CN1027372C - Sialosylcerbrosides and preparation thereof - Google Patents

Abstract

This invention provides a novel compound having a formula such as disclosed This invention also provides a process for preparing such a compound.

Description

Sialosylcerbrosides and preparation thereof

The invention relates to sialic acid (Sialosyl) cerebroside, more specifically get on very well, is sialic acid cerebroside about containing in the ganglioside sphingoglycolipid and preparation method thereof.

The glycolipid of in mammalian cell, finding, be that the glycosides between ceramide and the one or more sugar, said ceramide are that lipid acid is connected in the ceramide formation with amido linkage, said sugar is glucose, semi-lactosi, N-acetyl-glucosamine, N-acetyl-glucosamine, N-acetylgalactosamine, Fucose, sialic acid etc.In these glucosides, contain the sialic ganglioside that is called.

Ganglioside mainly is present in the outer molecular layer of mammalian cell membrane bilayer.Recent studies have shown that, information, acceptor mechanism, differentiation, cell proliferation in the cells involved are being accepted, discerning and answered to ganglioside, malignant cell metamorphosis, and aspects such as cell proterties play an important role.

In these compounds, sialic acid cerebroside ester GM ₄Be contained in brain on people's spinal cord in large quantities, in the grey matter of portion, and be considered to the special component of myelin film, in the kidney of the red blood corpuscle of animalcule, mouse and yolk, be found at these acid glycolipids.

But the ganglioside glycolipid is as also not fully research of the effect of cytolemma component, and separates from organism and carry sialic acid cerebroside GM ₄Be very difficult, therefore contain sialic acid cerebroside GM ₄The sour cerebronic precision of saliva base synthetic be necessary to research ganglioside glycolipid as the effect of cytolemma component.

The purpose of this invention is to provide new sialic acid cerebroside and preparation method thereof and sialic acid cerebroside GM ₄The preparation method.

New sialic acid cerebroside of the present invention is represented with the structural formula I

R wherein ₁Be hydrogen or ethanoyl, R ₂For-COOR ₄(R ₄Be hydrogen, sodium or methyl), R ₃For

(wherein, R ₅Be hydrogen or ethanoyl, R ₆For-C(CCl ₃)=NH or

R in this formula ₇Be hydrogen or benzoyl, R ₁₁For containing aliphatic saturated hydrocarbon, the R of 10 to 16 carbon atoms ₁₂For containing the aliphatic saturated hydrocarbon of 15 to 25 carbon atoms), or R ₂For:

(wherein, R ₅And R ₆Same with top definition) and R ₃For-COOR ₄(R ₄Same with top definition)

Now to the detailed description of the invention.

(a) the ceramide part is synthetic

Method preparation shown in the available Fig. 1 b of the ceramide part of ganglioside.Method preparation (seeing Japanese patent application 59-44913 specification sheets (Japanese patent application publication No. 60-190745)) shown in the available Fig. 1 a of compound (30).

2. compound can make by haloalkane (for example the 1-bromo-tetradecane and triphenylphosphine) reflux in the presence of solvent (for example dimethylbenzene) is spent the night.

1,2-O-isopropylidene-α-D-wood glutaraldehyde base-1, the 4-furanose 1. with compound 2. in the presence of the n-Butyl Lithium catalyzer, 3. reaction generates 4-alkyl vinyl derivative in solvent (as tetrahydrofuran (THF) or hexane), and temperature of reaction and time that this reaction is fit to are respectively-15 ℃ to 25 ℃ and 0.5 to 24 hour.

Compound 3. in anhydrous pyridine with methylsulfonyl chloride handle, generate 3-methylsulfonyl derivative 4., this reaction was adapted at carrying out under 0 ℃ to 25 ℃ 2 to 24 hours.

4. compound is handled in acetic acid/water, removes wherein isopropylidene, generates glycol 5., and this reaction is adapted at carrying out 0.5-5 hour under 70 to 90 ℃.

