Synthesis of the Reverse Amide Linked Series

The Reversed Amide (discussed: #301, #352, #358 has been synthesised as described here.

The initial approach of synthesising and reducing the azide to the amine worked only on a small scale (CCS-3-2, CCS-4-1). When upscaling this (TL-4-2, TL-4-3), the iminophosphorane was obtained rather than the amine. Basic methods of hydrolysis of the iminophosphorane failed to force the reaction to completion (CCS-5-1). However, hydrolysis could be forced using acidic conditions, although with long reaction times (NA-7-2). This provided pure amine product (OSM-W-2) and was therefore favoured over alternative methods involving catalytic hydrogenation or borohydride reduction of the azide, where yields were low and isolation of product was difficult (BM-5-1, NA-2-1, NA-2-4).

The amine (OSM-W-2) proved to be unreactive to carboxylic acids under standard peptide coupling conditions (CCS-6-1, NA-3-1, NA-3-2, FG-5-1, FG-5-2, FG-5-3, FG-5-4). An attempt to produce the urea also did not result in any reaction and only starting material remained (VD-4-1).

An alternative synthetic route was successfully executed via Buchwald–Hartwig amination of the chloro-substituted triazolopyrazine core to give OSM-W-6 and OSM-W-7 (JH-5-1, JH-5-2, JH-7-1). (Note that a para-cyanophenyl ring was used on the right hand side of the molecule to avoid any possible unwanted side products) (it might also be possible to replace the XantPhos with JohnPhos as we have had good success with JohnPhos before - AMS)

A quartet of important analogues of the reversed amide compounds have yet not been synthesized but can be prepared from inexpensive reagents:

InChI=1S/C19H13F2N5O2/c20-19(21)28-14-8-6-12(7-9-14)17-25-24-16-11-22-10-15(26(16)17)23-18(27)13-4-2-1-3-5-13/h1-11,19H,(H,23,27) HHRGGCROWSDATP-UHFFFAOYSA-N FC(OC1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(C2=CC=CC=C2)=O)F CLogP 3.04 (SwissADME)

InChI=1S/C19H12N6O/c20-10-13-6-8-14(9-7-13)18-24-23-17-12-21-11-16(25(17)18)22-19(26)15-4-2-1-3-5-15/h1-9,11-12H,(H,22,26) KVBLUVJYRHBFTE-UHFFFAOYSA-N C(#N)C1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(C2=CC=CC=C2)=O CLogP 2.29 (SwissADME)

InChI=1S/C18H12F2N6O2/c19-18(20)28-13-5-3-11(4-6-13)16-25-24-15-10-22-9-14(26(15)16)23-17(27)12-2-1-7-21-8-12/h1-10,18H,(H,23,27) CJRKQMLRWDZHOR-UHFFFAOYSA-N FC(OC1=CC=C(C=C1)C1=NN=C2N1C(=CN=C2)NC(=O)C=2C=NC=CC2)F CLogP 2.32 (SwissADME)

O=C(C1=CC(F)=C(F)C=C1)NC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C19H10F2N6O/c20-14-6-5-13(7-15(14)21)19(28)24-16-9-23-10-17-25-26-18(27(16)17)12-3-1-11(8-22)2-4-12/h1-7,9-10H,(H,24,28) IAUQUTZYIOSAOR-UHFFFAOYSA-N