(S)-5-fluoro-3-methylisobenzofuran-1(3H)-one

Preparation of (S)-5-Fluoro-3-methylisobenzofuran-1(3H)-one (6)

To a ................... Purity 99.9%, ee > 99.9%.

 

1H NMR (400 MHz, CDCl3): δ 7.88 (dd, J = 4.8, 8.4 Hz, 1 H), 7.21 (ddd, J = 2.0, 8.4, 8.8 Hz, 1 H), 7.12 (dd, J = 2.0, 8.8 Hz, 1 H), 5.53 (q, J = 6.4 Hz, 1 H), 1.63 (d, J = 6.4 Hz, 3 H) ppm;

 

13C NMR (100.6 MHz, CDCl3): δ 169.1, 166.5 (d, JCF = 256.6 Hz), 153.8 (d, JCF = 9.1 Hz), 128.0 (d, JCF = 10 Hz), 121.8, 117.2 (d, JCF = 24.1 Hz), 108.9 (d, JCF = 25.2 Hz), 77.0, 20.2 ppm;

 

19F NMR (376.5 MHz, CDCl3): δ −102.8 ppm.

 

HRMS: Calcd for C9H8O2F (M + H)+: 167.0503. Found: 167.0497.

Developing an Asymmetric Transfer Hydrogenation Process for (S)-5-Fluoro-3-methylisobenzofuran-1(3H)-one, a Key Intermediate to Lorlatinib

Shengquan Duan* , Bryan Li, Robert W. Dugger, Brian Conway, Rajesh Kumar, Carlos Martinez, Teresa Makowski, Robert Pearson, Mark Olivier, and Roberto Colon-Cruz

Chemical Research and Development and Analytical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00187

 

*E-mail: Shengquan.duan@pfizer.com.

 

Synthesis of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib, is described. A few synthetic methodologies, that is, boron reduction, enzymatic reduction, asymmetric hydrogenation, and asymmetric transfer hydrogenation, were evaluated for the chiral reduction of the substituted acetophenone intermediate (8). A manufacturing process, on the basis of the asymmetric transfer hydrogenation, was developed. This process was successfully scaled up to prepare 400 kg of 6.

   

1H AND 13C NMR PREDICT