Process for the preparation of substituted prolyl peptides and similar peptidomimetics

a technology of substituted prolyl peptides and peptidomimetics, which is applied in the direction of tetrapeptide ingredients, tripeptide ingredients, biocides, etc., can solve the problems of poor and/or unpredictable diastereoselectivity of known multicomponent reactions for the preparation of proline derivative comprising peptides and peptidomimetics, and achieves excellent yield and enantiomeric excess, high efficiency, and effectiv

Inactive Publication Date: 2012-12-27
VER VOOR CHRISTELIJK HOGER ONDERWIJS WETENSCHAPPELIJK ONDERZOEK & PATIENTENZORG TECH TRANSFER OFFICE VU & VUMC
View PDF5 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0061]Unlike prior art processes for the enantioselective preparation of compounds according to formula (I), the process of the present invention allows for the synthesis of either enantiomer of according to formula (I) in excellent yield and enantiomeric excess at mild conditions, and in a very small number of steps. In addition, the inventive process of the present invention allows for very effective use of readily available chiral starting information. Insofar, the process of the present invention is highly efficient as it does not prod

Problems solved by technology

However, as in most MCRs, controlling the newly formed stereocenter proves highly complex, and therefore the reaction suffers from poor and/or unpredictable (dia)stereoselectivity, as illustrated for instance by WO2006/061585.
The reported products are formed in only limited yields and mostly unpredictable diastereoselectivity, while requiring the use of prot

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for the preparation of substituted prolyl peptides and similar peptidomimetics
  • Process for the preparation of substituted prolyl peptides and similar peptidomimetics
  • Process for the preparation of substituted prolyl peptides and similar peptidomimetics

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0118]

Compound 5a:

[0119]General procedure 2 was followed using 3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), acetic acid (55 mg, 52 μl, 0.91 mmol) and t-butyl isocyanide (76 mg, 103 μl, 0.91 mmol) giving 5a as a white solid, yield 73%.

[0120]93:7 d.r. [HP-1, t (major)=14.852 min, t (minor)=16.773 min]; 95% ee [CP Chirasil-DEX CB, t (minor)=20.449 min, t (major)=20.860 min]; [α]D20=−47.8° (c=0.34, MeCN). 1H NMR (400.1 MHz, CDCl3): δ 6.58 (bs, 1H), 4.28 (d, J=2.1 Hz, 1H), 3.70 (dd, J=8.3, 10.6 Hz, 1H), 3.24 (dd, J=4.5, 10.6 Hz, 1H), 2.96-2.93 (m, 1H), 2.91-2.82 (m, 1H), 2.01 (s, 3H), 1.93-1.78 (m, 2H), 1.71-1.42 (m, 2H), 1.41-1.31 (m, 2H), 1.25 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 170.5, 170.0, 66.8, 54.4, 51.0, 45.0, 42.7, 32.5, 32.3, 28.7, 25.7, 22.6; IR (neat): νmax (cm−1)=3277 (m), 2957 (m), 1668 (s), 1630 (s), 1549 (s), 1447 (s), 1420 (s), 1223 (s), 667 (m), 606 (m); HRMS (ESI+) calcd for C14H24N2O2 ([M+H]+) 253.1916. found 253.1925.

example 2

[0121]

Compound 5b:

[0122]General procedure 2 was followed using 3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), benzoic acid (111 mg, 0.91 mmol) and t-butyl isocyanide (76 mg, 103 μl, 0.91 mmol) giving 5b as a white solid, yield 73%.

[0123]93:7 d.r. [HP-1, t (major)=23.672 min, t (minor)=25.601 min]; 95% ee [Daicel Chiralpak AD-H, hexane / 2-propanol=96 / 4, v=1.0 mL / min1, λ=254 nm, t (minor)=10.698 min, t (major)=11.620 min]; [α]D20=−53.7° (c=0.34, MeCN). 1H NMR (400.1 MHz, CDCl3): δ 7.49-7.38 (m, 5H), 6.66 (bs, 1H), 4.54 (d, J=2.8 Hz), 3.72 (dd, J=11.4, 7.8 Hz, 1H), 3.23 (d, J=11.0, 1H), 3.15-3.10 (m, 1H), 2.73-2.58 (m, 1H), 1.96-1.82 (m, 1H), 1.82-1.69 (m, 1H), 1.68-1.41 (m, 3H), 3.15-3.10 (m, 1H), 1.28 (s, 9H), 1.24-1.06 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ170.3, 170.1, 136.3, 130.1, 128.4, 126.9, 67.1, 60.4, 55.9, 51.1, 44.2, 43.3, 33.0, 32.7, 28.7, 26.2; IR (neat): νmax (cm−1)=3310 (m), 2961 (m), 1674 (s), 1618 (s), 1416 (s), 1223 (s), 698 (s); HRMS (ESI+) calcd for C19...

example 3

[0124]

Compound 5c:

[0125]General procedure 2 was followed using 3-azabicyclo[3,3,0]oct-2-ene ((3S,7R)-4, 76 mg, 0.70 mmol), 3-furoic acid (102 mg, 0.91 mmol) and isopropyl isocyanide (63 mg, 86 μl, 0.91 mmol) giving 5c as a white solid, yield 75%.

[0126]92:8 d.r. [HP-1, t (major)=21.290 min, t (minor)=23.012 min] 94% ee [Daicel Chiralpak AD-H, hexane / 2-propanol=90 / 10, v=1.0 mL·min1, λ=254 nm, t (minor)=7.417 min, t (major)=12.039 min]; [α]D20=−33.3° (c=0.30, MeCN). 1H NMR (400.1 MHz, CDCl3): δ 7.80 (bs, 1H), 7.43 (bs, 1H), 6.72 (bs, 1H), 6.51 (d, J=6.3 Hz, 1H), 4.56 (d, J=2.3 Hz, 1H), 4.03 (oct, J=7.1 1H), 3.88 (dd, J=10.4, 8.3 Hz, 1H), 3.53 (dd, J=10.4, 3.8 Hz, 1H), 3.09-3.01 (m, 1H), 2.95-2.84 (m, 1H), 2.00-1.84 (m, 2H), 1.74-1.65 (m, 1H), 1.64-1.54 (m, 1H), 1.53-1.43 (m, 1H), 1.43-1.33 (m, 1H), 1.17 (d, J=6.3 Hz, 3H) 1.13 (d, J=6.3 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 170.1, 163.2, 144.3, 142.8, 121.8, 110.4, 66.8, 54.8, 44.4, 43.3, 41.3, 32.4, 32.2, 25.6, 22.5, 22.4; IR (neat): ν...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Structureaaaaaaaaaa
Selectivityaaaaaaaaaa
Login to view more

Abstract

The present invention relates to a process for the stereoselective preparation of a compound having the general formula (I) or its respective diastereomers: comprising reacting a compound having the general formula (II) or its diastereomers: with a compound of the general formula III: R3—COOH and a compound of the general formula IV: R4—NC wherein R1 represents each independently, or jointly a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R2 represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R3 represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure.
R3—COOH  (III)
R4—NC  (IV)

Description

FIELD OF THE INVENTION[0001]The present invention relates to substituted prolyl peptides and similar peptidomimetics, methods for their preparation, and a variety of uses including as inhibitors of disease-associated targets as well as an organocatalyst component.BACKGROUND TO THE INVENTION[0002]Optically pure 3,4-substituted prolyl peptides and related peptidomimetic compounds are of considerable interest in organocatalysis and medicinal chemistry, specifically since they form key structural elements of the hepatitis C virus NS3 protease inhibitors telaprevir and boceprevir as disclosed in for instance WO2003 / 062265.[0003]Multicomponent reactions (MCRs) offer the ability to rapidly and efficiently generate collections of structurally and functionally diverse organic compounds. Although MCRs are very efficient by their nature, the stereocontrol in these reactions is mostly not trivial.[0004]The Ugi reaction is undoubtedly one of the most widely applied MCRs. It is of considerable in...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): A61K38/06C07K5/00A61P31/12C12P21/02
CPCC07C231/06C07D209/58C07C2101/04C07D403/12C07D209/52C07C291/10C07D241/24C07C2101/02C07D209/94C07C237/14C07D403/06C07C2601/02C07C2601/04A61P31/12
Inventor RUIJTER, EELCOORRU, ROMANOZNABET, ANASSPOLAK, MARLOESTURNER, NICHOLAS
Owner VER VOOR CHRISTELIJK HOGER ONDERWIJS WETENSCHAPPELIJK ONDERZOEK & PATIENTENZORG TECH TRANSFER OFFICE VU & VUMC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap