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A simple and commercially viable process for improved yields of Metopimazine, a dopamine D2-receptor antagonist Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth, Madhusudana Rao Gajula, and Kumar Pramod Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 27 Apr 2017 Downloaded from http://pubs.acs.org on April 27, 2017
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Organic Process Research & Development
A simple and commercially viable process for improved yields of Metopimazine, a dopamine D2-receptor antagonist Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth, Madhusudana Rao Gajula,* Kumar Pramod * Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, 4th phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore-560 105, Karnataka, India. Corresponding Authors:
[email protected],
[email protected] Abstract: An efficient, practical and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared to earlier reports (60 °C. To study the effect of NaOH on the course of the reaction, the same reaction was carried out in presence of NaOH, but the formation of compound 5 was low (68%) even after 6 h with increased formation of impurities (10% of 5a and 8% of 5b) compared to the reaction in KOH. Table 7. Selection of suitable solvent for deprotection and in situ N-alkylationa Entry
Solvent
1 2 3 4 5 6 7 8 9d 10d
Dichloromethane Ethyl acetate Acetone
Acetonitrile THF DMSO DMF
Time (h) 8 5 3 24 15 6 4 5 3 2
Tempˈ (°C)
Product
30-35 50-60 50-60 20-30 30-40 40-50 50-60 50-60 50-60 50-60
5 5 5 5 5 5 5 5 5 5
a
Selectivityc by HPLC 5 5a 5b 40 15 03 35 25 06 84 9 1.5 20 03 01 35 05 02 66 10 04 42 31 08 35 38 06 61 18 04 64 20 05
Reaction conditions: Compound 4 (10 g, 0.031 mol), powdered KOH (5.26 g, 0.094 mol), 1-bromo-3-chloropropane (14.6 g, 0.094 mol) in solvent (10 vol) at 50-60 °C. b Isolated yield after isolation and purification in Methanol. c Remaining unreacted substrate. d Solvent (3 vol).
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Organic Process Research & Development
It was planned to study the effect of temperature on the course of reaction, for example 20-30 °C, 30-40 °C and 40-50 °C in acetone, 20%, 35% and 66% of compound 5 was formed, respectively (entries 4-6, Table 7). The study disclosed that the optimum temperature for maximum formation (84%) of compound 5 was 50-60 °C (entry 3, Table 7 and Figure S40, supplementary information) Then, the effect of load of powdered KOH on the course of the reaction was studied in acetone, for example 1.0, 2.0, 3.0 and 4.0 eq. of powdered KOH, 4%, 20%, 84% and 69% of compound 5 was formed, respectively. In 1.0 eq. of KOH, low formation of compound 5 was observed. The de-protection of compound 4 was completed, but N-alkylation was not proceeding due to insufficient KOH. In case of 2.0 eq. of KOH, the same situation was observed but the formation of 5 was increased (20%) slightly. The same reaction in presence of 4.0 eq. of KOH, the formation of 5 decreased (69%) as the formation of impurities increased (20% of 5a and 4% of 5b). The study revealed that 3.0 eq. of powdered KOH in acetone provided the maximum formation of 5 (84%) along with 9% of impurity 5a and 1.5% of impurity 5b (Figure S40, supplementary information). The formation of potential impurity (5a) was in high level (9%) (entry 3, Table 7), which affects severely in producing required quality of final API. Hence, its removal is mandatory up to the level of not more than 2.5%. So it is planned to improve the quality of compound 5 by isolating in different solvents, for example acetone, methanol, ethanol, acetonitrile and ethyl acetate and the obtained results were presented in Table 8 (entries 1-5). The study disclosed that methanol was the best option to isolate the desired compound 5 and also to remove the potential impurity 5a up to the process capability level (
