Traceless solid-phase synthesis of 2,4,6-chlorodiamino and triaminopyrimidines

Tetrahedron

Volumn 59, Issue 36, 2003, Pages 7147-7156

  Montebugnoli, Dario ^a   Bravo, Pierfrancesco ^a,b   Brenna, Elisabetta ^a   Mioskowski, Charles ^c   Panzeri, Walter ^b   Viani, Fiorenza ^b   Volonterio, Alessandro ^a   Wagner, Alain ^c   Zanda, Matteo ^b  

^a POLITECNICO DI MILANO   (Italy)

^b CNR   (Italy)

^c UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

De chlorination; Regioisomers; Triaminopyrimidines

Indexed keywords

(2 CHLORO 6 PENTYLAMINOPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; (2 CHLORO 6 PHENETHYLAMINOPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; (2 CHLORO 6 PIPERIDIN 1 YLPYRIMIDIN 4 YL)PHENYLAMINE; (2 CHLORO 6 PIPERIDIN 1 YLPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; (6 CHLORO 2 MORPHOLIN 4 YLPYRIMIDIN 4 YL)PHENYLAMINE; (6 CHLORO 2 PENTYLAMINOPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; (6 CHLORO 2 PHENETHYLAMINOPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; (6 CHLORO 2 PIPERIDIN 1 YLPYRIMIDIN 4 YL)PHENYLAMINE; (6 CHLORO 2 PIPERIDIN 1 YLPYRIMIDIN 4 YL)PHENYLCARBAMIC ACID TERT BUTYL ESTER; 1 [4 (TERT BUTOXYCARBONYLPHENYLAMINO) 6 CHLOROPYRIMIDIN 2 YL]PYRROLIDINE 2 CARBOXYLIC ACID BENZYL ESTER; 1 [6 (TERT BUTOXYCARBONYLPHENYLAMINO) 2 CHLOROPYRIMIDIN 4 YL]PYRROLIDINE 2 CARBOXYLIC ACID BENZYL ESTER; 2 CHLORO 6 N PHENETHYLAMINO 4 N PHENYLAMINOPYRIMIDINE; 2 CHLORO 6 N,N DIBENZYLAMINO 4 N PHENYLAMINOPYRIMIDINE; 2 [TERT BUTOXYCARBONYL (2 CHLORO 6 PIPERIDIN 1 YLPYRIMIDIN 4 YL)AMINO] 3 PHENYLPROPIONIC ACID BENZYL ESTER; 2 [TERT BUTOXYCARBONYL (6 CHLORO 2 PIPERIDIN 1 YLPYRIMIDIN 4 YL)AMINO] 3 PHENYLPROPIONIC ACID BENZYL ESTER; 6 CHLORO 2 N PENTYLAMINO 4 N PHENYLAMINOPYRIMIDINE; 6 CHLORO 2 N PHENETHYLAMINO 4 N PHENYLAMINOPYRIMIDINE; 6 CHLORO 2 N,N DIBENZYLAMINO 4 N PHENYLAMINOPYRIMIDINE; AMINE; AMINOPYRIDINE DERIVATIVE; BENZYL (2 CHLORO 6 PHENETYLAMINOPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; BENZYL (2 CHLORO 6 PHENYLAMINOPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; BENZYL (2 CHLORO 6 PIPERIDIN 1 YLPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; BENZYL (6 CHLORO 2 PHENETYLAMINOPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; BENZYL (6 CHLORO 2 PHENYLAMINOPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; BENZYL (6 CHLORO 2 PIPERIDIN 1 YLPYRIMIDIN 4 YL)CARBAMIC ACID TERT BUTYL ESTER; POLYMER; UNCLASSIFIED DRUG; UNINDEXED DRUG; [4 (TERT BUTOXYCARBONYLPHENYLAMINO) 6 CHLOROPYRIMIDIN 2 YLAMINO]ACETIC ACID TERT BUTYL ESTER; [6 (TERT BUTOXYCARBONYLPHENYLAMINO) 2 CHLOROPYRIMIDIN 4 YLAMINO]ACETIC ACID TERT BUTYL ESTER;

ARTICLE; CHEMICAL REACTION; DECHLORINATION; DRUG PURIFICATION; DRUG RELEASE; DRUG SYNTHESIS; PRIORITY JOURNAL; REACTION ANALYSIS; SOLID;

EID: 0043022253     PISSN: 00404020     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4020(03)01097-4     Document Type: Article

References (22)

1. (a) Vorbruggen H. Adv. Heterocycl. Chem. 49:1990;117-192. and references therein
2. (b) Turck A., Plé N., Mongin F., Quéguiner G. Tetrahedron. 57:2001;4489-4505
3. (c) Schomaker J.M., Delia T.J. J. Org. Chem. 66:2001;7125-7128. and references therein.
4. (a) Franzén R.G. J. Comb. Chem. 2:2000;195-214
5. (b) Obrecht D., Abrecht C., Grieder A., Villalgordo J.M. Helv. Chem. Acta. 80:1997;65-72
6. (c) Guillier F., Roussel P., Moser H., Kane P., Bradley M. Chem. Eur. J. 5:1999;3450-3458
7. (d) Di Lucrezia R., Gilbert I.H., Floyd C.D. J. Comb. Chem. 2:2000;249-253
8. (e) Makara G.M., Ewing W., Ma Y., Wintner E. J. Org. Chem. 66:2001;5783-5789
9. (f) Barillari C., Barlocco D., Raveglia L.F. Eur. J. Org. Chem. 2001;4737-4741
10. (g) Krchnak V., Holladay M.W. Chem. Rev. 102:2002;61-91.
11. (a) Zanda M., Talaga P., Wagner A., Mioskowski C. Tetrahedron Lett. 41:2000;1757-1761
12. (b) Zucca C., Bravo P., Volonterio A., Zanda M., Wagner A., Mioskowski C. Tetrahedron Lett. 42:2001;1033-1035
13. (c) Montebugnoli D., Bravo P., Corradi E., Dettori G., Mioskowski C., Volonterio A., Wagner A., Zanda M. Tetrahedron. 58:2002;2147-2153.
14. For preparation of the Boc-like linker from Merrifield resin see: (d) Hernández A.S., Hodges J.C. J. Org. Chem. 62:1997;3153-3157.
15. See for example: D'Atri G., Gomarasca P., Resnati G., Tronconi G., Scolastico C., Sirtori C.R. J. Med. Chem. 27:1984;1621-1629.
16. Zanda, M.; Wagner, A. Unpublished results.
17. r than, respectively, 5 and 9.
18. 2 in the amino-de-chlorination affording N,N-dimethylamino-pyrimidine by-products. The same side-reaction was observed in the solid-phase version. Obviously, this undesired event could be avoided by using other solvents such as benzene, ethanol or THF, but we qualitatively observed slower and less efficient reactions. Direct formylation of amines by DMF has been previously described: (a) Birkofer L., Hartwig I. Chem. Ber. 89:1956;1608-1614 (b) Pettit G.R., Thomas E.G. J. Org. Chem. 24:1959;895-896. We are currently investigating the use of N,N-dimethylacetamide (DMA) and N-methyl-pyrrolidone (NMP).
19. 2 in the amino-de-chlorination affording N,N-dimethylamino-pyrimidine by-products. The same side-reaction was observed in the solid-phase version. Obviously, this undesired event could be avoided by using other solvents such as benzene, ethanol or THF, but we qualitatively observed slower and less efficient reactions. Direct formylation of amines by DMF has been previously described: (a) Birkofer L., Hartwig I. Chem. Ber. 89:1956;1608-1614 (b) Pettit G.R., Thomas E.G. J. Org. Chem. 24:1959;895-896. We are currently investigating the use of N,N-dimethylacetamide (DMA) and N-methyl-pyrrolidone (NMP).
20. Formation of N,N-dimethylamino-pyrimidines in the solid-phase was observed mainly with primary amines, when longer reaction times or higher temperatures than those reported in Table 2 were used.
21. See Ref. 3c for further details.
22. Surprisingly, a single regioisomer of 10b was detected by GC-MS. The regiochemistry portrayed in Scheme 4 was not assessed spectroscopically.