Supporting Information for: Improved One Pot Synthesis of Citalopram Diol and its Conversion to Citalopram

Transcription

1 Supporting Information for: Improved One Pot Synthesis of Citalopram Diol and its Conversion to Citalopram Ravindra Vedantham, a,b Prasadaraju VNKV Vetukuri, a Ambaiah Boini, a Mukkanti Khagga, b Rakeshwar Bandichhor a * Research and Development, API, Integrated Product Development, Innovation Plaza, Dr. Reddy s Laboratories Ltd, Bachupally, Qutubullapur, R.R.Dist , A.P., India Institute of Science and Technology, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad , A.P., India. * Corresponding author: Tel.: ; rakeshwarb@drreddys.com Pages 2-8: Mass, 1 H & 13 C NMR spectra of compounds 16 and 1. Pages 9-13: Spectral data of impurities iii and ix. Pages 14-16: Data related to Design of Experiments. Page 17: Comparison of Present process vs few reported diol procedures with better yield. Page-18-19: Additional description and optimization observations on butyryl impurity of diol (iii) 1

2 Spectra Mass Spectrum of compound 16 2

3 1 H NMR Spectrum of compound 16 3

4 13 C NMR Spectrum of compound 16 4

5 Mass Spectrum of compound 1 5

6 1 H NMR Spectrum of compound 1 6

7 13 C NMR Spectrum of compound 15 7

8 Identification of impurity iii in LCMS data of compound 16 8

9 Identification of compound 16 in LCMS data of compound 16 9

10 Mass Spectrum of compound iii 10

11 1 H NMR Mass Spectrum of compound iii 11

12 Mass Spectrum of compound ix 12

13 1 H NMR Mass Spectrum of compound ix 13

14 Data related to Design of Experiments Table S1. Operable ranges for DoE based on pre-doe experiments process variables low high process variables low high BFB (mol equiv.) Mg (mol equiv.) Iodine (% w/w) CPA (mol equiv.) Mg (mol equiv.) Iodine (% w/w) Table S2. Respose surface model augmented to three-variable full-factorial design for BFB Grignard reaction 14

15 Contour graphs for yield and purity for BFB Grignard reaction Table S3. Respose surface model augmented to three-variable full-factorial design for CPA Grignard reaction 15

16 Contour graphs for yield and purity for CPA Grignard reaction Table S4. Final validation conditions selected from the design space BFB (mol equiv.) Mg (mol equiv.) Iodine (% w/w) CPA (mol equiv.) Mg (mol equiv.) Iodine (% w/w) Design space obtained for double (BFB and CPA) Grignard reaction 16

17 Brief comparison of present diol process vs few reported diol procedures with better yield. Reference Solvents for Grignard reaction Brief steps involved in Diol work up process Comments Involves unsafe THF distillation and hot layer separations. Lengthy process due to acid-base US THF Quenching, solvent distillation, product extraction, salt formation treatments and extractions. As per the disclosed process, Diol can be converted to citalopram in two ways; using diol organic layer and using diol HBr salt. Hence, overall yield is not clearly mentioned for both approaches separately. Quenching, solvent distillation, carbon Involves unsafe THF distillation. treatment, toluene extractions and Seed and toxic bromo ethane were used for EP THF washings, in-situ cyclization of halo CPA Grignard. magnesate intermediate (instead of Over all yield was reported for citalopram diol) to citalopram. as 27%. Quenching, solvent distillation, acid- Involves unsafe THF distillation. WO2005/77927 THF, DCM, toluene base treatments, toluene extractions, in-situ cyclization of diol using aq. Involves usage of toxic dibromo ethane for CPA Grignard along with iodine. Sulfuric acid to citalopram. 56% Yield was reported for diol. WO2010/4575 US2011/92719 THF, DCM, toluene Quenching, acid-base treatments, toluene extractions, isolation of diol freebase 64% yield was reported for diol freebase. In US patent CPA Grignard was prepared at high temperature. ( C) J. Org. Chem. 2012, 77, THF Quenching, extraction with DCM, distillation of solvent, column chromatographic purification, recrystallization 90% yield, executed at milligram scale. Present work THF, DCM, toluene Quenching, unwanted solids filtration, isolation of Diol HBr solid from the filtrate. 68% yield, Doesn t involve distillation, extractions, acid-base treatments, chromatographic purifications, carbon treatment at Diol stage. 17

18 Additional Description on Butyryl impurity of diol iii Herein we have mentioned some of the experimental results of various process parameters affecting the formation of butyryl impurity as given below. The increment in butyryl impurity was observed when: a) there is increase in reaction temperature (higher percentage was observed when reaction temperature crosses 5 C) S. No. Reaction temp. Butyryl Imp. ( C) (%) 1-5 to to b) there is increase in addition time or maintenance time (>90 min) before reaction completion S. No. Addition time Butyryl Imp. (min) (%) c) we use large excess of reagent (> 3 mole equivalents of CPA) S. No. CPA mol. Butyryl Imp. equiv. (%) Reaction is incomplete below 1.2 equiv. Above results and experimental observations can be better described below. Instead of relating the formation of iii to only CPA quantity, we also focused on rate of addition/reaction of CPA Grignard reagent to the keto intermediate. When the addition time is more than 90 minutes, the increment in butyryl impurity is found to be higher side. At the same time, when we add the Grignard 18

19 reagent at once, the sudden exothermicity in reaction led to rise in temperature leads to increase in butyryl impurity. Further, when we add excess Grignard reagent >3 mol equiv., extent of formation of butyryl impurity is found to be higher side. Thus, as a part of optimization, we tried to balance all the factors (temperature, CPA quantity and rate of addition) during CPA Grignard addition in order to control the butyryl impurity to the possible extent and obtain optimal conversion without disturbing cyano functionality up to great extent. In summary, higher gestation period for reaction (> 90 min) with the lower quantity of reagent (1.2 equiv) would lead to increase in impurity where as faster rate of addition (60 min)/reaction with higher quantity of reagent (2.2 equiv) would not lead to increase in the impurity formation. Hence, we had designed the process conditions considering the experimental observations though they appear to be contradictory when compared to the known theoretical aspects. In our endeavor we found that the 2.2 to 3 mol equiv of CPA Grignard if added in a span of 60 min afforded optimal conversion (almost quantitative conversion of keto intermediate) and the impurity formation was within the specification. 19