CN111440176A - Metal complex promoted synthesis method of Reidesciclovir intermediate - Google Patents
Metal complex promoted synthesis method of Reidesciclovir intermediate Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
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- B01J31/2269—Heterocyclic carbenes
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
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- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0238—Complexes comprising multidentate ligands, i.e. more than 2 ionic or coordinative bonds from the central metal to the ligand, the latter having at least two donor atoms, e.g. N, O, S, P
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
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Abstract
The invention belongs to the fields of medicines, organic synthesis and fine chemicals, and particularly relates to a novel method for synthesizing a ridciclovir intermediate compound 3. The present invention proposes the use of unoxidized D-ribose derivatives, directly coupled to Compound 2. Taking a compound 8 and a compound 2 as raw materials, and placing the raw materials in a solvent to react in the presence of inorganic base and a metal complex to generate an intermediate compound 3; the method is simple and convenient to operate, does not need column chromatography, is cheap and easy to obtain reagents, is green and safe, efficient and environment-friendly, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the fields of medicines, organic synthesis and fine chemicals, and particularly relates to a novel method for synthesizing a Reidesvir intermediate.
Background
Reddeivir (CAS number 1809249-37-3) is a drug in the research of Gilidd science, a nucleoside analogue with antiviral activity, and is currently undergoing phase III clinical trials against Ebola virus (NCT 03719586). However, as the research progresses, it has been found that the antiviral effect of Remdesivir is not limited to filoviruses such as Ebola virus, but is also effective in inhibiting various viruses such as coronavirus. After 31 months at 1.2020 NEJM (New England journal of medicine) published an article of 2019-nCoV infected persons during the course of U.S. healing, clinical studies of Remdesivir in the treatment of new coronavirus (2019-nCoV) pneumonia have rapidly been developed with regard to the ability of Remdesivir to resist 2019-nCoV. According to the related report of 4 months and 17 days, in the phase 3 drug test carried out at Chicago university Hospital, 113 of 125 Xinguan patients were severe, fever and respiratory symptoms of the patients were rapidly recovered after receiving the Reidesvir treatment, most of the patients were discharged after 6 days of hospitalization, and the discharge time of only few patients required 10 days. Only 2 out of 125 patients in total died, meaning a severe mortality of only 1.6% after drug administration. Therefore, redexivir is likely to be the first approved drug for the treatment of new coronaviruses.
According to the existing RudeSewei synthesis route, 6 steps of reactions are carried out, the yield is respectively 40%, 85%, 86%, 90%, 70% and 69%, and the total yield is 12.7%. The reaction yield of the synthetic intermediate compound 3 is only about 40%, and the intermediate compound needs to be purified by column chromatography. The defect of column chromatography purification is that the productivity is very low, and for the purification of the reaction in the step in the prior art, a set of column chromatography equipment can only produce a few kilograms of intermediate compound 3 without stopping working for 24 hours, and cannot meet the market demand. Therefore, the existing production process of the Reidesvir is low in efficiency, and needs to be improved.
Disclosure of Invention
In the existing process route, an intermediate compound 3 is formed by oxidizing and protecting D-ribose and then coupling with a compound 2, namely 7-iodopyrrolo [2,1-f ] [1,2,4] triazine-4-amine, wherein a Grignard reagent is used in the coupling reaction. On the one hand, the grignard reagent involves the use of elemental magnesium as a reducing agent, meaning that the synthesis intermediate compound 3 actually undergoes a process of oxidation before reduction, with the net result that the oxidation state of the compound is not changed, but the oxidizing agent and the reducing agent are consumed, increasing the production cost; on the other hand, the coupling reaction has low yield and more byproducts, and column chromatography is needed.
In view of the above pain points, the present invention proposes the use of unoxidized D-ribose derivatives, directly coupled to Compound 2. The method eliminates the step of oxidizing D-ribose, shortens the synthetic route; meanwhile, the method has high selectivity and few reaction byproducts, and column chromatography is not needed in the separation and purification process, so that the production process is expected to be greatly simplified, and the labor cost is saved.
The invention aims to provide a method for synthesizing a Rudexilvir intermediate compound 3 with high efficiency and low cost. The method takes the compound 8 and the compound 2 as raw materials, the raw materials are placed in a solvent to react in the presence of inorganic base and metal complexes to generate the intermediate compound 3, column chromatography is not needed for post-reaction treatment, and the cost is greatly saved.
The reaction formula is as follows:
in the structure of the compound 8, Pg refers to a protective group and is selected from one of benzyl, acetyl, trimethylsilyl and tert-butyldimethylsilyl.
The metal complex used in the reaction is a complex formed by palladium, copper, nickel, cobalt, chromium or iron and an organic ligand, wherein the organic ligand is a monophosphorus ligand, a diphosphorus ligand, a P, O-ligand, a P, N-ligand or an N-heterocyclic carbene ligand;
further, the metal complex is preferably selected from a complex of cobalt and an N-heterocyclic carbene or a complex of chromium and an N-heterocyclic carbene.
The amount ratio of the metal complex to the compound 2 is 0.01 to 0.05: 1.
the inorganic base is selected from potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate and potassium tert-butoxide, and the amount ratio of the inorganic base to the compound 2 is 1-2: 1.
the solvent used in the reaction is one or more of toluene, tetrahydrofuran, diethyl ether, acetonitrile, acetone, 1, 4-dioxane, dimethyl sulfoxide or N, N-dimethylformamide.
The mass ratio of the compound 8 to the compound 2 is 1.05-1.2: 1.
the reaction temperature is 20-110 ℃, and the reaction time is 24-48 h.
The invention has the beneficial effects that:
the invention provides a method for synthesizing a Rudexilvir intermediate compound 3 with high efficiency and low cost. The method is simple and convenient to operate, does not need column chromatography, is cheap and easy to obtain reagents, is green and safe, efficient and environment-friendly, and is suitable for industrial production.
Drawings
FIG. 1 is a synthetic route of an intermediate compound 3 in the prior art;
fig. 2 shows a synthetic route of intermediate compound 3 designed by this patent.
Detailed Description
The first embodiment is as follows:
dimethylformamide (DMF)150m L, 50 g (0.12mol) of the compound 8, 26 g (0.1mol) of the compound 2, 23 g of potassium phosphate and 0.7 g of the metal complex A were sequentially added to a 500ml reaction flask, and after reaction at 100 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate, and the system concentrate was dried with a rotary evaporator at 100m L, slurried with 200m L t-butyl methyl ether, and filtered to obtain 44.1 g of the Reidesvir intermediate compound 3 with a yield of 80%.
The synthesized intermediate compound 3 completely coincided with the standard control, T L C.
Example two:
acetonitrile 150m L, 59 g (0.12mol) of compound 8a, 26 g (0.1mol) of compound 2, 15 g of potassium carbonate, 1.4 g of metal complex B were sequentially charged into a 500ml reaction flask, and after reacting at 80 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate, and the system concentrate was dried with a rotary evaporator at 100m L, slurried with 200m L t-butyl methyl ether, and filtered to obtain 51.2 g of Reidesciclovir intermediate compound 3a in 82% yield.
The synthesized intermediate compound 3a was completely matched with the standard control, T L C.
Example three:
after 1, 4-dioxane 150m L, 33 g (0.12mol) of compound 8b, 26 g (0.1mol) of compound 2, 13 g of potassium tert-butoxide, and 1.7 g of metal complex C were sequentially charged into a 500ml reaction flask, and reacted at 100 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the aqueous layer, and the organic layer was dried over anhydrous sodium sulfate, and the system concentrate was dried with a rotary evaporator at 100m L, slurried with 200m L of tert-butyl methyl ether, and filtered to obtain 35.3 g of ridciclovir intermediate compound 3b in 87% yield.
The synthesized intermediate compound 3b was completely matched with the standard control, T L C.
Example four:
after DMSO (150 m L), 50 g (0.12mol) of the compound (8), 26 g (0.1mol) of the compound (2), 35 g of cesium carbonate and 0.8 g of the metal complex (D) were sequentially charged into a 500ml reaction flask and reacted at 100 ℃ for 36 hours, the mixture was extracted three times with water and ethyl acetate to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate, and the system concentrate was dried over 100m L by a rotary evaporator, slurried with 200m L t-butyl methyl ether and filtered to obtain 49.8 g of Reidesciclovir intermediate compound (3), with a yield of 90%.
The synthesized intermediate compound 3 completely coincided with the standard control, T L C.
Claims (9)
1. The synthesis method of the Rudexilvir intermediate promoted by the metal complex is characterized in that a compound 8 and a compound 2 are used as raw materials, and the raw materials are placed in a solvent to react in the presence of inorganic base and the metal complex to generate an intermediate compound 3;
the reaction formula is as follows:
2. the method of synthesis of claim 1, wherein: in the structure of the compound 8, Pg refers to a protective group and is selected from one of benzyl, acetyl, trimethylsilyl and tert-butyldimethylsilyl.
3. The method of synthesis of claim 1, wherein: the metal complex used in the reaction refers to a complex formed by palladium, copper, nickel, cobalt, chromium or iron and an organic ligand, wherein the organic ligand is a monophosphorus ligand, a diphosphorus ligand, a P, O-ligand, a P, N-ligand or an N-heterocyclic carbene ligand.
4. A method of synthesis as claimed in claim 3, characterized in that: the metal complex is a complex of cobalt and N-heterocyclic carbene or a complex of chromium and N-heterocyclic carbene.
5. The method of synthesis of claim 1, wherein: the amount ratio of the metal complex to the compound 2 is 0.01 to 0.05: 1.
6. the method of synthesis of claim 1, wherein: the inorganic base is selected from potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate and potassium tert-butoxide, and the amount ratio of the inorganic base to the compound 2 is 1-2: 1.
7. the method of synthesis of claim 1, wherein: the solvent used in the reaction is one or more of toluene, tetrahydrofuran, diethyl ether, acetonitrile, acetone, 1, 4-dioxane, dimethyl sulfoxide or N, N-dimethylformamide.
8. The method of synthesis of claim 1, wherein: the mass ratio of the compound 8 to the compound 2 is 1.05-1.2: 1.
9. the method of synthesis of claim 1, wherein: the reaction temperature is 20-110 ℃, and the reaction time is 24-48 h.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021175296A1 (en) * | 2020-03-04 | 2021-09-10 | 中国科学院上海药物研究所 | Intermediate of remdesivir and preparation method therefor |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
| CN114573590A (en) * | 2022-03-18 | 2022-06-03 | 苏州旺山旺水生物医药有限公司 | Preparation method and application of tetraisobutyryl nucleoside analogue |
| US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
| US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
| US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
| US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
| WO2021175296A1 (en) * | 2020-03-04 | 2021-09-10 | 中国科学院上海药物研究所 | Intermediate of remdesivir and preparation method therefor |
| US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
| US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
| US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
| US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
| CN114573590A (en) * | 2022-03-18 | 2022-06-03 | 苏州旺山旺水生物医药有限公司 | Preparation method and application of tetraisobutyryl nucleoside analogue |
| CN114573590B (en) * | 2022-03-18 | 2023-11-14 | 苏州旺山旺水生物医药有限公司 | Preparation method and application of tetraisobutyryl nucleoside analogue |
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