CN112694421A - Preparation method and application of peramivir related substance - Google Patents
Preparation method and application of peramivir related substance Download PDFInfo
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- CN112694421A CN112694421A CN202011578706.8A CN202011578706A CN112694421A CN 112694421 A CN112694421 A CN 112694421A CN 202011578706 A CN202011578706 A CN 202011578706A CN 112694421 A CN112694421 A CN 112694421A
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- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 title claims abstract description 45
- 229960001084 peramivir Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000000126 substance Substances 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000012535 impurity Substances 0.000 claims abstract description 11
- 239000013558 reference substance Substances 0.000 claims abstract description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- -1 1H-1,2, 4-triazole formamidine hydrochloride Chemical group 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical group CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- HSEMFIZWXHQJAE-UHFFFAOYSA-N Amide-Hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(N)=O HSEMFIZWXHQJAE-UHFFFAOYSA-N 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 229960000789 guanidine hydrochloride Drugs 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 238000011160 research Methods 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 22
- 239000012071 phase Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960004198 guanidine Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
Abstract
The invention discloses a preparation method and application of a peramivir related substance I, wherein the related substance can be used as a peramivir impurity reference substance and is used for separating and determining the peramivir and the peramivir related substance I by a high performance liquid chromatography method. The preparation method provided by the invention has mild reaction conditions and simple post-treatment, and can be used for preparing the compound of the formula I with purity meeting the requirement in a large scale to serve as an impurity reference substance for quality research of peramivir.
Description
Technical Field
The invention relates to a synthesis technology of drug impurities, in particular to a preparation method and application of a peramivir related substance.
Background
The peramivir is a novel cyclopentane type anti-influenza virus medicament, is a novel anti-influenza virus NA inhibitor after the successful development of oseltamivir and zanamivir and the marketing in 1999, is used as a first intravenously administered neuraminidase inhibitor in China and is approved by the State food and drug administration in 2013, 4 and 5 days, and clinical data show that the peramivir is effective on influenza A and B. The structural formula of peramivir is shown as follows:
the quality control of raw material drugs and preparations is always the key and difficult point in the process of drug development, and the research on impurities is the key point in the quality control. The starting materials, intermediates, reaction by-products, degradation impurities, etc. in the synthesis process of peramivir may become impurities remaining in the final product (peramivir), thereby affecting the quality of the drug. At present, researches on related substances of peramivir and quality control analysis methods are rarely reported.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the prior art, the invention provides a peramivir related substance and application of the related substance in preparation of a peramivir raw material drug and a preparation impurity reference substance thereof.
The technical scheme is as follows: the preparation method of the peramivir related substance I comprises the following steps:
(1) hydrolyzing ester group of I-C into carboxylic acid under alkaline environment to obtain compound I-D;
(2) and carrying out guanidine-forming reaction on the amino of the I-D and a guanidine-forming reagent to obtain a compound I.
Further, in the step (1), the alkali added in the alkaline environment is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
In the step (2), the guanidine forming reagent is selected from 1H-1,2, 4-triazole formamidine hydrochloride or 1-pyrazole-guanidine hydrochloride.
Further, the preparation of the compounds I-C comprises the following steps:
1) reacting the I-A with an acetylation reagent in a solvent system to obtain I-B;
2) I-B removes the amino protecting group R to obtain a compound I-C;
wherein R is selected from Cbz, Boc, Fmoc, Alloc and Bn.
Preferably, R is Boc.
Wherein, in the step 1), the solvent is selected from one or more of toluene, dichloromethane, methanol and ethanol; the acetylation reagent is selected from acetyl chloride, acetic anhydride and glacial acetic acid.
In the step 2), the amino protective agent is removed in an acidic environment, wherein the acid added in the acidic environment is selected from one or more of formic acid, hydrochloric acid, trifluoroacetic acid and acetic acid.
The invention also discloses application of the peramivir related substance I prepared by the method in preparation of a peramivir raw material medicine and a preparation impurity reference substance thereof.
Specifically, the high performance liquid chromatography method for separating and measuring the peramivir and the peramivir related substance I comprises the following steps:
a. setting chromatographic conditions: gradient elution is carried out by taking hexadecylamide bonded silica gel as a chromatographic column filler, taking a mobile phase A at a position of 10mmol/L dipotassium hydrogen phosphate solution (pH value is adjusted to 4.5 by phosphoric acid) and taking mobile phase A-acetonitrile (40: 60) as a mobile phase B;
b. solution preparation: dissolving the peramivir bulk drug with water to prepare a peramivir solution with the concentration of 1 mg/mL;
c. and (3) detection: and injecting the prepared peramivir solution into a liquid chromatograph, recording a chromatogram and analyzing.
Preferably, the gradient elution procedure is as follows:
has the advantages that: the invention researches related substances possibly generated in the synthesis process of peramivir, and the impurities prepared by the method are used as impurity reference substances in the quality research of peramivir bulk drug. The invention also provides a liquid chromatography analysis method for separating and measuring the peramivir and the related substances (formula I), which can quickly detect whether the related substances (compounds in the formula I) are contained in the bulk drugs, provides a new selection method for qualitatively and quantitatively detecting the peramivir bulk drugs, and has important significance for quality control and research of the peramivir bulk drug process.
Detailed Description
The present application will be described in detail with reference to specific examples.
Example 1
Adding 10.0g of crude product of the compound I-A into a reaction bottle, adding 70ml of toluene as a reaction solvent, heating to 48-52 ℃, dropwise adding 2.85g of acetic anhydride at a controlled temperature within the temperature range, keeping the temperature of the system between 48-52 ℃ after finishing dropping, stirring and reacting while keeping the temperature, monitoring by TLC (thin layer chromatography) that the raw materials are reacted to disappear, cooling the reaction system to room temperature, adding sodium chloride aqueous solution for washing once, standing for liquid separation, washing the separated organic phase once with the sodium chloride aqueous solution, standing for liquid separation, and concentrating the obtained organic phase to dryness under reduced pressure to obtain 11.08g of crude product I-B.
And (3) carrying out column chromatography purification on the I-B crude product by using a 3% methanol-dichloromethane system to obtain 3.1g of an I-B pure product. Dissolving 3.1g of I-B pure product by 22ml of toluene, cooling to 0-10 ℃ in a low-temperature tank, then dropwise adding 3.14g of 36% hydrochloric acid solution at controlled temperature, keeping the temperature and stirring for reaction after the dropwise addition is finished, keeping the temperature and stirring for reaction after TLC monitors that the raw material reaction disappears, standing and layering a reaction system, separating out an aqueous phase, extracting an organic phase once by using 1.55g of water, standing and layering to obtain a secondary aqueous phase, and combining the two aqueous phases to obtain the aqueous solution of I-C.
And (3) putting the aqueous solution of the I-C into a low-temperature tank, cooling to 0-5 ℃, dropwise adding 30% sodium hydroxide solution at controlled temperature to enable the pH of the system to be about 11, keeping the temperature of 0-5 ℃ for reaction after dropwise adding is finished, and monitoring by TLC (thin layer chromatography) that the reaction of the raw materials disappears to obtain the aqueous solution of the I-D.
Adding 1.37g of 1H-1,2, 4-triazole formamidine hydrochloride into the system, stirring for dissolving, adjusting the pH of the system to 8-9 by using 30% sodium hydroxide solution at room temperature, stirring the reaction overnight at room temperature, concentrating the reaction solution under reduced pressure until the reaction solution is dry to obtain 1.25g of a crude compound of the formula I, carrying out liquid-phase preparation on the crude compound I, and concentrating the prepared solution under reduced pressure until the prepared solution is dry to obtain 0.35g of the compound of the formula I.
HPLC purity: 85.9 percent; 1H NMR (400MHz, D2O) δ 4.45(dd, J ═ 5.1,1.3Hz,1H),4.01(td, J ═ 10.0,5.0Hz,1H),3.77(dd, J ═ 18.1,8.0Hz,1H),2, 78-2.65 (m,1H),2.47(dt, J ═ 13.7,8.5Hz,1H), 2.22-2.10 (m,1H),1.93(s,3H), 1.76-1.65 (m,1H), 1.45-1.286 (m,4H),1.10(dt, J ═ 13.9,7.9Hz,1H),0.77(dt, J ═ 14.4,7.3Hz,6H).
Example 2
Liquid chromatography analysis method for separating and measuring peramivir and related substances (formula I)
The instrument comprises the following steps: agilent 1100/1260 high performance liquid chromatograph
A chromatographic column: agilent Zorbax Box RP (250X 4.6mm,3.5 μm)
Mobile phase: mobile phase a was 10mmol/L dipotassium hydrogen phosphate solution (pH adjusted to 4.5 with phosphoric acid) and mobile phase B was mobile phase a-acetonitrile 40:60, with a linear gradient elution according to the following table:
detection wavelength: 210nm
Flow rate: 0.8mL/min
Column temperature: 30 deg.C
Sample introduction amount: 10 μ L
The related substance (formula I) prepared above was precisely weighed, dissolved in water and diluted to a solution containing about 1mg per 1mL as a positioning solution.
Weighing a proper amount of peramivir, adding the positioning solution of the formula (I) into the positioning solution of the formula (I) to prepare solutions containing about 10mg of peramivir and about 2.5 mu g of the formula (I) per 1mL, and taking the solutions as system adaptive solutions.
An appropriate amount of peramivir is weighed, placed in a measuring flask, dissolved in water and diluted into a solution of 10mg/mL to be used as a test solution.
And (3) determination: respectively injecting 10 mu L of each of the positioning solution, the system adaptability solution and the peramivir sample solution in the formula I into a high performance liquid chromatograph, and recording chromatograms. The result shows that the method can realize good separation of the related substance (the compound shown in the formula I) and the peramivir, the peak of the peramivir is 18.480min, and the peak of the related substance (the compound shown in the formula I) is 20.063 min.
Claims (10)
1. The preparation method of the peramivir related substance I is characterized by comprising the following steps:
(1) hydrolyzing ester group of I-C into carboxylic acid under alkaline environment to obtain compound I-D;
(2) and carrying out guanidine-forming reaction on the amino of the I-D and a guanidine-forming reagent to obtain a compound I.
2. The preparation method according to claim 1, wherein in the step (1), the alkali added in the alkaline environment is one or more selected from lithium hydroxide, sodium hydroxide and potassium hydroxide.
3. The method according to claim 1, wherein in step (2), the guanidine-forming reagent is selected from 1H-1,2, 4-triazole formamidine hydrochloride or 1-pyrazole-guanidine hydrochloride.
4. The process for the preparation of peramivir related substance I according to any of claims 1 to 3, wherein the preparation of compound I-C comprises the steps of:
1) reacting the I-A with an acetylation reagent in a solvent system to obtain I-B;
2) I-B removes the amino protecting group R to obtain a compound I-C;
wherein R is selected from Cbz, Boc, Fmoc, Alloc and Bn.
5. The method of claim 4, wherein R is Boc.
6. The preparation method according to claim 4, wherein in step 1), the solvent is selected from one or more of toluene, dichloromethane, methanol and ethanol; the acetylation reagent is selected from acetyl chloride, acetic anhydride and glacial acetic acid.
7. The preparation method according to claim 4, wherein in the step 2), the amino protective agent is removed in an acidic environment, and the acid added in the acidic environment is selected from one or more of formic acid, hydrochloric acid, trifluoroacetic acid and acetic acid.
8. The use of peramivir related substance I prepared according to claim 1 in the preparation of peramivir bulk drug and impurity reference substance of the preparation.
9. The use according to claim 8, wherein the high performance liquid chromatography method for separating and determining peramivir and peramivir related substance I comprises the following steps:
a. setting chromatographic conditions: gradient elution is carried out by taking hexadecylamide bonded silica gel as a chromatographic column filler, taking a mobile phase A at a position of 10mmol/L dipotassium hydrogen phosphate solution (pH value is adjusted to 4.5 by phosphoric acid) and taking mobile phase A-acetonitrile (40: 60) as a mobile phase B;
b. solution preparation: dissolving the peramivir bulk drug with water to prepare a peramivir solution with the concentration of 1 mg/mL;
c. and (3) detection: and injecting the prepared peramivir solution into a liquid chromatograph, recording a chromatogram and analyzing.
10. Use according to claim 9, wherein the gradient elution procedure is as follows:
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| CN202011578706.8A CN112694421A (en) | 2020-12-28 | 2020-12-28 | Preparation method and application of peramivir related substance |
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| CN202011578706.8A CN112694421A (en) | 2020-12-28 | 2020-12-28 | Preparation method and application of peramivir related substance |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114295747A (en) * | 2021-12-30 | 2022-04-08 | 苏州正济药业有限公司 | Analysis method of peramivir starting material and impurities |
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|---|---|---|---|---|
| WO2007087056A2 (en) * | 2006-01-13 | 2007-08-02 | Scolr Pharma, Inc. | Peramivir derivative for oral administration |
| CN103524383A (en) * | 2013-10-10 | 2014-01-22 | 山东罗欣药业股份有限公司 | Method for preparing peramivir |
| CN105085328A (en) * | 2015-04-13 | 2015-11-25 | 广州南新制药有限公司 | Synthetic method for peramivir trihydrate |
| 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 |
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2020
- 2020-12-28 CN CN202011578706.8A patent/CN112694421A/en active Pending
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| CN114295747B (en) * | 2021-12-30 | 2023-10-20 | 苏州正济药业有限公司 | Analysis method of Parami Wei Qishi material and impurities |
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