CN114085173B - A kind of preparation method of 2-nitro-4-methylsulfonylbenzaldehyde - Google Patents

Abstract

The invention provides a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde, which comprises the following steps: taking 2-nitro-4-methylsulfonyl toluene as a raw material, carrying out condensation reaction by matching with a condensing agent to obtain an intermediate product [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine, and then carrying out oxidation reaction by using the intermediate product and an oxidant to obtain 2-nitro-4-methylsulfonyl benzaldehyde; the invention takes common chemical substances of 2-nitro-4-methylsulfonyl toluene, DMF-DMA and sodium periodate as raw materials, and can prepare the required 2-nitro-4-methylsulfonyl benzaldehyde product under the conventional reaction condition and the conventional instrument and equipment through the simple two chemical reaction steps, thereby having the advantages of simple operation, mild reaction condition and low requirement on reaction equipment.

Description

A kind of preparation method of 2-nitro-4-methylsulfonylbenzaldehyde

Technical Field

The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing 2-nitro-4-methylsulfonylbenzaldehyde.

Background technique

2-Nitro-4-methylsulfonylbenzaldehyde (CAS: 849035-66-1) has a structure as shown in the following formula I, and is an important pharmaceutical chemical intermediate. However, there are few reports on the preparation method of this compound at home and abroad, and there are a series of problems such as complex operation, many restrictions on production conditions, and high equipment requirements, resulting in the product currently being completely dependent on imports and expensive.

The American technical document "A mild method for the conversion of activated arylmethyl groups to carboxaldehydes via the uncatalyzed periodate cleavage of enamines" (Tetrahedron Letters, Vol.35, No.2, pp.219-222, 1994) records some preparation methods of substituted benzaldehydes, wherein the raw material is a compound substituted toluene, C=C is introduced by condensation reaction, and then the C=C formed by the methyl group is converted into an aldehyde group by oxidation. However, in the reaction, the compound substituted toluene molecular formula as the raw material contains only one methyl group that can participate in the reaction, so there will be no problem of multiple methyl groups reacting simultaneously, and the desired product can be accurately obtained in the end. However, the 2-nitro-4-methylsulfonyltoluene as the raw material in the present invention includes both the methyl group on the benzene ring and the methyl group on the methylsulfonyl group. If the method of the document is adopted for synthesis, the above-mentioned two methyl groups will react, and a large amount of by-products will appear, resulting in mixed components in the product and low yield.

On this basis, a preparation method of 2-nitro-4-methylsulfonylbenzaldehyde is needed, which has simple operation, mild reaction conditions, high yield, low requirements on reaction equipment and is easy for industrial production.

Summary of the invention

In view of the deficiencies in the prior art, the present invention provides a method for preparing 2-nitro-4-methylsulfonylbenzaldehyde, which solves the problems of complex operation, many restrictions on production conditions, high equipment requirements, low product yield, etc. in the prior art.

According to an embodiment of the present invention, a method for preparing 2-nitro-4-methylsulfonylbenzaldehyde comprises the following steps: using 2-nitro-4-methylsulfonyltoluene as a raw material, coordinating with a condensing agent to carry out a condensation reaction to obtain an intermediate product [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine, and then using the intermediate product to carry out an oxidation reaction with an oxidant to obtain 2-nitro-4-methylsulfonylbenzaldehyde, and the reaction formula is as follows:

Wherein: compound I is 2-nitro-4-methylsulfonylbenzaldehyde; compound II is [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine; and compound III is 2-nitro-4-methylsulfonyltoluene.

Preferably, the condensing agent is N,N-dimethylformamide dimethyl acetal, referred to as DMF-DMA.

Preferably, the oxidant is sodium periodate or ozone.

Preferably, a method for preparing 2-nitro-4-methylsulfonylbenzaldehyde comprises the following steps:

(1) 2-nitro-4-methylsulfonyltoluene, N,N-dimethylformamide, and DMF-DMA are mixed and stirred, and then heated to 30-140°C and reacted for 0.5-15 hours to obtain a red-black liquid product. After cooling to room temperature, a large amount of water is added until solids are precipitated, and then filtered and dried to obtain a dark brown crude product;

(2) using a solvent to recrystallize the crude product to obtain a light brown pure product of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine;

(3) dissolving [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine in a polar organic solvent, then adding an oxidant, and stirring at room temperature to allow the mixture to react fully to obtain a mixed solution containing the target product;

(4) Separating the organic phase from the mixed solution using an extractant, drying the organic phase using a desiccant, filtering out the desiccant, and removing the organic solvent by distillation under reduced pressure to obtain the target product, 2-nitro-4-methylsulfonylbenzaldehyde.

Preferably, in step (1), the molar ratio of 2-nitro-4-methylsulfonyltoluene to DMF-DMA is 1:(0.8-3), and the volume mass ratio of N,N-dimethylformamide to 2-nitro-4-methylsulfonyltoluene is (2-8) ml/g.

Preferably, the volume mass ratio of water added after the reaction in step (1) to 2-nitro-4-methylsulfonyltoluene is (30-80) ml/g.

Preferably, the recrystallization solvent in step (2) is one of methanol, ethanol and isopropanol; the volume mass ratio of the amount of the recrystallization solvent to the crude product of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine is (20-30) ml/g.

Preferably, the reaction temperature in step (1) is 42-50°C.

Preferably, the reaction time in step (1) is 6 to 11 hours.

Preferably, the polar organic solvent used in step (3) is tetrahydrofuran, referred to as THF; the extractant in step (4) is dichloromethane, and the desiccant is anhydrous magnesium sulfate.

The technical principle of the present invention is:

A condensation reaction is a reaction in which two or more organic molecules interact with each other and are combined by covalent bonds to form a large molecule, often accompanied by the loss of small molecules (such as water, hydrogen chloride, alcohol, etc.).

The central carbon atom of the condensing agent DMF-DMA in the present invention is connected with three heteroatoms with relatively large electronegativity, so that it has relatively strong electrophilicity. Under the action of hydrogen protons, the alkoxy group is easily removed to obtain a carbon cation with stronger electrophilic activity.

Correspondingly, in the raw material 2-nitro-4-methylsulfonyltoluene, the methyl group on the benzene ring is acted upon by the two electron-withdrawing groups of the ortho-nitro group and the para-methylsulfonyl group, so that the hydrogen on the methyl group has weak acidity, is easy to provide hydrogen protons, and forms a carbon anion. The carbon anion combines with the carbon cation obtained by dealkylation of DMF-DMA, and then removes a molecule of methanol to form [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine; however, because the methyl group in the methylsulfonyl group is acted upon by the electron-withdrawing effect of -SO ₂ , it also has weak acidity, and thus can also react with DMF-DMA. In this case, because the acidity of the hydrogen on the methyl group on the benzene ring is stronger than that of the hydrogen on the methyl group of the methylsulfonyl group, the desired product can be obtained by controlling the reaction conditions. The specific reaction principle is shown in Figure 1.

It should be noted that during the condensation reaction of the present invention, thin layer chromatography or other monitoring means can be used to detect the progress of the reaction, so as to terminate the reaction when the main reaction is basically completed and the side reaction has not started, thereby obtaining the highest purity; or provide sufficient time for all raw materials to fully react, ultimately obtaining the highest yield.

After obtaining the intermediate product [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine through condition control, it is oxidized to break C=C to form an aldehyde group, and finally the desired product 2-nitro-4-methylsulfonylbenzaldehyde is obtained.

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

1. The present invention provides a method, which uses common chemicals 2-nitro-4-methylsulfonyltoluene, DMF-DMA, and sodium periodate as raw materials, and can produce the desired 2-nitro-4-methylsulfonylbenzaldehyde product under conventional reaction conditions and conventional instruments and equipment through two simple chemical reaction steps, thereby having the advantages of simple operation, mild reaction conditions, and low requirements for reaction equipment;

2. In the present invention, by controlling the reaction conditions, the occurrence of side reactions is effectively avoided, so that the main product occupies the main part, and the reaction proceeds at a high degree, and the overall yield is high;

3. Although the present invention is a laboratory preparation method, no laboratory-specific instruments are used and no reaction conditions that can only be provided by a laboratory are required, so that the method can be easily extended to industrial production, thereby producing 2-nitro-4-methylsulfonylbenzaldehyde on a large scale, with high efficiency and low cost.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram showing the principle of the condensation reaction in the present invention.

Figure 2 is the mass spectrum of the intermediate product compound II.

FIG3 is a hydrogen nuclear magnetic resonance spectrum of the intermediate product compound II.

FIG4 is a mass spectrum of the target product compound I.

FIG5 is a hydrogen nuclear magnetic resonance spectrum of the target product compound I.

Detailed ways

The technical solution of the present invention is further described below in conjunction with the accompanying drawings and embodiments.

Example 1

Preparation of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine (II):

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 3.32mL (0.025mol) of DMF-DMA and 20mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 42°C for 11h, and a red-black liquid was obtained. After cooling to room temperature, 200mL of water was added, and solid precipitated. After suction filtration and drying, 5.28g of dark brown solid powder was obtained, with a yield of 93.12% and a purity of 97.75%. The crude product was recrystallized by adding 120mL of methanol to obtain 5.02g of brown solid powder with a purity of 99.72%. ¹ H-NMR (CD ₃ CN): δ: 8.24-8.34 (d, 1H, benzene ring hydrogen), δ: 7.71-7.77 (m, 2H, benzene ring hydrogen), δ: 7.52-7.55 (d, 1H, olefinic hydrogen), δ: 5.83-5.86 (d, 1H, olefinic hydrogen), δ: 3.06 (s, 3H, methylsulfonyl hydrogen), δ: 3.00 (s, 6H, amine hydrogen). HRMS, C ₁₁ H ₁₄ N ₂ O ₄ S [M+1] ⁺ calculated value: 271.3053, found value: 271.0729.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

1.35 g (5 mmol) of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II) was weighed and dissolved in 25 mL of THF. 2.75 g (12.86 mmol) of the oxidant sodium periodate was weighed and dissolved in 25 mL of water. The aqueous solution of the oxidant and the THF solution containing (II) were poured into a 100 mL three-necked flask, stirred at room temperature for 1 h, extracted with CH ₂ Cl ₂ (25 mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off after drying, and CH ₂ Cl ₂ was removed under reduced pressure to obtain 1.05 g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I), with a yield of 91.70% and a purity of 99.68%. HRMS, C ₈ H ₇ NO ₅ S [M+1] ⁺ calculated value: 230.9376, found value: 230.2543. ¹ H-NMR (CDCl ₃ ), δ: 10.49 (s, 1H, aldehyde hydrogen), δ: 8.71 (s, 1H, benzene ring hydrogen), δ: 8.36-8.14 (d, 1H, benzene ring hydrogen), δ: 8.13-8.15 (d, 1H, benzene ring hydrogen), δ: 3.16 (s, 3H, methylsulfonyl hydrogen).

As shown in Figures 2-4, the present invention accurately prepared [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine and 2-nitro 4-methylsulfonylbenzaldehyde during the implementation process.

Example 2

Preparation of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine (Ⅱ)

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 2.26mL (0.017mol) of DMF-DMA and 36mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 140°C for 0.5h, and a red-black liquid was obtained. After cooling to room temperature, 360mL of water was added, and solid was precipitated. After suction filtration and drying, 5.03g of dark brown solid powder was obtained, with a yield of 109.59% (in this embodiment, 2-nitro-4-methylsulfonyltoluene was excessive, so the yield was calculated based on DMF-DMA. Since there was some unreacted 2-nitro-4-methylsulfonyltoluene in the product, the yield exceeded 100%), and the purity was 47.35%. The crude product was recrystallized by adding 150mL of ethanol to obtain 3.71g of brown solid powder with a purity of 62.12%.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

1.35 g (5 mmol) of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II) was weighed and dissolved in 25 mL of THF. 2.75 g (12.86 mmol) of the oxidant sodium periodate was weighed and dissolved in 25 mL of water. The aqueous solution of the oxidant and the THF solution containing (II) were poured into a 100 mL three-necked flask, stirred at room temperature for 1 h, extracted with _CH2Cl2 ( ₂₅ mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, and the desiccant was filtered off after drying. After removing _CH2Cl2 under reduced pressure _, 1.05 g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I) was obtained, with a yield of 91.70% and a purity of 99.68%.

Example 3

Preparation of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine (Ⅱ)

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 2.79mL (0.021mol) of DMF-DMA and 15mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 80°C for 2h, and a red-black liquid was obtained. After cooling to room temperature, 150mL of water was added, and solid precipitated. After suction filtration and drying, 5.41g of dark brown solid powder was obtained, with a yield of 95.41% and a purity of 66.22%. The crude product was recrystallized by adding 150mL of methanol to obtain 4.34g of brown solid powder with a purity of 67.03%.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

1.35 g (5 mmol) of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II) was weighed and dissolved in 25 mL of THF. 2.75 g (12.86 mmol) of the oxidant sodium periodate was weighed and dissolved in 25 mL of water. The aqueous solution of the oxidant and the THF solution containing (II) were poured into a 100 mL three-necked flask, stirred at room temperature for 1 h, extracted with CH ₂ Cl ₂ (25 mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, and the desiccant was filtered off after drying. After removing CH ₂ Cl ₂ under reduced pressure, 1.07 g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I) was obtained, with a yield of 93.44% and a purity of 99.15%.

Example 4

Preparation of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine (Ⅱ)

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 8.36mL (0.063mol) of DMF-DMA and 9mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 30°C for 15h, and a red-black liquid was obtained. After cooling to room temperature, 135mL of water was added, and solid precipitated. After suction filtration and drying, 4.49g of dark brown solid powder was obtained, with a yield of 79.19% and a purity of 42.76%. The crude product was recrystallized by adding 90mL of methanol to obtain 1.78g of brown solid powder with a purity of 98.49%.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

1.35 g (5 mmol) of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II) was weighed and dissolved in 25 mL of THF. 2.75 g (12.86 mmol) of the oxidant sodium periodate was weighed and dissolved in 25 mL of water. The aqueous solution of the oxidant and the THF solution containing (II) were poured into a 100 mL three-necked flask, stirred at room temperature for 1 h, extracted with CH ₂ Cl ₂ (25 mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, and the desiccant was filtered off after drying. After removing CH ₂ Cl ₂ under reduced pressure, 1.04 g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I) was obtained, with a yield of 90.83% and a purity of 99.67%.

Example 5

Preparation of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyl dimethylamine (Ⅱ)

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 2.79mL (0.021mol) of DMF-DMA and 15mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 50°C for 6h, and a red-black liquid was obtained. After cooling to room temperature, 150mL of water was added, and solid precipitated. After suction filtration and drying, 5.44g of dark brown solid powder was obtained, with a yield of 95.94% and a purity of 87.25%. The crude product was recrystallized by adding 120mL of methanol to obtain 4.65g of brown solid powder with a purity of 87.99%.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

1.35 g (5 mmol) of [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II) was weighed and dissolved in 25 mL of THF. 2.75 g (12.86 mmol) of the oxidant sodium periodate was weighed and dissolved in 25 mL of water. The aqueous solution of the oxidant and the THF solution containing (II) were poured into a 100 mL three-necked flask, stirred at room temperature for 1 h, extracted with _CH2Cl2 ( ₂₅ mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, and the desiccant was filtered out after drying. After removing _CH2Cl2 under reduced pressure _, 1.05 g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I) was obtained, with a yield of 91.70% and a purity of 99.18%.

Example 6

4.52g (0.021mol) of 2-nitro-4-methylsulfonyltoluene (III), 2.79mL (0.021mol) of DMF-DMA and 20mL of DMF were placed in a 100mL three-necked flask with a reflux condenser and a thermometer, stirred with magnetic force, reacted at 42°C for 11h, and a red-black liquid was obtained. After cooling to room temperature, 200mL of water was added, and solid precipitated. After suction filtration and drying, 5.14g of dark brown solid powder was obtained, with a yield of 90.65% and a purity of 93.86%. The crude product was recrystallized by adding 155mL of methanol to obtain 4.31g of brown solid powder with a purity of 99.79%.

Preparation of 2-nitro-4-methylsulfonylbenzaldehyde (I)

In a 100mL three-necked flask, 1.35g (5mmol) [2-(2-nitro-4-methylsulfonyl)phenyl]vinyldimethylamine (II), 25mL THF and 25mL water were added, stirred to dissolve, ozone was continuously introduced, and stirring was carried out at room temperature for 1h. 2.00mL of dimethyl sulfide was added, and stirring was continued for 1h. Extraction was performed with _CH2Cl2 ( _25mL ×3), and the organic phases were combined and dried over anhydrous magnesium sulfate. After drying, the desiccant was filtered out, and _{CH2Cl2 was} removed under reduced pressure to obtain 0.65g of the product 2-nitro-4-methylsulfonylbenzaldehyde (I), with a yield of 56.83% and a purity of 85.68%.

From the comparison between Example 1 and Example 6, it can be seen that under the same reaction conditions, the product yield and purity obtained by using sodium periodate as the oxidant are higher than those obtained by using ozone as the oxidant, so sodium periodate is a more preferred oxidant.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims (4)

1. The preparation method of the 2-nitro-4-methylsulfonyl benzaldehyde is characterized by comprising the following steps of: taking 2-nitro-4-methylsulfonyl toluene as a raw material, and carrying out condensation reaction by matching with a condensing agent to obtain an intermediate product [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine, and then carrying out oxidation reaction by using the intermediate product and an oxidant to obtain 2-nitro-4-methylsulfonyl benzaldehyde, wherein the reaction scheme is as follows:

wherein: the compound I is 2-nitro-4-methylsulfonyl benzaldehyde; compound ii is [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine; the compound III is 2-nitro-4-methylsulfonyl toluene;

the condensing agent is N, N-dimethylformamide dimethyl acetal, which is called DMF-DMA for short;

the oxidant is sodium periodate or ozone;

the method comprises the following steps:

(1) Mixing and stirring 2-nitro-4-methylsulfonyl toluene, N-dimethylformamide and DMF-DMA, heating to 42-50 ℃, reacting for 6-11 h to obtain a red-black liquid product, standing and cooling to room temperature, adding a large amount of water until solid is separated out, filtering, and drying to obtain a dark brown crude product;

(2) Recrystallizing the crude product by using a solvent to obtain a light brown [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine pure product;

(3) Dissolving [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine in a polar organic solvent, adding an oxidant, and stirring at room temperature to fully react to obtain a mixed solution containing a target product;

(4) Separating the organic phase part of the mixed solution by using an extractant, drying the organic phase by using a drying agent, finally filtering the drying agent, and removing the organic solvent by reduced pressure distillation to obtain a target product 2-nitro-4-methylsulfonyl benzaldehyde;

in the step (1), the mol ratio of the 2-nitro-4-methylsulfonyl toluene to the DMF-DMA is 1 (0.8-3), and the volume mass ratio of the N, N-dimethylformamide to the 2-nitro-4-methylsulfonyl toluene is 2-8 ml/g.

2. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the volume-mass ratio of the water added after the reaction in the step (1) to the 2-nitro-4-methylsulfonyl toluene is (30-80) ml/g.

3. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the recrystallization solvent in the step (2) is one of methanol, ethanol and isopropanol; the volume mass ratio of the consumption of the recrystallization solvent to the crude product of the [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyl dimethylamine is (20-30) ml/g.

4. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the polar organic solvent used in the step (3) is tetrahydrofuran, which is called THF for short; in the step (4), the extractant is dichloromethane, and the drying agent is anhydrous magnesium sulfate.