1-Methylimidazole → HCID 69540464, compound

The new linker based solid support 1 (1.0 g) having substitution 0.4 meq/g was placed in reaction vessel and allowed to swell in dichloromethane (DCM) under nitrogen stirring. After 30 min. the resin was filtered and washed with DCM. To this resin a solution of Boc-Leu (0.45 g, 2 mmol) dimethylaminopyridine (DMAP) or N-methyl imidazole (NMI) (0.4 mmol) in DCM:DMF (1:1) 20 ml and was added. The reaction mixture was stirred for 8-10 hrs. The resin was washed three times with DCM and dried. An aliquot of this dried resin (2.5 mg) was tested for the loading and the loading was found to be 82% [Method B]. The resin was treated with 50% TFA in DCM for 30 min. to remove Boc group. After 30 min the resin was filtered and washed with DCM 20 ml×3, 20% DIEA in DCM 20 ml×3, DCM 20 ml×3 and finally suspended in 20% piperidine solution DMF:DCM (1:1) 20 ml and treated with DCM:DMF (1:1) 20 ml. The resin having free amino group of Leu, was reacted with a solution of Boc-Cys-(Trt) (0.56 g, 1 mmol) and HOBt (0.153 g, 1 mmol) in DCM:DMF (1:1) 20 ml under nitrogen stirring. To this suspension DIC (0.18 ml, 1.2 mmol) was added and the mixture was stirred for 3 hrs until the resin was negative to Kaiser test. It was filtered and washed with DCM:DMF (1:1) 15 ml×3 and finally with DCM. The resin was treated with 50% trifluoroacetic acid (TFA)/Bu3SiH in DCM for 30 min and then washed with 10% trifluoric acid (TFA)/Bu3SiH in DCM for 10 min (three times) to remove both Boc and trytyl group of Cys. After washing the resin with DCM 3 times, a solution of p-anisaldehyde (0.5 ml) in DCM:DMF (1:1) 10 ml was added under stirring. The stirring was continued for 8-10 hrs. The resin was washed three times with DCM. To this resin, a solution of Benzoyl chloride (0.2 ml, 2 mmol) and DIEA (0.4 ml, 2.0 mmol) in DCM:DMF (1:1) 10 ml were added and the stirring were continued for three hrs. After three hours, the resin was negative to Kaiser test. The resin was washed with DCM:DMF (1:1) 10 ml×3, with DMF 10 ml×3, DCM:DMF (1:1) 10 ml×2 and finally three times with DCM and dried. It was treated with a mixture of dioxan-MeOH-4N. NaOH (30:9:1, 20 ml) for 30 min under stirring and the resin was filtered and washed with 2 ml of water. The combined filtrate was evaporated in vacuo. The residue was taken in water and extracted with ether. The aqueous layer acidified with 1N hydrochloric acid to pH 2.0 and extracted with EtOAc (3×70 ml). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and evaporated in vacuo to yield N-Boc-2-(4-methoxyphenyl)thiazolidinyl-leucine as a glassy material. Yield: 0.11 g, 78%; FAB-MS [M+H]+ 453; 1H NMR (DMSO-d6) δ: 0.9 (m, 6H), 1.2 (bs, 9H), 1.7 (m, 2H), 4.3 (m 1H), 3.5 (m, 2H), 3.7 (s, 3H), 4.86 (bs, 1H), 5.9 (bs, 1H), 6.8-7.1 (Abq, 4H).

1. customwas placed in reaction vessel
2. filtrationAfter 30 min. the resin was filtered
3. washwashed with DCM
4. washThe resin was washed three times with DCM
5. customdried
6. additionThe resin was treated with 50% TFA in DCM for 30 min.
7. customto remove Boc group
8. filtrationAfter 30 min the resin was filtered
9. washwashed with DCM 20 ml×3, 20% DIEA in DCM 20 ml×3, DCM 20 ml×3
10. additiontreated with DCM:DMF (1:1) 20 ml
11. stirringthe mixture was stirred for 3 hrs until the resin
12. filtrationIt was filtered
13. washwashed with DCM:DMF (1:1) 15 ml×3 and finally with DCM
14. additionThe resin was treated with 50% trifluoroacetic acid (TFA)/Bu3SiH in DCM for 30 min
15. washwashed with 10% trifluoric acid (TFA)/Bu3SiH in DCM for 10 min (three times)
16. customto remove both Boc and trytyl group of Cys
17. washAfter washing the resin with DCM 3 times
18. additiona solution of p-anisaldehyde (0.5 ml) in DCM:DMF (1:1) 10 ml was added
19. stirringunder stirring
20. waitThe stirring was continued for 8-10 hrs
21. washThe resin was washed three times with DCM
22. waitthe stirring were continued for three hrs
23. waitAfter three hours
24. washThe resin was washed with DCM:DMF (1:1) 10 ml×3, with DMF 10 ml×3, DCM:DMF (1:1) 10 ml×2 and finally three times with DCM
25. customdried
26. additionIt was treated with a mixture of dioxan-MeOH-4N
27. stirringNaOH (30:9:1, 20 ml) for 30 min under stirring
28. filtrationthe resin was filtered
29. washwashed with 2 ml of water
30. customThe combined filtrate was evaporated in vacuo
31. extractionextracted with ether
32. extractionextracted with EtOAc (3×70 ml)
33. washThe combined EtOAc layer was washed with water and brine
34. dry with materialthen dried over Na2SO4
35. customevaporated in vacuo

ORD record

ord-d1485652785f4f15acba62dba1666486

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06492460B2