CN108676063A - A kind of double acyloxy bisamide class pharmaceutical intermediates of hydroxyl and preparation method thereof - Google Patents
A kind of double acyloxy bisamide class pharmaceutical intermediates of hydroxyl and preparation method thereof Download PDFInfo
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- CN108676063A CN108676063A CN201810507753.XA CN201810507753A CN108676063A CN 108676063 A CN108676063 A CN 108676063A CN 201810507753 A CN201810507753 A CN 201810507753A CN 108676063 A CN108676063 A CN 108676063A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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Abstract
The present invention provides a kind of double acyloxy bisamide class pharmaceutical intermediates of hydroxyl.General formula is following (I)(I), R in formula1For methyl, ethyl, isopropyl, iso-octyl, n-heptyl, R2For chlorine, bromine, methyl, iso-octyl, n-heptyl, R3For hydrogen or chlorine, R4For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl, R5For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl.Preparation method is to react adjacent acetoxybenzoic at 20 40 DEG C with keto-aldehyde, amine and isonitrile, reaction dissolvent is methanol, after the completion of reaction, reducing agent sodium borohydride is added, continue stirring 15 hours at 20 40 DEG C, after the completion of reaction, solvent methanol is sloughed under reduced pressure, and residue column chromatography obtains the target compound of logical formula (I).Such pharmaceutical intermediate can be further used for synthetic antimicrobial bioactive peptide drug.
Description
Technical field
The present invention relates to double acyloxy bisamide class pharmaceutical intermediates of a kind of hydroxyl and preparation method thereof, belong to organic
Synthesis technical field.
Background technology
Multi-component reaction is since using " one pot " reaction of multiple components, reaction efficiency is high, and Atom economy is good, substrate simultaneously
It is applied widely, it is increasingly taken seriously in recent years.Wherein Ugi reactions are the multi-component reactions (IMCR) based on isonitrile.Ugi
Reaction is that one pot of four component participated in by aldehyde ketone, carboxylic acid, amine and isonitrile prepares ɑ-amide groups amide reaction.To based on the more of isonitrile
Modification reaction after the functional group in a certain component in component reaction (IMCR) protects or reserves and then participate in again in advance, is close
One of the hot spot that multi-component reaction is studied over year.In this patent, we utilize the multi-component reaction based on isonitrile
(IMCR) i.e. double acyloxy bisamide classes that Ugi reacts and modification reaction is prepared for the hydroxyl of a kind of structure novel thereafter derive
Object.Such pharmaceutical intermediate can be used for the synthesis of antibacterial activity peptides drug.
Invention content
It is a primary object of the present invention to explore in the double acyloxy bisamide class drugs for providing pharmaceutical intermediate hydroxyl
Mesosome.
The present invention proposes double acyloxy bisamide class pharmaceutical intermediates (I) of hydroxyl：
Wherein, R in formula1For methyl, ethyl, isopropyl, iso-octyl, n-heptyl, R2For chlorine, bromine, methyl, iso-octyl, positive heptan
Base, R3For hydrogen or chlorine, R4For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl, R5
For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl.
Further preferably include the intermediate of following structural formula：
The method of double acyloxy bisamide class pharmaceutical intermediates of the synthesis hydroxyl, the method includes following conjunctions
At path：
The method specifically includes following steps：
By adjacent acetoxybenzoic and keto-aldehyde, amine and isonitrile in molar ratio 1：0.5-2：0.5-2：0.5-2 sequentially adds dress
Have in the flask of methanol, reacted at 30 DEG C, after reacting 24 hours, sodium borohydride is added, mole dosage is adjacent acyloxy benzene first
0.6-2 times of acid continues stirring 1-5 hours at 30 DEG C, and after the completion of reaction, reaction solution sloughs solvent methanol under reduced pressure, residual
Object column chromatography is stayed to obtain the target compound of logical formula (I).
The keto-aldehyde is the acetophenone aldehyde derivatives of contraposition substitution, including parachloroacetophenone aldehyde, parabromoacetophenone aldehyde, right
Methyl acetophenone aldehyde, to iso-octyl acetophenone aldehyde or to n-heptylphenyl ethyl ketone aldehyde.
The isonitrile is the isonitrile containing ester group, including methyl acetate isonitrile, ethyl acetate isonitrile or isohexyl acetate be different
Nitrile.
The carboxylic acid is substitution septichen, including adjacent acetoxybenzoic or 4- chlorine neighbour's acetoxybenzoics.
The amine is various aliphatic amines or aromatic amine, including methylamine, ethamine, isopropylamine, n-hexylamine, aniline, right
Any one in chloroaniline.
The molar ratio of the adjacent acetoxybenzoic and keto-aldehyde, amine and isonitrile is 1：0.5-2：0.5-2：0.5-2.
The present invention has the beneficial effect that：
1. the present invention reports double acyloxy bisamide class pharmaceutical intermediates of a kind of novel hydroxyl；
2. the present invention provides the preparation method of double acyloxy bisamide class pharmaceutical intermediates of a kind of novel hydroxyl,
Ugi specially occurs with adjacent acetoxybenzoic derivative and aryl keto-aldehyde, amine and isonitrile containing ester group to react, generation
Containing there are one hydroxyl, two acyloxy, two acyls while product generates a kind of novel under the action of reducing agent sodium borohydride
The new method of the double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl of amido.
Specific implementation mode
The preparation of compound and application effect in (I) formula are further illustrated the present invention with reference to embodiment.
Instrument and reagent：
Fusing point is measured with X4 types melting point apparatus (production of Beijing third optical instrument factory), and thermometer is not calibrated；1H NMR and13600 type 600MHz cores of C NMR 400 type 400MHz Nuclear Magnetic Resonance of Varian Mercury or Varian Mercury
Magnetic resonance device measures, deuterochloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) it is solvent, TMS is internal standard；MS is used
FinniganTrace mass spectrographs measure；Elemental analysis is measured using Vario EL III elemental analysers；Agents useful for same is domestic
(or import) chemistry is pure or analysis is pure.Solvent toluene is to be evaporated dry mistake through overweight, and triethylamine is also processed by steaming again.
Embodiment 1
Preparation
Acetoxybenzoic acid (1mmol), parachloroacetophenone aldehyde (1mmol), cyclopropylamine are added into 50mL flasks
(1mmol) and methyl acetate base isonitrile (1.1mmol), reacts at 30 DEG C, and reaction dissolvent is methanol (10mL), is reacted 24 hours
Afterwards, sodium borohydride (1.2mmol) is added, continues to stir 1 hour under reacting at 30 DEG C, after the completion of reaction, reaction solution is under reduced pressure
Solvent methanol is sloughed, residue column chromatography obtains 0.357g white solid 6a, yield 73%.
HRMS Calculatedfor[C24H25ClN2O7+H]+:489.1429,Found:489.1773.
Embodiment 2
Acetoxybenzoic acid (10mmol), parachloroacetophenone aldehyde (10mmol), cyclopropyl are added into 500mL flasks
Amine (10mmol) and methyl acetate base isonitrile (11mmol), react at 30 DEG C, and reaction dissolvent is methanol (100mL), reaction 24
After hour, sodium borohydride (12mmol) is added, continues to stir 1 hour under reacting at 30 DEG C, after the completion of reaction, reaction solution is depressurizing
Under slough solvent methanol, residue column chromatography obtains 3.42g white solid 6a, yield 70%.
Embodiment 3
Acetoxybenzoic acid (0.1mmol), parachloroacetophenone aldehyde (0.1mmol), cyclopropyl are added into 5mL flasks
Amine (0.1mmol) and methyl acetate base isonitrile (0.11mmol), react at 30 DEG C, and reaction dissolvent is methanol (1mL), reaction 24
After hour, sodium borohydride (0.12mmol) is added, continues to stir 1 hour under reacting at 30 DEG C, after the completion of reaction, reaction solution is subtracting
Solvent methanol is sloughed in pressure, and residue column chromatography obtains 0.036g white solid 6a, yield 74%.
Embodiment 4
Acetoxybenzoic acid (1mmol), parachloroacetophenone aldehyde (1mmol), cyclopropylamine are added into 50mL flasks
(1mmol) and methyl acetate base isonitrile (1.1mmol), reacts at 30 DEG C, and reaction dissolvent is dichloromethane (10mL), reaction 24
After hour, sodium borohydride (1.2mmol) is added, continues to stir 1 hour under reacting at 30 DEG C, after the completion of reaction, reaction solution is subtracting
Methylene chloride is sloughed in pressure, and residue column chromatography is unable to get 6a.
Embodiment 5
Acetoxybenzoic acid (1mmol), parachloroacetophenone aldehyde (1mmol), cyclopropylamine are added into 50mL flasks
(1mmol) and methyl acetate base isonitrile (1.1mmol), reacts at 30 DEG C, and reaction dissolvent is methanol (10mL), is reacted 24 hours
Afterwards, reaction solution sloughs solvent methanol under reduced pressure, and residue column chromatography is unable to get 6a.
Embodiment 6
Preparation
The chloro- o- 2,4 dichloro benzene formyloxy benzoic acid (1mmol) of 4-, parabromoacetophenone aldehyde are added into 50mL flasks
(1mmol), benzylamine (1mmol) and 2-ethyl hexyl ethanoate base isonitrile (1.1mmol), react, reaction dissolvent is methanol at 30 DEG C
(10mL) after reacting 24 hours, is added sodium borohydride (1.2mmol), continues to stir 1 hour under reacting at 30 DEG C, reaction completion
Afterwards, reaction solution sloughs solvent methanol under reduced pressure, and residue column chromatography obtains 0.508g white solid 6b, yield 60%.
HRMS Calculatedfor[C40H40BrCl3N2O7+H]+:845.1163,Found:845.1530.
Embodiment 7
Preparation
It is added into 50mL flasks to chlorine acetoxybenzoic acid (1mmol), melilotal aldehyde (1mmol), just
Hexylamine (1mmol) and acetic acid n-heptyl isonitrile (1.1mmol), react at 30 DEG C, and reaction dissolvent is methanol (10mL), reaction 24
After hour, sodium borohydride (1.2mmol) is added, continues to stir 1 hour under reacting at 30 DEG C, after the completion of reaction, reaction solution is subtracting
Solvent methanol is sloughed in pressure, and residue column chromatography obtains 0.423g faint yellow solid 6c, yield 67%.
HRMS Calculatedfor[C34H47ClN2O7+H]+:631.3150,Found:631.3782.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as the limitation for the present invention, this Shen
Please in embodiment and embodiment in feature in the absence of conflict, mutually can arbitrarily combine.The protection model of the present invention
Enclose the equivalent replacement side of technical characteristic in the technical solution that should be recorded with claim, including the technical solution of claim record
Case is protection domain.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.
Claims (9)
1. a kind of double acyloxy bisamide class pharmaceutical intermediates of hydroxyl, which is characterized in that have the knot of logical formula (I) expression
Structure：
Wherein, R in formula1For methyl, ethyl, isopropyl, iso-octyl, n-heptyl, R2For chlorine, bromine, methyl, iso-octyl, n-heptyl,
R3For hydrogen or chlorine, R4For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl, R5For
The alkyl such as methyl, ethyl, isopropyl, n-hexyl, the aryl such as phenyl, substituted-phenyl or heteroaryl.
2. double acyloxy bisamide class pharmaceutical intermediates of hydroxyl described in claim 1, which is characterized in that the structural formula
Including：
3. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of hydroxyl as claimed in claim 1 or 2, feature exist
In synthesis path is as follows：
Adjacent acetoxybenzoic and keto-aldehyde, amine and isonitrile are sequentially added in the flask equipped with methanol, reacted at 20-40 DEG C,
After reaction 20-30 hours, sodium borohydride is added, continues stirring 1-5 hours at 20-40 DEG C, after the completion of reaction, reaction solution is subtracting
Solvent methanol is sloughed in pressure, and residue column chromatography obtains the target compound of logical formula (I).
4. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, which is characterized in that
The keto-aldehyde be contraposition substitution acetophenone aldehyde derivatives, including parachloroacetophenone aldehyde, parabromoacetophenone aldehyde, to methylbenzene second
Keto-aldehyde, to iso-octyl acetophenone aldehyde or to n-heptylphenyl ethyl ketone aldehyde.
5. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, which is characterized in that
The isonitrile is the isonitrile containing ester group, including methyl acetate isonitrile, ethyl acetate isonitrile or isohexyl acetate isonitrile.
6. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, which is characterized in that
The carboxylic acid is substitution septichen, including adjacent acetoxybenzoic or 4- chlorine neighbour's acetoxybenzoics.
7. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, which is characterized in that
The amine is in various aliphatic amines or aromatic amine, including methylamine, ethamine, isopropylamine, n-hexylamine, aniline, parachloroanilinum
Any one.
8. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, it is characterised in that：
The molar ratio of the adjacent acetoxybenzoic and keto-aldehyde, amine and isonitrile is 1：0.5-2：0.5-2：0.5-2.
9. the preparation method of double acyloxy bisamide class pharmaceutical intermediates of the hydroxyl described in claim 3, it is characterised in that：
The reducing agent is sodium borohydride, and mole dosage is 0.6-2 times of adjacent acetoxybenzoic.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021215900A1 (en) * | 2020-04-20 | 2021-10-28 | (주)아이랩 | Method for producing benzopyranone compound and novel intermediate used therein |
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| US2850491A (en) * | 1955-07-05 | 1958-09-02 | Ciba Pharm Prod Inc | Peptide derivatives and process for their manufacture |
| WO1997008133A1 (en) * | 1995-08-22 | 1997-03-06 | Japan Tobacco Inc. | Amide compounds and use of the same |
| CN106905183A (en) * | 2017-02-24 | 2017-06-30 | 三峡大学 | ɑ acyloxy amide carbonyl class derivative of one class containing amino, preparation method and applications |
| CN106916081A (en) * | 2017-02-24 | 2017-07-04 | 三峡大学 | The double acyloxyamides analog derivatives of one class amino, preparation method and applications |
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2018
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2850491A (en) * | 1955-07-05 | 1958-09-02 | Ciba Pharm Prod Inc | Peptide derivatives and process for their manufacture |
| WO1997008133A1 (en) * | 1995-08-22 | 1997-03-06 | Japan Tobacco Inc. | Amide compounds and use of the same |
| CN106905183A (en) * | 2017-02-24 | 2017-06-30 | 三峡大学 | ɑ acyloxy amide carbonyl class derivative of one class containing amino, preparation method and applications |
| CN106916081A (en) * | 2017-02-24 | 2017-07-04 | 三峡大学 | The double acyloxyamides analog derivatives of one class amino, preparation method and applications |
Non-Patent Citations (1)
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| LONG WANG ET AL.: "Synthesis of 2,3-Dihydro-1H-2-benzazepin-1-ones and 3H-2-Benzoxepin-1-ones by Isocyanide-Based Multicomponent Reaction/Wittig Sequence Starting from Phosphonium Salt Precursors", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021215900A1 (en) * | 2020-04-20 | 2021-10-28 | (주)아이랩 | Method for producing benzopyranone compound and novel intermediate used therein |
| KR20210129411A (en) * | 2020-04-20 | 2021-10-28 | (주)아이랩 | A process for preparing benzopyranone compound and novel intermediates used for the process |
| KR102379963B1 (en) | 2020-04-20 | 2022-03-29 | (주)아이랩 | A process for preparing benzopyranone compound and novel intermediates used for the process |
| JP7449407B2 (en) | 2020-04-20 | 2024-03-13 | アイラブ | Method for producing benzopyranone compounds and new intermediates used therein |
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