CN103509074A - Synthesis method of nucleoside diphosphate 6-deoxy-L-pyranose - Google Patents

Synthesis method of nucleoside diphosphate 6-deoxy-L-pyranose Download PDF

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CN103509074A
CN103509074A CN201310469050.XA CN201310469050A CN103509074A CN 103509074 A CN103509074 A CN 103509074A CN 201310469050 A CN201310469050 A CN 201310469050A CN 103509074 A CN103509074 A CN 103509074A
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monophosphate
nucleoside diphosphate
nucleosides
glycosyl
nucleoside
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孙麒
龚珊珊
李星见
蒲守智
刘刚
刘国栋
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Jiangxi Science and Technology Normal University
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Abstract

The invention belongs to the field of chemical synthesis, and relates to a synthesis method of nucleoside diphosphate saccharide. The synthesis method comprises the following steps: 1) taking fully-protected nucleoside phosphoryl piperidine, removing all protecting groups through palladium carbon catalytic hydrogenation in an N,N-dimethylformamide or dimethylsulfoxide solution, and filtering to remove palladium and carbon to obtain corresponding deprotected nucleoside phosphoryl piperidine; 2) adding glycosyl-1-monophosphate and 4, 5-dicyanoimidazole (DCI) into the nucleoside phosphoryl piperidine, and reacting to obtain a nucleoside diphosphate saccharide product; 3) performing ethanol precipitation, reverse phase C18HPLC (high performance liquid chromatography) purification and final ion exchange on a crude product to obtain corresponding nucleoside diphosphate 6-deoxy-L-pyranose with high purity. By the synthesis method, the yield is high, the reaction time is short and the product separation is simple; therefore, the synthesis method has a high application value.

Description

The synthetic method of nucleoside diphosphate 6-deoxidation-L-pyranose
Technical field
The invention belongs to the chemical preparation technical field of natural product, relate to a kind of by the novel method of nucleosides phosphinylidyne piperidines method synthetic nucleosides bisphosphate 6-deoxidation-L-pyranose.
Technical background
The sugar principal mode that still cyto-architectural important component part and organism self-energy are not stored, and participate in many important signal transduction process in organism.The polysaccharide of cell surface is binding site and bacterium and the viral sites of infection of many important biomolecule molecules (as hormone, lectin and bacteriotoxin etc.).In the lipopolysaccharides on numerous gram negative bacterium surfaces, just contain 6-deoxidation-L-pyranose structural units such as a large amount of L-rhamnosyls.Meanwhile, 6-deoxidation-L-pyranose is also indispensable structural unit in the Multiple Classes of Antibiotics that produces of gram positive bacterium.The nucleotide sugar that bacterium glycosyltransferase utilizes builds cell walls and cell-surface antigens, and the glycosylation of many little bioactive moleculess.Glycosyltransferase, because having good substrate adaptability and stereoselectivity, just is more and more being applied to prepare oligosaccharides, glycoconjugate and is being contained glycosyl natural product, and the required glycosyl donor of glycosyltransferase is nucleoside diphosphate sugar.Therefore, synthetic nucleosides bisphosphate 6-deoxidation-L-pyranose is for disclosing microbial life process, and the biology Disciplinary Frontiers such as the microbiotic of development of new all have great significance.
Nucleoside diphosphate sugar is as the important intermediate of glycosyl compound, the kind existing at occurring in nature seldom, only have only a few nucleoside diphosphate sugar can by market buy and price very expensive.Mainly there is following difficult point in the chemosynthesis of nucleoside diphosphate sugar: 1), due to high polarity in molecular structure and charged groups existence, reaction raw materials solubleness in organic solvent is low; 2) reaction specificity is poor, and productive rate is low; 3) product is complicated, is difficult for purifying; 4) bisphosphate in product is easily hydrolyzed.
At present, synthetic nucleosides bisphosphate sugar mainly contains two class methods.First kind method is that nucleosides-5 of glycosyl-1-phosphoric acid and activation '-monophosphate is carried out to coupling.Activation nucleosides-5 of bibliographical information '-monophosphate mainly contains phosphinylidyne morpholine and phosphinylidyne imidazoles.Wherein phosphinylidyne imidazoles and glycosyl-1-monophosphate speed of response are slow, generally need 1 to 2 day, and productive rate only has 20% to 40% left and right conventionally.When phosphinylidyne morpholine and glycosyl-1-phosphoric acid linked reaction, speed is more slow, conventionally need several days to one week, and productive rate is lower, is only 20% left and right.According to the report of Wong and Kahne, weakly acidic 1 h-tetrazole and n-Methylimidazole hydrochloride can foreshorten to reaction 12 hours to 2 days effectively.In the situation that phosphinylidyne morpholine is excessive, reaction yield can obtain 70% left and right, but nucleosides monophosphate and product polarity that problem of the consequent is phosphinylidyne morpholine hydrolysis to be obtained are very close, extremely difficultly by conventional method, removes.Equations of The Second Kind method is that 1-halogeno-sugar or 1,2-anhydrosugar and nucleosides-5 '-bisphosphate are carried out to coupling, but the method reaction yield is relatively low, is only 30% to 50% left and right conventionally, and lacks the control to product end position steric configuration.Therefore, the method is subject to certain restrictions in actual applications.
Summary of the invention
The object of the invention is provides a kind of novelty, general and efficient method for the chemosynthesis of nucleoside diphosphate 6-deoxidation-L-pyranose.
