CN112209947A - Chiral indoxazinone compound and synthesis method thereof - Google Patents
Chiral indoxazinone compound and synthesis method thereof Download PDFInfo
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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
- C07D498/02—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 two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0231—Halogen-containing compounds
- B01J31/0232—Halogen-containing compounds also containing elements or functional groups covered by B01J31/0201 - B01J31/0228
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a chiral indoxazinone compound and a synthesis method thereof, wherein the compound is shown as a formula (1); the synthesis method comprises the steps of taking 2-indole methanol and nitrone as reaction raw materials, taking methylbenzene as a reaction solvent, adding anhydrous sodium sulfate, stirring and reacting under catalysis of chiral phosphoric acid and hexafluoroisopropanol, tracking and reacting by TLC (thin layer chromatography) until the reaction is complete, and filtering, concentrating and purifying to obtain the compound shown in the formula 1; wherein the reaction molar ratio of the 2-indolylmethanol to the nitrone is 1: 1-2: 1; the reaction temperature is 20-30 ℃; the chiral indoxazinone compound has certain cytotoxic activityHas application value in the research and development of novel anti-tumor drugs. The synthesis method has extremely high enantioselectivity, mild reaction process, suitability for industrial large-scale production and widening the application range of the method; adopts more kinds of substrates as reactants to obtain products with structural diversity and complexity and high yield.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a chiral indoxazinone compound and a synthesis method thereof.
Background
Chiral indolo rings have a variety of biological activities, for example: the document ACS med.chem.lett.,2014,5,1334 reports that such compounds may act as S1P1 receptor antagonists; the document org.lett.,2009,11,329 reports that such compounds can act as antimalarial compounds; the document Drug meta. dispos.2012,40,2354 reports that such compounds can act as androgen receptor modulators.
The chiral indole-fused ring compound has wide application prospect in the field of life science, and simultaneously, as the chiral indole-fused ring compound plays a role in biological activity in drug molecules and is often one enantiomer in a racemate, people urgently need to design a novel chiral indole-fused ring compound and develop a method for efficiently synthesizing the chiral indole-fused ring compound. At present, chiral indole-fused ring compounds in the prior art are insensitive to PC-3 human prostate cancer cells and have weak cytotoxic activity; and when the chiral indole ring compounds are synthesized, the reaction conditions are violent, misoperation is easy to occur, even safety accidents are caused, and high cost, low yield and low enantioselectivity are caused indirectly.
Disclosure of Invention
The invention aims to provide a chiral indoxazinone compound, which has certain cytotoxic activity on PC-3 human prostate cancer cells. The invention also aims to provide a synthesis method of the chiral indoxazinone compound, which has the advantages of mild reaction conditions, low cost, high yield and high enantioselectivity.
In order to achieve the purpose, the invention adopts the technical scheme that: a chiral indoxazinone compound, its chemical structural formula (formula 1) is as follows:
wherein R is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r1One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r2One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r3One selected from hydrogen, C1-C3 alkyl, phenyl and substituted phenyl; r4One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
The invention also provides a synthesis method of the chiral indoxazinone compound, which comprises the following specific steps:
taking 2-indolylmethanol and nitrone as reaction raw materials, taking methylbenzene as a reaction solvent, adding anhydrous sodium sulfate, stirring and reacting under the catalysis of chiral phosphoric acid and hexafluoroisopropanol, tracking and reacting by TLC (thin layer chromatography) until the reaction is complete, and filtering, concentrating and purifying to obtain a compound shown in a formula 1; wherein the reaction molar ratio of the 2-indolylmethanol to the nitrone is 1: 1-2: 1; the reaction temperature is 20-30 ℃;
the structural formula of the 2-indole methanol is shown as
Wherein R is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r1One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r2One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl;
the structural formula of the nitrone is shown in the specification
In the formula, R3One selected from hydrogen, C1-C3 alkyl, phenyl and substituted phenyl; r4One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
The reaction route is as follows:
preferably, the chiral phosphoric acid catalyst is selected from one or two of a binaphthyl skeleton derivative, an octahydrobinaphthyl skeleton derivative and a spiro skeleton derivative; the structural formula of the binaphthyl skeleton derivative is shown in the specification
Wherein G is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is shown in the specification
Wherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl; the structural formula of the spiro skeleton derivative is shown in the specification
Wherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl.
Preferably, the chiral phosphoric acid catalyst has a structural formula
Wherein G is selected from 9-phenanthryl.
Preferably, the reaction molar ratio of the 2-indolylmethanol to the nitrone is 1.2: 1.
Preferably, the reaction temperature is 30 ℃ and the reaction temperature is 30 ℃.
Preferably, the purification is performed by silica gel column chromatography, and the eluent adopts a mixed solution of petroleum ether and dichloromethane, and the volume ratio of the petroleum ether to the dichloromethane is 1: 1.
The chiral indoxazinone compound disclosed by the invention is shown to have certain cytotoxic activity on PC-3 human prostate cancer cells through biological activity tests, and the chiral indoxazinone compound synthesized by the invention has application value in research and development of novel antitumor drugs. According to the method for synthesizing the chiral indoxazinone compound, chiral phosphoric acid and hexafluoroisopropanol are used as catalysts in the process of synthesizing the chiral indoxazinone compound, so that extremely high enantioselectivity is obtained; the synthesis method has the advantages of more conventional reaction conditions, mild reaction process, suitability for industrial large-scale production and widening of the application range of the method; adopts more kinds of substrates as reactants to obtain products with structural diversity and complexity and high yield.
Detailed Description
The present invention will be described in further detail with reference to examples.
In the examples described below, unless otherwise indicated, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.
The 2-indolemethanol is prepared using a method reported in document j.org.chem.2017,82,2462; the nitrone is obtained by adopting a document org.lett.2006,8,3351, a chiral phosphoric acid catalyst and other reagents in a commercially available mode.
The synthetic route of the chiral indoxazinone compound 3 is as follows:
in the two reactions, the chiral phosphoric acid of the catalyst has the following structural formula:
example 1
Adding 0.12 mmol of 2-indolylmethanol a compound and 0.1 mmol of nitrone a compound as reactants, 100 mg of anhydrous sodium sulfate as an additive, 0.01 mmol of chiral phosphoric acid and 0.06 mmol of hexafluoroisopropanol as catalysts into 1 ml of toluene, reacting at 30 ℃ for 24 hours, tracking the reaction by TLC until the reaction is finished, filtering to remove the anhydrous sodium sulfate, washing a filter cake by ethyl acetate, concentrating the obtained filtrate, and separating by silica gel column chromatography (eluent is a mixed solution of petroleum ether and dichloromethane in a volume ratio of 1: 1) to obtain the chiral indolyxazinone aa 3 as a white solid.
The structural characterization data for product 3aa in example 1 is as follows:
m.p.115–117℃；[α]d20 ═ 126.3(c ═ 0.79, acetone); 1H NMR (400MHz, CDCl 3). delta.7.81 (s,1H), 7.79-7.72 (m,2H), 7.67-7.40 (m,13H), 7.36-7.30 (m,1H), 7.27-7.23 (m,1H), 7.13-6.96 (m,2H),5.34(s,1H),2.84(s, 3H); 13C NMR (100MHz, CDCl3) delta 144.6,143.4,139.9,137.1,136.7,129.9,128.5,128.1,125.7,122.0,120.1,119.6,113.1,111.4,85.2,70.3, 43.3; IR (KBr) 3057,3026,2960,2845,1749,1540,1507,1301,947,641 cm-1; ESI FTMS exact mass calcd for (C29H24N2O-H) -requires m/z 415.1816, found m/z 415.1810; enantiomer ratio 95%, defined by HPLC (Daicel Chiralpak OD-H, n-hexane/isopropanol 99/1, flow rate 1.0mL/min, T30 ℃,254nm): TR＝10.963(major),tR＝14.253(minor).
Examples 2 to 15
The reaction synthetic route is shown as follows:
the reaction raw materials and yields are shown in table 1:
TABLE 1 reaction starting materials and yields for examples 2-15
Examples 16 to 32
The reaction synthetic route is shown as follows:
the reaction raw materials and yields are shown in table 2:
TABLE 2 reaction starting materials and yields for examples 16-32
As shown in tables 1 and 2, the method of the present invention can not only realize the synthesis of chiral indoxazinone compounds in one step, obtain high enantioselectivity and excellent yield, and has the advantages of high atom economy, environmental friendliness, wide application range, easily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-treatment, and diversified product structures, thereby having great implementation value and potential social and economic benefits.
The chiral indoxazinone compounds of the present invention, the compounds synthesized in example 1, example 2, example 4, example 5, example 11, example 13, example 21 and example 27 were tested for cytotoxic activity against PC-3 human prostate cancer cells by CCK8 method, and the results are shown in table 3. The result shows that the compound synthesized by the invention has certain cytotoxic activity on PC-3 human prostate cancer cells. Among them, the most active compound 3ak showed the most potent inhibitory effect (IC) on PC-3 human prostate cancer cells50＝40.08μg/mL)。
TABLE 3 cytotoxic Activity of the Compounds of the present invention
Claims (7)
1. A chiral indoxazinone compound, characterized in that its chemical structural formula (formula 1) is as follows:
wherein R is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogenSeed growing; r1One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r2One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r3One selected from hydrogen, C1-C3 alkyl, phenyl and substituted phenyl; r4One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
2. A method for synthesizing a chiral indoxazinone compound is characterized by comprising the following specific steps:
taking 2-indolylmethanol and nitrone as reaction raw materials, taking methylbenzene as a reaction solvent, adding anhydrous sodium sulfate, stirring and reacting under the catalysis of chiral phosphoric acid and hexafluoroisopropanol, tracking and reacting by TLC (thin layer chromatography) until the reaction is complete, and filtering, concentrating and purifying to obtain a compound shown in a formula 1; wherein the reaction molar ratio of the 2-indolylmethanol to the nitrone is 1: 1-2: 1; the reaction temperature is 20-30 ℃;
the structural formula of the 2-indole methanol is shown as
Wherein R is selected from one of hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen; r1One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; r2One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl;
the structural formula of the nitrone is shown in the specification
In the formula, R3One selected from hydrogen, C1-C3 alkyl, phenyl and substituted phenyl; r4One selected from hydrogen, C1-C3 alkyl, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
3. The method for synthesizing a chiral indoxazinone compound according to claim 2, characterized in that the chiral phosphoric acid is catalyticThe agent is one or two of binaphthyl skeleton derivatives, octahydrobinaphthyl skeleton derivatives and spiro skeleton derivatives; the structural formula of the binaphthyl skeleton derivative is shown in the specification
Wherein G is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl; the structural formula of the octahydrobinaphthyl skeleton derivative is shown in the specification
Wherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl; the structural formula of the spiro skeleton derivative is shown in the specification
Wherein G' is one of 9-anthryl, 9-phenanthryl, 2,4, 6-triisopropylphenyl, 2-naphthyl or 1-naphthyl.
4. The method for synthesizing chiral indoxazinone compound according to claim 2, characterized in that the chiral phosphoric acid catalyst has a structural formula
Wherein G is selected from 9-phenanthryl.
5. The method for synthesizing a chiral indoxazinone compound according to claim 2, characterized in that the reaction molar ratio of the 2-indolylmethanol to the nitrone is 1.2: 1.
6. The method for synthesizing a chiral indoxazinone compound according to claim 2, characterized in that the reaction temperature is 30 ℃ and the reaction temperature is 30 ℃.
7. The method for synthesizing the chiral indoxazinone compound according to claim 2, characterized in that the purification is silica gel column chromatography, and the eluent adopts a mixed solution of petroleum ether and dichloromethane, and the volume ratio of petroleum ether to dichloromethane is 1: 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113735867A (en) * | 2021-10-18 | 2021-12-03 | 江苏师范大学 | Chiral indolo-oxa-heptatomic ring compound and synthesis method thereof |
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| CN113735867A (en) * | 2021-10-18 | 2021-12-03 | 江苏师范大学 | Chiral indolo-oxa-heptatomic ring compound and synthesis method thereof |
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