CN105732413A - Synthetic process of chiral N-aromatic amino acid amide - Google Patents

Synthetic process of chiral N-aromatic amino acid amide Download PDF

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CN105732413A
CN105732413A CN201610182803.2A CN201610182803A CN105732413A CN 105732413 A CN105732413 A CN 105732413A CN 201610182803 A CN201610182803 A CN 201610182803A CN 105732413 A CN105732413 A CN 105732413A
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chiral
amino acid
acid amide
configuration
fluoroform sulphonate
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CN105732413B (en
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曾庆乐
马昌
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Chengdu Univeristy of Technology
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Chengdu Univeristy of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Chiral N-aromatic amino acid amide is a core structure fragment of drugs and an intermediate of the drugs. Only if the chiral structure of the product is not required by special raw materials such aryl halide activated by functional groups of nitryl and the like, the chiral compound only can be synthesized by virtue of indirect multistep methods. The invention relates to a synthetic process of chiral N-aromatic amino acid amide, namely a process for synthesizing chiral N-aromatic amino acid amide by virtue of C-N coupling of chiral amino acid amide and diaryl iodonium salt through copper catalysis. The synthetic process has the beneficial effects that ligand is not used, the cost is low, reaction conditions are particularly mild (most raw materials react at the room temperature), and industrial production is hopefully realized.

Description

The synthesis technique of chiral N-aryl amino acid amide
Technical field
This patent relates to organic synthesis, pharmaceutical synthesis, organic chemical industry field, concretely, it is simply that in the presence of mantoquita from Chiral amino acid amide and the synthesis technique of diaryl group iodized salt one-step synthesis chiral N-aryl amino acid amide.
Background technology
N-aryl amino acid amide is the core texture [WO2012/61418A2,2012 of the multi-medicaments such as Loviride；Eur.J. Med.Chem.,2003,38,1001-1004],[US4246429A1,1981],useful as lead compounds for anti- cancerdrugs orpharmaceutical agents[J.Med.Chem.,2011,54,2902–2914；WO2012/129452A2, 2012],anti-HIV drugs[Proc NatlAcad Sci USA,1993,90,1711–1715；US5556886A1,1996； Bioorganic&MedicinalChemistryLetters,2001,11,2225-2228].Also there is several N-neighbour's halogen aryl amino acid Medicine [Bioorg.Med.Chem.Lett., 2001,11,2225-2228] in the medicine of amide structure or clinic.And, as The chirality of Loviride this kind of N-aryl amino acid amide medicine biological activity is had significant impact [ProcNatlAcadSci USA, 1993,90,1711–1715].Therefore, synthesis N-aryl amino acid amide is significant.
The N-aryl amino acid amide of racemization can by four components Ugi reaction one-step synthesis [J.Med.Chem., 2011,54 (8),2902–2914]；Or by a-keto acid and aniline condensation, the most original synthesis [Tetrahedron, 2006,62,6774 6781]；Or synthesize [US4246429A1,1981 by hydrolyzing N-arylamino nitrile；J.Indian Chem.Soc.,1976, 53,307]。
But, synthesis of chiral, non-racemization N-aryl amino acid amide, the synthesis technique such as Ugi is the most inapplicable.Hands Property the biological activity of N-aryl amino acid amide-type medicine is affected very big, a certain kind in two kinds of configurations of R and S, often have There is the biological activity [ProcNatlAcadSci USA, 1993,90,1711 1715] more much higher than corresponding raceme.Hands to be synthesized Property N-aryl amino acid amide, it is also possible to go out to send synthesis from chiral amino acid, (1) chiral amino acid and adjacent dihalo aromatic hydrocarbons C-N coupling synthesis N-neighbour's halogen aryl amino acid [Synlett, 2007, (12), 1,836 1842], (2) are again N-arylamino The carboxyl of acid reacts generation N-aryl amino acid amide [US5556886A1,1996] under carbethoxyl group chlorine activation with ammonia.
For the halogenated aryl hydrocarbon of special construction, such as, the fluorinated aromatic hydrocarbon such as nitro, cyano group, can directly pass through aromatic nucleophilic Replace (SNAr) fat amido with chiral amino acid amide reacts and generates chiral N-aryl amino acid amide [US5556886 A1,1996；Chem.Lett.,1997,(2),109-110；WO2012/61418A2,2012；Chinese J.Chem.,2011,29, 983-990].But, so far there are no diaryl group iodized salt and the literary composition of chiral amino acid amide one-step synthesis N-aryl amino acid amide Offer report.
Research before us finds, is no matter to make catalyst with palladium or with copper, it is impossible to directly from amino acid amide halogen Substituted aromatic hydrocarbons one-step synthesis chiral N-aryl amino acid amide.It was found that it is fragrant with CuI catalytic amino acid amide and halo Hydrocarbon obtains aminoacid virtue amide [application number CN201210285571.5, the applying date 20120813].Later, we were from aminoacid Amide and adjacent dihalo aromatic hydrocarbons one-step synthesis N-neighbour halogen aryl amino acid amide (Tetrahedron Lett.2013,54,6045- 6048)。
We further study show that, reacts with chiral amino acid amide as electrophilic reagent with diaryl group iodized salt substituted halogenated arene, Can be with one-step synthesis chiral N-aryl amino acid amide.This constitutes the main contents of this patent.
Summary of the invention
The present invention provides the synthesis technique of a kind of chiral N-aryl amino acid amide.
The synthetic method of chiral N-aryl amino acid amide disclosed by the invention is completed by a step, i.e. under mantoquita is catalyzed, and hands There is C-N coupling reaction, one-step synthesis chiral N-aryl amino at moderate temperatures in acidic amino acid amide and diaryl group iodized salt Acid amide.
General experimental operation sequence: diaryl group iodized salt, amino acid amide, mantoquita, alkali (optional) are weighed and adds mill Oral examination pipe, adds solvent, covers turned welt rubber stopper seal, replaces with argon, reacts one section under argon shield and proper temperature Time.Chiral N-aryl amino acid amide is obtained through post processing.
The present invention is explained in more detail in conjunction with the following examples, is not regarded as that they limit the scope of the present invention.
Detailed description of the invention
Embodiment one
In the dry test-tube containing magnetic stir bar, be sequentially added into by 1.0mmol diphenyl iodine fluoroform sulphonate, 0.5 Mmol L-phenylalanyl amine, 0.10mmol anhydrous cupric acetate, 1.0mmol anhydrous phosphoric acid potassium and 5mL dioxane.This examination Turned welt rubber stopper in lid, replaces three times with argon, under argon shield, is stirred at room temperature 24 hours.Then, add water Cancellation is reacted, and adds saturated aqueous common salt, extracts 3 times by 20mL ethyl acetate, merges organic facies.Organic facies anhydrous slufuric acid Magnesium is dried, and filters, and concentrated filtrate obtains crude product.Crude product is purified by silica gel column chromatography, by petroleum ether and acetic acid second Ester mixed solution gradient elution, obtains L-configuration N-phenyl phenylalanyl amine, productivity 95%.
Embodiment two
Replace the solvent dioxane in embodiment one with toluene, obtain L-configuration N-phenyl phenylalanyl amine, productivity 30%.
Embodiment three
Replace the solvent dioxane in embodiment one with DMF, obtain L-configuration N-phenyl phenylalanyl amine, produce Rate 40%.
Embodiment four
With 150 degrees Celsius and the 4 hours room temperatures replaced in embodiment one and 24 hours, obtain L-configuration N-phenyl phenylalanyl amine, Productivity 80%.
Embodiment five
Reaction temperature, by 0 degree Celsius of room temperature replaced in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 10%.
Embodiment six
Alkali potassium carbonate replaces the anhydrous phosphoric acid potassium in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 88%.
Embodiment seven
Alkali cesium carbonate replaces the anhydrous phosphoric acid potassium in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 70%.
Embodiment eight
Alkali potassium tert-butoxide replaces the anhydrous phosphoric acid potassium in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 40%.
Embodiment nine
Alkali sodium hydroxide replaces the anhydrous phosphoric acid potassium in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 30%.
Embodiment ten
Without the anhydrous phosphoric acid potassium in embodiment one, the most do not add any alkali, obtain L-configuration N-phenyl phenylalanyl amine, productivity 50%.
Embodiment 11
Mantoquita trifluoroacetic acid copper replaces the anhydrous cupric acetate in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 70%.
Embodiment 12
Mantoquita copper chloride replaces the anhydrous cupric acetate in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 60%.
Embodiment 13
Mantoquita Hydro-Giene (Water Science). replaces the anhydrous cupric acetate in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 35%.
Embodiment 14
Mantoquita replaces the anhydrous cupric acetate in embodiment one with a water copper acetate, obtains L-configuration N-phenyl phenylalanyl amine, productivity 55%.
Embodiment 15
Mantoquita Hydro-Giene (Water Science). replaces the anhydrous cupric acetate in embodiment one, obtains L-configuration N-phenyl phenylalanyl amine, productivity 35%.
Embodiment 16
Replace the L-phenylalanyl amine in embodiment one with D-phenylalanyl amine, obtain D configuration N-phenyl phenylalanyl amine, productivity 92%.
Embodiment 17
Replace the L-phenylalanyl amine in embodiment one with DL-phenylalanyl amine, obtain DL configuration N-phenyl phenylalanyl amine, produce Rate 92%.
Embodiment 18
Replace the L-phenylalanyl amine in embodiment one with L-benzene Aminoacetamide, obtain L-configuration N-phenyl benzene Aminoacetamide, productivity 94%.
Embodiment 19
Replace the L-phenylalanyl amine in embodiment one with L-tryptophanyl amine, obtain L-configuration N-phenyl tryptophanyl amine, productivity 80%.
Embodiment 20
Replace the L-phenylalanyl amine in embodiment one with L-tyramine amide, obtain L-configuration N-phenyl tyramine amide, productivity 93%.
Embodiment 21
Replace the L-phenylalanyl amine in embodiment one with L-valine amide, obtain L-configuration N-phenyl valine amide, productivity 65%.
Embodiment 22
Replace the L-phenylalanyl amine in embodiment one with L-2-amino-butanamide, obtain L-configuration N-phenyl-2-amino-butanamide, produce Rate 80%.
Embodiment 23
Replace the L-phenylalanyl amine in embodiment one with L-prolineamide, obtain L-configuration N-phenyl prolineamide, productivity 70%.
Embodiment 24
Replace the L-phenylalanyl amine in embodiment one with L-leucyl amine, obtain L-configuration N-phenyl leucyl amine, productivity 89%.
Embodiment 25
Replace the L-phenylalanyl amine in embodiment one with L-silk amide, obtain L-configuration N-phenyl silk amide, productivity 50%.
Embodiment 26
Replace the L-phenylalanyl amine in embodiment one with L-aminopropanamide, obtain L-configuration N-phenylalaninamide, productivity 92%.
Embodiment 27
Replace the L-phenylalanyl amine in embodiment one with DL-aminopropanamide, obtain DL configuration N-phenylalaninamide, productivity 93%.
Embodiment 28
Replace the L-phenylalanyl amine in embodiment one with D-aminopropanamide, obtain D configuration N-phenylalaninamide, productivity 92%.
Embodiment 29
Replace the L-phenylalanyl amine in embodiment one with L-threonyl amine, obtain L-configuration N-phenyl threonyl amine, productivity 35%.
Embodiment 30
Replace the L-phenylalanyl amine in embodiment one with D-benzene Aminoacetamide, obtain D configuration N-phenyl benzene Aminoacetamide, productivity 92%.
Embodiment 31
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (4-tert-butyl-phenyl) iodine fluoroform sulphonate, obtain L Configuration N-(4-tert-butyl-phenyl) phenylalanyl amine, productivity 75%.
Embodiment 32
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (4-aminomethyl phenyl) iodine fluoroform sulphonate, obtain L structure Type N-(4-tolyl) phenylalanyl amine, productivity 92%.
Embodiment 33
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (4-bromophenyl) iodine fluoroform sulphonate, obtain L-configuration N-(4-bromophenyl) phenylalanyl amine, productivity 85%.
Embodiment 34
The diphenyl iodine fluoroform sulphonate in embodiment one is replaced with two (2-methyl-4-tert-butyl-phenyl) iodine fluoroform sulphonate, Obtain L-configuration N-(2-methyl-4-tert-butyl-phenyl) phenylalanyl amine, productivity 85%.
Embodiment 35
The diphenyl iodine fluoroform sulphonate in embodiment one is replaced with two (2-methyl-4-tert-butyl-phenyl) iodine fluoroform sulphonate, Obtain L-configuration N-(2-methyl-4-tert-butyl-phenyl) phenylalanyl amine, productivity 85%.
Embodiment 36
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (2,4-xylyl) iodine fluoroform sulphonate, obtain L Configuration N-(2,4-xylyl) phenylalanyl amine, productivity 91%.
Embodiment 37
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (3,4-xylyl) iodine fluoroform sulphonate, obtain L Configuration N-(3,4-xylyl) phenylalanyl amine, productivity 89%.
Embodiment 38
Replace the diphenyl iodine fluoroform sulphonate in embodiment one with two (2,5-xylyl) iodine fluoroform sulphonate, obtain L Configuration N-(2,5-xylyl) phenylalanyl amine, productivity 92%.

Claims (5)

1. the synthesis technique of a chiral N-aryl amino acid amide, it is characterised in that: in the presence of mantoquita, chiral amino acid amide and diaryl group iodized salt are synthesized chiral N-aryl amino acid amide at moderate temperatures.
2. the synthesis technique of a kind of chiral N-aryl amino acid amide described in claim 1, it is characterised in that described chiral amino acid amide includes the phenylalanyl amine of chirality, benzene Aminoacetamide, tryptophanyl amine, tyramine amide, valine amide, 2-amino-butanamide, prolineamide, leucyl amine, silk amide, aminopropanamide, threonyl amine, glycyl amide hydrochloride；Their chiral configuration includes L-configuration, D configuration and DL configuration；The chiral configuration of raw material is effectively maintained in the product.
3. the synthesis technique of a kind of chiral N-aryl amino acid amide described in claim 1, it is characterized in that described diaryl group iodized salt include diphenyl iodine fluoroform sulphonate, two (4-tert-butyl benzene) iodine fluoroform sulphonate, two (4-toluene) iodine fluoroform sulphonate, two (4-bromobenzene) iodine fluoroform sulphonate, two (2-methyl-5-tert-butyl benzene) iodine fluoroform sulphonate, two (2,4-dimethylbenzene) iodine fluoroform sulphonate, two (3,4-dimethylbenzene) iodine fluoroform sulphonate, two (2,5-dimethylbenzene) iodine fluoroform sulphonate.
4. the synthesis technique of a kind of chiral N-aryl amino acid amide described in claim 1, it is characterised in that described mantoquita includes Salicylaldoxime, a water acetic acid copper, trifluoroacetic acid copper, copper chloride, Hydro-Giene (Water Science)..
5. the synthesis technique of a kind of chiral N-aryl amino acid amide described in claim 1, it is characterised in that described proper temperature includes from 0 degree Celsius to 150 degree Celsius.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108147982A (en) * 2018-02-07 2018-06-12 成都理工大学 The C-N coupling reaction techniques of the Tosylhydrazone of chemical property mutability
CN114349679A (en) * 2022-01-17 2022-04-15 五邑大学 Preparation method of biaryl axial chiral compound

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4246429A (en) * 1978-06-23 1981-01-20 Janssen Pharmaceutica, N.V. Novel α-amino-phenylacetic acid derivatives
CN102766004A (en) * 2012-08-13 2012-11-07 成都理工大学 Method for synthesizing aminoacyl arylamine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4246429A (en) * 1978-06-23 1981-01-20 Janssen Pharmaceutica, N.V. Novel α-amino-phenylacetic acid derivatives
CN102766004A (en) * 2012-08-13 2012-11-07 成都理工大学 Method for synthesizing aminoacyl arylamine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUK-KU KANG,ET AL.: ""Copper-Catalyzed N-Arylation of Amines with Hypervalent Iodonium Salts"", 《SYNLETT》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108147982A (en) * 2018-02-07 2018-06-12 成都理工大学 The C-N coupling reaction techniques of the Tosylhydrazone of chemical property mutability
CN114349679A (en) * 2022-01-17 2022-04-15 五邑大学 Preparation method of biaryl axial chiral compound

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