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WO2014094312A1 - Procédé de synthèse par catalyse enzymatique de dérivés aminés sous forme de nucléosides - Google Patents

Procédé de synthèse par catalyse enzymatique de dérivés aminés sous forme de nucléosides Download PDF

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Publication number
WO2014094312A1
WO2014094312A1 PCT/CN2012/087204 CN2012087204W WO2014094312A1 WO 2014094312 A1 WO2014094312 A1 WO 2014094312A1 CN 2012087204 W CN2012087204 W CN 2012087204W WO 2014094312 A1 WO2014094312 A1 WO 2014094312A1
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Prior art keywords
ester
reaction
serine
cysteine
lipase
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Chinese (zh)
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李金亮
张仙
赵楠
金圣芳
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Shanghai Desano Chemical Pharmaceutical Co Ltd
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Shanghai Desano Chemical Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/38—Nucleosides

Definitions

  • the invention belongs to the technical field of biocatalysis synthesis, and particularly relates to a method for enzymatically synthesizing a nucleoside amino acid derivative. Background technique
  • nucleoside drugs have received extensive attention for the treatment of viral diseases.
  • clinically used nucleoside drugs have problems such as toxic side effects and drug resistance.
  • Nucleoside prodrugs can improve the oral bioavailability and pharmacokinetics of nucleoside drugs, target drugs to specific lesions, prolong the action time, reduce toxic side effects, improve antiviral effect, expand antiviral spectrum, and modify nucleosides.
  • An important direction of drug-like structure For example, valacyclovir is acyclovir L-valine methyl ester, which can improve the malabsorption of acyclovir by oral administration. It can be well absorbed in the gastrointestinal tract after oral administration and completely hydrolyzed by enzyme.
  • Cytarabine is mainly used in the treatment of acute leukemia, including lung cancer, digestive tract cancer, head and neck cancer and malignant lymphoma. It is an anti-metabolic drug, which is improved by improving the molecular structure of the drug. An important way.
  • nucleoside drugs Modification of the molecular structure of nucleoside drugs by traditional chemical synthesis requires complex steps such as acylation and catalytic hydrogenolysis, and requires the use of special chemical catalysts, usually with low yield, poor selectivity, and contamination. And various disadvantages such as toxicity. Enzymatic synthesis has the characteristics of mild conditions and good selectivity, and is widely used in the derivatization of multi-functional drugs, especially nucleoside drugs. In recent years, many biocatalytic methods have been used to structurally modify nucleoside drugs. Reports such as Riva et al.
  • the present invention provides a method for synthesizing a nucleoside amino acid derivative by a protease or a lipase which is simple in operation, high in selectivity, mild in temperature, and low in solvent and low in pollution.
  • the first aspect of the present invention provides a method for enzymatically synthesizing a nucleoside amino acid derivative, comprising the steps of: reacting a nucleoside compound and an L-amino acid ester under a catalysis of a protease to obtain a nucleoside amino acid derivative;
  • the nucleoside compound is acyclovir, ganciclovir, inosine, guanosine, adenosine or cytarabine;
  • the L-amino acid ester is a liquid L-serine ester, a liquid L- Alanine ester, liquid L-cysteine ester or liquid L-phenylalanine ester;
  • the nucleoside amino acid derivative is acyclovir-L-serine ester, acyclovir-L-alanine ester, acyclovir-L-cysteine ester, acyclovir-L -phenylalaninate, ganciclovir-L-serine ester, ganciclovir-L-alaninate, ganciclovir-L-cysteine, ganciclovir-L-benzene Alanine ester, inosine-L-serine ester, inosine-L-alaninate, inosine-L-cysteine, inosine-L-phenylalaninate, guanosine-L- Serine ester, guanosine-L-alanine ester, guanosine-L-cysteine ester, guanosine-L-phenylalanine ester, adenosine-L-serine ester, adenosine-L-a
  • the proteinase is Bacillus subtilis alkaline protease, Bacillus licheniformis alkaline protease, alkaline protease 3. 0T, alkaline protease 2. 4L FG, Saiwei proteinase 8. 0T, Saiwei proteinase 16. 0 L, Yi Rui Protease 8. 0 L, Iverase 16. 0 L or thermolysin.
  • the protease is alkaline protease 3. 0T.
  • the L-serine ester is L-serine d- 4 ester; and/or the L-alanine ester is L-alanine d- 4 ester; and/or The L-cysteine ester is L-cysteine (and 4 ); and/or the L-phenylalanine ester is L-phenylalanine d- 4 ester.
  • the L-serine ester is L-serine methyl ester, L-serine ethyl ester, L-serine n-propyl ester or L-serine methyl ester.
  • the L-alanine ester is L-alanine methyl ester.
  • the L-cysteine ester is L-cysteine methyl ester.
  • the L-phenylalanine ester is L-phenylalanine methyl ester.
  • the second aspect of the present invention provides a method for enzymatically synthesizing a nucleoside amino acid derivative, comprising the steps of: reacting a nucleoside compound and an L-amino acid ester under the catalysis of a lipase to obtain a nucleoside amino acid derivative; ,
  • the nucleoside compound is acyclovir, ganciclovir, inosine, guanosine or adenosine;
  • the L-amino acid ester is a liquid L-valine ester, a liquid L-serine ester, a liquid L-alanine ester, a liquid L-cysteine ester or a liquid L-phenylalanine.
  • Acid ester is a liquid L-valine ester, a liquid L-serine ester, a liquid L-alanine ester, a liquid L-cysteine ester or a liquid L-phenylalanine.
  • the nucleoside amino acid derivatives are acyclovir-L-valine ester, acyclovir-L-serine ester, acyclovir-L-alaninate, acyclovir-L- Cysteine ester, acyclovir-L-phenylalanine ester, ganciclovir-L-valine ester, ganciclovir-L-serine ester, ganciclovir-L-alanine Acid ester, ganciclovir-L-cysteine ester, ganciclovir-L-phenylalanine ester, inosine-L-valine ester, inosine-L-serine ester, inosine- L-alanine ester, inosine-L-cysteine ester, inosine-L-phenylalanine ester, guanosine-L-valine ester, guanosine-L-serine ester, guanosine-L-
  • the lipase is Libo lipase 100T, ⁇ 435 lipase, lipase PS Amano SD, lipase AS Amano, lipase AK Amano, lipase G, lipase AYS Amano, Candida antarctica lipase B (CALB) ) or alkaline lipase Greasex 50L.
  • the L-valine ester is an L-valine C1-4 ester; and/or the L-serine ester is an L-serine d- 4 ester; and/or The L-alanine ester is L-alanine d- 4 ester; and/or the L-cysteine ester is L-cysteine CH ester; and/or the L- The phenylalanine ester is L-phenylalanine d- 4 ester.
  • the L-valine ester is L-valine methyl ester or L-valine ethyl ester.
  • the L-serine ester is L-serine methyl ester, L-serine ethyl ester, L-serine n-propyl ester or L-serine methyl ester.
  • the L-alanine ester is L-alanine methyl ester.
  • the L-cysteine ester is L-cysteine methyl ester.
  • the L-phenylalanine ester is L-phenylalanine methyl ester.
  • the L-amino acid ester is L-valine methyl ester.
  • the lipase is Candida antartica lipase B.
  • the nucleoside compound is acyclovir or ganciclovir.
  • the concentration of the nucleoside compound in the reaction system is 10 to 50 g/L. In another preferred embodiment, the concentration of the nucleoside compound in the reaction system is 20 to 30. g/L o In another preferred embodiment, the protease or lipase is present in the reaction system at a concentration of 8 to 65 g/L. In another preferred embodiment, the concentration of the protease or lipase in the reaction system is 15 to 30 g/L. In another preferred embodiment, the reaction is carried out at 20 to 70 ° C; and / Or the reaction described is carried out 24 ⁇
  • reaction is carried out at 30 to 50 °C.
  • reaction is carried out for 72 to 96 hours.
  • reaction is carried out at a relative vacuum of from -100 to -500 mbar.
  • nucleoside amino acid derivative is prepared by a solventless reaction of a nucleoside compound with an L-amino acid ester which is liquid at a reaction temperature by using a protease or a lipase as a catalyst. Economical, environmentally friendly, mild reaction conditions, high conversion rate, simple product purification and high purity. On this basis, the inventors have completed the present invention.
  • the L-valine d- 4 ester is L-valine decyl ester, such as L-valine methyl ester, L-valine ethyl ester, L-valine n-propyl Ester, L-valine isopropyl ester, L-valine n-butyl ester, L-valine isobutyl ester, L-valine t-butyl ester, or the like.
  • L-valine decyl ester such as L-valine methyl ester, L-valine ethyl ester, L-valine n-propyl Ester, L-valine isopropyl ester, L-valine n-butyl ester, L-valine isobutyl ester, L-valine t-butyl ester, or the like.
  • the L-serine d- 4 ester is L-serine d- 4 decyl ester, such as L-serine methyl ester, L-serine Ethyl ester, n-propyl L-serine, isopropyl L-serine, n-butyl L-serine, isobutyl L-serine, tert-butyl L-serine, or the like.
  • the L-alanine d- 4 ester is L-alanine CH-ester, such as L-alanine methyl ester, L-alanine ethyl ester, L-alanine n-propyl ester, L - isopropyl alaninate, n-butyl L-alanine, isobutyl L-alanine, tert-butyl L-alanine, or the like.
  • the L-cysteine d- 4 ester is L-cysteine CH-ester, such as L-cysteine methyl ester, L-cysteine ethyl ester, L-cysteine N-propyl ester, L-cysteine isopropyl ester, L-cysteine n-butyl ester, L-cysteine isobutyl ester, L-cysteine tert-butyl ester, or the like.
  • L-cysteine CH-ester such as L-cysteine methyl ester, L-cysteine ethyl ester, L-cysteine N-propyl ester, L-cysteine isopropyl ester, L-cysteine n-butyl ester, L-cysteine isobutyl ester, L-cysteine tert-butyl ester, or the like.
  • the L-phenylalanine d- 4 ester is L-phenylalanine d- 4 decyl ester, such as L-phenylalanine methyl ester, L-phenylalanine ethyl ester, L-phenyl propyl N-propyl propyl ester, isopropyl L-phenylalanine, n-butyl L-phenylalanine, isobutyl L-phenylalanine, tert-butyl L-phenylalanine, or the like .
  • nucleoside amino acid derivative is a compound shown in Table 1.
  • the present invention provides a preferred method for enzymatically synthesizing a nucleoside amino acid derivative, which comprises the steps of: reacting a nucleoside compound with an L-amino acid ester under the catalysis of a protease to obtain a nucleoside amino acid derivative.
  • the nucleoside compound is preferably acyclovir, ganciclovir, inosine, guanosine, adenosine or cytarabine.
  • the L-amino acid ester is preferably a liquid L-serine ester, a liquid L-alanine ester, a liquid L-cysteine ester or a liquid L-phenylalanine ester.
  • the L-serine ester is L-serine d- 4 ester; the L-alanine ester is L-alanine CH ester; and the L-cysteine ester is L- Cysteine d- 4 ester; the L-phenylalanine ester is L-phenylalanine ( ⁇ 4 ester).
  • the protease is preferably Bacillus subtilis alkaline protease, Bacillus licheniformis alkaline protease, Alcalase 3. 0T, Alcalase 2. 4L FG, Savinase protease 8. 0T , Savinase 16. 0 L, Esperase 8. 0 L, Eversase 16. 0 L or thermolys in; preferably, said Egg
  • the white enzyme is alkaline protease (Alcalase) 3. 0T, which has better catalytic effect and higher catalytic efficiency and selectivity.
  • the nucleoside amino acid derivatives are: acyclovir-L-serine ester, acyclovir-L-alanine ester, acyclovir-L-cysteine ester, acyclovir- L-phenylalanine ester, ganciclovir-L-serine ester, ganciclovir-L-alaninate, ganciclovir-L-cysteine, ganciclovir-L- Phenylalanine ester, inosine-L-serine ester, inosine-L-alanine ester, inosine-L-cysteine ester, inosine-L-phenylalanine ester, guanosine-L - Serine ester, guanosine-L-alanine ester, guanosine-L-cysteine ester, guanosine-L-phenylalanine ester, adenosine-L-serine ester
  • the present invention provides another preferred method for the enzyme-catalyzed synthesis of a nucleoside amino acid derivative, which comprises the steps of: reacting a nucleoside compound with an L-amino acid ester under the catalysis of a lipase to obtain a nucleoside amino acid derivative.
  • the nucleoside compound is preferably acyclovir, ganciclovir, inosine, guanosine or adenosine;
  • the L-amino acid ester is preferably a liquid L-valine ester, a liquid L-serine Ester, liquid L-alanine ester, liquid L-cysteine ester or liquid L-phenylalanine ester.
  • the L-amino acid ester is preferably a liquid L-valine ester, a liquid L-serine ester, a liquid L-alanine ester, a liquid L-cysteine ester or a liquid L. - phenylalanine ester.
  • the L-valine ester is L-valine d- 4 ester
  • the L-serine ester is L-serine d- 4 ester
  • the L-alanine ester is L - alanine d- 4 ester
  • the L-cysteine ester is L-cysteine ester
  • the L-phenylalanine ester is L-phenylalanine d- 4 ester.
  • the lipase is Lipolas e 100T, Novo435 lipase, lipase PS Amano SD, Lipase AS Amano, Lipase AK Amano ), Lipase G, lipase AYS L ipase AYS Amano, Candida antarctica lipase B (CALB) or alkaline lipase Greasex 50L.
  • the lipase is Candida antarctica lipase B, which has better catalytic effect and higher catalytic efficiency and selectivity.
  • the nucleoside amino acid derivatives are: acyclovir-L-valine ester, acyclovir-L-serine ester, acyclovir-L-alaninate, acyclovir-L -cysteine ester, acyclovir-L-phenylalanine ester, ganciclovir-L-valine ester, ganciclovir-L-serine ester, ganciclovir-L-propyl Acid ester, ganciclovir-L-cysteine ester, ganciclovir-L-phenylalanine ester, inosine-L-valine ester, inosine-L-serine ester, inosine -L-alanine ester, inosine-L-cysteine ester, inosine-L-phenylalanine ester, guanosine-L-valine ester, guanosine-L-serine ester, guanos
  • the above two methods of the present invention employ an L-amino acid ester (preferably L-amino acid- 4 ester) which is liquid at the reaction temperature, and can be enzymatically reacted without adding other solvents by utilizing its liquid state.
  • the liquid L-amino acid ester serves as both a reactant and a solvent, and an increase in the amount of the L-amino acid ester can increase the conversion efficiency of the product, and the excess L-amino acid ester can be recycled and reused. Therefore, the method has good selectivity, high conversion rate, high yield (yield exceeds 65%, preferably 65-95% or 70-90%), good quality, low cost, less environmental pollution, It is easy to operate and is suitable for industrialization.
  • the reaction system is composed of an L-amino acid ester and a nucleoside compound, and a protease or a lipase is added, and the enzyme is catalyzed at a certain temperature (for example, 20 to 70 ° C; preferably 30 to 50).
  • the reaction is carried out for a period of time (e.g., 24 to 120 hours; preferably 72 to 96 hours) to synthesize a series of nucleoside amino acid derivatives.
  • the reaction time refers to the time required until the conversion of the catalytic reaction is substantially constant, and the so-called "time at which the conversion rate is substantially constant" means a time when the conversion rate changes by 5% every 24 hours.
  • the concentration of the nucleoside compound in the reaction system is 10 to 50 g/L, preferably 20 to 30 g/Lo.
  • the present invention selects an appropriate amount of protease or lipase to facilitate the reaction.
  • the protease or lipase has a concentration in the reaction system of 8 to 65 g/L, preferably 15 to 30 g/L.
  • the protease or lipase is anhydrous or substantially anhydrous.
  • the enzyme used in the method is convenient in source, and can be used as a catalyst to catalyze the reaction of a nucleoside compound and an L-amino acid ester without a special treatment procedure, thereby producing a product with high optical purity and high yield.
  • the enzyme of the present invention has the characteristics of good selectivity and high conversion rate.
  • the L-amino acid ester in the method is a reactant and a solvent, and the reaction is carried out without adding other solvents, the reaction substrate concentration is high, the product conversion efficiency is high, the quality is good, and the excess L-amino acid ester can be recovered. Reuse, which reduces costs and reduces environmental pollution.
  • the method has mild reaction conditions, simple operation, simple post-treatment and wide industrial application prospects, and has important application value in the preparation and research of nucleoside prodrugs.
  • the invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in the following examples that do not specify the specific conditions are usually According to conventional conditions, such as those described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
  • Raw materials or reagents such as acyclovir, ganciclovir, inosine, guanosine, adenosine, cytarabine, L-amino acid ester hydrochloride, etc., which are used in the present invention, are commercially available products unless otherwise specified.
  • Example 1 Raw materials or reagents such as acyclovir, ganciclovir, inosine, guanosine, adenosine, cytarabine, L-amino acid ester hydrochloride, etc.
  • L-amino acid esters The preparation of the other L-amino acid esters is the same as this, except that different L-amino acid ester hydrochlorides are used instead of L-valine methyl ester hydrochloride.
  • Bacillus subtilis S01 Bacillus licheniformis S02 was purchased from the China General Microorganisms Collection and Management Center (CGMCC).
  • CGMCC China General Microorganisms Collection and Management Center
  • Bacillus subtilis S01 fermentation medium g/L: yeast extract 20, sucrose 10, Tween-80 5, magnesium sulfate 0 ⁇ 2, pH 9.
  • the above two kinds of medium were sterilized at 121 °C for 15 min, cooled, sterilized, inoculated with Bacillus subtilis S01 or Bacillus licheniformis S02, inoculated in 4%, fermented for 36 h at 37 ° C, 200 r/min.
  • the supernatant of the fermentation broth was collected by centrifugation at 7500 rcf for 10 min.
  • Conversion rate (%) product peak area / (product peak area + substrate peak area) * 100% content determination method - acyclovir and product acyclovir-L-alanine ester content using high-performance liquid phase
  • the chromatographic conditions were as follows: C18-XDB column (250 X 4. 6 mm, Agi lent), mobile phase methanol/water (volume ratio 20/80), column temperature 30 ° C; flow rate 0. 8 Ml/min, detection wavelength 254 nm, injection volume 5 ⁇ 1 .
  • the peak time of acyclovir standard was 3. 4 min, and the peak time of acyclovir-L-alanine standard was 5. 3 min.
  • Example 3-10 Enzymatic Reaction
  • the experimental method was the same as in Example 2, except that the reaction system was carried out under the conditions shown in Table 2, respectively.
  • alkaline protease Alcalase 3. 0T and Alcalase 2. 4L FG was selected as the catalyst to catalyze the highest catalytic activity of acyclovir for the synthesis of acyclovir-L-alanine ester, and lipase such as CALB. It exhibited a catalytic effect comparable to that of Alcalase 3. 0T and Alcalase 2. 4L FG.
  • Example 11 Enzyme catalytic reaction
  • the experimental procedure was the same as that of Example 11, except that the conversion of the above reaction was measured by liquid chromatography using a raw material or an enzyme catalyst as shown in Table 3, and the catalytic activity of the enzyme catalyst was evaluated.
  • the transesterification reaction can be used to structurally modify the polyfunctional nucleoside compound.
  • the lipase CALB is used to modify the acyclovir with L-valine methyl ester.
  • the catalytic activity is the highest, which is cytarabine 5 . Times around.
  • Inosine 200 mg (0.74 mmol) was added to a 50 ml round bottom flask, followed by L-alanine methyl ester 10 ml.
  • a reaction system having a substrate concentration of 20 g/L was formed, and Savinase 16.
  • OL O. 5 g was added, and the reaction was carried out under reduced pressure (vacuum degree - 700 mbar) at 60 ° C for 72 h.
  • the reaction rate of the reaction was determined to be 41.2%, and the reaction was continued for 24 hours.
  • the conversion of the reaction was determined to be 59.8%, and the reaction was continued for 24 hours.
  • the conversion of the reaction was 74.5%, and the reaction was continued for 24 hours. 8% ⁇
  • the conversion rate of the determination was 78.8%.
  • reaction was converted to a reaction rate of 75. 8 and the reaction was determined to be 75. 6% ⁇ The conversion of the reaction was determined to be 87.6%.
  • the reaction is completed, acidified by hydrochloric acid, filtered, concentrated, and recrystallized from ethanol to obtain ganciclovir-L-valine ester hydrochloride 488. 0 mg (0. 98 mmol, molar yield 83.7%), optical purity 98. 5%.
  • Inosine 200 mg (0.74 mmol) was added to a 50 ml round bottom flask, and 10 ml of L-serine methyl ester was added to form a reaction system having a substrate concentration of 20 g/L, and lipase PS Amano SD 0. 2 was added. g, the reaction was carried out under reduced pressure (vacuum degree -300 mbar) at 50 ° C for 48 h, and the conversion of the reaction was determined by liquid chromatography to be 41. 5%, the reaction was continued for 24 h, and the conversion of the reaction was determined to be 73. 9% ⁇ The reaction rate was determined to be 85.9%.
  • Examples 34 and 35 indicate that the conversion rate is poor after the addition of an organic solvent such as dimethyl sulfoxide or water.
  • organic solvents or water have a greater influence on the activity of the enzyme in the reaction system, which is not conducive to the continuation of the reaction, and will have a greater impact on the post-treatment.
  • the protease or lipase used is commercially available or can be obtained by a simple fermentation method without going through some special treatment process. This method can obtain a product of high purity without additional solvent addition. Under the catalysis of the protease or lipase of the present invention, the method has high conversion rate, high selectivity, few by-products, and simple post-treatment.

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Abstract

L'invention concerne un procédé de synthèse par catalyse enzymatique de dérivés aminés sous forme de nucléosides, selon lequel lors de la catalyse d'une protéase ou d'une lipase, on fait réagir des composés nucléosidiques et des esters d'acides L-aminés afin d'obtenir des dérivés aminés sous forme de nucléosides. Le procédé selon l'invention ne nécessite aucun solvant supplémentaire.
PCT/CN2012/087204 2012-12-21 2012-12-21 Procédé de synthèse par catalyse enzymatique de dérivés aminés sous forme de nucléosides Ceased WO2014094312A1 (fr)

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Cited By (2)

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CN115745997A (zh) * 2022-11-30 2023-03-07 湖北省宏源药业科技股份有限公司 一种高纯度伐昔洛韦杂质h制备方法
CN119818525A (zh) * 2025-01-17 2025-04-15 沈阳信达泰康医药科技有限公司 一种阿糖胞苷氨基酸酯组合物及其应用

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CN119818525A (zh) * 2025-01-17 2025-04-15 沈阳信达泰康医药科技有限公司 一种阿糖胞苷氨基酸酯组合物及其应用

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