The synthetic method of the nucleoside diphosphate 6-deoxidation-L-pyranose the present invention relates to comprises two consecutive steps: 1) full guard nucleosides phosphinylidyne piperidines 1-2? n, nin-dimethyl formamide or dimethyl sulphoxide solution, by palladium carbon catalytic hydrogenation, remove whole protecting groups, remove by filter after palladium carbon, obtain corresponding deprotection nucleosides phosphinylidyne piperidines; 2) to add in nucleosides phosphinylidyne piperidines glycosyl-1-monophosphate ( 3-4) and 4,5-dicyano imidazole (DCI), reaction obtains nucleoside diphosphate sugar product.Crude product precipitates through ethanol, anti-phase C18 HPLC purifying, and final ion-exchange obtains 4 kinds of high purity nucleoside diphosphate 6-deoxidation-L-pyranoses 5-8, productive rate is 70-75%.
As shown in Figure 1, in present method step 1), palladium carbon is 5% or 10% palladium carbon, itself and full guard nucleosides phosphinylidyne piperidines 1-2mass ratio be between 1:10 to 1:20; The organic bases of tiing up sour use in catalytic hydrogenation process is selected from Trimethylamine 99, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine, any one or several mixtures of diisopropyl ethyl amine, and the molar ratio of full guard nucleosides phosphinylidyne piperidines and organic bases is between 1:1 to 1:1.2; Hydrogenation pressure is 1 normal atmosphere; Reaction solvent is n, n-dimethyl formamide or dimethyl sulfoxide (DMSO), temperature of reaction is between 20 ℃ to 40 ℃; Reaction times was at 1 hour to 3 hours.
Present method step 2) in, described glycosyl-1-monophosphate is glycosyl-1-monophosphate (triethylamine) salt, and the molar ratio of nucleosides phosphinylidyne piperidines and glycosyl-1-monophosphate list (triethylamine) salt is between 1:1 to 1:2; The molar ratio of 4,5-dicyano imidazole and nucleosides phosphinylidyne piperidines is 3:1 to 6:1; Temperature of reaction is between 30 ℃ to 40 ℃; Reaction times was at 4 hours to 6 hours.
Nucleosides phosphinylidyne piperidines/4 that patent of the present invention relates to, 5-dicyano imidazole system and nucleosides phosphinylidyne morpholine/1 that Wong and Kahne report in the past h-tetrazole and nucleosides phosphinylidyne morpholine/ n-methylimidazole salt silicate system is compared, and in nucleoside diphosphate 6-deoxidation-L-pyranose synthetic, the reaction times can be shortened to 4 hours to 6 hours by original 12 hours to 48 hours.Meanwhile, this novel method is under the excessive condition of sugared monophosphate, and reaction yield still can reach more than 70%, solved the excessive hydrolysising by-product causing of phosphinylidyne morpholine in previous methods, be nucleosides monophosphate, very close with product polarity, be difficult to by a difficult problem for ordinary method separation.Therefore, this novel method is of very high actual application value in the chemosynthesis of nucleoside diphosphate saccharide compound.
Accompanying drawing explanation
Fig. 1. the synthetic method of nucleoside diphosphate 6-deoxidation-L-pyranose.
Embodiment
embodiment 1:
Uridine 5 '-bisphosphate-α-L-rhamnosyl disodium salt 5synthetic: will n-( o-benzyl- o-(2 ', 3 '-bis-carbobenzoxy-(Cbz)s) uridine-5 '-) phosphinylidyne piperidines 1(100 mg, 0.13 mmol), 10% palladium carbon (5 mg, part by weight 5%) and triethylamine (18 μ L, 0.13 mmol) are dissolved in dry n, n-dimethyl formamide (1 mL), 20 ℃ of normal pressure hydrogenations 3 hours.After hydrogenation, use aperture 0.45 μ m filter membrane to remove after palladium carbon, solution adds α-L-rhamnosyl-1-monophosphate (triethylamine) salt (67 mg, 0.195 mmol), 4, and 5-dicyano imidazole (61 mg, 0.52 mmol) stirs 6 hours at 30 ℃.After reaction finishes, concentrated solvent.After adding sodium acetate aqueous solution (10 M, 0.5 mL) to dissolve in residue, add ethanol (50 mL) precipitated product, centrifugal uridine 5 '-bisphosphate-α-L-rhamnosyl sodium salt crude product that obtains.Use reversed-phase HPLC (XTerra Prep MS C18 OBD tM10 μ m, 19 * 250 mm Column) linear elution (95% triethyl bicarbonate of ammonia (TEAB, 10 mM)/5% methyl alcohol to 80% triethyl bicarbonate of ammonia/20% methyl alcohol, 15 minutes), merge containing product elutriant, concentrating under reduced pressure obtains white uridine 5 '-bisphosphate-α-L-rhamnosyl triethylamine salt solid.Triethylamine salt type product is dissolved in deionized water (1 mL), and through sodium-ion type Zeo-karb exchange wash-out, then concentrating under reduced pressure obtains uridine 5 '-bisphosphate-α-L-rhamnosyl disodium salt white solid 58 mg, productive rate: 75%.
embodiment 2:
