CN113214263A - Synthetic method of Rudesiwei key intermediate - Google Patents
Synthetic method of Rudesiwei key intermediate Download PDFInfo
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- CN113214263A CN113214263A CN202010101228.5A CN202010101228A CN113214263A CN 113214263 A CN113214263 A CN 113214263A CN 202010101228 A CN202010101228 A CN 202010101228A CN 113214263 A CN113214263 A CN 113214263A
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Abstract
The invention provides a novel method for preparing a key intermediate of RudeSewei shown in a formula (VII). The compound shown in the formula (II) is obtained by ring opening by using benzyl fully-protected lactone shown in the formula (I) as an initial material. Protecting the hydroxyl of the compound (II) by a proper protecting group to obtain the compound shown as the formula (III). The intermediate shown in the formula (V) can be obtained by coupling, deprotection and cyclization of the compound (III) and the compound (IV) in a one-pot method. The intermediate (V) can be converted in two steps to obtain a key intermediate (VII) of the Reidesciclovir. The method provided by the invention uses the commercially available compound (I) as a starting material, and obtains the key intermediate compound (VII) for preparing the Reidesciclovir through five-step reaction in high yield, thereby greatly reducing the cost and being suitable for industrial mass production.
Description
Technical Field
The invention relates to a method for synthesizing and purifying a key intermediate of Rudexiluwei, belonging to the field of medicines.
Background
Rudeciclovir (CAS number: 1809249-37-3) an antiviral drug developed by Gilide, having the formula:
redysivir was used initially for the treatment of ebola virus disease and marburg virus infection and was later found to exhibit reasonable antiviral activity against more distantly related viruses such as respiratory syncytial virus, hunin virus, lassa fever virus and MERS. Recently, a laboratory test by Jilidide on Redexilvir with 2019-nCoV demonstrated "show activity on SARS and MERS" in non-human animals.
At present, the synthesis method of the Reidesciclovir is mainly a small-scale synthesis route reported by literature (Nature (London, United Kingdom), 531(7594), 381-385: 2016), which takes a sugar lactone fragment 01 and a base fragment 02 as starting materials, and carries out butt joint under a strong alkaline condition to obtain an intermediate 03, then carries out reaction with TMSCN under an acidic condition to replace a hydroxyl group with a cyano group to obtain a compound 04, then removes benzyl protection to obtain a compound 05, further uses propylidene to protect an adjacent dihydroxy to obtain a compound 06, then carries out butt joint with a phosphate fragment 07 to obtain a compound 08, and removes propylidene protection to obtain a final product Reidesciclovir. The detailed reaction route is shown as the following formula.
From the above routes, it can be seen that in the whole synthesis process route, the compounds 01 and 02 in the key step 1 are butted to construct the main fragment, but the yield is the lowest (only 40%) in the whole process route, and in the actual operation process, we further find that the reaction process has more byproducts and cannot be further optimized simply by adjusting the reaction conditions. Through experimental verification and analysis of byproducts, the impurities of the lactone are mainly derived from an intermediate state of ketone generated after the lactone ring is opened, and the intermediate state has high reactivity and can continuously react with excessive metal reagents to obtain other byproducts. Furthermore, we improved the synthetic route to compound 03, as detailed in the following formula:
we propose a transformation in two steps to convert the sugar lactone compound to the key intermediate III (Weinreb amide), which is a non-ketonic compound during the reaction with the metalorganic base and which only after quenching of the reaction produces an intermediate of the ketonic structure. Therefore, the yield of the third step is greatly improved. The yield of 40 percent of the original route is improved to about 70 to 85 percent, and the production cost of the Reidesvir is greatly reduced.
Disclosure of Invention
The invention aims to develop a novel method for preparing a key intermediate (VII) of the RudeSewei, and the method can improve the yield and reduce the production cost, so that the method is suitable for industrial mass production.
The invention provides a novel method for preparing a key intermediate (VII) of Rudesevir. The method comprises the following steps:
1) the ring opening of the full benzyl protection lactone shown in the formula (I) is used for obtaining an intermediate shown in the formula (II):
2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with a proper hydroxyl protecting group to obtain an intermediate as shown in the formula (III):
3) reacting the intermediate obtained in the step 2) and the compound (IV), removing protecting groups, and closing rings in molecules to obtain the compound shown in the formula (V):
4) carrying out substitution reaction on the intermediate obtained in the step 3) and shown in the formula (V) to obtain a compound shown in the formula (VI):
5) removing a protecting group from the intermediate obtained in the step 4) shown in the formula (VI) to obtain a compound shown in the formula (VI):
in the step 1), the compound (I) reacts with N, O-dimethylhydroxylamine hydrochloride with the assistance of Lewis acid or Grignard reagent to directly obtain Weinreb amide (II).
Furthermore, the dosage of the N, O-dimethylhydroxylamine hydrochloride is 1-5 times of the equivalent of the compound (I). Preferably 1.5 to 3 times equivalent.
The Lewis acid used in the step 1) is aluminum trichloride, zinc chloride or alkylaluminum, such as dimethylaluminum chloride, trimethylaluminum, triethylaluminum, tributylaluminum or triisobutylaluminum.
Further, the Lewis acid is preferably an alkylaluminum such as dimethylaluminum chloride or trimethylaluminum.
Furthermore, the dosage of the Lewis acid is 1-5 times of the dosage of the N, O-dimethylhydroxylamine hydrochloride. Preferably 1 to 2 times equivalent.
When a combination of lewis and N, O-dimethylhydroxylamine hydrochloride is used in the step 1), the solvent is selected from dichloromethane, chloroform, dichloroethane, benzene, toluene, N-hexane, cyclohexane, or the like.
The Grignard reagent used in the step 1) is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, propyl magnesium chloride, propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, n-pentyl magnesium chloride or n-pentyl magnesium bromide, etc.
Further, the Grignard reagent is preferably isopropyl magnesium chloride or isopropyl magnesium bromide.
Furthermore, the dosage of the Grignard reagent is 0.8-2 times of the dosage of the N, O-dimethylhydroxylamine hydrochloride.
In the step 1), when the combination of the grignard reagent and the N, O-dimethylhydroxylamine hydrochloride is used, the solvent is selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N-hexane, toluene, or the like.
In the step 2), R is 2-tetrahydropyranyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, dimethyl tert-butyl silyl or tert-butyl diphenyl silyl and the like.
Further, R is preferably 2-tetrahydropyranyl or trimethylsilyl.
The solvent used in the step 2) is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide, N-methylpyrrolidone, toluene or dimethyl sulfoxide and the like.
Optionally, a protecting group may be added or not added in step 3).
Further, it is preferable to add a protecting group such as trimethylchlorosilane and the like.
In the step 3), X can be halogen, such as bromine or iodine.
The step 3) is to couple the intermediate (III) and the compound (IV) in the presence of an organic base, wherein the organic base is n-butyllithium, sec-butyllithium, tert-butyllithium, phenylmagnesium chloride, phenylmagnesium bromide, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, n-pentylmagnesium chloride, n-pentylmagnesium bromide, or the like.
Further, when X is bromine, the organic base is preferably selected from n-butyllithium, sec-butyllithium or tert-butyllithium.
Further, when X is iodine, the organic base may be selected from one or a combination of two different organic bases as described above, such as phenylmagnesium chloride and isopropylmagnesium chloride.
Further, the organic base used is, for example, an organic magnesium compound, and a complex containing a lithium salt may be used, or a lithium salt may be added separately.
The dosage of the compound (IV) in the step 3) is 1-3 times of the dosage of the intermediate (III).
The dosage of the organic base in the step 3) is 1-5 times of the dosage of the compound (IV).
The deprotection and intramolecular cyclization in the step 3) are carried out under an acidic condition, and the acid used can be selected from p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, trifluoroacetic acid, sulfamic acid, camphorsulfonic acid, hydrochloric acid or sulfuric acid.
The solvent used in the step 3) is dichloromethane, chloroform, dichloroethane, tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide, N-methylpyrrolidone, toluene, xylene or dimethyl sulfoxide and the like.
The invention provides a novel method for preparing a key intermediate (VII) of Rudesevir. The method takes a compound available in the market as a starting material, prepares the high-purity intermediate (VII) through three-step reaction in high yield, has simple and convenient preparation and lower cost, and is suitable for industrial production.
Obviously, many modifications, substitutions, and alterations are possible in light of the above teachings of the invention, without departing from the basic technical ideas of the invention, as defined by the following general technical knowledge and conventional practices of the art.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Example 1: synthesis of intermediate (2R, 3R, 4R) -2, 3, 5-tris (phenyloxy) -4-hydroxy-N-methoxy-N-methylpentanamide.
Adding N, O-dimethylhydroxylamine hydrochloride and a tetrahydrofuran solution of a compound 01 into a reaction bottle, cooling the system to 15 ℃, then dropwise adding the tetrahydrofuran solution of an isopropyl Grignard reagent into the reaction system, and stirring for 2 hours at the temperature of 20 ℃. After the system TLC monitored reaction was completed, saturated aqueous ammonium chloride solution was added to quench, the mixture was extracted with ethyl acetate, and the organic phase was concentrated to give crude product of product 02 as a pale yellow oil which was used directly in the next reaction.
Example 2: synthesis of intermediate (2R, 3S, 4R) -2, 3, 5-tris (phenyloxy) -N-methoxy-N-methyl-4- ((trimethylallyl) oxy) pentanamide.
Dissolving the crude product of the compound 02 in dichloromethane, adding imidazole as a base, then dropwise adding a dichloro solution of trimethylchlorosilane, and reacting the system for 48 hours at room temperature. System TLC after the reaction was complete, quench the reaction with water, separate the layers, extract the aqueous phase 2 times with dichloromethane, combine the organic phases, concentrate the organic phases, and separate the crude product using column chromatography to afford compound 03 as a pale yellow oil (80% yield over two steps).
Example 3: synthesis of intermediate (3R, 4R, 5R) -2- (4-aminopyrrolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-ol.
The compound 04 is suspended in tetrahydrofuran solution, then trimethylchlorosilane is added, the system is stirred for 30 minutes at room temperature, then the system is cooled to 0 ℃, phenylmagnesium chloride is added into the reaction system, and the system is continuously stirred for 30 minutes. Further cooling the reaction system to 0 ℃, then dropwise adding isopropyl magnesium chloride into the reaction system, maintaining the temperature of the reaction system to be not higher than 5 ℃, continuously stirring the system for 15 minutes, then further cooling the system to-20 ℃, slowly dropwise adding a tetrahydrofuran solution of the compound 03 into the reaction system, and maintaining the reaction temperature to be not higher than-20 ℃ in the dropwise adding process. Slowly heating the system to 0 ℃, then quenching the reaction by using a methanol/acetic acid/water mixed solution, heating the reaction system to room temperature, stirring for 30 minutes, concentrating under reduced pressure to remove an organic phase, adding ethyl acetate and 1N hydrochloric acid into a residual water phase, separating liquid, sequentially washing the organic phase by using 10% sodium bicarbonate and a saturated sodium chloride aqueous solution, drying by using anhydrous sodium sulfate, filtering and concentrating the organic phase to obtain a crude product of the compound 05, and further purifying the crude product by using column chromatography to obtain the compound 05 (off-white solid, yield 80%).
Example 4: synthesis of intermediate (3R, 4R, 5R) -2- (4-aminopyrorrolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-ol
Suspending the compound 04 in tetrahydrofuran, adding trimethylchlorosilane, stirring the system at room temperature for 20 minutes, cooling to-78 ℃, slowly dropwise adding a butyl lithium n-hexane solution into the reaction system, and maintaining the temperature of the system to be not higher than-75 ℃ in the dropwise adding process. After the completion of the dropwise addition, the system was kept at the temperature and stirred for 10 minutes, and then a tetrahydrofuran solution of compound 03 was dropwise added to the reaction system. After TLC monitoring the reaction was completed, the reaction was quenched with acetic acid, then the system was concentrated under reduced pressure to remove the organic phase, the residue was separated by adding water and dichloromethane, the aqueous phase was extracted twice with dichloromethane, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude compound 05, which was further purified using column chromatography to give compound 05 (off-white solid, yield 75%).
Example 5: synthesis of intermediate (2R, 3R, 4R, 5R) -2- (4-aminopyraprolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-bis (phenyloxy) -5- ((phenyloxy) methyl) tetrahydrofu ran-2-carbonitrile
Compound 05 was dissolved in dichloromethane and then cooled to-78 ℃ and trifluoromethanesulfonic acid was added slowly. The temperature was maintained for 10 minutes with stirring, and then a solution of TMSOTf in tetrahydrofuran was added dropwise, during which the system was maintained at a temperature not higher than-78 ℃. After the dropwise addition, the TMSCN was slowly added dropwise to the reaction system, and after the dropwise addition was completed, the temperature was maintained and stirring was continued for 2 hours. After TLC monitoring reaction, triethylamine is added into the reaction system, then the system is warmed to room temperature, and then sodium bicarbonate water solution is slowly added. Separating, extracting the water phase with dichloromethane for 2 times, combining the organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain crude product. The crude product was purified using column chromatography to afford compound 06 (off-white solid, yield 80%).
Example 6: synthesis of intermediate (2R, 3R, 4S, 5R) -2- (4-aminopyraprolo [2, 1-f ] [1, 2, 4] triazin-7-yl) -3, 4-dihydroxy-5- (hydroxymethy) tetrahydrofuran-2-carbonitile
Dissolving the compound 06 in anhydrous dichloromethane, cooling the system to-78 ℃, and protecting the system with argon. And then, slowly dropwise adding boron trichloride into the reaction system, and after dropwise adding, slowly heating the system to-40 ℃ and reacting for 2 hours. And after TLC monitoring reaction, cooling the system to-78 ℃ again, adding methanol and triethylamine into the system to quench the reaction, and after quenching, heating the reaction to room temperature. And (3) concentrating the reaction system under reduced pressure, pulping the residue with n-hexane, and collecting the solid. Subsequently, methanol and water were added to the residue and heated to 45 ℃, the system was further concentrated under reduced pressure until methanol was removed, and white solids were precipitated by cooling, followed by collecting the solids by filtration to obtain compound 07 (white solid, yield 85%).
Claims (9)
1. A method for preparing a Rudesevir key intermediate compound shown as a formula (VII) is characterized by comprising the following steps:
1) the ring opening of the full benzyl protection lactone shown in the formula (I) is used for obtaining an intermediate shown in the formula (II):
2) reacting the intermediate obtained in the step 1) as shown in the formula (II) with a proper hydroxyl protecting group to obtain an intermediate as shown in the formula (III):
3) reacting the intermediate obtained in the step 2) and the compound (IV), removing protecting groups, and closing rings in molecules to obtain the compound shown in the formula (V):
4) carrying out substitution reaction on the intermediate obtained in the step 3) and shown in the formula (V) to obtain a compound shown in the formula (VI):
5) removing a protecting group from the intermediate obtained in the step 4) shown in the formula (VI) to obtain a compound shown in the formula (VI):
2. the process for preparing the intermediate of formula (VII) according to claim 1, wherein the compound (I) in step 1) is reacted with N, O-dimethylhydroxylamine hydrochloride with the aid of lewis acid or grignard reagent to directly obtain Weinreb amide (II).
3. The method of claim 1, wherein the lewis acid used in step 1) is aluminum trichloride, zinc chloride or an alkyl aluminum such as dimethylaluminum chloride, trimethylaluminum, triethylaluminum, tributylaluminum or triisobutylaluminum.
4. The method according to claim 1, wherein the Grignard reagent used in step 1) is methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, propyl magnesium chloride, propyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, n-butyl magnesium chloride, n-butyl magnesium bromide, isobutyl magnesium chloride, isobutyl magnesium bromide, n-pentyl magnesium chloride, n-pentyl magnesium bromide, or the like.
5. The method as claimed in claim 1, wherein R in step 2) is 2-tetrahydropyranyl, p-methoxybenzyl, methoxymethyl, trimethylsilyl, dimethyl-t-butylsilyl, t-butyldiphenylsilyl, or the like.
6. The method as claimed in claim 1, wherein in step 3), a silicon-based protecting group such as trimethylchlorosilane or the like is optionally added, or no protecting group is added.
7. The method as claimed in claim 1, wherein in step 3), X is halogen, such as bromine or iodine.
8. The method according to claim 1, wherein the organic base used in step 3) is n-butyllithium, isobutyllithium, tert-butyllithium, phenylmagnesium chloride, phenylmagnesium bromide, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium chloride, ethylmagnesium bromide, propylmagnesium chloride, propylmagnesium bromide, isopropylmagnesium chloride, isopropylmagnesium bromide, n-butylmagnesium chloride, n-butylmagnesium bromide, isobutylmagnesium chloride, isobutylmagnesium bromide, n-pentylmagnesium chloride, n-pentylmagnesium bromide, or the like.
9. The method of claim 1, wherein the deprotection and intramolecular cyclization in step 3) occurs under acidic conditions using an acid selected from the group consisting of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, glacial acetic acid, trifluoroacetic acid, sulfamic acid, camphorsulfonic acid, hydrochloric acid, sulfuric acid, and the like.
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| CN113354699A (en) * | 2020-03-04 | 2021-09-07 | 中国科学院上海药物研究所 | Intermediate of Reidesciclovir and preparation method thereof |
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