CN103509067B - By the method for hydrogen monophosphite intermediate synthesis sugar-1-monophosphate - Google Patents
By the method for hydrogen monophosphite intermediate synthesis sugar-1-monophosphate Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis, relate to the synthesis of sugar-1-monophosphate.The inventive method comprises 1) imidazoles and phosphorus trichloride react to obtain tricresyl phosphite imidazoles, and get the acetylize sugar raw material reaction of tricresyl phosphite imidazoles and end position deprotection, in-situ hydrolysis obtains corresponding glycosyl-1-hydrogen monophosphite; 2) with <i>N, two (trimethyl silicon based) ethanamide of O</i>-carries out silatedly obtaining tris phosphite intermediate to glycosyl-1-hydrogen monophosphite, organic bases/elemental iodine system oxidation, in-situ hydrolysis obtains the sugar-1-monophosphate of ethanoyl protection; 3) sodium methylate removes Acetyl Protecting Groups, and through sephadex chromatography purifying, and ion-exchange obtains corresponding high purity sugar-1-monophosphate.The inventive method obtains sugar-1-monophosphate through three steps, and overall yield can reach 75%-85%.Avoid in previous methods and remove by hydrogenation the loss that benzyl brings, be specially adapted to a large amount of preparations of sugar-1-monophosphate.
Description
Technical field
The present invention relates to a kind of novel method for synthesizing by glycosyl-1-hydrogen monophosphite intermediate synthesis sugar-1-monophosphate.
Technical background
Sugar is the principal mode of cyto-architectural important component part and the storage of organism self-energy, participates in signal transduction process much important in organism.Under Starch phosphorylase effect, sugared monophosphate is become after sugar enters cell, it is intermediate important in carbohydrate metabolism process, if G-6-P is the intermediate of many carbohydrate metabolism approach (anaerobic glycolysis, aerobic oxidation, phosphopentose pathway, Glycogen synthesis, glycogenolysis).In addition, in zymochemistry synthesis, utilize glycosyltransferase to prepare various oligosaccharides, glycoconjugate and be necessary for the nucleoside diphosphate sugar of activation containing the glycosyl donor used during glycosyl natural product.Sugar-1-monophosphate is then the important source material of synthetic nucleosides bisphosphate sugar.But owing to lacking the effective chemical synthesis process of this compounds, its market price is very expensive, and supply is few, and most sugar-1-monophosphate needs to be synthesized by multi-step, and productive rate is very low.
At present, chemosynthesis sugar-1-monophosphate mainly contains four kinds of methods.The first is that the people such as Wong report that use side position deprotection glycogen material and phosphoramidite dibenzyl ester alcoholysis reaction occur under acid catalysed conditions and obtain tris phosphite; then in-situ oxidation obtains the sugar-1-monophosphate of two benzyl protection, and last deprotection obtains the method for sugar-1-monophosphate.The method overall yield is generally about 50%, but phosphoramidite dibenzyl ester needs special preparation.The second is that the people such as Nikolaev report the sugar-1-monophosphate using 1-halogeno-sugar raw material and phosphate dibenzyl ester to be obtained by reacting two benzyl protection, and then deprotection obtains the method for sugar-1-monophosphate.The method overall yield is lower, generally about 40%.The third is that the people such as Fairbanks report that use side position deprotection glycogen material and lithium diisopropylamine and tetra-sodium four benzyl ester react, and obtain the sugar-1-monophosphate of two benzyl protection, then deprotection obtains the method for sugar-1-monophosphate.The method reaction overall yield is generally about 60%, but severe reaction conditions, and also tetra-sodium four benzyl ester number lattice are very expensive.4th kind is by glycosyl-1-hydrogen diphosphite, then in-situ oxidation, and deprotection obtains the method for sugar-1-monophosphate, and the productive rate of the report such as Brockhausen is only 8%.Therefore, all there is certain restriction when above method prepares sugar-1-monophosphate in actual applications in a large number.Therefore, set up general, simple and efficient sugar-1-monophosphate chemical synthesis process and there is important actual application value and meaning.
Summary of the invention
The object of the invention is for the chemosynthesis of a series of sugar-1-monophosphate provides a kind of novel, general and efficient method.
The synthesis of the glycosyl-1-monophosphate that the present invention relates to comprises following three steps: 1) imidazoles and phosphorus trichloride react to obtain tricresyl phosphite imidazoles, get tricresyl phosphite imidazoles and end position deprotection acetylize glycogen material (
1-
2,
9-
11) reaction, in-situ hydrolysis obtain glycosyl-1-hydrogen monophosphite (
3-
4,
12-
14), productive rate is 90-95%; 2) use
n,O-bis-(trimethyl silicon based) ethanamide (BSA) carries out silatedly obtaining tris phosphite intermediate to glycosyl-1-hydrogen monophosphite, organic bases/elemental iodine system oxidation, in-situ hydrolysis obtain ethanoyl protection sugar-1-monophosphate (
5-
6,
15-
17), productive rate is 85-89%; 3) sodium methylate removes Acetyl Protecting Groups, through sephadex chromatography purifying, and ion-exchange obtain 5 kinds of high purity sugar-1-monophosphates (
7-
8,
18-
20), productive rate is 96-98%.
As shown in Figure 1 and Figure 2, in present method step one, the molar ratio of phosphorus trichloride and imidazoles is 1:6, the acetylize glycogen material of end position deprotection (
1-
2,
9-
11) be 1:5 to 1:10 with the molar ratio of sub-phosphinylidyne three imidazoles, reaction solvent be selected from anhydrous methylene chloride, acetonitrile, ether, tetrahydrofuran (THF) or 1,2-ethylene dichloride any one, temperature of reaction is 0-30 DEG C, and the reaction times is 2 little of 4 hours; During hydrolysis, the acetylize glycogen material of end position deprotection and the molar ratio of water are 1:5 to 1:20, and temperature of reaction is between 0-30 DEG C, and the reaction times is 5 minutes to 15 minutes.
In present method step 2, silated reagent uses
n,O-bis-(trimethyl silicon based) ethanamide (BSA), glycosyl-1-hydrogen monophosphite (
3-
4,
12-
14) be 1:3 to 1:5 with the molar ratio of BSA, reaction solvent is anhydrous pyridine, tetrahydrofuran (THF), methylene dichloride, acetonitrile, and temperature of reaction is between 0-30 DEG C, and the reaction times is 10 minutes to 30 minutes.During organic bases/elemental iodine system oxidation, organic bases can use Trimethylamine 99, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or diisopropyl ethyl amine, the molar ratio of glycosyl-1-hydrogen monophosphite and organic bases is 1:3 to 1:5, be 1:1 to 1:1.5 with the molar ratio of elemental iodine, temperature of reaction is between 0-30 DEG C, and the reaction times is 10 minutes to 30 minutes; During hydrolysis, the molar ratio of glycosyl-1-hydrogen monophosphite and water is 1:10 to 1:20, and temperature of reaction is between 0-30 DEG C, and the reaction times is 5 minutes to 30 minutes.
In present method step 3, sodium methylate is used to remove ethanoyl, sodium methylate and acetylize sugar-1-monophosphate (
5-
6,
15-
17) molar ratio be 6:1 to 10:1, reaction solvent is anhydrous methanol or ethanol, and temperature of reaction is between 0-30 DEG C, and the reaction times is 2 little of 6 hours.
In order to reach better technique effect, whole building-up reactions is carried out under argon shield.
Patent of the present invention uses cheap phosphorus trichloride and imidazoles Reactive Synthesis tricresyl phosphite imidazoles in advance; do not need purifying directly with acetylize sugared raw material reaction high yield obtain glycosyl-1-hydrogen monophosphite intermediate; compared with the method reported with previous literature, the synthetic yield of glycosyl-1-hydrogen monophosphite brings up to more than 90% by 62%.Glycosyl-1-hydrogen monophosphite original position one pot is silated, and iodine is oxidized, and hydrolysis obtains the sugar-1-monophosphate protected, and the reaction times is at 1 hours, and Reaction Separation productive rate can reach 85-89%.What finally utilize sodium methylate to remove ethanoyl high yield obtains sugar-1-monophosphate.This novel method obtains sugar-1-monophosphate through three steps, and overall yield can reach 75%-85%.The method can be avoided in previous methods and removes by hydrogenation the loss that benzyl brings, and is specially adapted to a large amount of preparations of sugar-1-monophosphate.
Accompanying drawing explanation
The synthetic method of Fig. 1 .L-sugar-1-monophosphate.
The synthetic method of Fig. 2 .D-sugar-1-monophosphate.
Embodiment
embodiment 1:
α-L-rhamnosyl-1-monophosphate disodium salt
7synthesis:
1) under argon shield, imidazoles (14.1g, 207mmol) is dissolved in dry methylene dichloride (100mL), under 0 ° of C, adds phosphorus trichloride (3.0mL, 34.5mmol), react and obtain tricresyl phosphite imidazoles in 0.5 hour, then in reaction flask, instill 2,3,4-
othe dry methylene chloride solution (20mL) of-triacetyl-α-L-rhamnosyl (2.0g, 6.9mmol), rises to 30 ° of C and continues stirring 2 hours, add H
2o(0.62mL) stir 5 minutes, with methylene dichloride (70mL) dilute reaction solution, then wash with the aqueous ammonium chloride solution (50mL × 2) that pH value is 5, then use methylene dichloride (70mL × 2) aqueous phase extracted, collect and merge organic phase, using anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains 2,3,4-
o-triacetyl-α-L-rhamnosyl-1-hydrogen monophosphite crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 adds 0.5% triethylamine), obtains 2,3,4-of colorless oil
o-triacetyl-α-L-rhamnosyl-1-hydrogen monophosphite 2.98g, productive rate is 95%.
2) under argon shield, by 2,3,4-
o-triacetyl-α-L-rhamnosyl-1-hydrogen monophosphite (2.5g; 5.5mmol) be dissolved in dry pyridine (30mL), add BSA(6.75mL, 27.5mmol); silated 10 minutes of 30 ° of C; then add triethylamine (3.8mL, 27.5mmol), then add elemental iodine (2.1g; 8.25mmol); when the color of reaction solution is no longer faded, continue reaction 5 minutes, finally add H
2o(2mL) stir after 5 minutes, concentrating under reduced pressure reaction solution, obtains 2,3,4-
o-triacetyl-α-L-rhamnosyl-1-monophosphate crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 to 5:1 adds 0.5% triethylamine) obtains 2,3,4-
o-triacetyl-α-L-rhamnosyl-1-monophosphate triethylamine salt 2.3g, productive rate is 89%.
3) under argon shield, by 2,3,4-
o-triacetyl-α-L-rhamnosyl-1-monophosphate triethylamine salt (2.0g, 4.25mmol) be dissolved in dry methyl alcohol (30mL), add sodium methylate (1.38g, the methanol solution of sodium methylate (20mL) 25.5mmol) prepared, 30 ° of C react 2 hours, being neutralized to pH with methanol hydrochloride solution (0.1M) is 7, concentrating under reduced pressure reaction solution, obtain α-L-rhamnosyl-1-monophosphate crude product, dextrane gel (SephadexLH-20) column chromatography for separation (deionized water) obtains α-L-rhamnosyl-1-monophosphate sterling, wash-out is exchanged finally by sodium-ion type Zeo-karb, merge containing product elution liquid, concentrating under reduced pressure obtains α-L-rhamnosyl-1-monophosphate disodium salt white solid 1.2g, productive rate is 98%.
embodiment 2:
6-deoxidation-α-L-talose-1-monophosphate disodium salt
8synthesis:
1) under argon shield, imidazoles (14.1g, 207mmol) is dissolved in dry 1,2-ethylene dichloride (100mL); under 0 ° of C, add phosphorus trichloride (3.0mL, 34.5mmol), react and obtain tricresyl phosphite imidazoles in 0.5 hour; then in reaction flask, 2,3,4-is instilled
odrying 1, the 2-dichloroethane solution (20mL) of-triacetyl-6-deoxidation-α-L-talose (2.0g, 6.9mmol), continues stirring 4 hours, adds H under 0 ° of C
2o(1.24mL) stir 15 minutes, with 1,2-ethylene dichloride (70mL) dilute reaction solution, then wash with the aqueous ammonium chloride solution (50mL × 2) that pH value is 5, then use methylene dichloride (70mL × 2) aqueous phase extracted, collect and merge organic phase, using anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains 2,3,4-
o-triacetyl-6-deoxidation-α-L-talose-1-hydrogen monophosphite crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 adds 0.5% triethylamine), obtains 2,3,4-of colorless oil
o-triacetyl-6-deoxidation-α-L-talose-1-hydrogen monophosphite 2.92g, productive rate is 93%.
