Novel oxidation of Cyclosporin A: Preparation of Cyclosporin methyl vinyl ketone (Cs-MVK)

Synlett

Volumn , Issue 18, 2009, Pages 2935-2938

  Yang, Zhicai ^a   Pattamana, Kevin ^a   Molino, Bruce F ^a   Haydar, Simon N ^a   Cao, Yeyu ^a   Bois, Frederic ^a   Maeng, Jun Ho ^a   Hemenway, Michael S ^a   Rich, Joseph O ^a   Khmelnitsky, Yuri L ^a   Friedrich, Thomas D ^b   Peace, Denise ^b   Michels, Peter C ^a  

^a ALBANY MOLECULAR RESEARCH INC   (United States)

^b ALBANY MEDICAL COLLEGE   (United States)

Author keywords

Allylic oxidation; Cyclosporin A; Cyclosporin methyl vinyl ketone; Immunosuppression; Lac case oxidation

Indexed keywords

1 HYDROXYBENZOTRIAZOLE; CYCLOSPORIN A; CYCLOSPORIN DERIVATIVE; CYCLOSPORIN METHYL VINYL KETONE; KETONE DERIVATIVE; LACCASE; PERIODATE; POTASSIUM PERIODATE; TERT BUTYL HYDROPEROXIDE; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BIOCATALYST; BIOTRANSFORMATION; CATALYSIS; CHEMICAL REACTION; DRUG DESIGN; DRUG SYNTHESIS; HUMAN; IMMUNOMODULATION; OXIDATION;

EID: 72049090390     PISSN: 09365214     EISSN: 14372096     Source Type: Journal    
DOI: 10.1055/s-0029-1218011     Document Type: Article

References (16)

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15. 2 atmosphere for 3 d. Organic solvents were removed from the reaction mixture in vacuo. The remaining mixture was poured into ice-water (1 L) and extracted twice with a mixture of EtOAc?hexanes (200 mL, 1:1). The combined extracts were stirred in a 10% sodium sulfite solution for 2 h. The organic layer was separated, dried over Na2SO4 and concentrated. The crude product was purified by either preparative or semi-preparative HPLC, using acetonitrile (containing 0.05% TFA)/water (containing 0.05% TFA) solvent system, to provide CsA-MVK (2.5?3.5 g, 50?70%) as light-yellow solid. Analytical Data of 3: 1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 9.9 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.89 (dd, J = 16.1, 7.6 Hz, 1 H), 6.06 (d, J = 16.1 Hz, 1 H), 5.71 (dd, J = 11.0, 3.8 Hz, 1 H), 5.65 (br s, 1 H), 5.22 (dd, J = 11.5, 3.8 Hz, 1 H), 5.10 (d, J = 11.0 Hz, 2 H), 5.05 (dd, J = 15.7, 9.1 Hz, 1 H), 4.96 (dd, J = 10.1, 5.7 Hz, 1 H), 4.85 (q, J = 7.2 Hz, 1 H), 4.73 (d, J = 14.1 Hz, 1 H), 4.65 (q, J = 8.7 Hz, 1 H), 4.55 (q, J = 7.4 Hz, 1 H), 4.04 (br s, 2 H), 3.52 (s, 3 H), 3.39 (s, 3 H), 3.31 (s, 3 H), 3.20 (d, J = 13.9 Hz, 1 H), 3.12 (s, 3 H), 3.11 (s, 3 H), 2.72 (s, 3 H), 2.68 (s, 3 H), 2.54?2.34 (m, 3 H), 2.26 (s, 3 H), 2.20?1.76 (m, 11 H), 1.75?1.35 (m, 6 H), 1.32 (d, J = 7.3 Hz, 3 H), 1.26 (d, J = 7.3 Hz, 3 H), 1.10?0.81 (m, 39 H); 13C NMR (90 MHz, CDCl3): d = 198.6, 174.7, 174.1 (2 C), 173.8, 171.7, 171.6, 171.3, 170.6, 170.5, 170.3, 170.2, 148.9, 131.8, 74.9, 59.6, 58.2, 57.8, 55.7 (2 C), 55.2, 50.6, 48.9, 48.6, 48.3, 45.3, 40.7, 39.7, 39.5, 39.2, 38.0, 36.2, 35.0, 31.7, 31.6, 31.3, 30.1 (2 C), 29.8, 29.6, 27.5, 25.3, 25.1, 24.9 (2 C), 24.6, 24.0 (4 C), 23.8, 23.6, 22.0 (2 C), 21.3, 20.8, 20.0, 18.8 (2 C), 18.6, 18.4, 16.1; MS (ESI): m/z = 1216
16. The murine system uses the H2 disparate inbred mouse strains: Balb/c (H2d) and C57B1/6 (H2b). Splenocytes of the C57B1/6 mice are g-irradiated so as to act as stimulators of an immune response from the splenocytes from the Balb/c mice. IC50 values are the concentration of test compound that inhibit 3H-thymidine uptake by 50% relative to control cells and are determined from 7 point concentration-response curves using GraphPad software