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Synthesis 2008(6): 891-896  
DOI: 10.1055/s-2008-1032181
PAPER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthesis of an NMDA Receptor Antagonist via Stereoselective Fluorination

Matthew M. Bio*a, Marjorie Waters*b, Gary Javadib, Zhiguo Jake Songb, Fei Zhangb, Dave Thomasb
a Amgen, Inc., One Kendall Square, Bldg 1000, Cambridge, MA 02139, USA
Fax: +1(617)6213916; e-Mail: mbio@amgen.com;
b Merck Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Further Information

Publication History

Received 9 November 2007
Publication Date:
18 February 2008 (online)

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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

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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