An Efficient Synthesis of an NMDA Receptor Antagonist via Stereoselective Fluorination

Abstract

Herein is described the development and use of a novel bis(dialkylamino)sulfur difluoride reagent to effect the stereoselective conversion of a benzylic alcohol into a benzylic fluoride. A new method for the synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amines is reported. Additionally, a practical method for the addition of a hindered alkoxide to an epoxide is demonstrated.

Key words

fluorine - stereoselective synthesis - heterocycles - de­oxygenation - ethers

References

• 1 For an excellent recent review of fluorine in pharmaceuticals, see: Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 
• 2 Böhm H.-J. Banner D. Bendels S. Kansy M. Kuhn B. Müller K. Obst-Sander U. Stahl M. ChemBioChem  2004,  5:  637 
• 3a Thompson W, Young SD, Phillips BT, Munson P, Whitter W, Liverton N, Dieckhaus C, and Butcher J. inventors; WO Patent 2005019222  A1. 
• 3b Thompson W, Young SD, Phillips BT, Munson P, Whitter W, Liverton N, Dieckhaus C, Butcher J, McCauley JA, McIntyre ME, Layton ME, and Sanderson PE. inventors; US Patent 2007/0037829  A1. 
• 3c NR2B selective NMDA (N-methyl-d-aspartate) receptor antagonists have shown promise as non-dopaminergenic drugs for the treatment of Parkinson’s, see: Nash JE. Hill MP. Brotchie JM. Exp. Neurol.  1999,  155:  42 
• 3d For a discussion of the molecular and functional distinctions of the NMDA subtypes, see: Monyer H. Sprengel R. Schoepfer R. Herb A. Miyoko H. Lomeli H. Burnashev N. Sakmann B. Seeburg PH. Science  1992,  256:  1217 
• 4 Robbins RK. J. Am. Chem. Soc.  1956,  78:  784 
• 5 Posner GH. Rogers DZ. J. Am. Chem. Soc.  1977,  99:  8280 
• 6a Campbell JC. Greengrass CW. Plews RM. J. Med. Chem.  1988,  31:  516 
• 6b Kachinsky JLC. Salomon RG. J. Org. Chem.  1986,  51:  1393 
• 6c Tanaka Y. Nishimura K. Tomioka K. Tetrahedron  2003,  59:  4549 
• 8 Chung JYL. Cvetovich R. Amato J. McWilliams JC. Reamer R. DiMichele L. J. Org. Chem.  2005,  70:  3592 
• 9 While fluoride displacement reactions have a long history, they have a rather mixed record of success. Recent reports suggest that ionic liquids suppress competing reactions and favor fluoride displacement, see: Kim DW. Song CE. Chi DY. J. Am. Chem. Soc.  2002,  124:  10278 
• For benzylic sulfonates specifically, the stereoselectivity is rather substrate dependent. See for instance:
• 10a Fritz-Langhals E. Tetrahedron Lett.  1994,  35:  1851 
• 10b Fritz-Langhals E. Tetrahedron: Asymmetry  1994,  5:  981 
• 11 Singh RP. Shreeve JM. Synthesis  2002,  2561 
• 12 Hudlicky M. Fluorinations with Diethylaminosulfur Trifluoride and Related Aminosulfurans, In Organic Reactions   Vol. 35:  John Wiley & Sons, Inc.; New York: 1988.  p.513-637  
• 14a Paulsen H. Antons S. Brandes A. Lögers M. Müller SN. Naab P. Schmeck C. Schneider S. Stoltefuß J. Angew. Chem. Int. Ed.  1999,  38:  3373 
• 14b Walba DM. Razavi HA. Clark NA. Parmar DS. J. Am. Chem. Soc.  1988,  110:  8686 
• 15 The synthesis of bis(dialkylamino)sulfur difluorides has been reported, although the use of these compounds as fluorination reagents for organic synthesis is unknown to the best of our knowledge. See: Messina PA. Mange KC. Middleton WJ. J. Fluorine Chem.  1989,  42:  137 
• 16 Lal GS. Pez GP. Pesaresi RJ. Prozonic FM. Chem. Commun.  1999,  215 

7

Note that there was no need to protect the primary amine. Under these conditions, N-alkylation was not observed. In contrast, the use of bases generating a Mg, Li or Na counter-ion, resulted in epoxide opening by the amine, not the alkoxide.

13

In our early studies toward the synthesis of 1, the Cbz-protected amine (S)-12 was used in the fluorination studies. We have established that the nature of the amide or carbamate present at the nitrogen has no effect on the stereoselectivity of the fluorination reaction.

17

This salt formation improved the enantiomeric purity of (R)-2 to 98.4% ee, which was critical for preparing the final product with the required high optical purity.

18

The polymerization resulting from reaction of 3 with itself via displacement of the chloride by the pyrrazole ring nitrogen of another molecule of 3 (Scheme [7] ).

Scheme 7