Process for the preparation of alpha-sulfonylaminooxaldehydes from aliphatic aldehydes and sulfonamides

Abstract

The application provides a method for preparing alpha-sulfonamidyl acetal compounds from fatty aldehyde and sulfonamide, and belongs to the technical field of organic chemical synthesis, and comprises the following steps: step 1: fatty aldehyde, sulfonamide, sodium iodide, sodium carbonate peroxide and methanol or ethanol are added into a reaction container for mixing, a reaction mixture is obtained by reacting at a temperature of 50-80 DEG C for 16-24 hours; step 2: after the reaction mixture is purified, alpha-sulfonamidyl acetal compounds are obtained. The sulfonamide drugs used in the method are all commercially available, the fatty aldehyde is commercially available or is prepared by simply oxidizing commercially available fatty alcohol, and the pre-catalyst sodium iodide and the oxidant sodium carbonate peroxide are also cheap and easy to obtain; the method has a wide applicable range of substrates and good compatibility for sensitive groups; the reaction does not need transition metal catalysis, the alcohol used is used as a raw material and a solvent, and the only by-product is water, so that the method has the characteristics of high atom economy and green environmental protection.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing alpha-sulfonamidomethyl acetal compounds from aliphatic aldehyde and sulfonamide. BACKGROUND

[0002] Alpha-amino acid molecules are an important structural skeleton widely existing in nature. In addition to being the basic unit of polypeptides and proteins, alpha-amino acids also exist widely in natural products, drug molecules, food, cosmetics and multifunctional materials. Based on the advantages of alpha-amino acid drugs, such as good biocompatibility and wide indications, alpha-amino acids have become a large class of synthetic building blocks widely used in biological and chemical reactions. Compared with the 20 common protein-derived alpha-amino acids that make up protein macromolecules, there are also a variety of non-protein-derived alpha-amino acid units with different structures in polypeptide natural products, which play a crucial role in the unique biological functions of natural products. Therefore, the development of green and effective methods for synthesizing non-natural alpha-amino acid derivatives has attracted more and more attention.

[0003] On the other hand, sulfonamides exist widely in pesticides and pharmaceutical molecules, and their unique structural characteristics and biological activities have attracted great attention from researchers, and the research on the synthesis method of sulfonamide derivatives has also become one of the hotspots of organic synthesis chemistry research. Generally, pre-prepared chloramine T, sulfonimidate iodide, sulfonamide azide and the like are used as nitrogen sources for the synthesis of alpha-sulfonamidomethyl carbonyl compounds. However, the above synthesis methods have many defects such as high cost of raw materials and catalysts, narrow substrate range, harsh conditions and poor atom economy. SUMMARY

[0004] The present application provides a method for preparing alpha-sulfonamidomethyl acetal compounds from aliphatic aldehyde and sulfonamide, which addresses the technical problems of high cost of raw materials and catalysts, narrow substrate range, harsh conditions and poor atom economy in the prior art. From the environmental and economic perspectives, the method uses inexpensive and readily available aliphatic aldehyde and sulfonamide as raw materials, and realizes the synthesis of alpha-sulfonamidomethyl acetal compounds under the catalysis of commercially available and clean sodium iodide-sodium carbonate system.

[0005] Another purpose of the present application is to provide alpha-sulfonamidomethyl acetal compounds with potential drug activity and biological activity obtained by the above preparation method.

[0006] The technical solution adopted by the present application is: a method for preparing alpha-sulfonamidomethyl acetal compounds from aliphatic aldehyde and sulfonamide, comprising the following steps:

[0007] Step 1: fat aldehyde, sulfonamide, sodium iodide, sodium percarbonate and methanol or ethanol are added into a reaction container in a molar volume ratio of (0.4-1.2) mmol:(0.2-0.6) mmol:(0.06-0.18) mmol:(0.24-0.72) mmol:(0.80-2.4) mL, mixed, reacted at a temperature of 50-80℃ for 16-24 hours to obtain a reaction mixture;

[0008] Step 2: after the reaction mixture is purified, an α-sulfonamido acetal compound is obtained.

[0009] Preferably, in Step 1, the fat aldehyde is selected from any one of propyl aldehyde, hexyl aldehyde, isovaleraldehyde, phenylpropanal, cyclohexylmethanal, 6-((tert-butyldiphenylsilyl)oxy)hexanal, undecylenic aldehyde, oleyl aldehyde, 3-(5-methylfuran-2-yl)propanal, 2,6-dimethyl-5-heptenal, (-)-citronellal and (R)-4-((3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanal.

