Mar\u00adtin D John\u00adson<\/strong>, Scott A May, Joel R Calvin, Kevin P Cole Abstract<\/strong> \u2014 Con\u00adtin\u00adu\u00adous flow chem\u00adistry for met\u00adal cat\u00adalyzed organ\u00adic reac\u00adtions offers sev\u00ader\u00adal advan\u00adtages in the phar\u00adma\u00adceu\u00adti\u00adcal indus\u00adtry. Cap\u00adi\u00adtal cost was low\u00ader than batch for the high pres\u00adsure reac\u00adtors described in this pre\u00adsen\u00adta\u00adtion. The 1000 psig rat\u00aded hydro\u00adgena\u00adtion reac\u00adtors ranged from 7 L to 360 L, and cap\u00adi\u00adtal cost for just the reac\u00adtor ranged from $4000 to $120,000. Qual\u00adi\u00adty assur\u00adance was high\u00ader com\u00adpared to batch because the inex\u00adpen\u00adsive reac\u00adtors were ded\u00adi\u00adcat\u00aded to spe\u00adcif\u00adic types of catal\u00ady\u00adsis. For exam\u00adple, indi\u00advid\u00adual plug flow reac\u00adtors (PFRs) were ded\u00adi\u00adcat\u00aded to Ir, some for Rh\/Ru, some for Pd\/Pt, and each was not used for oth\u00ader met\u00adals. Safe\u00adty was improved com\u00adpared to batch, because the con\u00adtin\u00adu\u00adous reac\u00adtors were small\u00ader, less reagent gas was in the reac\u00adtor at any one time, and in some cas\u00ades the hydro\u00adgena\u00adtion reac\u00adtors oper\u00adat\u00aded out\u00adside. A 73L PFR was used for asym\u00admet\u00adric reduc\u00adtion of a tetra\u00adsub\u00adsti\u00adtut\u00aded enone, pro\u00adduc\u00ading 144 kg penul\u00adti\u00admate with 95% EE. Reac\u00adtion con\u00addi\u00adtions were Rh(COD)2OTf, diphos\u00adphine lig\u00adand, 2000:1 S:C, 5 mol% Zn(OTf), 30% MeOH in EtOAc (10 vol\u00adumes), 1000 psig H2, 1.3 molar eq H2 in flow, 70 \u00b0C, 12 h mean res\u00adi\u00addence time (\u03c4). The pipes in series PFRs proved to be supe\u00adri\u00ador to the coiled tubes for gas\/liquid high pres\u00adsure reac\u00adtions in terms of scal\u00ada\u00adbil\u00adi\u00adty, gas\/liquid mix\u00ading rate, % liq\u00aduid filled, and inspectabil\u00adi\u00adty. A direct asym\u00admet\u00adric reduc\u00adtive ami\u00adna\u00adtion (DARA) was run in a 32L hor\u00adi\u00adzon\u00adtal pipes in series reac\u00adtor, pro\u00adduc\u00ading 15 kg advanced inter\u00adme\u00addi\u00adate. Reac\u00adtion con\u00addi\u00adtions were [Ir(cod)Cl]2<\/sub> and (S)-Xyl-BINAP, 4000 S:C,ketal , aminote\u00adtra\u00adzole (1.1 eq), CSA (0.02 eq), TBAI (0.01 eq), H2<\/sub> (1000 psig), 12 h \u03c4. A reduc\u00adtive ami\u00adna\u00adtion was run in a 360 L ver\u00adti\u00adcal pipes in series reac\u00adtor in GMP man\u00adu\u00adfac\u00adtur\u00ading, pro\u00adduc\u00ading 2000 kg penul\u00adti\u00admate. Reac\u00adtion con\u00addi\u00adtions were [Ir(cod)Cl]2<\/sub>, no lig\u00adand, S:C 1100, 800 psig H2<\/sub>, 3 molar equiv\u00ada\u00adlents H2<\/sub> in flow, 0.5 equiv TBAI wrt Ir, 1.05 eq HOAc, 1.4 eq alde\u00adhyde wrt amine, 1 vol\u00adume water, 9 vol\u00adumes THF, 1 vol\u00adume MeTHF, 12 h \u03c4. The reac\u00adtor oper\u00adat\u00aded out\u00adside, and H2<\/sub> was stripped from prod\u00aduct solu\u00adtion before flow\u00ading back inside. A 32L oscil\u00adlat\u00ading flow tube reac\u00adtor was used for a selec\u00adtive hydro\u00adformy\u00adla\u00adtion in which the cat\u00ada\u00adlyst and lig\u00adand pre\u00adcip\u00adi\u00adtat\u00aded from solu\u00adtion in the reac\u00adtor, as they were less sol\u00adu\u00adble in the prod\u00aduct alde\u00adhyde than the methyl methacry\u00adlate reagent. Reac\u00adtion con\u00addi\u00adtions were (PPh)3HRhCO, S:C 1000, cat\u00ada\u00adlyst is dis\u00adsolved in neat methyl methacry\u00adlate, 1000 psi 50:50 CO:H2<\/sub>, 24 h \u03c4. The back and forth flow and cus\u00adtom meth\u00adods of pres\u00adsure con\u00adtrol kept the reac\u00adtor from foul\u00ading for the entire 314 h con\u00adtin\u00adu\u00adous run to pro\u00adduce 180 kg advanced inter\u00adme\u00addi\u00adate with high selec\u00adtiv\u00adi\u00adty of the branched alde\u00adhyde.<\/p>\n Biog\u00adra\u00adphy<\/strong> \u2014 Mar\u00adtin D. John\u00adson works for Eli Lil\u00adly and Com\u00adpa\u00adny in Small Mol\u00ade\u00adcule Design and Devel\u00adop\u00adment. He received his dual doc\u00adtor\u00adate in chem\u00adi\u00adcal engi\u00adneer\u00ading and envi\u00adron\u00admen\u00adtal engi\u00adneer\u00ading from the Uni\u00adver\u00adsi\u00adty of Michi\u00adgan in 2000, and his under\u00adgrad\u00adu\u00adate in Chem\u00adi\u00adcal Engi\u00adneer\u00ading from Vir\u00adginia Tech. Pri\u00ador to join\u00ading Eli Lil\u00adly in 2005, he worked as a process research engi\u00adneer at Union Car\u00adbide and The Dow Chem\u00adi\u00adcal Com\u00adpa\u00adny in the Engi\u00adneer\u00ading Sci\u00adences and Mar\u00adket Devel\u00adop\u00adment depart\u00adment, focus\u00ading on process devel\u00adop\u00adment and sep\u00ada\u00adra\u00adtions. At Eli Lil\u00adly, Dr. John\u00adson leads a group of engi\u00adneers who focus on design and devel\u00adop\u00adment of con\u00adtin\u00adu\u00adous process\u00ades. He has applied process tech\u00adnolo\u00adgies from the chem\u00adi\u00adcal indus\u00adtry to increase effi\u00adcien\u00adcy, decrease waste, and increase the types of chemistries that Eli Lil\u00adly can safe\u00adly scale up from research to pro\u00adduc\u00adtion of small mol\u00ade\u00adcule phar\u00adma\u00adceu\u00adti\u00adcal com\u00adpounds. Dr. Johnson\u2019s group has used con\u00adtin\u00adu\u00adous reac\u00adtions in the man\u00adu\u00adfac\u00adture of active phar\u00adma\u00adceu\u00adti\u00adcal ingre\u00addi\u00adents for high\u00adly exother\u00admic and haz\u00adardous reac\u00adtions, high pres\u00adsure reac\u00adtions with haz\u00adardous gas reagent like hydro\u00adgena\u00adtions, chemistries at extreme tem\u00adper\u00ada\u00adtures and pres\u00adsures, and process sep\u00ada\u00adra\u00adtions includ\u00ading dis\u00adtil\u00adla\u00adtion, extrac\u00adtion, crys\u00adtal\u00adliza\u00adtion, and fil\u00adtra\u00adtion. Eli Lil\u00adly has imple\u00adment\u00aded his con\u00adtin\u00adu\u00adous process\u00ades for the pro\u00adduc\u00adtion of active phar\u00adma\u00adceu\u00adti\u00adcal ingre\u00addi\u00adent in cGMP man\u00adu\u00adfac\u00adtur\u00ading both inter\u00adnal\u00adly at the Lil\u00adly facil\u00adi\u00adty in Ire\u00adland and exter\u00adnal\u00adly in mul\u00adti\u00adple con\u00adtract man\u00adu\u00adfac\u00adtur\u00ading orga\u00adni\u00adza\u00adtions. Dr. John\u00adson was award\u00aded the 2016 ACS Award for Afford\u00adable Green Chem\u00adistry, and the 2016 AIChE Award for Out\u00adstand\u00ading Con\u00adtri\u00adbu\u00adtion to QbD for Drug Sub\u00adstance.<\/p>\n","protected":false},"excerpt":{"rendered":" 2017 Spring Sym\u00adpo\u00adsium Mar\u00adtin D John\u00adson, Scott A May, Joel R Calvin, Kevin P Cole Eli Lil\u00adly and Com\u00adpa\u00adny, Indi\u00adanapo\u00adlis, IN Abstract \u2014 Con\u00adtin\u00adu\u00adous flow chem\u00adistry for met\u00adal cat\u00adalyzed organ\u00adic reac\u00adtions offers sev\u00ader\u00adal advan\u00adtages in the phar\u00adma\u00adceu\u00adti\u00adcal indus\u00adtry. Cap\u00adi\u00adtal cost was low\u00ader than batch for the high pres\u00adsure reac\u00adtors described in this pre\u00adsen\u00adta\u00adtion. The 1000 [\u2026]<\/p>\n","protected":false},"author":5,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"ngg_post_thumbnail":0,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-4741","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"_links":{"self":[{"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/posts\/4741","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/users\/5"}],"replies":[{"embeddable":true,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/comments?post=4741"}],"version-history":[{"count":1,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/posts\/4741\/revisions"}],"predecessor-version":[{"id":4742,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/posts\/4741\/revisions\/4742"}],"wp:attachment":[{"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/media?parent=4741"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/categories?post=4741"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/catalysisclubphilly.org\/awe9a91v\/wp-json\/wp\/v2\/tags?post=4741"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nEli Lil\u00adly and Com\u00adpa\u00adny, Indi\u00adanapo\u00adlis, IN<\/em><\/p>\n