Masterpieces in Process Chemistry

1 Masterpieces in Process ChemistryRichter11/3/04 Group MeetingSelected Syntheses Discussed:OOMeOHMeHOMeOHMeMeMeOHMeOMeHON H2 DiscodermolideNovartisEGFR Irreversible InhibitorPfizerNNHNHNOONOFClNCO2 HOHK etorolacSyntexOSONHOOHERa-SERMM erckSNHHNOCO2 HHHHB iotinTanabe Seiyaku H3PO4 TamifluHoffmann-LaRocheFMeOOHNHNHONCNMIV -105 ChironNHSMeHNOOMeNAmergeGlaxoSmithKlineN ClNOOMeNClNHClaritinSchering-PloughClari nexSchering-PloughNOMeHNNCF3 OCO2 HHSB-273005 GlaxoSmithKlineMasterpieces in Process ChemistryRichter11/3/04 Group MeetingSelected Syntheses Not Discussed:Ecteinascidin 743 CoreyNMeNNHSOHHHOHHHOMeOOAcOMeOOHOOMeMeN NOONCO2 MeCO2 MeClOCF3 IndoxacarbDuPontNOHMeOHCO2 NH3+HThienamycinMerckSee Jeremy richter , Baran Group Meeting, January 2004 NMeOClOHHONMeNFTI CandidatePfizerF3 CONHMeProzacEli LillyNHNSNNMeMeZyprexaEli LillyOOOOOOOOOOOOOOOOHMeMeHHHHMeMeHOHOHO HHHHHHHHHHHHHHHHHH alichondrinKishiDisclaimers:1.

2 This is by no means a comprehensive sampling of the many Masterpieces in Process Process syntheses are very difficult to locate and decipher, since most of the relevant literature is burried in patents and the words " Process scale" do not appear in the Some of the syntheses not discussed above were not done so because they were either not actual Process routes (Ecteinascidin 743, Halichondrin) or I was unable to locate the relevant literature in To give this topic the credit it deserves would require the publication of Classics in Process Many of the syntheses presented here are wonderfull full papers that delineate the entire conception Process along with problems encountered along the way. I recommend these papers for more List of Transforms:Zhao olefination, Parikh-Doering oxidation, Still-Genari olefination, Nozaki-Hiyama coupling, Evans-Saksena reduction, Kagan oxidation, Ullmann reaction, Strecker reaction, Moffit oxidation, Fukuyama coupling, Wohl-Zeigler brominationMasterpieces in Process ChemistryRichter11/3/04 Group MeetingOOMeOHMeHOMeOHMeMeMeOHMeOMeHONH2( )-Discodermolide1.

3 Non-taxane microtubule stabilizing agent (most potent known).2. Small amounts available naturally and must be harvested by manned submersibles. Fermentation has not been successful so all material must come from total Currently in phase I clinical Previous syntheses: a. Schreiber, JACS 1993, 115, 12621; ibid. 1996, 118, 11054 b. Smith, JACS 1995, 117, 12011; OL 1999, 1, 1823; ibid. 2000, 2, 1983; JACS 2000, 122, 8654 c. Myles, JOC 1997, 62, 6098 d. Marshall, JOC 1998, 63, 7885 e. Paterson, ACIEE 2000, 39, 377; TL 2000, 41, 6935; JACS 2001, 123, 9535; OL 2003, 5, Novartis Process Synthesis: a. Drew heavily upon the Smith and Paterson approaches b. OPRD 2004, 8, 92-130 HOCO2 MeMePMBOCCl3 NHPPTS, DCM> 98%PMBOCO2 MeMePMBOMeLiBH4, THF> 98%OH[LAH worked wellbut filtration = 24 hrs]TEMPO, Bleach, DCM100%[Swern not amenablefor large scale stench]Bu2 BOTf,TEA, > 75%PMBOMeONOMeOOBn[46-55% on20-25 kg scale]PMBOMeOHMeOXc[First purification:crystallization]i.

