A neokotalanol derivative, a preparation method and application thereof

Abstract

The application discloses a neokotalanol derivative with a structural formula I and a preparation method and application thereof, designs a brand-new synthesis method, uses cheap and easily-obtained benzyl glucoside as raw material, successfully constructs a seven-ring glycoside intermediate with the same chiral center as the side chain of a natural product through five steps of reaction, uses the key seven-ring glycoside intermediate as raw material, and goes through a series of reactions to construct a coupling precursor with trifluoromethylsulfonyl as a leaving group, reacts with a benzyl-protected sulfur sugar, and goes through deprotection, reduction and other reactions to synthesize the neokotalanol and the derivative thereof, and the method completes the total synthesis of the neokotalanol and the synthesis of the derivative at a yield of 17%, which is 8.5 times of the highest yield reported.

Description

Technical Field

[0001] This invention relates to a compound, and more particularly to a neokotalanol derivative thereof, its preparation method and application. Background Technology

[0002] Compounds derived from the genus *Pentaclostrobin* with thionium salt structures possess both unique chemical structures and excellent α-glucosidase inhibitory activity. Among them, neokotalanol has the longest side chain structure, exhibiting strong α-glucosidase inhibitory activity. Its longer, flexible side chain also provides more structural modification sites. Neokotalanol is currently a safe and effective oral hypoglycemic drug on the market, but its hypoglycemic effect still needs further improvement.

[0003] The reported synthetic routes for neokotalanol currently suffer from problems such as poor stereoselectivity in the construction of chiral centers in the side chain, low yields, or high cost of synthetic raw materials. These problems have also prevented the development of research on the structural modification of neokotalanol. Summary of the Invention

[0004] Objectives of the Invention: The first objective of this invention is to provide a neokotalanol derivative that enhances the hypoglycemic effect; the second objective of this invention is to provide a method for preparing the neokotalanol and its derivatives, thereby improving the stereoselectivity of chiral center construction during the construction of the side chain chiral center; the third objective of this invention is the application of the neokotalanol derivative.

[0005] The neokotalanol derivative described in this invention has the following structural formula:

[0006]

[0007] Wherein, R1 is H, C4-C12, arylethyl, arylpropyl or arylbutyl, and R2 is H, C4-C12, arylethyl, arylpropyl or arylbutyl. R1 and R2 are not both H.

[0008] Preferably, one of R1 or R2 is H, and the other is C4 to C12.

[0009] Preferably, R1 and R2 are both selected from C4 to C12.

[0010] The method for preparing neokotalanol and its derivatives according to the present invention includes the following steps:

[0011] (1) Compound 6 undergoes a substitution reaction with an alkyl bromide to give intermediate compound 7;

[0012] (2) The intermediate compound 7 undergoes a reduction reaction to remove the benzyl group, yielding the intermediate compound 8;

[0013] (3) Intermediate compound 8 undergoes a selective substitution reaction with triphenylmethyl chloride to replace the primary hydroxyl group at the 7-position, yielding intermediate compound 9;

[0014] (4) Intermediate compound 9 was reacted with an acid anhydride reagent to protect the remaining hydroxyl groups, thus obtaining intermediate compound 10;

[0015] (5) Triphenyl removal from intermediate compound 10 yields intermediate compound 11;

[0016] (6) Intermediate compound 11 reacts with trifluoromethanesulfonic anhydride or p-toluenesulfonyl chloride to give trifluoromethanesulfonyl-protected coupling precursor 12;

[0017] (7) The coupling precursor 12 reacts with benzyl-protected pentazose compound 13 to give coupling product 14;

[0018] (8) The coupling product 14 is subjected to ion exchange resin to convert trifluoromethanesulfonate ions into chloride ions, and then the methoxy and acetyl groups are hydrolyzed to obtain intermediate 15.

[0019] (9) Intermediate 15 undergoes a reduction reaction to remove benzyl, and then further reduction to obtain the final product 16.

[0020] The synthesis route is as follows:

[0021]

[0022] Wherein, R1 is selected from H, C4-C12, arylethyl, arylpropyl or arylbutyl, R2 is selected from H, C4-C12, arylethyl, arylpropyl or arylbutyl, and R3 is an alkyl group.

[0023] In step (1), when 6 eq NaH and 6 eq alkyl bromide are added and reacted, two alkyl products are obtained; when 2 eq NaH and 2 eq alkyl bromide are added and reacted, a product with an alkyl group at the 4 position is obtained; when 2 eq NaH and 1.2 eq bromobenzyl are reacted first to protect the hydroxyl group at the 4 position, and then 2 eq alkyl bromide is added and reacted, a product with an alkyl group at the 3 position is obtained.

[0024] Preferably, in step (1), the reaction solvent is DMF, the reaction temperature is 20-80℃, and the reaction time is 0.5-8h.

[0025] Preferably, in step (2), hydrogen is used as a reducing agent, Pd / C is used as a catalyst, methanol is used as a solvent, the reaction temperature is 20-80℃, and the reaction time is 12-24h.

[0026] Preferably, in step (3), the reaction solvent and base are anhydrous pyridine, and the reaction temperature is 50-120°C.

[0027] Preferably, in step (4), the acid anhydride is acetic anhydride, the reaction solvent is acetic anhydride, the catalyst is DMAP, the reaction temperature is 15-30℃, and the reaction time is 0.5-12 hours.

[0028] Preferably, in step (5), the reaction solvent is 80% acetic acid, the reaction temperature is 40-100℃, and the reaction time is 8-24h.

[0029] Preferably, in step (6), the coupling precursor 12 reacts with trifluoromethanesulfonic anhydride or p-toluenesulfonyl chloride under argon protection at a temperature of -50 to 0°C for 0.5 to 3 hours, selectively protecting the 7-position primary hydroxyl group with triphenylmethyl. The reaction solvent is anhydrous dichloromethane, and 2,6-dimethylpyridine is used as the base.

[0030] Preferably, in step (7), the reaction solvent is tetrahydrofuran, and the reaction temperature is 15-30°C.

[0031] In step (8), the coupling product 14 is subjected to an ion exchange resin to convert trifluoromethanesulfonate ions into chloride ions, followed by hydrolysis of the methoxy and acetyl groups. Preferably, the reaction solvent is anhydrous tetrahydrofuran, the reaction reagent is 4N HCl, the reaction temperature is 50–100°C, and the reaction time is 12–24 h.

[0032] In step (9), the benzyl group is removed in an 80% acetic acid methanol solution using hydrogen and palladium / carbon, and finally reduced with sodium borohydride to obtain the final product. Preferably, the reaction temperature for benzyl removal is 20–80°C, and the reaction time is 12–24 hours; preferably, the reduction reaction temperature is 0–30°C, and the reaction time is 0.5–5 hours.

[0033] The application of the neokotalanol derivative described in this invention in a drug for treating diabetes.

[0034] The synthetic route for compound 6 is as follows:

[0035]

[0036] The specific synthesis method includes the following steps:

[0037] First, using benzyl glucose as the starting material, (2R,3R,4S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2h-pyranose hexamethylene intermediate was synthesized in 85% yield according to a known method in the literature. See: Choutka J, Kratochvil M, Zyka J, et al. Carbohydrate Research, 2020, 496.

[0038] (a) Subsequently, the above (2R,3R,4S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2h-pyranose hexaglycoene intermediate was reacted with chloroform under concentrated sodium hydroxide conditions to give a carbene analog. Under TEBAC catalysis, the above substance underwent an addition reaction with glycoene to give a stereospecific cyclopropane intermediate, namely (1S,3R,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxy)methyl)-7,7-dichloro-2-oxabicyclo[4.1.0]heptane intermediate;

[0039] (b) The above (1S,3R,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxy)methyl)-7,7-dichloro-2-oxabicyclo[4.1.0]heptane intermediate was ring-opened with sodium methoxide to obtain (2R,3R,4S,7S)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-chloro-7-methoxy-2,3,4,7-tetrahydrooxacyclopropane heptacyclic intermediate;

[0040] (c) The above (2R,3R,4S,7S)-3,4,5-tris(benzyloxy)-2-(benzyloxyoxy)methyl)-6-chloro-7-methoxy-2,3,4,7-tetrahydrooxetane heptacyclic intermediate was oxidized with ruthenium trichloride sodium periodate to give the diketone analog (2S,5S,6R,7R)-5,6-bis(benzyloxy)-7-(benzyloxyoxy)methyl)-2-methoxyoxetane-3,4-diketone intermediate;

[0041] (d) The above (2S,5S,6R,7R)-5,6-bis(benzyloxy)-7-(benzyloxyoxy)methyl)-2-methoxyoxetine-3,4-dione intermediate was directly reduced to two hydroxyl groups to obtain the (2S,3R,4R,5R,6R,7R)-5,6-bis(benzyloxy)-7-((benzyloxy)methyl)-2-methoxyoxetine-3,4-diol intermediate.

[0042] Preferably, the reaction solvent in step (a) is chloroform; the base used is sodium hydroxide; the reaction reagent is TEBAC; the reaction temperature is room temperature; and the reaction time is 1 h.

[0043] Preferably, in step (b), the reaction solvent is 1,4-dioxane, methanol; the reaction reagent is sodium methoxide solution; the reaction temperature is 80-150℃; and the reaction time is 0.5-24h.

[0044] Preferably, in step (c), the reaction solvent is a mixture of acetonitrile and ethyl acetate or a mixture of acetonitrile and carbon tetrachloride, the reaction reagent is an aqueous solution of ruthenium trichloride and sodium periodate, the reaction temperature is -20 to 5°C, and the reaction time is 0.5 to 24 h.

[0045] Preferably, in step (d), the reaction solvent is methanol or water, the reaction reagent is sodium borohydride, the reaction temperature is -20 to 5°C, and the reaction time is 0.5 to 24 hours.

[0046] This invention presents a novel synthetic method for constructing the desired chiral center and synthesizing a seven-membered sugar ring. Pyranosene is prepared from readily available and inexpensive benzyl glucose, which then reacts with dichlorocarbene to form a cyclopropyl derivative. Sodium methoxide is then used to attack the anomeric position, leading to ring opening and expansion of the three-membered ring into a seven-membered heptose methyl glycoside analog. This is followed by oxidation to synthesize 2,3-dicarbonyl heptose methyl glycoside. Utilizing the steric effect of the ortho-substituent, the carbonyl group is reduced with high yield and high stereoselectivity using sodium borohydride, constructing a chiral center with the same 5', 6' configuration as the target product neokotalanol. The method also considers the selection of protecting groups at the 5', 6' positions in the derivative.

[0047] Beneficial effects: Compared with the prior art, the present invention has the following advantages: (1) The neokotalanol derivative synthesized by the present invention has a better hypoglycemic effect than natural neokotalanol. (2) The present invention designs a novel synthetic method, using inexpensive and readily available benzyl glucoside as raw material, and successfully constructs a heptaneous glycoside intermediate with the same chiral center as the side chain of the natural product through 5 steps; using this key heptaneous glycoside intermediate as raw material, a series of reactions are carried out to construct a coupling precursor with trifluoromethanesulfonyl as the leaving group, which reacts with benzyl-protected sulose, and synthesizes neokotalanol and its derivatives through deprotection, reduction and other reactions. The method completes the total synthesis of neokotalanol and the synthesis of its derivatives with a yield of 17%, which is 8.5 times the highest yield reported. Detailed Implementation

[0048] The present invention will be further described below with reference to specific embodiments.

[0049] Example 1

[0050] The neokotalanol derivative of this invention includes the following steps:

[0051] (1) The preparation of (1S,3R,4R,5S,6S)-4,5,6-tris(benzyloxy)-3-(benzyloxy)methyl)-7,7-dichloro-2-oxabicyclo[4.1.0]heptane was carried out via the following synthetic route:

[0052]

[0053] Compound (2R,3R,4S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-3,4-dihydro-2h-pyranose hexabenzene (4.7 g, 8.99 mmol) was dissolved in 40 mL of chloroform. 21 g of sodium hydroxide was dissolved in 21 mL of water and added dropwise to the chloroform system. After 0.5 hours, TEBAC (204 mg, 0.9 mmol) was added to the reaction system, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the mixture was quenched with ice water in an ice bath, and the pH was adjusted to neutral with hydrochloric acid. The mixture was extracted three times with water and dichloromethane, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 100:1) to give compound 2 (4.64 g, 85%), a pale yellow oil. The TLC solvent was petroleum ether / ethyl acetate = 10:1.

[0054] [a] D 20 = +46.9 (c = 1.0 in CHCl3); 1 H NMR (300MHz, Chloroform-d) δ7.50–7.28(m,20H),5.03–4.90(m,3H),4.75–4.64(m,3H),4.51(d,J=11.6Hz,1H),4.37(d,J=11.6Hz,1H),4.21(d,J= 10.1Hz,1H),4.11(dd,J=10.2,7.0Hz,1H),4.03(s,1H),3.94(dt,J=7.0,3.1Hz,1H),3.66(dd,J=10.5,2.7Hz,1H),3.53(dd,J=10.5,3.4Hz,1H)ppm. 13 C NMR(75MHz,Chloroform-d)δ138.14,137.93,137.46,128.51,128.49,128.44,128.41,128.26,128.14,127.94,127.87,127. 85,127.82,127.72,127.61,80.78,77.33,74.59,74.02,73.56,72.89,71.40,70.63,67.06,65.50,63.79ppm.HRMS(ESI)m / z calcd forC 35 H 34 Cl2O5Na + [M+Na] + 627.1681 found 627.1676.

[0055] (2) The preparation of (2R,3R,4S,7S)-3,4,5-tris(benzyloxy)-2-(benzyloxyoxy)methyl)-6-chloro-7-methoxy-2,3,4,7-tetrahydroxetane was carried out via the following synthetic route:

[0056]

[0057] Compound 2 (2.5 g, 4.1 mmol) was dissolved in 25 mL of 1,4-dioxane and 4 mL of methanol. A methanol solution of sodium methoxide (5.5 mol / L, 1 mL) was added, and the mixture was reacted in a sealed tube at 110 °C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, the filter layer was washed with dichloromethane, the reaction solution was evaporated to dryness, extracted three times with water and ethyl acetate, washed three times with saturated brine, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give compound 3 (1.86 g, 75%), a pale yellow oil. The TLC solvent was petroleum ether / ethyl acetate = 10:1.

[0058] [a] D 20 = -27.9 (c = 1.0 in CHCl3); 1 H NMR (300MHz, DMSO-d6) δ7.37–7.25(m,20H),5.17(s,1H),4.76–4.65(m,2H),4.61–4.53(m,3H),4.49(d,J=15.7Hz,3H ),4.40(d,J=2.2Hz,1H),3.97(td,J=5.8,3.1Hz,1H),3.78(dd,J=8.2,2.2Hz,1H),3.59–3.45(m,2H),3.39(s,3H)ppm. 13 C NMR (75MHz, DMSO-d6) δ152.43,138.64,138.39,138.02,137.12,128.79,128.75,128.72,128.58,128.45,128.36,128. 31,128.27,128.13,128.00,127.93,100.09,79.44,77.53,72.46,71.85,71.69,71.53,71.16,55.90ppm.HRMS(ESI)m / z calcdfor C 35 H 34 Cl2O5Na + [M+Na] + 623.2176 found 623.2171.

[0059] (3) The preparation of (2S,3R,4R,5R,6R,7R)-5,6-bis(benzyloxy)-7-((benzyloxy)methyl)-2-methoxyoxacyclopropane-3,4-diol was carried out via the following synthetic route:

[0060]

[0061] Compound 3 (3 g, 5 mmol) was dissolved in a mixture of 30 mL acetonitrile and 30 mL ethyl acetate. Ruthenium trichloride (103 mg, 0.5 mmol) and sodium periodate (2.13 g, 10 mmol) were dissolved in 10 mL water and slowly added dropwise to the above solvent system at 0 °C. The solution changed from yellow to red. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, methanol was added to quench the reaction. The reaction solution was filtered with diatomaceous earth, and the filter layer was washed with ethyl acetate and dichloromethane. The reaction solution was then evaporated to dryness to obtain crude compound 4. The above compound was unstable and was added directly without further purification. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0062] The crude product from the previous step was dissolved in 20 mL of methanol. Sodium borohydride (380 mg, 10 mmol) was slowly added under ice bath conditions, and bubble formation was observed. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, dilute hydrochloric acid was added to quench the reaction, and the pH was adjusted to neutral. The reaction solution was directly evaporated to dryness, extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 5 (1.5 g, 61%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0063] [a] D 20 = +180.3 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.46–7.27(m,15H),4.93(d,J=4.2Hz,1H),4.87–4.73(m,2H),4.58(d,J=12.2Hz,1H),4.53–4.43(m,2H),4.20( d,J=11.2Hz,1H),4.16–4.12(m,1H),4.09(d,J=1.5Hz,1H),4.06–3.98(m,2H),3.60–3.55(m,3H),3.51(s,3H),2.78(s,1H),2.47(s,1H)ppm. 13C NMR(75MHz,Chloroform-d)δ137.69,128.43,128.41,128.37,128.20,128.08,127.86,127.79,127.71, 127.60,99.19,79.97,78.20,73.51,73.22,72.75,71.29,71.17,70.31,69.82,56.27ppm.HRMS(ESI)m / z calcd for C 29 H 34 O7Na + [M+Na] + 517.2202 found 517.2200.

[0064] (4) The preparation of (2S,3S,4R,5S,6R,7R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5,6-dibutoxy-7-methoxyoxacyclopropane is carried out via the following synthetic route:

[0065]

[0066] Compound 5 (3 g, 6 mmol) was dissolved in 72 mL of LDM. At room temperature, 1.44 g of 6 eq NaH and 2.52 mL of 6 eq n-butyl bromide were slowly added to the solution, and the solution changed from pale yellow to orange. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction in an ice bath. The mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 6 (3.3 g, 91%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0067] 1H NMR(300MHz,Chloroform-d)δ7.45-7.27(m,13H),7.17(dd,J=6.9,2.8Hz,2H),4.83(d,J=3.0Hz,1H),4.81-4.72(m,2H) ,4.71-4.54(m,2H),4.51-4.32(m,2H),4.06-4.01(m,1H),3.99(dd,J=6.4,1.5Hz,1H),3.86-3.79(m,1H),3.79-3.75(m ,1H),3.73(d,J=3.0Hz,1H),3.72-3.69(m,1H),3.68(d,J=3.4Hz,1H),3.66(d,J=3.0Hz,1H),3.64(d,J=2.9Hz,1H),3.6 2-3.57(m,1H),3.56-3.50(m,1H),3.46(s,3H),1.58(tt,J=14.8,6.2Hz,4H),1.47-1.31(m,4H),0.95(dd,J=7.5Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ139.04,138.46,138.43,128.40,128.36,128.25,128.00,127.76,127.72,127.68,127.56,127.52,99.19 ,80.77,78.49,78.35,73.84,73.51,73.09,72.60,72.00,71.94,71.25,55.95,32.48,32.27,19.52,19.33,14.10,14.06.HRMS(ESI)m / z calcd for C 37 H 50 O7Na + [M+Na] + 629.3448 found 629.3439.

