CN107954906B - A kind of synthetic method of arylsulfonyl tertiary amine compound - Google Patents

Abstract

The invention provides a method for synthesizing arylsulfonyl tertiary amine compounds. React at 50~150°C for 1~12 hours, and obtain it after purification. The present invention is a method for synthesizing the arylsulfonyl tertiary amine in one step through the formation of the C-S bond and the cleavage of the C-N bond in the aprotic solvent directly between the sulfonyl chloride and the ditertiary amine. The raw materials are easily available, and the synthesis The process is simple, the operation is convenient, the cost is low, and the yield is high.

Description

A kind of synthetic method of arylsulfonyl tertiary amine compound

technical field

The invention relates to a method for synthesizing arylsulfonyl tertiary amine compounds, in particular to a method for synthesizing arylsulfonyl tertiary amine by direct reaction of arylsulfonyl chloride and ditertiary amine, and belongs to the technical field of chemical synthesis.

Background technique

Sulfonamides have a variety of biological activities. For example, as antibacterial drugs in clinical practice, sulfonamides have the advantages of broad antibacterial spectrum, stable properties, easy use and low price, and are currently the most commonly used antibacterial drugs after antibiotics. In addition, since sulfonamide compounds are also widely used in various fields such as pesticides and materials, their synthesis methods have been continuously developed.

Tertiary sulfonamide is a kind of compound with special structure among sulfonamide compounds, and its structural formula is as follows:

In the formula, R ¹ is any one or more of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl, alkynyl, and propargyl; wherein the alkyl group described in R ¹ is C ₁ -C ₂₀ , such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.; substituted aryl is halogen, nitro, alkoxy, benzyloxy, ethylene The group substituted by alkynyl group, alkynyl group or alkyl group is in the para position, ortho position or meta position on the aromatic ring, and can be mono-substituted or poly-substituted. Het is a heterocyclic compound, including furan, pyridine, thiophene, quinoline and other common aromatic heterocyclic compounds and their derivatives. R ² , R ³ are any one or more of alkyl, aryl and substituted aryl groups; wherein the alkyl group is C ₁ -C ₂₀ , such as methyl, ethyl, propyl, isopropyl, n-butyl Substituted aryl group is an aryl ring containing substituents such as halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl. The position of the substituent on the aromatic ring is para, ortho or meta, and may be mono- or polysubstituted.

Its properties are also different from other sulfonamides due to the absence of N-H bonds. For example, tertiary sulfonamides do not react with strong bases and are therefore more stable in structure. In terms of biological properties, sulfonyl tertiary amines are also the core building blocks of a variety of drugs, for example, Mefruside, also known as melfuscide, is a diuretic used in the treatment of various edema and hypertension. drug. Probenecid is a drug used to control hyperuricemia between attacks and chronic gout. Tertiary sulfonamides can also act as nonsteroidal liver X receptor antagonists (GENES & DEVELOPMENT, 2000, 14, 2831–2838; J. Med. Chem. 2010, 53, 3412), agonists of nuclear orphan receptors ( Bioorg. Med. Chem. Lett., 2014, 24, 2182) and so on. In addition, tertiary sulfonamides are also used as antioxidants (US Patent US5102934), plasticizers in high temperature processing of polymer resins. In synthetic chemistry, sulfonyl tertiary amine groups can also be used as positioning groups for ortho-metallation of aryl groups (Angew. Chem. Int. Ed., 2004, 43, 888).

The most commonly used method for the preparation of sulfonyl tertiary amines is through the reaction of sulfonyl chlorides with secondary amines. However, some secondary amines are more expensive or difficult to obtain than the corresponding tertiary amines. For example, dimethylamine is usually a gas and is not suitable for direct use in the reaction. The corresponding tetramethylethylenediamine is a liquid, which is easily available in the market, so it is easy to weigh and transfer. Alternatively, tertiary sulfonyl amines can also be accomplished by reacting sulfonyl chloride with a primary amine to give a sulfonamide followed by N-alkylation. This method has many reaction steps and is not suitable for industrial mass preparation.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for synthesizing arylsulfonyl tertiary amine compounds through the direct reaction of arylsulfonyl chloride and ditertiary amine in view of the problems existing in the synthesis of sulfonyl tertiary amines in the prior art.

In the method for synthesizing arylsulfonyl tertiary amine compounds of the present invention, under nitrogen protection, in an anhydrous aprotic solvent, arylsulfonyl chloride and di-tertiary amine are in a molar ratio of 1:1-1:20 at a concentration of 50-150 The reaction is carried out under the condition of ℃ for 1-12 hours, the solvent is evaporated under reduced pressure, and separated by column chromatography to obtain arylsulfonamide tertiary amines.

The structural formula of arylsulfonyl chloride is:

In the formula, R ¹ is any one of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl, alkynyl, and propargyl; wherein alkyl is C ₁ -C ₂₀ alkyl, such as Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; substituted aryl is halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl For the substituted aryl ring, the position of the substituent on the aromatic ring is para, ortho or meta; it can be mono- or poly-substituted.

Het is a heterocyclic compound, including furan, pyridine, thiophene, quinoline and other aromatic heterocyclic compounds and their derivatives.

The structural formula of ditertiary amine is:

In the formula, R ² , R ³ are any one or more of alkyl, aryl, and substituted aryl; wherein alkyl is C ₁ -C ₂₀ alkyl, such as methyl, ethyl, propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, etc.; Substituted aryl groups are aryl rings containing substituents such as halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl; The position of the substituent on the aromatic ring is para, ortho or meta, and may be mono- or polysubstituted.

The anhydrous aprotic solvent used is tetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane, N,N-dimethylformamide or dimethylsulfoxide.

The synthetic formula of arylsulfonyl tertiary amine compounds is as follows:

The characteristics of the synthesis of arylsulfonyl tertiary amine compounds in the present invention: the formation of C-S bond directly occurs between sulfonyl chloride and ditertiary amine in an aprotic solvent, and the cleavage of C-N bond occurs simultaneously, and the method for synthesizing arylsulfonyl tertiary amine in one step , the raw materials are readily available, the synthesis process is simple, the operation is convenient, the cost is low, and the yield is high.

Detailed ways

The synthesis of the arylsulfonyl tertiary amine compounds of the present invention will be further described below through specific examples.

Embodiment 1, the synthesis of N,N-dimethyl-4-methylbenzenesulfonamide

Use a flame-dried 50ml two-necked flask to replace nitrogen three times, use a syringe to inject p-toluenesulfonyl chloride (190mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, and heat the acetonitrile solution to reflux Then, N,N,N,N-tetramethylethylenediamine (139mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly added dropwise to the reaction flask containing p-toluenesulfonyl chloride with a syringe Then, the reaction was carried out for 1 hour under the reflux of acetonitrile, the heating was removed, the solvent was evaporated under reduced pressure, and the product was separated by flash column chromatography to obtain 183 mg of the product with a yield of 92%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.66 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.68 (s, 6H), 2.43 (s, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 143.4, 132.4, 129.6, 127.8, 37.9, 21.5.

Embodiment 2, the synthesis of N,N-diethyl-p-methylbenzenesulfonamide

Use a flame-dried 50ml two-necked flask to replace nitrogen three times, use a syringe to inject p-toluenesulfonyl chloride (190mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, and heat the acetonitrile solution to reflux Then, N,N,N,N-tetraethylethylenediamine (206mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly added dropwise to the reaction flask containing p-toluenesulfonyl chloride with a syringe , and then reacted for 1 hour under the refluxing state of acetonitrile, removed the heating, evaporated the solvent under reduced pressure, and separated by flash column chromatography to obtain 197 mg of the product with a yield of 87%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.68 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 3.21 (q, J = 7.2 Hz , 4H), 2.41 (s, 3H), 1.11 (t, J = 7.1 Hz, 6H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ(ppm): 142.9, 137.4, 129.6, 127.0, 42.0, 21.4, 14.1.

Embodiment 3, the synthesis of N,N-dipropyl p-methylbenzenesulfonamide

Use a flame-dried 50ml two-neck flask to replace nitrogen three times, use a syringe to inject p-toluenesulfonyl chloride (190mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, heat to reflux the acetonitrile solution Then, N,N,N,N-tetraisobutylethylenediamine (273mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly added dropwise to the reaction solution containing p-toluenesulfonyl chloride with a syringe. Then, the reaction was carried out for 1 hour under the refluxing state of acetonitrile, the heating was removed, the solvent was evaporated under reduced pressure, and the product was separated by flash column chromatography to obtain 216 mg of the product with a yield of 85%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.68 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 16.4 Hz, 2H), 3.05 (dd, J = 8.5, 6.9 Hz, 4H), 2.41 (s, 3H), 1.59– 1.49 (m, 4H), 0.86 (t, J = 7.4 Hz, 6H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 142.8 , 137.2, 129.5 127.1, 50.0, 22.0, 21.4, 11.2.

Embodiment 4, the synthesis of N,N-diisobutyl-p-toluenesulfonamide

Use a flame-dried 50ml two-necked flask to replace nitrogen three times, use a syringe to inject p-toluenesulfonyl chloride (190mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, and heat the acetonitrile solution to reflux Then, N,N,N,N-tetraisobutylethylenediamine (321mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly added dropwise to the reaction solution containing p-toluenesulfonyl chloride with a syringe Then, the reaction was carried out for 1 hour under the reflux of acetonitrile, the heating was removed, the solvent was evaporated under reduced pressure, and separated by flash column chromatography to obtain 237 mg of the product with a yield of 84%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.67 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 2.83 (d, J = 7.5 Hz) , 4H), 2.41 (s, 3H), 1.88 (dt, J= 13.6, 6.9 Hz, 2H), 0.88 (d, J = 6.7 Hz, 12H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ(ppm) ): 142.8, 136.7, 129.4, 127.3, 57.3, 27.3, 21.4, 20.2.

Example 5. Synthesis of 4-(4-trifluoromethoxy-benzenesulfonyl)-morpholine

Use a flame-dried 50ml two-neck flask to replace nitrogen three times, use a syringe to inject p-methylbenzenesulfonyl chloride (260mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, and heat the acetonitrile solution to reflux Then, N,N,N,N-tetraisobutylethylenediamine (240mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly added dropwise to the reaction solution containing p-toluenesulfonyl chloride with a syringe Then, the reaction was carried out for 1 hour under the refluxing state of acetonitrile, the heating was removed, the solvent was evaporated under reduced pressure, and the product was separated by flash column chromatography to obtain 255 mg of the product with a yield of 82%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.82 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 3.79 – 3.69 (m, 4H) , 3.11 – 2.90 (m, 4H), 0.00 (s, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 152.5 (q, J = 1.7 Hz), 133.6, 129.9, 120.9 (d, J = 0.9 Hz), 119.3, 66.0, 45.9.

Embodiment 6, the synthesis of N,N-two (N-methylaniline) p-toluenesulfonyl chloride

Use a flame-dried 50ml two-necked flask to replace nitrogen three times, use a syringe to inject p-toluenesulfonyl chloride (190mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, and heat the acetonitrile solution to reflux Then, N,N'-dimethyl-N,N'-diphenyl-ethane-1,2-diamine (288mg, 1.2mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly dripped with a syringe It was added to a reaction flask filled with p-toluenesulfonyl chloride, and then reacted for 1 hour under the reflux of acetonitrile. The heating was removed, the solvent was evaporated under reduced pressure, and separated by flash column chromatography to obtain 237 mg of the product with a yield of 91%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 7.42 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.27–7.21 (m, 3H) , 7.09 (d, J = 7.3 Hz, 2H), 3.16 (s, 3H), 2.41 (s, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 143.5, 141.6, 133.5, 129.3, 128.8, 127.9, 127.2, 126.6, 38.1, 21.5.

Embodiment 7, the synthesis of N,N-bis (N-methylaniline) quinoline-8-sulfonyl chloride

Use a flame-dried 50ml two-necked flask to replace nitrogen three times, use a syringe to inject quinoline-8-sulfonyl chloride (227mg, 1mmol) dissolved in acetonitrile (3ml) into the cooled reaction flask, heat to make the acetonitrile solution After refluxing, N,N'-dimethyl-N,N'-diphenyl-ethane-1,2-diamine ((288 mg, 1.2 mmol) was dissolved in 3 ml of anhydrous acetonitrile, and the It was slowly added dropwise to a reaction flask containing p-toluenesulfonyl chloride, and then reacted for 1 hour under the reflux of acetonitrile, the heating was removed, the solvent was evaporated under reduced pressure, and separated by flash column chromatography to obtain 244 mg of the product with a yield of 244 mg. 82%. Its synthetic formula is as follows:

Spectral data: ¹ H NMR (600 MHz, CDCl ₃ ) δ (ppm): 9.06 (dd, J = 4.2, 1.8 Hz, 1H), 8.31 (dd, J = 7.4, 1.4 Hz, 1H), 8.22 (dd, J = 8.3, 1.7 Hz, 1H), 7.97(dd, J = 8.1, 1.3 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.51 – 7.48 (m, 2H), 7.17 – 7.11 (m, 2H), 7.11 – 7.04 (m, 3H), 3.69 (s, 3H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ (ppm): 151.1, 144.2, 141.6, 137.3, 136.4, 133.5, 133.4 , 128.8, 128.8, 126.5, 126.1, 125.4, 122.0, 40.0.

Claims (3)

1. A synthetic method of an arylsulfonyl tertiary amine compound is, under nitrogen protection, in an anhydrous aprotic solvent, arylsulfonyl chloride and ditertiary amine in a mol ratio of 1:1～1:20, in The reaction is carried out at 50-150° C. for 1-12 hours, the solvent is evaporated under reduced pressure, and separated by column chromatography to obtain arylsulfonyl tertiary amines; The structural formula of the arylsulfonyl chloride is:

In the formula, R ¹ is any one of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl, and propargyl; The structural formula of ditertiary amine is:

In the formula, R ² and R ³ are any one of alkyl, aryl and substituted aryl; The substituted aryl group is a halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl substituted aryl ring, and the position of the substituent on the aromatic ring is para, ortho or meta ; The structure of the arylsulfonyl tertiary amine compound is:

. 2. the synthetic method of a kind of arylsulfonyl tertiary amine compound as claimed in claim 1, is characterized in that: described alkyl is C ₁ ～C ₂₀ alkyl. 3. the synthetic method of a kind of arylsulfonyl tertiary amine compound as claimed in claim 1, is characterized in that: described aprotic solvent is tetrahydrofuran, dichloromethane, acetonitrile, 1,4-dioxane, N,N-dimethylformamide or dimethylsulfoxide.