5. compound uses oxygenant (for example higher sodium iodide) to handle in solvent (for example ethanol), removes the glycol part, uses reductive agent (for example sodium borohydride) to handle, obtain diol compound 6. then.This oxidizing reaction was carried out 0.5-24 hour under 0 ℃-25 ℃, and this reduction reaction was carried out 0.5-2 hour under 0 ℃-10 ℃.

In the presence of catalyzer (for example pyridine tosilate), compound 6. with alkyl vinyl ether (for example ethyl vinyl ether) in solvent (for example methylene dichloride), react obtain two-alkyl vinyl ether 7., this reaction is adapted at carrying out 0.5-24 hour under 0 ℃-30 ℃.

8. 7. compound obtain compound with trinitride (for example sodiumazide) processing in solvent (for example dimethyl formamide), this reaction is adapted at carrying out under 70 ℃-120 ℃ 15 hours-6 days.

Trinitride 8. in solvent (for example ethanol or Virahol) with reductive agent (for example sodium borohydride or Lindler catalyzer/H ₂) handle and to obtain amine 9..When using sodium borohydride, this reaction is adapted at carrying out under the reflux temperature 1-6 days; When utilizing Lindler catalyzer/H ₂The time, this reaction is adapted at 0 ℃-30 ℃, hydrogen pressure and carried out 2-24 hour under 1-4 normal atmosphere.

Amine 9. in the presence of basic cpd (for example pyridine or dimethyl aminopyridine) with acyl halide reaction, obtain acid amides (10) or (11), this reaction was adapted at carrying out under 0 ℃ to 30 ℃ 0.5 to 24 hour.

Perhaps 9. amine be dissolved in methylene dichloride or with in the kind solvent, and in the presence of iodate α-chloro-1-picoline, three-n-butylamine etc. with fatty acid response, obtain amine (10) or (11).This is reflected in the rare gas element (for example argon), can react completely in 0.5-13 hour under reflux temperature.

Then, with amine (10) or (11) in solvent (for example methyl alcohol, methylene dichloride) with pyridine tosilate, Amberlite A-15(trade names) etc. reaction, remove the guarantor

The compound that so obtains (31) is handled with trityl chloride in pyridine; just obtain trityl derivative (32); compound (32) is handled with Benzoyl chloride and dimethyl aminopyridine then; obtain trityl-benzoyl derivative (33), thereafter, compound (33) is handled with tosic acid; remove trityl group; just obtain benzoyl ceramide (34), need not emanate compound (32) and (33) just can obtain compound (34).

Reaction scheme 2

(b) sialic acid derivative (10) and (20) is synthetic.

Be used for the synthetic cerebronic sialic acid of sialic acid of the present invention (10) and (20), can be by compound (b) and N-acetyl neuraminic acid methyl acetate (compd E) reaction be obtained.Compound (b) is to obtain from benzyl galactoside (A) (as shown in Figure 2), and compound (E) is then used Kahn ' s method synthetic.

Benzyl galactoside (A) forms suspension in acetone, and in the presence of tosic acid with 2,2-Propanal dimethyl acetal reaction and obtain 3,4-0-isopropylidene derivative (B),

(B) in the presence of NaH, in dimethyl formamide, react with cylite, obtain tribenzyl derivative (C), this derivative (C) is handled with acetic acid solution, remove isopropylidene, and obtain compound (D), compound (D) and reaction (E) are adapted at solvent (methylene dichloride, 1 for example, similar solvents such as 2-ethylene dichloride) in, under-20-150 ℃, carried out 1-120 hour, glycosidation catalyzer (for example Hg(CN) is arranged in the reaction ₂, HgB _R2, molecular sieve, AgCO ₃, AgClO ₄, AgOSO ₂CF ₃, (CH ₈) ₃COSO ₂CF ₃Etc. the class catalyzer) exist.

(c) sialic acid is cerebronic synthetic

Sialic acid cerebroside of the present invention can obtain (shown in Fig. 3 and 4) from sialic acid derivative (10) and (20).

Sialic acid derivative (10) carries out acetylization reaction and obtains compound (11) with diacetyl oxide and pyridine.Compound (11) is handled with Pd-C and methyl alcohol and is removed benzyl, then the product of gained is handled the generation acetylization reaction with diacetyl oxide and pyridine and obtains compound (12), and then, compound (12) is used NH ₂NH ₂A _cOH and dimethyl formamide are handled, and obtain deacetylation compound (13).

Compound (13) obtains compound (14) with the Trichloroacetonitrile reaction in the presence of NaH in solvent (for example methylene dichloride and same kind solvent).This reaction can be carried out under following condition: temperature-10-30 ℃, be preferably in ice-cooled stirring down 1-5 hour.

Compound (14) reacts with the benzoyl derivative benzoyl ceramide (34) of ceramide, in solvent (for example chloroform or same kind solvent), in 4A molecular sieve and BF ₄, E _tO ₂Carry out under the condition that exists, obtain compound (15) and (16), this reaction can be carried out under temperature-40-40 ℃ 0.5-2 hour, stirred 2-24 hour down at 0-40 ℃ then, and compound (15) separates with (16) available silica gel column chromatography.

Compound (17) and (18) can obtain by following reaction, compound (15) and (16) are handled with NaOMe in solvent (for example methyl alcohol/tetrahydrofuran (THF) etc.) respectively, necessary, above resultant is handled with Am berlist IRC50 or analogue.MaOMe handles to be preferably in and carried out under 0-30 ℃ 0.5-6 hour.

On the other hand, sialic acid derivative obtains compound (21) with 4-dimethoxy aminopyridine generation acetylization reaction in the mixture of pyridine and diacetyl oxide.Compound (21) is used P _d-C and methyl alcohol are handled the benzyl of removing wherein and are obtained compound (22).Compound (22) is handled with 4-dimethoxy aminopyridine in the mixture of pyridine and diacetyl oxide, acetylization reaction takes place obtain compound (23).Compound (23) is used NH in dimethyl formamide ₂NH ₂AcOH handles, and removes wherein ethanoyl, obtains compound (24).

Compound (24) and in the presence of dibutyl urea (DBU), with the Trichloroacetonitrile reaction, obtains compound (25) in solvent (as ethylene dichloride etc.).This reaction can be carried out 30 minutes to 60 hours under-10 to 30 ℃.

Compound (25) is in solvent (for example chloroform etc.); and at molecular sieve and boron trichloride; benzoyl derivative (IV) with ceramide under ether exists reacts; obtain compound (26); this is reflected at-10-40 ℃ temperature under; be preferably in 0-20 ℃ and stirred 2-5 hour down, then under 20-40 ℃ of temperature, stirred 1-24 hour.

Compound (26) is used NaOCH in solvent (for example tetrahydrofuran (THF) and carbinol mixture etc.) ₃Handle, remove benzyl, obtain compound (27), this reaction can be stirred the solution that contains compound (26) under 0-40 ℃ of temperature, kept 1-24 hour.This response procedures can be included in tetrahydrofuran (THF) and the carbinol mixture and use H ₂The O additional processing, and with Amberlite IRC-50 neutralization solution.

With compound (14), (15) that method of the present invention obtains, (16), (17), (25), (26) and (27) all are new compounds.

New compound of the present invention is used as a kind of tumor marker, a kind of identification symbol to cell with differentiation capability, and with this synthetic mesophase product.

The present invention will be described in detail with following embodiment now.

Reference example 1: by compound (11) preparation compound (12)

658 milligrams of (0.68 mmole) compounds (11) are dissolved in 25 ml methanol, and with 320 milligrams 10%Pd-C catalytic reduction 24 hours at room temperature.After the reaction, filter reaction mixture is removed the Pd-C mother liquor and is concentrated down in decompression, the residue that obtains (463 milligrams, 98%, Rf0.72, butanols: ethanol: water=4: 2: 2) be dissolved in 2 milliliters of acid anhydrides and the 2 milliliters of pyridine mixtures, at room temperature stirred 24 hours, then concentrating under reduced pressure.(toluene: ethyl acetate=1: 4) purification obtains 545 milligrams of compounds (12) (yield 85%) to residue for Wakogel C-300,35 grams with silicagel column

〔d〕 ²² _D+7.60（C＝0.96，CHCl ₃）

Rf=0.38, ethyl acetate, high performance thin-layer chromatography

Ultimate analysis:

Theoretical value: C 49.69, H 5.77, and N 1.70

Experimental value: C 49.73, H 5.78, and N 1.57

Nucleus magnetic resonance: (400MHz PPm, CDCl ₃, TMS) 1.71,1H, t, J=12.5, H-3bax, 2.60,1, H, m, H-3be q1.86-2.23 27H, CH ₃CO, 3.86, S ,-OCH ₃α-anomer, 3.85S ,-OCH ₃β-anomen 5.38d, J=8.3H-la β 6.29H-la α d, J=3.91

Reference example 2: by compound (12) preparation compound (13)

452 milligrams of (0.55 mmole) compounds (12) are dissolved in 1.0 milliliters of dimethyl formamides, are heated to 50 ℃, add 56 milligrams of NH ₂NH ₂AcoH stirred 5 minutes, and reaction mixture cooling back washes with water with the ethyl acetate dilution, uses MgSO ₄Dry ethyl acetate also concentrates mutually, obtains 414 milligrams of compounds (13) (yield 97%).The Rf=0.32 ethyl acetate, high performance thin-layer chromatography

Embodiment 1: by compound (13) preparation compound (14)

156 milligrams compound (13) is dissolved in 1.0 milliliters of methylene dichloride and adds 116 milligrams of (0.80 mmole) Trichloroacetonitrilees.The mixture that obtains stirs the NaH(60% oil that adds 9.0 milligrams down in the ice bath cooling), and then stirred 3 hours.The reaction mixture decompression is concentrated down, purify, obtain 84 milligrams of compounds (14) (yield 45%) Rf=0.37, ethyl acetate with silicagel column (Wakogel C-300,10g, ethyl acetate)

Embodiment 2: by compound (14) preparation compound (15) and (16)

Compound (14) and 51 milligrams of (0.067 mmole) benzoyl-ceramide compounds (34) with 62 milligrams (0.067 mmoles) of method shown in Fig. 1 a and 1b preparation are dissolved in 2 milliliters of chloroforms.This solution adds 1 gram activation 4A molecular sieve-4 A W300 in the ice bath cooling and under stirring, and adds 10 microlitres (0.08 mmole) boron trifluoride diethyl etherate.This reaction mixture stirred 1 hour under uniform temp, at room temperature stirred again 24 hours, then, use the chloroform diluted reaction mixture, filter with sellaite, decompression concentrates down, residue silicagel column (Wakogel C-300,20g, toluene: ethyl acetate=1: 2) purify, obtain 10.4 milligrams of compounds (15) (yield 10.2%) and 28 milligrams of compounds (16) (yield 27.5%)

Compound (15)

Rf=0.41(toluene: ethyl acetate=1: 2)

Ultimate analysis:

Theoretical value C 64.18, and H 8.64, and N 1.85

Experimental value C 64.14, H 8.71, and N 1.87

〔d〕 ²⁰ _D-17.2（C＝0.92，CHcl ₃）

Nucleus magnetic resonance (400 MHz PPm CDcl ₃TMS) 0.876CH ₃TJ=5.9,0.879, CH ₃TJ=5.4,1.252 CH ₂1.917-2.165 CH ₃CO, 3830 CH ₃O-, S

Compound (16)

Rf=0.25(toluene: ethyl acetate=1: 2)

〔α〕 ²¹ _D-0.37（C＝1.40，CHcl ₃）

Ultimate analysis: C ₈₁H ₁₃₀N ₂O ₂₄+ 1/2 C ₆H ₅CH ₃

Theoretical value: C 64.98, H 8.64, and N 1.79

Experimental value: C 65.07, H 8.77, and N 2.05

Embodiment 3: by compound (15) preparation compound (17)

25 milligrams of (0.0165 mmole) compounds (15) are dissolved in 2.0 milliliters of tetrahydrofuran (THF)s and methyl alcohol (tetrahydrofuran (THF): in mixture methyl alcohol=1: 1), add 70 microlitre 2.14N NaHCO ₃The aqueous solution, and at room temperature stirred 3 hours.Reaction mixture decompression concentrates down, adds 1.0 milliliters of tetrahydrofuran (THF)s and 1.0 ml waters in the residue and stirs 1 hour under room temperature.The mixture that obtains neutralizes with Amberlite IRC50, remove by filter ion exchange resin, decompression is dried filtrate down, the gained residue is dissolved in 2.0 milliliters of tetrahydrofuran (THF)s and methyl alcohol (tetrahydrofuran (THF): methyl alcohol=1: 1) in the mixture, make mixture be alkalescence with the NaOH aqueous solution, concentrating under reduced pressure, residue are dissolved in the mixture of chloroform methanol and water (60: 30: 46) then, purify with cross-linked glucose LH-20 post (1 * 45 centimetre), obtain 12 milligrams of compounds (17) (yield 66%) Rf=0.34 chloroform: methyl alcohol: water=60: 30: 46

Nucleus magnetic resonance (400MHz d, b DMSO 300 TMS)

5.54，H-5′，t，d，J＝6.0，16.4;5.55，H-4′，d，d，J＝7.0，15.6，4.66，bSH-1a eq，4.22，H-3a，ddJ＝4.0，7.0，3.98 H-4a d，J＝2.4，3.90H-3′tJ＝7.01 23，S CH ₂0.85，CH ₃，tJ＝6.4

Embodiment 4: by compound (16) preparation compound (18)

10 milligrams of (0.066 mmole) compounds (16) are dissolved in 2 milliliters of tetrahydrofuran (THF)s and methyl alcohol (1: the 1) mixture.Add 15 microlitre nNaOCH in the solution that obtains ₃And under room temperature, stir and spend the night.Add 10 microlitre n NaOCH in this reaction mixture ₃And at room temperature stirred 4 hours.The solvent in the reaction mixture is removed in decompression down then.Add 2 milliliters of tetrahydrofuran (THF)s and methyl alcohol (1: 1) mixture and 0.5 milliliter of H in the residue ₂O stirs under room temperature and spends the night, and the solvent in the mixture is removed in decompression down, residue cross-linked glucose LH-20 post (CHcl ₃: methyl alcohol: H ₂O=60: 30: 4.6) purifies, obtain 5 milligrams of compounds (18) (yield 68.5%)

Rf=0.386(CHcl ₃: methyl alcohol: H ₂O=60: 30: 4.6)

〔d〕 ²³ _D-2.545（C＝0.165，CHCl ₃∶MeOH＝2∶1）

Nucleus magnetic resonance (400MH ₂D-b DMSO, 300 TMS)

5.52，H-5′，dt，J＝6.6，15.1;

5.34，H-4′，dd，J＝15.4，7.1;

4.07，H-1，aaxJ＝7.6

276，H-3beq，dd，J＝12.5，4.9;

Reference example 3: by compound (20) preparation compound (21)