2) under argon shield, by 2,3,4-
o-triacetyl-6-deoxidation-α-L-talose-1-hydrogen monophosphite (2.5g; 5.5mmol) be dissolved in dry tetrahydrofuran (THF) (30mL), add BSA(4.05mL, 16.5mmol); silated 10 minutes of 30 ° of C; then add Tri-n-Propylamine (3.2mL, 16.5mmol), then add elemental iodine (1.68g; 6.6mmol); when the color of reaction solution is no longer faded, continue reaction 5 minutes, finally add H
2o(2mL) stir after 5 minutes, concentrating under reduced pressure reaction solution, obtains 2,3,4-
o-triacetyl-6-deoxidation-α-L-talose-1-monophosphate crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 to 5:1 adds 0.5% triethylamine) obtains 2,3,4-
o-triacetyl-6-deoxidation-α-L-talose-1-monophosphate triethylamine salt 2.25g, productive rate is 87%.
3) under argon shield, by 2,3,4-
o-triacetyl-6-deoxidation-α-L-talose-1-monophosphate triethylamine salt (2.0g, 4.25mmol) be dissolved in dry methyl alcohol (30mL), add sodium methylate (2.3g, the methanol solution of sodium methylate (30mL) 42.5mmol) prepared, 20 ° of C react 3 hours, being neutralized to pH with methanol hydrochloride solution (0.1M) is 7, concentrating under reduced pressure reaction solution, obtain 6-deoxidation-α-L-talose-1-monophosphate crude product, dextrane gel (SephadexLH-20) column chromatography for separation (deionized water) obtains 6-deoxidation-α-L-talose-1-monophosphate sterling, wash-out is exchanged finally by sodium-ion type Zeo-karb, merge containing product elution liquid, concentrating under reduced pressure obtains 6-deoxidation-α-L-talose-1-monophosphate disodium salt white solid 1.19g, productive rate is 97%.
embodiment 3:
α-D-MANNOSE-1-monophosphate disodium salt
18synthesis:
1) under argon shield, imidazoles (28.2g, 414mmol) is dissolved in dry acetonitrile (150mL), under 0 ° of C, adds phosphorus trichloride (6.0mL, 69mmol), react and obtain tricresyl phosphite imidazoles in 0.5 hour, then in reaction flask, instill 2,3,4,6-
othe dry acetonitrile solution (20mL) of-tetra-acetylated-α-D-MANNOSE (2.4g, 6.9mmol), rises to 30 ° of C and continues stirring 2 hours, add H
2o(0.62mL) stir 5 minutes.Concentrating under reduced pressure reaction solution, dissolves resistates with methylene dichloride (150mL), then washes with the aqueous ammonium chloride solution (50mL × 2) that pH value is 5, then uses methylene dichloride (70mL × 2) aqueous phase extracted, collect and merge organic phase, using anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains 2,3,4,6-
o-tetra-acetylated-α-D-MANNOSE-1-hydrogen monophosphite crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 adds 0.5% triethylamine), obtains 2,3,4,6-of colorless oil
o-tetra-acetylated-α-D-MANNOSE-1-hydrogen monophosphite 3.26g, productive rate is 92%.
2) under argon shield, by 2,3,4,6-
o-tetra-acetylated-α-D-MANNOSE-1-hydrogen monophosphite (2.82g; 5.5mmol) be dissolved in dry acetonitrile (40mL); add BSA(5.4mL, 22.0mmol), under 0 ° of C silated 30 minutes; then triethylamine (3.1mL is added; 22.0mmol), then add elemental iodine (1.54g, 6.0mmol); when the color of reaction solution is no longer faded, continue reaction 30 minutes.Finally under 0 ° of C, add H
2o(1mL) stir 30 minutes, concentrating under reduced pressure reaction solution, obtains 2,3,4,6-
o-tetra-acetylated-α-D-MANNOSE-1-monophosphate crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 to 5:1 adds 0.5% triethylamine) obtains 2,3,4,6-
o-tetra-acetylated-α-D-MANNOSE-1-monophosphate triethylamine salt 2.5g, productive rate is 86%.
3) under argon shield, by 2,3,4,6-
o-tetra-acetylated-α-D-MANNOSE-1-monophosphate triethylamine salt (2.25g, 4.25mmol) be dissolved in dry ethanol (30mL), add sodium methylate (1.84g, the sodium methylate ethanolic soln (25mL) 34mmol) prepared, 0 ° of C reacts 6 hours, being neutralized to pH with ethanol solution hydrochloride (0.1M) is 7, concentrating under reduced pressure reaction solution, obtain α-D-MANNOSE-1-monophosphate crude product, dextrane gel (SephadexLH-20) column chromatography for separation (deionized water) obtains α-D-MANNOSE-1-monophosphate sterling, wash-out is exchanged finally by sodium-ion type Zeo-karb, merge containing product elution liquid, concentrating under reduced pressure obtains α-D-MANNOSE-1-monophosphate disodium salt white solid 1.25g, productive rate is 97%.
embodiment 4:
D-semi-lactosi-1-monophosphate disodium salt
19synthesis:
1) under argon shield, imidazoles (14.1g, 207mmol) is dissolved in dry tetrahydrofuran (THF) (100mL), under 0 ° of C, adds phosphorus trichloride (3.0mL; 34.5mmol), react and obtain tricresyl phosphite imidazoles in 0.5 hour, then in reaction flask, instill 2; 3,4,6-
othe dry tetrahydrofuran solution (20mL) of-tetra-acetylated-D-semi-lactosi (2.4g, 6.9mmol, α: β=2.2:1), continues stirring 4 hours, adds H under 0 ° of C
2o(1.24mL) stir 15 minutes.Concentrating under reduced pressure reaction solution, dissolves resistates with methylene dichloride (150mL), then washes with the aqueous ammonium chloride solution (50mL × 2) that pH value is 5, then uses methylene dichloride (70mL × 2) aqueous phase extracted, collect and merge organic phase, using anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains 2,3,4,6-
o-tetra-acetylated-D-semi-lactosi-1-hydrogen monophosphite crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 adds 0.5% triethylamine), obtains 2,3,4,6-of colorless oil
o-tetra-acetylated-D-semi-lactosi-1-hydrogen monophosphite 3.29g, productive rate is 93%.
2) under argon shield, by 2,3,4,6-
o-tetra-acetylated-D-semi-lactosi-1-hydrogen monophosphite (2.82g; 5.5mmol) be dissolved in dry pyridine (30mL), 30 ° of C add BSA(6.75mL, 27.5mmol); silated 10 minutes; then add diisopropyl ethyl amine (4.8mL, 27.5mmol), then add elemental iodine (1.8g; 7.15mmol); when the color of reaction solution is no longer faded, continue reaction 10 minutes, finally add H
2o(2mL) stir after 5 minutes, concentrating under reduced pressure reaction solution, obtains 2,3,4,6-
o-tetra-acetylated-D-semi-lactosi-1-monophosphate crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 to 5:1 adds 0.5% triethylamine) obtains 2,3,4,6-
o-tetra-acetylated-D-semi-lactosi-1-monophosphate triethylamine salt 2.53g, productive rate is 87%.
3) under argon shield, by 2,3,4,6-
o-tetra-acetylated-D-semi-lactosi-1-monophosphate triethylamine salt (2.25g, 4.25mmol) be dissolved in dry methyl alcohol (30mL), add sodium methylate (2.3g, the methanol solution of sodium methylate (30mL) 42.5mmol) prepared, 30 ° of C react 2 hours, being neutralized to pH with methanol hydrochloride solution (0.1M) is 7, concentrating under reduced pressure reaction solution, obtain D-semi-lactosi-1-monophosphate crude product, dextrane gel (SephadexLH-20) column chromatography for separation (deionized water) obtains D-semi-lactosi-1-monophosphate sterling, wash-out is exchanged finally by sodium-ion type Zeo-karb, merge containing product elution liquid, concentrating under reduced pressure obtains D-semi-lactosi-1-monophosphate disodium salt white solid 1.25g(α: β=2.2:1), productive rate is 97%.
embodiment 5:
D-Glucose-1-monophosphate disodium salt
20synthesis:
1) under argon shield, imidazoles (14.1g, 207mmol) is dissolved in dry methylene dichloride (50mL), under 0 ° of C, adds phosphorus trichloride (3.0mL, 34.5mmol), react and obtain tricresyl phosphite imidazoles in 0.5 hour, then in reaction flask, instill 2,3,4,6-
othe dry methylene chloride solution (20mL) of-tetra-acetylated-D-Glucose (2.4g, 6.9mmol, α: β=3:1), rises to 30 ° of C and continues stirring 2 hours, add H
2o(0.62mL) stir 5min, with methylene dichloride (70mL) dilute reaction solution, then wash with the aqueous ammonium chloride solution (50mL × 2) that pH value is 5, then use methylene dichloride (70mL × 2) aqueous phase extracted, collect and merge organic phase, using anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains 2,3,4,6-
o-tetra-acetylated-D-Glucose-1-hydrogen monophosphite crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 adds 0.5% triethylamine), obtains 2,3,4,6-of colorless oil
o-tetra-acetylated-D-Glucose-1-hydrogen monophosphite 3.19g, productive rate is 90%.
2) under argon shield, by 2,3,4,6-
o-tetra-acetylated-D-Glucose-1-hydrogen monophosphite (2.82g, 5.5mmol) is dissolved in dry tetrahydrofuran (THF) (30mL), adds BSA(6.75mL; 27.5mmol), under 0 ° of C silated 30 minutes, tri-n-butylamine (6.5mL is then added; 27.5mmol), then add I
2(1.68g, 6.6mmol), when the color of reaction solution is no longer faded, continues reaction 30min, finally adds H
2o(2mL) stir after 20 minutes, concentrating under reduced pressure reaction solution, obtains 2,3,4,6-
o-tetra-acetylated-D-Glucose-1-monophosphate crude product, column chromatography for separation (methylene dichloride: methyl alcohol=20:1 to 5:1 adds 0.5% triethylamine) obtains 2,3,4,6-
o-tetra-acetylated-D-Glucose-1-monophosphate triethylamine salt 2.47g, productive rate is 85%.
3) under argon shield, by 2,3,4,6-
o-tetra-acetylated-D-Glucose-1-monophosphate triethylamine salt (2.25g, 4.25mmol) be dissolved in dry methyl alcohol (30mL), add sodium methylate (1.84g, the methanol solution of sodium methylate (25mL) 34mmol) prepared, 0 ° of C reacts 6 hours, being neutralized to pH with methanol hydrochloride solution (0.1M) is 7, concentrating under reduced pressure reaction solution, obtain D-Glucose-1-monophosphate crude product, dextrane gel (SephadexLH-20) column chromatography for separation (deionized water) obtains D-Glucose-1-monophosphate sterling, wash-out is exchanged finally by sodium-ion type Zeo-karb, merge containing product elution liquid, concentrating under reduced pressure obtains D-Glucose-1-monophosphate disodium salt white solid 1.24g(α: β=3:1), productive rate is 96%.
Claims (8)
1. by the method for hydrogen monophosphite intermediate synthesis sugar-1-monophosphate, its feature comprises the steps: 1) imidazoles and phosphorus trichloride react to obtain tricresyl phosphite imidazoles, get tricresyl phosphite imidazoles and L-type or the D-type acetylize sugar raw material reaction of holding position deprotection, in-situ hydrolysis obtains corresponding glycosyl-1-hydrogen monophosphite; The L-acetylize glycogen material of described end position deprotection is
, wherein R
1=OAc, R
2=H or R
1=H, R
2=OAc; D-acetylize glycogen material is
, wherein R
5=OAc, R
6=H, R
7=OAc, R
8=H or R
5=H, R
6=OAc, R
7=H, R
8=OAc or R
5=H, R
6=OAc, R
7=OAc, R
8=H; 2) use
n,O-bis-(trimethyl silicon based) ethanamide BSA carries out silatedly obtaining tris phosphite intermediate to glycosyl-1-hydrogen monophosphite, organic bases/elemental iodine system oxidation, and in-situ hydrolysis obtains the sugar-1-monophosphate of ethanoyl protection; 3) sodium methylate removes Acetyl Protecting Groups, and through sephadex chromatography purifying, and ion-exchange obtains corresponding high purity sugar-1-monophosphate.
2. the method for claim 1; it is characterized in that in described step 1); the molar ratio of phosphorus trichloride and imidazoles is 1:6; the acetylize glycogen material of end position deprotection and the molar ratio of sub-phosphinylidyne three imidazoles are 1:5 to 1:10; reaction solvent is selected from anhydrous methylene chloride, acetonitrile, ether, tetrahydrofuran (THF) or 1,2-ethylene dichloride any one; temperature of reaction is 0-30 DEG C, and the reaction times is 2 little of 4 hours.
3. the method for claim 1, is characterized in that in described step 1), and during in-situ hydrolysis, the acetylize glycogen material of end position deprotection and the molar ratio of water are 1:5 to 1:20, and temperature of reaction is between 0-30 DEG C, and the reaction times is 5 minutes to 15 minutes.
4. the method for claim 1, is characterized in that described step 2) in, silated reagent uses
n,O-bis-(trimethyl silicon based) ethanamide BSA, the molar ratio of glycosyl-1-hydrogen monophosphite and BSA is 1:3 to 1:5, and reaction solvent is selected from anhydrous pyridine, tetrahydrofuran (THF), methylene dichloride, or acetonitrile any one, temperature of reaction is between 0-30 DEG C, and the reaction times is 10 minutes to 30 minutes.
5. the method for claim 1, it is characterized in that described step 2) in, during organic bases/elemental iodine system oxidation, organic bases is selected from Trimethylamine 99, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine or diisopropyl ethyl amine, the molar ratio of glycosyl-1-hydrogen monophosphite and organic bases is 1:3 to 1:5, be 1:1 to 1:1.5 with the molar ratio of elemental iodine, temperature of reaction is between 0-30 DEG C, and the reaction times is 10 minutes to 30 minutes.
6. the method for claim 1, is characterized in that described step 2) in, during hydrolysis, the molar ratio of glycosyl-1-hydrogen monophosphite and water is 1:10 to 1:20, and temperature of reaction is between 0-30 DEG C, and the reaction times is 5 minutes to 30 minutes.
7. the method for claim 1; it is characterized in that in described step 3); sodium methylate is used to remove ethanoyl; the molar ratio of sodium methylate and acetylize sugar-1-monophosphate is 6:1 to 10:1; reaction solvent is anhydrous methanol or ethanol; temperature of reaction is between 0-30 DEG C, and the reaction times is 2 little of 6 hours.
8. the method for claim 1, is characterized in that whole building-up reactions is carried out under argon shield.
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| CN103242432A (en) * | 2013-02-07 | 2013-08-14 | 江西科技师范大学 | Method for synthesizing phosphoramidon by utilizing hydrogen phosphorous acid diester intermediate |
| CN103254260A (en) * | 2013-02-07 | 2013-08-21 | 江西科技师范大学 | Method for synthesizing symmetric dinucleoside diphosphate disodium salt from nucleoside hydrogen phosphite monoester |
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| CN103242432A (en) * | 2013-02-07 | 2013-08-14 | 江西科技师范大学 | Method for synthesizing phosphoramidon by utilizing hydrogen phosphorous acid diester intermediate |
| CN103254260A (en) * | 2013-02-07 | 2013-08-21 | 江西科技师范大学 | Method for synthesizing symmetric dinucleoside diphosphate disodium salt from nucleoside hydrogen phosphite monoester |
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