Rapid improvement of a reductive sulfonylation using design of experiment methods

Organic Process Research and Development

Volumn 7, Issue 3, 2003, Pages 313-317

  Chen, Jiong Jack ^a   Nugent, Thomas C ^b   Lu, Cuong V ^a   Kondapally, Sudharani ^b   Giannousis, Peter ^b   Wang, Ying ^a   Wilmot, Jeremy T ^a  

^a Chemical Process Research and Development   (United States)

^b SUGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SODIUM SULFITE; SULFONE; ZINC;

ARTICLE; CHEMICAL INTERACTION; CHEMICAL REACTION; EXPERIMENTATION; REACTION OPTIMIZATION; REACTION TIME; REDUCTION; SCALE UP; SULFONYLATION; SYNTHESIS;

EID: 0038384689     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op034018g     Document Type: Article

References (12)

1. Drabowicz, J.; Kielbasinski, P.; Mikolajczyk, M. In The Chemistry of Sulphinic Acids, Esters and Their Derivatives; Patai, S., Ed.; John Wiley & Sons: New York, 1990; p 351-430.
2. Zoller, U. In The Chemistry of Sulphinic Acids, Esters and Their Derivatives; Patai, S., Ed.; John Wiley & Sons: New York, 1990; p 185-
3. Sun, P. P.; Wang, L.; Zhang, Y. M. Tetrahedron Lett. 1997, 38, 5549.
4. Sun, X.-H.; Wang, L.; Zhang, Y.-M. Synth. Commun. 1998, 28, 1785.
5. Saikia, P.; Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Chem. Lett. 2001, 512.
6. To our knowledge this is the first reported use of DMF for this type of transfonnation. When the typical solvent THF was employed, ≥ 1 day was required for complete reaction.
7. The extreme insolubility of the product 2 and the sulfide 3, ruled out the use of traditional crystallization scenarios. Ultimately we found that enrichment could be effected by heating the sulfide-rich sulfone in an EtOAc/DMF (2:1) mixture for 15 min at 60°C, followed by hot filtration. When repeated twice, this allowed a 70 wt % recovery with a 50% reduction in the sulfide content.
8. Zinc dust (Aldrich Chemical Co., catalog no. 20, 998-8) aggregation was noted when overhead mechanical stirring was employed as the mode of stirring, and low yields (10-30%) resulted. The agglomeration phenomena observed with the zinc dust is relatively common. Magnetic stir bars have the advantage of physically grinding agglomerates against the face of the glass wall. This is not possible with an overhead stirrer. As a consequence, any reaction requiring physical action to liberate occluded material will not scale well unless something is used to provide this action. On scale-up, depending on the strength of the agglomerate, the use of a recirculating loop with a rotor/stator mill or a grinding sand mill generally corrects the problem. We would like to thank John VanAlsten of Pharmacia for his input regarding these insights.
9. Field, L.; Clark, R. D. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 674.
10. We used a parallel synthesizer, LabMate, that is made by Advanced ChemTech Inc. It has four temperature zones, six positions for each zone, and uses shaking for mixing.
11. Design Expert, version 6; DoE software developed by Stat-Ease, Inc. The software is intuitive, but some basic knowledge of DoE is desirable. Our company statisticians provided an overview in a 1-h demonstration.
12. The definition of these terminologies, such as normal probability plot, factor, interaction, etc. may be found in any statistics or experimental design books, such as DOE Simplified: Practical Tools for Effective Experimentation, written by the developers of Design Expert. We found a contribution published in this journal very informative: Owen, M. R.; Luscombe, C.; Lai, L.-W.; Godbert, S.; Crooke, D. L.; Emiabata-Smith, D. Org. Process Res. Dev. 2001 5, 308.