A method for preparing glycosyl (sulfinic) salt

Abstract

The invention discloses a method for preparing a novel glycosyl (sub)sulfonate, which comprises first reacting and oxidizing a glycosyl raw material with an arylthiophenol or a heteroarylthiophenol to obtain an oxidized glucosinolate compound, and then converting the obtained oxidized glucosinolate compound into the novel glycosyl (sub)sulfonate under the action of an alkaline substance in an organic solvent. The method of the invention has the advantages of low production cost, high yield, high reaction activity, simple operation, etc., and is suitable for industrial mass production.

Description

Technical Field

[0001] The invention belongs to the field of compound preparation, and specifically relates to a method for preparing a novel glycosyl (sulfinic) salt. Background Art

[0002] Glycoside compounds have extremely diverse structures and exhibit important biological functions, thus attracting the interest of a large number of scientific researchers. Usually, the synthesis of glycoside compounds is carried out under the action of a catalyst or a promoter, so that the glycosyl donor is transformed into a glycosyl cation, a glycosyl free radical or a glycosyl anion, and then combines with a nucleophile or an electrophile to form a glycoside product. The activity and stability of the glycosyl donor have an important influence on the construction of the glycosidic bond. Therefore, the development of new glycosyl donors for the synthesis of glycoside compounds has always been the focus of carbohydrate chemistry research. The widely used glycosyl donors in the early days include glycosyl halides, glycosyl trichloroacetimides, glycosyl- N -phenyl trifluoroacetimide, glycosyl o-alkynyl benzoate, etc. Although the development of these glycosyl donors has greatly promoted the synthesis of glycoside compounds, there are still problems such as poor stability, easy rearrangement and low selectivity of glycosyl donors. Therefore, it is of great value to study novel and easy-to-prepare glycosyl donors and use them to synthesize glycoside compounds. Summary of the invention

[0003] The object of the present invention is to provide a method for preparing a novel glycosyl (sulfinic) salt, which has a single product form and high yield and is suitable for industrial mass production.

[0004] To achieve the above object, the present invention adopts the following technical solutions:

[0005] A method for preparing a glycosyl (sulfinic) salt comprises the following steps:

[0006] 1) In a solvent, a sugar-based raw material is reacted with an arylthiophenol or heteroarylthiophenol under the action of a base to obtain an intermediate; the reaction flow is as follows:

[0007] ;

[0008] 2) Using an oxidant to carry out an oxidation reaction on the intermediate obtained in step 1) to obtain an oxidized glucosinolate compound; the reaction flow is as follows: ;

[0009] 3) In an organic solvent, the oxidized glucosinolate compound obtained in step 2) is converted under the action of an alkaline substance to generate the glycosyl (sub)sulfonate; the reaction flow is as follows:

[0010] ;

[0011] in, Selected from or , on which R 1 , R 2 , R 3 , R 4 Each is independently selected from H, C1-C6 alkyl, (CH2) n OBn, (CH2) n OTMS, (CH2) n OTBS, (CH2) n OMe、、(CH2) n NHAc, or (CH2) n OAc, n is an integer selected from 0-3; LG is a leaving group selected from halogen, trichloroacetimide or p-toluenesulfonate; is an aryl or heteroaryl group, and the heteroaryl group is specifically any one of furyl, thienyl, pyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyranyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, indolyl and purinyl; m is selected from 1 or 2; Y is a metal ion or an ammonium ion.

[0012] Furthermore, in step 1), the molar ratio of the glycosyl raw material to the arylthiophenol or heteroarylthiophenol is 1:0.5-1:5; the amount ratio of the glycosyl raw material to the solvent is in the range of 1g / 1mL-1g / 50mL; and the molar ratio of the base to the glycosyl raw material is 1:1-5:1.

[0013] Wherein, the solvent is any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone and ethyl acetate.

[0014] The base is any one of sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium acetate or sodium alcoholate and potassium alcoholate.

[0015] Furthermore, the molar ratio of the oxidant to the intermediate used in step 2) is 1:1-10:1.

[0016] Wherein, the oxidant is tert-butyl peroxide, hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate or oxygen.

[0017] Furthermore, in step 3), the amount ratio of the organic solvent used to the oxidized glucosinolate compound is 0.1 mL / g~100 mL / g; the molar ratio of the alkaline substance used to the oxidized glucosinolate compound is 0.1~10.

[0018] The organic solvent is one or more of nitrile solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, ketone solvents, and ether solvents. Furthermore, the nitrile solvent is one or more of acetonitrile, propionitrile, and benzonitrile; the amide solvent can be selected from N,N-dimethylformamide and / or N,N-dimethylacetamide; the hydrocarbon solvent can be selected from alkanes and aromatic hydrocarbons, wherein the general formula of the alkanes is C x H 2x+2 (x is an integer of 5-16), the general formula of aromatic hydrocarbons is C y H 2y-6 (y is an integer of 6-10); the halogenated hydrocarbon solvent can be selected from fluorinated hydrocarbon solvents, chlorinated hydrocarbon solvents, brominated hydrocarbon solvents, iodinated hydrocarbon solvents or hydrocarbons containing multiple halogen atoms, such as trifluoroethane, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, dibromomethane, 1,2-dibromoethane, 1,1-dibromoethane, iodomethane, 1-fluorobenzene, 1-chlorobenzene, 1-bromobenzene, 1-iodobenzene, etc.; the general formula of the ketone solvent is C z H 2z O (z is an integer of 3-10), which may specifically include acetone, butanone, pentanone, etc.; the ether solvent is one or more of tetrahydrofuran, substituted tetrahydrofuran, 1,4-dioxane, and diethyl ether.

[0019] The alkaline substance is an organic amine or an alkaline metal salt. Further, the organic amine is an alkyl-substituted amine or an aromatic amine, or a nitrogen-containing heterocycle; the alkaline metal salt is an alkaline metal carbonate, cyanate, thiocyanate, phosphate, phosphite, acetate, etc., or an alkaline metal hydroxide, alcoholate, or hydride.

[0020] Furthermore, the temperature of the reactions involved in steps 1), 2) and 3) is -50°C to 100°C, and the time is 1 minute to 48 hours; wherein, the preferred temperature of the reaction in step 1) is 25-100°C, and the preferred time is 1-24 hours, and the preferred temperature of the reaction involved in step 2) is -20-100°C, and the preferred time is 1-24 hours.

[0021] The glycosyl (sulfinate) salts obtained by the present invention can be used for O-glycosidation and N-glycosidation.

[0022] The significant advantages of the present invention are that the raw materials used in the present invention are cheap and easily available, the reaction operation is simple, the reaction selectivity is high, and the glycosyl donor with a (sulfonic acid) structure can be obtained in high yield, and the obtained glycosyl donor is in a specific form, which is suitable for industrial mass production. DETAILED DESCRIPTION

[0023] Taking D-glucose bromide and arylthiophenol as examples, the preparation method of the glycosyl (sulfinic) salt comprises the following steps:

[0024] 1) In an aprotic solvent, a sugar-based raw material is reacted with an aromatic thiophenol under the action of a base to obtain an intermediate;

[0025] 2) dissolving the obtained intermediate in a solvent and subjecting it to an oxidation reaction using an oxidant to obtain an oxidized glucosinolate compound;

[0026] 3) In an organic solvent, the obtained oxidized glucosinolate compound is converted into the glycosyl (sulfinic) salt under the action of an alkaline substance.

[0027] Furthermore, in step 1), the molar ratio of the glycosyl raw material to the arylthiophenol or heteroarylthiophenol is 1:0.5-1:5; the amount ratio of the glycosyl raw material to the aprotic solvent is in the range of 1g / 1mL-1g / 50mL; and the molar ratio of the base to the glycosyl raw material is 1:1-5:1.

[0028] Wherein, the aprotic solvent is any one of tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetone, and ethyl acetate.

[0029] The base is any one of sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium acetate or sodium alcoholate and potassium alcoholate.

[0030] Furthermore, in step 2), the ratio of the intermediate to the solvent is in the range of 1 g / 1 mL to 1 g / 50 mL; and the molar ratio of the oxidant to the intermediate is in the range of 1:1 to 10:1.

[0031] Wherein, the solvent is one or more of toluene, acetonitrile, chloroalkane, acetone, N,N-dimethylformamide, dioxane, dimethyl sulfoxide and water.

[0032] The oxidant is tert-butyl peroxide, hydrogen peroxide, m-chloroperbenzoic acid, sodium periodate or oxygen.

[0033] Furthermore, in step 3), the amount ratio of the organic solvent used to the oxidized glucosinolate compound is 0.1 mL / g~100 mL / g; the molar ratio of the alkaline substance used to the oxidized glucosinolate compound is 0.1~10.

[0034] Wherein, the organic solvent is one or more of nitrile solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, ketone solvents, and ether solvents.

[0035] The alkaline substance is an organic amine or an alkaline metal salt.

[0036] Furthermore, the temperature of the reactions involved in steps 1), 2) and 3) is -50°C to 100°C, and the time is 1 minute to 48 hours.

[0037] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0038] Example 1 Preparation of Sodium Tetrabenzyl Glucose Sulfonate

[0039] 1. Dissolve 2,3,4,6-tetra-O-benzyl-D-pyranose glucopyranose bromide (compound a2, CAS: 4196-35-4, 7.3 g, 0.012 mol) in dimethyl sulfoxide (50 ml), add thiophenol (compound b, 2.0 g, 0.018 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.54 mL, 0.017 mol), stir at room temperature overnight to obtain a crude product compound c2 (7.58 g, 0.012 mol), which is redissolved in dioxane (25 mL), and m-chloroperbenzoic acid (6.3 g, 0.036 mol) is added at 0°C. After stirring at room temperature for 2 h, compound 2 (5.09 g, 63%) is obtained. The reaction formula is as follows:

[0040] .

[0041] 2. The obtained compound 2 (1.0 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (15 ml), sodium ethoxide (0.1 g, 1.5 mmol) was added at 10°C, and the mixture was kept warm for 1 hour. Then, m-chloroperbenzoic acid (mCPBA, 516 mg, 2.99 mmol) was added to the reaction solution. After reacting at room temperature for 2 hours, the mixture was washed with petroleum ether to obtain the target compound (0.94 g, 100%). The reaction formula is as follows:

[0042] ,

[0043] Its NMR data are as follows: 1H NMR (400 MHz, CDCl3) δ 7.39-7.14 (m, 18H), 6.91-6.85 (m, 2H), 5.12 (d, J = 12.5 Hz, 1H), 4.92 (t, J = 10.5 Hz, 2H), 4.85-4.78(m, 2H), 4.70 (d, J = 10.4 Hz, 1H), 4.65-4.60 (m, 2H), 3.89 (t, J = 10.5 Hz,1H), 3.75 (q, J = 9.8, 8.9 Hz, 3H), 3.66-3.48 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 138.81, 128.95, 128.74, 128.64, 128.50, 128.46, 128.41, 128.18,128.10, 127.87, 127.81, 102.31, 92.85, 79.63, 78.25, 77.52, 75.70, 75.24,75.03, 73.49.

[0044] Example 2 Preparation of Sodium Tetrabenzyl Glucose Sulfinate

[0045] The compound 2 (1.0 g, 1.5 mmol) obtained in Example 1 was dissolved in N,N-dimethylformamide (15 ml), and sodium ethoxide (0.1 g, 1.5 mmol) was added at 10°C. After the mixture was kept warm for 1 hour, it was washed with petroleum ether to obtain the target compound (0.92 g, 100%). The reaction formula is as follows:

[0046] .

[0047] Its NMR data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.12 (m, 18H), 6.90 –6.84 (m, 2H), 4.93 (t, J = 10.3 Hz, 2H), 4.84– 4.77 (m, 2H), 4.69 (d, J =12.4 Hz, 1H), 4.63 – 4.58 (m, 2H), 4.11 (d, J = 10.8 Hz, 1H), 3.88 (t, J =9.5 Hz, 1H), 3.73 (q, J = 9.7, 8.9 Hz, 3H), 3.64 – 3.47 (m, 3H). 13 C NMR (101MHz, CDCl3) δ 137.81, 128.96, 128.64, 128.54, 128.50, 128.46, 128.31, 128.19,128.04, 127.87, 127.71, 92.73, 92.69, 79.56, 78.25, 77.36, 75.67, 75.19, 74.98, 73.43.

[0048] Example 3 Preparation of Sodium Tetraacetyl Glucose Sulfinate

[0049] 1. 2,3,4,6-tetraacetoxy-alpha-D-pyranose glucopyranose bromide (compound a1, CAS: 572-09-8, 5.0 g, 0.012 mol) was dissolved in dimethyl sulfoxide (50 ml), thiophenol (compound b, 2.0 g, 0.018 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.54 mL, 0.017 mol) were added, and the mixture was stirred at room temperature overnight to obtain a crude product, compound c1 (5.28 g, 0.012 mol), which was redissolved in dioxane (25 mL), and m-chloroperbenzoic acid (6.3 g, 0.036 mol) was added at 0°C. After stirring at room temperature for 2 h, compound 3 (4.20 g, 73%) was obtained, and the reaction formula is as follows:

[0050] .

[0051] 2. The obtained compound 3 (708 mg, 1.5 mmol) was dissolved in N,N-dimethylacetamide (15 ml), sodium ethoxide (0.1 g, 1.5 mmol) was added at 10°C, and the reaction was kept warm for 1 hour to obtain the target compound (602 mg, 96%). The reaction formula is as follows:

[0052] ,

[0053] Its NMR data are as follows: 1 H NMR (400 MHz, D2O) δ 5.36 – 5.43(m, 2H), 5.11 (t, J= 9.6 Hz, 1H), 4.43 (dd, J = 12.7, 3.7 Hz, 1H), 4.26 (d, J = 12.8 Hz, 1H), 4.04 (d, J = 10.5 Hz, 1H), 3.70 (d, J = 9.7 Hz, 1H), 2.24 – 2.02 (m, 12H). 13 CNMR (101 MHz, CDCl3) δ 170.2, 169.5, 169.4, 169.0, 99.9, 80.0, 70.0, 69.5, 65.5, 60.6, 23.3, 22.4, 21.2, 20.2.

[0054] Example 4 Synthesis of Tetramethylglucosesulfinic Acid Potassium Salt

[0055] 1. 2,3,4,6-Tetra-O-methyl-D-pyranose glucopyranose bromide (compound a3, CAS: 51705-30-7, 3.6 g, 0.012 mol) was dissolved in dimethyl sulfoxide (50 ml), thiophenol (compound b, 2.0 g), 0.018 mol, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.54 mL, 0.017 mol) were added, and the mixture was stirred at room temperature overnight to obtain a crude product compound c3 (3.94 g, 0.012 mmol), which was redissolved in dioxane (25 mL), and m-chloroperbenzoic acid (6.3 g, 0.036 mol) was added at 0°C. After stirring at room temperature for 2 h, compound 4 (3.02 g, 70%) was obtained, and its structural formula is as follows:

[0056] .

[0057] 2. The obtained compound 4 (540 mg, 1.5 mmol) was dissolved in N,N-dimethylacetamide (15 ml), potassium ethoxide (0.1 g, 1.5 mmol) was added at 10°C, and the reaction was kept warm for 1 hour to obtain the target compound (458 mg, 95%). The reaction formula is as follows:

[0058] ,

[0059] Its NMR data are as follows: 1 H NMR (400 MHz, D2O) δ 4.36 – 4.43(m, 2H), 4.11 (t, J= 9.6 Hz, 1H), 3.80 (dd, J = 12.7, 3.7 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.45 (d, J = 10.5 Hz, 1H), 3.25 (d, J = 9.7 Hz, 1H), 3.20 – 3.05 (m, 12H). 13 CNMR (101 MHz, CDCl3) δ102.36, 85.48, 79.56, 78.25, 77.36, 65.6, 59.23, 58.36,58.35, 58.3.

[0060] Application Example 1: Synthesis of (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-methoxytetrahydro-2H-pyran

[0061] The tetrabenzyl glucosylsulfinic acid sodium salt (200 mg) prepared in Example 2 was dissolved in dichloromethane (5 ml) together with I2 (84 mg) and K2CO3 (46 mg), and methanol (20 μL) was added. The mixture was stirred at room temperature for 12 h to obtain two products. The reaction formula is as follows. The total yield is 73% and the α / β ratio is 1:1, which proves that the obtained glycosylsulfinic acid sodium salt can be used as a glycosyl donor.

[0062]

[0063] β-Product: 1 H NMR (400 MHz, CDCl3) δ 7.41 – 7.27 (m, 18H), 7.20 – 7.17 (m,2H), 4.97 – 4.94 (m, 2H), 4.83 (t, J = 11.2 Hz, 2H), 4.74 (d, J = 11.0 Hz,1H), 4.66 (d, J = 12.2 Hz, 1H), 4.62 – 4.52 (m, 2H), 4.34 (d, J = 7.7 Hz,1H), 3.83 – 3.58 (m, 4H), 3.61 (s, 3H), 3.54 – 3.43 (m, 2H).

[0064] Alpha product: 1 H NMR (400 MHz, CDCl3) δ 7.44 – 7.25 (m, 18H), 7.19 – 7.16 (m,2H), 5.02 (d, J = 10.9 Hz, 1H), 4.88 – 4.80 (m, 3H), 4.73 – 4.63 (m, 3H), 4.53 – 4.48 (m, 2H), 4.03 (t, J = 9.2 Hz, 1H), 3.83 – 3.72 (m, 2H), 3.69 (s,1H), 3.66 (d, J = 9.0 Hz, 1H), 3.60 (m, 1H), 3.42 (s, 3H).

[0065] Application Example 2: Preparation of Azoglycosylation Products

[0066] The tetrabenzyl glucosylsulfinic acid sodium salt (60 mg) prepared in Example 2 was dissolved in 1,2-dichloroethane (5 ml) with NaI (2.5 mg), tert-butyl peroxide aqueous solution (70%) (TBHP) (6.16 μL), and piperidine (3.25 μL), and stirred at room temperature for 5 h to obtain the product, the reaction formula of which is as follows. The total yield is 63%, and the α / β ratio is less than 1:20, which proves that the obtained glycosylsulfinic acid sodium salt can be used as a glycosyl donor.

[0067]

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.40 – 7.21 (m, 20H), 5.01 – 4.95 (m, 2H), 4.84 (d, J = 10.6 Hz, 2H), 4.72 – 4.56 (m, 4H), 3.94 (d, J = 7.3 Hz, 1H),3.73 (d, J = 5.5 Hz, 2H), 3.65 (d, J = 7.3 Hz, 2H), 3.52 (t, J = 8.6 Hz, 1H),3.40 – 3.46 (m, 1H), 3.00 – 2.95 (m, 2H), 2.75 – 2.64 (m, 2H), 1.70 – 1.47(m, 6H). 13 C NMR (101 MHz, CDCl3) δ 138.90, 138.82, 138.69, 138.36, 128.38,128.37, 128.34, 128.28, 128.00, 127.85, 127.69, 127.63, 127.61, 127.53,127.46, 96.03, 86.21, 78.33, 77.63, 76.66, 75.72, 74.97, 74.00, 73.45, 69.16,49.55, 26.39, 24.93.

[0069] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. Use of a glycosyl sulfinate in a nitrogen-glycosidation reaction, characterized in that: Dissolve 60 mg of tetrabenzyl glucosylsulfinic acid sodium salt, 2.5 mg of NaI, 6.16 μL of 70% tert-butyl peroxide aqueous solution, and 3.25 μL of piperidine in 5 ml of 1,2-dichloroethane, and stir at room temperature for 5 h to obtain the product; The preparation process of the tetrabenzyl glucosyl sulfinic acid sodium salt is as follows: ， It specifically includes the following steps: 1) Dissolve 0.012 mol of 2,3,4,6-tetra-O-benzyl-D-pyranose glucopyranose bromide in 50 ml of dimethyl sulfoxide, add 0.018 mol of thiophenol and 0.017 mol of 1,8-diazabicyclo[5.4.0]undec-7-ene, and stir at room temperature overnight to obtain 0.012 mol of crude product compound c2, which is redissolved in 25 mL of dioxane, and 0.036 mol of m-chloroperbenzoic acid is added at 0°C. Stir at room temperature for 2 h to obtain compound 2; 2) 1.5 mmol of the obtained compound 2 was dissolved in 15 ml of N,N-dimethylformamide, and 1.5 mmol of sodium ethoxide was added at 10°C. After the mixture was kept warm for 1 hour, it was washed with petroleum ether to obtain the target compound.

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