CN103408624A - Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate - Google Patents
Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate Download PDFInfo
- Publication number
- CN103408624A CN103408624A CN2013102825822A CN201310282582A CN103408624A CN 103408624 A CN103408624 A CN 103408624A CN 2013102825822 A CN2013102825822 A CN 2013102825822A CN 201310282582 A CN201310282582 A CN 201310282582A CN 103408624 A CN103408624 A CN 103408624A
- Authority
- CN
- China
- Prior art keywords
- nucleosides
- methyl ester
- amino acid
- acid methyl
- nucleotide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention discloses a method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate by nucleotide H-phosphoramidate intermediate. The method comprises the following steps: obtaining nucleotide-5'-thionyl chloride by performing a non-substitution reaction of phosphorus trichloride with antiviral nucleotide zidovudine or stavudine, by using pyridine as an acid-binding agent, obtaining nucleotide-5'-H-phosphoramidate by performing a substitution reaction of nucleotide-5'-thionyl chloride with amino acid methyl ester, dissolving the nucleotide-5'-H-phosphoramidate in anhydrous pyridine, and then adding triethylamine, water, elemental iodine or elemental sulphur, stirring at room temperature, vacuum-concentrating reaction liquid, and column-chromatographing to obtain the nucleotide-5'-phosphoramidate or the nucleotide-5'-thiophosphoramidate. According to the method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate, the phosphorus trichloride with low cost is served as a phosphorus acylation reagent, and the target product with high yield can be obtained by controlling reaction conditions, selecting the appropriate acid-binding agent and performing the high-efficient gradual substitution reaction.
Description
Technical field
The present invention relates to a kind of by the method for the inferior phosphinylidyne amino acid methyl ester intermediate synthetic nucleosides phosphinylidyne amino acid methyl ester of nucleosides hydrogen and nucleosides thiophosphoryl amino acid methyl ester.
Background technology
Nucleoside medicine is widely used in the treatment of various virus infectiones and tumour clinically.As the analogue of natural nucleus glycoside, this class medicine can be used as the antagonist interference tumour of natural nucleus glycoside or biosynthesizing and the utilization of viral nucleic acid, suppresses copying of virus and cancer cells.But nucleoside medicine has easily the shortcoming such as develop immunity to drugs, cytotoxicity is larger, in clinical application, has been subject to certain limitation.
At first nucleoside medicine must transfer the nucleosides monophosphate to, and then be converted into ribonucleoside triphosphote by the bisphosphate intermediate after entering in body under zymogenesis, final blocking virus DNA reverse transcription reproduction process under the effect of varial polymerases.Pharmacokinetics research shows that monophosphate is the rate-limiting step of nucleoside medicine performance antivirus action.A little less than the avidity of human body cell kinases to nucleoside medicine, especially in the very low cell even lacked of nucleoside kinase activity, the monophosphateization of nucleoside medicine will be affected.Therefore; by in anti-viral nucleoside 5'-position, introducing phosphoryl group; making it enter cell offspring thanks as the nucleosides monophosphate; directly cross the monophosphate process in cell paste; thereby improve its pharmacokinetics character and therapeutic index, become a main focus of antiviral nucleoside prodrug research.
Nucleoside phosphoramidite is the important anti-viral nucleoside prodrug of a class.Such prodrug will contain amino acid ester and with 5'-phosphinylidyne nucleosides fragment, be connected as carrier group with chain alkyl amine etc.Comprising phosphoryl diamine, endoxan, phosphamide monoesters and phosphamide diester.After the phosphoramide types prodrug entered cell, hydrolysis obtained nucleosides-5'-monophosphate through phosphorus nitrogen key, and then the performance pharmacological action.The phosphinylidyne amino acid methyl ester is that effective nucleotide phosphate transmits system, and after the AZT coupling, has become a kind of effective anti-HIV prodrug.According to the literature,
OThe specific activity AZT of-AZT-5'-phosphinylidyne tryptophan methyl ester is high more than 8 times, and toxicity has reduced at least 10 times.In addition, the external activity test shows that nucleosides-5 ￠-thiophosphoryl amino acid methyl ester compound has HIV (human immunodeficiency virus)-resistant activity preferably equally, and hydrolase nucleic acid is had to very strong resistant to hydrolysis ability.The synthetic method of the nucleoside phosphoramidite prodrug of bibliographical information mainly contains following four kinds in recent years.
