CN115057902B - Preparation method of novel coronavirus resistant drug monatin - Google Patents
Preparation method of novel coronavirus resistant drug monatin Download PDFInfo
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- CN115057902B CN115057902B CN202210181103.7A CN202210181103A CN115057902B CN 115057902 B CN115057902 B CN 115057902B CN 202210181103 A CN202210181103 A CN 202210181103A CN 115057902 B CN115057902 B CN 115057902B
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- RMLYXMMBIZLGAQ-UHFFFAOYSA-N (-)-monatin Natural products C1=CC=C2C(CC(O)(CC(N)C(O)=O)C(O)=O)=CNC2=C1 RMLYXMMBIZLGAQ-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 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 title claims abstract description 22
- 239000003814 drug Substances 0.000 title claims abstract description 21
- 241000711573 Coronaviridae Species 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- QTEDUQSFCPUIOH-UEUBVZDRSA-N mastoparan-D Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)CC1=CC=CC=C1 QTEDUQSFCPUIOH-UEUBVZDRSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 22
- 230000015572 biosynthetic process Effects 0.000 claims description 19
- 238000003786 synthesis reaction Methods 0.000 claims description 19
- 239000012044 organic layer Substances 0.000 claims description 16
- NSFBOCKFBVQQKB-CQWNSWRRSA-N mastoparan-B Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(C)C)[C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)=CNC2=C1 NSFBOCKFBVQQKB-CQWNSWRRSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 238000010511 deprotection reaction 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
- 239000012295 chemical reaction liquid Substances 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
- 238000001035 drying Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- POCUPXSSKQAQRY-UHFFFAOYSA-N hydroxylamine;hydrate Chemical compound O.ON POCUPXSSKQAQRY-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229950009297 pivoxil Drugs 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 9
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 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
- 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 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
- 238000010438 heat treatment Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 229940075124 molnupiravir Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000014599 transmission of virus Effects 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
Abstract
The application relates to a preparation method of an anti-novel coronavirus drug monatin, 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) Synthesizing an intermediate MP-D and monapivir, wherein the structural formula of the intermediate MP-D is as follows:the preparation method of the monatin disclosed by the application is simple to operate, high in yield and high in product quality and purity, and is suitable for large-scale production.
Description
Technical Field
The application relates to a preparation method of a novel coronavirus resistant drug monatin.
Background
The new crown epidemic affects the life of people worldwide, especially the outbreak of the second wave epidemic in India of 4 months in this year, 30-40 ten thousand new patients are added every day, and the vision of people worldwide is pulled. There is an urgent need to develop a novel coronavirus drug capable of treating or preventing coronavirus.
Researchers at university of georgia, 12 months 7, 2020 may find a drug that kills viruses immediately after infection. The research team found in animal experiments that the new antiviral drug Molnupiravir, also known as monapirir, completely blocked viral transmission within 24 hours. Its mechanism of action causes mutations in the ribonucleic acid (RNA) of the virus, thereby preventing the virus from propagating. The clinical speed of the medicine is rapidly advancing, and at present, the medicine is authorized to be imitated by 27 imitated pharmaceutical companies worldwide in 20 days of 2021 in 1 month after a plurality of phase III clinical tests are carried out, and 105 low and medium income countries are provided for the produced medicine.
Because the clinical dosage of the medicine is particularly large, the medicine clinically comprises 200mg, 400mg and 800mg, and the medicine is taken 2 tablets a day for 5 days. Taking 400mg as an example, a patient needs to eat 4g, so far 3500W patients exist, and 140 tons of raw medicines are needed, and considering that the patient data in partial areas far exceeds the data reported by authorities, especially in developing countries such as India, brazil and the like. Patient conservation estimates are around 3 billion, meaning that the global drug substance is about 1200 tons. Thus, the development of a process for developing monatin is particularly important.
The synthetic route with cytidine as starting material was originally developed as follows:
in the route, cytidine is taken as a starting material, glycol protection is carried out to obtain A, A is esterified again to obtain B, B is subjected to hydroxylamine to obtain C, and C is deprotected to obtain monapivir; or B, hydroxylamine and deprotection are carried out simultaneously to obtain the monatin.
The greatest problem of the route is that the 2-step reaction of esterification and deprotection has relatively low 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 application aims to provide a preparation method of an anti-novel coronavirus drug monatin, which has the advantages of simple operation, high yield, high product quality and purity and suitability for large-scale production.
The aim of the application is realized by the following technical scheme: the preparation process of monatin as one new kind of coronavirus resisting medicine includes the following steps:
(1) Synthesis of intermediate MP-C: dissolving compound MP-B in an organic solvent, and adding isobutyric anhydride for esterification reaction under alkaline conditions and catalyst conditions to obtain an intermediate MP-C; the structural formula of the compound MP-B and the intermediate MP-C is respectively as follows:
(2) Synthesis of intermediate MP-D and monapivir:
synthesis of intermediate MP-D: deprotection of intermediate MP-C obtained in step (1) under the condition of acid as solvent to obtain intermediate MP-D, wherein the structural formula of intermediate MP-D is
Synthesis of monatin: the obtained intermediate MP-D oxime ester is hydrolyzed to obtain monazir (API), and the monazir has the structure as follows:
the specific synthetic route of Minmonapiri is as follows:
compared with the prior art, the application has the advantages that: the preparation method of the monatin disclosed by the application is simple to operate, high in yield and high in 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 application.
FIG. 2 is a nuclear magnetic resonance spectrum of intermediate MP-D of the present application.
Detailed Description
The following describes the present application in detail with reference to examples:
the preparation process of monatin as one new kind of coronavirus resisting medicine includes the following steps:
(1) Synthesis of intermediate MP-C: dissolving compound MP-B in an organic solvent, and adding isobutyric anhydride for esterification reaction under alkaline conditions and catalyst conditions to obtain an intermediate MP-C; the structural formula of the compound MP-B and the intermediate MP-C is respectively as follows:
wherein, the synthesis of the compound MP-B can be completed according to the process steps of patent WO 2016106050.
(2) Synthesis of intermediate MP-D and API:
synthesis of intermediate MP-D: deprotection of intermediate MP-C obtained in step (1) under the condition of acid as solvent to obtain intermediate MP-D, wherein the intermediate MP-D has the structural formula:
synthesis of monatin: the obtained intermediate MP-D oxime ester is hydrolyzed to obtain monazir (API), and the monazir has the structure 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 in an organic solvent A, adding an alkaline reagent and a catalytic reagent, slowly and dropwise adding isobutyric anhydride at 10-60 ℃ (preferably 20-30 ℃), and continuing to react at the temperature for 1-24h (preferably 3-5 h); after the reaction, EA and water are added into a reaction bottle, stirred for 15min, extracted 2 times with ethyl acetate, the obtained organic solution is washed 2 times with water, and the organic layer is concentrated 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, 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 a solid compound MP-C into a reaction bottle, using acid as a solvent, and then reacting for 2-24 hours (preferably 10-12 hours) at 20-100 ℃ (preferably 60-70 ℃); after the reaction is finished, the reaction solution is concentrated for standby.
Adding ammonia water solution into the standby solution, stirring for 1h, then adding 30% hydroxylamine water solution and organic solvent B, reacting for 0.5-10h (preferably 1-2 h) at 10-100 ℃ (preferably 20-30 ℃), adding MTBE and water after the reaction is finished, extracting and separating liquid, washing a filter cake obtained by concentrating an organic layer by using MTBE, and drying the filter cake to obtain monatevir.
The acid selected is 85% CH 3 COOH or formic acid, preferably 85% CH 3 COOH；
Selected MP-C (g): 85% CH 3 COOH (ml) was 1:1 to 10, more preferably 1:3.5;
the molar ratio of the MP-C to the hydroxylamine is 1:1 to 5, more preferably 1:1.2;
the organic solvent B is THF, methyltetrahydrofuran, DMF or NMP, more preferably methyltetrahydrofuran.
The following are specific embodiments of the present application:
example 1:
1.1 Synthesis of intermediate MP-C
Into a 2L three-necked flask, MP-B (29.9 g,0.10 mol), acetone (500 ml), TEA (50.6 g,0.50 mol) and DMAP (2.44 g,0.02 mol) were added and dissolved under stirring, and isobutyric anhydride (34.8 g,0.22 mol) was slowly added dropwise at 20 to 30℃and the reaction was continued under stirring at this temperature for 3 to 5 hours. After the reaction was completed, 500ml EA and 500ml water were added, stirred for 15min, the extract was separated, the aqueous layer was extracted 2 times with 300ml x 2 acetic acid, the organic layers were combined, the organic layer was washed 2 times with 300ml x 2 water, and the obtained organic layer was dried and concentrated to give 40.7g of solid with a yield of 92.6%.
Mass spectrometry analysis: MS (M+H): 440.42. The mass spectrum of intermediate MP-C is shown in figure 1.
1.2 Synthesis of intermediates MP-D and API
Solid MP-C (43.9 g,0.1 mol) and 85% formic acid (150 ml) are added into a 2L three-mouth bottle, stirred and clarified, heated to 60-70 ℃ for reaction for 10-12h, after the reaction is finished, the reaction solution is concentrated to obtain an intermediate MP-D, and the concentrated reaction solution is used.
Nuclear magnetic analysis of intermediate MP-D: 1H-NMR (400 MHz, DMSO-d 6): 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 intermediate MP-D is shown in FIG. 2.
Mass spectrometry of intermediate MP-D: 400.45.
adding ammonia water into the reaction liquid to adjust the pH to be approximately equal to 7, stirring for 1h, then adding 30% hydroxylamine aqueous solution (3.96 g hydroxylamine, 0.12 mol) and methyltetrahydrofuran, reacting for 1-2h at 20-30 ℃, adding MTBE and water after the reaction is finished, extracting and separating liquid, washing a filter cake obtained by concentrating an organic layer by using MTBE, and drying the filter cake to obtain monatevir;
and carrying out nuclear magnetic analysis on the obtained product to obtain the product obtained in the embodiment, namely monatin.
Example 2:
2.1 Synthesis of intermediate MP-C
Into a 2L three-necked flask, MP-B (29.9 g,0.10 mol), DMF (500 ml), DIPEA (64.6 g,0.50 mol), pyridine (1.58 g,0.02 mol) were added and dissolved under stirring, and isobutyric anhydride (34.8 g,0.22 mol) was slowly added dropwise at 10 to 20℃and reacted under stirring at this temperature for 10 to 12 hours. After the reaction was completed, 500ml EA and 500ml water were added, stirred for 15min, the extract was separated, the aqueous layer was extracted 2 times with 300ml x 2 acetic acid, the organic layers were combined, the organic layer was washed 2 times with 300ml x 2 water, and the obtained organic layer was dried and concentrated to give 35.3g of solid with a yield of 80.3%.
2.2 Synthesis of intermediates MP-D and API
In a 2L three-necked flask, solid compound MP-C (43.9 g,0.1 mol), 85% formic acid (150 ml) was added, followed by stirring and clarification, heating to 50-60℃and reacting for 8-10 hours at this temperature, and after the reaction was completed, the reaction solution was concentrated for use.
Ammonia water is added into the reaction liquid to adjust the pH to be approximately equal to 7, stirring is carried out for 1h, then 30 percent hydroxylamine aqueous solution (4.95 g hydroxylamine, 0.15 mol) and THF are added, the reaction is carried out for 4 to 5h at the temperature of 40 to 50 ℃, MTBE and water are added after the reaction is finished, the liquid is separated by extraction, the filter cake obtained by concentrating the organic layer is washed by MTBE, and the filter cake is dried to obtain the monatevir.
Example 3
3.1 Synthesis of intermediate MP-C
Into a 2L three-necked flask, MP-B (29.9 g,0.10 mol), DMF (500 ml), TEA (35.4 g,0.35 mol) and DMAP (4.88 g,0.04 mol) were added as solid substances, and stirred and dissolved, and isobutyric anhydride (47.5 g,0.30 mol) was slowly added dropwise at a temperature of 40 to 50℃and stirred and reacted for 7 to 8 hours at this temperature. After the reaction was completed, 500ml EA and 500ml water were added, stirred for 15min, the extract was separated, the aqueous layer was extracted 2 times with 300ml x 2 acetic acid, the organic layers were combined, the organic layer was washed 2 times with 300ml x 2 water, and the obtained organic layer was dried and concentrated to give solid compound MP-c36.7g, yield 83.6%.
3.2 Synthesis of intermediates MP-D and API
Into a 2L three-necked flask, solid compound MP-C (43.9 g,0.1 mol), 85% formic acid (250 ml) was added, followed by stirring and clarification, heating to 70-80℃and reacting for 5-6 hours under the temperature condition, and after the reaction was completed, the reaction solution was concentrated for use.
Ammonia water is added into the reaction liquid to adjust the pH to be approximately equal to 7, stirring is carried out for 1h, then 30 percent hydroxylamine aqueous solution (6.60 g hydroxylamine, 0.20 mol) and DMF are added, the reaction is carried out for 3 to 4h at the temperature of 40 to 50 ℃, MTBE and water are added after the reaction is finished, the liquid is separated by extraction, the filter cake obtained by concentrating the organic layer is washed by MTBE, and the filter cake is dried to obtain the monatevir.
The nuclear magnetic resonance analysis data or mass spectrometry analysis of the compounds of example 2 and example 3 of the present application are substantially identical to the data of the corresponding compound of example 1, and thus the present application does not provide the nuclear magnetic resonance analysis data or mass spectrometry analysis and spectrogram of the compounds of example 2 and example 3.
The present application can be realized by the upper and lower limit values and the interval values of the respective raw materials, and the present application can be realized by the respective raw materials, and examples are not limited to this.
It should be noted that all documents or patents mentioned in this specification are incorporated by reference herein as if each individual article or patent was individually incorporated by reference. It will be appreciated that the above description is of specific embodiments of the application and technical principles thereof, and that after reading the above description, those skilled in the art may make various modifications and alterations to the application without departing from the scope of the application, and these equivalents are also within the scope of the application.
Claims (5)
1. A preparation method of an anti-novel coronavirus drug monatin pivoxil is characterized by comprising the following steps: the method comprises the following process steps:
(1) Synthesis of intermediate MP-C: dissolving compound MP-B in an organic solvent, and adding isobutyric anhydride for esterification reaction under alkaline conditions and catalyst conditions to obtain an intermediate MP-C; the structural formula of the compound MP-B and the intermediate MP-C is respectively as follows:
the specific operation method of the step (1) comprises the following steps: adding a compound MP-B, an organic solvent A, an alkaline reagent and a catalytic reagent into a reaction bottle, slowly and dropwise adding isobutyric anhydride at the temperature of 10-60 ℃, and continuously reacting for 1-24 hours at the temperature; after the reaction is finished, EA (ethyl acetate) and water are added into a reaction bottle, stirring is carried out for 15min, extraction is carried out for 2 times by using ethyl acetate, the obtained organic solution is washed for 2 times by using water, and the organic layer is concentrated to obtain solid MP-C;
wherein the molar ratio of the compound MP-B to the alkaline reagent to the catalyst to the isobutyric anhydride is 1.0:3.0-7.0:0.1-1.0:1.5-3.5;
the organic solvent A is DMF, NMP, DMSO, THF or acetone;
the alkaline reagent is TEA or DIPEA;
the catalytic agent is pyridine or DMAP;
(2) Synthesis of intermediate MP-D and monapivir:
synthesis of intermediate MP-D: deprotection of intermediate MP-C obtained in step (1) under the condition of acid as solvent to obtain intermediate MP-D, wherein the structural formula of intermediate MP-D is
Synthesis of monatin: the intermediate MP-D oxime ester is hydrolyzed to obtain the monatin, and the monatin has the structure as follows:
2. the method for preparing the anti-new coronavirus drug monatin as claimed in claim 1, which is characterized in that: 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 2-24 hours at 20-100 ℃; concentrating the reaction liquid for later use after the reaction is finished;
adding ammonia water solution into the standby solution, stirring for 1h, then adding 30% hydroxylamine water solution and organic solvent B, reacting for 0.5-10h at 10-100 ℃, adding MTBE and water after the reaction is finished, extracting and separating liquid, washing a filter cake obtained by concentrating an organic layer with MTBE, and drying the filter cake to obtain monatevir;
the molar ratio of the compound MP-C to hydroxylamine is 1:1 to 5.
3. The method for preparing the anti-new coronavirus drug monatin as claimed in claim 2, which is characterized in that: the acid is 85% CH 3 COOH or formic acid.
4. A process for the preparation of the anti-novel coronavirus drug monatin as claimed in claim 3, characterized in that: the compound MP-C g:85% 3 COOH ml was 1:1 to 10.
5. The method for preparing the anti-new coronavirus drug monatin as claimed in claim 2, which is characterized in that: the organic solvent B is THF, methyltetrahydrofuran, DMF or NMP.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| Toward a Practical, Two-Step Process for Molnupiravir: Direct Hydroxamination of Cytidine Followed by Selective Esterification;Dinesh J. Paymode 等;《Org. Process Res. Dev.》;第25卷(第8期);第1822-1830页 * |
| Towards a Practical, Non-enzymatic Process for Molnupiravir from Cytidine;Gopalsamuthiram, Vijayagopal R. 等;《ChemRxiv》;第1-6页 * |
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