Thymidine 5 '-bisphosphate-α-L-rhamnosyl disodium salt 6synthetic: will n-( o-benzyl- o-(3 '-carbobenzoxy-(Cbz)) thymidine-5 '-) phosphinylidyne piperidines 2(80 mg, 0.13 mmol), 5% palladium carbon (8 mg, part by weight 10%) and Tri-n-Propylamine (25 μ L, 0.13 mmol) are dissolved in dry n, n-dimethyl formamide (1 mL), 30 ℃ of normal pressure hydrogenations 2 hours.After hydrogenation, use aperture 0.45 μ m filter membrane to remove after palladium carbon, solution adds α-L-rhamnosyl-1-monophosphate (triethylamine) salt (67 mg, 0.195 mmol), 4, and 5-dicyano imidazole (61 mg, 0.52 mmol) stirs 4 hours at 40 ℃.After reaction finishes, concentrated solvent.After adding sodium acetate aqueous solution (10 M, 0.5 mL) to dissolve in residue, add ethanol (50 mL) precipitated product, centrifugal thymidine 5 '-bisphosphate-α-L-rhamnosyl sodium salt crude product that obtains.Use reversed-phase HPLC (XTerra Prep MS C18 OBD tM10 μ m, 19 * 250 mm Column) linear elution (95% triethyl bicarbonate of ammonia (TEAB, 10 mM)/5% methyl alcohol to 80% triethyl bicarbonate of ammonia/20% methyl alcohol, 15 minutes), merge containing product elutriant, concentrating under reduced pressure obtains white thymidine 5 '-bisphosphate-α-L-rhamnosyl triethylamine salt solid.Triethylamine salt type product is dissolved in deionized water (1 mL), and through sodium-ion type Zeo-karb exchange wash-out, then concentrating under reduced pressure obtains thymidine 5 '-bisphosphate-α-L-rhamnosyl disodium salt white solid 56 mg, productive rate: 73%.
embodiment 3:
Uridine 5 '-bisphosphate-6-deoxidation-α-L-talose disodium salt 7synthetic: will n-( o-benzyl- o-(2 ', 3 '-bis-carbobenzoxy-(Cbz)s) uridine-5 '-) phosphinylidyne piperidines 1(100 mg, 0.13 mmol), 10% palladium carbon (10 mg, part by weight 10%) and diisopropyl ethyl amine (21 μ L, 0.13 mmol) are dissolved in dry n, n-dimethyl formamide (1 mL), 40 ℃ of normal pressure hydrogenations 1 hour.After hydrogenation, use aperture 0.45 μ m filter membrane to remove after palladium carbon, solution adds 6-deoxidation-α-L-talose-1-monophosphate (triethylamine) salt (89 mg, 0.26 mmol), 4, and 5-dicyano imidazole (77 mg, 0.65 mmol) stirs 6 hours at 30 ℃.After reaction finishes, concentrated solvent.After adding sodium acetate aqueous solution (10 M, 0.5 mL) to dissolve in residue, add ethanol (50 mL) precipitated product, the centrifugal uridine 5 '-bisphosphate-6-deoxidation-α-L-talose sodium salt crude product that obtains.Use reversed-phase HPLC (XTerra Prep MS C18 OBD tM10 μ m, 19 * 250 mm Column) linear elution (95% triethyl bicarbonate of ammonia (TEAB, 10 mM)/5% methyl alcohol to 80% triethyl bicarbonate of ammonia/20% methyl alcohol, 15 minutes), merge containing product elutriant, concentrating under reduced pressure obtains white uridine 5 '-bisphosphate-6-deoxidation-α-L-talose triethylamine salt solid.Triethylamine salt type product is dissolved in deionized water (1 mL), and through sodium-ion type Zeo-karb exchange wash-out, then concentrating under reduced pressure obtains uridine 5 '-bisphosphate-6-deoxidation-α-L-talose disodium salt white solid 55 mg, productive rate: 71%.
embodiment 4:
Thymidine 5 '-bisphosphate-6-deoxidation-α-L-talose disodium salt 8synthetic: will n-( o-benzyl- o-(3 '-carbobenzoxy-(Cbz)) thymidine-5 '-) phosphinylidyne piperidines 2(80 mg, 0.13 mmol), 10% palladium carbon (4 mg, part by weight 5%) and tri-n-butylamine (38 μ L, 0.16 mmol) are dissolved in dry dimethyl sulfoxide (DMSO) (1 mL), 20 ℃ of normal pressure hydrogenations 3 hours.After hydrogenation, use aperture 0.45 μ m filter membrane to remove after palladium carbon, solution adds 6-deoxidation-α-L-talose-1-monophosphate (triethylamine) salt (76 mg, 0.22 mmol), 4, and 5-dicyano imidazole (77 mg, 0.65 mmol) stirs 4 hours at 40 ℃.After reaction finishes, concentrated solvent.After adding sodium acetate aqueous solution (10 M, 0.5 mL) to dissolve in residue, add ethanol (50 mL) precipitated product, the centrifugal thymidine 5 '-bisphosphate-6-deoxidation-α-L-talose sodium salt crude product that obtains.Use reversed-phase HPLC (XTerra Prep MS C18 OBD tM10 μ m, 19 * 250 mm Column) linear elution (95% triethyl bicarbonate of ammonia (TEAB, 10 mM)/5% methyl alcohol to 80% triethyl bicarbonate of ammonia/20% methyl alcohol, 15 minutes), merge containing product elutriant, concentrating under reduced pressure obtains white thymidine 5 '-bisphosphate-6-deoxidation-α-L-talose triethylamine salt solid.Triethylamine salt type product is dissolved in deionized water (1 mL), and through sodium-ion type Zeo-karb exchange wash-out, then concentrating under reduced pressure obtains thymidine 5 '-bisphosphate-6-deoxidation-α-L-talose disodium salt white solid 54 mg, productive rate: 70%.

