CN114432308B - Application of nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparation of anti-influenza A virus drugs - Google Patents

Application of nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparation of anti-influenza A virus drugs Download PDF

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CN114432308B
CN114432308B CN202210109652.3A CN202210109652A CN114432308B CN 114432308 B CN114432308 B CN 114432308B CN 202210109652 A CN202210109652 A CN 202210109652A CN 114432308 B CN114432308 B CN 114432308B
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CN114432308A (en
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祝诗发
曹同祥
史秋
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South China University of Technology SCUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
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    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

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Abstract

The invention provides an application of a nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparing an anti-Influenza A Virus (IAV) medicament, wherein the nitrogenous spiro compound has a structure shown in a formula (4), a formula (5), a formula (6), a formula (7) or a formula (8): wherein X is a carbon atom or a nitrogen atom; n is selected from 0,1 or 2; r is R 1 Is one or more groups on the A ring or the B ring, R is 1 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl; when R is 1 When the number of (2) is plural, two R 1 The two can be connected through a saturated or unsaturated C1-C4 carbon chain; r is R 2 Selected from hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl; r is R 3 Selected from hydrogen or C1-C6 alkyl.

Description

Application of nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparation of anti-influenza A virus drugs
Technical Field
The invention relates to the technical field of medicines, in particular to an application of a nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparing an anti-Influenza A Virus (IAV) medicine.
Background
Influenza viruses are pathogens responsible for influenza and are one of the main causes of death in humans. Influenza viruses belong to the orthomyxoviridae family, and are classified into three types of A (A), B (B) and C (C) according to the antigenicity difference of internal proteins, the most closely related to human is influenza A virus, the genome of which consists of 8 single-stranded negative strand RNAs, and at least 10 proteins are encoded: hemagglutinin protein (HA), neuraminidase (NA), polymerase (Polymerase basic protein, PB1; polymerase basic protein 2,PB2;Polymerase acidic protein 3,PA), nucleoprotein (NP), matrix protein (1,M1;Matrix protein 2,M2), nonstructural protein (Non-structural protein1, NS1; non-structural protein 2, NS2). Influenza viruses are numerous, and influenza a viruses are divided into subtypes based on the antigenicity of the viral envelope proteins hemagglutinin HA and neuraminidase NA, it HAs now been found that 17 HA and 10 NA, the HA and NA subtypes can form different combinations, e.g., H1N1, H2N2, H3N2, H5N1, H7N9 subtypes, etc. The anti-influenza drugs applied clinically at present are mainly divided into two types according to action mechanisms: one class is amantadine and rimantadine, which inhibit M2 ion channel proteins; the other class is neuraminidase inhibitors that inhibit the release of influenza virus, oseltamivir, zanavir, and peramivir.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides application of a nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparation of anti-influenza A virus medicaments.
In order to achieve the above purpose, the invention adopts the following technical scheme:
use of a nitrogen-containing spiro compound having a structure represented by formula (4), formula (5), formula (6), formula (7) or formula (8), or a pharmaceutically acceptable salt thereof, in the preparation of an anti-influenza a virus medicament:
wherein X is a carbon atom or a nitrogen atom; n is selected from 0,1 or 2;
R 1 is one or more groups on the A ring or the B ring, R is 1 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl;
when R is 1 When the number of (2) is plural, two R 1 The two can be connected through a saturated or unsaturated C1-C4 carbon chain;
R 2 selected from hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen or C1-C6 alkyl;
the dotted line in formula (7) indicates that the chemical bond between the two carbon atoms is a single bond or a double bond.
The nitrogen-containing spiro compound contains nitrogen atoms and unsaturated bonds, so that technicians can freely perform simple oxidation, reduction, replacement of protecting groups and other operations on the nitrogen-containing spiro compound, such as oxidation of the nitrogen atoms or reduction of double bonds into single bonds.
Preferably, n is selected from 0 or 1.
Preferably, R 1 Selected from hydrogen, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino or phenyl.
Preferably, R 2 Selected from hydrogen, p-toluenesulfonyl or methanesulfonyl.
Substituent definition and general terminology
The term "alkyl" as used herein, means a saturated straight, branched or cyclic monovalent hydrocarbon radical containing from 1 to 6 carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 3 carbon atoms.
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
The term "ester group" refers to-C (=o) O-. The ester groups may be linked to the substituents described herein to form the corresponding ester substituents. Examples of ester groups include, but are not limited to, methyl, ethyl, propyl, butyl, and the like.
Preferably, the pharmaceutically acceptable salt is a pharmaceutically acceptable salt of a nitrogen spiro compound with an organic or inorganic acid.
More preferably, the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate salt.
More particularly preferred, the nitrogen spiro compound is exemplified in part by the following:
the preparation method of the compound shown in the formula (4), the formula (5) or the formula (6) comprises the following steps:
s1, reacting an alkenyl cyclopropane compound shown as a formula (3) in a solvent to obtain a compound shown as a formula (4);
s2, reducing the compound shown in the formula (4) to obtain a compound shown in the formula (5); alternatively, the compound of formula (4) is mixed with silica gel under alkaline conditions to react to obtain the compound of formula (6).
S3, if necessary, converting the obtained compound shown in the formula (4), the compound shown in the formula (5) and the compound shown in the formula (6) into pharmaceutically acceptable salts.
Preferably, the solvent is selected from one or more of toluene, chlorobenzene, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, methanol, ethanol, isopropanol, acetonitrile, water.
Preferably, the base is selected from triethylamine, methylamine, dimethylamine, ethylenediamine, isopropylamine, tert-butylamine, cyclohexylamine, pyridine, potassium tert-butoxide or sodium tert-butoxide.
Preferably, the reaction temperature of the preparation method is 50-120 ℃.
More preferably, the reaction temperature of the preparation method is 70 to 90 ℃.
Preferably, the reaction time of the preparation method is 4 to 60 hours.
More preferably, the reaction time of the preparation method is 4 to 24 hours.
More preferably, the alkenylcyclopropane compound represented by the formula (3) is commercially available or synthesized by referring to conventional literature reports.
As an alternative to the use of a single-layer polymer,the alkenylcyclopropane compound represented by formula (3) may be prepared by the following method: the dibromoolefin compound represented by the formula (1) is reacted with the alkenylcyclopropane compound represented by the formula (2) to produce the alkynylamine alkenylcyclopropane compound represented by the formula (3). Wherein R is 1 、R 2 、R 3 The substituents are defined in the invention, n is selected from 0 or 1.
More specifically, the reaction may be carried out as follows: in a nitrogen atmosphere, adding dibromoalkene compound shown in formula (1), alkene cyclopropane compound shown in formula (2), cuprous iodide, 1, 10-phenanthroline and cesium carbonate in sequence, adding dry tetrahydrofuran, and stirring at room temperature until the raw materials are completely reacted. After filtration, the solvent was evaporated in vacuo and purified by flash chromatography to give an alkenylcyclopropane compound represented by formula (3).
Use of a pharmaceutical composition comprising a therapeutically effective amount of a nitrogen-containing spiro compound having a structure according to formula (4), formula (5), formula (6), formula (7) or formula (8) above in the manufacture of an anti-influenza a virus medicament.
In some cases, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
In some cases, the pharmaceutical composition contains an additional active agent having anti-influenza a virus that reduces or decreases the anti-influenza a virus effect of the nitrogen-containing spiro compound.
A nitrogen-containing spiro compound having a structure represented by formula (7) or formula (8):
wherein X is a carbon atom or a nitrogen atom; n is selected from 0,1 or 2;
R 1 is one or more groups on the A ring or the B ring,the R is 1 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl;
when R is 1 When the number of (2) is plural, two R 1 The two can be connected through a saturated or unsaturated C1-C4 carbon chain;
R 2 selected from hydrogen, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen or C1-C6 alkyl;
the dotted line in formula (7) indicates that the chemical bond between the two carbon atoms is a single bond or a double bond.
Preferably, the nitrogen-containing spiro compound is selected from the following structures:
the preparation method of the nitrogen-containing spiro compound shown in the formula (7) or the formula (8) comprises the following steps:
s1, preparing a nitrogen-containing spiro compound with a structure shown in a formula (4);
s2, carrying out reduction reaction on the compound of the formula (4) in the presence of a cerium catalyst to obtain a nitrogen-containing spiro compound of the structure of the formula (7);
or the compound of the formula (4) is subjected to oxidation reaction to obtain the nitrogen-containing spiro compound of the formula (8).
The nitrogen-containing spiro compound with the structure shown in the formula (4), the formula (5), the formula (6), the formula (7) or the formula (8) has a strong inhibition effect on Influenza A Virus (IAV), and part of the compound and a positive control medicament ribavirin are at the same level or higher level, so that the nitrogen-containing spiro compound can be used for preparing anti-Influenza A Virus (IAV) virus medicaments.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel application of a nitrogen-containing spiro compound or a pharmaceutically acceptable salt thereof, which has the activity of inhibiting Influenza A Virus (IAV), so that the nitrogen-containing spiro compound or the pharmaceutically acceptable salt thereof can be used for preparing anti-Influenza A Virus (IAV) medicaments.
Detailed Description
Unless otherwise specified, the raw materials, reagents and solvents used in the present invention are commercially available without any treatment or may be prepared by literature methods. In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1
This example provides a 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a), prepared in particular as follows:
first, compound (1 a), compound (2 a), compound (3 a) were prepared:
(1) Preparation of compound (1 a): 2-nitrobenzaldehyde (1 a-s1,1.5g,10mmol,1 eq) was dissolved in dichloromethane (50 ml), carbon tetrabromide (1.1 eq) was added, cooled to 0℃and triphenylphosphine (2 eq) was added to the mixture in portions, stirred at 0℃and the reaction was monitored by TLC plates. Hexane (35 ml) was added to precipitate triphenylphosphine oxide. The solution was filtered through silica gel, rinsed with 10% ethyl acetate (hexane), the filtrate collected and the solvent removed in vacuo and purified by column chromatography (petroleum ether: ethyl acetate=30:1) to give the compound 2- (2, 2-dibromovinyl) -1-nitrobenzene (1 a,2.98g, 97%).
(2) Preparation of compound (2 a): 4-amino-1, 1-diethoxybutane (3.4 ml,20 mmol) and triethylamine (3.5 ml,25 mmol) were taken, methylene chloride (100 ml) was added, and toluene sulfonyl chloride (3.8 g,20 mmol) was added to the above solution at 0℃over 10 minutes and stirred at room temperature for 1 hour. Washed with saturated aqueous sodium bicarbonate (100 ml), extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the products 2a-s2. The crude product was used in the next step without further purification.
Dichloromethane (80 ml) was added to 2a-s2, di-tert-butyl carbonate (40 mmol,2 eq) and 4-dimethylaminopyridine (10%) were added sequentially, stirred at room temperature for 30 minutes, the reaction solution was washed with water, the resulting solution was extracted with dichloromethane, the combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure, and the crude product 2a-s3 was used in the next step without further purification.
2a-s3 was taken, hydrochloric acid solution (concentration 36%,0.1 eq), acetone (50 ml) and water (50 ml) were added, stirred at room temperature for 12 hours, the reaction mixture was washed with sodium bicarbonate solution and water, extracted with ethyl acetate, dried over sodium sulfate, and concentrated in vacuo, and purified by flash column chromatography (petroleum ether: ethyl acetate=4:1) to give 2a-s4 (6.3 g, 95%).
Under nitrogen atmosphere, cyclopropyltriphenylphosphine bromide (10.7 g,1.4 eq) was taken, anhydrous tetrahydrofuran (100 ml) was added, cooled to 0℃and a potassium tert-butoxide solution (1M, 1.1 eq) was slowly dropped into the above mixture by a syringe over 5 minutes, and stirred at room temperature, after 1 hour, a tetrahydrofuran solution (100 ml) of 2a-s4 (6.3 g,1 eq) was slowly added to the mixture by a syringe over 5 minutes, and after 1 hour, the mixture was reacted at room temperature, and then heated to 80 ℃. After completion of the reaction, it was filtered and concentrated in vacuo and finally purified by flash column chromatography (petroleum ether/ethyl acetate=5:1) to give 2a-s5 (5.4 g, 80%).
2a-s5 was taken, sodium hydroxide (3 eq) and ethanol (60 ml) were added and the mixture was stirred at 80 ℃ for 12 hours, after completion of the reaction mixture was washed with water, extracted with ethyl acetate, dried and concentrated in vacuo and purified by flash column chromatography (petroleum ether: ethyl acetate=5:1) to give 2a (3.5 g, 95%).
(3) Preparation of compound (3 a): 2- (2, 2-Dibromovinyl) -1-nitrobenzene 1a (307 mg,1mmol,1.0 eq), compound 2a (1 eq), cuprous iodide (3%), 1, 10-phenanthroline (5%) and cesium carbonate (3 eq) were added sequentially under nitrogen atmosphere, dried tetrahydrofuran (0.25M) and stirred at room temperature until the starting materials were reacted completely. After filtration through silica gel, the solvent was evaporated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 3a (361 mg, 88%).
1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a), the preparation method comprising the steps of:
s1, taking compound 3a (0.15 mmol,61 mg), adding tetrahydrofuran (5 ml), stirring at 70 ℃ for 12 hours, concentrating the reaction solution under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=2:1) to obtain compound 4a. Yield 74% (45 mg), pink solid, m.p.rf=0.3 (ethyl acetate/petroleum ether=1:2). 1h NMR (500 mhz, cdcl 3) delta 7.69 (d, j=8.2 hz, 2H), 7.28 (d, j=4.9 hz, 2H), 6.73 (dd, j=9.7, 5.6hz, 1H), 6.53 (dd, j=18.4, 9.5hz, 2H), 6.29 (dd, j=9.2, 5.6hz, 1H), 3.33-3.27 (M, 2H), 2.97-2.90 (M, 1H), 2.59 (ddd, j=12.9, 9.2,6.1hz, 1H), 2.49-2.43 (M, 1H), 2.41 (s, 3H), 2.00-1.86 (M, 4H), 1.81-1.74 (M, 1H), 1.70-1.58 (M, 1H). 13C NMR (126 mhz, cdcl 3) delta 210.5,205.6,179.6,144.1,135.9,135.4,132.9,129.4,128.5,122.7,121.4,84.7,59.2,58.0,44.3,40.3,30.9,23.4,22.0,21.6 ir (KBr, cm-1): 2959,2924,1772,1718,1637,1542,1490,1386,1170,746,661,587.HRMS (ESI-TOF)/M/z: [ M+Na ]]+calcd for C 22 H 22 N 2 O 4 SNa 433.1192；found 433.1189.
Example 2
Example 2 provides a 10-fluoro-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 b) prepared in particular as follows:
with 4-fluoro-2-nitrobenzaldehydeInstead of 2-nitrobenzaldehyde in step (1) of example 1, the remaining operations were unchanged to give 10-fluoro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 b). Yield 73% (47 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 )δ7.71(d,J＝8.1Hz,2H),7.29(d,J＝8.1Hz,2H),6.70(dd,J＝9.8,6.5Hz,1H),6.28–6.20(m,1H),6.15(d,J＝10.0Hz,1H),3.36–3.22(m,2H),2.90(dd,J＝11.2,4.8Hz,1H),2.65–2.55(m,1H),2.48(dt,J＝12.8,6.2Hz,1H),2.42(s,3H),2.01–1.94(m,1H),1.94–1.88(m,2H),1.85–1.79(m,1H),1.66–1.58(m,2H). 13 C NMR(126MHz,CDCl 3 )δ209.1,205.4,178.1(C-F, 3 J C-F ＝16.51Hz),178.0(C-F, 3 J C-F ＝16.51Hz),167.5(C-F, 1 J C-F ＝269.6Hz),165.3(C-F, 1 J C-F ＝269.6Hz),144.2,136.0,135.9(C-F, 3 J C-F ＝11.3Hz),135.3(C-F, 3 J C-F ＝11.3Hz),129.5,128.4,119.7(C-F, 2 J C-F ＝35.3Hz),119.4(C-F, 2 J C-F ＝35.3Hz),101.4(C-F, 2 J C-F ＝21.4Hz),101.2(C-F, 2 J C-F ＝21.4Hz),85.1,59.2,57.8,44.2,40.1,31.5,23.4,22.1,21.6. 19 F NMR(471MHz,CDCl 3 )δ-94.1.IR(KBr,cm -1 ):2956,2923,1780,1644,1491,1330,1154,1010,920,785,658.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 FN 2 O 4 SNa 451.1098；found 451.1099.
Example 3
Example 3 provides a 10-bromo-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 c), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-bromo-2-nitrobenzaldehyde, and the remaining operation was unchanged to give 10-bromo-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 c). Yield 78% (57 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:3). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝8.2Hz,2H),7.29(d,J＝8.1Hz,2H),6.87(s,1H),6.49(d,J＝9.6Hz,1H),6.38(dd,J＝9.6,1.2Hz,1H),3.36–3.25(m,2H),2.95–2.88(m,1H),2.65–2.55(m,1H),2.49–2.43(m,1H),2.42(s,3H),2.01–1.76(m,6H),1.64–1.56(m,1H). 13 C NMR(126MHz,CDCl 3 )δ209.2,205.2,177.6,144.3,135.3,133.2,132.3,129.5,128.4,128.0,123.0,84.9,58.2,57.9,44.2,40.1,31.0,23.4,21.9,21.6.IR(KBr,cm -1 ):2925,1768,1630,1398,1240,1157,1089,852,788,658,614.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 BrN 2 O 4 SNa 511.0298；found 511.0295.
Example 4
Example 4 provides a 9-methoxy-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 d), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 5-methoxy-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 9-methoxy-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 d). Yield 63% (42 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝8.2Hz,2H),7.29(d,J＝8.2Hz,2H),6.59(dd,J＝10.0,2.4Hz,1H),6.50(d,J＝10.0Hz,1H),5.43(d,J＝2.2Hz,1H),3.63(s,3H),3.32–3.24(m,2H),2.97–2.90(m,1H),2.62–2.53(m,1H),2.47–2.42(m,1H),2.41(s,3H),1.99–1.86(m,4H),1.83–1.76(m,1H),1.69–1.61(m,1H). 13 C NMR(126MHz,CDCl 3 )δ211.3,205.9,179.2,152.4,144.1,136.6,135.3,129.4,128.5,122.1,99.7,85.8,58.1,58.1,55.1,44.3,40.3,32.9,23.5,22.1,21.6.IR(KBr,cm -1 ):2955,2924,2855,1769,1588,1408,1277,1182,972,814,749,658.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 23 H 24 N 2 O 5 SNa 463.1298；found 463.1295.
Example 5
Example 5 provides a 10-methoxy-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 e), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-methoxy-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 10-methoxy-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 d). Yield 81% (53 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 )δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),6.61(d,J＝9.7Hz,1H),6.13(dd,J＝9.7,1.6Hz,1H),5.71(s,1H),3.81(s,3H),3.35(t,J＝11.7Hz,1H),3.26(d,J＝8.6Hz,1H),2.90–2.83(m,1H),2.62–2.45(m,2H),2.41(s,3H),2.01–1.87(m,4H),1.83–1.75(m,2H). 13 C NMR(126MHz,CDCl 3 )δ210.3,206.2,179.5,165.1,144.0,135.6,133.9,129.4,128.4,123.2,92.8,85.3,58.6,57.8,55.8,44.1,40.3,32.6,23.6,22.3,21.6.IR(KBr,cm -1 ):2956,1768,1448,1330,1231,1089,866,726,657,586.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 23 H 24 N 2 O 5 SNa 463.1298；found 463.1296.
Example 6
Example 6 provides 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,13 a-methano [1,3 ]]Dioxanes [4',5':4,5]Benzo [1,2-b]Pyrido [3,2-g]Aza-compounds-5,14 (1H) -dione (4 f), prepared in particular as follows:
by 6-nitrobenzo [ d ]][1,3]Dioxin-5-Formaldehyde was used instead of 2-nitrobenzaldehyde in step (1) of example 1, and the remaining operations were unchanged to give 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,13 a-methano [1,3 ]]Dioxanes [4',5':4,5]Benzo [1,2-b]Pyrido [3,2-g]Aza-compounds-5,14 (1H) -dione (4 f). Yield 76% (52 mg), purple solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=2:3). 1 H NMR(500MHz,CDCl 3 )δ7.74(d,J＝8.1Hz,2H),7.29(d,J＝8.2Hz,2H),5.93(s,1H),5.80(d,J＝10.8Hz,2H),5.77(s,1H),3.34(t,J＝11.6Hz,1H),3.24(d,J＝10.1Hz,1H),2.84(dd,J＝11.1,5.2Hz,1H),2.58–2.46(m,2H),2.42(s,3H),1.98(dt,J＝13.4,6.6Hz,1H),1.93–1.89(m,2H),1.88–1.79(m,2H),1.67–1.56(m,1H). 13 C NMR(126MHz,CDCl 3 )δ210.5,206.4,178.3,157.4,145.7,144.1,135.5,129.4,128.4,101.5,99.4,92.8,86.1,58.8,57.7,44.1,40.1,34.5,23.7,22.5,21.6.IR(KBr,cm -1 ):3044,2955,2924,1707,1528,1382,1203,1058,960,819,738,586.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 23 H 22 N 2 O 6 SNa 477.1091；found 477.1086.
Example 7
Example 7 provides a 9-chloro-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 g), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 5-chloro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 9-chloro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 g). Yield 63% (42 mg), white solid, m.p.R f =0.3 (ethyl acetate/petroleum ether). Delta.7.72 (d, j=8.1 hz, 2H), 7.30 (d, j=8.1 hz, 2H), 6.63 (dd, j=10.0, 1.7hz, 1H), 6.58-6.51 (m, 2H), 3.35 (t, j=11.2 hz, 1H), 3.26 (d, j=10.5 hz, 1H), 2.97-2.90 (m, 1H), 2.61 (ddd, j=12.8, 9.6,6.3hz, 1H), 2.48-2.43 (m, 1H), 2.42 (s, 3H), 2.03-1.79 (m, 5H), 1.61-1.54 (m, 1H) 13 C NMR(126MHz,CDCl 3 )δ209.1,205.1,177.1,144.3,138.0,135.3,129.5,128.4,128.2,127.9,122.9,85.3,59.8,58.0,44.2,40.1,30.6,23.3,21.9,21.6.IR(KBr,cm -1 ):2954,2867,1772,1625,1402,1272,1083,858,747,666,584.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 ClN 2 O 4 SNa 467.0803；found 467.0802.
Example 8
Example 8 provides a 9-fluoro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4H), the preparation method is as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 5-fluoro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 9-fluoro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4H). Yield 80% (51 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 δ7.72(d,J＝7.7Hz,2H),7.30(d,2H),6.68–6.54(m,2H),5.99(d,J＝9.0Hz,1H),3.35(t,J＝12.1Hz,1H),3.26(d,J＝11.5Hz,1H),2.97–2.89(m,1H),2.65–2.54(m,1H),2.49–2.43(m,1H),2.42(s,3H),2.03–1.77(m,5H),1.62–1.55(m,1H). 13 C NMR(126MHz,CDCl 3 )δ209.8,205.2,177.6,156.9(C-F, 1 J C-F ＝253.3Hz),154.9(C-F, 1 J C-F ＝253.3Hz),144.3,135.3,132.0(C-F, 2 J C-F ＝37.8Hz),131.7(C-F, 2 J C-F ＝37.8Hz),129.5,128.3,123.9(C-F, 3 J C-F ＝8.8Hz),123.8(C-F, 3 J C-F ＝8.8Hz),108.5(C-F, 2 J C-F ＝20.2Hz),108.4(C-F, 2 J C-F ＝20.2Hz),85.6,58.0,58.0,44.2,40.1,31.2,23.3,21.9,21.6. 19 F NMR(376MHz,CDCl 3 )δ-115.9.IR(KBr,cm -1 ):2955,1772,1640,1489,1331,1154,1009,962,854,732,696,587.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 FN 2 O 4 SNa 451.1098；found 451.1098.
Example 9
Example 9 provides a 10-methyl-1-tosyl group-2,3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 i) prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-methyl-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 10-methyl-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 i). Yield 74% (47 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝8.0Hz,2H),7.27(d,J＝5.3Hz,3H),6.52(d,J＝9.3Hz,1H),6.30(s,1H),6.15(d,J＝9.3Hz,1H),3.36–3.23(m,2H),2.93–2.87(m,1H),2.57(ddd,J＝14.4,8.9,6.2Hz,1H),2.49–2.43(m,1H),2.41(s,3H),2.10(s,3H),1.97–1.87(m,4H),1.75(ddd,J＝14.1,8.9,5.9Hz,1H),1.66–1.58(m,1H). 13 C NMR(126MHz,CDCl 3 )δ210.7,205.9,179.8,147.0,144.0,135.5,132.1,129.4,128.4,126.9,117.9,85.0,58.5,58.0,44.2,40.3,31.5,23.5,22.8,22.1,21.6.IR(KBr,cm -1 ):2954,2861,1770,1585,1391,1237,1089,968,813,735,659.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 23 H 25 N 2 O 4 S 425.153；found 425.1528.
Example 10
Example 10 provides a 10-trifluoromethyl-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 j), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-trifluoromethyl-2-nitrobenzaldehyde, and the rest was unchanged to give 10-trifluoromethyl-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 j). Yield 68% (49 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:4). 1 H NMR(500MHz,CDCl 3 )δ7.68(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,3H),6.89(s,1H),6.68(d,J＝9.5Hz,1H),6.35(d,J＝9.6Hz,1H),3.39–3.26(m,2H),3.01–2.94(m,1H),2.64(ddd,J＝12.6,10.0,6.5Hz,1H),2.47–2.41(m,4H),2.42(s,3H),2.02–1.93(m,2H),1.93–1.85(m,2H),1.76(ddd,J＝13.9,9.9,6.0Hz,1H),1.64–1.55(m,1H). 13 C NMR(126MHz,CDCl 3 )δ208.8,204.6,177.2,144.4,136.54(q,J＝32.6Hz),135.2,134.7,129.5,128.3,121.15(q,J＝273.1Hz),120.59(q,J＝5.5Hz),118.2,118.2,84.9,58.9,58.2,44.3,40.1,30.1,23.2,21.7,21.6. 19 F NMR(471MHz,CDCl 3 )δ-68.4.IR(KBr,cm -1 ):2932,2867,1773,1634,1445,1280,1140,976,863,663,582.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 23 H 22 F 3 N 2 O 4 S 479.1247；found 479.1241./>
Example 11
Example 11 provides an 8-fluoro-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 k), prepared in particular as follows:
example 1 step was replaced by 6-fluoro-2-nitrobenzaldehydeThe 2-nitrobenzaldehyde in step (1) is left unchanged, and 8-fluoro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] is obtained]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 k). Yield 62% (4 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:1). 1 H NMR(500MHz,CDCl 3 δ7.71(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,3H),6.74(dt,J＝9.6,6.4Hz,1H),6.39(d,J＝9.7Hz,1H),5.81(dd,J＝10.1,6.7Hz,1H),3.33–3.22(m,2H),2.95(dd,J＝9.1,7.0Hz,1H),2.77–2.67(m,1H),2.50(dt,J＝12.5,5.5Hz,1H),2.41(s,3H),2.38–2.31(m,1H),1.99–1.84(m,4H),1.65–1.56(m,1H. 13 C NMR(126MHz,CDCl 3 )δ205.9,204.6,177.8,162.6(C-F, 1 J C-F ＝287.3Hz),160.4(C-F, 1 J C-F ＝287.3Hz),144.3,135.9(C-F, 2 J C-F ＝7.6Hz),135.8(C-F, 2 J C-F ＝7.6Hz),135.2,129.5,128.4,118.3(C-F, 3 J C-F ＝6.3Hz),118.2(C-F, 3 J C-F ＝6.3Hz),101.9(C-F, 2 J C-F ＝17.6Hz),101.8(C-F, 2 J C-F ＝17.6Hz),84.4,58.6,58.4,58.3,44.2,40.3,28.9,28.9,23.1,21.6,21.4. 19 F NMR(471MHz,CDCl 3 )δ-108.0.IR(KBr,cm -1 ):2925,2862,1774,1633,1450,1236,1154,854,727,659,580.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 22 H 22 FN 2 O 4 S 429.1279；found 429.1272.
Example 12
Example 12 provides a methyl 5, 13-dioxo-1-p-tolyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-10-carboxylate (4 l), prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with methyl 4-formate-2-nitrobenzaldehyde, and the remaining operations were unchanged to give methyl 5, 13-dioxo-1-p-tolyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-10-carboxylate (4 l). Yield 81% (57 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,2H),7.33(s,1H),7.28(s,2H),6.75(d,J＝9.5Hz,1H),6.57(d,J＝9.5Hz,1H),3.87(s,3H),3.37(t,J＝12.0Hz,1H),3.26(d,J＝10.7Hz,1H),2.99–2.91(m,1H),2.65–2.55(m,1H),2.41(s,4H),2.01–1.85(m,4H),1.77–1.54(m,3H). 13 C NMR(101MHz,CDCl 3 )δ209.6,204.9,179.0,165.1,144.2,136.7,135.4,132.7,129.5,128.3,125.9,121.1,85.2,58.9,58.2,52.7,44.2,40.2,30.5,23.3,21.9,21.6.IR(KBr,cm -1 ):2925,1770,1634,1399,1251,1086,972,852,728,617.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 23 H 24 N 2 O 5 SNa 491.1247；found 491.1246.
Example 13
Example 13 provides a 9, 10-dimethoxy-1-p-tolyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 m) prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4, 5-dimethoxy-2-nitrobenzaldehyde, and the remaining operation was unchanged to give 9, 10-dimethoxy-1-p-tolyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 m). Yield 68% (48 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:1). 1 H NMR(500MHz,CDCl 3 )δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),5.75(s,1H),5.55(s,1H),3.87(s,3H),3.69(s,3H),3.36–3.23(m,2H),2.90–2.83(m,1H),2.59–2.51(m,1H),2.47(dt,J＝12.9,6.4Hz,1H),2.41(s,3H),2.00–1.86(m,4H),1.81(ddd,J＝13.9,8.5,5.8Hz,1H),1.62(dt,J＝12.8,6.6Hz,1H). 13 C NMR(101MHz,CDCl 3 ) 13 C NMR(126MHz,CDCl 3 )δ211.3,206.4,178.4,160.8,148.6,144.0,129.4,128.5,101.5,94.0,85.5,57.9,57.4,56.5,55.7,44.2,40.4,34.1,23.6,22.3,21.6.IR(KBr,cm -1 ):2955,1769,1635,1452,1331,1003,962,820,657.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 24 H 27 N 2 O 6 S 471.1584；found 471.1584.
Example 14
Example 14 provides a 5, 13-dioxo-1-p-tolyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-methyl 9-carboxylate (4 n), the preparation method is specifically as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with methyl 5-formate-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 5, 13-dioxo-1-p-tolyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-methyl 9-carboxylate (4 n). Yield 71% (50 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:2). 1h NMR (500 mhz, cdcl 3) δ 7.67 (d, j=8.1 hz, 2H), 7.49 (s, 1H), 7.29-7.26 (m, 2H), 7.26-7.23 (m, 1H), 6.59 (d, j=10.0 hz, 1H), 3.80 (s, 3H), 3.28-3.26 (m, 1H), 2.94 (dd),J＝10.5,5.7Hz,1H),2.62(ddd,J＝12.9,9.5,6.2Hz,1H),2.45(dt,J＝12.6,5.9Hz,1H),2.40(s,3H),1.99(dd,J＝13.2,6.4Hz,1H),1.96–1.92(m,1H),1.92–1.88(m,2H),1.80–1.76(m,1H),1.75–1.71(m,1H),1.67–1.55(m,1H).13C NMR(126MHz,CDCl3)δ208.9,205.0,177.9,164.8,144.3,139.6,135.1,133.9,129.5,128.4,127.1,121.8,85.1,59.0,58.0,52.4,44.2,40.1,30.2,23.3,21.8,21.6.IR(KBr,cm-1):2955,2869,1773,1631,1441,1334,1272,1088,968,813.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C 24 H 25 N 2 O 6 S 469.1428；found 469.1431..
Example 15
Example 15 provides a 10-chloro-1-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 o) prepared in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-chloro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 10-chloro-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 o). Yield 77% (51 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:3). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),6.62(s,1H),6.57(d,J＝9.6Hz,1H),6.25(d,J＝9.6Hz,1H),3.38–3.22(m,2H),2.95–2.87(m,1H),2.65–2.53(m,1H),2.50–2.43(m,1H),2.42(s,3H),2.02–1.87(m,4H),1.84–1.75(m,1H),1.63–1.52(m,1H). 13 C NMR(101MHz,CDCl 3 )δ209.1,205.1,177.4,144.2,142.6,135.4,133.6,129.5,128.4,126.1,119.2,85.0,58.4,58.0,44.2,40.1,31.2,23.4,22.0,21.6.IR(KBr,cm -1 ):2925,2859,1764,1654,1397,1239,1094,788,675,522.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 ClN 2 O 4 SNa 467.0803；found 467.0802.
Example 16
Example 16 provides 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,14 a-methylnaphtho [1,2-b ]]Pyrido [3,2-g]Aza-compounds-5,15 (1H) -dione (4 q), prepared in particular as follows:
1-nitro-2-naphthaldehyde was used instead of 2-nitrobenzaldehyde in step (1) of example 1, the remainder of the procedure being unchanged to give 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,14 a-methylnaphtho [1,2-b ]]Pyrido [3,2-g]Aza-compounds-5,15 (1H) -dione (4 q). Yield 62% (43 mg), white solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:1). 1 H NMR(500MHz,CDCl 3 )δ7.92(d,J＝7.6Hz,1H),7.58(d,J＝7.9Hz,2H),7.53(t,J＝7.5Hz,1H),7.38(t,J＝7.5Hz,1H),7.27(d,J＝8.0Hz,1H),7.12(d,J＝8.0Hz,2H),6.64(d,J＝9.4Hz,1H),6.44(d,J＝9.4Hz,1H),3.38(d,J＝10.7Hz,1H),3.28(t,J＝11.4Hz,1H),2.98(dd,J＝12.3,3.9Hz,1H),2.63(ddd,J＝12.2,10.3,6.7Hz,1H),2.44–2.38(m,1H),2.36(s,3H),2.03–1.95(m,2H),1.89(td,J＝10.8,9.8,4.8Hz,1H),1.78–1.71(m,1H),1.70–1.62(m,2H). 13 C NMR(126MHz,CDCl 3 )δ205.5,177.9,143.9,135.2,132.7,129.2,128.7,128.4,128.2,127.8,127.0,126.4,125.7,85.7,58.3,57.4,44.5,40.4,30.4,23.3,21.5,21.4.IR(KBr,cm -1 ):3064,2940,2224,1956,1659,1604,1577,1415,1169,1076,737.5,672.4,571.9,546.
Example 17
Example 17 provides a 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methoxy groupBipyrido [2,3-b:2',3' -g]Aza-compounds-5,13 (1H) -dione (4 r), prepared in particular as follows:
3-nitropyridine aldehyde was used instead of 2-nitrobenzaldehyde in the step (1) of example 1, and the remaining operation was unchanged to obtain 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methoxydipyrido [2,3-b:2',3' -g]Aza-compounds-5,13 (1H) -dione (4 r). Yield 58% (36 mg), yellow liquid, R f =0.3 (ethyl acetate/petroleum ether=3:1). 1 H NMR(500MHz,CDCl 3 )δ8.21(s,1H),7.77(d,J＝8.0Hz,2H),7.30(s,2H),6.93(d,J＝9.7Hz,1H),6.52(dd,J＝9.6,2.5Hz,1H),3.47(t,J＝12.2Hz,1H),3.24(d,J＝11.4Hz,1H),3.03(dd,J＝10.2,5.9Hz,1H),2.77–2.67(m,1H),2.46–2.40(m,4H),2.21–2.10(m,2H),2.00–1.89(m,3H),1.71–1.66(m,1H). 13 C NMR(126MHz,CDCl 3 )δ208.5,204.8,178.2,155.6,144.3,135.6,129.5,128.3,128.2,127.7,83.9,74.3,58.4,43.9,39.7,30.0,23.2,21.6,21.5.
Example 18
Example 18 provides a 4 a-ethyl-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -diketone (4 s) prepared in particular as follows:
2a-s2 (630 mg,2 mmol) was taken, hydrochloric acid solution (concentration 36%,0.1 eq), acetone (10 ml) and water (10 ml) were added and stirred at room temperature for 12 hours, the reaction mixture was washed with sodium bicarbonate solution and water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo and purified by flash column chromatography (petroleum ether: ethyl acetate=4:1) to give 2s-s3 (458 mg, 95%).
A solution of 2s-s3 (457 mg,1 eq) in tetrahydrofuran (10 ml) was cooled to-20℃under nitrogen, ethyl magnesium bromide solution (1.1 eq,1 mol/L) was added dropwise over 15 minutes, after reaction at-20℃for 1 hour, the solution was slowly warmed to 0℃and then quenched with saturated ammonium chloride solution and extracted with ethyl acetate, the extract was dried over sodium sulfate and dried under reduced pressure and the crude product 2s-s4 was used in the next step without further purification.
