CN115043823A - Synthetic method of emtricitabine - Google Patents

Synthetic method of emtricitabine Download PDF

Info

Publication number
CN115043823A
CN115043823A CN202210743245.8A CN202210743245A CN115043823A CN 115043823 A CN115043823 A CN 115043823A CN 202210743245 A CN202210743245 A CN 202210743245A CN 115043823 A CN115043823 A CN 115043823A
Authority
CN
China
Prior art keywords
emtricitabine
reaction
minutes
hydroxyethyl butyrate
molar ratio
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
Application number
CN202210743245.8A
Other languages
Chinese (zh)
Inventor
杨小利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Puxin Pharmaceutical Co ltd
Original Assignee
Jiangsu Puxin Pharmaceutical Co ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Jiangsu Puxin Pharmaceutical Co ltd filed Critical Jiangsu Puxin Pharmaceutical Co ltd
Priority to CN202210743245.8A priority Critical patent/CN115043823A/en
Publication of CN115043823A publication Critical patent/CN115043823A/en
Pending legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D411/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention discloses a synthetic method of emtricitabine, which comprises the steps of mixing ethylene glycol with butyryl chloride, reacting at constant temperature to obtain 2-hydroxyethyl butyrate, adding dimethyl sulfoxide and a catalyst, oxidizing hydroxyl in the 2-hydroxyethyl butyrate into aldehyde group, adding 2, 5-dihydroxy-1, 4-dithiolane, adjusting the pH value of a system to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, splitting to obtain an isomer with the chirality at the 2 position as R, and adding 5-fluorocytosine protected by trimethylsilane for reaction to obtain an intermediate; and (3) adding hydrochloric acid into the intermediate to adjust the pH value of the system, after hydrolysis reaction, recrystallizing the hydrolysis product by using ethanol, separating to obtain a product with a (2R-5S) -configuration, and finally performing deacidification treatment by using ionic resin to obtain the emtricitabine. The method for synthesizing the emtricitabine has the advantages of simplifying production process, shortening production time, reducing production cost, reducing impurity content in products and improving the production quality of the emtricitabine.

Description

Synthetic method of emtricitabine
Technical Field
The invention belongs to the technical field of drug synthesis, relates to a drug synthesis method, and particularly relates to a synthesis method of emtricitabine.
Background
Emtricitabine is a novel nucleoside reverse transcriptase inhibitor, belongs to antiviral drugs, is converted into 5' -triphosphate through phosphorylation of cellular enzyme, and the 5' -triphosphate competes with deoxidized 5' -triphosphate substrate to inhibit the activity of HIV-1 reverse transcriptase and is combined with virus DNA to cause chain termination, thereby playing a role in inhibiting viruses.
The existing synthesis method of emtricitabine has the following defects:
(1) the existing emtricitabine synthesis method has the problems that the process is complex in the actual production process, the production time is long, the production cost is increased, the impurity content of the final product is high, and the production quality of emtricitabine is low, and needs to be improved;
(2) in the preparation and pretreatment processes of reaction raw materials, a glass instrument is required to be used, impurities such as dust and the like can be easily adsorbed on the inner surface and the outer surface of the glass instrument, and if the impurities such as the dust and the like enter a reactant, the reactant is easily polluted, and the quality of a product is finally influenced;
(3) in the preparation process of the reaction intermediate, gases with pungent odor, volatile organic compounds or other by-products harmful to the body can be generated, and the direct emission can cause harm to the human body or the environment, and needs to be improved.
Disclosure of Invention
The invention aims to provide a method for synthesizing emtricitabine, which has the advantages of simplified production process, shortened production time and reduced production cost.
The invention also aims to provide a method for synthesizing emtricitabine, which can reduce the impurity content in the product and improve the production quality of emtricitabine.
The invention further aims to provide a method for synthesizing emtricitabine, which can purify and discharge waste gas generated in the reaction process, and avoid the harm to human bodies and environment caused by direct discharge.
In order to achieve the above purpose, the solution of the invention is:
a synthetic method of emtricitabine comprises the following steps:
step 1, mixing ethylene glycol and butyryl chloride, reacting at constant temperature to obtain 2-hydroxyethyl butyrate, then adding dimethyl sulfoxide and a catalyst, reacting at normal temperature for 20-40 minutes, oxidizing hydroxyl in the 2-hydroxyethyl butyrate into aldehyde group, then adding 2, 5-dihydroxy-1, 4-dithiane, adjusting the pH value of a system to be 4.5-5 by using acetic anhydride to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, then splitting to obtain an isomer with chirality at 2-position being R, and then adding 5-fluorocytosine protected by trimethylsilane for reaction to obtain an intermediate;
and 2, adding hydrochloric acid into the intermediate, adjusting the pH value of the system to 3.5-4, after hydrolysis reaction, recrystallizing the hydrolysis product through ethanol, separating to obtain a product with a (2R-5S) -configuration, and finally performing deacidification treatment through ion resin to obtain the emtricitabine.
In the step 1, the mixing molar ratio of the ethylene glycol to the butyryl chloride is 0.7-1.5: 2, and the reaction is carried out for 4-9 minutes at a constant temperature of 35-40 ℃ to obtain the 2-hydroxyethyl butyrate.
In the step 1, the molar ratio of the added dimethyl sulfoxide to the 2-hydroxyethyl butyrate is 0.4-0.7: 1, and the catalyst is phosphorus pentoxide and triethylamine.
In the step 1, the molar ratio of the added 2, 5-dihydroxy-1, 4-dithiothiane to the 2-hydroxyethyl butyrate is 2-4: 1.
In the step 1, after the 2, 5-dihydroxy-1, 4-dithiothiane is added, the temperature of a water bath is kept constant at 55-65 ℃, and the reaction is carried out for 15-25 minutes to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane.
In the step 1, the molar ratio of the 5-fluorocytosine protected by the trimethylsilyl ester to the 2-hydroxyethyl butyrate is 1-2: 1.
In the step 1, after 5-fluorocytosine protected by trimethylsilane is added, heating to 70-90 ℃, and reacting for 40-60 minutes to obtain an intermediate.
In step 1, before the reaction, the raw materials and the reaction vessel are cleaned and dried.
In the step 2, the temperature of the hydrolysis reaction is 86-95 ℃, and the hydrolysis is carried out for 70-85 minutes at high temperature.
After adopting the scheme, compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a synthesis method of emtricitabine, which comprises the steps of reacting ethylene glycol with butyryl chloride to obtain 2-hydroxyethyl butyrate, oxidizing hydroxyl of the 2-hydroxyethyl butyrate into aldehyde group by dimethyl sulfoxide, reacting the compound with 2, 5-dihydroxy-1, 4-dithiothiane, reacting with acetic anhydride to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, splitting to obtain a pair of isomers with 2-chirality being R, reacting with 5-fluorocytosine protected by trimethylsilane to obtain a pair of isomers, hydrolyzing to obtain hydrochloride, recrystallizing with ethanol, separating to obtain a product with a (2R-5S) -configuration, deacidifying with ion resin to obtain an emtricitabine solution, recrystallizing the product for multiple times to obtain emtricitabine crystals, and simplifying the production process, the production time is shortened, and the production cost is reduced;
(2) the invention provides a method for synthesizing emtricitabine, which comprises the steps of thoroughly cleaning a glass instrument containing raw materials, drying the glass instrument, and preventing the concentration of reactants added into the instrument from changing due to moisture in the glass instrument, so that the reaction result is inaccurate and the product quality is influenced;
(3) the invention provides a method for synthesizing emtricitabine, wherein a waste gas treatment device is arranged in the preparation process of a reaction intermediate, generated gases with pungent odor, volatile organic compounds or other byproducts harmful to human bodies are collected, sufficient corresponding chemical absorption liquid is added to react with the collected waste gases, and the waste gases are fully treated to gases or liquids harmless to human bodies and environments, so that the problem of influence on the human bodies or the environments caused by direct discharge is avoided.
Detailed Description
The following describes in detail embodiments of the present invention.
The invention provides a method for synthesizing emtricitabine, which comprises the following steps of preparing all reaction raw materials and various instruments according to a process flow, gradually reacting according to the requirements of the process flow to obtain a reaction intermediate, carrying out corresponding reaction on the intermediate according to the requirements of the process flow to obtain a product, and finally purifying the product to obtain the relatively pure emtricitabine, wherein the method specifically comprises the following steps:
step one, preparing and pretreating reaction raw materials;
in the first step, reactants and various chemical reaction devices required in the reaction process are prepared in advance, the partial chemical reaction devices are pretreated, the reaction devices are cleaned, and dust attached to the devices is removed, the chemical reactants required in the reaction process mainly comprise ethylene glycol, butyryl chloride, dimethyl sulfoxide, 2, 5-dihydroxy-1, 4-dithiothiane, acetic anhydride, 5-fluorocytosine protected by trimethylsilyl acetate, hydrochloric acid, ethanol and the like, the chemical reaction devices required in the reaction process mainly comprise flasks, beakers, pipettes, alcohol lamps, constant-temperature water bath boxes and the like, and the flasks, the beakers, the pipettes and other glass instruments are cleaned and then dried;
step two, preparing a reaction intermediate;
in the second step, firstly, ethylene glycol and butyryl chloride are mixed according to a molar ratio of 0.7-1.5: 2, then the mixture is subjected to constant temperature of 35-40 ℃ by a constant temperature water bath box and reacts for 4-9 minutes to obtain 2-hydroxyethyl butyrate, then dimethyl sulfoxide is added, the molar ratio of the dimethyl sulfoxide to the 2-hydroxyethyl butyrate is 0.4-0.7: 1, simultaneously catalysts of phosphorus pentoxide and triethylamine are added, the mixture is subjected to reaction at normal temperature for 20-40 minutes to oxidize hydroxyl in the 2-hydroxyethyl butyrate into aldehyde groups, then 2, 5-dihydroxy-1, 4-dithiothiane with the molar ratio of the dimethyl sulfoxide to the 2-hydroxyethyl butyrate being 2-4: 1 is added, simultaneously the pH value of a system is adjusted to be 4.5-5 by acetic anhydride, the water bath is subjected to constant temperature of 55-65 ℃ for 15-25 minutes to obtain 2-butyrylmethoxy-5-acetoxyl-1, separating four isomers of 3-oxathiolane to obtain an isomer with chirality at 2-position R, adding 5-fluorocytosine protected by trimethylsilane with the molar ratio of 1-2: 1 to 2-hydroxyethyl butyrate, reacting at 70-90 ℃ for 40-60 minutes to obtain an intermediate, continuously generating gases with pungent odor, volatile organic compounds or other byproducts harmful to a body in the reaction process, and collecting the gases, the volatile organic compounds or other byproducts harmful to the body through a waste gas treatment device, thereby facilitating centralized treatment;
step three, preparing emtricitabine;
in the third step, hydrochloric acid is added into the reaction intermediate prepared in the second step, the pH value of the system is adjusted to 3.5-4, the system is heated to 86-95 ℃ at the same time, high-temperature hydrolysis is carried out for 70-85 minutes, then recrystallization is carried out on the hydrolysate through ethanol, a (2R-5S) -configuration product is obtained through separation, finally deacidification is carried out through ionic resin, emtricitabine can be obtained, the recrystallization process needs to be carried out for 3-4 times, and through multiple dissolving and recrystallization processes, impurities can be gradually washed clean, so that a relatively pure (2R-5S) -configuration product is obtained; adding hydrochloric acid into the reaction intermediate to obtain an emtricitabine solution with impurities, repeating the recrystallization process for 3-4 times on the emtricitabine solution with the impurities, continuously washing the impurities into the solution in the recrystallization process to finally obtain relatively pure emtricitabine crystals with the purity of more than 99%;
