Polyhydroxy pyrrolidine derivative, pharmaceutically acceptable salt and synthetic method thereof, glycosidase inhibitor and application of glycosidase inhibitor

Abstract

The invention relates to the technical field of glycosidase inhibitors, and discloses a polyhydroxy pyrrolidine derivative, pharmaceutically acceptable salts thereof, a synthesis method, a glycosidase inhibitor and application. The derivative has a chemical structure as shown in a formula (1): # imgabs0 #, wherein R1 is selected from substituted or unsubstituted C5-C20 alkyl; r2, R3 and R4 are respectively and independently selected from H and substituted or unsubstituted benzyl; wherein a substituent group in the substituted benzyl is selected from alkoxy of C1-C6, alkyl of C1-C6, hydroxyl, nitryl or halogen; r5 is selected from H or carbobenzoxy; wherein in the formula (1), the spatial configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are respectively and independently R or S. The polyhydroxy pyrrolidine derivative and the pharmaceutically acceptable salt thereof prepared by the invention can be applied to a glycosidase inhibitor, have higher inhibitory activity on beta-glucosidase and beta-galactosidase, and can be applied to the field of medicine preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of glycosidase inhibitors, and in particular to a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, a synthesis method thereof, and a glycosidase inhibitor and application thereof. Background Art

[0002] Iminosugars are widely distributed in plants. Natural iminosugars can be divided into polyhydroxypyrrolidine, polyhydroxypiperidine, polyhydroxyindolizidine, polyhydroxypyrrolizidine and polyhydroxydemethyltropane according to their skeleton structures. They show good inhibitory activity against different glycosidases. For example, schoenolamine is a series of natural products isolated from schoenolamine. It has good inhibitory activity against β-glucosidase and β-galactosidase, while its enantiomer shows good α-glucosidase inhibitory activity. Such characteristics make it have potential medicinal value in antiviral, treatment of lysosomal storage diseases, Gaucher disease and diabetes. Therefore, it is necessary to obtain a polyhydroxypyrrolidine compound for in-depth research. Summary of the invention

[0003] The purpose of the present invention is to overcome the problem of low inhibitory activity on glycosidases in the prior art, especially low inhibitory activity on β-glucosidase and β-galactosidase, and to provide a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, a synthesis method, a glycosidase inhibitor and an application thereof.

[0004] In order to achieve the above object, the first aspect of the present invention provides a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, wherein the derivative has a chemical structure shown in formula (1):

[0005]

[0006] Among them, R 1 is selected from substituted or unsubstituted C 5 -C 20 alkyl;

[0007] R 2 , R 3 and R 4 Each is independently selected from H, substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, hydroxy, nitro or halogen;

[0008] R 5 is selected from H or benzyloxycarbonyl;

[0009] In formula (1), the stereo configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are each independently R or S.

[0010] The second aspect of the present invention provides a method for synthesizing a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, the method comprising:

[0011] (1) subjecting the compound represented by formula (2) to an addition reaction with an organic metal reagent having an R1 group in the presence of a catalyst and a first solvent; optionally, subjecting the product obtained by the addition reaction to a deprotection reaction in the presence of a base and a second solvent to obtain a compound represented by formula (3);

[0012]

[0013] Among them, R 2’ , R 3’ , R 4’ Each is independently selected from substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, hydroxy, nitro or halogen;

[0014] R 5’ is benzyloxycarbonyl;

[0015] (2) in the presence of a second solvent, contacting the compound represented by formula (3) with a deprotection agent, a hydrogen source and an acidic substance to carry out a hydrogenation reaction to obtain a derivative represented by formula (1) and a pharmaceutically acceptable salt thereof;

[0016]

[0017] Among them, R 1 , R 2 , R 3 , R 4 , R 5 The definition of is the same as that described in the first aspect of the present invention.

[0018] The third aspect of the present invention provides a polyhydroxypyrrolidine derivative prepared by the method described in the second aspect of the present invention and a pharmaceutically acceptable salt thereof.

[0019] The fourth aspect of the present invention provides a use of the polyhydroxypyrrolidine derivative and the pharmaceutically acceptable salt thereof according to the first aspect of the present invention and / or the third aspect of the present invention in the preparation of a drug;

[0020] Preferably, the drug is selected from at least one of the following drugs: drugs for preventing and / or treating diabetes, drugs for preventing and / or treating Gaucher's disease, drugs for preventing and / or treating lysosomal storage diseases, and / or drugs for treating tumors; antiviral drugs.

[0021] The fifth aspect of the present invention provides a glycosidase inhibitor, wherein the active ingredient contained in the glycosidase inhibitor includes the polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof described in the first aspect of the present invention and the third aspect of the present invention.

[0022] The sixth aspect of the present invention provides a use of the glycosidase inhibitor according to the fifth aspect of the present invention in inhibiting glycosidase,

[0023] Preferably, the glycosidase is selected from at least one of the group consisting of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α-L-fucosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase, preferably β-glucosidase and / or β-galactosidase, more preferably β-glucosidase and / or β-galactosidase derived from bovine liver for inhibiting.

[0024] Through the above technical scheme, the polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof prepared in the present invention can be applied to glycosidase inhibitors, have high inhibitory activity of β-glucosidase and β-galactosidase, and can be used in the field of drug preparation. DETAILED DESCRIPTION

[0025] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0026] In the present invention, the terms involved are uniformly interpreted as follows:

[0027] R and S represent two opposite absolute configurations known in the field of organic chemistry.

[0028] The carbon atoms at positions 1, 2, 3, 4, 5 and 6 represent the carbon atoms indicated in the compound represented by formula (1).

[0029] "Number (or number + a) + R or S" represents the carbon atom with the corresponding absolute configuration in formula (1), such as: 1S represents the carbon atom at position 1 with an absolute configuration of S in formula (1); 6R represents the carbon atom at position 6 with an absolute configuration of R in formula (1).

[0030] The first aspect of the present invention provides a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, wherein the compound has a chemical structure shown in formula (1):

[0031]

[0032] Among them, R 1 is selected from substituted or unsubstituted C 5 -C 20 alkyl;

[0033] R 2 , R 3 and R 4 Each is independently selected from H, substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, hydroxy, nitro or halogen;

[0034] R 5 is selected from H or benzyloxycarbonyl;

[0035] In formula (1), the stereo configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are each independently R or S.

[0036] In some embodiments of the present invention, preferably, in formula (1), R 1 is selected from substituted or unsubstituted C 5 -C 14 alkyl;

[0037] R 2 , R 3 and R 4 are each independently selected from H, substituted or unsubstituted benzyl, wherein the substituent in the substituted benzyl is selected from C 1 -C 4 Alkoxy, C 1 -C 4 Alkyl, hydroxy, nitro or halogen;

[0038] Preferably, R 2 , R 3 and R 4 All are hydrogen or all are benzyl;

[0039] More preferably, R 2 , R 3and R 4 All are hydrogen;

[0040] And / or, the stereo configuration of carbon atoms at positions 2, 3, 4, 5 and 6 of the compound is selected from "2R, 3R, 4R, 5R, 6S", "2R, 3R, 4R, 5R, 6R".

[0041] In some embodiments of the present invention, preferably, the derivative is selected from one of formula (1-1) to formula (1-20):

[0042]

[0043]

[0044] More preferably, the derivative is selected from one of formula (1-1) to formula (1-10) and formula (1-14) to formula (1-20); the above 16 compounds can achieve the technical effect of having high inhibitory activity against β-glucosidase and β-galactosidase derived from bovine liver.