1. 1996, the phosphate monoester DCC condensation method of the report such as Wagner.The method is to take cytosine arabinoside to be raw material, generates phosphate monoester under the effect of phosphorus oxychloride, and then with amino acid methyl ester under dicyclohexylcarbodiimide (DCC) effect, condensation reaction occurs generate nucleosides
N-Phosphinylidyne amino acid methyl ester, overall yield are 38%.Because condensing agent easily causes side reaction to the overactivity of phosphate monoester, product is difficult for separation and purification.
2. 2000, Wagner etc. reported again hydrogen phosphorous acid monoesters oxidative coupling method.The method is by 3'-azido--2', and 3'-Didansine (AZT, zidovudine) reacts the hydrogen phosphorous acid monoesters that generates AZT with DPP, afterwards again by its silica-basedization, and the iodine oxidation, then it is just synthetic to introduce amino acid methyl ester
O-AZT-5'-phosphinylidyne amino acid methyl ester, overall yield are only 34%, and hydrogen phosphorous acid monoesters reaction intermediate is difficult for purifying.
3. 2000, Stec etc. reported with 2-chloro-1,3, and 2-oxygen sulphur phospholane is as the synthetic method of phosphorus esterification reagent.The method is chloro-1,3 by amino acid methyl ester and 2-, and 2-oxygen sulphur phospholane and sulphur simple substance react the pentavalent phosphorus intermediate obtained in pyridine, then with AZT, react and obtain the thiophosphoryl amino acid methyl ester under strong alkaline condition, and productive rate is 77%.This method need to prepare special phosphorus esterification reagent, and the thioether by product produced is poisonous and stench.
4. 2002, doctor Miao Zhiwei reported the method with phosphorus thiochloride synthetic nucleosides-5 ￠-carbaminothioic acid methyl esters.The method is to occur progressively to replace respectively at amino acid methyl ester and nucleosides with phosphorus thiochloride, and hydrolysis obtains nucleosides-5'-carbaminothioic acid methyl esters in ammoniacal liquor subsequently, and productive rate is 63%-80%.Phosphorus thiochloride has very large toxicity, and speed of response is slow.
Summary of the invention
Purpose of the present invention just is to provide a kind of novelty, general and efficiently by the method for the inferior phosphinylidyne amino acid methyl ester intermediate synthetic nucleosides phosphinylidyne amino acid methyl ester of nucleosides hydrogen and nucleosides thiophosphoryl amino acid methyl ester.
Of the present invention by the method for the inferior phosphinylidyne amino acid methyl ester intermediate synthetic nucleosides phosphinylidyne amino acid methyl ester of nucleosides hydrogen and nucleosides thiophosphoryl amino acid methyl ester, comprise the following steps:
The synthetic method of the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen intermediate:
1, the phosphorus trichloride and the anti-viral nucleoside zidovudine (AZT that with 5-6, doubly measure, as material in Fig. 1 1) or stavudine (d4T, as material in Fig. 1 2) single substitution reaction occurs in dry methylene dichloride obtain the inferior phosphinylidyne dichloro (material 3 or 4 in as Fig. 1) of nucleosides-5'-.
2, using pyridine as acid binding agent, the inferior phosphinylidyne dichloro of nucleosides-5'-and amino acid methyl ester (as material 5-9 in Fig. 1) are carried out to substitution reaction, obtain chloro phosphoramidite intermediate, be hydrolyzed again and obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen crude product, through flash column chromatography for separation, obtain the inferior phosphinylidyne amino acid methyl ester (as material 10-19 in Fig. 1) of nucleosides-5'-hydrogen, productive rate is 65%-75%.
The synthetic method of nucleosides-5'-phosphinylidyne amino acid methyl ester: the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen is dissolved in to anhydrous pyridine, then add triethylamine, water, finally add elemental iodine, stirring at room 1 hour, the concentrating under reduced pressure reaction solution, obtain brown oil, column chromatography for separation obtains yellow oily nucleosides-5 ￠-phosphinylidyne amino acid methyl ester (as material 20-29 in Fig. 2), and productive rate is 85%-89%.
The synthetic method of nucleosides-5'-thiophosphoryl amino acid methyl ester: the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen is dissolved in to anhydrous pyridine, add again sulphur simple substance, after stirring at room 4 h, add triethylamine, reaction solution is flavescence immediately, after 5 minutes, the concentrating under reduced pressure reaction solution, resistates is dissolved in to methyl alcohol, precipitate and remove by filter sulphur simple substance, filtrate is concentrated into dry, obtains brown oil, column chromatography for separation obtains yellow oily nucleosides-5'-thiophosphoryl amino acid methyl ester (as material 30-39 in Fig. 2), and productive rate is 84%-91%.
Of the present invention by the method for the inferior phosphinylidyne amino acid methyl ester intermediate synthetic nucleosides phosphinylidyne amino acid methyl ester of nucleosides hydrogen and nucleosides thiophosphoryl amino acid methyl ester, the cheap phosphorus trichloride of take is phosphorus acylated reagent, by controlling reaction conditions and selecting suitable acid binding agent, by progressively substitution reaction efficiently, the inferior phosphinylidyne amino acid methyl ester of nucleosides chloro, in-situ hydrolysis and flash column chromatography can obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen new intermediate, by iodine oxidation and sulphur oxidation can high yield obtain anti-viral nucleoside-5'-phosphinylidyne amino acid methyl ester and thiophosphoryl amino acid methyl ester product.
The accompanying drawing explanation
Fig. 1 is the reactions steps diagram of the inventive method;
Fig. 2 is the reactions steps diagram of the inventive method.
Embodiment
Embodiment 1:
OSynthesizing of the inferior phosphinylidyne phenylalanine methyl ester of-AZT-5'-hydrogen (as material in Fig. 1 10): 1) under argon shield, phosphorus trichloride (1.37 g, 10 mmol) is dissolved in to dry methylene dichloride (10 mL).After reaction system is cooled to-20 ℃ with the cryosel bath, by nucleosides zidovudine AZT(267 mg, 1 mmol) add rapidly reaction flask, at low temperatures, AZT reacts and dissolves (approximately 1 h) gradually.Then, will react and automatically rise to room temperature, continue reaction 2 h.The concentrating under reduced pressure reactant, revolve and desolventize and excessive phosphorus trichloride, obtains the white foam shape
OThe inferior phosphinylidyne dichloro of-AZT-5'-.2) under argon shield, phenylalanine methyl ester hydrochloride (216 mg, 1 mmol) and dry triethylamine (0.14 mL, 1 mmol) are dissolved in to dry methylene dichloride (10 mL), stir after 10 minutes, the hydrochloride of amino acid methyl ester all dissolves.Under argon shield, incite somebody to action with dry methylene dichloride (10 mL) equally
OThe inferior phosphinylidyne dichloro of-AZT-5'-dissolution of solid, then, dropwise add anhydrous pyridine (0.2 mL, 2.5 mmol) wherein, after 5 minutes, produces gradually tiny uniform white particle in original limpid solution, and flavescence slightly.Under-20 ℃ of conditions, the dichloromethane solution of amino acid methyl ester slowly is added drop-wise in the inferior phosphinylidyne dichloro of nucleosides-5'-to whole dropping process need 2 h.Then continue at low temperatures reaction 1 h, then rose to room temperature reaction 30 minutes, then, add water (0.4 mL) in reaction system, it is mixed that reaction solution becomes rapidly.After 5 minutes, with methylene dichloride (80 mL) dilute reaction solution, organic phase is used 30 mL saturated sodium bicarbonate aqueous solutions successively, 2% dilute hydrochloric acid and saturated sodium-chloride water solution washing.Organic phase is after anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtain the white foam shape
OThe inferior phosphinylidyne phenylalanine methyl ester of-AZT-5'-hydrogen crude product.Flash column chromatography for separation (pure ethyl acetate), obtain the white foam shape
OThe inferior phosphinylidyne phenylalanine methyl ester of-AZT-5'-hydrogen sterling 320 mg, productive rate: 65%.
Embodiment 2:
OSynthesizing of the inferior phosphinylidyne phenylalanine methyl ester of-d4T-5'-hydrogen (as material in Fig. 1 15): 1) under argon shield, phosphorus trichloride (1.37 g, 10 mmol) is dissolved in to dry methylene dichloride (10 mL).After reaction system is cooled to-20 ℃ with the cryosel bath, by stavudine d4T(229 mg, 1 mmol) add rapidly reaction flask, at low temperatures, d4T reacts and dissolves (approximately 1 h) gradually.Then, will react and automatically rise to room temperature, continue reaction 2 h.The concentrating under reduced pressure reactant, revolve and desolventize and excessive phosphorus trichloride, obtains the white foam shape
OThe inferior phosphinylidyne dichloro of-d4T-5'-.2) under argon shield, phenylalanine methyl ester hydrochloride (216 mg, 1 mmol) and dry triethylamine (0.14 mL, 1 mmol) are dissolved in to dry methylene dichloride (10 mL), stir after 10 minutes, the hydrochloride of amino acid methyl ester all dissolves.Under argon shield, incite somebody to action with dry methylene dichloride (10 mL) equally
OThe inferior phosphinylidyne dichloro of-d4T-5'-dissolution of solid, then, dropwise add anhydrous pyridine (0.2 mL, 2.5 mmol) wherein, after 5 minutes, produces gradually tiny uniform white particle in original limpid solution, and flavescence slightly.Under-20 ℃ of conditions, the dichloromethane solution of amino acid methyl ester slowly is added drop-wise in the inferior phosphinylidyne dichloro of nucleosides-5'-to whole dropping process need 2 h.Then continue at low temperatures reaction 1 h, then rose to room temperature reaction 30 minutes, then, add water (0.4 mL) in reaction system, it is mixed that reaction solution becomes rapidly.After 5 minutes, with methylene dichloride (80 mL) dilute reaction solution, organic phase is used 30 mL saturated sodium bicarbonate aqueous solutions successively, 2% dilute hydrochloric acid and saturated sodium-chloride water solution washing.Organic phase is after anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtain the white foam shape
OThe inferior phosphinylidyne phenylalanine methyl ester of-d4T-5'-hydrogen crude product.Flash column chromatography for separation (pure ethyl acetate), obtain the white foam shape
OThe inferior phosphinylidyne phenylalanine methyl ester of-d4T-5'-hydrogen sterling 314 mg, productive rate: 70%.
Embodiment 3:
OSynthesizing of-AZT-5'-phosphinylidyne phenylalanine methyl ester (as material in Fig. 2 20): will
OThe inferior phosphinylidyne phenylalanine methyl ester of-AZT-5'-hydrogen is (as material in Fig. 1
10, 123 mg, 0.25 mmol) and be dissolved in anhydrous pyridine (2.5 mL), then add triethylamine (0.17 mL, 1.25 mmol), water (51 μ L), finally add elemental iodine (95 mg, 0.375 mmol).Stirring at room 1 h is until reaction solution becomes reddish-brown, and the concentrating under reduced pressure reaction solution, obtain brown oil.Column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=20:1:0.5%), obtain yellow oily
O-AZT-5'-phosphinylidyne phenylalanine methyl ester 131 mg, productive rate: 86%.
Embodiment 4:
O-d4T-5'-phosphinylidyne phenylalanine methyl ester is (as material in Fig. 2
25) synthetic: will
OThe inferior phosphinylidyne phenylalanine methyl ester of-d4T-5'-hydrogen is (as material in Fig. 1
15, 112 mg, 0.25 mmol) and be dissolved in anhydrous pyridine (2.5 mL), then add triethylamine (0.17 mL, 1.25 mmol), water (51 μ L), finally add elemental iodine (95 mg, 0.375 mmol).Stirring at room 1 h is until reaction solution becomes reddish-brown, and the concentrating under reduced pressure reaction solution, obtain brown oil.Column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=20:1:0.5%), obtain yellow oily
O-d4T-5'-phosphinylidyne phenylalanine methyl ester 123 mg, productive rate: 87%.
Embodiment 5:
OSynthesizing of-AZT-5'-thiophosphoryl phenylalanine methyl ester (as material in Fig. 2 30): will
OThe inferior phosphinylidyne phenylalanine methyl ester of-AZT-5'-hydrogen is (as material in Fig. 1
10, 123 mg, 0.25 mmol) and be dissolved in anhydrous pyridine (2.5 mL), then add sublimed sulphur (48 mg, 1.5 mmol).After stirring at room 4 h, add triethylamine (0.17 mL, 1.25 mmol), reaction solution is flavescence immediately.After 5 minutes, the concentrating under reduced pressure reaction solution.Resistates is dissolved in to methyl alcohol (2.5 mL), precipitates and remove by filter sulphur simple substance.Filtrate is concentrated into dry, obtains brown oil.Column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=20:1:0.5%), obtain yellow oily
O-AZT-5'-thiophosphoryl phenylalanine methyl ester 133 mg, productive rate: 85%.
Embodiment 6:
OSynthesizing of-d4T-5'-thiophosphoryl phenylalanine methyl ester (as material in Fig. 2 35): will
OThe inferior phosphinylidyne phenylalanine methyl ester of-d4T-5'-hydrogen is (as material in Fig. 1
15, 112 mg, 0.25 mmol) and be dissolved in anhydrous pyridine (2.5 mL), then add sublimed sulphur (48 mg, 1.5 mmol).After stirring at room 4 h, add triethylamine (0.17 mL, 1.25 mmol), reaction solution is flavescence immediately.After 5 minutes, the concentrating under reduced pressure reaction solution.Resistates is dissolved in to methyl alcohol (2.5 mL), precipitates and remove by filter sulphur simple substance.Filtrate is concentrated into dry, obtains brown oil.Column chromatography for separation (methylene dichloride: methyl alcohol: triethylamine=20:1:0.5%), obtain yellow oily
O-d4T-5'-thiophosphoryl phenylalanine methyl ester 128 mg, productive rate: 88%.
Claims (2)
1. one kind by the method for the inferior phosphinylidyne amino acid methyl ester of nucleosides hydrogen intermediate synthetic nucleosides phosphinylidyne amino acid methyl ester, and it is characterized in that: it comprises the following steps:
The synthetic method of the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen intermediate:
(1), single substitution reaction occurs and obtains the inferior phosphinylidyne dichloro of nucleosides-5'-in the phosphorus trichloride of doubly measuring with 5-6 and nucleosides zidovudine or stavudine in dry methylene dichloride;
(2), using pyridine as acid binding agent, the inferior phosphinylidyne dichloro of nucleosides-5'-and amino acid methyl ester are carried out to substitution reaction, obtain chloro phosphoramidite intermediate, be hydrolyzed again and obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen crude product, obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen through flash column chromatography for separation;
The synthetic method of nucleosides-5'-phosphinylidyne amino acid methyl ester: the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen is dissolved in to anhydrous pyridine, then add triethylamine, water, finally add elemental iodine, stirring at room 1 hour, the concentrating under reduced pressure reaction solution, obtain brown oil, column chromatography for separation obtains yellow oily nucleosides-5'-phosphinylidyne amino acid methyl ester.
2. one kind by the method for the inferior phosphinylidyne amino acid methyl ester of nucleosides hydrogen intermediate synthetic nucleosides thiophosphoryl amino acid methyl ester, and it is characterized in that: it comprises the following steps:
The synthetic method of the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen intermediate:
(1), single substitution reaction occurs and obtains the inferior phosphinylidyne dichloro of nucleosides-5'-in the phosphorus trichloride of doubly measuring with 5-6 and nucleosides zidovudine or stavudine in dry methylene dichloride;
(2), using pyridine as acid binding agent, the inferior phosphinylidyne dichloro of nucleosides-5'-and amino acid methyl ester are carried out to substitution reaction, obtain chloro phosphoramidite intermediate, be hydrolyzed again and obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen crude product, obtain the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen through flash column chromatography for separation;
The synthetic method of nucleosides-5'-thiophosphoryl amino acid methyl ester: the inferior phosphinylidyne amino acid methyl ester of nucleosides-5'-hydrogen is dissolved in to anhydrous pyridine, add again sulphur simple substance, stirring at room, add triethylamine, after 5 minutes, the concentrating under reduced pressure reaction solution, resistates is dissolved in to methyl alcohol, precipitates and remove by filter sulphur simple substance, filtrate is concentrated into dry, obtain brown oil, column chromatography for separation obtains yellow oily nucleosides-5'-thiophosphoryl amino acid methyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102825822A CN103408624A (en) | 2013-07-08 | 2013-07-08 | Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102825822A CN103408624A (en) | 2013-07-08 | 2013-07-08 | Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103408624A true CN103408624A (en) | 2013-11-27 |
Family
ID=49601679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013102825822A Pending CN103408624A (en) | 2013-07-08 | 2013-07-08 | Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103408624A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234102A (en) * | 2021-05-18 | 2021-08-10 | 宁波大学 | Three-coordinate phosphorus derivative and intermediate and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010135569A1 (en) * | 2009-05-20 | 2010-11-25 | Pharmasset, Inc. | N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production |
| CN102695513A (en) * | 2008-12-23 | 2012-09-26 | 吉利德制药有限责任公司 | Nucleoside phosphoramidates |
-
2013
- 2013-07-08 CN CN2013102825822A patent/CN103408624A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102695513A (en) * | 2008-12-23 | 2012-09-26 | 吉利德制药有限责任公司 | Nucleoside phosphoramidates |
| WO2010135569A1 (en) * | 2009-05-20 | 2010-11-25 | Pharmasset, Inc. | N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production |
Non-Patent Citations (5)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113234102A (en) * | 2021-05-18 | 2021-08-10 | 宁波大学 | Three-coordinate phosphorus derivative and intermediate and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5453496A (en) | Polynucleotide phosphorodithioate | |
| McGuigan et al. | Anti-cancer ProTides: tuning the activity of BVDU phosphoramidates related to thymectacin | |
| AU622930B2 (en) | Novel hydrogen phosphonodithioate compositions | |
| CN106795197B (en) | Modified oligonucleotide and preparation method thereof | |
| SLOTIN | Current methods of phosphorylation of biological molecules | |
| US20100137576A1 (en) | 5' o [(n acyl)amidophosphate] and 5' o [(n acyl)amidothiophosphate] and 5' o [(n acyl)amidodithiophosphate] and 5' o [(n acyl)amidoselenophosphate] derivatives of nucleosides and processes for the manufacture thereof | |
| CA3007347C (en) | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 | |
| FI61315B (en) | PROCEDURE FOR FRAMSTATION OF ANTIVIRAL 9- (BETA-D-ARABINOFURANOSYL) PURIN-5'-PHOSPHATE | |
| CN103980318A (en) | Novel nucleoside phosphate prodrug containing substituted benzyl, preparation method and application thereof | |
| WO2006066260A9 (en) | Compositions of and methods for producing phosphorus-chiral monomers and oligomers | |
| Stawinski et al. | Nucleoside H-phosphonates. 14. Synthesis of nucleoside phosphoroselenoates and phosphorothioselenoates via stereospecific selenization of the corresponding H-phosphonate and H-phosphonothioate diesters with the aid of new selenium-transfer reagent, 3H-1, 2-benzothiaselenol-3-one | |
| US10131685B2 (en) | Di- and triphosphate prodrugs | |
| Smith et al. | [94] Preparation of nucleotides and derivatives | |
| Liang et al. | Phosphoramidate and phosphate prodrugs of (−)-β-d-(2R, 4R)-dioxolane-thymine: Synthesis, anti-HIV activity and stability studies | |
| CN103408624A (en) | Method for synthesizing nucleotide phosphoramidate and nucleotide thio-phosphoramidate | |
| Cui et al. | Potential application of thymidylate kinase in nucleoside analogue activation in Plasmodium falciparum | |
| WO1990012022A1 (en) | Polynucleotide phosphorodithioates as therapeutic agents for retroviral infections | |
| EP0651758A4 (en) | Phosphite-borane compounds, and method of making the same. | |
| Králíková et al. | Nucleoside 5′-C-phosphonates: reactivity of the α-hydroxyphosphonate moiety | |
| Rubinstein et al. | A novel method for phosphodiester and internucleotide bond synthesis | |
| CN103193843A (en) | Method for synthesizing nucleoside triphosphate and nucleoside diphosphate from all-protected nucleoside phosphoramidite intermediate through acid catalysis | |
| Li et al. | Synthesis of nucleoside boranophosphoramidate prodrugs conjugated with amino acids | |
| Lin et al. | Synthesis of a boron analogue of glucose-conjugated nucleoside diphosphate: nucleoside α-P-boranodiphosphoglucose | |
| Peyrottes et al. | Mononucleotide prodrug synthetic strategies | |
| Lefebvre et al. | Synthesis, decomposition pathways and “In Vitro” evaluation of bioreversible phosphotriesters of Azt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20131127 |