2s-s4 was taken, 2-iodoxybenzoic acid (1.5 eq) and ethyl acetate (10 ml) were added, stirred at 80℃for 12 hours, after completion of the reaction, the solvent was filtered off, spun-dried, and purified by flash chromatography (petroleum ether: ethyl acetate=2:1) to give compound 2s-s5 (457 mg,1.7 mmol).
Under nitrogen atmosphere, cyclopropyltriphenylphosphine bromide (910 mg,1.4 eq) was taken, anhydrous tetrahydrofuran (10 ml) was added, cooled to 0℃and a potassium tert-butoxide solution (1.0M, 1.1 eq) was slowly dropped into the above mixture by syringe over 5 minutes, and stirred at room temperature, after 1 hour, a tetrahydrofuran solution (8 ml) of 2s-s5 (457 mg,1.7mmol,1 eq) was slowly added to the mixture by syringe over 5 minutes, and after 1 hour of reaction at room temperature, it was heated to 80 ℃. After completion of the reaction, it was filtered and concentrated in vacuo and finally purified by flash column chromatography (petroleum ether/ethyl acetate=5:1) to give compound 2s (400 mg, 81%).
2a in step (3) of example 1 was replaced with compound 2s, the rest of the procedure being unchanged, to give 4 a-ethyl-1-tosyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 s). Yield 34% (22 mg), white solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:3). 1 H NMR(500MHz,CDCl 3 )δ7.74(d,J＝8.3Hz,2H),7.28(d,J＝8.1Hz,2H),6.63(ddd,J＝9.7,5.6,1.1Hz,1H),6.45(d,J＝9.2Hz,1H),6.40(d,J＝9.7Hz,1H),6.21(dd,J＝9.2,5.6Hz,1H),3.51–3.44(m,1H),3.26(dd,J＝11.5,4.7Hz,1H),3.04–2.94(m,1H),2.42(s,3H),2.28–2.17(m,2H),2.09–2.00(m,2H),1.93–1.83(m,3H),1.81–1.73(m,1H),1.71–1.62(m,1H),0.61(t,J＝7.6Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ208.7,208.3,178.5,143.8,136.5,135.0,132.9,129.4,128.1,122.4,121.4,86.6,58.6,58.4,44.5,35.8,29.4,21.6,20.9,20.7,19.1,7.1.IR(KBr,cm -1 ):3060,2922,1763,1632,1456,1200,968,789.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 24 H 27 N 2 O 4 S 439.1686；found 439.1683.
Example 19
Example 19 provides a 5-hydroxy-1-tosyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ]]Pyrido [3,2-g]Aza-compounds-13-ketone (5 a) prepared by the following steps:
taking 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] obtained in example 1]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a,41mg,0.1 mmol), 1ml of methanol and sodium borohydride (3 eq) were added and stirred for 4 hours, and then purified and separated by column chromatography to give compound 5a. Yield 61% (25 mg). 1 H NMR(500MHz,CDCl3)δ7.88(d,J＝8.2Hz,2H),7.68(d,J＝8.1Hz,4H),7.31–7.23(m,8H),6.78–6.71(m,2H),6.57–6.48(m,4H),6.28–6.21(m,2H),6.11–5.97(m,2H),5.85(d,J＝9.3Hz,1H),5.64(d,J＝9.7Hz,1H),4.01(d,J＝9.3Hz,1H),3.89(d,J＝4.7Hz,2H),3.37–3.31(m,1H),3.29–3.18(m,4H),3.17–3.08(m,1H),2.41(d,J＝7.5Hz,9H),2.20–2.12(m,1H),2.12–1.99(m,10H),1.97–1.89(m,3H),1.85–1.63(m,15H),1.59–1.31(m,5H),1.25–1.18(m,3H). 13 CNMR(126MHz,CDCl3)δ209.2,209.1,182.7,143.9,143.7,136.9,136.0,135.5,134.5,129.3,129.3,128.5,128.3,127.2,124.7,123.7,121.6,121.4,121.2,88.6,88.0,74.0,73.5,72.7,58.7,52.9,51.5,44.3,44.2,43.8,31.8,29.7,28.4,27.3,24.2,24.13,24.06,24.0,22.5,21.6.IR(KBr,cm-1):2929,1768,1585,1490,1444,1330,1156,1087,904,744,692,582,540.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C22H25N2O4S 413.1530；found 413.1529.
Example 20
Example 20 provides 1-p-toluenesulfonyl-1, 2, 3a,5, 6-hexahydro-4H-6 a,11 a-methylbenzo [ b ]]Pyrrole [3,2-g]Aza-compounds-4, 12-dione (4 t) and 4-hydroxy-1-tosyl-2, 3a,4,5, 6-hexahydro-1H-6 a,11 a-methylbenzo [ b ]]Pyrrolo [3,2-g]Aza->-12-ketone (5 t), the preparation method is as follows:
replacement of 4-amino-1, 1-diethoxybutane in step (2) of example 1 with diethoxypropane-1-amine, the remainder of the procedure being unchanged, gives 1-p-toluenesulfonyl-1, 2, 3a,5, 6-hexahydro-4H-6 a,11 a-methylbenzo [ b ]]Pyrrole [3,2-g]Aza-compounds-4, 12-dione (4 t).
Further, the inventors added sodium borohydride (3 eq) to the reaction solution of the product 4t and continued stirring for 1 hour, and then reduced one of the carbonyl groups to a hydroxyl group, followed by column chromatography purification and separation to obtain the compound 5t. Yield 68% (40 mg), red liquid, R f =0.3 (ethyl acetate/petroleum ether=2:1). 1 H NMR(500MHz,CDCl 3 )δ7.80(d,J＝8.1Hz,2H),7.40(d,J＝8.8Hz,1H),7.24(d,J＝8.1Hz,2H),6.26–6.21(m,1H),6.20–6.14(m,1H),6.10(d,J＝17.3Hz,1H),5.85(s,1H),5.62(d,J＝10.3Hz,1H),5.44(s,1H),3.54–3.44(m,2H),3.11–3.03(m,1H),3.01(s,6H),2.40(s,3H),1.85–1.73(m,3H),1.65–1.57(m,1H). 13 C NMR(126MHz,CDCl 3 )δ198.6,192.8,160.3,157.1,143.4,136.3,136.1,129.3,129.1,128.6,126.0,110.8,107.0,92.4,78.3,51.8,44.5,40.3,23.7,23.4,21.6.IR(KBr,cm -1 ):2924,1617,1396,1238,1117,989,862,790,662,564.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 24 H 27 N 3 O 4 SNa 476.1614；found 476.1611.
Example 21
Example 21 provides a 3 a-methyl-1-p-tolyl-1, 2, 3a,5, 6-hexahydro-4H-6 a,11 a-methylbenzo [ b ]]Pyrrolo [3,2-g]Aza-compounds-4, 12-dione (4 u) and 4-hydroxy-3 a-methyl-1-p-tolyl-2, 3a,4,5, 6-hexahydro-1H-6 a,11 a-methylbenzo [ b ]]Pyrrolo [3,2-g]Aza->-12-ketone (5 u), the preparation method is as follows: />
N- (3, 3-diethoxypropyl) -4-toluenesulfonamide (2 u-s 1) and methyl magnesium bromide were used in place of 2a-s2 and ethyl magnesium bromide, respectively, in example 19, with the remainder of the procedure unchanged to give 3 a-methyl-1-p-tolyl-1, 2, 3a,5, 6-hexahydro-4H-6 a,11 a-methylbenzo [ b ]]Pyrrolo [3,2-g]Aza-compounds-4, 12-dione (4 u).
Further, the inventors added sodium borohydride (3 eq) to the reaction solution of the product 4u and continued stirring for 1 hour, and then reduced one of the carbonyl groups to a hydroxyl group, followed by column chromatography purification and separation to obtain the compound 5u. Yield 45% (27 mg), pink solid, m.p, R f =0.3 (ethyl acetate/petroleum ether=3:1). 1 H NMR(500MHz,CDCl 3 )δ7.73(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),6.73(dd,J＝9.6,5.6Hz,1H),6.50(d,J＝9.3Hz,1H),6.45(d,J＝9.7Hz,1H),6.29(dd,J＝9.3,5.7Hz,1H),3.78–3.69(m,2H),3.40(q,J＝9.4Hz,1H),2.93(q,J＝10.6Hz,1H),2.41(s,3H),2.12(s,1H),2.06–1.93(m,3H),1.90–1.84(m,1H),1.71(dd,J＝12.1,7.2Hz,1H),1.12(s,3H). 13 C NMR(126MHz,CDCl 3 )δ207.4,181.0,143.6,136.2,136.0,133.7,129.3,128.3,123.0,120.5,95.8,73.0,58.1,55.5,45.3,32.0,30.8,27.8,21.6,21.0.IR(KBr,cm -1 ):3469,2925,1771,1636,1399,1260,905,730,666.HRMS(ESI-TOF)/m/z:[M+H] + calcd for C 22 H 23 N 2 O 4 S 411.1373；found 411.1368.
Example 22
Example 22 provides a 1- (methylsulfonyl) -2,3, 4a,6, 7-hexahydro-7 a,12 a-methylaminobenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 v), prepared in particular as follows:
replacement of the tosyl chloride from step (2) of example 1 with methanesulfonyl chloride, the remainder of the procedure being unchanged, gives 1- (methanesulfonyl) -2,3, 4a,6, 7-hexahydro-7 a,12 a-methylaminobenzo [ b ]]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 v). Yield 78% (39 mg), white solid, rf=0.3 (ethyl acetate/petroleum ether=1:2). 1 H NMR(500MHz,CDCl3)δ6.68(dd,J＝9.8,5.6Hz,1H),6.45(t,J＝8.3Hz,2H),6.25(dd,J＝9.3,5.6Hz,1H),3.61(dt,J＝11.5,3.6Hz,1H),3.48(td,J＝12.2,2.9Hz,1H),2.96–2.90(m,1H),2.88(s,3H),2.57(ddd,J＝12.9,9.3,6.1Hz,1H),2.47–2.40(m,1H),2.11–2.03(m,1H),2.00–1.87(m,3H),1.86–1.70(m,2H). 13 C NMR(126MHz,CDCl3)δ210.3,205.6,179.7,136.0,132.7,122.7,121.2,85.0,59.2,57.9,44.6,40.1,30.8,23.8,22.2.IR(KBr,cm-1):3041,2938,1770,1578,1329,1199,1055,970,745,665,521.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C16H19N2O4S 335.1060；found 335.1059.
Example 23
Example 23 provides a 3' -acryloyl-1 ' -p-tolyl spiro [ indoline-2, 2' -piperidin ] -3-one (6 a), prepared as follows:
taking 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] obtained in example 1]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a,41mg,0.1 mmol), dichloromethane (1 mL), silica gel (10 mg) and triethylamine (3 eq) were added. Stirred at room temperature and monitored until the starting material was completely reacted. The silica gel was then filtered off, washed with water (1 mL), the organic phases were combined after extraction with dichloromethane, dried over sodium sulfate and purified by flash column chromatography (petroleum ether/ethyl acetate=1:1) to give 3' -acryloyl-1 ' -p-tolyl-spiro [ indoline-2, 2' -piperidine]-3-ketone (6 a). Yield 66% (24.6 mg). 1 H NMR(500MHz,CDCl 3 )δ7.73(d,J＝8.1Hz,2H),7.59(d,J＝7.7Hz,1H),7.44(t,J＝7.6Hz,1H),7.27(d,J＝8.1Hz,2H),6.88(t,J＝7.4Hz,1H),6.81(d,J＝8.2Hz,1H),6.15–6.02(m,2H),5.64(d,J＝9.9Hz,1H),5.49(s,1H),3.53–3.47(m,2H),3.08(td,J＝12.3,2.5Hz,1H),2.42(s,3H),1.89–1.77(m,3H),1.72–1.67(m,1H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ198.3,196.6,158.2,143.8,137.5,135.8,135.7,130.2,129.3,128.5,124.8,121.9,120.8,113.4,51.9,44.4,23.8,23.3,21.6.IR(KBr,cm-1):2924,1714,1617,1416,1315,1197,988,863,727,665,570.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C 22 H 22 N 2 O 4 SNa 433.1192；found 433.1191.
Example 24
Example 24 provides a 3' -acryloyl-6- (dimethylamino) -1' -p-tolyl spiro [ indoline-2, 2' -piperidin ] -3-one (6 p), prepared as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4- (dimethylamino) -2-nitrobenzaldehyde, and the remaining operations were unchanged to give 3' -acryloyl-6- (dimethylamino) -1' -p-tolyl spiro [ indoline-2, 2' -piperidine]-3-ketone (6 p). Yield 58% (40 mg), pink solid, m.p.R f =0.3 (ethyl acetate/petroleum ether=1:3). 1 H NMR(500MHz,CDCl 3 )δ7.70(d,J＝7.8Hz,2H),7.30(d,J＝7.8Hz,2H),6.62(s,1H),6.57(d,J＝9.6Hz,1H),6.25(d,J＝9.6Hz,1H),3.38–3.22(m,2H),2.95–2.87(m,1H),2.65–2.53(m,1H),2.50–2.43(m,1H),2.42(s,3H),2.02–1.87(m,4H),1.84–1.75(m,1H),1.63–1.52(m,1H). 13 C NMR(101MHz,CDCl 3 )δ209.1,205.1,177.4,144.2,142.6,135.4,133.6,129.5,128.4,126.1,119.2,85.0,58.4,58.0,44.2,40.1,31.2,23.4,22.0,21.6.IR(KBr,cm -1 ):2925,2859,1764,1654,1397,1239,1094,788,675,522.HRMS(ESI-TOF)/m/z:[M+Na] + calcd for C 22 H 21 ClN 2 O 4 SNa 467.0803；found 467.0802.
Example 25
Example 25 provides a 1-p-toluenesulfonyl-1, 2,3, 4a,5,7a, 10-octahydro-11H, 12H-5,11 a-ethylpyridine [2',3': the preparation method of the 3, 4-isoxazole [2,3-a ] indol-12-one (7 a) comprises the following steps:
taking 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] obtained in example 1]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a,41mg,0.1 mmol), under ice bath conditions, sodium borohydride (3.0 eq) and cerium trichloride hexahydrate were added(6.0 eq) was added to the mixture of tetrahydrofuran and methanol (1:1), stirred at room temperature for four hours, then quenched with water, extracted with ethyl acetate, and concentrated by rotary evaporation. By petroleum ether: ethyl acetate was 2:1 to give product 7a (39 mmg, 95%).
1 H NMR(500MHz,CDCl 3 )δ7.80(d,J＝8.2Hz,2H),7.20(d,J＝8.1Hz,2H),5.85–5.79(m,1H),5.55(dd,J＝9.7,2.2Hz,1H),3.92(d,J＝9.3Hz,1H),3.25(dt,J＝11.8,3.3Hz,1H),2.85(td,J＝12.4,3.2Hz,1H),2.34(s,3H),2.32–2.23(m,1H),2.13(dt,J＝13.6,9.0Hz,1H),2.09–2.00(m,1H),1.88(dd,J＝12.7,8.4Hz,1H),1.85–1.78(m,2H),1.74–1.69(m,1H),1.68–1.59(m,2H),1.50–1.40(m,1H),1.40–1.34(m,1H),1.33–1.25(m,1H),1.13(dd,J＝13.2,4.0Hz,1H). 13 C NMR(126MHz,CDCl 3 )δ207.0,142.5,135.6,128.1(2C),127.5(2C),127.1,124.2,88.2,72.7,50.8,43.2,42.4,27.6,27.1,23.9,23.0,22.9,21.2,20.5.IR(KBr,cm-1):3305,3031,2935,1766,1588,1454,1265,1091,962,879,746,622.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C 22 H 27 N 2 O 4 S 415.1686；found 415.1683.
Example 26
Example 26 provides a 1-p-toluenesulfonyl decahydro-9 h,12h-5,11 a-ethylpyridine [2',3': the preparation method of the 3, 4-isoxazole [2,3-a ] indol-12-one (7 b) comprises the following steps:
taking 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] obtained in example 1]Pyrido [3,2-g]Aza-compounds-5,13 (1H) -dione (4 a,41mg,0.1 mmol), sodium borohydride (3.0 eq) and nickel dichloride (6.0 eq) were added, a mixed solvent of tetrahydrofuran and methanol (1:1) was added, stirred at room temperature for four hours, then quenched with water, extracted with ethyl acetate, and concentrated by rotary evaporation. By petroleum ether: ethyl acetate was 2:1 developing agentColumn chromatography gave product 7b (28 mg, 68%).
1 H NMR(500MHz,CDCl 3 )δ7.94(d,J＝8.2Hz,2H),7.28(d,J＝8.2Hz,2H),3.92(d,J＝9.3Hz,1H),3.30–3.24(m,1H),2.89(td,J＝12.5,2.9Hz,1H),2.41(s,3H),2.22–2.14(m,1H),2.09(td,J＝13.9,3.8Hz,1H),1.93(d,J＝13.8Hz,1H),1.87–1.68(m,5H),1.67–1.60(m,5H),1.59–1.51(m,1H),1.50–1.40(m,2H),1.34–1.26(m,1H),1.11(dd,J＝13.2,3.8Hz,1H). 13 CNMR(126MHz,CDCl 3 )δ210.8,143.5,136.7,129.2(2C),128.6(2C),89.3,73.3,48.6,44.2,42.9,33.1,30.4,28.7,24.0,23.9,22.9,21.8,21.8,21.6.IR(KBr,cm-1):3770,3077,1849,1718,1540,1476,1269,1159,961,755,661.HRMS(ESI-TOF)/m/z:[M+H]+calcd for C 22 H 29 N 2 O 4 S 417.1843；found 417.1839.
Example 27
Example 27 provides a process for the preparation of 5, 13-dioxo-1-p-tolyl-1, 2,3, 4a,5,6, 7-octahydro-7 a,12 a-methylbenzo [ b ] pyridinyl [3,2-g ] azooxazine 12 oxide (8 a), the process comprising in particular:
taking 1-p-toluenesulfonyl-2, 3, 4a,6, 7-hexahydro-7 a,12 a-methylbenzo [ b ] obtained in example 1]Pyrido [3,2-g]Aza-compounds5,13 (1H) -dione (4 a,41mg,0.1 mmol) was added to dichloromethane (2 ml) and m-chloroperoxybenzoic acid (1.5 eq) was slowly added. The reaction was stirred at room temperature and monitored by TLC. After completion of the reaction, the reaction mixture was washed with water, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, etOAc/petroleum ether=1:1) to give compound 8a (26 mg, 61%). 1 H NMR(500MHz,CDCl 3 )δ7.69(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,2H),6.77(d,J＝9.7Hz,1H),6.49–6.40(m,2H),6.24(dd,J＝9.2,5.6Hz,1H),3.82(t,J＝10.3Hz,1H),3.36–3.29(m,1H),2.95(dd,J＝12.9,3.7Hz,1H),2.68(ddd,J＝12.4,10.0,7.4Hz,1H),2.55(dt,J＝12.5,5.6Hz,1H),2.4(s,3H),2.38–2.28(m,1H),2.09–1.99(m,2H),1.99–1.93(m,1H),1.84–1.77(m,1H),1.55(dtt,J＝17.5,9.1,4.4Hz,1H). 13 CNMR(126MHz,CDCl 3 )δ204.0,202.4,144.7,144.0,134.0,131.1,129.5(2C),128.9,128.5(2C),123.4,113.7,81.9,57.0,55.6,45.2,40.6,33.5,22.6,21.6,20.0.IR(KBr,cm-1):3695,2957,1718,1542,1339,1200,1088,912,755,660,552.HRMS(ESI-TOF)/m/z:[M+Na]+calcd for C 22 H 22 N 2 NaO 5 S 449.1142；found 449.1139.
Biological Activity test of Compounds
In vitro test for inhibitory Activity of Compounds against Influenza A Virus (IAV)
The test principle is as follows: the 293T-GLUC cells are used as virus hosts, and the activity of the sample for inhibiting the luciferase of the report gene carried by the virus is measured.
Test materials and methods:
1. virus strain: obtaining IAV (influenza A virus, WSN Strain) titres 10 by infection of MDCK cells 7 Preserving at-80 ℃.
2. Sample treatment: samples were dissolved in DMSO to give the appropriate initial concentration and single concentration points were taken for testing.
3. The testing method comprises the following steps: 293T-GLUC cells are inoculated into a 96-well culture plate and placed with 5 percent CO 2 The cells were incubated at 37℃for 24 hours. The drug was pre-added for 2 hours and then virus provisos were diluted to moi=0.15 to inoculate the virus. After 24 hours of incubation, luciferase activity in the infected cells was measured, and the inhibition ratio of each sample was calculated.
Test results:
inhibition of IAV by the compounds of Table 1
From the table 1, the nitrogen-containing spiro compounds have strong inhibitory activity on Influenza A Virus (IAV), and especially the inhibition rate of the compounds 4a, 4g, 4h, 4j and 6a on Influenza A Virus (IAV) at the concentration of 10 μm is 2-3.6 times that of the positive control drug ribavirin at the same concentration, which indicates that the nitrogen-containing spiro compounds have stronger inhibitory activity.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims (3)

1. An application of a nitrogenous spiro compound or pharmaceutically acceptable salt thereof in preparing an anti-influenza a virus medicament, which is characterized in that the nitrogenous spiro compound has the following structural formula:
。
2. use of a pharmaceutical composition for the preparation of an anti-influenza a virus medicament, said pharmaceutical composition comprising a therapeutically effective amount of a nitrogen-containing spiro compound having the structural formula:
。
3. a nitrogen-containing spiro compound or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing spiro compound has the structural formula:
。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017075A1 (en) * 1993-01-20 1994-08-04 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Diazepin derivatives and antiviral compositions
WO2013137456A1 (en) * 2012-03-15 2013-09-19 国立大学法人京都大学 Antivirus composition
CN111433201A (en) * 2017-12-21 2020-07-17 江苏恒瑞医药股份有限公司 Benzazepine derivatives, process for their preparation and their use in medicine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994017075A1 (en) * 1993-01-20 1994-08-04 A. Menarini Industrie Farmaceutiche Riunite S.R.L. Diazepin derivatives and antiviral compositions
WO2013137456A1 (en) * 2012-03-15 2013-09-19 国立大学法人京都大学 Antivirus composition
CN111433201A (en) * 2017-12-21 2020-07-17 江苏恒瑞医药股份有限公司 Benzazepine derivatives, process for their preparation and their use in medicine

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