[0045] The second aspect of the present invention provides a method for synthesizing a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, the method comprising:

[0046] (1) subjecting the compound represented by formula (2) to an addition reaction with an organic metal reagent having an R1 group in the presence of a catalyst and a first solvent; optionally, subjecting the product obtained by the addition reaction to a deprotection reaction in the presence of a base and a second solvent to obtain a compound represented by formula (3);

[0047]

[0048] Among them, R 2’ , R 3’ , R 4’ Each is independently selected from substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, hydroxy, nitro or halogen;

[0049] R 5’ is benzyloxycarbonyl;

[0050] (2) in the presence of a second solvent, contacting the compound represented by formula (3) with a deprotection agent, a hydrogen source and an acidic substance to carry out a hydrogenation reaction to obtain a derivative represented by formula (1) and a pharmaceutically acceptable salt thereof;

[0051]

[0052] Among them, R 1 , R 2 , R 3 , R 4 , R 5 The definition of is the same as that described in the first aspect of the present invention.

[0053] In some embodiments of the present invention, preferably, in step (1), the organometallic reagent is selected from at least one of an organomagnesium reagent, an organozinc reagent, an organolithium reagent and an organocopper reagent, preferably an organomagnesium reagent and / or an organozinc reagent;

[0054] In some embodiments of the present invention, preferably, the catalyst is selected from CuI, BuBr or CuCl, preferably CuI;

[0055] In some embodiments of the present invention, preferably, the first solvent is selected from aprotic solvents, preferably at least one of diethyl ether, tetrahydrofuran, dioxane and dichloromethane, more preferably tetrahydrofuran and / or dioxane;

[0056] In some embodiments of the present invention, preferably, the base is selected from KOH, NaOH or Ca(OH) 2 , preferably KOH;

[0057] In some embodiments of the present invention, preferably, relative to 1 g of the compound represented by formula (2), the amount of the first solvent used is 2-200 mL, more preferably 30-50 mL;

[0058] In some embodiments of the present invention, preferably, the molar ratio of the compound represented by formula (2) to the organic metal reagent is 1:(1.2-50), preferably 1:(1.2-3); this molar ratio range can enable step (1) to achieve the technical effect of fully reacting the compound represented by formula (2) to generate a sufficient amount of reaction intermediates.

[0059] In some embodiments of the present invention, preferably, the temperature of the addition reaction is -20°C to 50°C, preferably -10°C to 0°C; this temperature range can achieve the technical effect of lowering the temperature of the reaction system in step (1), so that the substances therein do not spray outward, thereby reducing the loss of reactants and products; the time of the addition reaction is 0.5-3h, preferably 0.5-1h;

[0060] In some embodiments of the present invention, preferably, the temperature of the deprotection reaction is 55-120°C, preferably 60-100°C; this temperature range can achieve the technical effect of fully reacting step (1) and maximizing the yield of the compound represented by formula (3); the time of the deprotection reaction is 6-18h, preferably 6-12h.

[0061] In some embodiments of the present invention, preferably, in step (2), the deprotection agent is selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide, platinum black, trimethylsilyl iodide, boron trichloride, boron tribromide, aluminum chloride and zinc / ammonium chloride, preferably selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, boron trichloride and boron tribromide;

[0062] In some embodiments of the present invention, preferably, when the deprotecting agent is selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide and platinum black, the mass ratio of the compound represented by formula (3) to the deprotecting agent is 1:(0.1-5), preferably 1:(0.1-0.2); this molar ratio range can enable step (1) to achieve the technical effect of fully reacting the compound represented by formula (3) to generate a sufficient amount of the derivative represented by formula (1) and its pharmaceutically acceptable salt.

[0063] In some embodiments of the present invention, preferably, when the deprotecting agent is selected from at least one of trimethylsilyl iodide, boron trichloride, boron tribromide, aluminum chloride and zinc / ammonium chloride, the molar ratio of the compound represented by formula (3) to the deprotecting agent is 1:(1-20), preferably 1:(5-10); this molar ratio range can achieve the technical effect of fully reacting the compound represented by formula (3) in step (1) to generate a sufficient amount of the derivative represented by formula (1) and its pharmaceutically acceptable salt.

[0064] In some embodiments of the present invention, preferably, the hydrogen source is selected from at least one of hydrogen, sodium borohydride and ammonium formate, preferably hydrogen;

[0065] In some embodiments of the present invention, preferably, the acidic substance is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, preferably hydrochloric acid;

[0066] In some embodiments of the present invention, preferably, the molar ratio of the compound represented by formula (3) to the hydrogen source is 1:(5-100), preferably 1:(10-50);

[0067] In some embodiments of the present invention, preferably, the second solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, acetic acid, water, dioxane, methanol, ethanol, acetonitrile, formamide and N,N-dimethylformamide;

[0068] In some embodiments of the present invention, preferably, relative to 1 mg of the compound represented by formula (3), the amount of the second solvent used is 0.02-2 mL, preferably 0.04-1.0 mL;

[0069] In some embodiments of the present invention, preferably, the temperature of the hydrogenation reaction is 0°C to 50°C, preferably 10°C to 30°C; this temperature range can achieve the technical effect of fully reacting step (2) and maximizing the yield of the derivative represented by formula (1) and its pharmaceutically acceptable salt; the time of the addition reaction is 6-100h, preferably 6-48h.

[0070] In some embodiments of the present invention, preferably, in step (1), the organomagnesium reagent is obtained in a homemade manner, and the homemade method comprises: adding magnesium chips, 1-bromohydrocarbon and an initiator to a reaction vessel in the presence of dry tetrahydrofuran and a protective gas, heating to 40-55° C., and reacting for 20-90 minutes to obtain an organomagnesium reagent of 1-bromohydrocarbon.

[0071] The third aspect of the present invention provides a polyhydroxypyrrolidine derivative prepared by the method described in the second aspect of the present invention and a pharmaceutically acceptable salt thereof.

[0072] The fourth aspect of the present invention provides a use of the polyhydroxypyrrolidine derivative and the pharmaceutically acceptable salt thereof according to the first aspect of the present invention and / or the third aspect of the present invention in the preparation of a drug;

[0073] Preferably, the drug is selected from at least one of the following drugs: drugs for preventing and / or treating diabetes, drugs for preventing and / or treating Gaucher's disease, drugs for preventing and / or treating lysosomal storage diseases, and / or drugs for treating tumors, and antiviral drugs.

[0074] The fifth aspect of the present invention provides a glycosidase inhibitor, wherein the active ingredient contained in the glycosidase inhibitor includes the polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof described in the first aspect of the present invention and the third aspect of the present invention.

[0075] The sixth aspect of the present invention provides a use of the glycosidase inhibitor according to the fifth aspect of the present invention in inhibiting glycosidase,

[0076] Preferably, the glycosidase is selected from at least one of the group consisting of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α-L-fucosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase, preferably β-glucosidase and / or β-galactosidase, more preferably β-glucosidase and / or β-galactosidase derived from bovine liver for inhibiting.

[0077] The present invention will be described in detail below through examples. In the following examples, the structures of the compounds are characterized by 300 MHz, 400 MHz or 500 MHz liquid nuclear magnetic resonance and Fourier transform infrared spectrometer; the commercially available nitrone product No.: 2742316|CAS: 537030-19-6 commercialized by J&K Company is used as the starting material for the preparation example.

