Supporting Information. Synthesis and Optimization of Canagliflozin by Employing QbD Principles

Transcription

1 Supporting Information Synthesis and Optimization of Canagliflozin by Employing QbD Principles Dattatray S. Metil, ab Swapnil P. Sonawane, a Sharad S. Pachore, a Aaseef Mohammad, a Vilas H. Dahanukar, a Peter J. McCormack, c Ch. Venkatramana Reddy b and Rakeshwar Bandichhor a* a API R & D, IPDO, Dr. Reddy s Laboratories Ltd. Bachupally, Hyderabad, Telangana, India b Department of Chemistry, JNTU college of Engineering, JNT university, Kukatpally, Hyderabad , Telangana, India c Dr. Reddy s Laboratories, Chirotech Technology Center, 410 Cambridge Science Park Milton Rd, Cambridge CB4 0PE, U.K. * To whom correspondence should be addressed. rakeshwarb@drreddys.com Tel: , Fax: Table of contents S. No. Content Page No. 1 General Information S2 2 Screening DoE parameters and results S2 2.1 Screening DoE parameters and results of C-arylation reaction S ANOVA analysis of response variables for screening DoE of C-arylation S4 reaction Contour plots of response variables for screening DoE of C-arylation S5-S6 reaction 2.2 Screening DoE parameters and results of reductive elimination reaction S6-S7 3 Thermal safety (RC1e) data S8 4 Spectral data, HPLC chromatogram, PXRD and DSC data S9-S24 S1

2 1. General Information HPLC analysis was performed using X-Bridge C mm, 3.5µ column on an Agilent 1100 LC equipped with variable wavelength detector. HPLC grade THF used in the analysis was purchased from Rankem, India, whereas acetonitrile, orthophosphoric acid and disodiumhydrogen phosphate, used in the HPLC analysis were purchased from Merck, Mumbai, India. Water used for preparing the mobile phase was purified using a Millipore milli-q plus (Milford, MA, USA) purification system. The 1 H and 13 C spectra were recorded in CDCl 3 and DMSO-d 6 using Bruker Advance 400MHz and 100MHz spectrometer respectively; the chemical shifts were reported in δ ppm downfield from tetramethylsilane (0.00 ppm).the following abbreviations were used to explain the multiplicities: s=singlet, d=doublet, t=triplet, m=multiplet The mass spectrum (70 ev) was recorded on HP 5989 A LC/MS spectrometer. HRMS was recorded on LCT. Premier, XE Spectrometer. The FT-IR spectrum was recorded on Perkin- Elmer model Spectrum series FT-IR instrument (KBr pellet method). Melting points (DSC) were determined using an Electro-thermal melting point apparatus DSC 2000 and are uncorrected. PXRD was recorded on Bruker AXS, D8 Advance detector PSD-Lynx Eye using radiation CuKα (wavelength= A ). Solvents and reagents were obtained from commercial sources and used without further purification. S2

3 2. Screening DoE parameters and results 2.1 Screening DoE parameters and results of C-arylation reaction Table S1. Factors (process parameters) for screening DoE studies a of 12 Symbol Factors (process parameters) Unit Low Range High A Temperature ºC B Quantity of n-buli Equiv C Quantity compound 3 Equiv D Volume of THF Vol 5 10 E Volume of toluene Vol 1 5 \a Five factors definitive screening factorial DoE design with one center point was performed to identify number of input process parameters that have impact on the response variables with all of the other parameters kept at predefined levels. Table S2. The screening DoE studies parameters and results of 12 S. No. Reaction temperature (ºC) Factors (process parameters) n-buli equiv Compound 3 equiv THF volume Toluene volume Response variables Purity (%) 13 (%) 2b (%) S3

4 2.1.1 ANOVA analysis of response variables for screening DoE of C-arylation reaction Table S3. ANOVA analysis of purity response for selected factorial model Degrees of Mean F- p-value prob > Source Sum of squares freedom squares value F Model significant A (temperature) B (n-buli equiv) B Residual Cor total Table S4. ANOVA analysis of impurity 13 response for selected factorial model Degrees of Mean F- p-value prob > Source Sum of squares freedom squares value F Model significant A (temperature) D (THF) Residual Cor total Table S5. ANOVA analysis of 2b response for selected factorial model Degrees of Mean F- p-value prob > Source Sum of squares freedom squares value F Model < significant B (n-buli equiv) < B Residual Cor total S4

5 2.1.2 Contour plots of response variables for screening DoE of C-arylation reaction Figure S1. Contour plot for the variation in purity of 12 with respect to n-buli equiv and temperature. Green region indicates purity <70%, while progression towards orange and red region, indicates increasing purity by increasing n-buli equiv and decreasing temperature. Figure S2. Contour plot for the variation in impurity 13 with respect to THF volume and temperature. Contour plot indicates increasing impurity 13 content by increasing temperature and THF volume, S5

6 Figure S3. Contour plot for the variation in 2b (%) with respect to n-buli equiv and temperature. Green region indicates 2b >20%, while moving towards blue region, indicates decreaseing 2b content by increasing n-buli equiv. 2.2 Screening DoE parameters and results of reductive elimination reaction Table S6. Factors (process parameters) for scrrening DoE studies of 1 Symbol Factors (process parameters) Unit Low Range A Quantity of BF 3 Et 2 O Equiv 1 3 B Quantity of TES Equiv High C Volume of DCM Vol 8 16 D Temperature ºC E Addition time Min \a Five factors definitive screening factorial DoE design with three center points was performed to identify number of input process parameters that have impact on the response variables with all of the other parameters kept at predefined levels. S6

7 Table S7. The screening DoE studies parameters and results of 1 S. No. BF 3 Et 2 O equiv TES equiv Factors (process parameters) DCM volume Temperature (ºC) Addition time Response variables Purity (%) 14 (%) S7

8 3. Thermal safety (RC1e) data Table S8. Enthalpy results from RC1e experiment for TMDS reduction reaction in the synthesis of aglycon 2b Process step Reaction mass temperature ( C) Heat of reaction (kj/mol) * T ad ( K) TMDS addition into the reaction mass Heating the reaction mass to 50 C * T ad = adiabatic temperature rise. Note: TMDS addition is slightly exothermic, hence slow addition of TMDS by maintaining reaction mass temperature at C was proposed. Table S9. Enthalpy results from RC1e experiment for reductive elimination reaction in the synthesis of 1 Process step Reaction mass temperature ( C) Heat of reaction (kj/mol) T ad ( K) *MTSR ( C) BF 3 Et 2 O addition into the reaction mass *MTSR= maximum temperature of a synthetic reaction mixture. Note: BF 3 Et 2 O addition is exothermic, hence controlled addition of BF 3 Et 2 O solution by maintaining reaction mass temperature at -35 to -45 C was proposed. S8

9 4. Spectral data, HPLC chromatogram, PXRD and DSC data 2-(4-fluorophenyl)-5-(5-iodo-2-methylbenzyl)thiophene (2b) Figure S4. 1 H NMR spectrum of aglycon 2b in DMSO-d 6 S9

10 Figure S5. Mass spectrum of aglycon 2b Figure S6. IR spectrum of aglycon 2b S10

11 Figure S7. DSC of aglycon 2b S11

12 (2R,3S,4R,5R)-1-(3-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-2,3,4,5,6- pentahydroxyhexan-1-one (12) Figure S8. 1 H NMR spectrum of compound 12 in DMSO-d 6 (recorded immediately after dissolution) S12

13 Figure S9. Overlayed timed 1 H NMR spectrum of compound 12 in DMSO-d 6 S13

14 Figure S C NMR spectrum of compound 12 in DMSO-d 6 Figure S11. COSY spectrum NMR spectrum of compound 12 in DMSO-d 6 S14

15 Figure S12. HSQC NMR spectrum of compound 12 in DMSO-d 6 Figure S13. HMBC NMR spectrum of compound 12 in DMSO-d 6 S15

16 Figure S14. NOESY NMR spectrum of compound 12 in DMSO-d 6 Figure S F NMR spectrum with 1H decoupling (bottom) and without 1H decoupling (top) of compound 12 in DMSO-d 6 (The additional fluorine signals showing some tautomerisation to ring closed species) S16

17 Figure S16. ve ion Mass spectrum of compound 12 showing weak [M-H] - (Mw 459.2) and [M+formate] - (Mw 505.0) ions Figure S17. HRMS of compound 12 S17

18 Figure S18. IR spectrum of compound 12 Figure S19. PXRD of compound 12 S18

19 Figure S20. DSC of compound 12 S19

20 Figure S21. HPLC chromatograph of isolated compound 12 S20

21 Canagliflozin 1 Figure S22. 1 H NMR spectrum of canagliflozin 1 in DMSO-d 6 Figure S C NMR spectrum of canagliflozin 1 in DMSO-d 6 S21

22 Figure S24. One-dimensional dept135 of canagliflozin 1 in DMSO-d 6 Figure S25. HRMS of canagliflozin 1 S22

23 Figure S26. Mass spectrum of canagliflozin 1 Figure S27. IR spectrum of canagliflozin 1 S23

24 Figure S28. DSC of canagliflozin 1 Figure S29. TGA of canagliflozin 1 S24