CN108727467A - Four peptides pharmaceutical intermediate of a kind of double acyloxy and preparation method thereof - Google Patents
Four peptides pharmaceutical intermediate of a kind of double acyloxy and preparation method thereof Download PDFInfo
- Publication number
- CN108727467A CN108727467A CN201810509072.7A CN201810509072A CN108727467A CN 108727467 A CN108727467 A CN 108727467A CN 201810509072 A CN201810509072 A CN 201810509072A CN 108727467 A CN108727467 A CN 108727467A
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- Prior art keywords
- phenyl
- acyloxy
- methyl
- double
- isopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- NQCVZXFOTFUJKP-UHFFFAOYSA-N CC(Nc(cccc1)c1C(N(C(C(C1C=CC(Cl)=CC1)OC(C)=O)C(NCC(OC)=O)=O)C1CC1)=O)=O Chemical compound CC(Nc(cccc1)c1C(N(C(C(C1C=CC(Cl)=CC1)OC(C)=O)C(NCC(OC)=O)=O)C1CC1)=O)=O NQCVZXFOTFUJKP-UHFFFAOYSA-N 0.000 description 1
- 0 CCCCCC(OC(C(C(NCC(OCC)=O)=O)N(C1CCCCC1)C(c(cccc1)c1NC(C1CC1)=O)=O)c1ccc(C)cc1)=* Chemical compound CCCCCC(OC(C(C(NCC(OCC)=O)=O)N(C1CCCCC1)C(c(cccc1)c1NC(C1CC1)=O)=O)c1ccc(C)cc1)=* 0.000 description 1
- STSJCWHCYACXOF-UHFFFAOYSA-N CCCCCCCOC(CNC(C(C(c1ccc(C)cc1)OC(c1ccc(cccc2)c2c1)=O)N(CCCCCC)C(c(ccc(Cl)c1)c1OC(C)=O)=O)=O)=O Chemical compound CCCCCCCOC(CNC(C(C(c1ccc(C)cc1)OC(c1ccc(cccc2)c2c1)=O)N(CCCCCC)C(c(ccc(Cl)c1)c1OC(C)=O)=O)=O)=O STSJCWHCYACXOF-UHFFFAOYSA-N 0.000 description 1
- DMYQRPOGVSLMOS-UHFFFAOYSA-N CCCCCCN(C(C(c1ccc(C)cc1)OC(c(c(OC)c1)ccc1OC)=O)C(NCC(OCCCCCC(C)C)=O)=O)C(c1ccc(C)cc1NC(C)=O)=O Chemical compound CCCCCCN(C(C(c1ccc(C)cc1)OC(c(c(OC)c1)ccc1OC)=O)C(NCC(OCCCCCC(C)C)=O)=O)C(c1ccc(C)cc1NC(C)=O)=O DMYQRPOGVSLMOS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- 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
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
Abstract
The present invention provides a kind of double acyloxy four peptides pharmaceutical intermediates.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, R6For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl.Preparation method is that acyl chlorides is added in the flask equipped with hydroxyl tetrapeptide, and diisopropyl ethyl amine is then added, and reaction dissolvent is dichloromethane, reaction 1-5 hours, after the completion of reaction, methylene chloride 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 synthesis of biologically active peptide medicament.
Description
Technical field
The present invention relates to four peptides pharmaceutical intermediates of a kind of double acyloxy and preparation method thereof.
Background technology
In human body, many active materials be all in the form of peptide existing for.Polypeptide is that amino acid is connected to one with peptide bond
The compound for rising and being formed, polypeptide are that protein hydrolyzes the product obtained later.It is formed by two amino acid molecular dehydrating condensations
Compound be called dipeptides, similarly analogize also tripeptides, tetrapeptide, pentapeptide etc..Peptide is related to the hormone, nerve, cell growth of human body,
Each field of reproduction, importance are to adjust the physiological function of each system and cell in vivo, activate related enzyme system in vivo, promote
The permeability of intermediate supersession film, or synthesized by controlling DNA transcriptions or influencing special albumen, finally generate specific physiology effect
It answers.Peptide is the important substance for being related to various kinds of cell function in human body.Peptide can be with synthetic cell, and adjusts the functional activity of cell.
Peptide can be in human body as means of transport, the various nutriments that human body is eaten and various vitamins, biotin, calcium and to human body
Beneficial trace element is transported to each cell of human body, organ and tissue.Peptide is the important physiological regulator of human body, it can be adjusted comprehensively
Human body physiological function, enhancing and performance Human Physiology activity are saved, it has important biological function.Peptide lives to the cell of people
Property, functional activity, life presence are all extremely important.In this patent, we are prepared for double acyloxy of a kind of structure novel
Four peptide derivatives.Such pharmaceutical intermediate can be used for the synthesis of bioactivity peptides drug.
Invention content
It is a primary object of the present invention to explore to provide pharmaceutical intermediate four peptides pharmaceutical intermediate of double acyloxy.
The present invention proposes four peptides pharmaceutical intermediate (I) of double acyloxy：
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, R6For methyl, ethyl, different
The alkyl such as propyl, n-hexyl, the aryl such as phenyl, substituted-phenyl or heteroaryl.
Based on above-mentioned chemical formula, preferred structural formula includes as follows in the technical solution of the application：
The method of the synthesis four peptides pharmaceutical intermediate of double acyloxy, the method includes following synthesis paths：
The method specifically includes following steps：
By acyl chlorides and hydroxyl tetrapeptide and diisopropyl ethyl amine 0.5-2 in molar ratio：1：0.5-2 is sequentially added equipped with dichloro
It in the flask of methane, is reacted at 20-40 DEG C, reacts 1-5 hours, after the completion of reaction, slough methylene chloride under reduced pressure,
Residue column chromatography obtains the target compound of logical formula (I).
The acyl chlorides be to various aliphatic acyl chlorides or aromatic series acyl chlorides, including formyl chloride, chloroacetic chloride, isopropyl acyl chlorides,
Positive caproyl chloride, chlorobenzoyl chloride, parachlorobenzoyl chloride.
The acyl chlorides is 0.5-2 with the molar ratio of hydroxyl tetrapeptide and diisopropyl ethyl amine：1：0.5-2.
The alkali is diisopropyl ethyl amine, and mole dosage is 0.6-2 times of hydroxyl tetrapeptide.
Wired reaction temperature is 30 DEG C.
The present invention has the beneficial effect that：
1. the present invention reports a kind of novel four peptides pharmaceutical intermediate of double acyloxy；
2. the present invention provides the preparation method of a kind of novel four peptides pharmaceutical intermediate of double acyloxy, specially hydroxyl
Tetrapeptide reacts under 30o under the action of negative sour agent diisopropyl ethyl amine with acyl chlorides in methylene chloride can generate one kind
Containing there are two the new methods of the four peptides pharmaceutical intermediate of double acyloxy of acyloxy, three amide groups while novel.
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
Hydroxyl tetrapeptide 1a (1mmol), chloroacetic chloride 2a (1.1mmol) and diisopropyl ethyl amine are added into 50mL flasks
(1.2mmol) reacts at 30 DEG C, and reaction dissolvent is dichloromethane (10mL), and after reacting 2 hours, reaction solution takes off under reduced pressure
Methylene chloride, residue column chromatography is gone to obtain 0.488g white solid 3a, yield 92%.
Embodiment 2
Preparation
Hydroxyl tetrapeptide 1a (10mmol), chloroacetic chloride 2a (11mmol) and diisopropyl ethyl amine are added into 500mL flasks
(12mmol) reacts at 30 DEG C, and reaction dissolvent is dichloromethane (100mL), and after reacting 2 hours, reaction solution takes off under reduced pressure
Methylene chloride, residue column chromatography is gone to obtain 4.77g white solid 3a, yield 90%.
Embodiment 3
Preparation
Hydroxyl tetrapeptide 1a (0.1mmol), chloroacetic chloride 2a (0.11mmol) and diisopropyl ethyl amine are added into 5mL flasks
(0.12mmol) reacts at 30 DEG C, and reaction dissolvent is dichloromethane (1mL), and after reacting 2 hours, reaction solution takes off under reduced pressure
Methylene chloride, residue column chromatography is gone to obtain 0.050g white solid 3a, yield 95%.
Embodiment 4
Preparation
Hydroxyl tetrapeptide 1a (1mmol), chloroacetic chloride 2a (1.1mmol) and diisopropyl ethyl amine are added into 50mL flasks
(1.2mmol) reacts at 30 DEG C, and reaction dissolvent is methanol (10mL), and after reacting 2 hours, reaction solution is sloughed molten under reduced pressure
Agent methanol, residue column chromatography are unable to get 3a.
Embodiment 5
Preparation
Hydroxyl tetrapeptide 1a (1mmol) and chloroacetic chloride 2a (1.1mmol) is added into 50mL flasks, is reacted at 30 DEG C, instead
It is dichloromethane (10mL) to answer solvent, and after reacting 2 hours, reaction solution sloughs methylene chloride, residue column layer under reduced pressure
Analysis obtains 0.307g white solid 3a, yield 58%.
Embodiment 6
Preparation
Hydroxyl tetrapeptide 1a (1mmol), chloroacetic chloride 2a (1.1mmol) and diisopropyl ethyl amine are added into 50mL flasks
(1.2mmol) reacts at 0 DEG C, and reaction dissolvent is dichloromethane (10mL), and after reacting 2 hours, reaction solution is sloughed under reduced pressure
Methylene chloride, residue column chromatography obtain 0.398g white solid 3a, yield 75%.
Embodiment 7
Preparation
Hydroxyl tetrapeptide 1b (1mmol), 2,4- dimethoxy-benzoyl chlorides 2b (1.1mmol) and two are added into 50mL flasks
Diisopropylethylamine (1.2mmol), reacts at 30 DEG C, and reaction dissolvent is dichloromethane (10mL), after reacting 2 hours, reaction
Liquid sloughs methylene chloride under reduced pressure, and residue column chromatography obtains 0.555g white solid 3b, yield 67%.
Embodiment 8
Preparation
Hydroxyl tetrapeptide 1c (1mmol), 2- naphthoyl chlorides 2c (1.1mmol) and diisopropyl ethyl are added into 50mL flasks
Amine (1.2mmol), reacts at 30 DEG C, and reaction dissolvent is dichloromethane (10mL), and after reacting 2 hours, reaction solution is under reduced pressure
Methylene chloride is sloughed, residue column chromatography obtains 0.683g white solid 3c, yield 87%.
Embodiment 9
Preparation
Hydroxyl tetrapeptide 1d (1mmol), positive caproyl chloride 2d (1.1mmol) and diisopropyl ethyl amine are added into 50mL flasks
(1.2mmol) reacts at 30 DEG C, and reaction dissolvent is dichloromethane (10mL), and after reacting 2 hours, reaction solution takes off under reduced pressure
Methylene chloride, residue column chromatography is gone to obtain 0.551g white solid 3d, yield 85%.
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 (7)
1. four peptides pharmaceutical intermediate of a kind of double acyloxy, which is characterized in that have the structure of logical formula (I) expression：
Wherein, R in formula1For any one in methyl, ethyl, isopropyl, iso-octyl, n-heptyl；R2For chlorine, bromine, methyl, different
Any one in octyl, n-heptyl；R3For hydrogen or chlorine；R4For methyl, ethyl, isopropyl, n-hexyl, phenyl, substituted-phenyl
Any one in aryl or heteroaryl, R5For methyl, ethyl, isopropyl, n-hexyl, phenyl, substituted-phenyl aryl or miscellaneous
Any one in aryl, R6For methyl, the alkyl of ethyl, isopropyl, n-hexyl, phenyl, the aryl of substituted-phenyl or heteroaryl
Any one in base.
2. four peptides pharmaceutical intermediate of double acyloxy described in claim 1, which is characterized in that the structural formula includes as follows：
3. the preparation method of the four peptides pharmaceutical intermediate as claimed in claim 1 or 2 containing double acyloxy, which is characterized in that synthesis
Path is as follows：
Acyl chlorides and hydroxyl tetrapeptide and diisopropyl ethyl amine are sequentially added in the flask equipped with dichloromethane, at 20-40 DEG C
Reaction is reacted 1-5 hours, after the completion of reaction, sloughs methylene chloride under reduced pressure, residue column chromatography obtains logical formula (I)
Target compound contain double four peptide medicaments of acyloxy.
4. the preparation method of the four peptides pharmaceutical intermediate of double acyloxy described in claim 3, which is characterized in that the acyl chlorides
For to various aliphatic acyl chlorides or aromatic series acyl chlorides, including formyl chloride, chloroacetic chloride, isopropyl acyl chlorides, positive caproyl chloride, chlorobenzoyl chloride,
Parachlorobenzoyl chloride.
5. the preparation method of four peptides pharmaceutical intermediate of double acyloxy according to claim 3, it is characterised in that：Described
Acyl chlorides is 0.5-2 with the molar ratio of hydroxyl tetrapeptide and diisopropyl ethyl amine：1：0.5-2.
6. the preparation method of four peptides pharmaceutical intermediate of double acyloxy according to claim 3, it is characterised in that：Described
Alkali is diisopropyl ethyl amine, and mole dosage is 0.6-2 times of hydroxyl tetrapeptide.
7. method according to claim 3, it is characterised in that：The reaction temperature is 30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810509072.7A CN108727467A (en) | 2018-05-24 | 2018-05-24 | Four peptides pharmaceutical intermediate of a kind of double acyloxy and preparation method thereof |
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| CN201810509072.7A CN108727467A (en) | 2018-05-24 | 2018-05-24 | Four peptides pharmaceutical intermediate of a kind of double acyloxy and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0849256B1 (en) * | 1995-08-22 | 2005-06-08 | Japan Tobacco Inc. | Amide compounds and use of the same |
| 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 |
-
2018
- 2018-05-24 CN CN201810509072.7A patent/CN108727467A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0849256B1 (en) * | 1995-08-22 | 2005-06-08 | Japan Tobacco Inc. | Amide compounds and use of the same |
| 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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Application publication date: 20181102 |