CN111393478A - Synthetic method of medicine for treating pneumonia infected by new coronavirus COVID-19 - Google Patents
Synthetic method of medicine for treating pneumonia infected by new coronavirus COVID-19 Download PDFInfo
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- CN111393478A CN111393478A CN202010172995.5A CN202010172995A CN111393478A CN 111393478 A CN111393478 A CN 111393478A CN 202010172995 A CN202010172995 A CN 202010172995A CN 111393478 A CN111393478 A CN 111393478A
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Abstract
The invention relates to the field of drug synthesis, in particular to a synthesis method of a new coronavirus COVID-19 pneumonia infection drug. The method comprises the following steps: and under the protection of nitrogen, adding phosphorus oxychloride A and phosphorus oxychloride B into a solvent, adding a chiral imidazole catalyst and alkali, and reacting for 0.5-48h to obtain the Reidesvir C. The invention provides a synthesis method of a new coronavirus COVID-19 infection pneumonia drug, which can catalyze phosphorus oxychloride A and B to react to obtain high-yield and high-selectivity Reidcisvir C by selecting a proper chiral imidazole catalyst and controlling reaction conditions, wherein the yield of a product obtained by the method is more than 80%, and the enantioselectivity can be 99: 1 or more.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of a new coronavirus COVID-19 pneumonia infection drug.
Background
By 10 days 2 months 2020, 2019-nCoV cases have been reported in 25 countries in four continents, with over 40000 diagnosed cases and an estimated risk of death of approximately 2%. Unfortunately, there is no approved drug or vaccine for the treatment of human coronavirus. Several approaches can be envisaged to control or prevent the emerging 2019-nCoV infection, including vaccines, monoclonal antibodies, oligonucleotide-based therapies, peptides, interferon therapies and small molecule drugs.
The documents Remdesivir and chloroquinone effect inhibiting the oriented modified novel corvovir (2019-nCoV) in vitro Cell Research (2020)0: 1-3; it is reported that the new clinical drug Remdesivir (Reed-Wevir), originally used for treating Ebola virus by Gilidad (Gilead), has a better effect in vitro experiments on the novel coronavirus, and EC500.77 uM. There has also been a previous report in the United states of First Case of 2019Novel Coronavir in the United states StatesNEngl J Med 2020.https:// www.nejm.org/doi/10.1056/NEJMoa2001191 cured with this drug. Further clinical trials are actively being conducted. Therefore, the Reidesciclovir is very likely to be used for treating the novel coronavirus toxin.
The synthesis of the existing Ruidexiwei has two methods: wherein method 1 is as follows:
Reagents conditions：(a)n-BuLi，TMSCl，THF，-78℃，25％；(2)1，2-bis(chlorodimethylsilyl)ethane，NaH，n-BuLi， THF，-78℃，60％；(c)TMSCN，BF3Et2O，-78℃，58％；(d)BCl374％3，CH2Cl2，-78℃，74％；(e)NMI，OP(OMe)3，21％； (f)OP(OPh)Cl2，0℃，23％.
method 2 is as follows:
Reagents and conditions：(a)TMSCI，PhMgCl，iPrMgCILiCI，THF，-20℃，40％；(b)TMSCN，TfOH，TMSOTf，CH2Cl2， -78℃，85％，(c)BCl3，cH2Cl2，-20℃，86％；(d)2，2-dimethoxypropane，H2SO4，acetone，rt，90％；(e)22b，MgCl2，(i-Pr)2NEt，MeCN，50℃，70％；(f)37％HCI，THF，69％，(g)OP(OPh)Cl2，Et3N，CH2Cl2，-78℃，then 4-nitrophenol，Et3N，0℃； 80％；(h)i-Pr2O，39％.，
since the drug itself contains multiple chiral centers. Other chiral centers can be obtained from natural products, and only phosphorus chiral centers are difficult to construct. Both of the above methods are constructed by a resolution method, and the yield is very low. Therefore, it is necessary to find a good chiral synthesis method to obtain high yield and selectivity if mass production is required.
Disclosure of Invention
In order to solve the problems, the invention provides a method for synthesizing a new coronavirus COVID-19 infection pneumonia medicament, which comprises the following steps: adding phosphorus oxychloride A and B into a solvent under the protection of nitrogen, adding a chiral imidazole catalyst and alkali, reacting for 0.5-48h, and separating and purifying to obtain Reidesciclovir C;
the structural formula of the phosphoryl chloride A is shown as a formula 1;
the structural formula of B is shown as formula 2:
the structural formula of the Reidesciclovir C is shown as a formula 3:
as a preferred technical scheme of the present invention, the chiral imidazole catalyst is a mono-imidazole catalyst D, and the structural formula of the mono-imidazole catalyst is shown in formula 4:
the R is one or more of alkoxy, aryloxy, alkyl dimethyl siloxy and N-alkyl amido oxygroup; the alkoxy is selected from one or more of linear alkoxy, branched alkoxy and cycloalkoxy;
the spatial configuration of the single imidazole catalyst D marked by the letter is (S) or (R).
As a preferred technical scheme of the invention, the alkoxy is C1-C6 alkoxy.
As a preferred technical scheme of the invention, the aryloxy is selected from one or more of phenoxy, benzyloxy, naphthoxy and derivatives thereof.
In a preferred embodiment of the present invention, the alkyl groups in the alkyl dimethylsilyloxy group and the N-alkylamidooxy group are each a C3-C8 alkyl group.
As a preferable technical scheme, the chiral imidazole catalyst is a bisimidazole catalyst E, and the structural formula of the bisimidazole catalyst E is shown as a formula 5;
r' is selected from one or more of alkyl, 1, 5-dialkyl phenyl and 1, 5-dialkyl phenyl derivatives;
the spatial configurations of the position marked by the double imidazole catalyst E are both (S) or both (R).
In a preferred embodiment of the present invention, R' is C6-C10 alkyl.
In a preferred embodiment of the present invention, the alkyl group in the 1, 5-dialkylphenyl group is a C2-C4 alkyl group.
As a preferable technical scheme of the invention, the molar percentage of the imidazole catalyst in B is 0.1-20 mol%.
The second aspect of the invention provides an application of the synthetic method of the new coronavirus COVID-19 infection pneumonia medicine, which is used for synthesizing the new coronavirus COVID-19 infection pneumonia medicine.
Compared with the prior art, the invention has the following beneficial effects: the invention provides a method for synthesizing a new coronavirus COVID-19 infection pneumonia drug, which can catalyze phosphorus oxychloride A and B to react to obtain high-yield and high-selectivity Reidcisvir C by selecting a proper imidazole catalyst and controlling reaction conditions, wherein the yield of a product obtained by the method is more than 80%, and the enantioselectivity is more than 99: 1.
Detailed Description
The disclosure may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.
The term "prepared from …" as used herein is synonymous with "comprising". The terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
The conjunction "consisting of …" excludes any unspecified elements, steps or components. If used in a claim, the phrase is intended to claim as closed, meaning that it does not contain materials other than those described, except for the conventional impurities associated therewith. When the phrase "consisting of …" appears in a clause of the subject matter of the claims rather than immediately after the subject matter, it defines only the elements described in the clause; other elements are not excluded from the claims as a whole.
When an amount, concentration, or other value or parameter is expressed as a range, preferred range, or as a range of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted to include the ranges "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. When a range of values is described herein, unless otherwise stated, the range is intended to include the endpoints thereof and all integers and fractions within the range.
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. "optional" or "any" means that the subsequently described event or events may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Approximating language, as used herein throughout the specification and claims, is intended to modify a quantity, such that the invention is not limited to the specific quantity, but includes portions that are literally received for modification without substantial change in the basic function to which the invention is related. Accordingly, the use of "about" to modify a numerical value means that the invention is not limited to the precise value. In some instances, the approximating language may correspond to the precision of an instrument for measuring the value. In the present description and claims, range limitations may be combined and/or interchanged, including all sub-ranges contained therein if not otherwise stated.
In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are not intended to limit the number requirement (i.e., the number of occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural unless the stated number clearly indicates that the singular form is intended.
The present invention is illustrated by the following specific embodiments, but is not limited to the specific examples given below.
The invention provides a method for synthesizing a new coronavirus COVID-19 infection pneumonia medicament, which comprises the following steps: adding phosphorus oxychloride A and B into a solvent under the protection of nitrogen, adding a chiral imidazole catalyst and alkali, reacting for 0.5-48h, and separating and purifying to obtain Reidesciclovir C;
phosphorylic chloride A
In one embodiment, the phosphorus oxychloride A of the invention has a structural formula shown in formula 1;
B
preferably, the structural formula of B according to the present invention is represented by formula 2:
in a preferred embodiment, the molar ratio of phosphorus oxychloride A to phosphorus oxychloride B is (1-4) to 1.
Reidesciclovir C
Reidesciclovir C is a broad-spectrum antiviral drug, a thesis about the success of Reinde Remdesivir to cure the first diagnosed cases of American novel coronavirus (2019-nCoV) is published on line in New England Journal of Medicine (NEJM) at 31/1/2020, and immediately at 2/2, the drug review Center (CDE) of the State drug administration has accepted a clinical test application of Reidesciclovir (Remdesivir) which is a drug for novel coronavirus pneumonia (2019-nCoV), and if the clinical test application is clinically effective, the Reidesciclovir C is likely to become a drug for treating novel coronavirus toxicity. The most difficult step in the synthesis of the Reidesciclovir is the construction of a phosphorus chiral center, and experiments show that the one-step reaction of phosphorus oxychloride A and B under the action of alkali is realized by using a chiral imidazole catalyst, so that the Reidesciclovir is synthesized with high enantioselectivity and high selectivity.
In one embodiment, the structural formula of the Reidesciclovir C of the invention is shown in formula 3:
chiral imidazole catalysts
(Single imidazole catalyst)
In one embodiment, the chiral imidazole catalyst of the present invention is a mono-imidazole catalyst D, wherein the structural formula of the mono-imidazole catalyst is represented by formula 4:
the R is one or more of alkoxy, aryloxy, alkyl dimethyl siloxy and N-alkyl amido oxygroup;
the spatial configuration of the single imidazole catalyst D marked by the letter is (S) or (R).
Preferably, the alkoxy group is selected from one or more of linear alkoxy, branched alkoxy and cycloalkoxy; further, the alkoxy is C1-C6 alkoxy.
Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy.
Examples of branched alkoxy groups include, but are not limited to, isopropoxy, isobutoxy ((CH)3)2CHCH2O), tert-butoxy.
Examples of cycloalkoxy include, but are not limited to, cyclohexyloxy, cyclopentyloxy.
More preferably, R in the present invention is aryloxy; further, the aryloxy group is selected from one or more of phenoxy, benzyloxy, naphthoxy and derivatives thereof; further, the aryloxy group is selected from one or more of phenoxy, benzyloxy and derivatives thereof.
The phenoxy derivative and benzyloxy derivative of the present invention is obtained by substituting the hydrogen on the aromatic ring of phenoxy and benzyloxy group with various substituents, and is not particularly limited.
Further preferably, R in the invention is an alkyl dimethylsiloxy group; further, the alkyl group in the alkyl dimethyl siloxane group is C3-C8 alkyl; further, the alkyl group in the alkyl dimethylsiloxy group of the present invention is a branched alkyl group.
Examples of the alkyldimethylsiloxy group include, but are not limited to, an isobutyldimethylsiloxy group, a tert-butyldimethylsiloxy group, a neopentyldimethylsiloxy group, an isooctyldimethylsiloxy group (2-ethylhexyldimethylsiloxy group).
Still further preferably, said R of the present invention is an N-alkylamidooxy group; further, the alkyl group in the N-alkylamidooxy group is a C3-C8 alkyl group; further, the alkyl group in the N-alkylamidooxy group is a branched alkyl group.
Examples of N-alkylamidooxy groups include, but are not limited to, N-isobutylamidooxy, N-tert-butylamidooxy, N-neopentylamidooxy, N-isooctylamidooxy.
Applicants have found that when a mono-imidazole catalyst wherein R is an alkyl dimethylsiloxy, N-alkylamidooxy group, especially a branched alkyl dimethylsiloxy, N-alkylamidooxy group, is used, there is a higher selectivity than when R is an alkoxy, aryloxy group, but the yield is lower when a mono-imidazole catalyst is used.
(bis-imidazole catalyst)
In one embodiment, the chiral imidazole catalyst is a bisimidazole catalyst E, and the structural formula of the bisimidazole catalyst E is shown in formula 5;
r' is selected from one or more of alkyl, 1, 5-dialkyl phenyl and 1, 5-dialkyl phenyl derivatives;
the spatial configurations of the position marked by the double imidazole catalyst E are both (S) or both (R).
Preferably, R' is C6-C10 alkyl; further, the C6-C10 alkyl is (CH)2) n, wherein n is selected from one of 6, 7, 8, 9 and 10; further, the C6-C10 alkyl is (CH)2)8。
More preferably, R' in the present invention is a 1, 5-dialkylphenyl group; further, the alkyl group in the 1, 5-dialkyl phenyl group is C2-C4 alkyl group; further, the 1, 5-dialkylphenyl group of the present invention is (CH)2)mC6H4(CH2) m, wherein m is selected from one of 2, 3 and 4.
The 1, 5-dialkyl phenyl derivative is a derivative obtained by substituting hydrogen on a benzene ring by a substituent in the 1, 5-dialkyl phenyl derivative, and is not particularly limited.
Further preferably, the molar percentage of the chiral imidazole catalyst in B is 0.1-20 mol%; furthermore, the molar percentage of the single imidazole catalyst in B is 10-20 mol%; further, the molar percentage of the bisimidazole catalyst in B is 0.1-10 mol%; further, the molar percentage of the bisimidazole catalyst in B is 1-6 mol%.
Applicants have found that when a bisimidazole catalyst is used, it is possible to have higher yields and selectivity at lower catalytic concentrations than a monoimidazole catalyst, possibly because the bisimidazole catalyst has higher catalytic activity, catalyzing processes by similar enzyme mediated processes, activating both the phosphorus donor and the reactive hydroxyl group, reducing the barriers to P-O bond formation and P (v) conversion. In addition, applicants have found that as the chain length of the R 'alkyl chain of the bisimidazole catalyst increases, the yield and activity also increases, with R' being the highest when it is C8 alkyl, and then increasing the chain length results in a decrease in catalytic activity, probably due to poor flexibility, so applicants have formulated R 'as a 1, 5-dialkylphenyl group, but have unexpectedly found that the yield and activity decreases compared to R' as a C8.
Alkali
The base is not specifically limited, and in one embodiment, the base is selected from one or more of pyridine, triethylamine, lutidine, triethylenediamine (DABCO), azomethine, and dimethylaminopyridine.
Preferably, the molar ratio of the base and A in the invention is (1.3-2) to 1.
Solvent(s)
The present invention is not particularly limited to the solvent. In one embodiment, the solvent of the present invention is selected from one or more of toluene, dichloromethane, dichloroethane, 1, 4-dioxane, 1, 3-dioxane, acetonitrile, diethyl ether, tetrahydrofuran.
In one embodiment, in the synthesis method of the drug for treating the pneumonia infected by the novel coronavirus COVID-19, the reaction temperature is-40 ℃; further, the reaction temperature is-20 to 25 ℃.
Preferably, in the method for synthesizing the medicament for treating the pneumonia infected by the novel coronavirus COVID-19, the reaction time is 36-48 h.
The second aspect of the invention provides an application of the synthetic method of the new coronavirus COVID-19 infection pneumonia medicine, which is used for synthesizing the new coronavirus COVID-19 infection pneumonia medicine.
Examples
The present invention will be specifically described below by way of examples. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention.
Example 1
The embodiment provides a method for synthesizing a new coronavirus COVID-19 infection pneumonia drug, which comprises the following steps:
adding phosphorus oxychloride A and B into tetrahydrofuran under the protection of nitrogen, adding a chiral imidazole catalyst and lutidine, reacting for 48 hours at-5 ℃, and separating and purifying to obtain Reidesvir C; the mol ratio of the phosphoryl chloride A to the phosphoryl chloride B is 1.3: 1, the mol percentage of the chiral imidazole catalyst in the phosphoryl chloride B is 15 mol%, and the mol ratio of the dimethyl pyridine to the phosphoryl chloride A is 1.7: 1.
The structural formula of the phosphoryl chloride A is shown as a formula 1;
the structural formula of B is shown as formula 2:
the structural formula of the Reidesciclovir C is shown as a formula 3:
the pyridine catalyst is a mono-imidazole catalyst D, and the structural formula of the mono-imidazole catalyst is shown as a formula 4:
the R is hexyloxy;
the spatial configuration marked by the single imidazole catalyst D is (S).
Example 2
The embodiment of the method for synthesizing the new coronavirus COVID-19 infection pneumonia medicine is the same as that in example 1, except that R is benzyloxy.
Example 3
The embodiment of the method for synthesizing the new coronavirus COVID-19 infection pneumonia medicine is the same as that in example 1, except that R is phenoxy.
Example 4
This example provides a method for synthesizing a novel coronavirus COVID-19 infection pneumonia drug, which is described in example 1, except that R is neopentyl dimethylsilyloxy.
Example 5
The embodiment of the method for synthesizing the new coronavirus COVID-19 infection pneumonia medicine is the same as that in example 1, except that R is isooctyldimethylsilanyloxy.
Example 6
The present example provides a method for synthesizing a novel coronavirus COVID-19 infection pneumonia drug, which is specifically implemented as in example 1, except that R is N-tert-butylamidooxy.
Example 7
The embodiment of the invention provides a method for synthesizing a new coronavirus COVID-19 infection pneumonia drug, which is the same as that in example 1, and is characterized in that the chiral imidazole catalyst accounts for 4 mol% of B, the reaction time is 36h, the chiral imidazole catalyst is a bisimidazole catalyst E, and the structural formula of the bisimidazole catalyst E is shown as formula 5;
r' is (CH)2)6；
The spatial configuration of the position marked by the double imidazole catalyst E is (S).
Example 8
This example provides a method for synthesizing a novel coronavirus COVID-19 infection pneumonia drug, which is specifically performed as in example 7, except that R' is (CH)2)10。
Example 9
This example provides a method for synthesizing a novel coronavirus COVID-19 pneumonia infection drug, which is carried out in the same manner as example 7, except that R' is(CH2)8。
Example 10
This example provides a method for synthesizing a novel coronavirus COVID-19 infection pneumonia drug, which is specifically performed as in example 7, except that R' is (CH)2)2C6H4(CH2)2。
Evaluation of Performance
1. The products obtained according to the synthesis method of the examples were tested for yield and enantioselectivity, the results are shown in table 1.
Table 1 performance characterization test
| Examples | Yield% | Enantioselectivity S: r |
| 1 | 65％ | 74:26 |
| 2 | 70％ | 85:15 |
| 3 | 68％ | 83:17 |
| 4 | 74％ | 87:13 |
| 5 | 70％ | 80:20 |
| 6 | 75％ | 86:14 |
| 7 | 84％ | 96:4 |
| 8 | 86％ | 94:6 |
| 9 | 91％ | 99:1 |
| 10 | 81％ | 99:1 |
The test results in Table 1 show that the method for synthesizing the novel coronavirus COVID-19 pneumonia infection medicine can efficiently synthesize the Reidcisvir, the yield can be up to more than 90%, and the enantioselectivity can be up to more than 99: 1.
The foregoing examples are merely illustrative and serve to explain some of the features of the method of the present invention. The appended claims are intended to claim as broad a scope as is contemplated, and the examples presented herein are merely illustrative of selected implementations in accordance with all possible combinations of examples. Accordingly, it is applicants' intention that the appended claims are not to be limited by the choice of examples illustrating features of the invention. Also, where numerical ranges are used in the claims, subranges therein are included, and variations in these ranges are also to be construed as possible being covered by the appended claims.
Claims (10)
1. A method for synthesizing a new coronavirus COVID-19 pneumonia infection drug is characterized by comprising the following steps: adding phosphorus oxychloride A and B into a solvent under the protection of nitrogen, adding a chiral imidazole catalyst and alkali, reacting for 0.5-48h, and separating and purifying to obtain Reidesciclovir C;
the structural formula of the phosphoryl chloride A is shown as a formula 1;
the structural formula of B is shown as formula 2:
the structural formula of the Reidesciclovir C is shown as a formula 3:
2. the method for synthesizing the medicine for treating the pneumonia caused by the infection of the new coronavirus COVID-19 according to claim 1, wherein the chiral imidazole catalyst is a mono-imidazole catalyst D, and the structural formula of the mono-imidazole catalyst is shown as a formula 4:
the R is one or more of alkoxy, aryloxy, alkyl dimethyl siloxy and N-alkyl amido oxygroup; the alkoxy is selected from one or more of linear alkoxy, branched alkoxy and cycloalkoxy;
the spatial configuration of the single imidazole catalyst D marked by the letter is (S) or (R).
3. The method for synthesizing the medicine for treating pneumonia caused by infection with new coronavirus COVID-19 as described in claim 2, wherein said alkoxy is C1-C6 alkoxy.
4. The method for synthesizing a medicament for treating pneumonia caused by infection with new coronavirus COVID-19 as claimed in claim 2, wherein the aryloxy group is selected from one or more of phenoxy group, benzyloxy group, naphthoxy group and their derivatives.
5. The method for synthesizing the medicine for treating pneumonia caused by infection with coronavirus COVID-19 as described in claim 2, wherein the alkyl groups in said alkyl dimethylsilyloxy group and N-alkyl amidoxy group are C3-C8 alkyl groups, respectively.
6. The method for synthesizing the drug for treating the pneumonia infected by the new coronavirus COVID-19 according to claim 1, wherein the chiral imidazole catalyst is a bisimidazole catalyst E, and the structural formula of the bisimidazole catalyst E is shown as a formula 5;
r' is selected from one or more of alkyl, 1, 5-dialkyl phenyl and 1, 5-dialkyl phenyl derivatives;
the spatial configurations of the position marked by the double imidazole catalyst E are both (S) or both (R).
7. The method for synthesizing the medicine for treating pneumonia caused by infection with new coronavirus COVID-19 as claimed in claim 6, wherein R' is C6-C10 alkyl.
8. The method for synthesizing the medicine for treating pneumonia caused by infection with new coronavirus COVID-19 as described in claim 6, wherein the alkyl group in said 1, 5-dialkyl phenyl group is C2-C4 alkyl group.
9. The method for synthesizing the medicine for treating pneumonia caused by infection with new coronavirus COVID-19 according to any one of claims 1 to 8, wherein the molar percentage of the imidazole catalyst in B is 0.1-20 mol%.
10. The application of the method for synthesizing the medicament for treating the pneumonia caused by the new coronavirus COVID-19 infection according to any one of claims 1 to 9, which is used for synthesizing the medicament for treating the pneumonia caused by the new coronavirus COVID-19 infection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113754694A (en) * | 2020-06-03 | 2021-12-07 | 上海交通大学 | Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
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| CN113754694A (en) * | 2020-06-03 | 2021-12-07 | 上海交通大学 | Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside |
| CN113754694B (en) * | 2020-06-03 | 2022-10-25 | 上海交通大学 | Method for synthesizing Reidesvir by asymmetric catalysis of non-protecting group nucleoside |
| WO2022029704A1 (en) | 2020-08-06 | 2022-02-10 | Richter Gedeon Nyrt. | Remdesivir intermediates |
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