3 milliliters of pyridines and 3 milliliters of acid anhydrides are joined in 150 milligrams of (0.16 mmole) compounds (20), and make this compound dissolution, 50 milligrams of 4-dimethoxy aminopyridine will be added in the mixture that obtain, and at room temperature stirred 2 days, remove the contained solvent of reaction mixture, (Wakogel C-300,20 restrain toluene to the residue that obtains: methyl alcohol=10: 1) purify with column chromatography.Obtain 180 milligrams of compounds (21) (yield 89%)

Rf=0.439(toluene: methyl alcohol=10: 1)

〔d〕 ¹⁰ _D-19.29（C＝0.985，CHCl ₃）

Reference example 4: by compound (21) preparation compound (22)

Digesting compound (21) with 1.1449 is dissolved in 50 milligrams of methyl alcohol, and under room temperature, carried out catalytic reduction reaction 4 hours with 600 milligrams of 10%Pd-C, use the sellaite filter reaction mixture, underpressure distillation obtains 807 milligrams of compounds (22) (yield 97.9%) Rf=0.64(butanols: ethanol: water=4: 2: 1)

Reference example 5: by compound (22) preparation compound (23)

121 milligrams of (0.174 mmole) compounds (22) are dissolved in the mixture of 3 milliliters of pyridines and 3 milliliters of acid anhydrides, add 20 milligrams of 4-dimethoxy aminopyridine and stir and spend the night, reaction mixture decompression distillation down, residue column chromatography (C-300,20 grams, toluene: methyl alcohol=10: 1) purify, obtain 110.4 milligrams of compounds (23) (yield 72.2%).

Rf=0.259(toluene: methyl alcohol=10: 1)

〔d〕 ¹⁰ _D+26.63（C＝0.995，CHCl ₃）

Ultimate analysis: C ₃₄H ₄₇O ₂₂N ₁+ 1/2 C ₆H ₅CH ₃

Theoretical value: C51.90%, H5.92%, N1.61%

Experimental value: C51.71%, H5.91%, N1.69%

Reference example 6: by compound (23) preparation compound (24)

96 milligrams of (0.12 mmole) compounds (23) are dissolved in 1 milliliter of dimethyl formamide, add 122 milligrams of H ₂NNH ₂AcOH, and under 50 ℃, stirred 5 minutes, in reaction mixture, add ethyl acetate, wash the mixture that obtains anhydrous magnesium sulfate drying, underpressure distillation more then with water.(acetone: tetracol phenixin=1: 1) purify, obtain 69.5% compound (24) yield is 76.4% to residue for C-300,25 grams with column chromatography.

Rf=0.509(acetone: tetracol phenixin)

〔d〕 ¹⁰ _D+36.16（C＝1.015，CHCl ₃）

Embodiment 5: by compound (24) preparation compound (25)

133 milligrams of (0.17 mmole) compounds (24) are dissolved in 1 milliliter of anhydrous ethylene dichloride, under the ice bath cooling, add 0.358 milliliter of cl ₃The DBU of CCN and 12 microlitres (0.085 mmole) also stirred 3 hours.(acetone: purification tetracol phenixin=1: 2) obtains 122 milligrams of compounds (25) (yield 77.4%) to reaction mixture for C-300,20 grams with column chromatography

Rf=0.393(acetone: tetracol phenixin=1: 2)

〔d〕 ¹⁰ _D+35.18（C＝1.00，CHCl ₃）

Embodiment 6: by compound (25) preparation compound (26)

100 milligrams of (0.108 mmole) compounds (25) and 83 milligrams of (0.109 mmole) benzoyl-ceramides of being dissolved in 3 milliliters of chloroforms are added in the 1 mol sieve (acid resistance).Under with ice-methanol bath cooling situation, in mixture, add 15 microlitres (0.124 mmole) boron trifluoride diethyl etherate, under uniform temp, stirred 1 hour, thereafter under room temperature, stir and used the sellaite filter reaction mixture in 24 hours, underpressure distillation, residue column chromatography (C-300,20 grams, toluene: ethyl acetate=1: 2) purify, obtain 20.9 milligrams of compounds (26) yield 12.7%.

Rf=0.25(toluene: ethyl acetate=1: 2)

〔d〕 ¹⁸ _D+8.80（C＝0.25，CHCl ₃）

Ultimate analysis

Theoretical value: C64.18, H8.64, N2.05

Experimental value: C64.03, H8.50, N1.80

Embodiment 7: by compound (26) preparation compound (27)

15 milligrams of (0.0989 mmole) compounds (26) are dissolved in the mixture of 1 milliliter of tetrahydrofuran (THF) and 1 ml methanol, add 25 microlitre 1N NaOCH ₃Under room temperature, stir and spend the night, add 1 milliliter of tetrahydrofuran (THF) in the residue that reaction mixture obtains after underpressure distillation, 1 ml methanol and 0.5 ml water, under room temperature, stir and spend the night, this reaction mixture neutralizes with Amberlite IRC50, filter, decompression distillation down, the gained residue (use trichloromethane: methyl alcohol: water=expansion in 60: 30: 46 with thin-layer chromatography, water=5: 5: 1 extraction) and cross-linked glucose LH-20(trichloromethane use trichloromethane: methyl alcohol:: methyl alcohol: purification water=60: 30: 46) obtains 7.3 milligrams of compounds (27) (yield 67%) and 2.5 milligrams of compounds (28) (yield 23%) compounds (28)

Rf=0.412(trichloromethane: methyl alcohol: water=60: 30: 46)

〔d〕 ²⁴ _D+15.60（C＝0.125，CHCl ₃∶MeOH＝2∶1）

Nucleus magnetic resonance: (400MHzd-bDMSO650TMS)

5.56，H-5′d、t，J＝15.1，7.1;

5.37，H-4′d，d，J＝15.4，6.6;

4.67 H-lae q bS;4.10，H-4a bS

Compound (27)

Rf=0.333(trichloromethane: methyl alcohol: water=60: 30: 46)

(d) ²⁴ _D-13.34(C=0.365, trichloromethane: methyl alcohol=2: 1)

Nucleus magnetic resonance (400MHz d-b DMSO 650 TMS)

5.54，H-5′d，t，J＝1.54，6.6;

5.39，H-4′cd，cd，J＝6.8，15.6;

4.06，H-laax，d，J＝7b;

4.03，H-4a bS

Claims (1)

1, prepare the cerebronic method of representing by the formula III of sialic acid,

R wherein ₈For:

R ₇Be hydrogen or benzoyl, R ₁₁For containing the aliphatic saturated hydrocarbon of 13 carbon atoms, R ₁₂For containing the aliphatic saturated hydrocarbon of 23 carbon atoms; R ₉Be hydrogen or methyl; R ₁Be alone hydrogen or ethanoyl; This method comprises: in methylene dichloride, exist down in DBU, with R ₈Be hydrogen, R ₁Formula II sialic acid derivative for the second ethanoyl

With the Trichloroacetonitrile reaction, generate R ₈For-C (NH) CCl ₃, R ₉Be methyl, R ₁Formula II sialic acid derivative for ethanoyl; In chloroform, at 4A molecular sieve and BF ₃Et ₂O exists down and-10 to 40 ℃, with the benzoyl derivative of the formula II sialic acid derivative that obtains above and following formula ceramide (R wherein ₁₁R ₂₂As above institute

Definition) reaction is 2-5 hour, and then in 20 ℃-40 ℃ reactions 1-24 hour, obtains the mixture of sialic acid cerebroside ester; As needs, in methyl alcohol and tetrahydrofuran compound, to handle the gained mixture with NaOMe and be hydrolyzed, the chromatographic separation hydrolysed mix obtains R ₈, R ₉, R ₁Be the formula III compound of H.