidation reaction, the polarity of by-products is successfully changed, the polarity of main by-products is obviously smaller than that of target products, the products are easy to separate, the column chromatography separation efficiency is greatly improved, the yield is increased, and the post-treatment time is shortened.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide. Background Technology

[0002] N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide is a commonly used isomer regulator. The mechanism of action of this regulator is to bind to the allosteric site of the receptor, resulting in conformational changes or changes in protein kinetics, thereby regulating protein activity.

[0003] It possesses biological significance and promising applications. Allosteric modulators have several distinct advantages over traditional normal modulators: 1. High selectivity: Allosteric ligands can achieve high selectivity by binding to relatively unique sites within the receptor subtype family. 2. Protection of native ligands: Allosteric modulators lacking agonistic function only function in the presence of endogenous ligands, thus protecting the steric effect of native ligands. 3. Easily modifiable physicochemical properties: Compared to normal compounds, the physicochemical properties of many allosteric compounds are easily modulated to achieve better biological efficacy. These advantages make allosteric modulators a promising candidate for drug development, especially in drug design requiring high selectivity and low side effects.

[0004] Currently, there is no particularly good method for synthesizing this substance, making mass production impossible. Therefore, it is necessary to develop a new synthesis method to achieve better synthesis results. Summary of the Invention

[0005] The technical problem to be solved by this invention is that there is no method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide, and existing amide synthesis methods cannot achieve mass production when applied to the synthesis of this compound, resulting in low reaction yield.

[0006] To address the aforementioned technical problems, this invention provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide, characterized in that the preparation method comprises the following steps:

[0007] The compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate were mixed and reacted, and then the compound shown in Formula II was added to carry out an amidation reaction to obtain the N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0008]

[0009] Where R is a hydroxyl or chlorine atom.

[0010] The preparation method provided by this invention innovatively changes the reaction sequence by first activating the raw materials and then carrying out the amidation reaction, which successfully changes the polarity of the by-products. The polarity of the main by-products is significantly less than that of the target product, making the products easier to separate, greatly improving the column chromatography separation efficiency, thereby increasing the yield and shortening the post-processing time.

[0011] Preferably, R in the compound of Formula I is a hydroxyl group.

[0012] In this invention, when R is a chlorine atom, the reaction substrate is an acyl chloride, which has high substrate activity and will generate impurities with other raw materials during the reaction, making subsequent processing difficult and resulting in a low yield. When the reaction substrate is a carboxyl group, there are fewer impurities and a higher yield. Therefore, hydroxyl is preferred.

[0013] Preferably, the molar ratio of the compound shown in Formula I, N,N-diisopropylethylamine (DIPEA), and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate (TSTU) is 1:1 to 1.2:1 to 1.2, for example, it can be 1:1.1, 1:1:1.1, 1:1.1:1.2, or 1:1.2:1.2.

[0014] Preferably, the temperature of the mixing reaction is 20 to 40°C, for example, 20°C, 30°C, or 40°C.

[0015] Preferably, the mixing reaction time is 1 to 4 hours, for example, 1 hour, 2 hours, 3 hours or 4 hours.

[0016] Preferably, the molar ratio of the compound shown in Formula II to the compound shown in Formula I is 1:1.1 to 1.3, for example, it can be 1:1.1, 1:1.2 or 1:1.3, etc.

[0017] Preferably, the temperature of the amidation reaction is 50 to 80°C, for example, 50°C, 60°C, 70°C or 80°C.

[0018] Preferably, the amidation reaction takes 12 to 20 hours, for example, 12 hours, 14 hours, 18 hours, or 20 hours.

[0019] As a preferred technical solution, the preparation method is as follows:

[0020] The compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate were mixed and reacted at 20–40 °C for 1–4 h. Then, the compound shown in Formula II was added and subjected to an amidation reaction at 50–80 °C for 12–20 h to obtain the N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0021]

[0022] Where R is a hydroxyl or chlorine atom;

[0023] The molar ratio of the compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate is 1:1 to 1.2:1 to 1.2.

[0024] The molar ratio of the compound shown in Formula II to the compound shown in Formula I is 1:1.1 to 1.3.

[0025] Implementing this invention has the following beneficial effects:

[0026] The preparation method provided by this invention innovatively changes the reaction sequence by first activating the raw materials and then carrying out the amidation reaction, which successfully changes the polarity of the by-products. The polarity of the main by-products is significantly less than that of the target product, making the products easier to separate, greatly improving the column chromatography separation efficiency, thereby increasing the yield and shortening the post-processing time. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1

[0029] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0030]

[0031] Raw material d (2.15 g, 1.2 eq) was dissolved in 2 L of dichloromethane (DCM), followed by the addition of DIPEA (2 g, 1.2 eq) and TSTU (4.6 g, 1.2 eq) at 0 °C. The reaction was carried out at room temperature for 2 h, followed by the addition of raw material a (2 g, 1.0 eq) and the reaction at 60 °C for 16 h. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was quenched with water. The layers were extracted and separated. The organic phase was treated with 10% sulfuric acid to remove the byproduct 1,1,3,3-tetramethylurea produced by TSTU. The organic phase was dried and concentrated to obtain 5 g of crude product. The crude product was purified by column chromatography, and the product was eluted with petroleum ether to ethyl acetate at a volume ratio of 50:1 to obtain 3 g of pure product (yield 85%, purity 98%).

[0032] The proton NMR spectrum of the product: 1H NMR (400MHz, DMSO) δ12.67 (s, 1H), 7.94 (t, J=9.1Hz, 2H), 7.53 (dd, J=45.5, 3.8Hz, 2H), 6.82 (s, 1H), 1.30 (s, 9H).

[0033] Nuclear magnetic resonance fluorine spectrum: 19 F NMR (376MHz, DMSO) δ-112.47 (s, 1F).

[0034] Example 2

[0035] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0036]

[0037] Raw material d (215 g, 1.2 eq) was dissolved in 2 L of dichloromethane, followed by the addition of DIPEA (200 g, 1.2 eq) and TSTU (460 g, 1.2 eq) at 0 °C. The reaction was carried out at room temperature for 2 h, followed by the addition of raw material a (200 g, 1.0 eq) and the reaction at 60 °C for 16 h. The reaction was monitored by thin-layer chromatography (TLC), and the reaction was quenched with water. The layers were extracted and separated. The organic phase was treated with 10% sulfuric acid to remove the byproduct 1,1,3,3-tetramethylurea produced by TSTU. The organic phase was dried and concentrated to obtain 530 g of crude product. The crude product was purified by column chromatography, and the product was eluted with petroleum ether to ethyl acetate at a volume ratio of 50:1 to obtain 310 g of pure product (yield 88%, purity 98%).

[0038] Example 3

[0039] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0040]

[0041] Raw material a (2g, 1.0eq) was dissolved in 20ml of dichloromethane, and raw material b (2.4g, 1.2eq) was added. The reaction was carried out at room temperature for 3h. The reaction was monitored by TLC. After the raw materials were consumed, water was added to quench the reaction, and the mixture was extracted, separated into layers, and the organic phase was dried and concentrated to obtain 4.2g of crude product. The product was then eluted by column chromatography with petroleum ether and ethyl acetate in a volume ratio of 50:1 to obtain 1.1g of pure product (yield 30%, purity 97%).

[0042] Example 4

[0043] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0044]

[0045] Dissolve raw material a (2g, 1.0eq) in 20ml of dichloromethane, add raw material b (2.4g, 1.2eq), add DIPEA (2g, 1.2eq), and react at room temperature for 3h. The reaction was monitored by TLC, and no effective improvement was observed.

[0046] Example 5

[0047] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0048]

[0049] Dissolve raw material a (2g, 1.0eq) in 20ml of dichloromethane, add raw material d (2.15g, 1.2eq), EDCI (2.95g, 1.2eq), and TEA (1.55g, 1.2eq), and react at room temperature for 3h. The reaction was detected by TLC, and the reaction was not effectively improved.