[0078] Preparation Example

[0079] This embodiment is used to illustrate the preparation method of raw materials 2-4 and 2-5 in the following examples (Zi, D.; Song, YY; Lu, TT; Kise, M.; Kato, A.; Wang, JZ; Jia, YM; Li, YX; Fleet, GWJ; Yu, CY Nanomolar β-glucosidase and β-galactosidase inhibition by enantiomeric α-1-C-alkyl-1,4-dideoxy-1,4-imino-arabinitol derivatives. Eur. J. Med. Chem. 2023, 247, 115056).

[0080]

[0081] At -10°C, commercially purchased nitrone 2-1 (2.0 g) was dissolved in 20 mL of ultra-dry tetrahydrofuran, and vinylmagnesium bromide (9.5 mL) was slowly injected into the reaction system. After reacting at this temperature for 30 minutes, the raw material reacted completely, and 10 mL of saturated ammonium chloride solution was added to the reaction system to quench the reaction. The mixture was extracted three times with ethyl acetate (3×30 mL), and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product 2-2, which could be directly fed to the next step without purification.

[0082] The crude product 2-2 was dissolved in 15 mL of acetic acid, and a catalytic amount of copper acetate dihydrate and zinc powder were added to the reaction. The mixture was reacted at room temperature for 12 hours. The insoluble matter in the reaction system was filtered out with diatomaceous earth, and the acetic acid was removed to obtain a residue. The residue was dissolved in 15 mL of tetrahydrofuran, and sodium bicarbonate was added. Benzyl chloroformate was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. 30 mL of water was added, the mixture was separated, and the mixture was extracted three times with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product 2-3.

[0083] Compound 2-3 was dissolved in 10 mL of dichloromethane, and sodium bicarbonate and m-chloroperbenzoic acid were added to the reaction in sequence. The reaction was allowed to react at room temperature for 2 days. After the reaction of the raw materials was complete, the reaction was quenched with a saturated sodium thiosulfate solution and extracted three times with ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product, which was separated by silica gel column chromatography to obtain compounds 2-4 and 2-5.

[0084] The infrared spectrum and liquid NMR spectrum of the compound shown in formula (2-4) are as follows:

[0085] [α] D 21 -22.2(c 1.3in CH 2 Cl 2 ); ν max 3063w,3030w,2929w,2866w,1703vs,1496w,1453m,1405s,1349s,1256w,1215m,1095s,1028m,735s,697scm -1 ;δH(400MHz,CDCl 3 )7.51-7.20(m,20H),5.27(d,J=12.6Hz,1H),5.12(d,J=12.3Hz,0.5H),5.06(d, J=11.8Hz,0.5H),4.75-4.38(m,7H),4.31-4.27(m,2H),4.11(dd,J=4.3Hz,J=8. 7Hz, 0.5H), 3.81 (dd, J=4.1Hz, J=8.8Hz, 0.5H), 3.65-3.50 (m, 1.5H), 3.44 (d, J= 8.7Hz,0.5H),3.21-2.98(m,2H),2.65(t,J=4.6Hz,0.5H),2.52-2.45(m,0.5H); δ C (100MHz,CDCl 3)154.9,154.8,138.5,138.2,137.6(2C),137.5,137.4,136.3,136.0,133.3,12 9.8,128.7,128.6(2C),128.5(2C),128.4,128.2,128.1,127.8(2C),127.7,127. 6(2C),127.0,84.8,83.5,82.4,81.0,73.2,73.1,71.5,71.4,71.3,71.1,68.5,6 7.6,67.5,67.2,66.9,66.4,63.9,63.6,51.5,51.2,50.9,50.6; HRMS(ESI)calcd for C 36 H 38 NO 6 + [M+H] + m / z 580.2694, found m / z580.2686.

[0086] The infrared spectrum and liquid NMR spectrum of the compound shown in formula (2-5) are as follows:

[0087] [α] D 21 -22.9(c 1.4inCH 2 Cl 2 ); ν max 3063w,3031w,2929w,2863w,1699vs,1496w,1453m,1406s,1350s,1257m,1214m,1094vs,1028m,912w,770w,737s,697s cm -1 ; δ H (400MHz,CDCl 3 )7.47-7.10(m,20H),5.27-5.00(m,2H),4.67-4.52(m,1.5H),4.50-4.29(m,5H),4.24- 4.17(m,0.5H),4.17-4.12(m,1H),4.02(dd,J=3.8Hz,J=8.4Hz,0.5H),3.94(d,J=5.6Hz ,0.5H),3.88(s,1H),3.78(d,J=5.8Hz,0.5H),3.75-3.66(m,0.5H),3.56-3.45(m,1H), 3.41-3.33(m,0.5H),3.22-3.15(m,0.5H),2.70-2.55(m,1.5H),2.54-2.46(m,0.5H); δC (125MHz, CDCl3)155.1,154.7,138.4,138.2,137.6,137.2,136.5,136.4,128.5(2C),128.4,128.1(2C),127.9,127.8(2C),127.7(2C),127 .6,84.6,83.0,82.1,80.7,73.1,71.4,71.3,71.2,71.1,68.4,67.6,67.3,66.2,66.1,63.5,63.3,53.1,52.2,44.2,44.1; HRMS(ESI)calcd for C 36 H 38 NO 6 + [M+H] + m / z 580.2694, found m / z 580.2686.

[0088] The above characterization spectrum results prove that the chemical structures of compounds 2-4 and 2-5 prepared according to the preparation example method are consistent with the chemical structures shown in formula (2-4) and formula (2-5), respectively. Therefore, compounds 2-4 and 2-5 can be used as starting materials in any one of the methods in the following embodiments 1-10 and 11-20, respectively.

[0089] Example 1

[0090] This example is used to illustrate the C6 alkylated polyhydroxypyrrolidine derivative and its preparation method of the present invention.

[0091]

[0092] In the presence of 15 mL of dry tetrahydrofuran and argon, magnesium chips (96 mg, 4 mmol), 1-bromobutane (411.06 mg, 3 mmol) and a grain of iodine (about 50 mg) were added to a two-necked bottle to form a reaction system, and the reaction system was heated to 45°C and reacted for 30 min to obtain an organomagnesium reagent of 1-bromobutane. spare.

[0093] In the presence of 20 mL of dry tetrahydrofuran and CuI (19.5 mg, 0.1 mmol), compound 2-4 was subjected to an addition reaction with an organomagnesium reagent of 1-bromobutane at room temperature for 40 min, and then saturated NH 4 The reaction was quenched with aqueous Cl solution. Ethyl acetate was then added to extract the aqueous phase, and the organic phases were combined and dried by spin drying. Then, 541.5 mg of the compound represented by formula (2-6) was obtained by column chromatography. The yield of this step was 85%;

[0094] In the presence of 20 mL of methanol, the compound represented by formula (2-6) (541.5 mg) was contacted with 54.0 mg of 10% Pd / C, hydrogen and hydrochloric acid (6N, 1 mL) for hydrogenation reaction. The reaction time was 12 hours. The mixture was filtered and the filter cake was discarded to obtain a filtrate. The solvent was removed under reduced pressure of -0.1 MPa to obtain a derivative represented by formula (1-1) and a pharmaceutically acceptable salt thereof, with a yield of 98%.

[0095] The characterization analysis of compound 1-1 is as follows: IR (neat, cm -1 )3371vs,2931m,2360s,2340m,1640m,1404w,1067w,668m; 1 H NMR (400 MHz, D 2 O)δ4.16(t,J=7.3Hz,1H),3.99-3.95(m,1H),3.93-3.89(m,1H),3.85-3.73(m,2H),3.47- 3.42(m,2H),1.54-1.48(m,2H),1.38-1.36(m,1H),1.27-1.17(m,5H),0.80-0.75(m,3H), 13 C{ 1 H}NMR (100MHz, D 2 O)δ74.5,73.3,68.7,63.5,62.1,57.2,32.3,30.6,24.5,21.7,13.2.

[0096] The above characterization spectrum results show that the chemical structure of the compound 1-1 prepared according to the method of Example 1 conforms to the chemical structure shown in formula (1-1). Therefore, the compound 1-1 can be prepared according to the method of Example 1. 1 H NMR and 13 C NMR can characterize compound 1-1. The starting materials of Examples 2-10 have the same molecular formula as that of Example 1, and the only difference is the different configuration of individual carbon atoms. Since the functional groups and reaction conditions for addition reaction and deprotection reaction in each example are conventional operations well known to those skilled in the art and are exactly the same, it can be inferred that the compounds represented by the following formula (1-2) to the compounds represented by the following formula (1-10) can all be successfully synthesized. 1 H NMR and 13 C{ 1 H}NMR can characterize their respective final products.

[0097] Example 2

[0098]

[0099] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromopentane to finally obtain the compound represented by formula (1-2). The yield of this step was 87%.

[0100] The characterization analysis of compound 1-2 is as follows: IR (neat, cm -1 )3343m, 2928m, 2360s, 2339m, 1724w, 1660w, 1629w, 1409w, 1068m; mp 53-56℃; 1 H NMR (400 MHz, D 2 O)δ4.25(t,J=7.1Hz,1H),4.06(t,J=7.7Hz,1H),4.01-3.98(m,1H),3.95-3.82(m,2H),3.58- 3.49(m,2H),1.64-1.56(m,2H),1.51-1.42(m,1H),1.38-1.22(m,7H),0.85(t,J=6.4Hz,3H); 13 C{ 1 H}NMR (100MHz, D 2 O)δ74.5,73.0,68.7,63.6,62.2,57.2,32.4,30.9,28.2,24.9,21.9,13.4.

[0101] The above characterization spectrum results indicate that the chemical structure of compound 1-2 prepared according to the method of Example 2 conforms to the chemical structure shown in formula (1-2). Therefore, compound 1-2 can be prepared according to the method of Example 2.

[0102] Example 3

[0103]

[0104] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromohexane to finally obtain the compound represented by formula (1-3). The yield of this step was 85%.

[0105] The characterization analysis of compounds 1-3 is as follows: IR (neat, cm -1 )3334vs,2926vs,2856m,1585m,1404m,1117m,1069m; mp 83-85℃; 1 H NMR (400 MHz, D 2O) δ4.25(t,J=7.2Hz,1H),4.06(t,J=7.5Hz,1H),4.03-3.96(m,1H),3.92(dd,J=12.9,2.5Hz,1H),3.85(dd,J=12. 6,5.1Hz,1H),3.58–3.49(m,2H),1.79-1.58(m,3H),1.48-1.42(m,1H),1.28-1.22(m,8H),0.85(t,J=6.1Hz,3H); 13 C{ 1 H}NMR (100MHz, D 2 O)74.6,73.3,68.8,63.6,62.2,57.2,32.5,31.1,28.5,28.4,25.0,22.1,13.5.

[0106] The above characterization spectrum results indicate that the chemical structure of compound 1-3 prepared according to the method of Example 3 conforms to the chemical structure shown in formula (1-3). Therefore, compound 1-3 can be prepared according to the method of Example 3.

[0107] Example 4

[0108]

[0109] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromo-n-heptane to finally obtain the compound represented by formula (1-4). The yield of this step was 88%.

[0110] The characterization analysis of compounds 1-4 is as follows: IR (neat, cm -1 )3323w, 2924m, 2855m, 1819m, 1579m, 1462w, 1379w, 1075m, 767w; mp 94-97℃; 1H NMR (400MHz, D 2 O)δ4.27(t,J=7.2Hz,1H),4.10(t,J=8.2Hz,1H),4.05-3.98(m,1H),3.93(dd,J=12.4,2.7Hz,1H),3.86( dd,J=12.7,5.3Hz,1H),3.60-3.52(m,2H),1.66-1.57(m,2H),1.51-1.23(m,12H),0.87(t,J=6.6Hz,3H); 13 C{ 1 H}NMR (100MHz, D 2O) δ74.6,73.4,68.8,63.9,62.5,57.3,32.7,31.6,29.2,29.15,29.1,25.5,22.4,13.7; Dept-135 (100MHz; D 2 O)δ C positive,74.6,73.4,68.8,63.9,62.5,13.7; negative,57.3,32.7,31.6,29.2,29.1,29.06,25.5,22.4.

[0111] The above characterization spectrum results indicate that the chemical structure of compound 1-4 prepared according to the method of Example 4 conforms to the chemical structure shown in formula (1-4). Therefore, compound 1-4 can be prepared according to the method of Example 4.

[0112] Example 5

[0113]

[0114] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromooctane to finally obtain the compound represented by formula (1-5). The yield of this step was 92%.

[0115] The characterization analysis of compounds 1-5 is as follows: IR (neat, cm -1 )3422s, 3248m, 2920s, 2849m, 1819m, 1719w, 1462m, 1384m, 1312m, 1096m, 1079m, 980m; mp 96-98℃; 1 H NMR (300 MHz, D 2 O)δ4.30(t,J=7.0Hz,1H),4.13(t,J=7.8Hz,1H),4.09-4.01(m,1H),3.98- 3.86(m,2H),3.61-3.58(m,2H),1.63-1.31(m,16H),0.89(t,J=6.9Hz,3H); 13 C{ 1 H}(75MHz,D 2 O) δ74.7,73.4,68.9,63.9,62.5,57.4,32.8,31.9,29.6,29.5,29.4,29.3,25.7,22.6,13.9; Dept-135 (75MHz, D 2 O)δ Cpositive,74.7,73.4,68.9,63.9,62.5,13.8; negative,57.4,32.8,31.9,29.6,29.5,29.4,29.3,25.7,22.6.

[0116] The above characterization spectrum results indicate that the chemical structure of compound 1-5 prepared according to the method of Example 5 conforms to the chemical structure shown in formula (1-5). Therefore, compound 1-5 can be prepared according to the method of Example 5.

[0117] Example 6

[0118]

[0119] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromo-n-nonane to finally obtain the compound represented by formula (1-6). The yield of this step was 91%.

[0120] The characterization analysis of compounds 1-6 is as follows: IR (neat, cm -1 )3320s, 2924m, 2833m, 2360vs, 2339s, 1579m, 1456m, 1121m, 1032m, 669m; mp 91-92℃; 1 H NMR (400 MHz, D 2 O)δ4.30(t,J=6.9Hz,1H),4.13(t,J=6.4Hz,1H),4.08-4.02(m,1H),3.99- 3.86(m,2H),3.60-3.56(m,2H),1.64-1.31(m,18H),0.89(t,J=6.5Hz,3H), 13 C{ 1 H}NMR (125MHz, D 2 O) δ74.7,73.5,68.9,64.0,62.5,57.4,32.9,32.0,29.9,29.8,29.78,29.6,29.57,25.9,22.7,13.8; Dept-135 (125MHz; D 2 O)δ C positive,74.7,73.5,68.9,64.0,62.5,13.8; negative,57.4,32.9,32.0,29.9,29.8,29.78,29.6,29.57,25.9,22.7.

[0121] The above characterization spectrum results indicate that the chemical structure of compound 1-6 prepared according to the method of Example 6 conforms to the chemical structure shown in formula (1-6). Therefore, compound 1-6 can be prepared according to the method of Example 6.

[0122] Example 7

[0123]

[0124] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromodecane to finally obtain the compound represented by formula (1-7). The yield of this step was 88%.

[0125] The characterization analysis of compounds 1-7 is as follows: IR (neat, cm -1 )3333s, 2923s, 2853s, 1652m, 1593m, 1464w, 1115m, 1065m; mp 95-97℃; 1 H NMR (400 MHz, D 2 O)δ4.30(t,J=7.0Hz,1H),4.14(t,J=7.3Hz,1H),4.08-4.02(m,1H),3.99 -3.85(m,2H),3.63-3.57(m,2H),1.69-1.22(m,20H),0.89-0.86(m,3H); 13 C{ 1 H}NMR (100MHz, D 2 O)δ74.6,73.4,68.9,64.0,62.6,57.4,32.9,32.1,30.1(2),30.0(2),29.7,26.0,22.7,13.8.

[0126] The above characterization spectrum results indicate that the chemical structure of compound 1-7 prepared according to the method of Example 7 conforms to the chemical structure shown in formula (1-7). Therefore, compound 1-7 can be prepared according to the method of Example 7.

[0127] Example 8

[0128]

[0129] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromoundecane to finally obtain the compound represented by formula (1-8). The yield of this step was 89%.

[0130] The characterization analysis of compounds 1-8 is as follows: IR (neat, cm -1)3340m,2922m,2852m,2360vs,1718w,1652m,1560m,1464m,1398m,1071m; 1 H NMR (300 MHz, D 2 O)δ4.32(t,J=6.8Hz,1H),4.15(t,J=7.9Hz,1H),4.10-4.02(m,1H),4.00- 3.86(m,2H),3.68-3.55(m,2H),1.63-1.25(m,22H),0.91(t,J=6.3Hz,3H); 13 C{ 1 H}NMR (125MHz, D 2 O)δ74.7,73.5,68.9,64.1,62.6,57.4,33.0,32.2,30.3(2),30.1(2),29.8,26.0,22.8,13.9.

[0131] The above characterization spectrum results indicate that the chemical structure of compound 1-8 prepared according to the method of Example 8 conforms to the chemical structure shown in formula (1-8). Therefore, compound 1-8 can be prepared according to the method of Example 8.

[0132] Example 9

[0133]

[0134] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromododecane to finally obtain the compound represented by formula (1-9). The yield of this step was 93%.

[0135] The characterization analysis of compounds 1-9 is as follows: 1 H NMR (400MHz, CD 3 OD)δ4.23(t,J=6.9Hz,1H),3.97(dd,J=8.4,6.8Hz,1H),3.96-3.77(m,3H),3.42 -3.37(m,2H),1.62(q,J=7.1Hz,2H),1.53-1.25(m,22H),0.90(t,J=6.6Hz,3H); 13 C{ 1 H}NMR (125MHz, CD 3 OD)δ76.4,74.8,69.8,65.7,64.5.58.3,34.4,32.9,30.6(3),30.5,30.5,30.4,30.3,26.6,23.5,14.2; HRMS(ESI)calcd.for C19 H 40 NO 4 + [M+H] + m / z 346.29519; found m / z 346.29508.

[0136] The above characterization spectrum results indicate that the chemical structure of compound 1-9 prepared according to the method of Example 9 conforms to the chemical structure shown in formula (1-9). Therefore, compound 1-9 can be prepared according to the method of Example 9.

[0137] Example 10

[0138]

[0139] The method described in Example 1 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromotridecane to finally obtain the compound represented by formula (1-10). The yield of this step was 97%.

[0140] The characterization analysis of compounds 1-10 is as follows: IR (neat, cm -1 )3362s,2918s,2850s,1635w,1467m,1106m; 1 H NMR (500MHz, CD 3 OD)δ4.23(t,J=7.1Hz,1H),3.98(t,J=6.5Hz,1H),3.91-3.78(m,3H),3.42-3.27(m,2 H),1.64-1.61(m,2H),1.54-1.47(m,1H),1.38-1.25(m,23H),0.90(t,J=6.6Hz,3H); 13 C{ 1 H}NMR (125MHz, CD 3 OD)δ76.4,74.8,69.8,65.7,64.5,58.3,34.4,32.8,30.6,30.5(3),30.4,30.2,26.6,23.5,14.2.

[0141] The above characterization spectrum results indicate that the chemical structure of compound 1-10 prepared according to the method of Example 10 conforms to the chemical structure shown in formula (1-10). Therefore, compound 1-10 can be prepared according to the method of Example 10.

[0142] Embodiment 11

[0143]

[0144] Prepare an equal amount of 1-butylmagnesium bromide Grignard reagent according to Example 1 for later use;

[0145] In the presence of 20 mL of dry tetrahydrofuran and CuI (19.5 mg, 0.1 mmol), the compound represented by formula (2-5) (579.0 mg, 1.0 mmol) was subjected to an addition reaction with an organomagnesium reagent of 1-bromobutane at room temperature for 40 min, and then saturated NH 4 The reaction was quenched with Cl aqueous solution. Ethyl acetate was then added to extract the aqueous phase, the organic phases were combined and dried, the residue was dissolved in 15 mL of ethanol, KOH (20.0 mmol) was added, refluxed for 6 hours, and after cooling, the salt was filtered off, the sample was concentrated and mixed, and the compound represented by formula (2-16) was obtained by column chromatography separation;

[0146] In the presence of 20 mL of methanol, the compound represented by formula (2-16) (360.1 mg) was contacted with 50.0 mg of 10% Pd / C, hydrogen and hydrochloric acid (6N, 1 mL) for hydrogenation reaction. The reaction time was 12 hours. The mixture was filtered and the filter cake was discarded to obtain a filtrate. The solvent was removed under reduced pressure of -0.1 MPa to obtain a derivative represented by formula (1-11) and a pharmaceutically acceptable salt thereof, with a yield of 91%.

[0147] The characterization analysis of compounds 1-11 is as follows: IR (neat, cm -1 )3336s,2931m,1580m,1402m,1118m,1064m; 1 H NMR (500 MHz, D 2 O)δ4.10-4.06(m,2H),3.94-3.85(m,3H),3.56-3.51(m,1H),3.38(t,J=6.1Hz,1H ),1.64-1.60(m,1H),1.52-1.45(m,2H),1.37-1.30(m,5H),0.86(t,J=6.2Hz,3H); 13 C{ 1 H}NMR (125MHz, D 2 O)δ75.1,74.2,68.1,65.2,62.0,57.4,32.9,30.6,24.1,21.8,13.3; Dept-135 (125MHz, D 2 O)δ C positive,75.1,74.2,68.1,65.2,62.0,13.3; negative,57.4,32.9,30.6,24.1,21.8.

[0148] The above characterization spectrum results show that the chemical structure of compound 1-11 prepared according to the method of Example 11 conforms to the chemical structure shown in formula (1-11). Therefore, compound 1-11 can be prepared according to the method of Example 11. 1 HNMR and 13 C NMR can characterize compound 1-11. The starting materials of Examples 12-20 have the same molecular formula as that of Example 11, and the only difference is the different configuration of individual carbon atoms. Since the functional groups and reaction conditions for coupling reaction and deprotection reaction in each example are conventional operations well known to those skilled in the art and are exactly the same, it can be inferred that the following compounds represented by formula (1-12) to the compounds represented by formula (1-20) can all be successfully synthesized. 1 H NMR and 13 C{ 1 H}NMR can characterize their respective final products.

[0149] Example 12

[0150]

[0151] According to the method described in Example 11, the difference is that 1-bromobutane is replaced with the same molar amount of 1-bromopentane to finally obtain the compound represented by formula (1-12). The yield of this step is 93%. The characterization analysis of compound 1-12 is as follows: IR (neat, cm -1 )3335m, 2932m, 1582w, 1404m, 1119m, 1065m; 1 H NMR (500 MHz, D 2 O)δ4.08-4.04(m,2H),3.92-3.83(m,3H),3.55-3.49(m,1H),3.36(t,J=6.4Hz,1H ),1.62-1.57(m,1H),1.51-1.44(m,2H),1.34-1.25(m,7H),0.83(t,J=6.3Hz,3H); 13 C{ 1 H}NMR (125MHz, D 2 O)δ75.1,74.2,68.1,65.2,62.1,57.4,32.9,30.9,28.0,24.4,21.9,13.4; Dept-135 (125MHz, D 2 O)δ C positive,75.1,74.2,68.1,65.2,62.1,13.4; negative,57.4,32.9,30.9,28.0,24.4,21.9.

[0152] The above characterization spectrum results indicate that the chemical structure of compound 1-12 prepared according to the method of Example 12 conforms to the chemical structure shown in formula (1-12). Therefore, compound 1-12 can be prepared according to the method of Example 12.

[0153] Example 13

[0154]

[0155] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromohexane to finally obtain the compound represented by formula (1-13). The yield of this step was 91%.

[0156] The characterization analysis of compounds 1-13 is as follows: IR (neat, cm -1 )3338m,2926m,2856w,1622m,1457m,1120m,1066m; 1 H NMR (400 MHz, D 2 O)δ4.11-4.05(m,2H),3.95-3.85(m,3H),3.56-3.53(m,1H),3.39(t,J=6.7Hz,1H ),1.66-1.57(m,1H),1.52-1.45(m,2H),1.35-1.23(m,9H),0.85(t,J=6.6Hz,3H); 13 C{ 1 H}NMR (100MHz, D 2 O)δ75.2,74.2,68.1,65.2,62.1,57.4,33.0,31.0,28.3,28.3,24.5,22.0,13.4.

[0157] The above characterization spectrum results indicate that the chemical structure of compound 1-13 prepared according to the method of Example 13 conforms to the chemical structure shown in formula (1-13). Therefore, compound 1-13 can be prepared according to the method of Example 13.

[0158] Embodiment 14

[0159]

[0160] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromoheptane to finally obtain the compound represented by formula (1-14). The yield of this step was 93%. The characterization analysis of compound 1-14 is as follows: IR (neat, cm -1)3334m,2924m,2855w,1591m,1464m,1121m,1066m; 1 H NMR (500 MHz, D 2 O)δ4.14-4.10(m,1H),4.07(t,J=6.8Hz,1H),3.96-3.87(m,3H),3.61-3.55(m,1H),3.40(t,J =6.6Hz,1H),1.68-1.62(m,1H),1.57-1.47(m,2H),1.42-1.22(m,11H),0.87(t,J=6.7Hz,3H); 13 C{ 1 H}NMR (125MHz, D 2 O) δ75.4,74.3,68.4,65.5,62.3,57.5,33.3,31.7,29.3,29.1,25.1,22.4,13.7; Dept-135 (125MHz, D 2 O)δ C positive,75.4,74.3,68.4,65.5,62.3,13.7; negative,57.5,33.3,31.7,29.3,29.1,25.1,22.4.

[0161] The above characterization spectrum results indicate that the chemical structure of compound 1-14 prepared according to the method of Example 14 conforms to the chemical structure shown in formula (1-14). Therefore, compound 1-14 can be prepared according to the method of Example 14.

[0162] Embodiment 15

[0163]

[0164] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromooctane to finally obtain the compound represented by formula (1-15). The yield of this step was 94%. The characterization analysis of compound 1-15 is as follows: IR (neat, cm -1 )3338m,2923m,2854w,1457m,1396m,1121m,1065m; 1 H NMR (500 MHz, D 2O) δ4.17-4.14(t,J=7.0Hz,1H),4.10-4.07(t,J=7.0Hz,1H),3.99-3.90(m,3H),3.63-3.60(m,1H),3. 43(t,J=6.9Hz,1H),1.67-1.65(m,1H),1.55-1.44(m,2H),1.44-1.26(m,13H),0.90(t,J=6.8Hz,3H); 13 C{ 1 H}NMR (125MHz, D 2 O)δ75.5,74.4,68.5,65.6,62.4,57.5,33.4,31.9,29.6(2),29.3(2),25.3,22.6,13.8; Dept-135(125MHz, D 2 O)δ C positive,75.5,74.4,68.5,65.6,62.4,13.8; negative,57.5,33.4,31.9,29.6(2),29.3(2),25.3,22.6.

[0165] The above characterization spectrum results indicate that the chemical structure of compound 1-15 prepared according to the method of Example 15 conforms to the chemical structure shown in formula (1-15). Therefore, compound 1-15 can be prepared according to the method of Example 15.

[0166] Example 16

[0167]

[0168] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromo-n-nonane to finally obtain the compound represented by formula (1-15). The yield of this step was 92%. The characterization analysis of compound 1-16 is as follows: IR (neat, cm -1 )3336s,2923s,2853m,1589m,1463m,1379m,1122m,1066m; 1 H NMR (500 MHz, D 2 O) δ4.16-4.13(t,J=7.0Hz,1H),4.10-4.07(t,J=7.0Hz,1H),3.98-3.89(m,3H),3.63-3.58(m,1H),3. 42(t,J=6.8Hz,1H),1.70-1.64(m,1H),1.58-1.50(m,2H),1.38-1.26(m,15H),0.89(t,J=6.7Hz,3H);13 C{ 1 H}NMR (125MHz, D 2 O)δ75.4,74.3,68.4,65.5,62.3,57.5,33.3,31.8,29.6,29.5(2),29.3,29.2,25.2,22.5,13.7; Dept-135 (125MHz, D 2 O)δ C positive,75.4,74.3,68.4,65.5,62.3,13.7; negative,57.5,33.3,31.8,29.6,29.5(2),29.3,29.2,25.2,22.5.

[0169] The above characterization spectrum results indicate that the chemical structure of compound 1-16 prepared according to the method of Example 16 conforms to the chemical structure shown in formula (1-16). Therefore, compound 1-16 can be prepared according to the method of Example 16.

[0170] Embodiment 17

[0171]

[0172] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromodecane to finally obtain the compound represented by formula (1-17). The yield of this step was 94%. The characterization analysis of compound 1-17 is as follows: IR (neat, cm -1 )3338s,2923s,2853w,1458m,1124m,1065m; 1 H NMR (500 MHz, D 2 O)δ4.20-4.15(m,1H),4.12-4.08(m,1H),4.02-3.93(m,3H),3.68-3.61(m,1H),3.47-3. 44(m,1H),1.73-1.65(m,2H),1.61-1.51(m,3H),1.44-1.26(m,15H),0.92-0.89(m,3H); 13 C{ 1 H}NMR (125MHz, D 2 O)δ75.6,74.4,68.6,65.7,62.5,57.6,33.6,32.1,30.0(2),29.9,29.6,25.5,22.7,13.9; Dept-135 (125MHz, D 2 O)δ Cpositive,75.6,74.4,68.6,65.7,62.5,13.9; negative,57.6,33.6,32.1,30.0(2),29.9,29.6,25.5,22.7.

[0173] The above characterization spectrum results indicate that the chemical structure of compound 1-17 prepared according to the method of Example 17 conforms to the chemical structure shown in formula (1-17). Therefore, compound 1-17 can be prepared according to the method of Example 17.

[0174] Embodiment 18

[0175]

[0176] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromoundecane to finally obtain the compound represented by formula (1-18). The yield of this step was 89%. The characterization analysis of compound 1-18 is as follows: IR (neat, cm -1 )3337s,2923s,2853w,1457m,1123m,1063m; 1 H NMR (500MHz, CD 3 OD)δ4.04-3.99(m,2H),4.89-3.81(m,3H),3.44-3.38(m,1H),3.29-3.24(m,1H),1.66-1.53(m,3H),1.40-1.23(m,19H),0.90-0.87(m,3H); 13 C{ 1 H}NMR (125MHz, CD 3 OD)δ77.0,75.8,68.6,67.4,64.6,58.6,35.2,32.8,30.5(4),30.4,30.3,30.2,26.2,23.5,14.2; Dept-135 (125MHz, CD 3 OD)δ C positive,77.0,75.8,68.6,67.4,64.6,14.2; negative,58.6,35.2,32.8,30.5(4),30.4,30.3,30.2,26.2,23.5.

[0177] The above characterization spectrum results indicate that the chemical structure of compound 1-18 prepared according to the method of Example 18 conforms to the chemical structure shown in formula (1-18). Therefore, compound 1-18 can be prepared according to the method of Example 18.

[0178] Embodiment 19

[0179]

[0180] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromododecane to finally obtain the compound represented by formula (1-19). The yield of this step was 90%. The characterization analysis of compound 1-19 is as follows: IR (neat, cm -1 )3423s,2923s,2852w,1459m,1393m,1067m; 1 H NMR (400MHz, CD 3 OD)δ4.08-3.98(m,2H),3.91-3.79(m,3H),3.45-3.37(m,1H),3.29-3.2 3(m,1H),1.61-1.50(m,4H),1.44-1.25(m,20H),0.90(t,J=6.7Hz,3H); 13 C{ 1 H}NMR (100MHz, CD 3 OD)δ77.0,75.7,68.6,67.4,64.6,58.6,35.1,32.8,30.5,30.4(2),30.3,30.2,26.2,23.4,14.2.

[0181] The above characterization spectrum results indicate that the chemical structure of compound 1-19 prepared according to the method of Example 19 conforms to the chemical structure shown in formula (1-19). Therefore, compound 1-19 can be prepared according to the method of Example 19.

[0182] Embodiment 20

[0183]

[0184] The method described in Example 11 was followed, except that 1-bromobutane was replaced with the same molar amount of 1-bromotridecane to finally obtain the compound represented by formula (1-20). The yield of this step was 97%.

[0185] The characterization analysis of compounds 1-20 is as follows: IR (neat, cm -1 )3424s,2923s,2853w,1460m,1394m,1068m; 1 H NMR (500MHz, CD 3OD)δ4.05-3.99(m,2H),3.88-3.81(m,3H),3.43-3.37(m,1H),3.28-3.2 3(m,1H),1.62-1.53(m,3H),1.39-1.25(m,23H),0.90(t,J=6.2Hz,3H); 13 C{ 1 H}NMR (125MHz, CD 3 OD)δ77.0,75.7,68.6,67.4,64.6,58.6,35.2,32.8,30.5(2),30.4,30.3,30.2,26.2,23.4,14.2; Dept-135 (125MHz, CD 3 OD)δ C positive,77.0,75.7,68.6,67.4,64.6,14.2; negative,58.6,35.2,32.8,30.5(2),30.4,30.3,30.2,26.2,23.4.

[0186] The above characterization spectrum results indicate that the chemical structure of compound 1-20 prepared according to the method of Example 20 conforms to the chemical structure shown in formula (1-20). Therefore, compound 1-20 can be prepared according to the method of Example 20.

[0187] Test Example 1

[0188] This test example is used to illustrate the glycosidase inhibitory activity of the polyhydroxypyrrolidine derivatives and their pharmaceutically acceptable salt derivatives in the present invention.

[0189] (1) Test materials and sources

[0190] (2) Test compounds: polyhydroxypyrrolidine derivatives represented by formula (1-1) to formula (1-20) provided by the present invention and pharmaceutically acceptable salts thereof.

[0191] Experimental Materials: 4-Nitrophenolpyranoside substrates, disaccharides and glycosidases (α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α-L-fucosidase, α-trehalase, α-L-rhamnase, amyloglucosidase and β-glucuronidase, etc.) used in the following tests were purchased from Sigma-Aldrich.

[0192] (3) Test method

[0193] Activity test was performed with 4-nitrophenol pyranoside as substrate at the optimal activity pH of each enzyme. The substrate, enzyme solution (0.1-0.5 mg / mL) and inhibitor (polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salt derivatives thereof of the present invention) were incubated at 37° C. for 30 minutes, and then the reaction was started in a UV-visible spectrophotometer to test its absorption of 400 nm wavelength light. Finally, the GraFit program was used for data analysis [see Leatherbarrow, RJ Grafit 4.0; Erithacus Software: Staines, UK, 1998.].

[0194] (4) Evaluation results

[0195] The results of the inhibitory activity of the polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof provided by the present invention and the comparative example compounds on glycosidase are shown in Table 1.

[0196] In Table 1, the percentage is the inhibition rate of the corresponding compound on the enzyme, indicating its IC 50 (μM) values ​​greater than 1000 indicate low inhibitory activity; non-percentage values ​​are the IC values ​​of the corresponding compounds on the enzyme 50 (μM) value, the smaller the value, the higher the inhibitory activity. ND means that the activity of the compound on the enzyme was not tested. The glycosidases used below were purchased from Sigma-Aldrich.

[0197] Table 1

[0198]

[0199]

[0200] Table 1

[0201]

[0202]

[0203] Table 1

[0204]

[0205] Table 1

[0206]

[0207]

[0208] It can be seen from the data in Table 1 that the polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof prepared in Examples 1-20 of the present invention have higher inhibitory activity against β-glucosidase and β-galactosidase derived from bovine liver, which is higher than that in the literature (Best, D.; Wang, C.; Weymouth-Wilson, AC; Clarkson, RA; Wilson, FX; Nash, RJ; Miyauchi, S.; Kato, A.; Fleet, GWJ Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-L-bulgecinine from D-glucuronolactone and of L-DNJ, L-DMDP, and (3S)-3-hydroxy-D-bulgecinine from L-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas L-DMDP is a potent and specific inhibitor of α-glucosidases. Tetrahedron: Asymmetry 2010,21,311-319) reported that the inhibitory activity of DMDP on β-glucosidase (IC 50 =9.7 μM), compounds 1-8 synthesized in the present invention have an inhibitory effect on β-glucosidase (IC 50 =2.1 nM), its activity increased by 4619 times. The inhibitory activity of DMDP on β-galactosidase reported in the literature (IC 50 =3.3 μM), the inhibitory activity of compounds 1-9 synthesized in the present invention against β-galactosidase (IC 50 =3.0 nM), its activity increased by 1100 times; Compound 1-20 prepared in the embodiment of the present invention also has high inhibitory activity against β-glucosidase and β-galactosidase derived from bovine liver.

[0209] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, wherein: The derivative has a chemical structure shown in formula (1): Among them, R 1 is selected from substituted or unsubstituted C5-C 20 The alkyl group; R 2 , R 3 and R 4 Each is independently selected from H, substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro or halogen; R 5 is selected from H or benzyloxycarbonyl; In formula (1), the stereo configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are each independently R or S.

2. The derivative and pharmaceutically acceptable salt thereof according to claim 1, wherein: In formula (1), R 1 Selected from substituted or unsubstituted C5-C 14 alkyl; R 2 , R 3 and R 4 Each is independently selected from H, substituted or unsubstituted benzyl, wherein the substituent in the substituted benzyl is selected from C1-C4 alkoxy, C1-C4 alkyl, hydroxyl, nitro or halogen; Preferably, R 2 , R 3 and R 4 All are H or all are benzyl; More preferably, R 2 , R 3 and R 4 All are H; and / or, in formula (1), the stereo configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are selected from "2R, 3R, 4R, 5R, 6S", "2R, 3R, 4R, 5R, 6R".

3. The derivative according to claim 1 or 2 and a pharmaceutically acceptable salt thereof, wherein: The derivative is selected from one of formula (1-1) to formula (1-20):

4. A method for synthesizing a polyhydroxypyrrolidine derivative and a pharmaceutically acceptable salt thereof, the method comprising: (1) subjecting the compound represented by formula (2) to an addition reaction with an organic metal reagent having an R1 group in the presence of a catalyst and a first solvent; optionally, subjecting the product obtained by the addition reaction to a deprotection reaction in the presence of a base and a second solvent to obtain a compound represented by formula (3); Among them, R 2’ , R 3’ , R 4’ Each is independently selected from substituted or unsubstituted benzyl; wherein the substituent in the substituted benzyl is selected from C1-C6 alkoxy, C1-C6 alkyl, hydroxyl, nitro or halogen; R 5’ is benzyloxycarbonyl; (2) in the presence of a second solvent, contacting the compound represented by formula (3) with a deprotection agent, a hydrogen source and an acidic substance to carry out a hydrogenation reaction to obtain a derivative represented by formula (1) and a pharmaceutically acceptable salt thereof; Among them, R 1 , R 2 , R 3 , R 4 , R 5 And in formula (1), the definitions of the stereo configurations of carbon atoms at positions 2, 3, 4, 5 and 6 are the same as those in any one of claims 1 to 3.

5. The method according to claim 4, wherein: In step (1), the organometallic reagent is selected from at least one of an organomagnesium reagent, an organozinc reagent, an organolithium reagent and an organocopper reagent, preferably an organomagnesium reagent and / or an organozinc reagent; and / or, the catalyst is selected from CuI, BuBr or CuCl, preferably CuI; and / or, the first solvent is selected from aprotic solvents, preferably at least one of diethyl ether, tetrahydrofuran, dioxane and dichloromethane, more preferably tetrahydrofuran and / or dioxane; and / or, the base is selected from KOH, NaOH or Ca(OH)2, preferably KOH; and / or, relative to 1 g of the compound represented by formula (2), the amount of the first solvent used is 2-200 mL, more preferably 30-50 mL; and / or, the molar ratio of the compound represented by formula (2) to the organometallic reagent is 1:(1.2-50), preferably 1:(1.2-3); And / or, the temperature of the addition reaction is -20°C to 50°C, preferably -10°C to 0°C; the time of the addition reaction is 0.5-3h, preferably 0.5-1h; And / or, the temperature of the deprotection reaction is 55-120° C., preferably 60-100° C.; the time of the deprotection reaction is 6-18 h, preferably 6-12 h.

6. The method according to claim 4 or 5, wherein: In step (2), the deprotection agent is selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide, platinum black, trimethylsilyl iodide, boron trichloride, boron tribromide, aluminum chloride and zinc / ammonium chloride, preferably selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, boron trichloride and boron tribromide; And / or, when the deprotecting agent is selected from at least one of Raney nickel, Pd / C, palladium black, palladium hydroxide, palladium acetate, palladium chloride, platinum oxide and platinum black, the mass ratio of the compound represented by formula (3) to the deprotecting agent is 1:(0.1-5), preferably 1:(0.1-0.2); When the deprotecting agent is selected from at least one of trimethylsilyl iodide, boron trichloride, boron tribromide, aluminum chloride and zinc / ammonium chloride, the molar ratio of the compound represented by formula (3) to the deprotecting agent is 1:(1-20), preferably 1:(5-10); and / or, the hydrogen source is selected from at least one of hydrogen, sodium borohydride and ammonium formate, preferably hydrogen; and / or, the acidic substance is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoroacetic acid, preferably hydrochloric acid; And / or, the molar ratio of the compound represented by formula (3) to the hydrogen source is 1:(5-100), preferably 1:(10-50); and / or, the second solvent is selected from at least one of dichloromethane, chloroform, tetrahydrofuran, diethyl ether, ethyl acetate, acetic acid, water, dioxane, methanol, ethanol, acetonitrile, formamide and N,N-dimethylformamide; and / or, relative to 1 mg of the compound represented by formula (3), the amount of the second solvent used is 0.02-2 mL, preferably 0.04-1 mL; And / or, the temperature of the hydrogenation reaction is 0-50°C, preferably 10-30°C; the time of the addition reaction is 6-100h, preferably 6-48h.

7. The polyhydroxypyrrolidine derivatives and pharmaceutically acceptable salts thereof obtained by the method according to any one of claims 4 to 6.

8. Use of the polyhydroxypyrrolidine derivative and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 7 in the preparation of a drug; Preferably, the drug is selected from at least one of the following drugs: drugs for preventing and / or treating diabetes, drugs for preventing and / or treating Gaucher's disease, drugs for preventing and / or treating lysosomal storage diseases, and / or drugs for treating tumors, and antiviral drugs.

9. A glycosidase inhibitor, characterized in that The active ingredient of the glycosidase inhibitor comprises the polyhydroxypyrrolidine derivative and the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 7.

10. Use of the glycosidase inhibitor according to claim 9 in inhibiting glycosidase, Preferably, the glycosidase is at least one selected from the group consisting of α-glucosidase, β-glucosidase, α-galactosidase, β-galactosidase, α-mannosidase, β-mannosidase, α-L-fucosidase, α,α-trehalase, α-L-rhamnosidase, amyloglucosidase and β-glucuronidase, preferably β-glucosidase and / or β-galactosidase, more preferably β-glucosidase and / or β-galactosidase derived from bovine liver is used to inhibit.

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