CN114181117B - Preparation method of peramivir intermediate - Google Patents
Preparation method of peramivir intermediate Download PDFInfo
- Publication number
- CN114181117B CN114181117B CN202010966511.4A CN202010966511A CN114181117B CN 114181117 B CN114181117 B CN 114181117B CN 202010966511 A CN202010966511 A CN 202010966511A CN 114181117 B CN114181117 B CN 114181117B
- Authority
- CN
- China
- Prior art keywords
- reaction
- nickel chloride
- methanol
- compound
- water
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a peramivir intermediate, which comprises the following steps: adding (3 aR,4R,6S,6 aS) -4- ((tert-butoxycarbonyl) amino) -3- (pentane-3-yl) -3a,5,6 a-tetrahydro-4H-cyclopentane [ d ] isoxazole-6-carboxylic acid methyl ester and nickel chloride into a mixed solution of methanol and dichloromethane, adding a methanol solution of sodium borohydride and sodium hydroxide, adding an aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid and ammonia water after the reaction is finished, stirring and quenching, extracting, decompressing and concentrating, crystallizing an alcohol-water mixed solvent, and obtaining a peramivir intermediate (1S, 2S,3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester.
Description
Technical Field
The invention relates to a preparation method of a drug intermediate, in particular to a preparation method of a peramivir intermediate (1S, 2S,3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester.
Background
Peramivir, english name: peramivir trihydrate the chemical name is (1S, 2S,3R,4R,1' S) -3- [ (1 ' -acetylamino-2 ' -ethyl) ] -4- [ [ (amino imino) -methyl ] amino ] -2-carboxyl cyclopentane-1-carboxylic acid is a cyclopentane derivative neuraminidase inhibitor developed in the United states Biocryst Pharmaceuticals, and the release and proliferation of virus particles of tissue filial generation in host cells reach the effect of preventing and treating influenza A and influenza B by inhibiting the interaction between influenza neuraminidase, so that the drug has the advantages of good tolerance, low toxicity, suitability for injection and the like, and is an anti-influenza virus drug with wide prospect. But the production cost and price of the drug are relatively high for different patients. With the gradual expansion of the demand of anti-influenza drugs in the market, new requirements are also put on technology for further improvement of the process and reduction of the production cost, and the work in this aspect is very significant for enterprises and society, while in the step of synthesizing the compound 2 from the compound 1, the system is complex because the system is a metal-catalyzed reduction reaction, and each synthesis route which has been reported at present has own defects.
The reported synthesis methods mainly comprise:
1.Biocryst Pharmaceutical reported in j.med.chem.,2000,43,3482-3486, the synthetic route is as follows:
the specific method comprises the following steps: compound 1 was dissolved in methanol and reacted with hydrogen and 100psi of hydrogen chloride under the presence of platinum dioxide as a catalyst to form compound 2. It is clear that this method uses platinum as a noble metal and requires a high pressure reaction and is not suitable for industrial scale production.
2. The synthesis route is as follows, reported in CN101367750B, institute of toxicological drugs, academy of military medicine:
the specific method comprises the following steps: preparing a methanol solution of sodium hydroxide and sodium borohydride for later use, dissolving a compound 1 and nickel chloride hexahydrate in methanol, cooling to the temperature of between 10 ℃ below zero and 5 ℃, slowly dropwise adding the methanol solution of sodium hydroxide and sodium borohydride at a constant temperature, stirring after the addition, adding an aqueous solution of sodium nitrite, ammonium chloride and ammonia water, stirring at room temperature, filtering, washing, adding toluene and ammonia water into a filter cake, heating to 75 ℃ to 80 ℃ for stirring and dissolving, re-dissolving, washing an organic phase with the aqueous solution of ammonia water and disodium ethylenediamine tetraacetate at the temperature of between 70 ℃ to 80 ℃, analyzing, cooling, stirring and crystallizing the organic phase, and finally obtaining the compound 2 with the final yield of 73.2 percent. Compared with the former method, the method has been greatly improved, but the system has the advantages of difficult post-treatment, longer reduction time, longer solid-liquid separation time, larger material viscosity and difficult material transfer, and in addition, because the nickel chloride hexahydrate used in the process is equivalent, a large amount of heavy metal Ni examples exist in the waste liquid, the treatment cost is increased, and the environmental protection work is not facilitated.
Disclosure of Invention
The invention aims to: the invention aims to provide a preparation method of a peramivir intermediate (1S, 2S,3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester, which solves the objective and practical problems existing in the preparation of the peramivir intermediate in the prior art and reduces the cost of industrial production.
The technical scheme is as follows: the preparation method of the peramivir intermediate (1S, 2S,3S, 4R) -3- ((S) -1-amino-2-ethylbutyl) -4- ((tert-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylic acid methyl ester provided by the invention comprises the following reactions:
compound 1, nickel chloride, was reacted with a methanol solution of sodium borohydride and sodium hydroxide in a mixed solvent of methanol and methylene chloride.
The preparation method also comprises the step of quenching reaction of aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid and ammonia water.
The preparation method also comprises the steps of adding aqueous solution of sodium nitrite, ethylene diamine tetraacetic acid and ammonia water for quenching reaction, extracting, concentrating, and crystallizing by using mixed solvent of alcohol and water.
The nickel chloride is selected from anhydrous nickel chloride and hydrated nickel chloride, preferably hydrated nickel chloride.
The preparation method is characterized in that the nickel chloride is nickel chloride hexahydrate.
According to the preparation method, the mass volume ratio of the compound 1 to the dichloromethane is selected from 1:1-1: 10, preferably 1:2-1: 8, more preferably 1:3-1: 5.
the molar ratio of the compound 1 to the nickel chloride is selected from 1:0.05-1: 0.5, preferably 1:0.1-1: 0.2.
in the preparation method, the extraction solvent is dichloromethane.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable characteristics: the method has the characteristics of simple operation, high raw material conversion rate, low byproduct content, simple subsequent purification treatment and low nickel-containing wastewater, obviously reduces the production cost, is suitable for industrial production, and has remarkable social and economic benefits.
Detailed Description
Example 1 (1.1 eq Nickel chloride hexahydrate)
Into a beaker was added 0.18g of sodium hydroxide, 6.41g of sodium borohydride, 60mL of methanol, and the mixture was dissolved by stirring.
To the reaction flask was added 20.00g of Compound 1, 14.75g of Nickel chloride hexahydrate, 60mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
Into the beaker, 19.79g of ethylenediamine tetraacetic acid, 11.68g of sodium nitrite, 20mL of ammonia water and 100mL of water were added and stirred for dissolution.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 14.58g of Compound 2. Purity: 97.44%, yield: 70.2%.
Example 2 (0.05 eq Nickel chloride hexahydrate)
Into a beaker was added 0.17g of sodium hydroxide, 6.44g of sodium borohydride, 60mL of methanol, and the mixture was dissolved by stirring.
To the reaction flask was added 20.00g of Compound 1,0.67g of Nickel chloride hexahydrate, 60mL of dichloromethane, 20mL of methanol, and the temperature was lowered to 20 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
1.98g of ethylenediamine tetraacetic acid, 3.89g of sodium nitrite, 20mL of ammonia water and 100mL of water are added into a beaker, and the mixture is stirred and dissolved.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 14.84g of Compound 2. Purity: 97.31%, yield: 71.4%.
Example 3 (0.2 eq Nickel chloride hexahydrate)
Into a beaker was added 0.17g of sodium hydroxide, 6.47g of sodium borohydride, 60mL of methanol, and the mixture was dissolved by stirring.
To the reaction flask was added 20.00g of Compound 1,2.68g of Nickel chloride hexahydrate, 60mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
Into the beaker, 3.63g of ethylenediamine tetraacetic acid, 3.92g of sodium nitrite, 20mL of ammonia water and 100mL of water were added and stirred for dissolution.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 15.90g of Compound 2. Purity: 97.56%, yield: 76.7%.
Example 4 (1.1 eq Nickel chloride comparative experiment 1 without dichloromethane)
Into a beaker was added 0.18g of sodium hydroxide, 6.43g of sodium borohydride, 100mL of methanol, and the mixture was dissolved by stirring.
Into the reaction flask was charged 20.00g of Compound 1, 14.79g of Nickel chloride hexahydrate, 100mL of methanol, and the temperature was lowered to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
19.81g of ethylenediamine tetraacetic acid, 11.65g of sodium nitrite, 20mL of ammonia water and 100mL of water are added to the beaker, and the mixture is stirred and dissolved.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 14.40g of Compound 2. Purity: 96.39%, yield: 68.6%.
Example 5 (comparative experiment 2 where 0.2eq of Nickel chloride hexahydrate was added without methylene chloride)
Into a beaker was added 0.18g of sodium hydroxide, 6.43g of sodium borohydride, 100mL of methanol, and the mixture was dissolved by stirring.
Into the reaction flask was charged 20.00g of Compound 1,2.69g of Nickel chloride hexahydrate, 80mL of methanol, and cooled to-5 ℃. Dropwise adding the prepared sodium borohydride and sodium hydroxide methanol solution at the internal temperature of-5 ℃, then reacting for 15min at the temperature of-5 ℃, continuously stirring for 1h, wherein the residual TLC detection compound 1 is basically consistent with 15min, and the HPLC detection result is as follows: compound 2:29.23%, compound 1:16.50%, other maximum single impurity: 24.58%.
Example 6 (0.2 eq Nickel chloride hexahydrate, 1-fold dichloromethane test)
Into a beaker was added 0.17g of sodium hydroxide, 6.44g of sodium borohydride, 60mL of methanol, and the mixture was dissolved by stirring.
To the reaction flask was added 20.00g of Compound 1,2.67g of nickel chloride hexahydrate, 20mL of methylene chloride, 20mL of methanol, and the temperature was lowered to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
Into the beaker, 3.64g of ethylenediamine tetraacetic acid, 3.96g of sodium nitrite, 20mL of ammonia water and 100mL of water were added and stirred for dissolution.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 14.74g of Compound 2. Purity: 95.96%, yield: 69.9%.
Example 7 (0.2 eq Nickel chloride hexahydrate, 10 times the amount of dichloromethane experiments)
Into a beaker was added 0.16g of sodium hydroxide, 6.35g of sodium borohydride, 60mL of methanol, and the mixture was dissolved by stirring.
To the reaction flask was added 20.00g of Compound 1,2.74g of Nickel chloride hexahydrate, 200mL of dichloromethane, 20mL of methanol, and the temperature was lowered to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
Into the beaker, 3.69g of ethylenediamine tetraacetic acid, 3.99g of sodium nitrite, 20mL of ammonia water and 100mL of water were added and stirred for dissolution.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, extracting with 200mL of dichloromethane, and separating out the aqueous phase; the organic phase was washed with 100mL of water 1 time and evaporated to dryness under reduced pressure. 200mL of methanol, 100mL of water, and crystallization, filtration and drying gave 15.94g of Compound 2. Purity: 97.36%, yield: 76.7%.
Example 8 (comparative experiment with toluene extractive crystallization)
Into a beaker was added 0.18g of sodium hydroxide, 6.44g of sodium borohydride, 100mL of methanol, and the mixture was dissolved with stirring.
Into the reaction flask was charged 20.00g of Compound 1, 14.71g of Nickel chloride hexahydrate, 100mL of methanol, and cooled to-5 ℃. The internal temperature is kept at minus 5 ℃ to 5 ℃ and the prepared sodium borohydride and sodium hydroxide methanol solution are added dropwise, then the reaction is carried out for 15min at minus 5 ℃ to 5 ℃, and the reaction is stopped when TLC detects that the 1 point of the compound disappears.
Into the beaker, 19.85g of ethylenediamine tetraacetic acid, 11.69g of sodium nitrite, 20mL of ammonia water and 100mL of water were added and stirred for dissolution.
Adding the prepared aqueous solution of ethylenediamine tetraacetic acid, sodium nitrite and ammonia water into the reaction solution, quenching the reaction, heating 140mL of toluene to 70-80 ℃ for extraction, and separating out a water phase; the organic phase was washed 1 time with 100mL of water, cooled to room temperature, crystallized, filtered and dried to give 11.66g of Compound 2. Purity: 97.28%, yield: 56.1%. (the viscosity of the material is high during suction filtration, and the material transfer is difficult)
From the experimental results, it was found that the reaction for reducing the amount of nickel chloride hexahydrate was not completely converted and the selectivity was poor when methanol was used alone as a solvent. When equivalent amounts of nickel chloride hexahydrate are used, the reaction can be completely converted and the selectivity is better, which is consistent with literature reports. When a proper amount of dichloromethane is added into a reaction system for reaction, the reduction of the dosage of the nickel chloride hexahydrate has no great influence on the conversion rate and the selectivity of the reaction. The reaction proves that the nickel chloride consumption can be reduced practically, and the reaction can be completely carried out by only adding the catalytic amount of the nickel chloride hexahydrate.
In the post-reaction treatment process, methylene dichloride is used for replacing toluene to carry out extraction operation, extraction can be completed under normal temperature conditions, high-temperature extraction operation is avoided, process safety risk is reduced, an alcohol-water mixed system is used for crystallization, in the suction filtration process, the fluidity of the crystallization liquid is good, and the problem of great material viscosity and difficult transfer is solved.
Claims (4)
1. A process for the preparation of the peramivir intermediate methyl (1S, 2S,3S,4 r) -3- ((S) -1-amino-2-ethylbutyl) -4- ((t-butoxycarbonyl) amino) -2-hydroxycyclopentane-1-carboxylate comprising the following reactions:
the method comprises the steps of reacting a compound 1 and nickel chloride with a methanol solution of sodium borohydride and sodium hydroxide in a mixed solvent of methanol and dichloromethane; the nickel chloride is selected from anhydrous nickel chloride and hydrated nickel chloride; the mass volume ratio of the compound 1 to the dichloromethane is selected from 1:1-1:10 g/mL; the molar ratio of the compound 1 to the nickel chloride is selected from 1:0.05-1:0.5.
2. The preparation method according to claim 1, further comprising the step of quenching the reaction with an aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid, and ammonia water.
3. The method according to claim 1, further comprising the steps of adding aqueous solution of sodium nitrite, ethylenediamine tetraacetic acid, ammonia water, quenching reaction, extraction, concentration, crystallization of mixed solvent of alcohol and water.
4. A process according to claim 3, wherein the extraction solvent is dichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010966511.4A CN114181117B (en) | 2020-09-15 | 2020-09-15 | Preparation method of peramivir intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010966511.4A CN114181117B (en) | 2020-09-15 | 2020-09-15 | Preparation method of peramivir intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114181117A CN114181117A (en) | 2022-03-15 |
| CN114181117B true CN114181117B (en) | 2023-05-05 |
Family
ID=80601168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010966511.4A Active CN114181117B (en) | 2020-09-15 | 2020-09-15 | Preparation method of peramivir intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114181117B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114853636B (en) * | 2022-05-27 | 2024-04-02 | 温州海鹤药业有限公司 | Preparation method of peramivir intermediate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1367776A (en) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | Process for preparing substituted cyclopentane derivatives and novel crystalline structures |
| CN101314579A (en) * | 2007-05-30 | 2008-12-03 | 天津泰普药品科技发展有限公司 | Waterless Peramivir crystal and medicament composition thereof |
| CN101367750A (en) * | 2007-08-14 | 2009-02-18 | 中国人民解放军军事医学科学院毒物药物研究所 | (1S,2S,3S,4R)-3-[(1S)-1-acet-ammonia-2-ethyl-butyl]-4- guanidino-2-hydroxyl-cyclopentyl-1-carboxylic acid aqua compound and medical uses thereof |
| CN101538228A (en) * | 2008-03-21 | 2009-09-23 | 北京普世康医药技术有限公司 | Method for synthesizing medical compound peramivir for resisting influenza viruses and avian influenza viruses |
| CN102372657A (en) * | 2011-11-14 | 2012-03-14 | 暨南大学 | Synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir |
| CN103524383A (en) * | 2013-10-10 | 2014-01-22 | 山东罗欣药业股份有限公司 | Method for preparing peramivir |
| CN104640540A (en) * | 2012-04-14 | 2015-05-20 | 中央研究院 | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
| CN105837632A (en) * | 2016-05-20 | 2016-08-10 | 中山大学 | Neuraminidase inhibitor, preparation method of neuraminidase inhibitor and application of neuraminidase inhibitor to preparation of anti-influenza virus drugs |
-
2020
- 2020-09-15 CN CN202010966511.4A patent/CN114181117B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1367776A (en) * | 1999-06-28 | 2002-09-04 | 生物晶体药品股份有限公司 | Process for preparing substituted cyclopentane derivatives and novel crystalline structures |
| CN101314579A (en) * | 2007-05-30 | 2008-12-03 | 天津泰普药品科技发展有限公司 | Waterless Peramivir crystal and medicament composition thereof |
| CN101367750A (en) * | 2007-08-14 | 2009-02-18 | 中国人民解放军军事医学科学院毒物药物研究所 | (1S,2S,3S,4R)-3-[(1S)-1-acet-ammonia-2-ethyl-butyl]-4- guanidino-2-hydroxyl-cyclopentyl-1-carboxylic acid aqua compound and medical uses thereof |
| CN101538228A (en) * | 2008-03-21 | 2009-09-23 | 北京普世康医药技术有限公司 | Method for synthesizing medical compound peramivir for resisting influenza viruses and avian influenza viruses |
| CN102372657A (en) * | 2011-11-14 | 2012-03-14 | 暨南大学 | Synthesis method of anti-influenza and avian influenza virus resistant medicine peramivir |
| CN104640540A (en) * | 2012-04-14 | 2015-05-20 | 中央研究院 | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
| CN103524383A (en) * | 2013-10-10 | 2014-01-22 | 山东罗欣药业股份有限公司 | Method for preparing peramivir |
| CN105837632A (en) * | 2016-05-20 | 2016-08-10 | 中山大学 | Neuraminidase inhibitor, preparation method of neuraminidase inhibitor and application of neuraminidase inhibitor to preparation of anti-influenza virus drugs |
Non-Patent Citations (4)
| Title |
|---|
| "Facile Synthesis of the Neuraminidase Inhibitor Peramivir";Jia Fei等;《Synthetic Communications》;20131231;第43卷;Scheme 1, Table 2, 第2645页第3段 * |
| "Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors";Wang Peng-Cheng等;《J. Med. Chem.》;20161231;第59卷;第5305页左栏倒数第1段 * |
| Jia Fei等."Facile Synthesis of the Neuraminidase Inhibitor Peramivir".《Synthetic Communications》.2013,第43卷 * |
| 帕拉米韦三水合物的合成工艺改进与路线;胡震等;《化工管理》;20181011(第29期);第129页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114181117A (en) | 2022-03-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN113999142B (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| CN114181117B (en) | Preparation method of peramivir intermediate | |
| CN108997128B (en) | Preparation method of pregabalin intermediate 3-nitromethyl-5-ethyl methylhexanoate | |
| CN103044468A (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN103183673A (en) | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| CN101735159A (en) | Method for producing monoacetylated homopiperazine | |
| CN114685349B (en) | Process for preparing cis-exo-bicyclo [2.2.1] heptane-2, 3-dicarboximide | |
| CN110668958B (en) | Method for preparing (R) -3-aminobutanol | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN101088999A (en) | Process of synthesizing 3-amino quinine dihydrochloride | |
| CN110790690A (en) | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid | |
| CN113563417B (en) | Continuous flow synthesis method of argatroban intermediate | |
| CN114853619B (en) | Preparation method of N-methyltyramine hydrochloride suitable for industrial production | |
| CN103265616A (en) | N(2)-L-alanyl-L-glutamine synthesis method | |
| CN116655481B (en) | Industrial synthesis method of levocarnitine | |
| CN112375031B (en) | Preparation method of cilnidipine | |
| RU2092478C1 (en) | Method of preparing m-chlorodiphenyl methylurea | |
| CN102491954B (en) | Preparation method of linezolid | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| CN110627672B (en) | Preparation method of dimemorfan phosphate and intermediate thereof | |
| CN114426524A (en) | Method for purifying metformin hydrochloride European pharmacopoeia impurity B | |
| CN115974703A (en) | Preparation method of hydroxymethyl-substituted N, N-dimethyl alicyclic amine | |
| CN117586155A (en) | Preparation method of bumetanide |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |