CN115057902A - Preparation method of anti-novel coronavirus medicine monatipivir - Google Patents
Preparation method of anti-novel coronavirus medicine monatipivir Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
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- RMLYXMMBIZLGAQ-HZMBPMFUSA-N (2s,4s)-4-amino-2-hydroxy-2-(1h-indol-3-ylmethyl)pentanedioic acid Chemical compound C1=CC=C2C(C[C@](O)(C[C@H](N)C(O)=O)C(O)=O)=CNC2=C1 RMLYXMMBIZLGAQ-HZMBPMFUSA-N 0.000 claims description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 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 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- -1 MP-D oxime ester Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- POCUPXSSKQAQRY-UHFFFAOYSA-N hydroxylamine;hydrate Chemical compound O.ON POCUPXSSKQAQRY-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
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- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229950009297 pivoxil Drugs 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
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- 230000003203 everyday effect Effects 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940075124 molnupiravir Drugs 0.000 description 1
- HTNPEHXGEKVIHG-ZJTJHKMLSA-N molnupiravir Chemical compound CC(C)C(=O)OC[C@H]1O[C@H](C(O)C1O)N1C=C\C(NC1=O)=N\O HTNPEHXGEKVIHG-ZJTJHKMLSA-N 0.000 description 1
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- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- 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
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Abstract
The invention relates to a preparation method of a novel coronavirus resistant medicine monatipivir, which comprises the following process steps: (1) synthesizing an intermediate MP-C, wherein the structural formula of the intermediate MP-C is as follows:
(2) the synthesis of intermediate MP-D and monatipivir, wherein the intermediate MP-D has the structural formula:
the preparation method of the monatipivir is simple to operate, can be boiled in one pot, has high yield and high product quality and purity, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of a novel coronavirus resistant medicine monatipivir.
Background
The new crown epidemic situation affects the life of people all over the world, especially the outbreak of the second wave epidemic situation in India in 4 month of the year, and 30-40 ten thousand of new patients are added every day to arouse the sight of people all over the world. The development of drugs capable of treating or preventing novel coronaviruses is imminent.
Researchers at the university of georgia, 7-day united states, 12-month-2020 may find a drug that kills the virus immediately after infection. The research team found in animal experiments that the new antiviral drug, Molnupiravir (also known as monatipivir), completely blocked viral transmission within 24 hours. The mechanism of action causes mutations in the viral ribonucleic acid (RNA) which prevent viral propagation. The clinical speed of the medicine is rapidly promoted, a plurality of phase III clinical tests are carried out on the medicine at present, the medicine is authorized to be manufactured by 27 imitating pharmaceutical companies all over the world in 2021, 1 month and 20 days, and the manufactured medicine provides 105 countries with medium-low income.
Because the clinical dosage of the medicine is very large, the clinical dosage is 200mg, 400mg and 800mg, 2 tablets are taken in one day, and the total taking time is 5 days. In the case of 400mg, one patient needs to eat 4g, and 3500W patients exist at present, the supply and demand of 140 tons of raw material medicines, and considering that the data of patients in partial regions far exceed the data reported by authorities, particularly in the population countries of developing countries, such as India and Brazil, and the like. A conservative estimate of the patient is expected to be around 3 billion, which means that around 1200 tons of drug substance are used globally. Therefore, the development of a process for the development of monatipivir is of particular importance.
The original synthetic route using cytidine as the starting material was as follows:
according to the route, cytidine is used as a starting material and is subjected to diol protection to obtain A, the A is esterified to obtain B, the B is subjected to hydroxylamination to obtain C, and the C is subjected to deprotection to obtain monatipivir; or the obtained B, hydroxylamine amination and deprotection are carried out simultaneously to obtain the monatin.
The 2 steps of esterification and deprotection have relatively low reaction yield and long reaction time, so that a route which is simple to operate, high in yield, high in product quality and purity and suitable for large-scale production needs to be developed.
Disclosure of Invention
The invention aims to provide a preparation method of the novel coronavirus resistant medicine monatipivir, which is simple to operate, high in yield, high in product quality and purity and suitable for large-scale production.
The purpose of the invention is realized by the following technical scheme: a preparation method of a novel coronavirus resistant medicine monatipivir comprises the following process steps:
(1) and (3) synthesis of an intermediate MP-C: dissolving a compound MP-B in an organic solvent, and adding isobutyric anhydride to perform esterification reaction under the alkaline condition and the catalyst condition to obtain an intermediate MP-C; the structural formulas of the compound MP-B and the intermediate MP-C are respectively as follows:
(2) synthesis of intermediate MP-D and monatipivir:
and (3) synthesis of intermediate MP-D: deprotecting the intermediate MP-C obtained in the step (1) under the condition that acid is used as a solvent to obtain an intermediate MP-D, wherein the structural formula of the intermediate MP-D is shown in the specification
Synthesis of monatipivir: hydrolyzing the obtained intermediate MP-D oxime ester to obtain the monatin (API), wherein the structure of the monatin is as follows:
the specific synthetic route of the monatipivir provided by the invention is as follows:
compared with the prior art, the invention has the advantages that: the preparation method of the monatipivir is simple to operate, can be boiled in one pot, has high yield and high product quality and purity, and is suitable for large-scale production.
Drawings
FIG. 1 is a mass spectrum of intermediate MP-C of the present invention.
FIG. 2 is a nuclear magnetic spectrum of intermediate MP-D of the present invention.
Detailed Description
The present invention will be described in detail with reference to the following examples:
a preparation method of a novel coronavirus resistant medicine monatipivir comprises the following process steps:
(1) and (3) synthesis of intermediate MP-C: dissolving a compound MP-B in an organic solvent, and adding isobutyric anhydride to perform esterification reaction under the alkaline condition and the catalyst condition to obtain an intermediate MP-C; the structural formulas of the compound MP-B and the intermediate MP-C are respectively as follows:
wherein, the synthesis of the compound MP-B can be completed according to the process steps of the patent WO 2016106050.
(2) Synthesis of intermediate MP-D and API:
and (3) synthesis of intermediate MP-D: deprotecting the intermediate MP-C obtained in the step (1) under the condition that acid is used as a solvent to obtain an intermediate MP-D, wherein the structural formula of the intermediate MP-D is as follows:
synthesis of monatipivir: hydrolyzing the obtained intermediate MP-D oxime ester to obtain the monatin pivoxil (API), wherein the structure of the monatin pivoxil is as follows:
the specific operation method of the step (1) comprises the following steps:
adding a compound MP-B into a reaction bottle, dissolving the compound MP-B by using an organic solvent A, adding an alkaline reagent and a catalytic reagent, slowly dropwise adding isobutyric anhydride under the condition of 10-60 ℃ (preferably 20-30 ℃), and continuously reacting for 1-24h (preferably 3-5h) at the temperature; and after the reaction is finished, adding EA and water into a reaction bottle, stirring for 15min, extracting for 2 times by using ethyl acetate, washing the obtained organic solution for 2 times by using water, and concentrating the organic layer to obtain solid MP-C.
Wherein the molar ratio of the compound MP-B, the alkaline reagent, the catalyst and the isobutyric anhydride is 1.0: 3.0-7.0: 0.1-1.0: 1.5-3.5 (more preferably 1.0:5.0:0.2: 2.2).
The organic solvent A is DMF, NMP, DMSO, THF or acetone, and preferably acetone;
the alkaline reagent is TEA or DIPEA, preferably TEA;
the catalytic agent is pyridine or DMAP, preferably DMAP;
the specific operation method of the step (2) is as follows:
adding solid compound MP-C into a reaction bottle, using acid as a solvent, and then reacting for 2-24h (preferably 10-12h) at 20-100 ℃ (preferably 60-70 ℃); after the reaction is finished, concentrating the reaction solution for later use.
Adding an ammonia water solution into the standby solution, stirring for 1h, then adding a 30% hydroxylamine aqueous solution and an organic solvent B, reacting for 0.5-10h (preferably 1-2h) at the temperature of 10-100 ℃ (preferably 20-30 ℃), adding MTBE and water after the reaction is finished, extracting, separating, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain the monatepivir.
The acid selected was 85% CH 3 COOH or formic acid, preferably 85% CH 3 COOH；
Selected from MP-C (g) 85% CH 3 COOH (ml) is 1: 1-10, more preferably 1: 3.5;
the molar ratio of MP-C to hydroxylamine is 1: 1-5, more preferably 1: 1.2;
the organic solvent B is THF, methyltetrahydrofuran, DMF or NMP, and more preferably methyltetrahydrofuran.
The following are specific embodiments of the present invention:
example 1:
1.1 Synthesis of intermediate MP-C
In a 2L three-necked flask, MP-B (29.9g, 0.10mol), acetone (500ml), TEA (50.6g, 0.50mol), DMAP (2.44g, 0.02mol) as a solid compound were charged and dissolved with stirring, and isobutyric anhydride (34.8g,0.22mol) was slowly added dropwise at 20 to 30 ℃ and the reaction was further continued with stirring at that temperature for 3 to 5 hours. After completion of the reaction, 500ml of EA and 500ml of water were added, stirred for 15min, the liquid was separated by extraction, the aqueous layer was extracted 2 times with 300ml of 2 acetic acid, the organic layers were combined, the organic layer was washed 2 times with 300ml of 2 water, and the resulting organic layer was dried and concentrated to give 40.7g of a solid with a yield of 92.6%.
Mass spectrometry analysis: MS (M + H) 440.42. The mass spectrum of the intermediate MP-C is shown in figure 1.
1.2 Synthesis of intermediates MP-D and API
Adding solid MP-C (43.9g,0.1mol) and 150ml of 85% formic acid into a 2L three-necked bottle, stirring and clarifying, heating to 60-70 ℃, reacting for 10-12h at the temperature, concentrating the reaction solution after the reaction is finished to obtain an intermediate MP-D, and keeping the concentrated reaction solution for later use.
Nuclear magnetic resolution of intermediate MP-D: 1H-NMR (400MHz, DMSO-d6) 10.94(1H, s),7.21-7.19 (1H, d),5.78-5.76(2H, t),5.48-5.46(1H, d),5.29-5.28(1H, d),4.28-4.18(2H, m),4.08-4.05 (1H, m),4.01-3.95(2H, m),2.87-2.80(1H, m),2.65-2.58(1H, m),1.15(3H, s),1.14-1.13(6H, d),1.12(3H, s). The nuclear magnetic spectrum of the intermediate MP-D is shown in figure 2.
Mass spectrometry of intermediate MP-D: 400.45.
adding ammonia water into the reaction liquid to adjust the pH value to be approximately equal to 7, stirring for 1h, then adding 30% hydroxylamine aqueous solution (3.96g of hydroxylamine, 0.12mol) and methyl tetrahydrofuran, reacting for 1-2h at 20-30 ℃, adding MTBE and water after the reaction is finished, extracting and separating, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain monatepivir;
the obtained product was subjected to nuclear magnetic resonance analysis, and the product obtained in this example was monatipivir.
Example 2:
2.1 Synthesis of intermediate MP-C
A2L three-necked flask was charged with MP-B (29.9g, 0.10mol), DMF (500ml), DIPEA (64.6g, 0.50mol), pyridine (1.58g, 0.02mol) as a solid compound, stirred to dissolve, isobutyric anhydride (34.8g,0.22mol) was slowly added dropwise at 10 to 20 ℃ and the reaction was further stirred at that temperature for 10 to 12 hours. After completion of the reaction, 500ml of EA and 500ml of water were added, stirred for 15min, the liquid was separated by extraction, the aqueous layer was extracted 2 times with 300ml of 2 acetic acid, the organic layers were combined, the organic layer was washed 2 times with 300ml of 2 water, and the resulting organic layer was dried and concentrated to give 35.3g of a solid with a yield of 80.3%.
2.2 Synthesis of intermediates MP-D and API
Adding a solid compound MP-C (43.9g,0.1mol) and 150ml of 85% formic acid into a 2L three-necked flask, stirring for clarification, heating to 50-60 ℃, reacting for 8-10h at the temperature, and concentrating the reaction solution for later use after the reaction is finished.
Adding ammonia water into the reaction liquid to adjust the pH value to be approximately 7, stirring for 1h, then adding 30% hydroxylamine aqueous solution (4.95g hydroxylamine, 0.15mol) and THF, reacting for 4-5 h at 40-50 ℃, adding MTBE and water after the reaction is finished, extracting, separating liquid, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain the monatepivir.
Example 3
3.1 Synthesis of intermediate MP-C
In a 2L three-necked flask, the solid compound MP-B (29.9g, 0.10mol), DMF (500ml), TEA (35.4g, 0.35mol), DMAP (4.88g, 0.04mol) was added and dissolved with stirring, and isobutyric anhydride (47.5g,0.30mol) was slowly added dropwise at a temperature of 40 to 50 ℃ and the reaction was stirred at that temperature for 7 to 8 hours. After completion of the reaction, 500ml of EA and 500ml of water were added, stirred for 15min, the aqueous layer was separated by extraction with 300ml of 2 acetic acid for 2 times, the organic layers were combined, the organic layer was washed with 300ml of 2 water for 2 times, and the resulting organic layer was dried and concentrated to obtain MP-c36.7g, a solid compound in 83.6% yield.
3.2 Synthesis of intermediate MP-D and API
Adding solid compound MP-C (43.9g,0.1mol) and 250ml of 85% formic acid into a 2L three-necked flask, stirring for clarification, heating to 70-80 ℃, reacting for 5-6h at the temperature, and concentrating the reaction solution for later use after the reaction is finished.
Adding ammonia water into the reaction liquid to adjust the pH value to be approximately 7, stirring for 1h, then adding 30% hydroxylamine aqueous solution (6.60g hydroxylamine, 0.20mol) and DMF, reacting for 3-4 h at 40-50 ℃, adding MTBE and water after the reaction is finished, extracting, separating liquid, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain the monatepivir.
The nuclear magnetic analysis data or mass spectrometry analysis of the compounds of examples 2 and 3 of the present invention substantially agreed with the data of the corresponding compounds of example 1, and therefore the nuclear magnetic analysis data or mass spectrometry analysis and spectra of the compounds of examples 2 and 3 were not provided.
The upper and lower limit values and interval values of the raw materials of the invention can realize the invention, and the enumerated raw materials can realize the invention, so the examples are not necessarily listed.
It is noted that all references or patents mentioned in this application are incorporated herein by reference as if each individual reference or patent were individually incorporated by reference. Further, it should be understood that the above-described specific embodiments and technical principles of the present invention, and after reading the above-described contents of the present invention, those skilled in the art may make various modifications and alterations to the present invention without departing from the scope of the present invention, and those equivalents also fall within the scope of the present invention.
Claims (9)
1. A preparation method of a novel coronavirus resistant medicine monatipivir is characterized in that: the method comprises the following process steps:
(1) and (3) synthesis of intermediate MP-C: dissolving a compound MP-B in an organic solvent, and adding isobutyric anhydride to perform esterification reaction under the alkaline condition and the catalyst condition to obtain an intermediate MP-C; the structural formulas of the compound MP-B and the intermediate MP-C are respectively as follows:
(2) synthesis of intermediate MP-D and monatipivir:
and (3) synthesis of intermediate MP-D: deprotecting the intermediate MP-C obtained in the step (1) under the condition that acid is used as a solvent to obtain an intermediate MP-D, wherein the structural formula of the intermediate MP-D is shown in the specification
Synthesis of monatipivir: hydrolyzing the obtained intermediate MP-D oxime ester to obtain the monatin (API), wherein the structure of the monatin is as follows:
2. the process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 1, wherein: the specific operation method of the step (1) comprises the following steps: adding a compound MP-B and an organic solvent A into a reaction bottle, adding an alkaline reagent and a catalytic reagent, slowly dropwise adding isobutyric anhydride at the temperature of 10-60 ℃, and continuing to react for 1-24h at the temperature; after the reaction is finished, adding EA and water into a reaction bottle, stirring for 15min, extracting for 2 times by using ethyl acetate, washing the obtained organic solution for 2 times by using water, and concentrating the organic layer to obtain solid MP-C;
wherein the molar ratio of the compound MP-B, the alkaline reagent, the catalyst and the isobutyric anhydride is 1.0: 3.0-7.0: 0.1-1.0: 1.5-3.5.
3. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 2, wherein: the organic solvent A is DMF, NMP, DMSO, THF or acetone.
4. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 2, wherein: the alkaline agent is TEA or DIPEA.
5. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 2, wherein: the catalytic agent is pyridine or DMAP.
6. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 1, wherein: the specific operation method of the step (2) is as follows:
adding a solid compound MP-C into a reaction bottle, using acid as a solvent, and then reacting for 2-24h at 20-100 ℃; after the reaction is finished, concentrating the reaction solution for later use;
adding an ammonia water solution into the standby solution, stirring for 1h, then adding a 30% hydroxylamine water solution and an organic solvent B, reacting for 0.5-10h at the temperature of 10-100 ℃, adding MTBE and water after the reaction is finished, extracting, separating liquid, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain monatipivir;
the mol ratio of the compound MP-C to hydroxylamine is 1: 1 to 5.
7. The process for preparing monatipivir, an anti-novel coronavirus drug, according to claim 6, characterized in that: the acid is 85% CH 3 COOH or formic acid.
8. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 7, wherein: the compound MP-C (g) is 85% of CH 3 (COOH ml) 1: 1 to 10.
9. The process for the preparation of monatipivir, an anti-novel coronavirus drug, as claimed in claim 6, wherein: the organic solvent B is THF, methyltetrahydrofuran, DMF or NMP.
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| CN111548384A (en) * | 2020-03-29 | 2020-08-18 | 常州安蒂卫生物科技有限公司 | Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111548384A (en) * | 2020-03-29 | 2020-08-18 | 常州安蒂卫生物科技有限公司 | Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy |
| CN112608357A (en) * | 2020-12-21 | 2021-04-06 | 杭州科巢生物科技有限公司 | Preparation method of antiviral drug Molnbupiravir |
| CN113880903A (en) * | 2021-09-23 | 2022-01-04 | 厦门蔚嘉制药有限公司 | Preparation method of monabivir |
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| DINESH J. PAYMODE 等: "Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification", 《ORG. PROCESS RES. DEV.》, vol. 25, no. 8, pages 1822 - 1830, XP093038654, DOI: 10.1021/acs.oprd.1c00033 * |
| GOPALSAMUTHIRAM, VIJAYAGOPAL R. 等: "Towards a Practical, Non-enzymatic Process for Molnupiravir from Cytidine", 《CHEMRXIV》, pages 1 - 6 * |
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