CN111484508A - Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof - Google Patents

Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof Download PDF

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CN111484508A
CN111484508A CN202010077289.2A CN202010077289A CN111484508A CN 111484508 A CN111484508 A CN 111484508A CN 202010077289 A CN202010077289 A CN 202010077289A CN 111484508 A CN111484508 A CN 111484508A
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compound
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amino protecting
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CN111484508B (en
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王祖元
段浩田
甄志彬
程晓峰
霍彩霞
邓声菊
徐艳君
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Beijing Tianxinyuan Pharmaceutical Science And Technology Development Co ltd
Beijing Sihuan Pharmaceutical Co Ltd
Beijing Ao He Research Institute Co Ltd
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Beijing Tianxinyuan Pharmaceutical Science And Technology Development Co ltd
Beijing Sihuan Pharmaceutical Co Ltd
Beijing Ao He Research Institute Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
    • 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 invention relates to a preparation method of a compound shown in a formula 1, which comprises the following steps that a compound shown in a formula 2 is prepared by reacting a compound shown in a formula 3, and then a compound shown in a formula 1 is prepared by reacting the compound shown in the formula 2, wherein R is1The amino protecting group is preferably any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl; r3Is selected from-CH2OH, aldehyde group, ester group, amide group, cyano group and carboxyl group. The method has the advantages of simple operation, high yield, safety, environmental protection, low cost, suitability for industrial production and the like.

Description

Compound for preparing balsalavir or derivatives thereof, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a compound for preparing balsamic acid or derivatives thereof, a preparation method and application thereof.
Background
WTO statistics show that each year worldwide influenza infection accounts for approximately 300 to 500 million cases, and thus approximately 25 to 50 million influenza-infected patients die. CN102803260A, CN10322865A and CN107709321A disclose anti-influenza drugs of balosuzavir maculote and derivatives thereof. The 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4 oxazinyl [3,4-c ] pyridyl [2,1-f ] [1,2,4] triazine-6, 8-diketone (structure shown in formula I) is an intermediate for preparing the Barosuvir and the derivatives thereof.
Figure BDA0002378835540000011
CN107709321A discloses a preparation method of balosulfamate and 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridyl [2,1-f ] [1,2,4] triazine-6, 8-dione (i.e. compound 2-9), comprising the following steps:
Figure BDA0002378835540000012
Figure BDA0002378835540000021
the method utilizes the compound 2-4 to prepare the compound 2-9, but the preparation conditions of the compound 2-4 are very harsh, firstly, two preparation steps exist, the reaction is required to be carried out under harsh ultralow temperature (such as-78 ℃), the production conditions are high, secondly, a reaction reagent, namely diisobutylaluminum hydride (DIBA L-H), has strong hygroscopicity, the diisobutylaluminum hydride is sensitive to air and moisture and is easy to react violently with water to release hydrogen, the reaction is highly flammable, thirdly, the compound 2-4 is unstable, the compound 2-1 is required to be temporarily prepared by taking the compound 2-1 as a substrate, and fourthly, tin tetrachloride (SnCl) is required to be used for preparing the compound 2-5 by utilizing the compound 2-44). Tin tetrachloride is exposed in the air and is easy to react with moisture in the air to generate white smoke, the white smoke has strong irritation and corrosivity, operators inhale, ingest or absorb the white smoke through skin, the health is damaged due to the strong irritation and corrosivity, reaction byproducts pollute water and the environment, and the production requirements of safety and environmental protection are not met; fifthly, the total yield of the reaction is low. Therefore, the method has the defects of potential safety hazard, high cost, unsuitability for industrial production and the like, and the technical improvement is urgently needed.
TW201802097A discloses a process for the preparation of 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (i.e., compound 1-9), which comprises the steps of:
Figure BDA0002378835540000031
firstly, a control reagent hydrazine hydrate with strong reducibility, strong corrosivity, permeability and genetic toxicity is required to be used in the preparation of the compounds 1-4, so that the method has the defects of environmental pollution, harsh reaction conditions, high production protection requirements, high cost, unsuitability for industrial production and the like; secondly, the compound 1-2 (namely 2-bromo-1, 1-dimethoxyethane) is a dangerous reagent, and the compound 1-1 and the compound 1-2 need to react under strict anhydrous conditions, so that the method is not suitable for industrial production.
Figure BDA0002378835540000032
Therefore, how to prepare the 7- (benzyloxy) -3,4,12,12 a-tetrahydro-1H- [1,4 with high yield, safety, environmental protection and low cost]
Figure BDA0002378835540000033
Oxazinyl [3,4-c ]]Pyridyl [2, 1-f)][1,2,4]Triazine-6, 8-dione is a technical problem to be solved urgently in the field.
Disclosure of Invention
The invention aims to provide a preparation method of a compound shown in a formula 1, which comprises the following steps that a compound shown in a formula 2 is prepared by reacting a compound shown in a formula 3, and then a compound shown in a formula 1 is prepared by reacting a compound shown in a formula 2,
Figure BDA0002378835540000041
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R3is selected from-CH2OH, aldehyde group, ester group, amide group, cyano group and carboxyl group.
In the preferred technical scheme of the invention, when R is3is-CH2OH, said compound of formula 2 is prepared by reacting a compound of formula 3 in the presence of an oxidizing agent, preferably said oxidizing agent is selected from the group consisting of pyrithione Salts (SO)3·Py)、NaOCl/TEMPO (sodium hypochlorite/2, 2,6, 6-tetramethylpiperidine oxide), sodium periodate (NaIO)4)、H2O2NaOH, ammonium ceric nitrate, lead tetraacetate (L TA), chromic anhydride-acid anhydride (CrO)3-Ac2O)、CrO2Cl2、CrO3(Py)2、SeO2Pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), dichromate, MnO2DMSO-DCC (dicyclohexylcarbodiimide), DMSO-Ac2O、DMSO-(COCl)2DMS/NCS (N-chlorosuccinimide), DESS-Martin (DESS-Martin oxide (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoxy-3 (1H) -one, DMP) oxidant, or a combination thereof.
In the preferable technical scheme of the invention, in the preparation step of the compound shown in the formula 2, when the oxidant is added, the temperature of the reaction system is-10-25 ℃, and is preferably-5-20 ℃.
In the preferable technical scheme of the invention, in the preparation step of the compound shown in the formula 2, the oxidation reaction temperature of the reaction system is 0-40 ℃, preferably 5-35 ℃, and more preferably 10-35 ℃.
In a preferred embodiment of the present invention, in the step of preparing the compound of formula 2, the oxidizing agent is added at one time or in multiple portions.
In a preferred technical scheme of the invention, in the preparation step of the compound shown in the formula 2, the oxidizing agent is added in 2-5 times, preferably 3-4 times.
In a preferred technical scheme of the invention, in the preparation step of the compound shown in the formula 2, organic base is added in the oxidation reaction.
In a preferred embodiment of the present invention, in the step of preparing the compound of formula 2, the organic base is selected from ethylamine, diethylamine, diisopropylamine, and triethylamine (Et)3N), Diisopropylethylamine (DIPEA), pyridine, 1-methylpiperidine, imidazole, 4-methylmorpholine, piperidine, 4-Dimethylaminopyridine (DMAP), triethylenediamine (DABCO), 1, 8-diazabicycloundecen-7-ene (DBU), 1, 5-diazabicyclo [4.3.0 ]]-5-nonene (DBN), 1-methylpyrrolidine, or a combination thereof.
In a preferred technical scheme of the invention, the compound of the formula 1 is prepared by reacting the compound of the formula 2 in the presence of an organic acid.
In a preferred technical scheme of the invention, in the preparation of the compound shown in the formula 1, the organic acid is selected from any one of methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, acetic acid and acetic anhydride.
In the preferred technical scheme of the invention, when R is3When the compound is aldehyde group, the compound of formula 3 is the compound of formula 2, the compound of formula 2 is prepared into the compound of formula 1 in the presence of organic acid, and the organic acid is preferably selected from any one of methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, acetic acid and acetic anhydride.
In the preferred technical scheme of the invention, when R is3When the compound is selected from any one of ester group, amide group, cyano group and carboxyl group, the compound of the formula 2 is prepared from the compound of the formula 3 in the presence of a reducing agent.
In a preferred embodiment of the present invention, in the preparation of the compound of formula 2, the reducing agent is selected from any one of diisobutylaluminum hydride, diethoxyaluminum hydride, triethoxyaluminum hydride, lithium tetrahydroaluminum, sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride, or a combination thereof.
In a preferred embodiment of the present invention, the compound of formula 3 is prepared by reacting a compound of formula 4 with a compound of formula 7:
Figure BDA0002378835540000061
wherein R is1Is an amino protecting group, preferably the amino protecting group is any one selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R3is selected from-CH2Any one of OH, aldehyde group, ester group, amide group, cyano group and carboxyl group;
R4selected from-OH, lower alkyl-substituted oxyAny of them, preferably the lower alkyl is C1-C4An alkyl group.
In the preferred technical scheme of the invention, when R is4In the case of OH, the compound of formula 3 is prepared by condensation of a compound of formula 4 with a compound of formula 7 in the presence of a condensing agent, preferably selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDC), N, N '-Carbonyldiimidazole (CDI), 2- (7-oxybenzotriazole) -N, N, N', N '-tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), N, N' -Diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), 1, 8-diazabicycloundecen-7-ene (DBU), Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PYBOP) or a combination thereof.
In a preferred embodiment of the present invention, the condensing agent is used in combination with an activator in the condensation reaction.
In a preferred embodiment of the present invention, the condensing agent is selected from any one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDC), N' -Diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), or a combination thereof.
In a preferred embodiment of the present invention, the activating agent is selected from any one of 1-Hydroxybenzotriazole (HOBT), 4-Dimethylaminopyridine (DMAP), and pyrrolidinyl-pyridine, or a combination thereof.
In a preferred embodiment of the present invention, the condensing agent: the molar ratio of the activating agent is 1:0.05 to 1:2, preferably the molar ratio is 1:0.1 to 1:1, more preferably the molar ratio is 1:0.2 to 1: 0.5.
In a preferred embodiment of the present invention, the condensing agent is selected from any one or a combination of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-ethyl-3-dimethylaminopropylcarbodiimide (EDC) in combination with the activator 1-Hydroxybenzotriazole (HOBT), and is preferably a condensing agent: the molar ratio of the activators is from 1:0.1 to 1:1, more preferably from 1:0.2 to 1: 0.5.
In a preferred embodiment of the present invention, the compound of formula 3 is optionally added with an organic base in the condensation reaction step, preferably the organic base is selected from any one of triethylamine, diisopropylethylamine, 4-Dimethylaminopyridine (DMAP), pyridine, 1, 8-diazabicycloundecen-7-ene (DBU), or a combination thereof.
In a preferred embodiment of the present invention, the condensation reaction of the compound of formula 3 is performed in the presence of an organic solvent, wherein the organic solvent is selected from any one or a combination of DMF, DCM, THF and ethyl acetate.
In a preferred embodiment of the present invention, the compound of formula 3-3 is prepared by reacting a compound of formula 4 with a compound of formula 7-1, and comprises the following steps:
Figure BDA0002378835540000081
1) weighing required amounts of a compound of formula 4, a compound of formula 7-1 and an organic base, adding the compounds into an organic solvent, placing a reaction system at 0-65 ℃ for reaction, and concentrating the obtained reaction solution under reduced pressure after complete reaction to obtain a concentrate;
2) adding ethyl acetate into the concentrate prepared in the step 1), stirring until the ethyl acetate is completely dissolved, washing the obtained ethyl acetate dissolved solution with a potassium bisulfate aqueous solution, extracting the water phase with ethyl acetate for multiple times, combining the ethyl acetate extract phases, drying the obtained organic solvent extract phase with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and drying the obtained ethyl acetate extract phase under reduced pressure;
3) adding ethyl acetate into the dried substance obtained in the step 2), stirring for dissolving, filtering, drying to obtain a compound of a formula 3-3,
wherein R is1Is an amino protecting group; preferably, the amino protecting group is any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
said R4Is OH.
In the preferred technical scheme of the invention, the preparation reaction temperature of the compound shown in the formula 3-3 is 40-65 ℃, and preferably 55-65 ℃.
In a preferred embodiment of the present invention, in the preparation of the compound of formula 3-3, a catalyst is optionally added, preferably the catalyst is an organic base, more preferably the catalyst is selected from any one of hexamethyldisilazane sodium diazoxide (NaHMDS), sodium ethylate (NaOEt), n-butyllithium (Bu L i), ethylmagnesium bromide (EtMgBr), potassium tert-butoxide (KOtBu), 1, 8-diazabicycloundecen-7-ene (DBU), 1-hydroxybenzotriazole (HOBt), 4-Dimethylaminopyridine (DMAP), or a combination thereof.
In a preferred embodiment of the present invention, a condensing agent is optionally added in the preparation of the compound of formula 3-3, and preferably, the condensing agent is selected from any one of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), Dicyclohexylcarbodiimide (DCC), O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU), or a combination thereof.
In a preferred embodiment of the present invention, in the preparation method of the compound of formula 3-3, the organic solvent is selected from any one of DMF, acetone, ethanol, methanol, dichloromethane, THF, and ethyl acetate, or a combination thereof.
In the preferred technical scheme of the invention, R4When it is an alkoxy group, R4In the case of alkoxy, the compound of formula 3 is prepared by ester aminolysis of a compound of formula 4 with a compound of formula 7 in the presence of a catalyst, preferably the catalyst is selected from any one or combination of sodium metal, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, 1, 8-diazabicycloundecen-7-ene (DBU), aluminum chloride, ferric chloride, boron trifluoride, hexamethyldisilazane (NaHMDS).
In a preferred embodiment of the present invention, the compound of formula 3-2 is prepared by reacting a compound of formula 4-1 with a compound of formula 7-1, and comprises the following steps:
Figure BDA0002378835540000101
in a preferred embodiment of the present invention, in the preparation method of the compound of formula 3-2, the reaction solvent is THF, the reaction temperature is 55-65 ℃, the catalyst is 1, 8-diazabicycloundecen-7-ene (DBU), and optionally, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) is added as a condensing agent.
In a preferred embodiment of the present invention, the compound of formula 4 is prepared by reacting a compound of formula 5 with a compound of formula 8, and comprises the following steps:
Figure BDA0002378835540000102
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R4is selected from OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
Another object of the present invention is to provide another process for preparing a compound of formula 1, comprising the steps of,
Figure BDA0002378835540000111
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R3is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano and carboxyl;
R4is selected from any one of-OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
Another object of the present invention is to provide a method for preparing a compound of formula 3, comprising the steps of:
Figure BDA0002378835540000112
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R3is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano group and carboxyl group;
R4is selected from OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
In the preferred technical scheme of the invention, when R is2Is O, and R3Is CH2The preparation method of the compound of formula 3-3 comprises the following steps:
Figure BDA0002378835540000121
wherein R is1As the amino-protecting group, it is preferable that the amino-protecting group is any one selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl, and methoxycarbonyl.
In a preferred embodiment of the present invention, in the preparation method of the compound of formula 3-3, a catalyst is optionally added in step (b), preferably the catalyst is an organic base, more preferably the organic base is selected from any one of hexamethyldisilazane (NaHMDS), sodium ethoxide (NaOEt), n-butyllithium (Bu L i), ethylmagnesium bromide (EtMgBr), potassium tert-butoxide (KOtBu), 1, 8-diazabicycloundecan-7-ene (DBU), 1-hydroxybenzotriazole (HOBt), 4-Dimethylaminopyridine (DMAP), or a combination thereof.
In a preferred embodiment of the present invention, in the preparation method of the compound represented by formula 3-3, a condensing agent is optionally added in step (b), and preferably, the condensing agent is any one selected from 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), Dicyclohexylcarbodiimide (DCC), and O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU).
In a preferred embodiment of the present invention, in the preparation method of the compound of formula 3-3, the reaction solvent is an organic solvent, and preferably, the organic solvent is any one or a combination of DMF, acetone, ethanol, methanol, dichloromethane, and THF.
In a preferred technical scheme of the invention, the compound shown in the formula 3-3 is prepared under an acidic condition, and preferably, the acid is any one or combination of sulfuric acid, hydrochloric acid, acetic acid and trifluoroacetic acid.
Another object of the present invention is to provide a method for preparing a compound of formula 1, comprising the steps of:
Figure BDA0002378835540000131
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R3is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano group and carboxyl group;
R4is selected from any one of-OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
It is another object of the present invention to provide a compound of formula 9 for use in the preparation of piroxicam or derivatives thereof,
Figure BDA0002378835540000141
wherein R is3Is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano group and carboxyl group;
R5selected from N-NR1O, S.
In the preferred technical scheme of the invention, when R is5Is N-NR1When R is1Is an amino protecting group; preferably, the amino protecting group is any one selected from t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any one of pharmaceutically acceptable salts, esters, isomers and solvates of the balosuvir.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any of the balosuvir derivatives disclosed in CN102803260A, CN10322865A and CN107709321A or structural analogues thereof.
In the preferred embodiment of the present invention, the compound of formula 9 is selected from any one of compounds of formula 3 and compounds of formula 10:
Figure BDA0002378835540000142
wherein R is1Is an amino protecting group; preferably, the amino protecting group is any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R3is selected from-CH2OH, aldehyde group, ester group, amide group, cyano group and carboxyl group.
In a preferred embodiment of the present invention, the compound of formula 9 is selected from any one of a compound of formula 3-1, a compound of formula 3-2, a compound of formula 10-1, and a compound of formula 10-2,
Figure BDA0002378835540000151
another object of the present invention is to provide the use of the compound of formula 9 for the preparation of pirosacvir or derivatives thereof.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any one of pharmaceutically acceptable salts, esters, isomers and solvates of the balosuvir.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any of the balosuvir derivatives disclosed in CN102803260A, CN10322865A and CN107709321A or structural analogues thereof.
Another object of the present invention is to provide the use of baroxavir or a derivative thereof for the manufacture of a medicament for the prevention and/or treatment of 2019-nCoV (a novel coronavirus).
The invention also aims to provide the application of the baroxavir or the derivatives thereof in preparing the medicines for preventing and/or treating the infectious pneumonia.
The invention also aims to provide the application of the baroxavir or the derivatives thereof in preparing the medicines for preventing and/or treating severe specific infectious pneumonia.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any one of pharmaceutically acceptable salts, esters, isomers and solvates of the balosuvir.
In a preferred technical scheme of the invention, the derivatives of the balosuvir are selected from any of the balosuvir derivatives disclosed in CN102803260A, CN10322865A and CN107709321A or structural analogues thereof.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention adopts the compound of formula 9 to prepare 7- ((benzyloxy)) -3,4,12,12 a-tetrahydrogen-1H- [1,4]
Figure BDA0002378835540000161
Oxazinyl [3,4-c ]]Pyridyl [2, 1-f)][1,2,4]The method for preparing the triazine-6, 8-diketone has the advantages of being easy to obtain reagents in a conventional mode, low in cost, capable of avoiding using virulent tube products or dangerous preparations such as hydrazine hydrate, bromoacetaldehyde dimethyl acetal, DIBA L-H and the like, reducing dangerous factors in production, free of reaction under extremely harsh extremely low temperature (such as-78 ℃), simple and convenient to operate, high in yield (the average yield of each step is about 80% or more, the reaction yield is more than 55%), high in purity of prepared products (the purity of each step can reach more than 95%), safe, environment-friendly, low in cost, suitable for industrial production and the like.
2. The invention adopts chemicals
Figure BDA0002378835540000162
The method for preparing the compound shown in the formula 9 has the advantages of simple preparation, low cost and the like, and is compared with the method
Figure BDA0002378835540000163
The preparation cost of the preparation method is reduced by nearly one hundred times.
Drawings
FIG. 1 Mass Spectrometry map of example 5 Compound of formula 3-1
FIG. 2 Mass Spectrometry of example 2 Compounds of formula 3-2
FIG. 3 Mass Spectrometry of example 3 Compound of formula 10-2
FIG. 4 NMR spectra of the compound of example 2 formula 3-2
FIG. 5 NMR spectra of example 5 Compound of formula 1
Detailed Description
The present invention is illustrated by the following examples, which should be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Other insubstantial modifications and adaptations of the present invention can be made without departing from the scope of the present invention.
The detection method and the detection conditions of nuclear magnetism and mass spectrometry of the invention are conventional techniques in the field, and the detection conditions are as follows:1HNMR(400MHz,CDCl3) The specific detection conditions are shown in the attached drawing.
Example 1Preparation of Compounds of formula 4-1
Figure BDA0002378835540000171
A process for preparing a compound of formula 4-1 comprising the steps of:
1) adding 200ml of DMF (dimethyl formamide) into a reaction bottle, adding 132.70g of pyridinium p-toluenesulfonate and 50.00g of 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid methyl ester, heating to 60 ℃, and slowly dropping a DMF solution of tert-butyl carbazate (35.55g of tert-butyl carbazate is dissolved in 50ml of DMA) until the reaction is completed;
2) after the reaction solution was cooled to 15 to 25 ℃, 100ml of ethanol and 400ml of water were added to the reaction solution to precipitate a pale yellow precipitate, which was filtered, and the filtrate was purified by a mixed solution of ethanol and water (ethanol: water volume ratio of 1:4) and drying to obtain 58.8g of light yellow solid with yield of 78%.
Example 2Preparation of Compounds of formula 3-2
Figure BDA0002378835540000181
A process for preparing a compound of formula 3-2 comprising the steps of:
1) adding 225ml of THF into a reaction bottle, then adding 45.00g of the compound shown in the formula 4-1, 1.74g of DBU and 72.34g of diglycolamine, and heating to 55-65 ℃ until the reaction is completed;
2) concentrating the reaction solution under reduced pressure, evaporating to dryness, adding 200ml of ethyl acetate for dissolving, adding 200ml of 20% potassium bisulfate aqueous solution for washing, separating and collecting an ethyl acetate phase, extracting the potassium bisulfate aqueous solution with 200ml of ethyl acetate, combining and collecting an ethyl acetate extract phase, drying with anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, and drying the ethyl acetate extract phase under reduced pressure;
3) adding 100ml ethyl acetate into the decompressed dried substance prepared in the step 2), stirring, dissolving, filtering and drying to obtain 48.43g of light yellow solid, namely the compound of the formula 3-2 with the yield of 94.42%. The product map is shown in figure 2.
Example 3Preparation of Compounds of formula 10-2
Figure BDA0002378835540000182
A process for preparing a compound of formula 10-2, comprising the steps of:
1) adding 1.54g of the compound of formula 4-2, 2.88g of EDCI, 0.41g of HOBt, 20ml of DMF and 2.10g of diglycolamine into a reaction bottle, and reacting for 24 hours under stirring;
2) adding 100ml of water into the reaction liquid prepared in the step 1), extracting with dichloromethane (50ml of × 6), combining dichloromethane extract phases, adding water to wash the dichloromethane extract phases (50ml of × 2), then washing the dichloromethane extract phases with saturated aqueous sodium chloride solution (50ml of × 1), drying the washed dichloromethane extract phases with anhydrous sodium sulfate, filtering, and drying under reduced pressure to obtain 1.97g of yellow oily matter, namely the compound shown as the formula 10-2, wherein the yield is 94.71 percent, and the product spectrum is shown as the attached figure 3.
Example 4Preparation of Compounds of formula 3-2
Figure BDA0002378835540000191
A process for preparing a compound of formula 3-2 comprising the steps of:
1) adding 1.50g of the compound shown as the formula 10-2, 3.17g of pyridine p-toluenesulfonate, 0.83g of tert-butyl carbazate and 10ml of DMF (dimethyl formamide) into a reaction bottle, and heating to 60 ℃ until the reaction is completed;
2) pouring the reaction liquid into 50ml water, extracting with dichloromethane (20ml × 3), collecting and collecting dichloromethane extract phase, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, removing anhydrous sodium sulfate, drying dichloromethane extract phase under reduced pressure to obtain light yellow solid 1.61g, namely the compound of formula 3-2, wherein the yield is 80.3%, and the product spectrum is shown in figure 2.
Example 5Preparation of the Compound of formula 1
Figure BDA0002378835540000192
A process for the preparation of a compound of formula 1 comprising the steps of:
1) to a reaction flask was added 1.50g of the compound of formula 3-2, followed by 15ml of DCM and 6ml of Et3N, 3.00g DMSO; the reaction system is cooled to 0 ℃, and 1.07g of SO is added in 3 times3Py is added into the reaction solution, and the reaction is completed at room temperature;
2) cooling the reaction solution to below 10 ℃, washing with 20ml of water, washing with 20ml of saturated saline, drying with anhydrous sodium sulfate, and drying under reduced pressure to obtain a dried product;
3) dissolving the dried product obtained in the step 2) with 12ml of acetonitrile, adding 1.5ml of water, heating the reaction system to 60 ℃, adding 0.97g of methanesulfonic acid, completely reacting at 60 ℃, cooling the reaction liquid to room temperature, adding an aqueous solution of sodium hydroxide dropwise, adjusting the pH value to neutrality, and distilling under reduced pressure to remove the acetonitrile;
4) adding 5ml of water into the distillate prepared in the step 3), distilling under reduced pressure to remove acetonitrile, stirring, filtering, leaching a filter cake with water, and drying to obtain 0.88g of yellow crystalline solid, namely the compound shown in the formula 1, with the yield of 78%. The product spectrum is shown in figure 5.
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined by the appended claims.

Claims (10)

1. A method for preparing a compound of formula 1, which comprises the steps of reacting a compound of formula 2 with a compound of formula 3 to obtain a compound of formula 1, and reacting the compound of formula 2 to obtain a compound of formula 1,
Figure FDA0002378835530000011
wherein R is1The amino protecting group is preferably any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R3is selected from-CH2OH, aldehyde group, ester group, amide group, cyano group and carboxyl group.
2. The method according to claim 1, when R is3is-CH2OH, the compound of formula 2 is prepared by reacting a compound of formula 3 in the presence of an oxidizing agent, preferably the oxidizing agent is selected from the group consisting of pyridinium trioxide (SO)3Py), NaOCl/TEMPO (sodium hypochlorite/2, 2,6, 6-tetramethylpiperidine oxide), sodium periodate (NaIO)4)、H2O2NaOH, ammonium ceric nitrate, lead tetraacetate (L TA), chromic anhydride-acid anhydride (CrO)3-Ac2O)、CrO2Cl2、CrO3(Py)2、SeO2Pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), dichromate, MnO2DMSO-DCC (dicyclohexylcarbodiimide), DMSO-Ac2O、DMSO-(COCl)2Any one of DMS/NCS (N-chlorosuccinimide), DESS-Martin (DESS-Martin oxide (1,1, 1-triacetoxy) -1, 1-dihydro-1, 2-phenyliodoxy-3 (1H) -one, DMP) oxidant or a combination thereof.
3. The method according to claim 1, when R is3When the compound is aldehyde group, the compound of formula 3 is the compound of formula 2, the compound of formula 2 is prepared into the compound of formula 1 in the presence of an organic acid, and the organic acid is preferably selected from methanesulfonic acid, p-toluenesulfonic acid, etc,Camphorsulfonic acid, trifluoroacetic acid, acetic acid, and acetic anhydride.
4. The method according to claim 1, when R is3When the compound of formula 2 is selected from any one of ester group, amide group, cyano group and carboxyl group, the compound of formula 2 is prepared from the compound of formula 3 in the presence of a reducing agent, preferably, the reducing agent is selected from any one of diisobutylaluminum hydride, diethoxyaluminum hydride, triethoxyaluminum hydride, lithium tetrahydroaluminum, sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride or a combination thereof.
5. The method according to any one of claims 1 to 4, wherein the compound of formula 3 is prepared by reacting a compound of formula 4 with a compound of formula 7:
Figure FDA0002378835530000021
wherein R is1Is an amino protecting group, preferably the amino protecting group is any one selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R3is selected from-CH2Any one of OH, aldehyde group, ester group, amide group, cyano group and carboxyl group;
R4is selected from any one of-OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
6. The process according to any one of claims 1 to 5, when R is4In the case of OH, the compound of formula 3 is prepared by condensation of a compound of formula 4 with a compound of formula 7 in the presence of a condensing agent, preferably selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDC), N, N ' -Carbonyldiimidazole (CDI), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethylimidazoleAny one of, or a combination of, phenyluronium Hexafluorophosphate (HATU), O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), N' -Diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), 1, 8-diazabicycloundecen-7-ene (DBU), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PYBOP).
7. The method according to any one of claims 1 to 4, wherein the compound of formula 3-3 is prepared by reacting a compound of formula 4 with a compound of formula 7-1, comprising the steps of:
Figure FDA0002378835530000031
1) weighing required amounts of a compound of formula 4, a compound of formula 7-1 and organic base, adding the compounds into an organic solvent, reacting the reaction system at 0-65 ℃ until the reaction is complete, and concentrating the obtained reaction solution under reduced pressure to obtain a concentrate;
2) adding ethyl acetate into the concentrate prepared in the step 1), stirring until the ethyl acetate is completely dissolved, washing the obtained ethyl acetate dissolved solution with a potassium bisulfate aqueous solution, extracting the water phase with ethyl acetate for multiple times, combining the ethyl acetate extract phases, drying the obtained organic solvent extract phase with anhydrous sodium sulfate, filtering to remove the anhydrous sodium sulfate, and drying the obtained ethyl acetate extract phase under reduced pressure;
3) adding ethyl acetate into the dried substance obtained in the step 2), stirring for dissolving, filtering, drying to obtain a compound of a formula 3-3,
wherein R is1Is an amino protecting group; preferably, the amino protecting group is any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
said R4Is OH.
8. A process for preparing a compound of formula 1, comprising the steps of,
Figure FDA0002378835530000041
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R3is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano and carboxyl;
R4is selected from any one of-OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
9. A process for preparing a compound of formula 1, comprising the steps of,
Figure FDA0002378835530000051
wherein R is1Is an amino protecting group, preferably the amino protecting group is selected from any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, ethoxycarbonyl, trichloroethoxycarbonyl, phthaloyl, trityl, p-methoxybenzyl, p-toluenesulfonyl and methoxycarbonyl;
R2any one selected from NH, O and S;
R3is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano group and carboxyl group;
R4is selected from any one of-OH and lower alkyl substituted oxy, preferably the lower alkyl is C1-C4An alkyl group.
10. A compound of formula 9 for use in the preparation of piroxicam or derivatives thereof,
Figure FDA0002378835530000052
wherein R is3Is selected from-CH2Any one of OH, aldehyde group, ester, amide, cyano group and carboxyl group;
R5selected from N-NR1O, S.
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