Synthesis method of 5-formyl-2, 4-dimethylbenzoic acid

Abstract

The invention discloses a synthesis method of 5-formyl-2, 4-dimethyl benzoic acid, which comprises the following steps: taking 5-iodine-2, 4-dimethyl benzoic acid as an initial raw material, and synthesizing a target compound 5-formyl-2, 4-dimethyl benzoic acid through the action of tert-butylmagnesium chloride, n-butyllithium and N, N-dimethyl formamide in sequence. According to the synthetic method, tert-butylmagnesium chloride is creatively added as alkali with large steric hindrance to neutralize hydrogen on carboxyl, so that carbon anions obtained by iodine extraction from butyl lithium can be effectively prevented from being quenched, the generation of by-products is reduced, and finally, 5-formyl-2, 4-dimethylbenzoic acid is prepared with low cost, safe, simple and convenient post-treatment and ideal yield. The application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing 5-formyl-2,4-dimethylbenzoic acid. Background Art

[0002] The compound 5-formyl-2,4-dimethylbenzoic acid is an important molecular building block. For example, in patent WO2015 / 095767A1, 5-formyl-2,4-dimethylbenzoic acid is used as a key intermediate in the synthesis of heterocyclic compounds that can be used as fatty acid synthesis regulators. The heterocyclic compounds can be used to treat diseases characterized by fatty acid synthase dysfunction such as hepatitis C infection, cancer and metabolic diseases, non-alcoholic steatohepatitis (NASH), etc. by regulating fatty acid synthase function or fatty acid synthase pathways. In patent WO2018 / 089433A1, 5-formyl-2,4-dimethylbenzoic acid is also used as a key intermediate in the synthesis of mTORC inhibitors. Therefore, it is of great significance to study the synthesis method of 5-formyl-2,4-dimethylbenzoic acid.

[0003] In the prior art, 5-iodo-2,4-dimethylbenzoic acid is used as a raw material to synthesize 5-formyl-2,4-dimethylbenzoic acid under the action of n-butyl lithium and N,N-dimethylformamide. Post-reaction treatment requires column chromatography purification, which is time-consuming and not suitable for process scale-up. Summary of the invention

[0004] In view of the above-mentioned shortcomings of the synthesis method of 5-formyl-2,4-dimethylbenzoic acid in the prior art, the object of the present invention is to provide a synthesis method of 5-formyl-2,4-dimethylbenzoic acid, the whole synthesis process is low in cost, short in steps and has an ideal yield.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a method for synthesizing 5-formyl-2,4-dimethylbenzoic acid. The method uses compound 1, i.e., 5-iodo-2,4-dimethylbenzoic acid, as a starting material, and sequentially reacts with tert-butylmagnesium chloride, n-butyllithium and N,N-dimethylformamide to obtain a target compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid. The synthesis route is as follows:

[0007]

[0008] The synthesis method of 5-formyl-2,4-dimethylbenzoic acid comprises the following steps:

[0009] (1) Compound 1 (5-iodo-2,4-dimethylbenzoic acid) is added to an organic solvent I, and the temperature is lowered to -30 to -20°C under the protection of an inert gas, and a tert-butylmagnesium chloride solution is added dropwise. After the addition is complete, the mixture is stirred and reacted for 15 to 30 minutes; the temperature is then lowered to -80 to -55°C, and an n-butyllithium solution is added dropwise. The mixture is stirred and reacted for 15 to 30 minutes; N,N-dimethylformamide is added dropwise, the temperature is raised to room temperature, and the mixture is stirred and reacted for 10 to 20 minutes;

[0010] (2) After the reaction is completed, the reaction solution is post-treated to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid.

[0011] Furthermore, in step (1), the molar ratio of the compound 1 to tert-butylmagnesium chloride is 1.0:1.0-1.5.

[0012] Furthermore, in step (1), the molar ratio of the compound 1 to n-butyl lithium is 1.0:1.0-1.5.

[0013] Furthermore, in step (1), the molar ratio of compound 1 to N,N-dimethylformamide is 1.0:1.0-8.0.

[0014] Furthermore, in step (1), the molar ratio of compound 1, tert-butylmagnesium chloride, n-butyllithium and N,N-dimethylformamide is 1:1.1:1.2:5.

[0015] Furthermore, in step (1), the inert gas is selected from nitrogen and / or argon.

[0016] Furthermore, in step (1), the organic solvent I is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene.

[0017] Furthermore, in step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

[0018] Furthermore, the post-treatment process in step (2) is as follows: flushing the reaction solution into ice water, first adjusting the pH of the mixed solution to 4-6 with an acidic aqueous solution, then extracting with an organic solvent II, combining the organic phases, washing the organic phases, drying, filtering, and concentrating to obtain a crude product, and purifying the crude product to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid.

[0019] Furthermore, in step (2), the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0020] Furthermore, in step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0021] Furthermore, in step (2), the purification method is selected from one or more of beating, column chromatography, recrystallization, and distillation.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The invention provides a method for synthesizing 5-formyl-2,4-dimethylbenzoic acid. 5-iodo-2,4-dimethylbenzoic acid is used as a starting material, and tert-butylmagnesium chloride, n-butyllithium and N,N-dimethylformamide are sequentially reacted to synthesize a target compound 5-formyl-2,4-dimethylbenzoic acid. The method creatively adds tert-butylmagnesium chloride as a large sterically hindered base to neutralize hydrogen on a carboxyl group, thereby effectively preventing carbon anions obtained by iodination of butyllithium from being quenched, thereby reducing the generation of by-products. Finally, 5-formyl-2,4-dimethylbenzoic acid is obtained with low cost, safe and simple post-treatment and ideal yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the H-NMR spectrum of 5-formyl-2,4-dimethylbenzoic acid prepared in Example 1. DETAILED DESCRIPTION

[0025] In order to more fully understand and demonstrate the technical solutions, purposes and advantages of the present invention, the technical effects produced by the present invention are further described in detail and completely in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all. It should be pointed out that for those of ordinary skill in the art, other embodiments obtained without departing from the concept of the present invention all belong to the protection scope of the present invention, and the present invention is specifically described in conjunction with the accompanying drawings and embodiments.

[0026] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0027] The following example provides a method for synthesizing 5-formyl-2,4-dimethylbenzoic acid. Compound 1, i.e., 5-iodo-2,4-dimethylbenzoic acid, is used as a starting material, and tert-butylmagnesium chloride, n-butyllithium, and N,N-dimethylformamide are sequentially reacted to synthesize target compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid. The synthetic route is as follows:

[0028]

[0029] In some embodiments, the synthesis method of 5-formyl-2,4-dimethylbenzoic acid comprises the following steps:

[0030] (1) Compound 1 (5-iodo-2,4-dimethylbenzoic acid) is added to an organic solvent I, and the temperature is lowered to -30 to -20°C under the protection of an inert gas, and a tert-butylmagnesium chloride solution is added dropwise. After the addition is complete, the mixture is stirred and reacted for 15 to 30 minutes; the temperature is then lowered to -80 to -55°C, and an n-butyllithium solution is added dropwise. The mixture is stirred and reacted for 15 to 30 minutes; N,N-dimethylformamide is added dropwise, the temperature is raised to room temperature, and the mixture is stirred and reacted for 10 to 20 minutes;

[0031] (2) After the reaction is completed, the reaction solution is post-treated to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid.

[0032] The invention will be further described below by way of examples and the like.

[0033] Example 1

[0034] In this example, the compound 5-formyl-2,4-dimethylbenzoic acid was synthesized by the following steps:

[0035] (1) Compound 1, i.e., 5-iodo-2,4-dimethylbenzoic acid (100.00 g, 362.22 mmol, 1.00 eq) was added to anhydrous tetrahydrofuran (1.0 L). Under argon protection, the temperature was lowered to -25°C, and a tert-butylmagnesium chloride solution (398.44 mL, 398.44 mmol, 1.10 eq, 1.00 M in THF) was added dropwise. After the addition was complete, the mixture was stirred and reacted for 15 min. The temperature was then lowered to -65°C, and a n-butyllithium solution (173.87 mL, 434.67 mmol, 1.20 eq, 2.50 M in cyclohexane) was added dropwise. The mixture was stirred and reacted for 15 min. N,N-dimethylformamide (132.38 g, 1.81 mol, 5.00 eq) was added dropwise. The temperature was raised to room temperature, and the mixture was stirred and reacted for 10 min.

[0036] (2) After the reaction was completed, the reaction solution was added to ice water (1.0 L), the pH of the mixed solution was adjusted to about 5 with 1M hydrochloric acid aqueous solution, extracted three times with ethyl acetate (800 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was slurried with a mixed organic solvent (1.0 L) of petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid (light yellow solid, weight 62.90 g, purity 98%, yield 96%).

[0037] The H NMR spectrum of the obtained compound 5-formyl-2,4-dimethylbenzoic acid is as follows Figure 1 The obtained characterization data are as follows:

[0038] 1 H NMR (400MHz, dmso) δ13.05(s,1H),10.19(s,1H),8.29(s,1H),7.30(s,1H),2.62(s,3H),2.57(s,3H).

[0039] Embodiments 2 to 4

[0040] Examples 2 to 4 are the same as Example 1, except that the amount of tert-butylmagnesium chloride, organic solvent I, etc. in the reaction are adjusted, as shown in Table 1.

[0041] Table 1: Synthesis conditions and results of examples and comparative examples

[0042]

[0043] Comparative Example 1

[0044] (1) Compound 1 5-iodo-2,4-dimethylbenzoic acid (100.00 g, 362.22 mmol, 1.00 eq) was added to anhydrous tetrahydrofuran (1.0 L). Under argon protection, the temperature was lowered to -78 °C. n-Butyl lithium solution (173.87 mL, 434.67 mmol, 1.20 eq, 2.50 M in cyclohexane) was added dropwise and stirred for 1 h. N,N-dimethylformamide (132.38 g, 1.81 mol, 5.00 eq) was added dropwise and stirred at -78 °C for 30 min.

[0045] (2) After the reaction is completed, the reaction solution is poured into ice water (1.0 L), the pH of the mixed solution is adjusted to about 5 with 1M hydrochloric acid aqueous solution, and extracted with ethyl acetate three times (800 mL×3), the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product is purified by column chromatography to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid (light yellow solid, weight 42.90 g, purity 98%, yield 65%).

[0046] Through Examples 1 to 4 and Comparative Example 1, the effects of various reaction conditions on the reaction yield during the synthesis of 5-formyl-2,4-dimethylbenzoic acid were studied. Combined with the above results, it can be seen that:

[0047] Comparing Example 1 with Comparative Example 1, it is found that the addition of tert-butyl magnesium chloride in the present invention achieves outstanding effects.

[0048] Comparing Examples 1 to 3, when the molar ratio of compound 1 to tert-butyl magnesium chloride is 1.00:1.10, the reaction effect is better.

[0049] Comparing Examples 1 and 4, the reaction can be smoothly carried out in a mixed solvent of tetrahydrofuran and diethyl ether, wherein tetrahydrofuran is more effective as a solvent.

[0050] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 5-formyl-2,4-dimethylbenzoic acid, characterized in that: The synthesis method uses compound 1, i.e. 5-iodo-2,4-dimethylbenzoic acid, as a starting material, and sequentially reacts with tert-butylmagnesium chloride, n-butyllithium and N,N-dimethylformamide to synthesize compound 2, i.e. 5-formyl-2,4-dimethylbenzoic acid. The synthesis route is as follows: The synthesis method of 5-formyl-2,4-dimethylbenzoic acid comprises the following steps: (1) Compound 1 is added to an organic solvent I, and under the protection of an inert gas, the temperature is lowered to -30 to -20°C, and a tert-butyl magnesium chloride solution is added dropwise. After the addition is complete, the mixture is stirred and reacted for 15 to 30 minutes; the temperature is then lowered to -80 to -55°C, and an n-butyl lithium solution is added dropwise. The mixture is stirred and reacted for 15 to 30 minutes; N,N-dimethylformamide is added dropwise, the temperature is raised to room temperature, and the mixture is stirred and reacted for 10 to 20 minutes; (2) After the reaction is completed, the reaction solution is post-treated to obtain compound 2, i.e., 5-formyl-2,4-dimethylbenzoic acid.

2. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the molar ratio of the compound 1 to tert-butylmagnesium chloride is 1.0:1.0-1.

5.

3. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the molar ratio of the compound 1 to n-butyl lithium is 1.0:1.0-1.

5.

4. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to N,N-dimethylformamide is 1.0:1.0-8.

0.

5. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the molar ratio of compound 1, tert-butylmagnesium chloride, n-butyllithium and N,N-dimethylformamide is 1:1.1:1.2:

5.

6. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the mass volume ratio of the compound 1 to the organic solvent I is 1:5 to 40 g / mL.

7. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the inert gas is selected from nitrogen and / or argon.

8. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (1), the organic solvent I is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene.

9. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 1, characterized in that: In step (2), the post-treatment process includes: flushing the reaction solution into ice water, first adjusting the pH of the mixed solution to 4-6 with an acidic aqueous solution, then extracting with an organic solvent II, combining the organic phases, washing the organic phases, drying, filtering, and concentrating to obtain a crude product, and purifying the crude product to obtain compound 2.

10. The method for synthesizing 5-formyl-2,4-dimethylbenzoic acid according to claim 9, characterized in that: In step (2), the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution; and / or the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane; And / or the purification method is selected from one or more of beating, column chromatography, recrystallization, and distillation.

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