[0050] Example 6

[0051] This embodiment provides a method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide.

[0052]

[0053] Dissolve raw material a (2g, 1.0eq) in 20ml DCM, add raw material d (2.15g, 1.2eq), add DIPEA (2g, 1.2eq), add TSTU (4.6g, 1.2eq), and react at room temperature for 3h. The reaction was detected by TLC, and the reaction was not effectively improved.

[0054] Comparative Example 1

[0055] The difference between this comparative example and Example 1 is that DIPEA and TSTU are replaced with triethylamine in this comparative example.

[0056] Based on the results of this comparative reaction, it is difficult to purify the product through post-processing.

[0057] Comparative Example 2

[0058] The difference between this comparative example and Example 1 is that DIPEA and TSTU are replaced with potassium carbonate in this comparative example.

[0059] Based on the results of this comparative reaction, the reaction could not proceed.

[0060] Comparing Examples 1-2 with other examples, it is evident that by first using TSTU to generate the active intermediate with raw material d, and then using raw material a in the reaction, the byproducts generated in the TLC reaction are significantly less polar than the products. Therefore, they can be quickly separated during column chromatography, resulting in a significant increase in yield. Post-processing time is also greatly reduced. This is because the byproduct 1,1,3,3-tetramethylurea, generated by the ureonium salt condensing agent in the reaction, has high solubility in organic solvents and will elute along with the product during column purification, reducing product purity.

[0061] The mother liquor was washed multiple times with 10% sulfuric acid solution in the post-processing stage to remove the byproduct 1,1,3,3-tetramethylurea, thus significantly improving the purity of the product during column chromatography purification.

[0062] As can be seen from Examples 3-6, although the reaction can generate products, the polarity of the impurities and products is not much different. During column purification, the two are easily washed out, resulting in significant losses.

[0063] Raw material d was dissolved in dichloromethane and reacted with TSTU at room temperature for 30 min. Raw material a was then added and reacted for 16 h. The reaction was monitored by TLC. The reaction effect was not good, and an extra impurity was found.

[0064] Raw material d was dissolved in dichloromethane and reacted with TSTU at room temperature for 8 hours. Raw material a was then added and reacted for 16 hours. The reaction was monitored by TLC. The reaction effect was not good, and an extra impurity was found.

[0065] Onion salt condensing agents were selected to optimize the reaction, but no significant improvement was observed in the actual results. Therefore, after mixing the raw materials in one pot, the direct condensation yield and purity were both low.

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide, characterized in that, The preparation method includes the following steps: The compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate were mixed and reacted, and then the compound shown in Formula II was added to carry out an amidation reaction to obtain the N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide. Where R is a hydroxyl or chlorine atom.

2. The preparation method according to claim 1, characterized in that, In the compound shown in Formula I, R represents a hydroxyl group.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate is 1:1 to 1.2:1 to 1.

2.

4. The preparation method according to claim 1, characterized in that, The temperature of the mixing reaction is 20–40°C.

5. The preparation method according to claim 1, characterized in that, The mixing reaction takes 1 to 4 hours.

6. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula II to the compound shown in Formula I is 1:1.1 to 1.

3.

7. The preparation method according to claim 1, characterized in that, The amidation reaction is performed at a temperature of 50–80 °C.

8. The preparation method according to claim 1, characterized in that, The amidation reaction takes 12–20 hours.

9. The preparation method according to any one of claims 1-8, characterized in that, The preparation method is as follows: The compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate were mixed and reacted at 20–40 °C for 1–4 h. Then, the compound shown in Formula II was added and subjected to an amidation reaction at 50–80 °C for 12–20 h to obtain the N-(4-(tert-butyl)thiazolyl-2-yl)-3-fluorobenzamide. Where R is a hydroxyl or chlorine atom; The molar ratio of the compound shown in Formula I, N,N-diisopropylethylamine, and 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate is 1:1 to 1.2:1 to 1.

2. The molar ratio of the compound shown in Formula II to the compound shown in Formula I is 1:1.1 to 1.3.

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