[0010] Preferably, in Step 1, the sulfonamide is selected from any one of sulfanilamide, p-toluenesulfonamide, 4-chlorobenzenesulfonamide, 4-nitrobenzenesulfonamide, p-cyanobenzenesulfonamide, m-aminobenzenesulfonamide, o-toluenesulfonamide, methylsulfonamide, celecoxib, etoricoxib, glimepiride, danusamid, purothionamide, hydrochlorothiazide, brinzolamide and zonisamide.

[0011] Preferably, in Step 1, a solvent is further included, which is methanol or ethanol other than participating in the reaction. That is, an excess of methanol or ethanol is added in Step 1, and the excess part serves as a solvent.

[0012] Preferably, in Step 1, no inert environment is required, and the operation is carried out in air.

[0013] Preferably, in Step 2, the reaction mixture is purified by thin layer chromatography, and the developing agent system is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether is 1 / 5-1 / 1.

[0014] The present application further discloses an α-sulfonamido acetal compound obtained by the above preparation method, and the chemical structural formula of the compound is shown in the following formula (I):

[0015]

[0016] In formula (I), R 1 is selected from Me, n Bu, iat least one of Pr, Bn, (tert-butyl)diphenylsilyl-4-butoxy, -(CH2)5-, 8-nonenyl, (Z)-hexadec-7-enyl, 3-(5-methylfuran-2-yl)propyl, 6-methylhept-5-enyl, 4-methylpent-3-enyl and (3R,5R,8R,9S,10S,12S,13R,14S,17R)-3,12-bis(benzyloxy)-17-isopropyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene;

[0017] R 2 at least one selected from Me, -(CH2)5- and 4-methylpent-3-enyl;

[0018] R 3 at least one selected from 4-H2NC6H4-, 4-MeC6H4-, 4-ClC6H4-, 4-O2NC6H4-, 4-NCC6H4-, 3-H2NC6H4-, 2-MeC6H4-, Me, 4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl, 4-(5-methyl-3-phenylisoxazol-4-yl)phenyl, 3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxamide-N-(4-phenethyl)-, 5-(dimethylamino)naphthyl, 6-methylthiochromane-1,1-dioxide, 6-chloro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide, (R)-4-(ethylamino)-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide and benzo[d]isoxazol-3-ylmethyl;

[0019] R 4 at least one selected from Me, Et.

[0020] Compared with the prior art, the present application has the beneficial effects that:

[0021] (1) The sulfonamide drugs used in the method of the present application are all commercially available, the aliphatic aldehyde is commercially available or is prepared by simple oxidation of a commercially available aliphatic alcohol, and the pre-catalyst sodium iodide and the oxidant sodium carbonate used are also cheap and easy to obtain; the substrate of the present application has a wide range of applications and good compatibility with sensitive groups, and is suitable for a variety of aliphatic aldehydes and sulfonamides described above, such as aliphatic aldehydes having a double bond, a siloxane bond, a heterocyclic ring, an α-tertiary carbon center and a complex molecular structure, and sulfonamide drugs having a primary amine and an active heterocyclic ring; the method does not require a transition metal catalytic reaction, the alcohol used is used as both a raw material and a solvent, and the only by-product is water, so the method has the characteristics of high atom economy and green environmental protection; the reaction conditions required by the method are very mild, an inert environment is not required, the reaction steps are few, and the method has the characteristic of simple operation.

[0022] (2) The α-sulfonamido acetal compound prepared by the present application is widely distributed in biologically and pharmaceutically active molecules, and has a broad application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of 4-amino-N-(1,1-dimethoxyhexan-2-yl)benzenesulfonamide in Example 1 of the present application;

[0024] Figure 2 is the nuclear magnetic resonance carbon spectrum of 4-amino-N-(1,1-dimethoxyhexan-2-yl)benzenesulfonamide in Example 1 of the present application;

[0025] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of N-(1,1-dimethoxy-3-(5-methylfuran-2-yl)propan-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide in Example 2 of the present application;

[0026] Figure 4 is the nuclear magnetic resonance carbon spectrum of N-(1,1-dimethoxy-3-(5-methylfuran-2-yl)propan-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide in Example 2 of the present application;

[0027] Figure 5 is the nuclear magnetic resonance fluorine spectrum of N-(1,1-dimethoxy-3-(5-methylfuran-2-yl)propan-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide in Example 2 of the present application;

[0028] Figure 6is the nuclear magnetic resonance hydrogen spectrum of N-(1,1-dimethoxy-2,6-dimethylhept-5-en-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzenesulfonamide in Example 3 of the present application;

[0029] Figure 7 is the nuclear magnetic resonance carbon spectrum of N-(1,1-dimethoxy-2,6-dimethylhept-5-en-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzenesulfonamide in Example 3 of the present application;

