CN111233870A - Method for rapidly preparing Rudeseivir drug intermediate - Google Patents
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- C—CHEMISTRY; METALLURGY
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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
- C07D487/04—Ortho-condensed systems
Abstract
The invention relates to a method for rapidly preparing a Remdeicvir (Remdeicvir) drug intermediate of a formula (I) without complex purification and separation, wherein X is halogen. The method for preparing the intermediate (I) of the RudeSewei drug is simple, high in yield and single in product, and can be obtained by simple filtration and separation without complex separation operation such as column chromatography, so that the RudeSewei drug intermediate of the formula (I) can be rapidly and efficiently prepared in large quantity, and sufficient intermediate raw material basis can be provided for large-quantity preparation of the final RudeSewei drug possibly used for resisting the neocoronaviruses.
Description
Technical Field
The invention relates to a method for rapidly preparing a Remdeicvir (Remdeicvir) drug intermediate.
Background
Since the epidemic situation of new coronary pneumonia (COVID-19), how to prevent and treat the new coronary pneumonia becomes a problem to be solved urgently. In the diagnosis and treatment scheme for pneumonia infected by novel coronavirus (trial fifth edition) published by Wei Jian Wei in 2020, 2, 5, China, it is pointed out that no effective antiviral treatment method is confirmed at present, so the screening and large-scale preparation of antiviral drugs become critical work for epidemic prevention and control. Reidesciclovir, an antiviral nucleoside analog, has previously demonstrated activity against Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) viral pathogens in vitro and in vivo animal models, both coronaviruses being structurally similar to the novel coronavirus COVID-19: are coronaviruses and encode non-structural, structural and accessory proteins, etc. Preclinical data for SARS and MERS limits indicate that reidesavir has potential activity on COVID-19. Recently, the international health organization has considered Reidesciclovir as perhaps the only effective drug against COVID-19. A group of researchers at alberta canada discovered why the drug redciclovir was effective in treating coronavirus causing Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), they expected that it might also be effective in treating patients infected with a new covi-19 strain (j.biol.chem.2020.doi: 10.1074/jbc.ac 120.01305).
Ridciclovir is a monophosphate prodrug of adenosine analogs, which is triphosphorylated in humans, inhibits RNA-dependent RNA synthetase (RdRp), thereby blocking replication of viral RNA, and has broad-spectrum antiviral activity (Nature, 2016, 531, 381). In 2018, 3 months, Reidesciclovir has been identified as effective in inhibiting coronavirus infection. Reidesciclovir is used in clinical trials to treat Ebola virus infections. Subsequent studies found that Reidesciclovir also has inhibitory effects on respiratory syncytial virus, coronavirus, Nipah virus (Nipah virus) and Hendra virus (Hendra virus). In particular, a three-phase clinical trial of Reidesciclovir is being conducted in Wuhan and has been previously successfully used to treat patients with the United states example COVID-19. However, nucleoside analog prodrugs face many challenges in practical synthesis, their synthetic steps are complex, overall yield is low, purification of multiple drug intermediates requires column chromatography or column chromatographic separation, which greatly limits large-scale preparation.
Triazine amine derivatives are important intermediates for synthesizing prodrugs, and nucleoside drugs such as Reidesciclovir can be prepared through multi-step reactions (J.Med.chem.2017, 60, 1648). The procedure of multi-step column chromatography separation required for post-synthetic treatment of triazinamine intermediates of the Reidsievir drugs employed in the synthesis of Pyrrolo [7, 1-f ] [1, 2, 4] triazine Congenerers of Nucleic Acid Purines via the N-amplification of 2-sterilized ceramics Using organic Suzuki-Miyaura Cross-Coupling Reactions (J.heterocyclic. chem., 31, 781, 1994) by Robert S.Klein et al is not suitable for large-scale production.
Therefore, there is an urgent need in the art for a new process for the large-scale preparation of triazinamine intermediates of ridiflower drugs that is simple and fast and does not require column chromatography.
Disclosure of Invention
The invention aims to provide a novel method for rapidly synthesizing triazine amine intermediates of the Rudesevir medicaments in large quantities without column chromatography separation or purification treatment, thereby providing sufficient intermediate raw material basis for the large-scale preparation of the Rudesevir medicaments for resisting the new coronavirus.
To this end, the present invention provides a process for the preparation of a pharmaceutical intermediate of ridciclovir of formula (I),
wherein X is a halogen atom, and X is a halogen atom,
the method comprises the following four successive steps:
(1) reacting an aldehyde compound of formula (II) with sulfamic acid in an aqueous solvent to obtain a cyano compound of formula (III);
(2) obtaining a cyanamide compound of formula (IV) from a cyanide compound of formula (III) by adding a base to the aqueous reaction solution obtained in step (1) to make it basic;
(3) reacting the cyanamide compound of formula (IV) obtained in step (2) with formamidine acetate in the presence of a base and an organic solvent to obtain a triazine amine compound of formula (V); and
(4) reacting the triazine amine compound of formula (V) obtained in step (3) with a halogenating agent to obtain the desired intermediate compound of formula (I),
in a preferred embodiment, the reaction temperature in steps (1), (2) and (4) is from 0 ℃ to 25 ℃ and the reaction temperature in step (3) is from 60 ℃ to 100 ℃.
In a preferred embodiment, in step (1), the sulfamic acid is used in an excess amount relative to the stoichiometric amount of the aldehyde compound of formula (II) used; preferably, the aldehyde compound of formula (II) and sulfamic acid are used in a mass ratio of 1: 2-5.
In a further preferred embodiment, in step (2), the base is directly added to the aqueous reaction solution obtained in step (1) without subjecting the aqueous reaction solution obtained in step (1) to any treatment.
In a preferred embodiment, in step (3), the organic solvent is directly added to the aqueous reaction solution obtained in step (2), or the aqueous solvent in step (2) is replaced with the organic solvent by solvent replacement.
In a preferred embodiment, the organic solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, dimethylformamide, dichloromethane, and chloroform; preferably, the organic solvent used in step (3) is one or more selected from methanol, ethanol and isopropanol; preferably, the organic solvent used in step (4) is one or more selected from the group consisting of dimethylformamide, dichloromethane and chloroform.
In a preferred embodiment, the base used in step (2) or (3) is each independently one or more selected from the group consisting of potassium hydroxide, sodium carbonate and potassium carbonate.
In a preferred embodiment, the halogenating agent used in step (4) is one or more selected from the group consisting of N-iodosuccinimide, N-chlorosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin and N-bromosuccinimide.
In a preferred embodiment, the reaction solution obtained in step (2), (3) and/or (4) is subjected to only filtration and drying treatment without column chromatography treatment.
In a preferred embodiment, the crude product obtained in step (3) is subjected to recrystallization after filtration treatment.
The present invention has, but is not limited to, the following advantages:
1. by the method, under the condition of no need of complicated separation or purification operation such as column chromatography, the Reidsievir drug intermediate of the formula (I) can be quickly and efficiently prepared in large scale by only four continuous steps of simply changing the reaction temperature and replacing the reaction solvent, and the method is simple and convenient to operate and environment-friendly.
2. Compared with the existing method, the method has the advantages of short synthesis steps, mild reaction conditions, high yield and high purity of the synthesized Rudexiluwei drug intermediate shown in the formula (I);
3. the method can be used for preparing the intermediate of the RudeSewei drug of the formula (I) in a large scale, so that kilogram-grade RudeSewei drugs can be synthesized in a large scale, and a solid foundation is laid for clinical tests of the drug for treating the new coronary pneumonia (COVID-19).
Drawings
FIG. 1 is a diagram of the needle-like crystals of a triazinamine compound of formula (V) synthesized according to one embodiment of the present invention.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum (i.e., iodotriazinylamine compound wherein X is iodine) of a Redcisvir pharmaceutical intermediate of formula (I) synthesized according to one embodiment of the present invention1H NMR) spectrum.
Detailed Description
The invention provides a method for preparing a RudeSeivir drug intermediate of a formula (I),
wherein X is a halogen atom. In the present invention, the halogen atom means a Cl, Br or I atom.
The method comprises the following four continuous steps:
(1) from aldehyde compounds of the formula (II) with sulfamic acid (NH)2OSO3H) Carrying out a reaction in an aqueous solvent to obtain a cyano compound of formula (III);
(2) obtaining a cyanamide compound of formula (IV) from a cyanide compound of formula (III) by adding a base to the aqueous reaction solution obtained in step (1) to make it basic;
(3) reacting the cyanamide compound of formula (IV) obtained in step (2) with formamidine acetate (C3H8N2O2) in the presence of a base and an organic solvent to obtain a triazine amine compound of formula (V); and
(4) reacting the triazine amine compound of formula (V) obtained in step (3) with a halogenating agent to obtain the desired intermediate compound of formula (I),
the reaction process is as follows:
preferably, step (1), (2) or (4) may be carried out at ambient temperature; more preferably, the reaction temperature in step (1), (2) or (4) may be from 0 ℃ to 25 ℃, even more preferably from 0 ℃ to 10 ℃, for example at 0 ℃.
Preferably, step (3) may be carried out at a suitably elevated temperature; more preferably, the reaction temperature in step (3) may be in the range of 60 ℃ to 100 ℃, for example at 80 ℃.
Preferably, in step (1), sulfamic acid is used in an excess amount with respect to the stoichiometric amount of aldehyde compound of formula (II) used; for example, the aldehyde compound of the formula (II) and sulfamic acid are used in a mass ratio of 1: 2 to 5 or in a molar ratio of 1: 2 to 5.
Preferably, after step (1), the aqueous reaction solution obtained in step (1) is directly subjected to step (2) without any treatment, i.e., the conversion in step (2) is completed by directly adding a base to the aqueous reaction solution obtained in step (1) to make it basic.
Preferably, in step (3), the reaction may be carried out by directly adding the organic solvent to be used to the aqueous reaction solution obtained in step (2), that is, a mixed solvent of water and an organic solvent may be used in step (3). In this case, it is also possible to dispense with the addition of an additional base in step (3), since the base is already present in the aqueous solution obtained in step (2).
Alternatively, in step (3), the aqueous solvent in step (2) may also be replaced with the organic solvent to be used by solvent replacement. This can be achieved, for example, by: firstly, the aqueous reaction solution obtained in the step (2) is simply filtered (such as suction filtration) and dried, such as dried by using anhydrous sodium sulfate or directly air-dried, and then the obtained dry crude product is stirred and dissolved by using a corresponding organic solvent and then is subjected to a corresponding temperature-rising reaction in the presence of alkali.
Preferably, the organic solvent used in the present invention may be one or more selected from the group consisting of methanol, ethanol, isopropanol, dimethylformamide, dichloromethane and chloroform.
Preferably, the organic solvent used in step (3) may be one or more selected from the group consisting of methanol, ethanol and isopropanol.
Preferably, the organic solvent used in step (4) may be one or more selected from the group consisting of dimethylformamide, dichloromethane and chloroform.
Preferably, the bases used in step (2) or (3) may be the same or different, and may be one or more selected from potassium hydroxide, sodium carbonate and potassium carbonate.
Preferably, the halogenating agent used in step (4) may be any suitable halogenating agent well known in the art. More preferably, the halogenating agent used in step (4) may be one or more selected from the group consisting of N-iodosuccinimide, N-chlorosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin and N-bromosuccinimide.
Preferably, no column chromatography treatment is required for the reaction solution or product obtained in step (2), (3) and/or (4), and, as required, only simple filtration (e.g., suction filtration) and drying treatment such as drying with anhydrous sodium sulfate or direct air drying may be carried out.
Preferably, in step (3), after being subjected to a filtration treatment, the crude product obtained in step (3) may be subjected to a recrystallization treatment to obtain a pure triazine amine compound of formula (V), which may further ensure the purity of the finally obtained intermediate of formula (I).
In one embodiment, the continuous synthetic process of the present invention without column chromatography separation or purification may be as follows: treating the aldehyde compound of formula (II) with an excess of sulfamic acid at ambient temperature to produce a cyano compound of formula (III), followed by adding a base to adjust the reaction solution to basic, thereby obtaining a cyanamide compound of formula (VI) by continuous reaction with an excess of sulfamic acid; followed by condensation with formamidine acetate to give the triazin compound of formula (V) in an overall yield of about 32% (overall yield of the previous three-step reaction) after heating and/or solvent shift, wherein the reaction solution obtained from the reaction can be subjected to a simple filtration treatment and drying treatment and optionally a recrystallization treatment, without requiring complicated separation or purification operations such as column chromatography. Finally, the triazine amine compound of formula (V) is iodinated with a halogenating agent such as N-iodosuccinimide to produce an intermediate of formula (I), and this step of reaction also requires no column chromatography, and only requires water washing and drying, with a yield of more than 95%. Therefore, the total yield of the four-step continuous reaction of the invention can reach more than about 30 percent.
The continuous synthesis of the present invention by column-free chromatography is further illustrated below by reference to specific embodiments, but the present invention is not limited to these examples.
The starting materials, reagents and reaction apparatus used in the examples of the present invention are those conventionally used in the art or commercially available, unless otherwise specified, and these starting materials or reagents are used without further treatment.
Synthesis of aldehyde compounds of formula (II) and cyanamide compounds of formula (VI):
in a 10L flask, an aldehyde compound of formula (II) (100g) and an excess of sulfamic acid (NH)2OSO3H) (400g) to 3L of distilled water, and after the reaction was magnetically stirred at 0 ℃ for 1.5 hours, a yellow solution containing the cyano compound of the formula (III) was obtained.
Then, an aqueous KOH solution obtained by dissolving 1200g of potassium hydroxide (KOH) in 1000ml of water was directly dropwise added to the above yellow solution containing the cyano compound of formula (III) through a dropping funnel while the temperature was maintained at 0 ℃, and the temperature of the reaction mixture was controlled to 10 ℃ or less during the dropwise addition. After completion of the dropwise addition, the reaction mixture was magnetically stirred for 2 hours, followed by suction filtration and extraction of the aqueous phase with dichloromethane 3 times. The combined organic phases were dried over anhydrous sodium sulfate to obtain 90g of a crude product containing the cyanamide compound of formula (VI). The product is used for subsequent reaction without separation.
Synthesis of triazine amine compounds of formula (V):
in a 10L flask, 90g of the crude product obtained above, 1050g of formamidine acetate and 1650g of potassium carbonate were added to 1500mL of ethanol, and the reaction was magnetically stirred at 80 ℃ for 2 hours by heating in a water bath to obtain a brown suspension solution. Then, 2000mL of water was added to the suspension solution, and suction filtration was performed to obtain a brown cake. This filter cake was dissolved with hot water and gradually cooled for recrystallization to obtain 45g of a white acicular solid of the triazine amine compound of formula (V), and fig. 1 shows a photographic image of the obtained needle-like crystals of the triazine amine compound of formula (V).
Synthesis of iodo intermediates of formula (I) (i.e., X in formula (I) is iodine):
in a 1000ml round bottom flask, 40g of the triazine amine compound of formula (V) obtained above and 200ml of DMF are added. After the resulting mixture was cooled to 0 ℃, 70g of N-iodosuccinimide was added in one portion, and the reaction was magnetically stirred for 1 hour. After that, the resulting reaction mixture was poured into 500mL of 1M aqueous NaOH solution, resulting in a large amount of pale white precipitate. Finally, suction filtration is carried out, and the filter residue is washed with water and dried over anhydrous sodium sulfate to obtain the iodo intermediate compound of formula (I) in high purity (yield about 95%). Nuclear magnetic analysis of this compound (Bruker BioSpin)1H400 MHz with deuterated DMSO as solvent) as shown in fig. 2.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A process for the preparation of a pharmaceutical intermediate of Reidesvir of formula (I),
wherein X is a halogen atom, and X is a halogen atom,
the method comprises the following four successive steps:
(1) reacting an aldehyde compound of formula (II) with sulfamic acid in an aqueous solvent to obtain a cyano compound of formula (III);
(2) obtaining a cyanamide compound of formula (IV) from a cyanide compound of formula (III) by adding a base to the aqueous reaction solution obtained in step (1) to make it basic;
(3) reacting the cyanamide compound of formula (IV) obtained in step (2) with formamidine acetate in the presence of a base and an organic solvent to obtain a triazine amine compound of formula (V); and
(4) reacting the triazine amine compound of formula (V) obtained in step (3) with a halogenating agent to obtain the desired intermediate compound of formula (I),
2. the process according to claim 1, wherein the reaction temperature in steps (1), (2) and (4) is from 0 ℃ to 25 ℃ and the reaction temperature in step (3) is from 60 ℃ to 100 ℃.
3. The process according to claim 1, characterized in that in step (1), sulfamic acid is used in an excess amount with respect to the stoichiometric amount of aldehyde compound of formula (II) used; preferably, the aldehyde compound of formula (II) and sulfamic acid are used in a mass ratio of 1: 2-5.
4. The method according to claim 3, wherein in the step (2), the base is directly added to the aqueous reaction solution obtained in the step (1) without any treatment of the aqueous reaction solution obtained in the step (1).
5. The method according to claim 1, wherein in step (3), the organic solvent is directly added to the aqueous reaction solution obtained in step (2), or the aqueous solvent in step (2) is replaced with the organic solvent by solvent replacement.
6. The method according to claim 1, wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, dimethylformamide, dichloromethane, and chloroform; preferably, the organic solvent used in step (3) is one or more selected from methanol, ethanol and isopropanol; preferably, the organic solvent used in step (4) is one or more selected from the group consisting of dimethylformamide, dichloromethane and chloroform.
7. The process according to claim 1, wherein the base used in step (2) or (3) is independently one or more selected from potassium hydroxide, sodium carbonate and potassium carbonate.
8. The process according to claim 1, wherein the halogenating agent used in step (4) is one or more selected from the group consisting of N-iodosuccinimide, N-chlorosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin and N-bromosuccinimide.
9. The method according to claim 1, wherein the reaction solution obtained in step (2), (3) and/or (4) is subjected to only filtration and drying treatment without column chromatography treatment.
10. The process according to claim 9, wherein the crude product obtained in step (3) is subjected to recrystallization after filtration treatment.
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