[0068] (5) Preparation of (2S,3S,4S,5S,6R,7R)-5,6-dibutyl-2-(hydroxymethyl)-7-methoxyoxacyclopropane-3,4-diol, the synthetic route is as follows:

[0069]

[0070] Compound 6 (2.9 g, 4.85 mmol) was dissolved in 10 mL of methanol, and 10% palladium / carbon (500 mg) was added. Hydrogen gas was bubbled into the reaction system, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter layer was washed with methanol, the filtrates were combined and evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / methanol = 10:1) to give compound 7 (1.5 mg, 91%), a white solid. The solvent for TLC was dichloromethane:methanol = 10:1.

[0071] Mp123-124℃; [a] D 20 = +17.3 (c = 1.0 in MeOH); 1 H NMR(300MHz,Chloroform-d)δ4.68(d,J=2.4Hz,1H),3.95-3.86(m,1H),3.84-3.79(m,2H),3.78-3.71(m,2H),3.70-3.62(m,2H),3.61-3.55(m,2H), 3.54-3.49(m,1H),3.48-3.44(m,1H),3.42(s,3H),3.06(s,1H),2.72(s,1 H),1.62-1.47(m,4H),1.34(h,J=7.4Hz,4H),0.89(td,J=7.3,3.5Hz,6H). 13 CNMR(75MHz,Chloroform-d)δ99.85,80.87,79.50,73.41,72.71,72.53,72.33,71.25,64.03,56.44,32.22,19.34,13.98,13.95.HRMS(ESI)m / z calcd for C 16 H 32 O7Na + [M+Na] + 359.20402found 629.20337.

[0072] (6) Preparation of (2S,3S,4S,5S,6R,7S)-5,6-dibutoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4-diol, the synthetic route is as follows:

[0073]

[0074] Compound 7 (225 mg, 0.67 mmol) was dissolved in 0.7 mL of anhydrous pyridine and stirred at room temperature for 10 minutes. Then, triphenylmethyl chloride (210 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction system was then heated to 70 °C and reacted at this temperature for 8 hours. TLC monitoring revealed that a small amount of starting material remained. The reaction system was quenched with methanol, and the reaction solution was azeotropically treated with toluene, evaporated to dryness, extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The aqueous layer was directly evaporated to dryness. The crude aqueous layer was purified by column chromatography (ethyl acetate / methanol = 10:1) to obtain starting material 105 (20 mg). The crude organic layer was purified by column chromatography (ethyl acetate) to obtain compound 8 (59.6 mg, 89%), a white solid. The TLC solvent was dichloromethane:methanol = 10:1.

[0075] MPa 139-140℃; [a] D 20 = +1.0 (c = 1.0 in MeOH); 1 H NMR (300MHz, Chloroform-d)δ

[0076] 8.02-7.26(m,15H),4.88(s,1H),4.37-4.27(m,1H),4.14-4.01(m,2H),4.01-3.92(m,1H),3.86(t,J=7.7Hz,1H),3.84-3.73(m,2H),3.65 (d,J=11.0Hz,2H),3.49(s,3H),2.94(brs,1H),2.71-2.24(m,1H),2.21(s,2H),1.81-1.65(m,4H),1.61-1.50(m,4H),1.11-1.01(m,6H). 13 C NMR(75MHz,Chloroform-d)δ143.91,128.83,127.96,127.18,99.12,87.01,79.40,73.78,72.77,7 2.52,72.15,70.72,64.92,60.53,56.10,32.32,29.82,19.43,19.39,14.32,14.06.HRMS(ESI)m / z calcd for C 35 H 46 O7Na + [M+Na] + 601.31357 found 601.31245.

[0077] (7) Preparation of (2S,3S,4S,5S,6R,7R)-5,6-dibutoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4-dimethyldiacetate, the synthetic route is as follows:

[0078]

[0079] Compound 8 (603 mg, 0.91 mmol) was dissolved in 1.5 mL of anhydrous pyridine. Acetic anhydride (0.5 mL, 4.55 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) were added at room temperature. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, the reaction system was quenched with water. The mixture was extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 9 (578 mg, 96%) as a white solid. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0080] MPa 10⁴-10⁵℃; [a] D 20 = +59.1 (c = 1.0 in CHCl3); 1 H NMR (300MHz, Chloroform-d)δ

[0081] 7.54-7.50(m,6H),7.38-7.26(m,9H),5.54-5.43(m,2H),4.82(d,J=3.1Hz,1H),4.3 9(tt,J=5.7,2.4Hz,1H),3.91(dd,J=6.5,1.6Hz,1H),3.85-3.73(m,3H),3.67-3.54 (m,2H),3.44(s,3H),3.31(dd,J=10.2,2.3Hz,1H),3.19(dd,J=10.2,5.3Hz,1H),2. 09(s,3H),1.79(s,4H),1.68-1.58(m,4H),1.52-1.40(m,4H),0.99(q,J=7.3Hz,6H). 13C NMR(75MHz,Chloroform-d)δ170.22,169.06,143.76,128.98,127.76,127.01,99.19,86.61,78.03,77.82, 74.05,72.95,72.51,71.49,69.77,63.59,56.22,32.21,21.14,20.85,19.29,19.26,14.04.HRMS(ESI)m / z calcd for C 39 H 50 O9Na + [M+Na] + 685.33470found685.33316.

[0082] (8) Preparation of (2S,3S,4S,5S,6R,7R)-5,6-dibutoxy-2-(hydroxymethyl)-7-methoxyoxacyclopropane-3,4-dimethyldiacetate, the synthetic route is as follows:

[0083]

[0084] Compound 9 (550 mg, 0.83 mmol) was dissolved in a mixed solvent of 4 mL acetic acid and 1 mL water, and reacted at 50 °C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 10 (328 mg, 94%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0085] [a] D 20 = +15.6 (c = 1.0 in CHCl3); 1H NMR(300MHz,Chloroform-d)δ5.26(dd,J=8.8,2.6Hz,1H),4.69(d,J=3.5Hz,1H),4.39-4.2 3(m,2H),4.19(dq,J=13.8,5.0,4.5Hz,1H),4.09-3.81(m,2H),3.80-3.69(m,2H),3.69-3.5 7(m,1H),3.52(ddt,J=11.8,5.2,2.7Hz,2H),3.44(s,J=4.2Hz,3H),2.69(br,J=5.5Hz,1H) ,2.07(dd,J=14.6,6.8Hz,6H),1.60-1.45(m,4H),1.44-1.24(m,4H),0.89(t,J=7.3Hz,6H). 13 C NMR(75MHz,Chloroform-d)δ171.61,171.25,99.48,80.01,77.71,73.05,72.43,70.93,69 .73,69.13,65.31,56.06,32.16,32.12,21.33,21.12,19.24,13.99,13.96.HRMS(ESI)m / z calcd for C 20 H 36 O9Na + [M+Na] + 443.22515found 443.22426.

[0086] (9) Preparation of (2S,3S,4S,5S,6R,7R)-5,6-dibutoxy-7-methoxy-2-((((trifluoromethyl)sulfonyl)oxy)methyl)oxetane-3,4-dimethyldiacetate, the synthetic route is as follows:

[0087]

[0088] At -20°C, 2,6-dimethylpyridine (0.225 mL, 1.9 mmol) was dissolved in 5 mL of anhydrous dichloromethane. Trifluoromethanesulfonic anhydride (0.24 mL, 1.4 mmol) was added under argon protection. After 5 minutes, compound 10 (538 mg, 1.28 mmol) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the above reaction system. The reaction was carried out at the above temperature for 30 minutes, monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and dichloromethane, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 11 (452.65 mg, 64%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0089] [a] D 20 = +13.5 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ5.50-5.37(m,1H),5.16-4.97(m,1H),4.85-4.76(m,1H),4.54-4.23(m,1H),4.23-4.13(m,1H),4.12-3.99(m,1H),3.7 7-3.58(m,3H),3.56-3.48(m,2H),3.46-3.40(m,1H),3.40-3.21(m,3H),2 .10-1.99(m,6H),1.63-1.43(m,4H),1.39-1.25(m,4H),0.95-0.82(m,6H). 13 C NMR (75MHz, CDCl3) δ170.74,170.43,170.02,99.08,75.93,75.86,72.07,70.21,67.94,66.56,65.9 6,62.70,55.55,32.22,32.01,20.95,20.90,19.25,19.23,14.02,13.96,1.14.HRMS(ESI)m / zcalcd for C 21 H 35 F3O 11 Na + [M+Na] + 575.19523 found 575.19561.

[0090] (10) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4R,5S,6R,7S)-3,4-diacetoxy-5,6-dibutoxy-7-methoxyoxacyclopropane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium trifluoromethanesulfonate, the synthetic route is as follows:

[0091]

[0092] Compound 11 (420 mg, 0.76 mmol) and compound 12 (470 mg, 1.1 mmol) were dissolved in 3 mL of anhydrous tetrahydrofuran and reacted at room temperature for 24 hours, monitored by TLC. After the reaction was complete, the reaction solution was directly evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 80:1) to give compound 13 (643 mg, 71%), a colorless oil. The TLC solvent was dichloromethane:methanol = 15:1.

[0093] [a] D 20 = +1.2 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.42-7.27(m,13H),7.25-7.11(m,2H),5.47(dd,J=9.0,2.7Hz,1H),5.18(t,J=9.2Hz, 1H),4.79(dd,J=9.6,4.8Hz,1H),4.75-4.70(m,1H),4.61(ddd,J=23.9,7.4,4.6Hz,5H),4.53-4.42(m,2H),4.37(dd ,J=13.1,5.0Hz,1H),4.13-3.96(m,3H),3.93-3.79(m,4H),3.75(dd,J=10.8,4.6Hz,1H),3.63(dt,J=9.7,6.8Hz,1H ),3.58-3.43(m,3H),3.38(s,3H),2.10(d,J=15.9Hz,6H),1.63-1.50(m,4H),1.44-1.37(m,4H),0.98-0.87(m,6H). 13C NMR(75MHz,Chloroform-d)δ171.19,170.00,136.92,136.10,128.87,128.82, 128.69,128.62,128.51,128.31,128.16,128.05,100.96,83.17,82.63,77.42 ,73.80,73.75,73.72,72.79,72.47,72.37,71.88,67.70,66.82,66.30,57.15 ,49.72,48.48,32.20,29.80,20.96,19.26,13.95,13.93,1.15.HRMS(ESI)m / z calcd for C 46 H 63 O 11 S + [M+Na] + 823.40856 found 823.40803.

[0094] (11) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4S,5S,6R)-5,6-dibutoxy-3,4,7-trihydroxyoxetane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium chloride (a:b=1:1), the synthetic route is as follows:

[0095]

[0096] Compound 13 (181 mg, 0.22 mmol) was dissolved in 5 mL of methanol, and 1 g of IRA 402 chloride ion exchange resin was added. The mixture was reacted at room temperature for 3 hours. The resin was removed by filtration, and the mixture was washed with methanol. The filtrates were combined and evaporated to dryness to obtain 180 mg of white syrup. The above substance was dissolved in 1 mL of tetrahydrofuran, and 1 mL of 4 mol / L hydrochloric acid was added. The mixture was reacted at 50 °C for 12 hours. TLC was used for monitoring. After the reaction was completed, the reaction solution was evaporated to dryness, and the hydrochloric acid was removed. When the pH of the system was observed to be 7 using pH paper, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / methanol = 5:1) to obtain a mixture 14 (α:β 1:1, 135 mg, 85%) with an anisotropic 1:1 configuration, which was a white syrup. The TLC solvent was dichloromethane:methanol = 10:1.

[0097] 1H NMR(300MHz, Methanol-d4)δ7.39-7.29(m,13H),7.27-7.16(m,2H),4.74-4.62(m,3H),4.62-4.50(m,3H),4.50-4.41(m,2H),4.40-4.32(m,1H),4.2 1-4.03(m,2H),3.95-3.82(m,4H),3.81-3.72(m,2H),3.71-3.48(m,6H),3 .47-3.41(m,1H),1.62-1.52(m,4H),1.46-1.33(m,4H),1.02-0.91(m,6H). 13 C NMR(75MHz,Methanol-d4)δ138.62,138.15,138.01,129.74,129.70,129.61,1 29.40,129.34,129.17,129.12,98.93,84.37,84.26,80.96,78.72,77.64,74.3 9,73.98,73.28,73.08,72.08,70.87,69.74,68.10,68.02,67.80,67.66,67.50 ,67.26,66.93,52.15,33.26,33.01,20.34,20.31,14.31,14.21.HRMS(ESI)m / z calcd for C 41 H 57 O9S + [M+Na] + 725.3728 found 725.3735.

[0098] (12) Preparation of (1R, 2R, 3S, 4S)-1-((2S, 3S, 4S, 5S, 6S)-5,6-dibutoxy-2,3,4,7-tetrahydroxyheptyl)-3,4-dihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium chloride, the synthetic route is as follows:

[0099]

[0100] Mixture 14 (73 mg, 0.1 mmol) was dissolved in a mixed solvent of 2 mL acetic acid and 0.5 mL methanol. 10% palladium / carbon (200 mg) was added, and hydrogen gas was introduced into the reaction system. The reaction was carried out at 50 °C for 12 hours and monitored by TLC. After the reaction was completed, the reaction solution was filtered with diatomaceous earth. The filter layer was washed with a mixed solvent of water and methanol (volume ratio 1:1). The filtrates were combined and evaporated to dryness to obtain 35 mg of white syrup. The crude product was dissolved in 3 mL of water and stirred in an ice bath for 10 minutes. Sodium borohydride (20 mg, 0.5 mmol) was slowly added, and the reaction was carried out at the above temperature for 1.5 hours. TLC was used for monitoring. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 4. The filtrate was evaporated to dryness, and the crude product was subjected to reversed-phase silica gel column chromatography (Spherical C18 Monomeric, 120A) (water → water / methanol = 50:1) to obtain a colorless amorphous dibutyl-modified neokotalanol derivative (31 mg, 68%). The 1H and 13C NMR spectra were consistent with those reported in the literature. The TLC solvent was ethyl acetate:methanol:water = 10:2:1.

[0101] [a] D 20 = +7.4 (c = 1.0 in MeOH); 1 H NMR (300MHz, Methanol-d4) δ4.62 (s, 1H), 4.38 (d, J = 2.8Hz, 1H), 4.19-4.12 ( m,1H),4.12-4.06(m,1H),4.06-4.01(m,1H),4.00-3.95(m,1H),3.95-3.90( m,1H),3.89-3.85(m,1H),3.78-3.67(m,5H),3.67-3.59(m,3H),3.59-3.48( m,2H),3.35(s,2H),1.64-1.53(m,4H),1.43-1.34(m,4H),0.97-0.88(m,6H). 13 C NMR(75MHz,Methanol-d4)δ81.42,79.53,79.16,73.83,73.76,73.36,72.45,69.95,69.78, 64.34,61.85,61.09,52.76,51.99,33.52,33.40,20.39,20.31,14.32,14.30.HRMS(ESI)m / z calcd for C 20 H 41 O9S + [M+] +457.24658 found 457.24591.

[0102] Example 2

[0103] The neokotalanol derivative of this invention includes the following steps:

[0104] Steps (1) to (3) are the same as in Example 1.

[0105] (4) Preparation of (2S,3S,4R,5S,6R,7R)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-7-methoxyoxacyclopropane-6-ol, the synthetic route is as follows:

[0106]

[0107] Compound 5 (3 g, 6 mmol) was dissolved in 72 mL of LDM. At room temperature, 480 mg of 2 eq NaH and 0.84 mL of 1.2 eq benzyl bromide were slowly added to the solution, and the solution changed from pale yellow to orange. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water in an ice bath, extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 6 (3.3 g, 91%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0108] 1 H NMR(300MHz,Chloroform-d)δ7.43(td,J=14.2,13.1,5.9Hz,20H),4.91(d,J=4.5Hz,1H),4.82(s,3H),4.78-4.67(m,2H) ,4.67-4.53(m,3H),4.36(d,J=10.5Hz,1H),4.30-3.99(m,4H),3.69(d,J=7.2Hz,2H),3.54(d,J=7.3Hz,3H),2.79(s,1H). 13 C NMR(101MHz,Chloroform-d)δ138.59,138.33,138.04,128.61,128.43,128.38,128.30,128.24,128.11,127.7 8,127.59,99.02,80.59,78.65,77.88,74.17,73.46,73.28,73.09,71.29,69.78,69.46,56.31.HRMS(ESI)m / z calcd for C36 H 40 O7Na + [M+Na] + 607.27344 found 607.27740.

[0109] (5) The preparation of (2S,3S,4R,5S,6R,7R)-3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl)-6-(butoxy)-7-methoxyoxane is carried out via the following synthetic route:

[0110]

[0111] Compound 6 (3.5 g, 6 mmol) was dissolved in 72 mL of LDM. At room temperature, 480 mg of 2 eq NaH and 0.78 mL of 1.2 eq n-butyl bromide were slowly added to the solution, and the solution changed from pale yellow to orange. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, water was added under ice bath conditions to quench the reaction. The mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 7 (3.3 g, 91%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0112] 1 H NMR(300MHz,Chloroform-d)δ7.37-7.06(m,20H),4.73(d,J=4.1Hz,1H),4.7 1-4.59(m,4H),4.59-4.46(m,2H),4.43-4.24(m,2H),4.02-3.90(m,2H),3.78 (dd,J=7.5,3.1Hz,1H),3.74-3.68(m,1H),3.68-3.62(m,1H),3.61-3.47(m,4 H),3.40(s,3H),1.57-1.42(m,2H),1.40-1.28(m,2H),0.87(t,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ139.12,138.54,128.59,128.46,128.37,128.24,127.90,127.79,127.73,99.61,8 0.78,78.64,77.27,74.55,73.95,73.53,73.31,72.09,71.91,71.43,56.21,32.60,19.71,14.31.HRMS(ESI)m / z calcd for C40 H 48 O7Na + [M+Na] + 663.34122 found 663.34000.

[0113] (6) The preparation of (2S,3S,4S,5S,6R,7R)-6-butoxy-2-(hydroxymethyl)-7-methoxyoxacyclopropane-3,4,5-triol was carried out via the following synthetic route:

[0114]

[0115] Compound 7 (3.1 g, 4.85 mmol) was dissolved in 10 mL of methanol, and 10% palladium / carbon (500 mg) was added. Hydrogen gas was bubbled into the reaction system, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter layer was washed with methanol, the filtrates were combined and evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / methanol = 10:1) to give compound 8 (1.235 mg, 91%), a white solid. The TLC solvent was dichloromethane:methanol = 10:1.

[0116] Mp123-124℃; [a] D 20 = +17.3 (c = 1.0 in MeOH); 1 H NMR (300MHz, Chloroform-d)δ

[0117] 4.67(d,J=3.0Hz,1H),4.09(dd,J=6.2,3.0Hz,1H),3.98(d,J=8.5Hz,1H),3.92-3.70(m,6H),3.61(td,J=6.8,2 .4Hz,3H),3.48(s,3H),3.43(s,1H),3.31(s,1H),1.60-1.49(m,2H),1.38-1.28(m,2H),0.90(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ99.57,79.30,74.20,72.97,72.20,71.80,70.44,63.25,56.15,32.15,19.30,14.02.HRMS(ESI)m / z calcd for C 12 H 24 O7Na + [M+Na] + 303.15255 found 303.15220.

[0118] (7) The preparation of (2S,3S,4S,5S,6R,7S)-6-butoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4,6-triol was carried out via the following synthetic route:

[0119]

[0120] Compound 8 (187 mg, 0.67 mmol) was dissolved in 0.7 mL of anhydrous pyridine and stirred at room temperature for 10 minutes. Then, triphenylmethyl chloride (210 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction system was then heated to 70 °C and reacted at this temperature for 8 hours. TLC monitoring revealed that a small amount of starting material remained. The reaction system was quenched with methanol, and the reaction solution was azeotropically treated with toluene, evaporated to dryness, extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The aqueous layer was directly evaporated to dryness. The crude aqueous layer was purified by column chromatography (ethyl acetate / methanol = 10:1) to obtain starting material 105 (20 mg). The crude organic layer was purified by column chromatography (ethyl acetate) to obtain compound 8 (325 mg, 89%), a white solid. The TLC solvent was dichloromethane:methanol = 10:1.

[0121] MPa 139-140℃; [a] D 20 = +1.0 (c = 1.0 in MeOH); 1 H NMR (300MHz, Chloroform-d)δ

[0122] 7.57-7.33(m,15H),4.82(s,1H),4.19(q,J=7.1Hz,1H),4.05-3.91(m,4H),3.72(t,J=6.7Hz,2H),3.56(d,J=9.9Hz,1 H),3.47-3.40(m,1H),3.37(s,3H),2.82(s,3H),1.66(q,J=7.1Hz,2H),1.33(t,J=7.2Hz,2H),1.00(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ143.71,128.77,127.98,127.24,97.66,87.18,79.93,7 3.71,72.42,72.00,70.69,70.14,64.85,55.74,32.27,19.37,14.04.HRMS(ESI)m / z calcd forC 31 H 38 O7Na+ [M+Na] + 550.26157 found 550.26175.

[0123] (8) Preparation of (2S,3S,4S,5S,6R,7R)-6-butoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4,5-trimethyltriacetate, the synthetic route is as follows:

[0124]

[0125] Compound 9 (500 mg, 0.91 mmol) was dissolved in 1.5 mL of anhydrous pyridine. Acetic anhydride (0.5 mL, 4.55 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) were added at room temperature. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, the reaction system was quenched with water. The mixture was extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 9 (570 mg, 96%) as a white solid. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0126] MPa 10⁴-10⁵℃; [a] D 20 = +59.1 (c = 1.0 in CHCl3); 1 H NMR (300MHz, Chloroform-d) δ7.54-7.47(m,7H),7.37-7.30(m,9H),5.50(t,J=9.0Hz,1H),5.40(dd,J=9. 0,1.9Hz,1H),5.32(dd,J=6.3,3.1Hz,1H),4.92(d,J=3.1Hz,1H),4.25(ddd,J=8.7,5.5,2.6Hz,1H),3.81( dd,J=6.2,2.0Hz,1H),3.78-3.72(m,1H),3.64-3.59(m,1H),3.38(s,3H),3.34-3.31(m,1H),3.30-3.25(m ,1H),2.21(s,3H),2.09(s,3H),1.86(s,3H),1.67-1.58(m,2H),1.50-1.43(m,2H),0.99(t,J=7.3Hz,3H). 13C NMR(75MHz,Chloroform-d)δ170.11,169.99,169.00,143.51,128.85,127.79,127.10,96.85,86.89,72 .81,72.38,72.31,70.09,69.21,63.18,56.33,32.00,21.09,20.96,20.76,19.14,13.94.HRMS(ESI)m / z calcd forC 37 H 44 O 10 Na + [M+Na] + 671.29170 found 671.29345.

[0127] (9) The preparation of (2S,3S,4S,5S,6R,7R)-6-butoxy-2-(hydroxymethyl)-7-methoxyoxacyclopropane-3,4,5-trimethyltriacetic acid ester was carried out via the following synthetic route:

[0128]

[0129] Compound 10 (537 mg, 0.83 mmol) was dissolved in a mixed solvent of 4 mL acetic acid and 1 mL water, and reacted at 50 °C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 11 (317 mg, 94%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0130] [a] D 20 = +15.6 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ5.40-5.20(m,3H),4.90(d,J=3.7Hz,1H),3.99(ddd,J=8.5,4.9,3.0Hz,1H),3.78(dd,J=6.9,2.2Hz,1H),3.72-3.58( m,3H),3.58-3.46(m,2H),3.44(s,3H),2.27(s,1H),2.14(s,3H),1.51(dt ,J=12.3,6.5Hz,2H),1.35(dd,J=15.2,7.4Hz,2H),0.89(t,J=7.3Hz,3H). 13C NMR(75MHz,Chloroform-d)δ170.27,170.09,169.97,97.69,76.47,72.94,72.49,71.5 9,69.87,69.65,62.85,56.55,32.03,21.08,21.01,20.95,19.20,13.94.HRMS(ESI)m / z calcd forC 18 H 30 O 10 Na + [M+Na] + 429.18515found 429.18390.

[0131] (10) Preparation of (2S,3S,4S,5S,6R,7R)-6-butoxy-7-methoxy-2-((((trifluoromethyl)sulfonyl)oxy)methyl)oxetane-3,4,5-trimethyltriacetate, the synthetic route is as follows:

[0132]

[0133] At -20°C, 2,6-dimethylpyridine (0.225 mL, 1.9 mmol) was dissolved in 5 mL of anhydrous dichloromethane. Trifluoromethanesulfonic anhydride (0.24 mL, 1.4 mmol) was added under argon protection. After 5 minutes, compound 11 (519 mg, 1.28 mmol) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the above reaction system. The reaction was carried out at the above temperature for 30 minutes, monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and dichloromethane, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 12 (437.45 mg, 64%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0134] [a] D 20 = +13.5 (c = 1.0 in CHCl3); 1H NMR(300MHz,Chloroform-d)δ5.74-5.50(m,2H),5.46-5.26(m,1H),4.80-4.65(m,1H) ,4.60-4.47(m,1H),4.36(ddd,J=11.9,5.3,2.5Hz,1H),4.09(dd,J=12.0,2.6Hz,1H), 3.95-3.87(m,1H),3.85-3.75(m,1H),3.67-3.58(m,1H),3.57-3.46(m,3H),2.19(s,3 H),2.14(s,3H),2.06(s,3H),1.69-1.56(m,2H),1.49-1.39(m,2H),1.01-0.92(m,3H). 13 C NMR (75MHz, CDCl3) δ170.03,169.70,169.55,159.75,144.23,137.47,124.18,123.10,97.85,76.33,75.43 ,72.91,72.72,70.14,69.10,68.86,58.35,56.79,32.03,24.44,20.99,20.79,19.19,13.91.HRMS(ESI)m / z calcd forC 19 H 29 F3O 12 Na + [M+Na] + 561.13318 found 561.13323.

[0135] (11) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4R,5S,6R,7S)-3,4,6-triacetoxy-6-butoxy-7-methoxyoxacyclopropane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium trifluoromethanesulfonate, the synthetic route is as follows:

[0136]

[0137] Compound 12 (408 mg, 0.76 mmol) and Compound 12 (470 mg, 1.1 mmol) were dissolved in 3 mL of anhydrous tetrahydrofuran and reacted at room temperature for 24 hours. The reaction was monitored by TLC. After the reaction was complete, the reaction solution was directly evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 80:1) to give Compound 14 (436 mg, 71%), a colorless oil. The TLC solvent was dichloromethane:methanol = 15:1.

[0138] [a] D 20 = +1.2 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.30-7.22(m,10H),7.22-7.14(m,5H),5.31(dd,J=7.3,4.3Hz,1H),5.26(d d,J=8.5,2.4Hz,1H),5.09(t,J=8.9Hz,1H),4.69(d,J=4.3Hz,1H),4.58-4.45(m,6H),4.37(d,J=4.3Hz,2H ),4.34-4.27(m,2H),3.94-3.86(m,4H),3.81-3.70(m,3H),3.55-3.48(m,1H),3.43-3.34(m,1H),3.24(s ,3H),2.09(s,3H),2.06(s,3H),1.96(s,3H),1.62-1.51(m,2H),1.45-1.36(m,2H),0.81(t,J=7.2Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ171.16,169.76,136.89,135.98,128.92,128.8 9,128.72,128.67,128.53,128.35,128.16,128.06,99.01,83.18,82.84,76. 09,73.76,73.01,72.76,72.47,72.44,71.61,68.79,67.61,66.81,66.11,5 7.51,49.73,48.74,32.04,20.95,20.92,20.88,19.18,13.92.HRMS(ESI)m / z calcd forC 46 H 63 O 11 S + [M+] + 809.35688 found 809.35652.

[0139] (12) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4S,5S,6R)-6-butoxy-3,4,5,7-tetrahydroxyoxetane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium chloride (a:b=1:1), the synthetic route is as follows:

[0140]

[0141] Compound 14 (178 mg, 0.22 mmol) was dissolved in 5 mL of methanol, and 1 g of IRA 402 chloride ion exchange resin was added. The mixture was reacted at room temperature for 3 hours. The resin was removed by filtration, and the mixture was washed with methanol. The filtrates were combined and evaporated to dryness to obtain 180 mg of white syrup. The above substance was dissolved in 1 mL of tetrahydrofuran, and 1 mL of 4 mol / L hydrochloric acid was added. The mixture was reacted at 50 °C for 12 hours. TLC was used for monitoring. After the reaction was completed, the reaction solution was evaporated to dryness, and the hydrochloric acid was removed. When the pH of the system was observed to be 7 using pH paper, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / methanol = 5:1) to obtain a mixture 14 (α:β 1:1, 125 mg, 85%) with an anisotropic 1:1 configuration, which was a white syrup. The TLC solvent was dichloromethane:methanol = 10:1.

[0142] 1 H NMR(300MHz, Methanol-d4)δ7.40-7.05(m,15H),4.65-4.53(m,3H),4.53-4.39(m,4H),4.38-4.29(m,1H),4.29-4.22(m,1H),4.14-3.89(m ,3H),3.83-3.59(m,6H),3.59-3.51(m,1H),3.50-3.36(m,3H),3.26- 3.16(m,1H),1.38-1.25(m,2H),1.24-1.15(m,2H),0.94-0.69(m,3H). 13 C NMR(75MHz,Methanol-d4)δ138.52,138.12,137.98,129.70,129.64,129.56,129.40,129.33,129.27,129.12,129.04,74.33,73.9 0,73.26,73.02,71.58,71.18,69.74,69.19,68.05,67.75,67.52,67.38,52.22,45.68,32.97,20.25,14.33,14.23.HRMS(ESI)m / z calcd for C 41 H 57 O9S + [M+] + 669.30918 found 669.30635.

[0143] (13) Preparation of (1R, 2R, 3S, 4S)-1-((2S, 3S, 4S, 5S, 6S)-6-butoxy-2,3,4,7-tetrahydroxyheptyl)-3,4,5-trihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium chloride, the synthetic route is as follows:

[0144]

[0145] Mixture 15 (81 mg, 0.1 mmol) was dissolved in a mixed solvent of 2 mL acetic acid and 0.5 mL methanol. 10% palladium / carbon (200 mg) was added, and hydrogen gas was introduced into the reaction system. The reaction was carried out at 50 °C for 12 hours and monitored by TLC. After the reaction was completed, the reaction solution was filtered with diatomaceous earth. The filter layer was washed with a mixed solvent of water and methanol (volume ratio 1:1). The filtrates were combined and evaporated to dryness to obtain 45 mg of white syrup. The crude product was dissolved in 3 mL of water and stirred in an ice bath for 10 minutes. Sodium borohydride (20 mg, 0.5 mmol) was slowly added, and the reaction was carried out at the above temperature for 1.5 hours. TLC was used for monitoring. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 4. The filtrate was evaporated to dryness, and the crude product was subjected to reversed-phase silica gel column chromatography (Spherical C18 Monomeric, 120A) (water → water / methanol = 50:1) to obtain a colorless amorphous dibutyl-modified neokotalanol derivative (27 mg, 68%). The 1H and 13C NMR spectra were consistent with those reported in the literature. The TLC solvent was ethyl acetate:methanol:water = 10:2:1.

[0146] [a] D 20 = +7.4 (c = 1.0 in MeOH); 1 H NMR(300MHz, Methanol-d4)δ4.67(d,J=2.8Hz,1H),4.42(d,J=2.5Hz,1H),4.21(s,1H),4.14- 4.08(m,1H),4.05(d,J=4.8Hz,1H),4.01(s,1H),3.99(s,1H),3.96(d,J=2.9Hz,2H),3.91(d, J=2.5Hz,2H),3.85-3.76(m,1H),3.70(q,J=4.5,4.0Hz,3H),3.66-3.61(m,1H),3.51(d,J=8. 5Hz,1H),3.49-3.38(m,1H),1.61(p,J=6.5Hz,2H),1.49-1.38(m,2H),0.97(t,J=7.3Hz,3H). 13C NMR(75MHz,Methanol-d4)δ79.46,79.26,73.73,73.51,72.55,69.82,69.68,64.21,61.06,52.73,51.98,33.55,20.39,14.36.HRMS(ESI)m / z calcd for C 20 H 41 O9S + [M+] + 401.18398 found 401.18344.

[0147] Example 3

[0148] The neokotalanol derivative of this invention includes the following steps:

[0149] Steps (1) to (3) are the same as in Example 1.

[0150] (4) The preparation of (2S,3S,4R,5S,6R,7R)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-5-butoxy-7-methoxyoxacyclopropane-6-ol is carried out via the following synthetic route:

[0151]

[0152] Compound 5 (3 g, 6 mmol) was dissolved in 72 mL of LMF. At room temperature, 480 mg of 2 eq NaH and 0.78 mL of 1.2 eq n-butyl bromide were slowly added to the solution, and the solution changed from pale yellow to orange. The reaction was carried out at the above temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, the mixture was quenched with water in an ice bath, extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound 6 (3.15 g, 91%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0153] 1H NMR(300MHz,Chloroform-d)δ7.47-7.27(m,11H),7.23(d,J=3.7Hz,2H),7.12(dd,J=6.8,3.0Hz,2H), 4.91(q,J=4.9,4.4Hz,1H),4.79(q,J=12.1Hz,2H),4.57(d,J=12.2Hz,1H),4.45(dt,J=11.9,4.8Hz,2H ),4.23-4.08(m,2H),4.01(s,2H),3.87(dt,J=8.9,4.3Hz,1H),3.71(dt,J=10.1,6.3Hz,1H),3.57(dq ,J=9.0,6.2,4.6Hz,3H),3.46(d,J=6.1Hz,4H),1.39-1.34(m,2H),1.26(s,2H),0.91(d,J=7.8Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ138.64,138.36,137.91,128.47,128.31,128.16,127.81,127.62,98.83,80.2 8,78.64,78.53,73.64,73.28,72.77,71.88,71.38,69.54,69.25,56.44,32.13,19.31,13.99.HRMS(ESI)m / z calcd for C 37 H 50 O7Na + [M+Na] + 578.29305 found 578.28314.

[0154] (5) Preparation of (2S,3S,4S,5S,6R,7R)-5-butyl-2-(hydroxymethyl)-7-methoxyoxacyclopropane-3,4,6-triol, the synthetic route is as follows:

[0155]

[0156] Compound 6 (2.7 g, 4.85 mmol) was dissolved in 10 mL of methanol, and 10% palladium / carbon (500 mg) was added. Hydrogen gas was bubbled into the reaction system, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filter layer was washed with methanol, the filtrates were combined and evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate / methanol = 10:1) to give compound 7 (1.24 mg, 91%), a white solid. The TLC solvent was dichloromethane:methanol = 10:1.

[0157] Mp123-124℃; [a] D 20 = +17.3 (c = 1.0 in MeOH); 1 H NMR(300MHz,Chloroform-d)δ4.93(brs,1H),4.84-4.65(m,1H),4.33(brs,1H),4.19(d,J=6.8Hz,1H),3.88(m,4H),3.70(q,J=8.0,7 .0Hz,3H),3.51-3.45(m,1H),3.42(s,J=7.5Hz,3H),1.50(q,J=7.1Hz,2H),1.29(dq,J=12.4,6.5,5.4Hz,2H),0.88(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ99.57,79.30,74.20,72.97,72.20,71.80,70.44,63.25,56.15,32.15,19.30,14.02.HRMS(ESI)m / z calcd for C 16 H 32 O7Na + [M+Na] + 303.15220 found 303.14090.

[0158] (6) The preparation of (2S,3S,4S,5S,6R,7S)-5-butoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4,6-triol was carried out via the following synthetic route:

[0159]

[0160] Compound 7 (187 mg, 0.67 mmol) was dissolved in 0.7 mL of anhydrous pyridine and stirred at room temperature for 10 minutes. Then, triphenylmethyl chloride (210 mg, 0.74 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction system was then heated to 70 °C and reacted at this temperature for 8 hours. TLC monitoring revealed that a small amount of starting material remained. The reaction system was quenched with methanol, and the reaction solution was azeotropically treated with toluene, evaporated to dryness, extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The aqueous layer was directly evaporated to dryness. The crude aqueous layer was purified by column chromatography (ethyl acetate / methanol = 10:1) to obtain starting material 105 (20 mg). The crude organic layer was purified by column chromatography (ethyl acetate) to obtain compound 8 (325 mg, 89%), a white solid. The TLC solvent was dichloromethane:methanol = 10:1.

[0161] MPa 139-140℃; [a] D 20 = +1.0 (c = 1.0 in MeOH); 1 H NMR(300MHz,Chloroform-d)δ7.63-7.31(m,15H),4.85(d,J=3.1Hz,1H),4.23(d,J=6.9Hz,1H),4.08-3.95(m,3H),3.80-3.71(m,2H),3. 60-3.49(m,2H),3.41(s,3H),3.38-3.27(m,1H),3.12(s,1H),2.91(s,2H),1.64-1.54(m,2H),1.43-1.35(m,2H),0.94(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ143.67,128.67,128.08,127.32,99.23,87.09,79.33,7 3.67,72.62,72.54,71.34,70.51,65.12,56.24,32.14,19.32,13.97.HRMS(ESI)m / z calcd forC 35 H 46 O7Na + [M+Na] + 545.26175 found 545.25005.

[0162] (7) Preparation of (2S,3S,4S,5S,6R,7R)-5-butoxy-7-methoxy-2-((tributoxy)methyl)oxacyclopropane-3,4,6-trimethyltriacetate, the synthetic route is as follows:

[0163]

[0164] Compound 8 (500 mg, 0.91 mmol) was dissolved in 1.5 mL of anhydrous pyridine. Acetic anhydride (0.5 mL, 4.55 mmol) and 4-dimethylaminopyridine (12 mg, 0.09 mmol) were added at room temperature. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by TLC. After the reaction was completed, the reaction system was quenched with water. The mixture was extracted three times with water and ethyl acetate, and washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 9 (578 mg, 96%) as a white solid. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0165] MPa 10⁴-10⁵℃; [a] D 20 = +59.1 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.49-7.43(m,7H),7.30-7.21(m,9H),5.50(dd,J=7.0,2.5Hz,1H),5.4 6-5.35(m,2H),4.70(d,J=3.8Hz,1H),4.39(ddd,J=8.9,4.3,2.2Hz,1H),3.82(dd,J=7.0,3.8Hz,1H) ,3.78-3.68(m,1H),3.61-3.51(m,1H),3.43(s,3H),3.33-3.26(m,1H),3.07(dd,J=10.1,4.4Hz,1H) ,2.18(s,3H),1.98(s,3H),1.67(s,3H),1.58-1.49(m,2H),1.44-1.32(m,3H),0.90(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ170.55,170.10,168.92,143.64,128.91,127.72,127.00,99.21,86.51,73 .38,72.40,70.19,69.92,69.86,63.63,56.33,32.03,21.19,20.90,20.73,19.18,13.93.HRMS(ESI)m / z calcd for C 39 H 50 O9Na + [M+Na] + 671.29345 found 671.28116.

[0166] (8) Preparation of (2S,3S,4S,5S,6R,7R)-5-oxy-2-(hydroxymethyl)-7-methoxyoxetine-3,4,6-trimethyltriacetate, the synthetic route is as follows:

[0167]

[0168] Compound 9 (550 mg, 0.83 mmol) was dissolved in a mixed solvent of 4 mL acetic acid and 1 mL water, and reacted at 50 °C for 8 hours. The reaction was monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give compound 10 (328 mg, 94%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0169] [a] D 20 = +15.6 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ5.40-5.20(m,3H),4.90(d,J=3.7Hz,1H),3.99(ddd,J=8.5,4.9,3.0Hz,1H),3.78(dd,J=6.9,2.2Hz,1H),3.72-3.58( m,3H),3.58-3.46(m,2H),3.44(s,3H),2.27(s,1H),2.14(s,3H),1.51(dt ,J=12.3,6.5Hz,2H),1.35(dd,J=15.2,7.4Hz,2H),0.89(t,J=7.3Hz,3H). 13 C NMR(75MHz,Chloroform-d)δ171.71,170.91,170.45,128.02,99.38,77.58,77.16,76.74,76.58,74.9 4,73.46,70.21,70.13,69.82,65.28,56.16,32.03,21.15,21.05,20.98,19.22,13.98.HRMS(ESI)m / z calcd for C 20 H 36 O9Na + [M+Na] + 429.18390 found 429.17242.

[0170] (9) Preparation of (2S,3S,4S,5S,6R,7R)-5-butoxy-7-methoxy-2-((((trifluoromethyl)sulfonyl)oxy)methyl)oxetane-3,4,6-trimethyltriacetate, the synthetic route is as follows:

[0171]

[0172] At -20°C, 2,6-dimethylpyridine (0.225 mL, 1.9 mmol) was dissolved in 5 mL of anhydrous dichloromethane. Trifluoromethanesulfonic anhydride (0.24 mL, 1.4 mmol) was added under argon protection. After 5 minutes, compound 10 (519 mg, 1.28 mmol) was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the above reaction system. The reaction was carried out at the above temperature for 30 minutes, monitored by TLC. After the reaction was complete, water was added to quench the reaction mixture. The mixture was extracted three times with water and dichloromethane, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 11 (437.45 mg, 64%), a colorless oil. The TLC solvent was petroleum ether / ethyl acetate = 2:1.

[0173] [a] D 20 = +13.5 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ5.74-5.50(m,2H),5.46-5.26(m,1H),4.80-4.65(m,1H) ,4.60-4.47(m,1H),4.36(ddd,J=11.9,5.3,2.5Hz,1H),4.09(dd,J=12.0,2.6Hz,1H), 3.95-3.87(m,1H),3.85-3.75(m,1H),3.67-3.58(m,1H),3.58-3.47(m,3H),2.19(s,3 H),2.14(s,3H),2.06(s,3H),1.69-1.56(m,2H),1.49-1.39(m,2H),1.01-0.92(m,3H). 13 C NMR (75MHz, CDCl3) δ170.88,170.38,170.00,169.38,99.41,76.36,73.60,72.24,69.8 5,69.61,68.43,63.96,56.12,31.95,20.99,20.89,20.81,19.12,13.88.HRMS(ESI)m / z calcd for C 21 H 35 F3O 11 Na + [M+Na] + 561.13318 found 561.12228.

[0174] (10) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4R,5S,6R,7S)-3,4,6-triacetoxy-5-butoxy-7-methoxyoxacyclopropane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium trifluoromethanesulfonate, the synthetic route is as follows:

[0175]

[0176] Compound 11 (408 mg, 0.76 mmol) and compound 12 (470 mg, 1.1 mmol) were dissolved in 3 mL of anhydrous tetrahydrofuran and reacted at room temperature for 24 hours, monitored by TLC. After the reaction was complete, the reaction solution was directly evaporated to dryness, concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane / methanol = 80:1) to give compound 13 (436 mg, 71%), a colorless oil. The TLC solvent was dichloromethane:methanol = 15:1.

[0177] [a] D 20 = +1.2 (c = 1.0 in CHCl3); 1 H NMR(300MHz,Chloroform-d)δ7.33-7.15(m,12H),7.15-7.03(m,3H),5.53-5.32(m,2H),5.04(t,J=8.9Hz,1H ),4.70(ddt,J=8.5,6.1,3.2Hz,1H),4.64-4.56(m,2H),4.54(s,1H),4.51-4.44(m,3H),4.43-4.35(m,1H),4 .33-4.19(m,2H),4.16-3.99(m,1H),3.93(dd,J=13.7,4.0Hz,1H),3.86-3.60(m,5H),3.55-3.39(m,2H),3.3 9-3.32(m,1H),3.31(s,3H),2.11-1.90(m,9H),1.62-1.50(m,2H),1.39-1.28(m,2H),0.86(t,J=7.3Hz,3H). 13C NMR(75MHz,Chloroform-d)δ171.08,170.33,169.98,137.04,136.25,136.20,129.10 ,129.03,128.91,128.78,128.71,128.57,128.39,128.20,100.55,83.65,82.72,77.7 9,77.36,76.94,76.66,74.03,72.78,72.59,71.92,71.73,70.90,69.52,67.86,67.12 ,66.78,57.52,49.80,49.32,32.22,21.03,20.99,20.93,19.40,14.12.HRMS(ESI)m / z calcd for C 46 H 63 O 11 S + [M+] + 809.35652found809.35505.

[0178] (11) Preparation of (1S,2R,3S,4S)-3,4-bis(benzyloxy)-2-(benzyloxy)methyl)-1-(((3S,4S,5S,6R)-5-butoxy-3,4,6-trihydroxyoxetane-2-yl)methyl)tetrahydro-1H-thiophene-1-onium chloride (a:b=1:1), the synthetic route is as follows:

[0179]

[0180] Compound 13 (178 mg, 0.22 mmol) was dissolved in 5 mL of methanol, and 1 g of IRA 402 chloride ion exchange resin was added. The mixture was reacted at room temperature for 3 hours. The resin was removed by filtration, and the mixture was washed with methanol. The filtrates were combined and evaporated to dryness to obtain 180 mg of white syrup. The above substance was dissolved in 1 mL of tetrahydrofuran, and 1 mL of 4 mol / L hydrochloric acid was added. The mixture was reacted at 50 °C for 12 hours. TLC was used for monitoring. After the reaction was completed, the reaction solution was evaporated to dryness, and the hydrochloric acid was removed. When the pH of the system was observed to be 7 using pH paper, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / methanol = 5:1) to obtain a mixture 14 (α:β 1:1, 125 mg, 85%) with an anisotropic 1:1 configuration, which was a white syrup. The TLC solvent was dichloromethane:methanol = 10:1.

[0181] 1H NMR (300MHz, Methanol-d4) δ7.43-7.24 (m, 15H), 4.70 (d, J = 3.9Hz, 3H), 4.64-4.5 3(m,4H),4.49(t,J=6.8Hz,2H),4.39(dq,J=8.5,4.4,3.7Hz,1H),4.27-4.02(m,2H ),3.91(td,J=12.2,9.5,5.7Hz,5H),3.84-3.73(m,2H),3.71-3.52(m,3H),3.52-3 .43(m,1H),1.62(dt,J=9.2,6.1Hz,2H),1.48-1.31(m,2H),0.96(t,J=7.4Hz,3H). 13 C NMR(75MHz,Methanol-d4)δ138.52,138.12,137.98,129.70,129.64,129.56,129.40,129.33,129.27,129.12,129.04,74.33,73.9 0,73.26,73.02,71.58,71.18,69.74,69.19,68.05,67.75,67.52,67.38,52.22,45.68,32.97,20.25,14.33,14.23.HRMS(ESI)m / z calcd forC 41 H 57 O9S + [M+] + 669.30918 found 669.30635.

[0182] (12) Preparation of (1R, 2R, 3S, 4S)-1-((2S, 3S, 4S, 5S, 6S)-5-butoxy-2,3,4,7-tetrahydroxyheptyl)-3,4,6-trihydroxy-2-(hydroxymethyl)tetrahydro-1H-thiophene-1-onium chloride, the synthetic route is as follows:

[0183]

[0184] Mixture 14 (81 mg, 0.1 mmol) was dissolved in a mixed solvent of 2 mL acetic acid and 0.5 mL methanol. 10% palladium / carbon (200 mg) was added, and hydrogen gas was introduced into the reaction system. The reaction was carried out at 50 °C for 12 hours and monitored by TLC. After the reaction was completed, the reaction solution was filtered with diatomaceous earth. The filter layer was washed with a mixed solvent of water and methanol (volume ratio 1:1). The filtrates were combined and evaporated to dryness to obtain 35 mg of white syrup. The crude product was dissolved in 3 mL of water and stirred in an ice bath for 10 minutes. Sodium borohydride (20 mg, 0.5 mmol) was slowly added, and the reaction was carried out at the above temperature for 1.5 hours. TLC was used for monitoring. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 4. The filtrate was evaporated to dryness, and the crude product was subjected to reversed-phase silica gel column chromatography (Spherical C18 Monomeric, 120A) (water → water / methanol = 50:1) to obtain a colorless amorphous dibutyl-modified neokotalanol derivative (27 mg, 68%). The 1H and 13C NMR spectra were consistent with those reported in the literature. The TLC solvent was ethyl acetate:methanol:water = 10:2:1.

[0185] [a] D 20 = +7.4 (c = 1.0 in MeOH); 1 H NMR (300MHz, Methanol-d4) δ4.66 (s, 1H), 4.22-3.97 (m, 2H), 3.89 (d, J = 8.2Hz, 3H), 3.82-3.72 (m, 5H), 3.71-3.60 (m, 3H),3.38(s,1H),2.94-2.81(m,1H),2.81-2.67(m,1H),1.69-1.55(m,2H),1.49-1.35(m,2H),0.97(t,J=7.2Hz,3H). 13 C NMR (75MHz, Methanol-d4) δ79.93,74.58,72.58,72.47,72.28,71.74,71.23,70. 13,62.43,60.18,37.07,36.97,33.39,23.43,20.27,14.32.HRMS(ESI)m / zcalcd for C 20 H 41 O9S + [M+] + 401.18398 found 401.18314.

[0186] Performance Characterization

[0187] (1) Preparation of mouse-derived α-glucosidase

[0188] Ten SD rats (5 males, 140g-160g; 5 females, 120g-140g) were fasted (with continuous water supply) for 72 hours to empty their small intestines. The rats were euthanized by cervical vertebrae dislocation, and the small intestine was separated from the abdominal cavity. The small intestine contents were rinsed clean with ice-cold saline. The rinsed small intestine was placed on an ice plate and longitudinally cut open. The small intestinal mucosa was gently scraped off with a glass slide, and the resulting tissue was homogenized using a tissue homogenizer until no obvious tissue remained. The homogenized tissue was collected and an equal volume of saline was added. The mixture was placed in a centrifuge tube and centrifuged at 4000 rpm for 15 minutes at below 4°C. The supernatant was collected, sealed, and refrigerated. Long-term storage requires -20°C.

[0189] (2) Construction of the glucose concentration / absorbance standard curve

[0190] A 30.5 mM glucose standard solution was prepared and diluted with serial dilution and 1 / 2 dilution methods to obtain glucose solutions with concentrations of 0.1 mM, 1 mM, 10 mM, 20 mM, and 30 mM, respectively. The absorbance was measured using the glucose oxidase method, and a standard curve was plotted using GraphPad. The absorbance of each concentration was measured using the glucose oxidase-peroxidase method at an absorption wavelength of 490 nm. Three parallel measurements were performed, and the average absorbance was taken. A concentration-absorbance standard curve was plotted using GraphPad-prism, and the regression equation was calculated as Y = 0.03890*X + 0.05890 (R square = 0.9991).

[0191] (3) Preparation of the test sample solution

[0192] Weigh 1–2 mg of the test derivative and prepare a 1 mM solution with 0.1 mol / L phosphate buffer (pH 6.8). Serially dilute this solution to 20 μM, 10 μM, 1 μM, 0.5 μM, and 0.1 μM solutions. Roughly determine the IC50 value of each derivative using these six concentration groups. Then, divide the derivative into six groups based on the IC50 concentration for further IC50 determination.

[0193] (4) Determination of glucose production

[0194] Mix 50 ml of substrate, 25 ml of enzyme solution, and 25 ml of sample solution and incubate at 37°C for 30 minutes. After incubation, immediately immerse the 96-well plate in boiling water to quench the enzymatic reaction. Then, measure the absorbance of each well using the glucose oxidase-peroxidase method. Substitute the obtained absorbance values ​​into the standard curve above to determine the glucose concentration C produced.

[0195] (5) Data Processing

[0196] The glucose concentration in the blank control group was set to 100% activity, and the inhibition rate for each sample concentration was calculated. The obtained inhibition rates and corresponding sample concentrations were used to calculate the IC50 of the analyte derivative using GraphPad-prism. 50 value.

[0197] (6) Results and Discussion

[0198] The inhibitory activities of the butyl-substituted compound L-19-A on maltase and sucrase are shown in Table 1. Experimental data show that L-19-A exhibits stronger maltase inhibitory activity than the positive control drug voglibose, and better activity than the natural product neokotalanol (IC50 4.8 μM).

[0199] Table 1

[0200]

Claims

1. A method for preparing neokotalanol, characterized in that, Includes the following steps: (1) Compound 7 undergoes a reduction reaction to remove the benzyl group, yielding intermediate compound 8; (2) Intermediate compound 8 undergoes a selective substitution reaction with triphenylmethyl chloride to replace the primary hydroxyl group at position 7, yielding intermediate compound 9; (3) Intermediate compound 9 reacts with an acid anhydride reagent to protect the remaining hydroxyl groups, yielding intermediate compound 10; (4) The intermediate compound 10 was detriphenylened to obtain the intermediate compound 11; (5) Intermediate compound 11 reacts with trifluoromethanesulfonic anhydride to give trifluoromethanesulfonyl-protected coupling precursor 12; (6) The coupling precursor 12 reacts with the benzyl-protected pentazose compound 13 to give the coupling product 14; (7) The coupling product 14 is converted into chloride ions by ion exchange resin and then hydrolyzed to obtain intermediate 15. (8) Intermediate 15 undergoes a reduction reaction to remove benzyl, and then undergoes further reduction to obtain the final product 16; The synthesis route is as follows: ， Wherein, R1 is H, R2 is H, and R3 is an alkyl group.

2. The method for preparing neokotalanol according to claim 1, characterized in that, In step (2), the reaction solvent and base are anhydrous pyridine, and the reaction temperature is 50~120℃.

3. The method for preparing neokotalanol according to claim 1, characterized in that, In step (6), the reaction solvent is tetrahydrofuran, and the reaction temperature is 15~30℃.

4. The method for preparing neokotalanol according to claim 1, characterized in that, In step (1) or (8), the benzyl removal reaction uses hydrogen as a reducing agent, palladium on carbon as a catalyst, the reaction temperature is 20~80℃, and the reaction time is 12~24h.

5. The method for preparing neokotalanol according to claim 1, characterized in that, In step (8), the reduction reaction uses sodium borohydride as the reducing agent, the reaction temperature is 0~30℃, and the reaction time is 0.5~5 h.

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