1-Methylimidazole → n-Benzoyl-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid

Commercially available Fmoc-Cys(Trt) was attached to the linker based solid support # by DIC/DMAP procedure. The solid support (0.50 g) having substitution 0.34 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 Fmoc-Cys(Trt) (0.56 g, 1.0 mmol) dimethylaminopyridine (DMAP) or N-methyl imidazole (NMI) (0.25 mmol) in DCM:DMF (1:1) 20 ml were added. This mixture was stirred for 8-10 hrs. An aliquot of the resin was washed three times with DCM and dried. An aliquot of this resin was tested to check the loading by the treatment with 20% piperidine and subsequently recording the absorbance indicating approximately 88% loading [Method A]. The resin bearing Fmoc-Cys(Trt) was treated 20% piperidine in DCM:DMF (1:1) 12 ml for 20 min to remove Fmoc group. The resin was washed three times with DCM and then treated with 10% trifluroacetic acid (TFA)/Bu3SiH in DCM for 30 min (three times) to remove the trityl 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 was continued for 3 hrs until 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 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-Benzoyl-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid as white crystalline material. Yield: 0.043 g, 72%; m.p. 108-110° C.; FAB-MS [M+H]+ 344; 1H NMR (DMSO-d6) δ: 3.3 (m, 2H), 3.9 (s, 3H), 4.7 (bs, 1H), 5.7 (bs, 1H), 6.6 (m 5H), 6.9-7.2 (Abq, 4H).

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

ORD record

ord-5c923fbe1f684f54a5dfd990bc1bb683

Source dataset

uspto-grants-2002_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06492460B2