4 LiOH, H2O2, MeOHii. (R)-PhenylethylaminePMBOMeOHMeOONH3Me84% i. HClii. iBuOCOC liii. MeNHOMe 75-80%PMBOMeOHMeOMeNNNNClOMeMeOi. LiOH " ,therearenoanswerstothesesupplyproblems; ,thisprojectwasafirstforNovartis,anditsp rogresswasavidlyfollowedbytheentiredepar tmentwhowereallinterestedinthe"disco".Th esuccessofthisprojectanditschemistrypave sthewayforother,perhapsevenmorecomplex,n aturalproductstobe prepared for early-phase clinical evaluations and sends a positive message to both theisolationandsyntheticacademiccommunit yandpossiblyotherpharmaceuticalcompanies that:"yourworkneednotjustbeofacademicint erest" ,experimentaldesign, Smith ,andwe are confident of climbing this mountain as the situation demands." Masterpieces in Process ChemistryRichter11/3/04 Group MeetingPMBOMeOHMeONMeOMeTBSOTf, 2,6-Lut.,Tol., 0 C90%PMBOMeTBSOMeONMeOMeRed-Al,Tol.

5 , 20 C68%[Chromatographicpurification 12 kg][DIBAL-H reduction workedbut 78 C was unacceptable][Chromatography required]PMBOMeTBSOMeONaHMDS, THF,Ph3 PMeINaHMDS, I2Ph3 PMeIIPMBOMeTBSOMeMeI(15:1 cis:trans, 31%)[Chromatography required][No larger than kg]Name?PMBOMeTBSOMeONMeOMei. H2, Pd/C, tBuOHii. TEMPO, PhI(OAc)2 OMeTBSOMeONMeOMei. MeMgBrii. SO3, Py, DMSOMeTBSOMeONMeOMeMeO[Chromatography Required]66% overallPMBOMeOHMeONMeOMeDDQ, Tol., , 0 C61%MeOMeONMeOMeOOMeMeOMeOHOOMei. LAH, THFii. Bu2 BOTf, TEA, 78 C to 10 C,MeONOOBnNOMeOOBn85%[Crystalline]i. TBSOTf, 2,6-Lut, 100%ii. LiBH4, THF 30 C to RT, 60%MeOMeOTBSOOMeMeOH[Chromatography Required]Ph3P, I2, imid.,Tol., RT, 90%MeOMeOTBSOOMeMeI24% overallName? Masterpieces in Process ChemistryRichter11/3/04 Group MeetingMeOMeTBSOOOMeMeIMeTBSOMeMeIi.

6 TBuLi, 9-MeOBBN, THF, 78 Cii. Cs2CO3, DMF, Pd(dppf)2Cl2, RTMeOMeOTBSOOMeMeMeTBSOMeMei. DIBAL H, 92%ii. SO3, Pyr., DMSO, 93%MeOPMBMeOTBSMeMeTBSOMeMeOi. CrCl2,ii. KOHBrTMSMeOPMBMeOTBSMeMeTBSOMeMePMBOPMBO PMBOPMBO81%[Chromatographyrequired]Name? i. DDQ, H2O, 88%ii. PhI(OAc)2, TEMPOiii. KHMDS, 18-c-6, 76%POCO2 MeF3CH2 COF3CH2 COMeOHMeOTBSMeMeTBSOMeMeMeO2 CName?i. CCl3 CONCO; Na2CO3, MeOH, 100%ii. DIBAL H, DCM, 78 Ciii. PhI(OAc)2, TEMPO, 80%[Chromatographyrequired]MeOCONH2 MeOTBSMeMeTBSOMeMe[Chromatographyrequire d]OMeTBSOMeOMeOMeNMeO+(+)-DIP-Cl, TEA, 55%MeOCONH2 MeOTBSMeMeTBSOMeMeHOMeTBSOMeOMeOMeNO4:1 dr, recyclable[Chromatography requiredon reverse-phase silica]Me4N+(OAc)3BH, 73%[problems with commercialpurity of (+)-DIP-Cl]Name?MeOCONH2 MeOTBSMeMeTBSOMeMeHOMeTBSOMeOMeOMeNOHHCl , MeOH[Chromatographyrequired]OOMeOHMeHOMe OHMeMeMeOHMeOMeHONH2discodermolide[ > 60 g produced]39 steps, 17 chromatographic purifications, 20 months7 problematic steps identified and being optimizedMasterpieces in Process ChemistryRichter11/3/04 Group MeetingEGFR Irreversible Inhibitor1.

7 Treatment of solid Inhibits Epidermal Growth Factor Tyrosine Process synthesis Rober Hughes, Pfizer, Gordon Research Conference Route Problems Improved RouteNNHNHNOONOFClCO2 HNH2F AcOHCH3 OCH2CH2 OHHNH2 NHNFNHOi. 65% HNO3/ H2SO4, 70 C, 81%ii. HOAc, 57%98%NFNHOO2Ni. SOCl2, 98%ii. TEA, iPrOH,H2 NFClNFNHNO2 NFCl86%ONOHKOtBu, THF98%[83% after recrystallization]NNHNO2 NONOFClRa-Ni, THFH2, 99%NNHNH2 NONOFCl[Observed losses to dechlorination]TEA, EtOAc,51%[2 recrystallizations]COCl[Yield loss]NNHNHNOONOFClUsed DMF instead ofHOAc for Recrystallization74%[ :1 regioselectivity]Could not improveCombined 3 operationsinto one pot, 95%1% Pt/C, THF, H280% from EtOH< deschloro[Material still lost in cyrstalization]Last step was optimizable, but forlegal reasons they had to develop:i.

8 Ac2O, 85%ii. Pt/C, H2, THF, 99%iii. TEA, THF, 0 C; NaOH, 80%iv. MeSO3H/AcOH/THF; NaOH, 90%ClCOClFinal:8 steps (3 pots)55% overall yieldproduced multikilo'sMasterpieces in Process ChemistryRichter11/3/04 Group MeetingKetorolac1. Non-steroidal antiinflammatory drug (NSAID).2. Powerful antiinflammatory and analgesic 10 mg equiefficacious with morphine (10 mg) for post-operative 10 mg equiefficacious with aspirin (650 mg) for 10 mg equiefficacious with acetaminophen (1 g) or acetominophen (600 mg)/codein (60 mg) Syntex development: Muchowski, Adv. Med. Chem. 1992, 1, Generation Routei. NCS, DMS DCM, 30 Cii. D, 60%HNSMePhCONMe2 POCl3, DCEDHNOSMeNaH, DMF;55 C,OOOONOSMeOOOOi. mCPBAii. MeOH, HClNOSO2 MeCO2 MeMeO2Ci. NaH, DMF, 85 Cii. NaOHKetorolac,21% from pyrroleracemic2nd Generation Route3rd Generation Route Begins from Pyrrole and proceeds in 45% overall yield: See US Patent 6,197,976 HNOBr20 CHNOBrBrDMF, 80 COOOONOBrOOOOBri.

9 MeOH, HClii. NaH, DMF, 75 CNCO2 MeOCO2 MeBri. HO ii. H2, Pd/C, MgOiii. HClKetorolac,47% from benzoyl pyrroleracemicNew Chemistry Discovered:1. Selective substitution of pyrrole at C 3 when protected as N Acid induced isomerization of C 2 substituted pyrroles to C New routes to New routes to Mild reduction of acylpyrroles to Conversion of acylpyrroles to First reported intramolecular carbenoid addition to a pyrrole in Process ChemistryRichter11/3/04 Group MeetingERa-SERM1. SERM = selective estrogen receptor Potentially useful for the treatment of bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence and Synthesis: Merck, PNAS, 2004, 101, (H2N)2CS,HCl, 92%HOOSOi.

10 BnBr, NaI, K2CO3, 84%ii. NaOHBnOSHOHONMeOMeIBnOMgBrOIOBnPhMe3N+Br 3 DME, 100%80%OIOBnOIOBnSOHBnO88%PhPOCl2 MeCN, 90%OSIBnOOBnD-DIPTTi(OiPr)4 CumenehydroperoxideOS+IBnOOBnO Name?BH3 THF10 C88%, 99% eeOSIBnOOBnCuI, K2CO3,2,2'-bipyridyl, 140 CNOHOSONBnOOBnOSONHOOHTMSI81%92%ERa-SERM 8 steps37% overall yield+Mechanism?Mechanism?BrMasterpieces in Process ChemistryRichter11/3/04 Group MeetingBiotin1. Important in human nutrition and animal > 80 tons produced synthetically Synthesis: Tanabe Seiyaku Co., Chem. Eur. J. 2004, For a comprehensive review of Biotin syntheses see: Ryan Shenvi, Baran Lab Group Meeting, July HClHSCO2 HHi. PhOCOCl, NaOH, H2O, Tol., RTii. BnCl, NaOH, DMSO, H2O, RTNBnSCO2 HHOi. NaBH4, H2SO4, THF, Dii. DCC, TFA, Pyr., DMSO, EtOAc, 50 C83%, >99% eeNBnSHOO86%, >99% eei.