Claims (3)

1. the synthetic method of nucleoside diphosphate 6-deoxidation-L-pyranose, is characterized in that comprising the steps: 1) get full guard nucleosides phosphinylidyne piperidines , R wherein 1=H, R 2=OCbz; Or R 1=CH 3, R 2=H; ? n, nin-dimethyl formamide or dimethyl sulphoxide solution, by palladium carbon catalytic hydrogenation, remove whole protecting groups, remove by filter after palladium carbon, obtain corresponding deprotection nucleosides phosphinylidyne piperidines; 2) in nucleosides phosphinylidyne piperidines, add glycosyl-1-monophosphate and 4,5-dicyano imidazole DCI, reaction obtains nucleoside diphosphate sugar product; 3) crude product precipitates through ethanol, anti-phase C18 HPLC purifying, and final ion-exchange obtains corresponding high purity nucleoside diphosphate 6-deoxidation-L-pyranose.
2. synthetic method as claimed in claim 1, is characterized in that in described step 1), and palladium carbon is 5% or 10% palladium carbon, and the mass ratio of itself and full guard nucleosides phosphinylidyne piperidines is between 1:10 to 1:20; The organic bases of tiing up sour use in catalytic hydrogenation process is selected from Trimethylamine 99, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine, diisopropyl ethyl amine; The molar ratio of full guard nucleosides phosphinylidyne piperidines and organic bases is between 1:1 to 1:1.2; Hydrogenation pressure is 1 normal atmosphere; Temperature of reaction is between 20 ℃ to 40 ℃; Reaction times was at 1 hour to 3 hours.
3. synthetic method as claimed in claim 1, it is characterized in that described step 2) in, described glycosyl-1-monophosphate is glycosyl-1-monophosphate (triethylamine) salt, and the molar ratio of nucleosides phosphinylidyne piperidines and glycosyl-1-monophosphate (triethylamine) salt is between 1:1 to 1:2; The molar ratio of 4,5-dicyano imidazole and nucleosides phosphinylidyne piperidines is 3:1 to 6:1; Temperature of reaction is between 30 ℃ to 40 ℃; Reaction times was at 4 hours to 6 hours.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910774A (en) * 2014-04-09 2014-07-09 江西科技师范大学 Method for synthesizing dinucleoside diphosphate and dinucleoside triphosphote
WO2016187522A1 (en) * 2015-05-20 2016-11-24 Noramco, Inc. Process for the preparation of oxymorphone freebase

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WO2008028050A2 (en) * 2006-08-30 2008-03-06 Wisconsin Alumni Research Foundation Reversible natural product glycosyltransferase-catalyzed reactions, compounds and related methods
CN1944661A (en) * 2006-09-28 2007-04-11 苏州天马医药集团天吉生物制药有限公司 Process for preparing citicoline sodium
CN101451126A (en) * 2008-12-26 2009-06-10 北京大学 Uridine diphosphate-4-one-6-deoxyglucose heterogeneous reductase and coding gene thereof and application
CN103193843A (en) * 2013-04-15 2013-07-10 江西科技师范大学 Method for synthesizing nucleoside triphosphate and nucleoside diphosphate from all-protected nucleoside phosphoramidite intermediate through acid catalysis

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910774A (en) * 2014-04-09 2014-07-09 江西科技师范大学 Method for synthesizing dinucleoside diphosphate and dinucleoside triphosphote
WO2016187522A1 (en) * 2015-05-20 2016-11-24 Noramco, Inc. Process for the preparation of oxymorphone freebase

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Application publication date: 20140115