[0030] Figure 8 is the nuclear magnetic resonance fluorine spectrum of N-(1,1-dimethoxy-2,6-dimethylhept-5-en-2-yl)-4-(5-(p-tolyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)benzenesulfonamide in Example 3 of the present application;

[0031] Figure 9 is the nuclear magnetic resonance hydrogen spectrum of N-(1,1-dimethoxyhexan-2-yl)-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide in Example 4 of the present application;

[0032] Figure 10 is the nuclear magnetic resonance carbon spectrum of N-(1,1-dimethoxyhexan-2-yl)-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide in Example 4 of the present application;

[0033] Figure 11 is the nuclear magnetic resonance hydrogen spectrum of 1-(benzo[d]isoxazol-3-yl)-N-(1,1-dimethoxyhexan-2-yl)methanesulfonamide in Example 5 of the present application;

[0034] Figure 12 is the nuclear magnetic resonance carbon spectrum of 1-(benzo[d]isoxazol-3-yl)-N-(1,1-dimethoxyhexan-2-yl)methanesulfonamide in Example 5 of the present application;

[0035] Figure 13 is the nuclear magnetic resonance hydrogen spectrum of 4-amino-N-(1,1-diethoxyhexan-2-yl)benzenesulfonamide in Example 6 of the present application;

[0036] Figure 14 is the nuclear magnetic resonance carbon spectrum of 4-amino-N-(1,1-diethoxyhexan-2-yl)benzenesulfonamide in Example 6 of the present application. DETAILED DESCRIPTION

[0037] In order for those skilled in the art to better understand the technical solutions of the present application, the present application will be described in detail below in combination with the drawings and specific examples.

[0038] Example 1

[0039] The embodiment of the present application provides a method for preparing an alpha-sulfonamido acetal compound from a fatty aldehyde and a sulfonamide, which comprises the following steps:

[0040] Step 1: in a 10 mL test tube, under an air environment, sequentially adding n-hexyl aldehyde 0.4 mmol, sulfanilamide 0.2 mmol, sodium iodide 0.06 mmol, sodium percarbonate 0.24 mmol, methanol 0.8 mL, stirring at 60 DEG C for 20 hours, and the reaction equation is as follows:

[0041]

[0042] Step 2: after TLC monitoring reaction is completed, dissolving the mixture with dichloromethane, separating the product by thin layer chromatography, developing agent system is petroleum ether / ethyl acetate=1:1, the product is colorless oily compound 1, and the yield is 79%. The chemical structure and nuclear magnetic resonance diagram of the colorless liquid are as shown in Figures 1-2 .

[0043] Example 2

[0044] The embodiment of the present application provides a method for preparing an alpha-sulfonamido acetal compound from a fatty aldehyde and a sulfonamide, which comprises the following steps:

[0045] Step 1: in a 10 mL test tube, under an air environment, sequentially adding 3-(5-methylfuran-2-yl) propyl aldehyde 0.4 mmol, celecoxib 0.2 mmol, sodium iodide 0.06 mmol, sodium percarbonate 0.24 mmol, methanol 0.8 mL, stirring at 60 DEG C for 20 hours, and the reaction equation is as follows:

[0046]

[0047] Step 2: after TLC monitoring reaction is completed, dissolving the mixture with dichloromethane, separating the product by thin layer chromatography, developing agent system is petroleum ether: ethyl acetate=3:1, the product is colorless liquid compound 2, and the yield is 99%. The chemical structure and nuclear magnetic resonance diagram of the colorless liquid are as shown in Figures 3-5 .

[0048] Example 3

[0049] The embodiment of the present application provides a method for preparing an alpha-sulfonamido acetal compound from a fatty aldehyde and a sulfonamide, which comprises the following steps:

[0050] Step 1: In a 10 mL test tube, under air atmosphere, citronellal 0.4 mmol, celecoxib 0.2 mmol, sodium iodide 0.06 mmol, sodium percarbonate 0.24 mmol, methanol 0.8 mL were added successively, and the reaction was stirred at 60 °C for 20 hours, and the reaction equation was as follows:

[0051]

[0052] Step 2: After TLC monitoring the reaction was complete, the mixture was taken out with dichloromethane, and the product was separated by thin layer chromatography, and the developing agent system was petroleum ether: ethyl acetate = 3:1, and the product was a colorless oily compound 3 with a yield of 90%. The chemical structure and nuclear magnetic resonance diagram of the colorless liquid were as shown in Figures 6-8 .

[0053] Example 4

[0054] The embodiment of the present application provides a method for preparing an alpha-sulfonamido acetal compound from a fatty aldehyde and a sulfonamide, which comprises the following steps:

[0055] Step 1: In a 10 mL test tube, under air atmosphere, n-hexanal 0.4 mmol, darthecoxib 0.2 mmol, sodium iodide 0.06 mmol, sodium percarbonate 0.24 mmol, methanol 0.8 mL were added successively, and the reaction was stirred at 60 °C for 20 hours, and the reaction equation was as follows:

[0056]

[0057] Step 2: After TLC monitoring the reaction was complete, the mixture was taken out with dichloromethane, and the product was separated by thin layer chromatography, and the developing agent system was petroleum ether: ethyl acetate = 3:1, and the product was a white solid compound 4 with a yield of 86%. The chemical structure and nuclear magnetic resonance diagram of the white solid were as shown in Figures 9-10 .

[0058] Example 5

[0059] The embodiment of the present application provides a method for preparing an alpha-sulfonamido acetal compound from a fatty aldehyde and a sulfonamide, which comprises the following steps:

[0060] Step 1: In a 10 mL test tube, under air atmosphere, n-hexanal 0.4 mmol, zonisamide 0.2 mmol, sodium iodide 0.06 mmol, sodium percarbonate 0.24 mmol, methanol 0.8 mL were added successively, and the reaction was stirred at 60 °C for 20 hours, and the reaction equation was as follows:

[0061]

[0062] Step 2: After the reaction is completed, the mixture is dissolved in dichloromethane and the product is separated by thin layer chromatography using a developing solvent system of petroleum ether / ethyl acetate = 1:1. The product is a yellow oily compound 5 with a yield of 70%. The chemical structure and NMR image of the yellow liquid are shown in FIG. Figures 11-12 shown.

[0063] Example 6

[0064] An embodiment of the present invention provides a method for preparing an α-sulfonylamino acetal compound from an aliphatic aldehyde and a sulfonamide, comprising the following steps:

[0065] Step 1: In a 10 mL test tube, add 0.4 mmol of n-hexanal, 0.2 mmol of sulfonamide, 0.06 mmol of sodium iodide, 0.24 mmol of sodium percarbonate, and 0.8 mL of ethanol in sequence under air. Stir and react at 80°C for 20 hours. The reaction equation is:

[0066]

[0067] Step 2: After the reaction is completed, the mixture is dissolved in dichloromethane and the product is separated by thin layer chromatography using a developing solvent system of petroleum ether / ethyl acetate = 1:1. The product is a colorless oily compound 6 with a yield of 97%. The chemical structure and NMR spectrum of the colorless liquid are shown in Figure 2. Figures 13-14 shown.

[0068] Examples 7 to 15

[0069] Examples 7 to 15 were synthesized using substantially the same method as Example 1, with the only difference being the use of different fatty aldehydes and sulfonamides. The differences are shown in Table 1 below:

[0070] Table 1 Comparison of differences

[0071]

[0072]

[0073] The present invention has been described in detail above through the embodiments, but the contents described are only exemplary embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The scope of protection of the present invention is defined by the claims. Any use of the technical solution described in the present invention, or any person skilled in the art who, inspired by the technical solution of the present invention, designs a similar technical solution within the essence and scope of protection of the present invention to achieve the above-mentioned technical effects, or any equivalent changes and improvements made to the scope of application, shall still fall within the scope of protection covered by the patent of the present invention.

Claims

1. A method for preparing α-sulfonylamino acetal compounds from fatty aldehydes and sulfonamides, characterized in that: The following steps are involved: Step 1: Add fatty aldehyde, sulfonamide, sodium iodide, sodium percarbonate, and methanol or ethanol in a molar volume ratio of (0.4-1.2) mmol: (0.2-0.6) mmol: (0.06-0.18) mmol: (0.24-0.72) mmol: (0.80-2.4) mL into a reaction vessel, mix, and react at 50-80° C. for 16-24 hours to obtain a reaction mixture; Step 2: Purify the reaction mixture to obtain an α-sulfonylamino acetal compound; In step 1, the fatty aldehyde is selected from any one of n-hexanal and 3-(5-methylfuran-2-yl)propanal; The sulfonamide is selected from any one of sulfonamide, celecoxib, dalicoxib, and zonisamide; The structural formula of the α-sulfonylamino acetal compound is as follows: ； ； ； ； ； In step 1, a solvent is also included, and the solvent is methanol or ethanol other than those participating in the reaction.

2. The method for preparing α-sulfonylamino acetal compounds from aliphatic aldehydes and sulfonamides according to claim 1, wherein: In step 1, no inert environment is required and the operation is carried out in air.

3. The method for preparing α-sulfonylamino acetal compounds from aliphatic aldehydes and sulfonamides according to claim 1, wherein: In step 2, the reaction mixture is purified by thin layer chromatography, and the developing solvent system is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1 / 5 to 1 / 1.

Images