Preparation method of m-nitrophenylacetylene

Abstract

The invention discloses a preparation method of m-nitrophenylacetylene, which comprises the following steps: S1001, dissolving m-nitrobenzaldehyde and Ph3P = CHBr in tetrahydrofuran, adding alkali, and stirring to generate m-nitrophenyl vinyl bromide; s1002, adding a strong base into the reaction product, heating to 80-100 DEG C, and removing HBr to generate m-nitrophenylacetylene; and S1003, carrying out water washing, extraction and drying on the reaction liquid obtained in the step S1002, and then carrying out reduced pressure distillation to obtain the m-nitrophenylacetylene.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for preparing m-nitrophenylacetylene. Background Art

[0002] m-Nitrobenzeneacetylene is an important organic intermediate widely used in the fields of medicine, pesticides, optoelectronic materials and coordination chemistry. Currently, a variety of synthesis methods have been reported, but their industrial application is still limited by problems such as harsh reaction conditions, cumbersome steps, low yield or high cost. The following is an analysis of several typical existing technologies. The first is the nitration method of halogenated phenylacetylene, which uses halogenated phenylacetylene (such as bromophenylacetylene) as raw material and undergoes nitration reaction in concentrated sulfuric acid or mixed acid system. However, the nitration reaction has poor selectivity and easily generates ortho and para position by-products, requiring complex separation and purification, which makes the preparation steps cumbersome; secondly, the reaction requires strong acidic conditions, severe equipment corrosion, and high waste liquid treatment costs. The preparation of halogenated raw materials requires multiple steps and low overall efficiency, such as the patent with Chinese publication number CN102643252A.

[0003] The second method is the direct nitration of phenylacetylene, which directly reacts phenylacetylene with nitric acid or a mixture of nitric and sulfuric acids to produce nitrophenylacetylene. However, in the reaction, the nitro group is a strong electron-withdrawing group, resulting in low reactivity of phenylacetylene and requiring high temperature and high pressure conditions (>150°C). In addition, there are many side reactions, and polynitro products or oxidation by-products (such as carboxylic acids) are easily generated, resulting in low product purity, as shown in the U.S. patent publication number US20150018521A1.

[0004] The third method is the metal-catalyzed cross-coupling method, which is prepared by palladium or copper-catalyzed coupling reaction of nitrobenzene halide and terminal alkyne (such as Sonogashira reaction). It requires the use of precious metal catalysts (such as PdCl2), which are expensive and difficult to recycle. However, in the reaction, the nitrobenzene halide raw material has poor stability and harsh storage and operating conditions; secondly, the reaction requires an anhydrous and oxygen-free environment, which makes industrialization difficult, such as the patent with Japanese publication number JP2019151677A.

[0005] The fourth method is the reduction-alkynylation method, in which nitrobenzene is reduced to form aniline, which is then reacted with an alkynylation reagent and oxidized to yield the target product. However, its drawbacks include low overall yields (<60%) due to the multiple reaction steps, rarely exceeding 85%. Furthermore, the intermediate aniline is easily oxidized, requiring strict temperature and oxygen control, resulting in a complex process. For example, this method is described in patent DE102011083432B3. Summary of the Invention

[0006] In response to the problems of multiple reaction steps, harsh conditions, high cost and poor selectivity in the existing technology, the present application provides a method for efficiently preparing m-nitrobenzaldehyde and bromomethylenetriphenylphosphine ylide (Ph3P=CHBr) through the Wittig reaction, which has the advantages of simple operation, high yield and environmental friendliness, and can easily reach more than 85%.

[0007] Specifically, the preparation method of m-nitrophenylacetylene comprises:

[0008] S1001, dissolving m-nitrobenzaldehyde and Ph3P=CHBr in tetrahydrofuran, adding a base and stirring to generate m-nitrostyryl bromide;

[0009] S1002, adding a strong base to the above reaction product and heating it to 80-100° C. to remove HBr and generate m-nitrophenylacetylene;

[0010] S1003, washing the reaction solution obtained in S1002 with water, extracting, drying, and then distilling under reduced pressure to obtain m-nitrophenylacetylene.

[0011] In one embodiment, the preparation method of m-nitrophenylacetylene satisfies at least one of the following conditions:

[0012] In the step S1001, stirring the reaction at 0-25°C;

[0013] In step S1001, the stirring reaction time is 2 to 4 hours;

[0014] In step S1002, the reaction is carried out for 1 to 3 hours.

[0015] In one embodiment, in step S1001, the added base is at least one of NaH or K2CO3.

[0016] In one embodiment, in step S1002, the strong base added is at least one of DBU or t-BuOK.

[0017] This application has at least the following advantages:

[0018] (1) High selectivity: The Wittig reaction is highly specific and only produces meta-substituted products, avoiding isomer interference.

[0019] (2) Mild conditions: The reaction is carried out at normal pressure and medium to low temperature, without the need for precious metal catalysts or highly corrosive reagents.

[0020] (3) High yield: The total yield of the two-step reaction reaches 85% to 90%, which is much higher than the existing technology (<60%).

[0021] (4) Raw materials are readily available: m-nitrobenzaldehyde and Ph3P=CHBr are both commercial reagents and do not require complex pretreatment.

[0022] (5) Green and environmentally friendly: the by-products are only triphenylphosphine oxide (Ph3PO) and HBr, which can be recovered by neutralization to reduce pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The NMR spectrum of the product obtained in Example 1 of the present application is shown;

[0024] Figure 2 The HPLC purity spectrum of the product obtained in Example 1 of the present application is shown. DETAILED DESCRIPTION

[0025] The preferred embodiments described below are for illustrative purposes only, and those skilled in the art may readily conceive of other obvious variations. The basic principles of the present invention defined in the following description may be applied to other embodiments, variations, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the present invention.

[0026] In a preferred embodiment of the present application, a method for preparing m-nitrophenylacetylene is provided, and the method for preparing m-nitrophenylacetylene comprises:

[0027] S1001, dissolving m-nitrobenzaldehyde and Ph3P=CHBr in tetrahydrofuran, adding a base and stirring to generate m-nitrostyryl bromide;

[0028] S1002, adding a strong base to the above reaction product and heating it to 80-100° C. to remove HBr and generate m-nitrophenylacetylene;

[0029] S1003, washing the reaction solution obtained in S1002 with water, extracting, drying, and then distilling under reduced pressure to obtain m-nitrophenylacetylene.

[0030] In a preferred embodiment, the preparation method of m-nitrophenylacetylene satisfies at least one of the following conditions:

[0031] In the step S1001, stirring the reaction at 0-25°C;

[0032] In step S1001, the stirring reaction time is 2 to 4 hours;

[0033] In step S1002, the reaction is carried out for 1 to 3 hours.

[0034] In a preferred embodiment, in step S1001, the base added is at least one of NaH or K2CO3.

[0035] In a preferred embodiment, in step S1002, the strong base added is at least one of DBU or t-BuOK.

[0036] Example 1:

[0037] Dissolve m-nitrobenzaldehyde (1.51 g, 10 mmol) and Ph3P=CHBr (3.63 g, 10 mmol) in 30 mL of THF and cool to 0°C in an ice bath.

[0038] Subsequently, NaH (0.48 g, 20 mmol) was slowly added and the mixture was stirred for 3 hours. The reaction was completed after monitoring by TLC.

[0039] Then, the temperature was raised to 80° C., DBU (1.52 g, 10 mmol) was added, and the reaction was continued for 2 hours.

[0040] Finally, the reaction solution was quenched with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain 1.31 g of a light yellow solid with a yield of 89% and a purity of 98.1%.

[0041] The purity was determined by HPLC. Figure 2 The diagram shown.

[0042] Example 2

[0043] Raw materials and ratio:

[0044] m-Nitrobenzaldehyde (1.51 g, 10 mmol)

[0045] Bromomethylenetriphenylphosphine ylide (Ph3P=CHBr, 3.63g, 10mmol)

[0046] Base (step a): K2CO3 (2.76 g, 20 mmol)

[0047] Base (step b): potassium tert-butoxide (t-BuOK, 1.12 g, 10 mmol)

[0048] Steps:

[0049] (a) Wittig reaction:

[0050] Dissolve m-nitrobenzaldehyde and Ph3P=CHBr in 30 mL of tetrahydrofuran (THF), add K2CO3 at room temperature (25°C), and stir to react for 4 hours.

[0051] The reaction progress was monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 5:1), and the reaction was stopped after the starting material spot disappeared.

[0052] (b) Elimination reaction:

[0053] t-BuOK was added to the reaction solution, and the temperature was raised to 100°C, and the reaction was stirred for 3 hours.

[0054] (c) Post-processing:

[0055] The reaction solution was cooled to room temperature, the pH was adjusted to neutral with 10% dilute hydrochloric acid, and extracted with ethyl acetate (3×20 mL).

[0056] The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 1.28 g of a light yellow solid product with a yield of 87%.

[0057] Example 3

[0058] Raw materials and ratio:

[0059] m-Nitrobenzaldehyde (1.51 g, 10 mmol)

[0060] Bromomethylenetriphenylphosphine ylide (Ph3P=CHBr, 3.63g, 10mmol)

[0061] Base (step a): potassium tert-butoxide (t-BuOK, 1.12 g, 10 mmol)

[0062] Base (step b): DBU (1.52 g, 10 mmol)

[0063] Steps:

[0064] (a) Wittig reaction:

[0065] Dissolve m-nitrobenzaldehyde and Ph3P=CHBr in 30 mL of THF and cool to 0°C in an ice bath.

[0066] Slowly add t-BuOK, maintain the temperature ≤ 5°C, and react for 2 hours.

[0067] (b) Elimination reaction:

[0068] DBU was directly added to the reaction solution, and the temperature was raised to 90° C. and the reaction was carried out for 1.5 hours.

[0069] (c) Post-processing:

[0070] The reaction solution was quenched with ice water, extracted with dichloromethane (3×20 mL), and dried over anhydrous magnesium sulfate.

[0071] After distillation under reduced pressure, the product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain 1.33 g of white crystals with a yield of 90%.

[0072] Example Step a: Base Step b: Base Reaction temperature Yield Features Example 1 NaH DBU 80℃ 89％ Low temperature and high efficiency Example 2 <![CDATA[K2CO3]]> t-BuOK 100℃ 87％ Mild alkaline system Example 3 t-BuOK DBU 90℃ 90％ High-purity column chromatography

[0073] By adjusting the type of base and reaction temperature, the method of the present invention can maintain high selectivity (>85% yield) under various conditions, and the by-products are easy to handle, fully verifying the universality and industrial potential of the process.

[0074] Comparative Example 1: Nitration of halogenated phenylacetylene

[0075] Reference: CN102643252A

[0076] step:

[0077] Using 3-bromophenylacetylene as raw material, nitration reaction was carried out in mixed acid (HNO3 / H2SO4) at 60℃ for 6 hours.

[0078] The product was neutralized, extracted, and purified by column chromatography. Yield: 52%.

[0079] Key drawbacks include poor nitration selectivity, with byproducts (ortho- and para-nitro isomers) accounting for approximately 30%, requiring multiple purification steps. Furthermore, the need for a strong acid system leads to equipment corrosion and high wastewater treatment costs.

[0080] Comparative Example 2: Direct Nitration of Phenylacetylene

[0081] Reference: US20150018521A1

[0082] step:

[0083] Phenylacetylene was reacted with fuming nitric acid (90%) in concentrated sulfuric acid at 120°C for 8 hours.

[0084] The product was quenched with ice water, extracted, and distilled under reduced pressure. Yield: 38%.

[0085] The key drawbacks are that the strong electron-withdrawing effect of the nitro group inhibits the reaction activity, requiring high temperature and high pressure conditions. Side reactions generate polynitro products (about 25%) and oxidation byproducts (benzoic acids).

[0086] Comparative Example 3: Metal-catalyzed cross-coupling method (Sonogashira reaction)

[0087] Reference: JP2019151677A, Steps: m-Nitroiodobenzene and phenylacetylene are reacted in DMF at 80°C for 12 hours under the catalysis of PdCl2 (5 mol%) and CuI (10 mol%). The product is extracted and purified on a silica gel column. Yield: 65%. The key drawback is that the precious metal catalyst (Pd) is expensive and difficult to recycle, increasing the industrial cost by more than 30%. The nitroiodobenzene raw material is unstable and needs to be stored at low temperature and away from light, making the operation complicated.

[0088] Comparative Example 4: Reduction-alkynylation method

[0089] Reference: DE102011083432B3, Steps: Nitrobenzene is reduced to aniline via H2 / Pd-C with an 85% yield. Aniline is then alkynylated with propargyl bromide under alkaline conditions to produce a phenylacetylene derivative with a 60% yield. The intermediate is then oxidized with nitric acid to restore the nitro group with a 70% yield. Total yield: 85% × 60% × 70% ≈ 35.7%

[0090] Key drawbacks: The cumulative yield of the multi-step reaction is low and takes >24 hours.

[0091] The oxidation step produces a large amount of nitrogen-containing wastewater, which puts great pressure on the environmental protection.

[0092]

[0093]

[0094] Comparisons show that existing technologies generally suffer from low yields (<65%), harsh conditions (high temperature / strong acid / precious metals), and poor environmental performance. The present method, through a tandem Wittig reaction and elimination reaction, uses commercially available raw materials to synthesize the target product in a single step, achieving an overall yield of 85%-90%. Without the need for precious metals or highly corrosive reagents, it combines high efficiency with green chemistry, significantly outperforming existing technologies.

[0095] Those skilled in the art will appreciate that the embodiments of the present invention described above are intended to be illustrative only and are not intended to limit the present invention. The objectives of the present invention have been fully and effectively achieved. The functional and structural principles of the present invention have been demonstrated and illustrated in the embodiments. Any variations or modifications may be made to the embodiments of the present invention without departing from the principles described.

Claims

1. A method for preparing m-nitrophenylacetylene, characterized in that: The preparation method of the m-nitrophenylacetylene comprises the following steps: S1001, dissolving m-nitrobenzaldehyde and Ph3P=CHBr in tetrahydrofuran, adding a base and stirring to generate m-nitrostyryl bromide; S1002, adding a strong base to the above reaction product and heating it to 80-100° C. to remove HBr and generate m-nitrophenylacetylene; S1003, washing the reaction solution obtained in S1002 with water, extracting, drying, and then distilling under reduced pressure to obtain m-nitrophenylacetylene.

2. The method for preparing m-nitrophenylacetylene according to claim 1, wherein The preparation method of m-nitrophenyl acetylene satisfies at least one of the following conditions: In the step S1001, stirring the reaction at 0-25°C; In step S1001, the stirring reaction time is 2 to 4 hours; In step S1002, the reaction is carried out for 1 to 3 hours.

3. The method for preparing m-nitrophenylacetylene according to claim 1, wherein In step S1001, the added base is at least one of NaH or K2CO3.

4. The method for preparing m-nitrophenylacetylene according to claim 1, wherein In step S1002, the strong base added is at least one of DBU and t-BuOK.

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