in the step, the recrystallization process is to dissolve the product obtained by production in a certain amount of hot ethanol solution, so that the dissolved solution is approximately in a saturated state, the product is continuously precipitated in a crystal form in the process of the temperature reduction of the solution, the product crystal is separated by a suction filtration method, so that impurities are left in the solution, and the process is repeated for several times, so that a relatively pure product can be obtained.
Example 1
Step 1, mixing ethylene glycol and butyryl chloride according to a molar ratio of 1:2, and reacting for 5 minutes at a constant temperature of 35 ℃ in a constant-temperature water bath tank to obtain 2-hydroxyethyl butyrate;
step 2, adding dimethyl sulfoxide into 2-hydroxyethyl butyrate, adding dimethyl sulfoxide and 2-hydroxyethyl butyrate with the molar ratio of 0.5:1, simultaneously adding catalysts of phosphorus pentoxide and triethylamine, reacting at normal temperature for 25 minutes, oxidizing hydroxyl in 2-hydroxyethyl butyrate into aldehyde group, adding 2, 5-dihydroxy-1, 4-dithiane with the molar ratio of 2:1 to 2-hydroxyethyl butyrate, adjusting the pH value of a system to be 4.5 by acetic anhydride, reacting for 15 minutes at constant temperature of 60 ℃ in a water bath to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, splitting to obtain an isomer with chirality R at 2 position, adding trimethylsilyl protected 5-fluorocytosine with the molar ratio of 2-hydroxyethyl butyrate of 1:1, heating to 75 ℃, reacting for 45 minutes to obtain an intermediate, and collecting and treating generated gas with pungent odor, volatile organic compounds or other by-products harmful to the body by using an exhaust gas treatment device in the reaction process;
and 3, adding hydrochloric acid into the reaction intermediate prepared in the second step, adjusting the pH value of the system to be 4, simultaneously heating to 90 ℃, hydrolyzing at high temperature for 85 minutes, recrystallizing the hydrolysate with ethanol for 3 times, separating to obtain a product with a (2R-5S) -configuration, and finally deacidifying with ionic resin to obtain the emtricitabine.
The purity of emtricitabine obtained in example 1 was 99.2%.
Example 2
Step 1, mixing ethylene glycol and butyryl chloride according to a molar ratio of 1.2:2, and reacting for 8 minutes by keeping the temperature of the mixture constant at 40 ℃ in a constant-temperature water bath tank to obtain 2-hydroxyethyl butyrate;
step 2, adding dimethyl sulfoxide into 2-hydroxyethyl butyrate, adding dimethyl sulfoxide and 2-hydroxyethyl butyrate with the molar ratio of 0.6:1, simultaneously adding catalysts of phosphorus pentoxide and triethylamine, reacting at normal temperature for 40 minutes, oxidizing hydroxyl in 2-hydroxyethyl butyrate into aldehyde group, adding 2, 5-dihydroxy-1, 4-dithiane with the molar ratio of 2:1 to 2-hydroxyethyl butyrate, adjusting the pH value of a system to be 5 by acetic anhydride, keeping the temperature of a water bath at 65 ℃, reacting for 20 minutes to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, splitting to obtain an isomer with chirality R at 2 position, adding trimethylsilyl protected 5-fluorocytosine with the molar ratio of 2-hydroxyethyl butyrate to react, heating to 90 ℃, reacting for 40 minutes to obtain an intermediate, and collecting and treating generated gas with pungent odor, volatile organic compounds or other by-products harmful to the body by using an exhaust gas treatment device in the reaction process;
and 3, adding hydrochloric acid into the reaction intermediate prepared in the second step, adjusting the pH value of the system to be 4, simultaneously heating to 95 ℃, hydrolyzing at high temperature for 70 minutes, recrystallizing the hydrolysate with ethanol for 3 times, separating to obtain a product with a (2R-5S) -configuration, and finally deacidifying with ionic resin to obtain the emtricitabine.
The purity of emtricitabine obtained in example 2 was 99.4%.
Example 3
Step 1, mixing ethylene glycol and butyryl chloride according to a molar ratio of 0.8:2, and reacting for 9 minutes by keeping the temperature of the mixture constant at 40 ℃ in a constant-temperature water bath tank to obtain 2-hydroxyethyl butyrate;
step 2, adding dimethyl sulfoxide into 2-hydroxyethyl butyrate, adding dimethyl sulfoxide and 2-hydroxyethyl butyrate with the molar ratio of 0.7:1, simultaneously adding catalysts of phosphorus pentoxide and triethylamine, reacting at normal temperature for 20 minutes, oxidizing hydroxyl in 2-hydroxyethyl butyrate into aldehyde group, adding 2, 5-dihydroxy-1, 4-dithiane with the molar ratio of 2-hydroxyethyl butyrate of 4:1, adjusting the pH value of a system to be 5 by acetic anhydride, reacting for 25 minutes at constant temperature of 60 ℃ in a water bath to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, resolving to obtain an isomer with chirality R at 2 position, adding trimethylsilyl protected 5-fluorocytosine with the molar ratio of 2-hydroxyethyl butyrate of 2:1, heating to 90 ℃, reacting for 60 minutes to obtain an intermediate, and collecting and treating generated gas with pungent odor, volatile organic compounds or other by-products harmful to the body by using an exhaust gas treatment device in the reaction process;
and 3, adding hydrochloric acid into the reaction intermediate prepared in the second step, adjusting the pH value of the system to be 4, simultaneously heating to 95 ℃, hydrolyzing at high temperature for 85 minutes, recrystallizing the hydrolysate with ethanol for 3 times, separating to obtain a product with a (2R-5S) -configuration, and finally deacidifying with ionic resin to obtain the emtricitabine.
The purity of emtricitabine obtained in example 3 was 99.4%.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (9)

1. The method for synthesizing emtricitabine is characterized by comprising the following steps:
step 1, mixing ethylene glycol and butyryl chloride, reacting at constant temperature to obtain 2-hydroxyethyl butyrate, then adding dimethyl sulfoxide and a catalyst, reacting at normal temperature for 20-40 minutes, oxidizing hydroxyl in the 2-hydroxyethyl butyrate into aldehyde group, then adding 2, 5-dihydroxy-1, 4-dithiane, adjusting the pH value of a system to be 4.5-5 by using acetic anhydride to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane, then splitting to obtain an isomer with chirality at 2-position being R, and then adding 5-fluorocytosine protected by trimethylsilane for reaction to obtain an intermediate;
and 2, adding hydrochloric acid into the intermediate, adjusting the pH value of the system to 3.5-4, after hydrolysis reaction, recrystallizing the hydrolysis product through ethanol, separating to obtain a product with a (2R-5S) -configuration, and finally performing deacidification treatment through ion resin to obtain the emtricitabine.
2. The method of claim 1, wherein: in the step 1, the mixing molar ratio of the ethylene glycol to the butyryl chloride is 0.7-1.5: 2, and the reaction is carried out for 4-9 minutes at a constant temperature of 35-40 ℃ to obtain the 2-hydroxyethyl butyrate.
3. The method of claim 1, wherein: in the step 1, the molar ratio of the added dimethyl sulfoxide to the 2-hydroxyethyl butyrate is 0.4-0.7: 1, and the catalyst is phosphorus pentoxide and triethylamine.
4. The method of claim 1, wherein: in the step 1, the molar ratio of the added 2, 5-dihydroxy-1, 4-dithiothiane to the 2-hydroxyethyl butyrate is 2-4: 1.
5. The method of claim 1, wherein: in the step 1, after the 2, 5-dihydroxy-1, 4-dithiothiane is added, the temperature of a water bath is kept constant at 55-65 ℃, and the reaction is carried out for 15-25 minutes to obtain four isomers of 2-butyrylmethoxy-5-acetoxyl-1, 3-oxathiolane.
6. The method of claim 1, wherein: in the step 1, the molar ratio of the 5-fluorocytosine protected by the added trimethylsilane to the 2-hydroxyethyl butyrate is 1-2: 1.
7. The method of claim 6, wherein: in the step 1, 5-fluorocytosine protected by trimethylsilane is added, heated to 70-90 ℃, and reacted for 40-60 minutes to obtain an intermediate.
8. The method of claim 1, wherein: in the step 1, before the reaction, the raw materials and the reaction vessel are cleaned and dried.
9. The method of claim 1, wherein: in the step 2, the temperature of the hydrolysis reaction is 86-95 ℃, and the hydrolysis is carried out for 70-85 minutes at high temperature.
CN202210743245.8A 2022-06-28 2022-06-28 Synthetic method of emtricitabine Pending CN115043823A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210743245.8A CN115043823A (en) 2022-06-28 2022-06-28 Synthetic method of emtricitabine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210743245.8A CN115043823A (en) 2022-06-28 2022-06-28 Synthetic method of emtricitabine

Publications (1)

Publication Number Publication Date
CN115043823A true CN115043823A (en) 2022-09-13

Family

ID=83163857

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210743245.8A Pending CN115043823A (en) 2022-06-28 2022-06-28 Synthetic method of emtricitabine

Country Status (1)

Country Link
CN (1) CN115043823A (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6670300A (en) * 1991-02-22 2001-01-11 Emory University Antiviral activity of 2-hydroxymethyl-5-(5- fluorocytosin-1-yl)-1,3-oxathiolane
CN1313858A (en) * 1998-08-12 2001-09-19 三角药物公司 Manufacture of 1,3-oxathiolane nucleosides
CN106187988A (en) * 2016-07-28 2016-12-07 厦门市蔚嘉化学科技有限公司 A kind of new technology preparing emtricitabine intermediate
CN109553610A (en) * 2018-12-21 2019-04-02 江西富祥药业股份有限公司 A kind of preparation method of emtricitabine isomers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6670300A (en) * 1991-02-22 2001-01-11 Emory University Antiviral activity of 2-hydroxymethyl-5-(5- fluorocytosin-1-yl)-1,3-oxathiolane
CN1313858A (en) * 1998-08-12 2001-09-19 三角药物公司 Manufacture of 1,3-oxathiolane nucleosides
CN106187988A (en) * 2016-07-28 2016-12-07 厦门市蔚嘉化学科技有限公司 A kind of new technology preparing emtricitabine intermediate
CN109553610A (en) * 2018-12-21 2019-04-02 江西富祥药业股份有限公司 A kind of preparation method of emtricitabine isomers

Similar Documents

Publication Publication Date Title
Adams et al. Hindered dialkylamino nucleoside phosphite reagents in the synthesis of two DNA 51-mers
KR101666038B1 (en) Production of ethylenically unsaturated acids or esters thereof
CN115043823A (en) Synthetic method of emtricitabine
CN109553610B (en) Preparation method of emtricitabine isomer
RU2732578C2 (en) Method of producing carboxylic acid anhydride
WO2019027222A1 (en) Method for decolorizing and deodorizing polyhydric alcohol
CN112608313B (en) Treatment method of mother liquor precipitate in production of triacetyl ganciclovir
CN112479960B (en) Vitamin D 3 Purification method of (2)
CN112062696B (en) Production method of N-acetyltaurine magnesium
CN111592484B (en) Preparation method of 5-aminolevulinic acid hydrochloride intermediate
CN108822033B (en) Synthesis method of 7-chloroquinaldine
CN111620838A (en) Preparation method of chloro-benzothiepin compound, product prepared by preparation method and application of chloro-benzothiepin compound
CN115232185A (en) Preparation process of monatibavir
FI66195B (en) FOERFARANDE FOER NEDSAETTNING AV KCENTRATION AV EN FOERORENING
CN111732589A (en) Improved entecavir intermediate synthesis process and improved entecavir synthesis process
JPH0434537B2 (en)
CN115433188B (en) Preparation method of entecavir
CN110790810B (en) Rocuronium bromide intermediate and preparation method of rocuronium bromide
RU2150473C1 (en) Method of synthesis of betulinol diacetate
CN108997119B (en) Method for purifying condensation reaction intermediate in loxoprofen sodium synthesis process
CN107973800B (en) Preparation method of zaleplon
US3932441A (en) Process for the production of pure tetrazole-1-acetic acid
JPS61106532A (en) Preparation of karahanaenone
CN114773341A (en) Preparation method of olprinone hydrochloride
CN117756823A (en) Eptification Kang Zazhi and synthesis method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination