CN107954906B - Synthetic method of aryl sulfonyl tertiary amine compound - Google Patents
Synthetic method of aryl sulfonyl tertiary amine compound Download PDFInfo
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- CN107954906B CN107954906B CN201711189620.4A CN201711189620A CN107954906B CN 107954906 B CN107954906 B CN 107954906B CN 201711189620 A CN201711189620 A CN 201711189620A CN 107954906 B CN107954906 B CN 107954906B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
- C07B45/04—Formation or introduction of functional groups containing sulfur of sulfonyl or sulfinyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
Abstract
The invention provides a synthesis method of an arylsulfonyl tertiary amine compound, which comprises the steps of reacting arylsulfonyl chloride and di-tertiary amine in an anhydrous aprotic solvent at a molar ratio of 1: 1-1: 20 under the protection of nitrogen for 1-12 hours at 50-150 ℃, and purifying to obtain the arylsulfonyl tertiary amine compound. According to the method for synthesizing the arylsulfonyl tertiary amine in one step, C-S bonds are directly formed and C-N bonds are broken in the aprotic solvent through the sulfonyl chloride and the di-tertiary amine, so that the raw materials are easy to obtain, the synthesis process is simple, the operation is convenient, the cost is low, and the yield is high.
Description
Technical Field
The invention relates to a method for synthesizing an arylsulfonyl tertiary amine compound, in particular to a method for synthesizing the arylsulfonyl tertiary amine by directly reacting arylsulfonyl chloride and di-tertiary amine, belonging to the technical field of chemical synthesis.
Background
The sulfonamide compound has a plurality of biological activities, for example, the sulfonamide compound used as an antibacterial drug clinically has the advantages of wide antibacterial spectrum, stable property, simple and convenient use and low price, and is a common antibacterial drug second to antibiotics at present. In addition, because sulfonamide compounds are also widely used in various fields such as pesticides, materials and the like, synthetic methods thereof are continuously developed.
The tertiary sulfonamide is a compound with a special structure in the sulfonamide compounds, and the structural formula of the tertiary sulfonamide is as follows:
in the formula, R1Is any one or more of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl, alkynyl and propargyl; wherein R is1The alkyl is C1-C20Such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.; the substituted aryl is a group substituted by halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl, and the position on the aromatic ring is para, ortho or meta, and can be mono-substituted or multi-substituted. Het is heterocyclic compound, including common aromatic heterocyclic compound such as furan, pyridine, thiophene, quinoline and the like and derivatives thereof. R2，R3Is any one of alkyl, aryl and substituted aryl orSeveral kinds of the raw materials; wherein alkyl is C1-C20Such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.; the substituted aryl group is an aryl ring containing a substituent 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 can be mono-substituted or multi-substituted.
Their properties differ from other sulfonamides due to the absence of an N-H bond. For example, tertiary sulfonamides do not react with strong bases and are therefore more structurally stable. In terms of biological properties, tertiary sulfonamides are also the core building blocks of many drugs, for example, Mefruside, also known as mefuracit, a diuretic, which is used in the treatment of various edemas and hypertension. Probenecid (probenecid) is a drug used during the interpupillary and chronic phases of gout to control hyperuricemia. Tertiary sulfonamides may also act as non-steroidal 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 the like. In addition, tertiary sulfonylamines are also used as antioxidants (US 5102934), plasticizers during high temperature processing of polymer resins. Tertiary sulphonyl amine groups can also be used as directing groups for aryl ortho metallation reactions in synthetic chemistry (angelw. chem. int. ed., 2004, 43, 888).
The most common preparation of tertiary sulfonamides is by reaction of a sulfonyl chloride with a secondary amine. 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 and is easily available on the market, so that it is easy to weigh and transfer. Alternatively, tertiary sulfonylamines can be obtained by reacting sulfonyl chlorides with a primary amine to give sulfonamides, which are then N-alkylated again. This method has many reaction steps and is not suitable for industrial mass production.
Disclosure of Invention
The invention aims to solve the problems existing in the synthesis of tertiary sulfonyl amine in the prior art, and provides a method for synthesizing an aryl sulfonyl tertiary amine compound by directly reacting aryl sulfonyl chloride and di-tertiary amine.
The method for synthesizing the aryl sulfonyl tertiary amine compound comprises the steps of reacting aryl sulfonyl chloride and di-tertiary amine in an anhydrous aprotic solvent at a molar ratio of 1: 1-1: 20 at 50-150 ℃ for 1-12 hours under the protection of nitrogen, decompressing, steaming to remove the solvent, and performing column chromatography separation to obtain the aryl sulfonyl tertiary amine.
Arylsulfonyl chloride has the structural formula:
in the formula, R1Is any one of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl, alkynyl and propargyl; wherein alkyl is C1-C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl; the substituted aryl is an aryl ring substituted by halogen, nitryl, alkoxy, benzyloxy, vinyl, alkynyl or alkyl, and the position of the substituent on the aromatic ring is para, ortho or meta; may be mono-or polysubstituted.
Het is heterocyclic compound, including furan, pyridine, thiophene, quinoline and other aromatic heterocyclic compounds and derivatives thereof.
The di-tertiary amine has the structural formula:
in the formula, R2，R3Is any one or more of alkyl, aryl and substituted aryl; wherein alkyl is C1-C20Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like; the substituted aryl is an aryl ring containing halogen, nitro, alkoxy, benzyloxy, vinyl, alkynyl or alkyl and other substituents; the position of the substituent on the aromatic ring is para, ortho or meta, and can be mono-substituted or multi-substituted.
The anhydrous aprotic solvent is tetrahydrofuran, dichloromethane, acetonitrile, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide.
The synthesis of tertiary arylsulfonyl amine compounds is as follows:
the synthesis method of the aryl sulfonyl tertiary amine compound has the following characteristics: the method for synthesizing the arylsulfonyl tertiary amine by one step has the advantages of easily obtained raw materials, simple synthesis process, convenient operation, low cost and high yield.
Detailed Description
The synthesis of tertiary arylsulfonyl amine compounds of the present invention is further illustrated by the following specific examples.
EXAMPLE 1 Synthesis of N, N-dimethyl-4-methylbenzenesulfonamide
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-toluenesulfonyl chloride (190 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N-tetramethylethylenediamine (139 mg, 1.2 mmol) was dissolved in 3ml anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with the syringe, followed by reaction for 1 hour under the acetonitrile reflux condition, heating was removed, the solvent was evaporated under reduced pressure, and the product was isolated by flash column chromatography at 183mg, 92% yield. The synthetic formula is as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3)(ppm): 143.4, 132.4, 129.6, 127.8, 37.9, 21.5。
EXAMPLE 2 Synthesis of N, N-diethyl-p-methylbenzenesulfonamide
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-toluenesulfonyl chloride (190 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N-tetraethylethylenediamine (206 mg, 1.2 mmol) was dissolved in 3ml anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with a syringe, and then, in the acetonitrile reflux state, reaction was carried out for 1 hour, heating was removed, the solvent was evaporated under reduced pressure, and flash column chromatography was carried out to obtain 197mg of the product, with a yield of 87%. The synthetic formula is as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3) (ppm): 142.9, 137.4，129.6, 127.0,42.0, 21.4, 14.1。
EXAMPLE 3 Synthesis of N, N-dipropyl-p-methylbenzenesulfonamide
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-toluenesulfonyl chloride (190 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N-tetraisobutylethylenediamine (273 mg, 1.2 mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with a syringe, followed by reaction for 1 hour under the acetonitrile reflux state, heating was removed, the solvent was evaporated under reduced pressure, and the product was isolated by flash column chromatography at 216mg in 85% yield. The synthetic formula is as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3) (ppm):142.8, 137.2, 129.5 127.1, 50.0, 22.0, 21.4, 11.2。
example 4 Synthesis of N, N-diisobutyl-p-methylbenzenesulfonamide
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-toluenesulfonyl chloride (190 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N-tetraisobutylethylenediamine (321 mg, 1.2 mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with a syringe, followed by reaction for 1 hour under the acetonitrile reflux state, heating was removed, the solvent was evaporated under reduced pressure, and flash column chromatography was performed to obtain 237mg of the product, yield 84%. The synthetic formula is as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3)(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
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-toluenesulfonyl chloride (260 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N-tetraisobutylethylenediamine (240 mg, 1.2 mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with the syringe, followed by reaction for 1 hour under the acetonitrile reflux state, heating was removed, the solvent was evaporated under reduced pressure, and flash column chromatography was performed to obtain 255mg of the product with a yield of 82%. The synthetic formula is as follows:
spectral data:1H NMR (400 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3) (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。
example 6 Synthesis of N, N-bis (N-methylaniline) p-methylbenzenesulfonyl chloride
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, p-methylbenzenesulfonyl chloride (190 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken up into the cooled reaction flask with a syringe, and after heating to reflux the acetonitrile solution, N '-dimethyl-N, N' -diphenyl-ethane-1, 2-diamine (288mg, 1.2 mmol) was dissolved in 3ml of anhydrous acetonitrile, and slowly dropped into the reaction flask containing p-methylbenzenesulfonyl chloride with a syringe, followed by reaction for 1 hour under the reflux state of acetonitrile, heating was removed, the solvent was evaporated under reduced pressure, and flash column chromatography was performed to obtain 237mg of the product in 91% yield. The synthetic formula is as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz, CDCl3) (ppm): 143.5, 141.6, 133.5,129.3, 128.8, 127.9, 127.2, 126.6, 38.1, 21.5。
example 7 Synthesis of N, N-bis (N-methylaniline) quinoline-8-sulfonyl chloride
The nitrogen gas was replaced three times with a flame-dried 50ml two-necked flask, quinoline-8-sulfonyl chloride (227 mg, 1 mmol) dissolved in acetonitrile (3 ml) was taken in a cooled reaction flask with a syringe, after heating to reflux the acetonitrile solution, N '-dimethyl-N, N' -diphenyl-ethane-1, 2-diamine ((288 mg, 1.2 mmol) was dissolved in 3ml of anhydrous acetonitrile, and then slowly dropped into the reaction flask containing p-toluenesulfonyl chloride with a syringe, followed by reaction for 1 hour under reflux of acetonitrile, heating was removed, the solvent was evaporated under reduced pressure, and flash column chromatography was performed to obtain 244mg of a product, yield 82%, which was synthesized as follows:
spectral data:1H NMR (600 MHz, CDCl3) (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);13C NMR (151 MHz,CDCl3) (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 comprises the steps of reacting arylsulfonyl chloride and di-tertiary amine in an anhydrous aprotic solvent at a molar ratio of 1: 1-1: 20 at 50-150 ℃ for 1-12 hours under the protection of nitrogen, evaporating the solvent under reduced pressure, and performing column chromatography separation to obtain arylsulfonyl tertiary amine;
the aryl sulfonyl chloride has a structural formula:
in the formula, R1Is any one of hydrogen, alkyl, aryl, substituted aryl, vinyl, allyl and propargyl;
the di-tertiary amine has the structural formula:
in the formula, R2，R3Is any one of alkyl, aryl and substituted aryl;
the substituted aryl 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 aryl sulfonyl tertiary amine compound is as follows:
2. the method of claim 1 for synthesizing a tertiary arylsulfonyl amine compound, comprising: the alkyl group is C1~C20An alkyl group.
3. The method of claim 1 for synthesizing a tertiary arylsulfonyl amine compound, comprising: the aprotic solvent is tetrahydrofuran, dichloromethane, acetonitrile, 1, 4-dioxane, N-dimethylformamide or dimethyl sulfoxide.
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