Continuous Reactors for Homogeneous Catalysis in Pharmaceutical Manufacturing

2017 Spring Symposium

Mar­tin D John­son, Scott A May, Joel R Calvin, Kevin P Cole
Eli Lil­ly and Com­pa­ny, Indi­anapo­lis, IN

Abstract — Con­tin­u­ous flow chem­istry for met­al cat­alyzed organ­ic reac­tions offers sev­er­al advan­tages in the phar­ma­ceu­ti­cal indus­try. Cap­i­tal cost was low­er than batch for the high pres­sure reac­tors described in this pre­sen­ta­tion. The 1000 psig rat­ed hydro­gena­tion reac­tors ranged from 7 L to 360 L, and cap­i­tal cost for just the reac­tor ranged from $4000 to $120,000. Qual­i­ty assur­ance was high­er com­pared to batch because the inex­pen­sive reac­tors were ded­i­cat­ed to spe­cif­ic types of catal­y­sis. For exam­ple, indi­vid­ual plug flow reac­tors (PFRs) were ded­i­cat­ed to Ir, some for Rh/Ru, some for Pd/Pt, and each was not used for oth­er met­als. Safe­ty was improved com­pared to batch, because the con­tin­u­ous reac­tors were small­er, less reagent gas was in the reac­tor at any one time, and in some cas­es the hydro­gena­tion reac­tors oper­at­ed out­side. A 73L PFR was used for asym­met­ric reduc­tion of a tetra­sub­sti­tut­ed enone, pro­duc­ing 144 kg penul­ti­mate with 95% EE. Reac­tion con­di­tions were Rh(COD)2OTf, diphos­phine lig­and, 2000:1 S:C, 5 mol% Zn(OTf), 30% MeOH in EtOAc (10 vol­umes), 1000 psig H2, 1.3 molar eq H2 in flow, 70 °C, 12 h mean res­i­dence time (τ). The pipes in series PFRs proved to be supe­ri­or to the coiled tubes for gas/liquid high pres­sure reac­tions in terms of scal­a­bil­i­ty, gas/liquid mix­ing rate, % liq­uid filled, and inspectabil­i­ty. A direct asym­met­ric reduc­tive ami­na­tion (DARA) was run in a 32L hor­i­zon­tal pipes in series reac­tor, pro­duc­ing 15 kg advanced inter­me­di­ate. Reac­tion con­di­tions were [Ir(cod)Cl]2 and (S)-Xyl-BINAP, 4000 S:C,ketal , aminote­tra­zole (1.1 eq), CSA (0.02 eq), TBAI (0.01 eq), H2 (1000 psig), 12 h τ. A reduc­tive ami­na­tion was run in a 360 L ver­ti­cal pipes in series reac­tor in GMP man­u­fac­tur­ing, pro­duc­ing 2000 kg penul­ti­mate. Reac­tion con­di­tions were [Ir(cod)Cl]2, no lig­and, S:C 1100, 800 psig H2, 3 molar equiv­a­lents H2 in flow, 0.5 equiv TBAI wrt Ir, 1.05 eq HOAc, 1.4 eq alde­hyde wrt amine, 1 vol­ume water, 9 vol­umes THF, 1 vol­ume MeTHF, 12 h τ. The reac­tor oper­at­ed out­side, and H2 was stripped from prod­uct solu­tion before flow­ing back inside. A 32L oscil­lat­ing flow tube reac­tor was used for a selec­tive hydro­formy­la­tion in which the cat­a­lyst and lig­and pre­cip­i­tat­ed from solu­tion in the reac­tor, as they were less sol­u­ble in the prod­uct alde­hyde than the methyl methacry­late reagent. Reac­tion con­di­tions were (PPh)3HRhCO, S:C 1000, cat­a­lyst is dis­solved in neat methyl methacry­late, 1000 psi 50:50 CO:H2, 24 h τ. The back and forth flow and cus­tom meth­ods of pres­sure con­trol kept the reac­tor from foul­ing for the entire 314 h con­tin­u­ous run to pro­duce 180 kg advanced inter­me­di­ate with high selec­tiv­i­ty of the branched alde­hyde.

Biog­ra­phy — Mar­tin D. John­son works for Eli Lil­ly and Com­pa­ny in Small Mol­e­cule Design and Devel­op­ment.  He received his dual doc­tor­ate in chem­i­cal engi­neer­ing and envi­ron­men­tal engi­neer­ing from the Uni­ver­si­ty of Michi­gan in 2000, and his under­grad­u­ate in Chem­i­cal Engi­neer­ing from Vir­ginia Tech.  Pri­or to join­ing Eli Lil­ly in 2005, he worked as a process research engi­neer at Union Car­bide and The Dow Chem­i­cal Com­pa­ny in the Engi­neer­ing Sci­ences and Mar­ket Devel­op­ment depart­ment, focus­ing on process devel­op­ment and sep­a­ra­tions.  At Eli Lil­ly, Dr. John­son leads a group of engi­neers who focus on design and devel­op­ment of con­tin­u­ous process­es.  He has applied process tech­nolo­gies from the chem­i­cal indus­try to increase effi­cien­cy, decrease waste, and increase the types of chemistries that Eli Lil­ly can safe­ly scale up from research to pro­duc­tion of small mol­e­cule phar­ma­ceu­ti­cal com­pounds.  Dr. Johnson’s group has used con­tin­u­ous reac­tions in the man­u­fac­ture of active phar­ma­ceu­ti­cal ingre­di­ents for high­ly exother­mic and haz­ardous reac­tions, high pres­sure reac­tions with haz­ardous gas reagent like hydro­gena­tions, chemistries at extreme tem­per­a­tures and pres­sures, and process sep­a­ra­tions includ­ing dis­til­la­tion, extrac­tion, crys­tal­liza­tion, and fil­tra­tion.  Eli Lil­ly has imple­ment­ed his con­tin­u­ous process­es for the pro­duc­tion of active phar­ma­ceu­ti­cal ingre­di­ent in cGMP man­u­fac­tur­ing both inter­nal­ly at the Lil­ly facil­i­ty in Ire­land and exter­nal­ly in mul­ti­ple con­tract man­u­fac­tur­ing orga­ni­za­tions.  Dr. John­son was award­ed the 2016 ACS Award for Afford­able Green Chem­istry, and the 2016 AIChE Award for Out­stand­ing Con­tri­bu­tion to QbD for Drug Sub­stance.